Compound with PTPN2 (protein tyrosine phosphatase N2) inhibiting effect and application thereof

Abstract

Disclosed are a compound having a PTPN2 inhibitory effect and a use thereof. Specifically, the invention discloses a compound with a protein tyrosine phosphatase inhibition effect or a pharmaceutically acceptable salt thereof, and application of the compound or the pharmaceutically acceptable salt in treating and / or preventing diseases or symptoms related to abnormal expression of protein tyrosine phosphatase. The compound is represented by formula (I):

Description

Compounds with PTPN2 inhibitory effect and uses thereof Technical Field

[0001] The present invention relates to a class of compounds having protein tyrosine phosphatase inhibitory effects or pharmaceutically acceptable salts thereof, and uses thereof for treating and / or preventing diseases or conditions associated with abnormal protein tyrosine phosphatase expression. Background Art

[0002] Tyrosine-protein phosphatase non-receptor type 2 (PTPN2) is a member of the protein tyrosine phosphatase (PTP) family. There are 17 classical PTP isoforms: nine non-transmembrane phosphatases and eight receptor phosphatases. PTPs regulate a variety of cellular processes, including cell growth, differentiation, mitotic cycle, and oncogenic transformation, by catalyzing protein dephosphorylation. PTPN2 and PTPN1 share a high degree of homology.

[0003] PTPN2 is expressed in immune cells and plays a key role in immune system homeostasis. PTPN2 inhibits the phosphorylation of signaling factors such as JAK and STAT family members, blocking signaling pathways mediated by cytokines (such as IFN-γ, IL-2, and IL-6), thereby suppressing the secretion of downstream pro-inflammatory cytokines such as IFN, IL-6, TNF, and CXCL9 / 10 / 11, inhibiting immune cell proliferation and differentiation, and suppressing immune responses. PTPN2 is also highly expressed in tumor cells such as ovarian serous cystadenocarcinoma, esophageal cancer, sarcoma, and uterine sarcoma. Inhibiting PTPN2 in tumors can enhance antigen presentation and sensitize tumor cells to the killing of tumor suppressor cytokines such as IFNγ.

[0004] PTPN1 regulates the leptin and insulin signaling pathways. PTPN1 dephosphorylation negatively regulates leptin and insulin metabolic signaling, leading to obesity, diabetes, and other diseases. PTPN1 inhibition improves insulin resistance and glucose tolerance in diseased mice, thereby controlling blood sugar levels. Therefore, PTPN1 inhibitors hold promise for treating type 2 diabetes, obesity, and other metabolic diseases or conditions.

[0005] Summary of the Invention

[0006] In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0007] in:

[0008] Dashed lines indicate the presence or absence of a bond;

[0009] X1, X2 and X3 are independently selected from carbon, nitrogen, oxygen and sulfur atoms, and the ring A in which they are located may be optionally substituted n times by R2;

[0010] R1 is -L1-L2-R x ;

[0011] R2 is selected from hydrogen, halogen, cyano, hydroxy, oxo, amino, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Amine, C 3～7 Cycloalkyl, C 3～7 Heterocyclic and C 5～7 Aromatic heterocyclic group, wherein R2 can form a 7-12 membered fused ring, spiro ring or fused ring with ring A, wherein the fused ring, spiro ring or fused ring can optionally contain 1-4 N, O, S heteroatoms, and the R2 can optionally be replaced by R a Replace 1 to 3 times;

[0012] R3 is selected from hydrogen, halogen, cyano, C 1～3 Alkyl, C 1～3 Alkoxy and cyclopropyl, said R3 may be optionally substituted 1 to 3 times by halogen;

[0013] L1 is selected from a single bond, -(CH2) p1 -、-(CH2) p1 -O- and -(CH2) p1 -NH-;

[0014] L2 is selected from -(CH2) p2 -、-NH-(CH2) p2 -、-C(O)-(CH2) p2 -、-NH-C(O)-(CH2) p2 - and -C(O)-NH-(CH2) p2 -, wherein L2 can be optionally replaced by R under conditions permitting by chemical valence. a substituted 1 to 3 times; wherein, when L2 is optionally replaced by R a When replacing 2 or more times, two independent R a Can form 3-6 membered carbon rings;

[0015] R x Selected from hydrogen, amino, halogen, cyano, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, C 3～7 Heterocycloalkyl, C 5～6 Aryl and C 5～7 Heteroaryl, any of the Rx Optionally R b Replace 1 to 3 times;

[0016] p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5;

[0017] n is selected from 1, 2, 3 or 4;

[0018] When n is greater than or equal to 2, the R2 can exist independently, and any two R2 can form a ring B under the condition of valence permission, and the ring B is selected from a 3-6 membered carbocyclic ring, or a 3-6 membered carbocyclic ring having 1-3 heteroatoms independently selected from N, O and S, and the ring B can be optionally substituted by halogen, C 1～3 Alkyl, C 1～3 Haloalkyl substituted 1 to 3 times;

[0019] R a independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1～4 Alkyl and C 1～3 Alkoxy, said NH2 may be optionally replaced by C 1～3 Alkyl substituted once, and the C 1～4 Alkyl and C 1～3 The alkoxy group may be optionally substituted 1 to 3 times by halogen;

[0020] R b Independently selected from H, F, Cl, Br, I, NH2, OH, C 1-6 Alkyl, C 1-3 Alkoxy and CN, said NH2 may be optionally replaced by C 1～3 Alkyl substituted once, and the C 1～6 Alkyl and C 1～3 The alkoxy group may be optionally substituted 1 to 3 times by halogen.

[0021] In some embodiments, R x Selected from hydrogen, amino, halogen, cyano, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～7 Heterocycloalkyl, C 5～6 Aryl and C 5～7 Heteroaryl, any of the R x Optionally R b Replace 1 to 3 times.

[0022] In some embodiments, X1 is selected from S, O, CH2, CH, C, NH and N, wherein CH2, CH, NH can be optionally substituted 1 to 2 times by R2.

[0023] In some embodiments, X2 is selected from S, O, CH2, CH and C, wherein CH2 and CH can be optionally substituted by R2 1 to 2 times.

[0024] In some embodiments, said X3 is selected from CH and C, wherein said CH is substituted once by R2.

[0025] In some embodiments, the compound of Formula I is a compound as shown in Formula II or a pharmaceutically acceptable salt thereof:

[0026] In some embodiments, the compound is a compound represented by Formula II-1 or a pharmaceutically acceptable salt thereof:

[0027] in:

[0028] X1 is selected from S, O, CH2, CH, C, NH and N, wherein said CH2, CH, NH may be optionally substituted 1 to 2 times by R2, and

[0029] X2 is selected from S, O, CH2, CH and C, wherein said CH2 and CH may be optionally substituted by R2 1 to 2 times.

[0030] In some embodiments, the compound is a compound as shown in Formula II-2 or a pharmaceutically acceptable salt thereof:

[0031] in:

[0032] X1 is selected from CH, C and N, wherein said CH may be optionally substituted once by R2, and

[0033] X2 is selected from CH and C, wherein said CH may be optionally substituted once by R2.

[0034] In some embodiments, the ring A is selected from wherein the ring A may be optionally substituted n times by R2.

[0035] In some preferred embodiments, the ring A is selected from Preferred wherein the ring A may be optionally substituted n times by R2.

[0036] In some preferred embodiments, the compound is a compound represented by Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, more preferably Formula II-G, or a pharmaceutically acceptable salt thereof:

[0037] In some embodiments, L1 is selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH(CH3)2-, -O-, and -O-CH2-. In some preferred embodiments, L1 is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, and -O-. In some more preferred embodiments, L1 is selected from -CH2-, -CH2CH2-, and -CH2CH2CH2-. In further more preferred embodiments, L1 is -CH2-.

[0038] In some embodiments, said L2 is selected from -NH-(CH2) p2 -, the L2 may optionally be replaced by R a Replace 1 to 3 times.

[0039] In some preferred embodiments, the L2 is selected from -NHCH2-, -NHCH2CH2-, -NHCH2CH2CH2- and -NHCH2CH2CH2CH2-, and the L2 may be optionally replaced by R a In some preferred embodiments, R a independently selected from hydrogen, halogen (preferably F) and C 1～4 Alkyl, the C 1～4 The alkyl group may be optionally substituted 1 to 3 times with halogen (preferably F). In some more preferred embodiments, the L2 is selected from -NHCH2-, -NHCH2CH2-, -NHCH2CF2-, -NHCH(CH3)CH2-, -NHCH2CH2CH2-, -NHCH2CF2CH2-, -NHCH2CH2CF2-, -NHCH2CH2CH(CHF2)-, -NHCH2CH(CHF2)CH2-, -NHCH2CH2CH2CH2-, -NHCH2CH2C(CH3)2-, -NHCH2CH(CH3)CH2-, -NHCH2CH2CH(CHF2)CH2- and -NHCH2CH2CH2CF2-.

[0040] In other embodiments, when the L2 is optionally replaced by R a When replacing 2 or more times, two independent R a It can form a 3-membered or 4-membered carbon ring, and the 3-membered or 4-membered carbon ring can be optionally substituted 1 to 3 times by halogen. In some preferred embodiments, the 3-membered or 4-membered carbon ring is selected from

[0041] In some embodiments, R1 is -O-NH-(CH2) p2 -Rx , or preferably -(CH2) 1-3 -NH-(CH2) p2 -R x , or more preferably -CH2-NH-(CH2) p2 -R x , where -NH-(CH2) p2 - denotes L2, as defined above.

[0042] In some embodiments, the R x Selected from hydrogen, halogen, C 1～3 Alkyl, C 3～6 Cycloalkyl and phenyl, any of the R x Optionally R b In some preferred embodiments, the R x Selected from H, F, Cl, -CH3, -CH2CH3, -CH(CH3)CH2CH3, -CH(CH3)2, The arbitrary R x Optionally R b In some more preferred embodiments, the R x Selected from H, F, Cl, -CH3, The arbitrary R x Optionally R b In some preferred embodiments, R b independently selected from H, F, Cl and C 1-3 Alkyl, wherein the C 1～3 The alkyl group may be optionally substituted 1 to 3 times by F or Cl.

[0043] In some more preferred embodiments, R x Selected from H, F, Cl, -CH3, -CH2CH3, -CH(CH3)2,

[0044] In an even more preferred embodiment, said R1 is selected from

[0045] In some embodiments, the R2 is selected from -H, -Cl, -F, -CH3, -OCH3, wherein the -CH3 or -OCH3 may be optionally substituted by halogen 1 to 3 times.

[0046] In some embodiments, when n is greater than or equal to 2, any two R2 can form the ring B together with the ring atoms of the ring A to which they are connected, and the ring B is selected from: a 3-6 membered carbon ring, preferably cyclopropane, cyclobutane, cyclopentane or cyclohexane; or a 3-6 membered carbon heterocycle having 1-3 heteroatoms independently selected from N, O and S, preferably azetidine, oxetane, azopentane or oxolan, and the ring B can be optionally substituted by halogen, C 1～3 Alkyl, C 1～3 In some preferred embodiments, the ring B and the ring A together form a structural unit selected from a spiro ring, more preferably The structural unit may optionally be replaced by R a In some preferred embodiments, R a are independently halogen, C 1～3 Alkyl or C 1～3 Halogenated alkyl.

[0047] In some embodiments, R3 is selected from -H, -Cl, -F, -CH3, -CF3 and -OCH3.

[0048] In a second aspect, the present invention provides a compound of formula I as described below or a pharmaceutically acceptable salt thereof:

[0049] in:

[0050] Dashed lines indicate the presence or absence of a bond;

[0051] X1, X2 and X3 are independently selected from carbon, nitrogen, oxygen and sulfur atoms, and the ring A in which they are located may be optionally substituted n times by R2;

[0052] R1 is -L1-L2-R x ;

[0053] R2 is selected from hydrogen, halogen, cyano, hydroxy, oxo, amino, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Amine, C 3～7 Cycloalkyl, C 3～7 Heterocyclic and C 5～7 Aromatic heterocyclic group, wherein the R2 can form a 7-12 membered fused ring, spiro ring or fused ring with ring A, wherein the fused ring, spiro ring or fused ring can optionally contain 1-4 N, O, S heteroatoms, and the R2 can optionally be replaced by R a Replace 1 to 3 times;

[0054] R3 is selected from hydrogen, halogen, cyano, C 1～3 Alkyl, C 1～3Alkoxy and cyclopropyl, said R3 may be optionally substituted 1 to 3 times by halogen;

[0055] L1 is selected from a single bond, -(CH2) p -、-(CH2) p -O- and -(CH2) p -NH-;

[0056] L2 is selected from -(CH2) p -、-NH-(CH2) p -、-C(O)-(CH2) p -、-NH-C(O)-(CH2) p - and -C(O)-NH-(CH2) p -, wherein L2 can be optionally replaced by R under conditions permitting by chemical valence. a substituted 1 to 3 times; wherein, when L2 is optionally replaced by R a When substituted 2 or more times independently, two independent R a Can form 3-6 membered carbon rings;

[0057] R x Selected from hydrogen, amino, halogen, cyano, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～7 Heterocycloalkyl, C 5～6 Aryl and C 5～7 Heteroaryl, any of the R x Optionally R b Replace 1 to 3 times;

[0058] p is independently selected from 0, 1, 2, 3, 4 or 5;

[0059] n is selected from 1, 2, 3 or 4;

[0060] When n is greater than or equal to 2, the R2 can exist independently, and any two R2 can form a ring B under the condition of valence permission, and the ring B is selected from a 3-6 membered carbocyclic ring, or a 3-6 membered carbocyclic ring having 1-3 heteroatoms independently selected from N, O, and S; and the ring B can be optionally substituted by halogen, C 1～3 Alkyl, C 1～3 Haloalkyl substituted 1 to 3 times;

[0061] R a independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1～4 Alkyl and C 1～3 Alkoxy, said NH2 may be optionally replaced by C 1～3Alkyl substituted once, and the C 1～4 Alkyl and C 1～3 The alkoxy group may be optionally substituted 1 to 3 times by halogen;

[0062] R b Independently selected from H, F, Cl, Br, I, NH2, OH, C 1-6 Alkyl, C 1-3 Alkoxy and CN, said NH2 may be optionally replaced by C 1～3 Alkyl substituted once, and the C 1～6 Alkyl and C 1～3 The alkoxy group may be optionally substituted 1 to 3 times by halogen.

[0063] In some embodiments, X1 is selected from S, O, CH2, CH, C, NH and N, wherein CH2, CH, NH can be optionally substituted by R2 1 to 2 times.

[0064] In some embodiments, X2 is selected from S, O, CH2, CH and C, wherein CH2 and CH can be optionally substituted by R2 1 to 2 times.

[0065] In some embodiments, said X3 is selected from CH and C, wherein said CH is substituted once by R2.

[0066] In some embodiments, the ring A is selected from wherein the ring A may be optionally substituted n times by R2.

[0067] In some embodiments, when n is greater than or equal to 2, the R2 can exist independently, and any two R2 can form a ring B under valence permitting conditions, wherein the ring B is selected from cyclopropane, cyclobutane, cyclopentane, azetidine, oxetane, azetidine, oxetane and cyclohexane, and the ring B can be optionally substituted with halogen, C 1～3 Alkyl, C 1～3 Haloalkyl substituted 1 to 3 times;

[0068] In some embodiments, when n is greater than or equal to 2, any two R2 can form a ring B with ring A, and the ring B and ring A form a ring selected from The structural unit may be optionally substituted n times by R2.

[0069] In some embodiments, the ring A is selected from The ring A may be optionally substituted n times by R2.

[0070] In some embodiments, L1 is selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH(CH3)2-, -O-, and -O-CH2-.

[0071] In some embodiments, said L2 is selected from -NH-(CH2) p -, the L2 may optionally be replaced by R a Replace 1 to 3 times.

[0072] In some embodiments, the L2 is selected from -NHCH2-, -NHCH2CH2-, -NHCH(CH3)CH2-, -NHCH2CH2CH2-, -NHCH2CH2CH2CH2-, -NHCH2CH2C(CH3)2-, -NHCH(CH3)CH2- and -NHCH2CH(CH3)CH2-, and the L2 may be optionally replaced by R a Replace 1 to 3 times.

[0073] In some embodiments, when L2 is optionally replaced by R a When replacing 2 or more times, two independent R a It can form a 3-membered carbocyclic ring or a 4-membered carbocyclic ring.

[0074] In some embodiments, the R x Selected from -CH3, -CH(CH3)2, And the R x Optionally R b Replace 1 to 3 times.

[0075] In some embodiments, R3 is selected from -H, -Cl, -F, -CH3, -CF3 and -OCH3.

[0076] In some embodiments, the R2 is selected from -H, -Cl, -F, -CH3 and -OCH3, wherein the -CH3 and -OCH3 of R2 may be optionally substituted by halogen 1 to 3 times.

[0077] In some embodiments, the R1 is selected from

[0078] In some embodiments, the present invention further provides a compound represented by the following formula I' or a pharmaceutically acceptable salt thereof, which is selected from

[0079] The remaining groups are as defined above.

[0080] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0081] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof: (include ),

[0082] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0083] The present invention also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of drugs related to protein tyrosine phosphatase inhibitors.

[0084] In some embodiments, the protein tyrosine phosphatase inhibitor-related drug is a drug for treating and / or preventing tumors and / or cancers, including solid tumors and hematological tumors.

[0085] The compounds provided by the present invention are protein tyrosine phosphatase inhibitors, wherein the compounds and pharmaceutically acceptable salts thereof have excellent protein tyrosine phosphatase inhibitory activity. These protein tyrosine phosphatase inhibitor compounds can treat and / or prevent protein tyrosine phosphatase-mediated diseases or conditions and related diseases or conditions.

[0086] The compounds provided herein and their pharmaceutically acceptable salts can be used alone or in combination with at least one other therapeutic agent in therapy.

[0087] The present invention also provides a pharmaceutical composition comprising the compound as described above or a pharmaceutically acceptable salt thereof, and one or more other therapeutically active ingredients.

[0088] The present invention also provides a pharmaceutical composition comprising the compound as described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0089] The pharmaceutically acceptable salts described herein include acid addition salts and base salts.

[0090] The pharmaceutically acceptable salts described herein can exist in unsolvated as well as solvated forms.

[0091] The present invention also provides the compounds described above and pharmaceutically acceptable salts thereof for use in treating and / or preventing protein tyrosine phosphatase-related diseases or disorders, and related diseases or disorders.

[0092] The present invention also provides a method for preventing and / or treating a disease or condition, comprising administering a therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above to an individual in need thereof, wherein the disease or condition is a protein tyrosine phosphatase-related or protein tyrosine phosphatase-mediated disease or condition and related diseases or conditions.

[0093] In some embodiments, the protein tyrosine phosphatase-mediated disease or condition is a tumor and / or cancer. In some embodiments, the tumor and / or cancer includes, but is not limited to, melanoma, thyroid tumor, head and neck cancer, cervical cancer, lung cancer, bronchial cancer, brain cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small intestine cancer, kidney cancer, liver cancer, hepatocellular carcinoma, malignant mesothelioma, bile duct cancer, cholangiocarcinoma, renal cell carcinoma, pancreatic cancer, uterine cancer, bladder cancer, bone cancer, myeloma, glioma, mesothelioma, adenocarcinoma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, neuroblastoma, Wilms' tumor, retinoblastoma, and germ cell tumor.

[0094] In some embodiments, the disease or illness mediated by the protein tyrosine phosphatase is a metabolic disease. In some embodiments, the metabolic disease includes but is not limited to: diabetes (including type 1 diabetes, preferably type 2 diabetes), hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, metabolic syndrome, phenylketonuric acid, atherosclerosis, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis and liver fibrosis.

[0095] Definition and Description

[0096] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0097] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0098] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0099] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0100] Unless otherwise indicated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0101] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0102] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0103] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0104] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0105] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0106] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0107] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0108] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0109] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0110] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0111] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0112] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0113] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 R's, the group may be optionally substituted with up to two R's, with each occurrence of R being independently selected. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0114] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0115] When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R)0 means that the structure is actually -A.

[0116] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0117] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0118] When a substituent's bond can cross-link to two or more atoms in a ring, the substituent can be bonded to any atom in the ring, e.g. The substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituent does not specify the atom through which it is bonded to the substituted group, the substituent can be bonded through any atom. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0119] When the listed linking groups do not indicate the direction of their attachment, the direction of their attachment is arbitrary.

[0120] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines express.

[0121] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0122] The terms "halo", "halogen" and "halogen atom" herein mean fluorine atom, chlorine atom, bromine atom, iodine atom, etc. Preferred halogen atoms as substituents of the aryl group herein are fluorine atom and chlorine atom.

[0123] The term "C 1～6 "Alkyl" is a straight or branched chain alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl and 2-ethylbutyl. The term "C 1～3 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 3 carbons, including but not limited to methyl, ethyl, n-propyl, and isopropyl.

[0124] In this article, the term “C 1～6 "Alkoxy" means a group C 1-6 Alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy and 2-ethylbutoxy. The term "C 1～3 "Alkoxy" means a group C 1-3 Alkyl-O- includes, but is not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0125] The term "aryl" herein refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably a 6- to 10-membered ring, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, including a benzo 3- to 8-membered cycloalkyl or a benzo 3- to 8-membered heterocyclyl, wherein the heterocyclyl is a heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

[0126] The term "heteroaryl" or "heteroaryl ring" herein refers to a heteroaromatic system having 5 to 14 ring atoms, which has 1 to 4 heteroatoms independently selected from N, O and S. The heteroaryl group is preferably 5 to 10-membered, more preferably 5-membered or 6-membered, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl and the like.

[0127] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably herein. The term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule via a heteroatom or carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.

[0128] The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halogens.

[0129] The term "3-8 membered heterocyclyl" as used herein means a non-aromatic cyclic group having 3 to 8 ring atoms, which contains one or more heteroatoms independently selected from N, O and S, and which may be fully saturated (i.e., 3-8 membered heterocycloalkyl) or partially unsaturated. The heterocycle may be a 3-8 membered monocyclic, bicyclic or spirocyclic ring. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl.

[0130] In this article, the term “C 3～8 "Cycloalkyl" means a monovalent group derived from a cyclic saturated aliphatic hydrocarbon having 3 to 8 carbons by removing any single hydrogen atom, i.e., a cycloalkyl group of 3 to 8 carbons.

[0131] The term "fused ring" herein refers to a 5-20 membered all-carbon polycyclic group, wherein each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, and wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. The fused ring is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. The carbon atoms in the fused rings may optionally be replaced by heteroatoms of O, S, or N, i.e., "fused heterocycles" are also included.

[0132] The term "fused heterocycle" as used herein refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, and in which one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, and in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. The fused heterocyclic ring is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group.

[0133] The term "spiro ring" herein refers to a polycyclic group of 5 to 20 members, wherein a carbon atom (called spiro atom) is shared between the monocycles, and the spiro ring may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spiro ring is preferably 6 to 14 members, for example 6 to 10 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, spiroalkyl is divided into monospiroalkyl, dispiroalkyl or polyspiroalkyl, preferably monospiroalkyl and dispiroalkyl. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiroalkyl. The carbon atoms in the spiro ring can be optionally replaced by the heteroatoms of O, S, N, i.e., also including "spiroheterocycle".

[0134] The term "spiroheterocycle" herein refers to a 5- to 20-membered polycyclic heterocyclic group in which the single rings share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. Spiro heterocycle may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spiro heterocycle is preferably 6 to 14 members, for example 6 to 10 members, more preferably 7 to 10 members. Spiro heterocyclic group is divided into single spiro heterocyclic group, double spiro heterocyclic group or multiple spiro heterocyclic group according to the number of shared spiro atoms between rings, preferably single spiro heterocyclic group and double spiro heterocyclic group. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiro heterocyclic group.

[0135] The compounds herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0136] The compounds described herein are named according to their chemical formulas. If the compound nomenclature and chemical formula for the same compound do not match, the chemical formula shall prevail.

[0137] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: / scan, and after collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0138] The solvents used herein are commercially available.

[0139] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. Beneficial effects

[0140] As a novel protein tyrosine phosphatase inhibitor, the compound of the present invention has strong inhibitory activity on protein tyrosine phosphatase. DETAILED DESCRIPTION

[0141] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0142] Preparation Example

[0143] Preparation of intermediate int1:

[0144] (1) Compound int-1a (20 g, 87.32 mmol) and cesium carbonate (71.13 g, 218.3 mmol) were dissolved in N,N-dimethylformamide (200 mL), water (7.86 g, 436.6 mmol) was added, and then RockPhos Pd G3 (732 mg, 0.87 mmol) was added. The mixture was stirred at 60°C under nitrogen protection for 16 h, and the reaction was monitored by LCMS to be complete. The reaction solution was cooled to room temperature, benzyl bromide (17.9 g, 104.78 mmol) was added, and the mixture was stirred at room temperature for 1.5 h, and the reaction was monitored by LCMS to be complete. The mixture was diluted with ethyl acetate (200 mL) and extracted with water (400 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate (3:1) to obtain compound int1-1b (21.6 g). LCMS (ESI) m / z: 257.0 [M+H] + .

[0145] (2) Compound int-1b (21.6 g, 84.28 mmol) was dissolved in ethylene glycol dimethyl ether (324 mL), p-methylbenzenesulfonylmethyl isocyanide (29.6 g, 151.61 mmol) was added, and sodium ethoxide (20%) (63.1 g, 185.41 mmol) was added thereto at 0°C under nitrogen protection. The mixture was stirred at room temperature under hydrogen protection for 16 h, and the reaction was monitored by LCMS to completion. The reaction solution was quenched with water, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate (3:1) to obtain compound int-1c (15.0 g). LCMS (ESI) m / z: 268.0 [M+H] + .

[0146] (3) Compound int-1c (5.0 g, 18.72 mmol) was dissolved in 1,4-dioxane (40 mL) and tetrahydrofuran (20 mL), the temperature was lowered to 0°C, and lithium aluminum hydride (2.6 g, 69.26 mmol) was added. The mixture was stirred at 0°C for 10 min, then heated to 100°C and stirred for 30 min. The reaction was monitored for completion by LCMS. The reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was concentrated in vacuo to obtain compound int-1d (3.5 g).

[0147] (4) Compound int-1d (3.5 g, 12.90 mmol) was dissolved in tetrahydrofuran (40 mL) and water (12 mL), and sodium bicarbonate (3.3 g, 38.70 mmol) and di-tert-butyl dicarbonate (4.2 g, 19.35 mmol) were added thereto at 0°C. The mixture was warmed to room temperature and stirred for 4 h. The reaction was monitored by LCMS to completion. The reaction solution was extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate (5:1) to obtain compound int1 (2.0 g). LCMS (ESI) m / z: 158.1 [M+H-100] + .

[0148] Preparation of intermediate int2:

[0149] (1) Compound int1 (4.5 g, 12.11 mmol) was dissolved in N,N-dimethylformamide (112.5 mL), the mixture was cooled to 0°C, and sodium hydride (1.45 g, 60.55 mmol) was added to the solution in batches. The reaction mixture was stirred for 65 minutes, and p-methoxybenzyl bromide (2.66 g, 13.32 mmol) was added. The resulting mixture was stirred at 80°C for 16 hours, quenched with saturated aqueous ammonium chloride at 20°C, and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 95 / 5) to obtain compound int-1-5 (4.32 g).

[0150] (2) 2,2,6,6-tetramethylpiperidine (0.66 mL, 3.96 mmol) was dissolved in tetrahydrofuran (12 mL), the reaction solution was cooled to 0°C, and a solution of n-butyllithium (1.6 M) (2.48 mL, 3.96 mmol) was slowly added. After stirring for 1 hour, the temperature was lowered to -78°C, and a solution of compound int-1-5 (0.6 g, 1.32 mmol) in tetrahydrofuran (12 mL) was slowly added, keeping the internal temperature below -65°C. After 2 hours, 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.095 mL, 0.79 mmol) was slowly added to keep the internal temperature below -60°C. After complete addition, the reaction mixture was warmed to room temperature for 16 hours, then quenched with saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The obtained crude product was purified by silica gel column (petroleum ether:ethyl acetate=91:9) to obtain compound int-1-6 (520 mg).

[0151] (3) Compound int-1-6 (483 mg, 0.85 mmol) was dissolved in 1,4-dioxane (10 mL), and glycine methyl ester hydrochloride (214 mg, 1.7 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (77 mg, 0.085 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-isopropyl-11'-biphenyl (46 mg, 0.085 mmol) and cesium carbonate (1.1 g, 3.4 mmol) were added. The mixture was reacted at 90°C under nitrogen protection for 16 h, and the reaction was monitored by LCMS to completion. The reaction solution was concentrated, and the obtained concentrate was purified by silica gel column (petroleum ether:ethyl acetate=10:1) to obtain compound int-1-7 (200 mg).

[0152] Chlorosulfonic acid isocyanate (79 mg, 0.56 mmol) was dissolved in dichloromethane (4 mL), tert-butanol (41 mg, 0.56 mmol) was added, and the mixture was stirred at 0 ° C for 0.5 h. Then, a mixture of compound int-1-7 (213 mg, 0.37 mmol) and triethylamine (75 mg, 0.74 mmol) dissolved in dichloromethane (2 mL) was added. Stir at 0 ° C for 0.5 h, then warm to room temperature and stir for 1 h. The reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain compound int-1-8 (200 mg).

[0153] (4) Compound int-1-8 (212 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate, diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain compound int-1-9 (150 mg).

[0154] (5) Compound int-1-9 (150 mg, 0.29 mmol) was dissolved in tetrahydrofuran (2 mL), and a methanol solution of sodium methoxide (0.4 mL, 0.44 mmol) was added, and the mixture was stirred at room temperature for 20 min. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 7 with 1N hydrochloric acid, diluted with ethyl acetate (30 mL) and extracted with water (100 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane: methanol = 15:1) to obtain compound int-2 (100 mg). MS m / z (ESI): 526.1 [M+H] + .

[0155] Example 1: Preparation of Compound 1

[0156] Synthesis route:

[0157] (1) Intermediate int1 (1.0 g, 2.69 mmol) was dissolved in N,N-dimethylformamide (25 mL), the mixture was cooled to 0°C, and sodium hydride (0.32 g, 13.45 mmol) was added to the solution in batches. The reaction mixture was stirred for 65 minutes, and 1-bromo-4-methylpentane (1.33 g, 8.08 mmol) was added. The resulting mixture was stirred at 80°C for 16 hours, quenched with saturated aqueous ammonium chloride solution (200 mL) at 20°C, and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (2×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 90 / 10) to obtain compound 1a (600 mg). MS m / z (ESI): 478.0 [M+Na] + .

[0158] (2) 2,2,6,6-tetramethylpiperidine (0.66 mL, 3.96 mmol) was dissolved in tetrahydrofuran (12 mL), the reaction solution was cooled to 0°C, and a solution of n-butyllithium (1.6 M) (2.48 mL, 3.96 mmol) was slowly added. After stirring for 1 hour, the temperature was lowered to -78°C and a solution of compound 1a (0.6 g, 1.32 mmol) in tetrahydrofuran (12 mL) was slowly added, keeping the internal temperature below -65°C. After 2 hours, 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.095 mL, 0.79 mmol) was slowly added to keep the internal temperature below -60°C. After complete addition, the reaction mixture was warmed to room temperature for 16 hours, then quenched with saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=91:9) to obtain compound 1b (520 mg). MS m / z (ESI): 557.9 [M+Na] + .

[0159] (3) Compound 1b (450 mg, 0.85 mmol) was dissolved in 1,4-dioxane (10 mL), and glycine methyl ester hydrochloride (214 mg, 1.7 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (77 mg, 0.085 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-isopropyl-11'-biphenyl (46 mg, 0.085 mmol) and cesium carbonate (1.1 g, 3.4 mmol) were added. The mixture was reacted at 90°C under nitrogen protection for 16 h. The reaction was monitored by LCMS to completion. The reaction solution was concentrated, and the resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 1c (200 mg). MS m / z (ESI): 543.0 [M+H] + .

[0160] (4) Chlorosulfonic acid isocyanate (79 mg, 0.56 mmol) was dissolved in dichloromethane (4 mL), tert-butanol (41 mg, 0.56 mmol) was added, and the mixture was stirred at 0°C for 0.5 h. Then, a mixture of compound 1c (200 mg, 0.37 mmol) and triethylamine (75 mg, 0.74 mmol) dissolved in dichloromethane (2 mL) was added. The mixture was stirred at 0°C for 0.5 h, then warmed to room temperature and stirred for 1 h. The reaction was monitored by LCMS to completion. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain compound 1d (200 mg). MS m / z (ESI): 722.0 [M+H] + .

[0161] (5) Compound 1d (200 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate, diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound 1e (150 mg). MS m / z (ESI): 522.0 [M+H] + .

[0162] (6) Compound 1e (150 mg, 0.29 mmol) was dissolved in tetrahydrofuran (2 mL), and a methanol solution of sodium methoxide (0.4 mL, 0.44 mmol) was added. The mixture was stirred at room temperature for 20 min. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 7 with 1N hydrochloric acid, diluted with ethyl acetate (30 mL) and extracted with water (100 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane: methanol = 15:1) to obtain compound 1f (100 mg). MS m / z (ESI): 490.0 [M+H] + .

[0163] (7) Compound 1f (100 mg, 0.2 mmol) was dissolved in dichloromethane (2 mL), pentamethylbenzene (59 mg, 0.4 mmol) was added, and the temperature was lowered to -78°C. Then, boron trichloride (1.2 mL, 1.2 mmol) was slowly added thereto. The mixture was stirred at -78°C for 20 min. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by an alkaline reverse phase method to obtain compound 1 (8.9 mg).

[0164] Example 2: Preparation of Compound 2

[0165] Synthesis route:

[0166] (1) Intermediate int1 (4.5 g, 12.11 mmol) was dissolved in N,N-dimethylformamide (112.5 mL), the mixture was cooled to 0°C, and sodium hydride (1.45 g, 60.55 mmol) was added to the solution in batches. The reaction mixture was stirred for 65 minutes, and 1-bromo-3-methylbutane (5.49 g, 36.33 mmol) was added. The resulting mixture was stirred at 80°C for 16 hours, quenched with saturated aqueous ammonium chloride solution (200 mL) at 20°C, and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (2×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 98 / 2) to obtain compound 2a (3.95 g). MS m / z (ESI): 386.2 [M-56] - .

[0167] (2) 2,2,6,6-tetramethylpiperidine (4.53 mL, 26.82 mmol) was dissolved in tetrahydrofuran (79 mL), the reaction solution was cooled to 0°C, and a solution of n-butyllithium (1.6 M) (16.76 mL, 26.82 mmol) was slowly added. After stirring for 1 hour, the temperature was lowered to -78°C and a solution of compound 2a (3.95 g, 8.94 mmol) in tetrahydrofuran (79 mL) was slowly added, keeping the internal temperature below -65°C. After 2 hours, 1,2-dibromo-1,1,2,2-tetrafluoroethane (1.28 mL, 10.73 mmol) was slowly added, keeping the internal temperature below -60°C. After complete addition, the reaction mixture was warmed to room temperature for 16 hours, then quenched with saturated aqueous ammonium chloride solution (100 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=97:3) to obtain compound 2b (2 g). MS m / z (ESI): 544.2 [M+23] + .

[0168] (3) Compound 2b (400 mg, 0.77 mmol) was dissolved in 1,4-dioxane (5 mL), and glycine methyl ester hydrochloride (194 mg, 1.54 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (70 mg, 0.077 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-isopropyl-11'-biphenyl (41 mg, 0.077 mmol) and cesium carbonate (1 g, 3.08 mmol) were added. The mixture was reacted at 90°C under nitrogen protection for 16 h. The reaction was monitored by LCMS to completion. The reaction solution was concentrated, and the resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 2c (200 mg). MS m / z (ESI): 529.0 [M+H] + .

[0169] (4) Chlorosulfonic acid isocyanate (72 mg, 0.51 mmol) was dissolved in dichloromethane (2 mL), tert-butanol (38 mg, 0.51 mmol) was added, and the mixture was stirred at 0°C for 0.5 h. Then, a mixture of compound 2c (180 mg, 0.34 mmol) and triethylamine (69 mg, 0.68 mmol) dissolved in dichloromethane (2 mL) was added. The mixture was stirred at 0°C for 0.5 h, then warmed to room temperature and stirred for 1 h. The reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain compound 2d (180 mg). MS m / z (ESI): 708.0 [M+H] + .

[0170] (5) Compound 2d (180 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate, diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound 2e (120 mg). MS m / z (ESI): 508.0 [M+H] + .

[0171] (6) Compound 2e (130 mg, 0.26 mmol) was dissolved in tetrahydrofuran (2 mL), and a methanol solution of sodium methoxide (0.39 mL, 0.39 mmol) was added. The mixture was stirred at room temperature for 20 min. The reaction was monitored by LCMS. The reaction solution was adjusted to pH 7 with 1N hydrochloric acid, diluted with ethyl acetate (30 mL), and extracted with water (100 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol=15:1) to obtain compound 2f (60 mg). MS m / z (ESI): 476.0 [M+H] + .

[0172] (7) Compound 2f (50 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL), pentamethylbenzene (30 mg, 0.2 mmol) was added, and the temperature was lowered to -78°C, followed by the slow addition of boron trichloride (0.6 mL, 0.6 mmol). The mixture was stirred at -78°C for 20 min. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by an alkaline reverse phase method to afford compound 2 (11 mg).

[0173] Example 3: Preparation of Compound 3

[0174] Synthesis route:

[0175] (1) Intermediate int1 (2.0 g, 5.38 mmol) was dissolved in N,N-dimethylformamide (50 mL), the mixture was cooled to 0°C, and sodium hydride (0.64 g, 12.8 mmol) was added to the solution in batches. The reaction mixture was stirred for 65 minutes, and 4-methylbenzenesulfonic acid 4,4-difluorobutyl ester (4.27 g, 16.14 mmol) was added. The resulting mixture was stirred at 80°C for 2 hours, quenched with saturated aqueous ammonium chloride solution (150 mL) at 20°C, and extracted with ethyl acetate (3×80 mL). The combined organic layer was washed with brine (2×100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 98 / 2) to obtain compound 3a (1.5 g).

[0176] (2) 2,2,6,6-tetramethylpiperidine (1.65 mL, 9.7 mmol) was dissolved in tetrahydrofuran (30 mL), the reaction solution was cooled to 0°C, and a solution of n-butyllithium (1.6 M) (6.1 mL, 9.7 mmol) was slowly added. After stirring for 1 hour, the temperature was lowered to -78°C and a solution of compound 3a (1.5 g, 3.24 mmol) in tetrahydrofuran (30 mL) was slowly added, keeping the internal temperature below -65°C. After 2 hours, 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.46 mL, 3.9 mmol) was slowly added to keep the internal temperature below -60°C. After complete addition, the reaction mixture was warmed to room temperature for 16 hours, then quenched with saturated aqueous ammonium chloride solution (150 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The obtained crude product was purified by silica gel column (petroleum ether:ethyl acetate=96:4) to obtain compound 3b (820 mg).

[0177] (3) Compound 3b (800 mg, 1.48 mmol) was dissolved in 1,4-dioxane (10 mL), and glycine methyl ester hydrochloride (373 mg, 2.96 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (136 mg, 0.15 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-isopropyl-11'-biphenyl (81 mg, 0.15 mmol) and cesium carbonate (1.9 g, 5.92 mmol) were added. The mixture was reacted at 90°C under nitrogen protection for 16 h. The reaction was monitored by LCMS to completion. The reaction solution was concentrated, and the resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 3c (500 mg). MS m / z (ESI): 551.0 [M+H] + .

[0178] (4) Chlorosulfonic acid isocyanate (193 mg, 1.37 mmol) was dissolved in dichloromethane (2 mL), tert-butanol (101 mg, 1.37 mmol) was added, and the mixture was stirred at 0°C for 0.5 h. Then, a mixture of compound 3c (500 mg, 0.91 mmol) and triethylamine (184 mg, 1.82 mmol) dissolved in dichloromethane (2 mL) was added. The mixture was stirred at 0°C for 0.5 h, then warmed to room temperature and stirred for 1 h. The reaction was monitored by LCMS to completion. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain compound 3d (500 mg). MS m / z (ESI): 730.0 [M+H] + .

[0179] (5) Compound 3d (500 mg, 0.69 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate, diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound 3e (350 mg). MS m / z (ESI): 530.0 [M+H] + .

[0180] (6) Compound 3e (350 mg, 0.66 mmol) was dissolved in tetrahydrofuran (5 mL), and a methanol solution of sodium methoxide (1 mL, 0.99 mmol) was added. The mixture was stirred at room temperature for 20 min. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 7 with 1N hydrochloric acid, diluted with ethyl acetate (30 mL) and extracted with water (100 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol=15:1) to obtain compound 3f (200 mg). MS m / z (ESI): 497.0 [M+H] + .

[0181] (7) Compound 3f (80 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL), pentamethylbenzene (47 mg, 0.32 mmol) was added, and the temperature was lowered to -78°C. Then, boron trichloride (0.96 mL, 0.96 mmol) was slowly added thereto. The mixture was stirred at -78°C for 20 min. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by an alkaline reverse phase method to obtain compound 3 (9 mg).

[0182] Example 4: Preparation of Compound 4

[0183] Synthesis route:

[0184] (1) Compound 4a (3 g, 27.27 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (8 g, 81.82 mmol) and p-toluenesulfonyl chloride (10.3 g, 54.54 mmol) were added. The mixture was reacted at room temperature for 16 h. The reaction was monitored by TLC until completion. The mixture was extracted with dichloromethane and water, and the organic phase was dried and concentrated. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 4b (4.7 g).

[0185] (2) Intermediate 4b (5 g, 15.6 mol) was added to a solution of N,N-dimethylformamide (100 mL), sodium hydride (3 g, 16.38 mmol) was added at 0°C under nitrogen, and the mixture was stirred at 0°C for 1 hour. Intermediate int1 was then added, and the mixture was stirred at 80°C for 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate (2500 mL) and extracted with ethyl acetate (500 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrated solution was eluted with 10% ethyl acetate in petroleum ether to give compound 4c (3 g).

[0186] (3) 2,2,6,6-Tetramethylpiperidine (275 mg, 1.94 mmol) was dissolved in tetrahydrofuran (3 mL). n-Butyl lithium (1.2 mL, 1.94 mmol) was added at 0°C. The mixture was reacted at 0°C for 1 h. Compound 4c (300 mg, 0.64 mmol) was added at -78°C. The mixture was reacted at -78°C for 2 h. 1,2-Dibromoethane (202 mg, 0.78 mmol) was added at -78°C. The reaction was monitored by TLC. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was dried and concentrated. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 15:1) to obtain compound 4d (100 mg). MS m / z (ESI): 528.3 [M+H]+.

[0187] (4) Compound 4d (600 mg, 1.11 mmol) was dissolved in 1,4-dioxane (8 mL), and glycine methyl ester hydrochloride (280 mg, 2.22 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (100 mg, 0.11 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-isopropyl-11'-biphenyl (59 mg, 0.11 mmol) and cesium carbonate (1.45 g, 4.44 mmol) were added. The mixture was reacted at 90°C under nitrogen protection for 16 h. The reaction was monitored by LCMS to completion. The reaction solution was concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 4e (250 mg). MS m / z (ESI): 537.0 [M+H] + .

[0188] (5) Chlorosulfonic acid isocyanate (402 mg, 2.85 mmol) was dissolved in dichloromethane (10 mL), tert-butanol (211 mg, 2.85 mmol) was added, and the mixture was stirred at 0°C for 0.5 h. Then, a mixture of compound 4e (1 g, 1.9 mmol) and triethylamine (384 mg, 3.8 mmol) dissolved in dichloromethane (2 mL) was added. The mixture was stirred at 0°C for 0.5 h, then warmed to room temperature and stirred for 1 h. The reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound 4f (250 mg). MS m / z (ESI): 738.7 [M+Na]+.

[0189] (6) Compound 4f (1 g, 1.4 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate, diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound 4g (250 mg). MS m / z (ESI): 516.6 [M+H] +.

[0190] (7) Compound 4g (200 mg, 0.32 mmol) was dissolved in tetrahydrofuran (2 mL), and a methanol solution of sodium methoxide (0.48 mL, 0.48 mmol) was added. The mixture was stirred at room temperature for 20 min. The reaction was monitored by LCMS. The reaction solution was adjusted to pH 7 with 1N hydrochloric acid, diluted with ethyl acetate (30 mL), and extracted with water (100 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol=15:1) to obtain compound 4h (100 mg). MS m / z (ESI): 484.1 [M+H]+.

[0191] (8) Compound 4h (100 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (2 mL), and palladium on carbon (100 mg) and palladium hydroxide on carbon (100 mg) were added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by reverse phase column chromatography to obtain compound 4 (33 mg).

[0192] Example 5: Preparation of Compound 5

[0193] Synthesis route:

[0194] (1) Benzoyl chloride 5a (10 g, 71.43 mmol) was dissolved in tetrahydrofuran (100 mL), and 4-hydroxy-2-butanone (6.9 g, 78.57 mmol) and triethylamine (15.6 g, 142.86 mmol) were added. The mixture was reacted at room temperature for 3 h. The reaction was monitored by TLC to completion, and then quenched with water and extracted with dichloromethane. The organic phase was dried and concentrated, and the resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 5b (11 g).

[0195] (2) Compound 5b (10 g, 52.08 mmol) was dissolved in dichloromethane (100 mL). Diethylaminosulfur trifluoride (100.8 g, 624.96 mmol) was added at 0°C. The mixture was reacted at room temperature for 16 h. The reaction was monitored for completion by TLC. The mixture was then quenched with an ice-cold aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried and concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 5c (9 g).

[0196] (3) Compound 5c (9 g, 42.06 mmol) was dissolved in a solution of methanol (80 mL) and water (20 mL). Sodium hydroxide (5.1 g, 127.8 mmol) was added at 0°C. The mixture was reacted at room temperature for 2 h. The reaction was monitored for completion by TLC. The mixture was extracted with ether and water, the organic phase was dried and concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 5d (3 g).

[0197] (4) Compound 5d (3 g, 27.27 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (8 g, 81.82 mmol) and p-toluenesulfonyl chloride (10.3 g, 54.54 mmol) were added. The mixture was reacted at room temperature for 16 h. The reaction was monitored for completion by TLC. The mixture was extracted with dichloromethane and water, and the organic phase was dried and concentrated. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 5e (4.7 g). MS m / z (ESI): 265.0 [M+H]+.

[0198] (5) Compound 1a (2 g, 7.37 mmol) was dissolved in acetonitrile (20 mL), and compound 5e (2.4 g, 8.84 mmol), potassium carbonate (2.5 g, 18.42 mmol), and potassium iodide (122 mg, 1.84 mmol) were added. The mixture was reacted at 70°C for 48 h, and the reaction completion was monitored by TLC. The organic phase was filtered, dried, and concentrated, and the resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 5f (1.7 g). MS m / z (ESI): 350.2 [M+H]+.

[0199] (6) Compound 5f (1.7 g, 4.68 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (1.4 g, 14.05 mmol) and di-tert-butyl dicarbonate (2.1 g, 9.36 mmol) were added at 0°C. The mixture was reacted at 50°C for 16 h, and the reaction completion was monitored by TLC. The organic phase was filtered, dried, and concentrated, and the resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 7:1) to obtain compound 5g (2.1 g). MS m / z (ESI): 486.2 [M+Na]+.

[0200] (7) 2,2,6,6-Tetramethylpiperidine (275 mg, 1.94 mmol) was dissolved in tetrahydrofuran (3 mL). n-Butyl lithium (1.2 mL, 1.94 mmol) was added at 0°C. The mixture was reacted at 0°C for 1 h, and then compound 5g (300 mg, 0.64 mmol) was added at -78°C. The mixture was reacted at -78°C for 2 h, and 1,2-dibromoethane (202 mg, 0.78 mmol) was added at -78°C. The reaction was monitored by TLC until completion, and then the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was dried and concentrated, and the resulting concentrate was purified on a silica gel column using petroleum ether:ethyl acetate (15:1) to obtain compound 5h (100 mg). MS m / z (ESI): 542.3 [M+H]+.

[0201] (8) Compound 5h (600 mg, 1.11 mmol) was dissolved in 1,4-dioxane (8 mL), and glycine methyl ester hydrochloride (280 mg, 2.22 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (100 mg, 0.11 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-isopropyl-11'-biphenyl (59 mg, 0.11 mmol) and cesium carbonate (1.45 g, 4.44 mmol) were added. The mixture was reacted at 90°C under nitrogen protection for 16 h. The reaction was monitored by LCMS to completion. The reaction solution was concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 5i (250 mg). MS m / z (ESI): 573.9 [M+Na] + .

[0202] (9) Chlorosulfonic acid isocyanate (296 mg, 2.1 mmol) was dissolved in dichloromethane (10 mL), tert-butanol (155 mg, 2.1 mmol) was added, and the mixture was stirred at 0°C for 0.5 h. Then, a mixture of compound 5i (800 mg, 1.45 mmol) and triethylamine (293 mg, 2.9 mmol) dissolved in dichloromethane (2 mL) was added. The mixture was stirred at 0°C for 0.5 h, then warmed to room temperature and stirred for 1 h. The reaction was monitored by LCMS to completion. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound 5j (800 mg). MS m / z (ESI): 752.8 [M+Na]+.

[0203] (10) Compound 5j (800 mg, 1.1 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate, diluted with ethyl acetate (50 mL), and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 5:1) to give compound 5k (500 mg). MS m / z (ESI): 530.2 [M+H] +.

[0204] (11) Compound 5k (500 mg, 0.95 mmol) was dissolved in tetrahydrofuran (5 mL), and a methanol solution of sodium methoxide (1.4 mL, 1.43 mmol) was added. The mixture was stirred at room temperature for 20 min. The reaction was monitored by LCMS. The reaction solution was adjusted to pH 7 with 1N hydrochloric acid, diluted with ethyl acetate (30 mL), and extracted with water (100 mL), which was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol=15:1) to give compound 5l (300 mg). MS m / z (ESI): 498.2 [M+H]+.

[0205] (12) Compound 51 (100 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (2 mL), and palladium on carbon (100 mg) and palladium hydroxide on carbon (100 mg) were added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by reverse phase column chromatography to obtain compound 5 (21 mg).

[0206] Example 6: Preparation of Compound 6

[0207] Synthesis route:

[0208] (1) A mixture of compound 6a (1.43 g, 7.45 mmol) and compound 6b (1.73 g, 8.0 mmol) in tetrahydrofuran (20 mL) was cooled to -50°C, and potassium tert-butoxide (3.0 g, 26.8 mmol) was slowly added. The mixture was stirred at -50°C for 45 min, and the reaction was monitored for completion by TLC. The reaction solution was poured into water and extracted with ethyl acetate (10 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography using (petroleum ether:ethyl acetate = 10:1) as the eluent to obtain compound 6c (0.9 g).

[0209] (2) Compound 6c (0.9 g, 3.98 mmol) was dissolved in ultra-dry methanol (10 mL), and Pd / C (0.9 g) was added. The mixture was replaced with hydrogen three times and stirred for 3 h. The reaction was monitored for completion by TLC. The reaction solution was filtered through celite, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 6d (0.4 g).

[0210] (3) Compound 6d (0.4 g, 2.9 mmol) and p-toluenesulfonyl chloride (0.55 g, 2.9 mmol) were dissolved in dichloromethane (10 mL). Triethylamine (0.586 g, 5.8 mmol) and 4-dimethylaminopyridine (10 mg) were then slowly added. The mixture was stirred at room temperature for 60 min. The reaction was monitored for completion by TLC. The reaction solution was directly concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain compound 6e (0.7 g). MS m / z (ESI): 293.1 [M+H]+.

[0211] (4) A mixture of compound 6e (1.43 g, 7.45 mmol) and intermediate int1 (1.73 g, 8.0 mmol) was dissolved in N,N-dimethylformamide (20 mL) and cooled to 0°C. Then, sodium hydride (3.0 g, 26.8 mmol) was slowly added. The mixture was stirred at 70°C for 60 min. The reaction was monitored by TLC for completion. The reaction solution was poured into water and extracted with ethyl acetate (10 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 6f (0.9 g).

[0212] (5) 2,2,6,6-Tetramethylpiperidine (0.66 mL, 3.96 mmol) was dissolved in tetrahydrofuran (12 mL), the reaction solution was cooled to 0°C, and a 1.6 M solution of n-butyllithium (2.48 mL, 3.96 mmol) was slowly added. After stirring for 1 hour, the temperature was lowered to -78°C and a solution of compound 6f (0.6 g, 1.32 mmol) in tetrahydrofuran (12 mL) was slowly added, keeping the internal temperature below -65°C. After 2 hours, 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.095 mL, 0.79 mmol) was slowly added, keeping the internal temperature below -60°C. After complete addition, the reaction mixture was warmed to room temperature for 16 hours, then quenched with saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=91:9) to obtain compound 6g (520 mg). MS m / z (ESI): 557.9 [M+Na] + .

[0213] (6) Compound 6 g (450 mg, 0.85 mmol) was dissolved in 1,4-dioxane (10 mL), and glycine methyl ester hydrochloride (214 mg, 1.7 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (77 mg, 0.085 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-isopropyl-11'-biphenyl (46 mg, 0.085 mmol) and cesium carbonate (1.1 g, 3.4 mmol) were added. The mixture was reacted at 90°C under nitrogen protection for 16 h. The reaction was monitored by LCMS to completion. The reaction solution was concentrated, and the resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 6h (200 mg). MS m / z (ESI): 565.2 [M+Na] + .

[0214] (7) Chlorosulfonic acid isocyanate (79 mg, 0.56 mmol) was dissolved in dichloromethane (4 mL), tert-butanol (41 mg, 0.56 mmol) was added, and the mixture was stirred at 0°C for 0.5 h. Then, a mixture of compound 6h (200 mg, 0.37 mmol) and triethylamine (75 mg, 0.74 mmol) dissolved in dichloromethane (2 mL) was added. The mixture was stirred at 0°C for 0.5 h, then warmed to room temperature and stirred for 1 h. The reaction was monitored by LCMS to completion. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound 6i (200 mg). MS m / z (ESI): 744.2 [M+Na]+.

[0215] (8) Compound 6i (200 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate, diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound 6j (150 mg). MS m / z (ESI): 522.3 [M+H] +.

[0216] (9) Compound 6j (150 mg, 0.29 mmol) was dissolved in tetrahydrofuran (2 mL), and a methanol solution of sodium methoxide (0.4 mL, 0.44 mmol) was added. The mixture was stirred at room temperature for 20 min. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH 7 with 1N hydrochloric acid, diluted with ethyl acetate (30 mL), and extracted with water (100 mL), which was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol=15:1) to obtain compound 6k (100 mg, yield: 70%) as a brown oil. MS m / z (ESI): 490.0 [M+H]+.

[0217] (10) Compound 6k (100 mg, 0.2 mmol) was dissolved in dichloromethane (2 mL), pentamethylbenzene (59 mg, 0.4 mmol) was added, and the temperature was lowered to -78°C. Then, boron trichloride (1.2 mL, 1.2 mmol) was slowly added thereto. The mixture was stirred at -78°C for 20 min. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by an alkaline reverse phase method to give compound 6 (8.9 mg).

[0218] Example 7: Preparation of Compound 7

[0219] Synthesis route:

[0220] (1) Compound 7a (5 g, 27 mmol) was dissolved in tetrahydrofuran (50 mL) and diethylaminosulfur trifluoride (21.7 g, 135 mmol) was added at 0°C. The mixture was stirred at 40°C for 48 h. The reaction was monitored for completion by TLC. The reaction was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 7b (3 g).

[0221] (2) Compound 7b (3 g, 14.6 mmol) was dissolved in tetrahydrofuran (40 mL) and lithium aluminum hydride (21.9 mL, 21.9 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 h. The reaction was monitored for completion by TLC. The reaction was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 7c (2 g).

[0222] (3) Compound 7c (2 g, 12.2 mmol) was dissolved in dichloromethane (30 mL) and Dawes-Martin reagent (7.8 g, 18.3 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction was monitored for completion by TLC. The reaction was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 7d (1 g).

[0223] (4) Intermediate int2 (120 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and compound 7d (106 mg, 1.15 mmol), sodium triacetoxyborohydride (204 mg, 1.15 mmol), and tetraisopropyl titanate (13 mg, 0.046 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH = 5, diluted with ethyl acetate (5 mL), and extracted with water (20 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol = 10:1) to obtain compound 7e (104 mg). MS m / z (ESI): 672.3 [M+H]+.

[0224] (5) Compound 7e (90 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), and palladium on carbon (90 mg) and palladium hydroxide on carbon (100 mg) were added. The mixture was stirred at 50°C for 16 h. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by reverse phase alkaline method to obtain compound 7 (14.61 mg).

[0225] Examples 8 and 9: Preparation of Compounds 8, 9a, 9b, 9c and 9d

[0226] Synthesis route:

[0227] (1) Compound 8a (20 g, 117.50 mmol) was dissolved in dichloromethane (200 mL) and diethylaminosulfur trifluoride (132.6 g, 822.5 mmol) was added at 0°C. The mixture was stirred at room temperature for 12 h, and the reaction was monitored for completion by thin-layer chromatography. The reaction solution was quenched with aqueous sodium thiosulfate and sodium bicarbonate solutions, the aqueous phase was extracted with ether, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified on a silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 8b (2.5 g).

[0228] (2) Compound 8b (2.5 g, 13.01 mmol) was dissolved in tetrahydrofuran (25 mL) and lithium aluminum hydride (0.99 g, 26.02 mmol) was added at 0°C. The mixture was stirred at room temperature for 20 minutes and the reaction was monitored for completion by thin-layer chromatography. The reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filter cake was washed with ether. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified on a silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound 8c (1.5 g).

[0229] (3) Compound 8c (1.5 g, 9.43 mmol) was dissolved in dichloromethane (15 mL) and Dess-Martin reagent (4.4 g, 10.38 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 h, and the reaction was monitored for completion by thin-layer chromatography. The reaction solution was quenched with sodium thiosulfate and sodium bicarbonate aqueous solutions, the aqueous phase was extracted with ether, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified on a silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 8d (900 mg).

[0230] (4) Intermediate int2 (120 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and compound 8d (86 mg, 1.15 mmol), sodium triacetoxyborohydride (194 mg, 1.15 mmol), and tetraisopropyl titanate (13 mg, 0.046 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH = 5, diluted with ethyl acetate (5 mL), and extracted with water (20 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol = 10:1) to obtain compound 8e (101 mg). MS m / z (ESI): 658.3 [M+H]+.

[0231] (5) Compound 8e (101 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), and palladium on carbon (90 mg) and palladium hydroxide on carbon (100 mg) were added. The mixture was stirred at 50°C for 16 h. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by reverse phase alkaline method to obtain compound 8 (9.61 mg).

[0232] Compound 8 was chirally resolved to afford compounds 9a, 9b, 9c and 9d.

[0233] Example 10

[0234] Synthesis route:

[0235] (1) Compound 10a (5.0 g, 28 mmol) was dissolved in ultra-dry N,N-dimethylformamide (50 mL), triethylamine (12 mL) and compound 10b (3.3 g, 30 mmol) were added, and then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (13 g, 30 mmol) were added. The mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 10c (5.8 g).

[0236] (2) Compound 10c (1 g, 4.5 mmol) was dissolved in ultra-dry tetrahydrofuran (10 mL), cooled to 0°C, and after N2 replacement, compound 10d (9 mL, 9 mmol) was slowly added. The mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL), and the mixture was repeated three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 10e (0.8 g).

[0237] (3) A mixture of compound 10e (0.8 g, 3.44 mmol) and compound 10f (0.66 g, 3.44 mmol) in tetrahydrofuran (20 mL) was cooled to -50°C, and potassium tert-butoxide (0.77 g, 6.88 mmol) was slowly added. The mixture was stirred at -50°C for 45 min, and the reaction was monitored for completion by TLC. The reaction solution was poured into water and extracted with ethyl acetate (10 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain compound 10g (0.4 g).

[0238] (4) Compound 10g (1.2g, 4.5mmol) and palladium on carbon (1.2g) were dissolved in methanol (20mL), stirred at room temperature overnight, and reacted for 16 hours. The reaction solution was filtered and dried to obtain compound 10h (750mg).

[0239] (5) Compound 10h (750 mg, 4.2 mmol) was dissolved in dichloromethane (10 mL), the temperature was lowered to 0°C, and Dess-Martin periodinane (2.14 g, 5.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was filtered, dried, and concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (dichloroethane 100%) to obtain compound 10i (0.4 g).

[0240] (6) Intermediate int2 (120 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and 10i (150 mg, 1.15 mmol), sodium triacetoxyborohydride (204 mg, 1.15 mmol), and tetraisopropyl titanate (13 mg, 0.046 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH = 5, diluted with ethyl acetate (5 mL), and extracted with water (20 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol = 10:1) to obtain compound 10j (98 mg). MS m / z (ESI): 686.3 [M+H]+.

[0241] (7) Compound 10j (90 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), and palladium on carbon (90 mg) and palladium hydroxide on carbon (100 mg) were added. The mixture was stirred at 50°C for 16 h. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by reverse phase alkaline method to obtain compound 10 (18.61 mg).

[0242] Example 11: Preparation of Compound 11

[0243] Synthesis route:

[0244] (1) Compound 11a (5 g, 27.82 mmol) was dissolved in ultra-dry tetrahydrofuran (50 mL), cooled to 0°C, and lithium aluminum hydride (1.06 g, 27.82 mmol) was slowly added under nitrogen. The mixture was allowed to warm to room temperature under nitrogen and stirred for 0.5 h. The reaction was monitored for completion by TLC. The reaction mixture was quenched with water (25 mL) and 15% sodium hydroxide solution. After stirring for 10 min, ether (50 mL) was added to dilute the mixture, filtered, and the filtrate was concentrated in vacuo to obtain compound 11b (4.3 g, crude product).

[0245] (2) Compound 11b (4.3 g) was dissolved in ultra-dry dichloromethane (50 mL), 4-dimethylaminopyridine (355 mg, 2.90 mmol) was added, and the temperature was lowered to 0°C. Triethylamine (5.9 g, 58.05 mmol) and p-toluenesulfonyl chloride (5.5 g, 29.02 mmol) were added. The mixture was warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC to determine completion. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (100 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 11c (7 g).

[0246] (3) Compound 11c (2 g, 6.62 mmol) was dissolved in dimethyl sulfoxide (20 mL), and 18-crown ether-6 (2.6 g, 9.92 mmol) and sodium cyanide (774 mg, 19.85 mmol) were added. The mixture was stirred at 80°C for two days. The reaction was monitored by TLC. The reaction solution was adjusted to alkaline pH by adding 1N sodium hydroxide solution, diluted with dichloromethane (30 mL) and extracted with water (100 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound 11d (950 mg).

[0247] (4) Compound 11d (950 mg, 6.36 mmol) was dissolved in a 2:1:1 mixed solvent of pyridine:acetic acid:water (8 / 4 / 4 mL). The temperature was cooled to 0°C, and wet Raney nickel (1.9 g) and hydrated sodium hypophosphite (3.4 g, 31.81 mmol) were added. The mixture was stirred at room temperature under nitrogen for 3 h. The reaction was monitored for completion by TLC. The reaction solution was filtered, and the filtrate was concentrated in vacuo to obtain compound 11e (800 mg).

[0248] (5) Int2 (120 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and compound 11e (16 mg, 1.35 mmol), sodium triacetoxyborohydride (204 mg, 1.15 mmol), and tetraisopropyl titanate (13 mg, 0.046 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH = 5, diluted with ethyl acetate (5 mL), and extracted with water (20 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol = 10:1) to obtain compound 11 (6 mg).

[0249] Example 12: Preparation of Compound 12

[0250] Synthesis route:

[0251] (1) Benzoyl chloride 12a (20 g, 142.85 mmol) was dissolved in tetrahydrofuran (200 mL), and 5-hydroxy-2-pentanone (14.57 g, 157.14 mmol) and triethylamine (38.92 g, 357.125 mmol) were added at 0°C. The mixture was stirred at room temperature for 3 h, and the reaction was monitored for completion by thin-layer chromatography. The reaction solution was quenched with water, the aqueous phase was extracted with ether, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified on a silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 12b (20 g).

[0252] (2) Compound 12b (20 g, 117.50 mmol) was dissolved in tetrahydrofuran (200 mL) and diethylaminosulfur trifluoride (132.6 g, 822.5 mmol) was added at 0°C. The mixture was stirred at room temperature for 12 h, and the reaction was monitored for completion by thin-layer chromatography. The reaction solution was quenched with aqueous sodium thiosulfate and sodium bicarbonate solutions. The aqueous phase was extracted with ether, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified on a silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 12c (11 g).

[0253] (3) Compound 12c (11 g, 48.22 mmol) was dissolved in methanol (120 mL) and water (30 mL), and sodium hydroxide (9.6 g, 241.1 mmol) was added at 0°C. The mixture was stirred at room temperature for 3 h, and the reaction was monitored for completion by thin-layer chromatography. The reaction solution was extracted with water and diethyl ether, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified on a silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain compound 12d (5 g).

[0254] (4) Compound 12d (2.5 g, 20.16 mmol) was dissolved in dichloromethane (25 mL) and Dess-Martin reagent (9.4 g, 22.17 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 h, and the reaction was monitored for completion by thin-layer chromatography. The reaction solution was quenched with sodium thiosulfate and sodium bicarbonate aqueous solutions, the aqueous phase was extracted with ether, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified on a silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 12e (1.5 g, yield: 70.2%) as a colorless liquid.

[0255] (5) Intermediate int2 (110 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and compound 12e (106 mg, 1.15 mmol), sodium triacetoxyborohydride (204 mg, 1.15 mmol) and tetraisopropyl titanate (13 mg, 0.046 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH = 5, diluted with ethyl acetate (5 mL) and extracted with water (20 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol = 10:1) to obtain compound 12f (98 mg). MS m / z (ESI): 632.3 [M+H]+.

[0256] (6) Compound 12f (95 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), and palladium on carbon (90 mg) and palladium hydroxide on carbon (100 mg) were added. The mixture was stirred at 50°C for 16 h. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by reverse phase alkaline method to obtain compound 12 (15.61 mg).

[0257] Example 13: Preparation of Compound 13

[0258] Synthesis route:

[0259] (1) 1-(Trifluoromethyl)cyclopentane-1-carboxylic acid 13a (5 g, 27.45 mmol) was dissolved in ultra-dry tetrahydrofuran (50 mL), cooled to 0°C, and lithium aluminum hydride (17.57 mL, 43.92 mmol, 2.5 mol / L) was slowly added under nitrogen. The mixture was allowed to warm to room temperature under nitrogen and stirred for 1 h. The reaction was monitored by TLC to complete. The reaction solution was quenched with water (25 mL) and 15% sodium hydroxide solution. After stirring for 10 min, ether (50 mL) was added to dilute the solution and water (500 mL) was added for extraction, which was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain compound 13b (3.3 g).

[0260] (2) Compound 13b (3.3 g, 19.62 mmol) was dissolved in ultra-dry dichloromethane (35 mL), 4-dimethylaminopyridine (239 mg, 1.96 mmol) was added, and the temperature was lowered to 0°C. Triethylamine (3.97 g, 39.24 mmol) and p-toluenesulfonyl chloride (5.61 g, 29.43 mmol) were added. The mixture was warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC to determine completion. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (500 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 13c (3.4 g).

[0261] (3) Compound 13c (2 g, 6.20 mmol) was dissolved in dimethyl sulfoxide (20 mL), and 18-crown ether-6 (2.46 g, 9.30 mmol) and sodium cyanide (912 mg, 18.60 mmol) were added. The mixture was stirred at 100°C for two days. The reaction was monitored by TLC. The pH of the reaction solution was adjusted to alkaline by adding 1N sodium hydroxide solution, diluted with dichloromethane (30 mL) and extracted with water (100 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound 13d (900 mg).

[0262] (4) Compound 13d (950 mg, 5.36 mmol) was dissolved in ultra-dry dichloromethane (19 mL), cooled to -78°C, and diisobutylaluminum hydride (3.90 mL, 5.90 mmol, 1.5 mol / L) was slowly added under nitrogen protection. The mixture was stirred at -78°C under nitrogen protection for 1 h, and the reaction was monitored by TLC. Sodium methoxide (3.3 mL, 17.74 mmol) was slowly added. The mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC. The reaction solution was adjusted to pH = 6 with dilute hydrochloric acid, diluted with dichloromethane (20 mL) and extracted with water (80 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound 13e (400 mg).

[0263] (5) Intermediate int2 (120 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and compound 13e (96 mg, 1.15 mmol), sodium triacetoxyborohydride (304 mg, 1.15 mmol), and tetraisopropyl titanate (13 mg, 0.046 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH = 5, diluted with ethyl acetate (5 mL), and extracted with water (20 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 13f (121 mg). MS m / z (ESI): 690.3 [M+H]+.

[0264] (6) Compound 13f (121 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), and palladium carbon (90 mg) and palladium hydroxide carbon (100 mg) were added. The mixture was replaced with hydrogen and stirred at 50°C for 16 h. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by reverse phase alkaline method to obtain compound 13 (19.61 mg).

[0265] Example 14: Preparation of Compound 14

[0266] Synthesis route:

[0267] (1) Intermediate int2 (120 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and compound 14a (96 mg, 1.15 mmol), sodium triacetoxyborohydride (244 mg, 1.15 mmol), and tetraisopropyl titanate (13 mg, 0.046 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH = 5, diluted with ethyl acetate (5 mL), and extracted with water (20 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column (dichloromethane:methanol = 10:1) to obtain compound 14b (100 mg). MS m / z (ESI): 630.3 [M+H]+.

[0268] (2) Compound 14b (100 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), and palladium on carbon (90 mg) and palladium hydroxide on carbon (100 mg) were added. The mixture was stirred at 50°C for 16 h. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by reverse phase alkaline method to obtain compound 14 (34.61 mg).

[0269] Example 15: Preparation of Compound 15

[0270] Synthesis route:

[0271] (1) (1-(Trifluoromethyl)cyclopropyl)methanol 15a (9 g, 64.3 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (19.5 g, 192.9 mmol), 4-dimethylaminopyridine (784 mg, 6.43 mmol), and p-toluenesulfonyl chloride (18.4 g, 96.5 mmol) were added at 0°C. The mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC. The reaction was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 15b (16 g).

[0272] (2) Compound 15b (16 g, 54.4 mmol) was dissolved in tetrahydrofuran (80 mL), and sodium cyanide (4 g, 81.6 mmol) and 18-crown-6 (21.5 g, 81.6 mmol) were added. The mixture was stirred at 70°C for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL) and extracted with water (200 mL) three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain compound 15c (8 g).

[0273] (3) Compound 15c (500 mg, 3.4 mmol) was dissolved in pyridine (4 mL), acetic acid (2 mL) and water (2 mL), and sodium hypophosphite (1.8 g, 17 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by TLC. The reaction was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 15d (100 mg, 19% yield) as a brown oil.

[0274] (4) Intermediate int2 (120 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and compound 15d (107 mg, 1.15 mmol), sodium triacetoxyborohydride (254 mg, 1.15 mmol), and tetraisopropyl titanate (13 mg, 0.046 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH = 5, diluted with ethyl acetate (5 mL), and extracted with water (20 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 15e (97 mg, yield: 65%) as a brown oil. MS m / z (ESI): 610.3 [M+H]+.

[0275] (5) Compound 15e (97 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), and palladium on carbon (90 mg) and palladium hydroxide on carbon (100 mg) were added. The mixture was stirred at 50°C for 16 h. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by reverse phase alkaline method to obtain compound 15 (15.61 mg).

[0276] Example 16: Preparation of Compound 16

[0277] Synthesis route:

[0278] (1) 3,3-Difluorocyclobutylmethanol 16a (20 g, 208.32 mmol) was dissolved in dichloromethane (200 mL), and triethylamine (84.2 g, 416.64 mmol) and p-toluene yellow acid chloride (40.2 g, 252.13 mmol) were added. The mixture was stirred at room temperature for 16 h, and the reaction was monitored by thin layer chromatography. The reaction solution was quenched with water, extracted with dichloromethane, and concentrated in vacuo. The concentrate was purified by silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain compound 16b (25.1 g). MS m / z (ESI): 277.1 [M+H]+

[0279] (2) Compound 16b (10 g, 36.23 mmol) was dissolved in dimethyl sulfoxide (100 mL) and sodium cyanide (4.4 g, 90.58 mmol) was added. The mixture was stirred at room temperature for 3 h and then at 80°C for 2 h. The reaction was monitored for completion by thin-layer chromatography. The reaction solution was quenched with alkaline water, extracted with dichloromethane, and back-extracted with brine. The aqueous phase was treated with sodium hypochlorite, and the organic phase was concentrated in vacuo. The concentrate was purified by silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain compound 16c (11 g). MS m / z (ESI): 131.9 [M+H]+

[0280] (3) Compound 16c (3 g, 22.90 mmol) was dissolved in pyridine (30 mL), acetic acid (15 mL), and water (15 mL). Raney nickel (1.5 g, 15.34 mmol) and sodium hypophosphite hydrate (12.1 g, 114.5 mmol) were added at 0°C. The mixture was stirred at room temperature for 3 h. The reaction was monitored for completion by thin-layer chromatography. The reaction mixture was filtered and extracted with diethyl ether. The organic phase was washed with 1 M hydrochloric acid and concentrated in vacuo. The concentrate was purified on a silica gel column (petroleum ether:ethyl acetate = 8:1) to obtain compound 16d (1.2 g).

[0281] (4) Intermediate int2 (120 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and compound 16d (106 mg, 1.15 mmol), sodium triacetoxyborohydride (204 mg, 1.15 mmol), and tetraisopropyl titanate (13 mg, 0.046 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH = 5, diluted with ethyl acetate (5 mL), and extracted with water (20 mL), and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 16e (100 mg). MS m / z (ESI): 644.3 [M+H]+.

[0282] (5) Compound 16e (100 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), and palladium on carbon (90 mg) and palladium hydroxide on carbon (100 mg) were added. The mixture was stirred at 50°C for 16 h. The reaction was monitored for completion by LCMS. The filtrate was concentrated in vacuo. The resulting concentrate was purified by reverse phase alkaline method to obtain compound 16 (10.61 mg).

[0283] Example 17: Preparation of Compound 17

[0284] Compound 17 was prepared using intermediate int2 and compound 17-a as raw materials according to the method described in steps (4) and (5) of Example 7.

[0285] The compounds of each example 1 The H NMR and MS data are shown in the following table:

[0286] Table 1: 1 H NMR and MS data

[0287] Biological tests

[0288] The positive control used in this article is PN2-1, also known as ABBV-CLS-484 (CAS No. 2489404-97-7), which can be obtained commercially or prepared according to the method described in WO2020186199A1.

[0289] Experimental Example 1: In vitro PTPN2 enzymology assay

[0290] A.Main Materials

[0291] Reagents: Human PTPN2 protein (10570-HNCB, Sino Biological), Phosphatase Assay Kit (E12020, Invitrogen), DMSO (D8418, Sigma)

[0292] Materials: 96-well polypropylene microplate (249944, Nunc), 384-well microplate (784075, Greiner)

[0293] Instruments: Microplate shaker (QB-9002, Qilinbeier), centrifuge (5804R, Eppendorf), Vivtor Nivo35 multifunctional microplate reader (PerkinElmer), vortex mixer (MS3 digital, IKA)

[0294] B. Methods

[0295] Principle: This method evaluates the ability of compounds to inhibit PTPN2 phosphatase activity. The assay is based on the fact that PTPN2 phosphatase removes the phosphate group from the substrate DIFMUP, producing the fluorescent product DIFMU. PTPN2 enzymatic activity is then determined by measuring changes in the fluorescence intensity of the assay system. A weaker fluorescence signal in response to the compound indicates lower PTPN2 phosphatase activity, demonstrating a higher inhibitory activity against PTPN2 tyrosine phosphatase.

[0296] Assay Procedure: Compounds were dissolved in DMSO to obtain a 10 mM stock solution. The compound stock solution was diluted in DMSO in a 96-well plate to a final starting concentration of 10 μM, with 10 concentration points. The compound dilutions were transferred to a 384-well assay plate using an Echo 550, with 100 nL per well. The plate was then sealed and centrifuged at 1000 rpm for 1 minute. A 2X PTPN2 solution was prepared in assay buffer and added to the assay plate at 10 μL per well. The plate was centrifuged at 1000 rpm for 1 minute. A 2X DIFMUP solution was prepared in assay buffer and added to the assay plate at 10 μL per well to initiate the reaction. After a 1-hour reaction, the fluorescence signal from the assay plate was read using a Vivtor Nivo35 multi-function microplate reader. Signal intensity was used to indicate phosphatase activity.

[0297] Data analysis: Phosphatase activity data were expressed as the comparison of the enzyme activity of the test compound and the blank group (containing only DMSO), and the IC was obtained by curve fitting using Prism software (GraphPad 8.0). 50 The experimental results are shown below.

[0298] C. Experimental results:

[0299] Table 2: Results of in vitro activity test of protein tyrosine phosphatase

[0300] Conclusion: The compounds of the present invention have strong inhibitory activity against protein tyrosine phosphatase, which is equivalent to or higher than the activity of the positive control compound PN2-1.

[0301] Experimental Example 2: Cell Viability Test (CTG)

[0302] Reagents and materials: DMEM medium (11995-065, Gibco), PBS (P1010, Solarbio), CellTiter-Glo chemiluminescent cell viability detection kit (G7573, Promega), T75 culture flask (430641, Corning), 96-well cell culture plate (3599, Corning),

[0303] Instruments: CO2 incubator (CLM-240B-8-TC, ESCO), centrifuge (5810R, Eppendorf), cell counter (AMQAX1000, Invitrogen), microplate reader (PHERAstar FSX, BMG)

[0304] Test method: Collect B16F10 cells in the logarithmic growth phase, count them, and resuspend them in culture medium. Take the cell suspension and inoculate it into a 96-well cell culture plate, 100 μL per well, and culture it at 37°C overnight to allow the cells to adhere. Pipette the pre-diluted test compound and mIFNγ into the 96-well cell plate, the final concentration of mIFNγ is 3 ng / mL, the maximum concentration of the test compound is 30 μM, and it is diluted 3 times. After placing the 96-well plate in an incubator and culturing for 4 days, add an equal volume of CellTiter-Glo to the cell culture medium. TM The reagent was added and the luminescence value was measured with an enzyme-labeled instrument. The intensity of the light signal indicated the activity of the cells. The IC 50 value.

[0305] Table 3: Results of the B16F10 IFN-γ-induced cell growth inhibition (GI) test of exemplary compounds

[0306] Conclusion: The compounds of the present invention have strong inhibitory activity against B16F10 cells, which is comparable to the activity of the positive control compound PN2-1. In fact, the inhibitory activity of compound 9a is significantly better than that of PN2-1.

[0307] The various technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the various technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in: Dashed lines indicate the presence or absence of a bond; X1, X2, X3 are independently selected from carbon, nitrogen, oxygen and sulfur atoms, and the ring A in which they are located may be optionally substituted by R2 n times; R1 is -L1-L2-R x ; R2 is selected from hydrogen, halogen, cyano, hydroxy, oxo, amino, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Amine, C 3～7 Cycloalkyl, C 3～7 Heterocyclic and C 5～7 The aromatic heterocyclic group, wherein the R2 can form a 7-12-membered fused ring, spiro ring or fused ring with the ring A, wherein the fused ring, spiro ring or fused ring can optionally contain 1-4 N, O, S heteroatoms, and the R2 can optionally be replaced by R a Replace 1 to 3 times; R3 is selected from hydrogen, halogen, cyano, C 1～3 Alkyl, C 1～3 Alkoxy and cyclopropyl, said R3 may be optionally substituted 1 to 3 times by halogen; L1 is selected from a single bond, -(CH2) p1 -、-(CH2) p1 -O- and -(CH2) p1 -NH-; L2 is selected from -(CH2) p2 -、-NH-(CH2) p2 -、-C(O)-(CH2) p2 -、-NH-C(O)-(CH2) p2 - and -C(O)-NH-(CH2) p2 -, where L2 can be optionally replaced by R under conditions where valence permits a substituted 1 to 3 times; wherein, when L2 is optionally replaced by R a When replacing 2 or more times, two independent R a Can form 3-6 membered carbon rings; R x Selected from hydrogen, amine, halogen, cyano, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, C 3～7 Heterocycloalkyl, C 5～6 Aryl and C 5～7 Heteroaryl, any of the R x Optionally R b Replace 1 to 3 times; p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5; n is selected from 1, 2, 3 or 4; When n is greater than or equal to 2, the R2 can exist independently, and any two R2 can form a ring B under the condition of valence permission, and the ring B is selected from a 3-6 membered carbocyclic ring, or a 3-6 membered carbocyclic ring having 1-3 heteroatoms independently selected from N, O and S, and the ring B can be optionally substituted by halogen, C 1～3 Alkyl, C 1～3 Alkyl halide is substituted 1 to 3 times; R a are independently selected from hydrogen, halogen, amine, hydroxyl, cyano, C 1～4 Alkyl and C 1～3 Alkoxy, the NH2 may be optionally replaced by C 1～3 Alkyl is substituted once, and the C 1～4 Alkyl and C 1～3 The alkoxy group may be optionally substituted 1 to 3 times by halogen; R b independently selected from H, F, Cl, Br, I, NH2, OH, C 1-6 Alkyl, C 1-3 Alkoxy and CN, the NH2 may be optionally replaced by C 1～3 Alkyl is substituted once, and the C 1～6 Alkyl and C 1～3 The alkoxy group may be optionally substituted 1 to 3 times by halogen.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R x Selected from hydrogen, amine, halogen, cyano, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～7 Heterocycloalkyl, C 5～6 Aryl, C 5～7 Heteroaryl, any of the R x Optionally R b Replace 1 to 3 times.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: The X1 is selected from S, O, CH2, CH, C, NH and N, wherein the CH2, CH and NH may be optionally substituted 1 to 2 times by R2; and / or The X2 is selected from S, O, CH2, CH and C, wherein the CH2 and CH may be optionally substituted by R2 1 to 2 times; and / or The X3 is selected from CH and C, wherein the CH is substituted once by R2.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound or pharmaceutically acceptable salt thereof as shown in Formula II: or It is a compound as shown in formula II-1 or a pharmaceutically acceptable salt thereof: in: X1 is selected from S, O, CH2, CH, C, NH and N, wherein said CH2, CH, NH may be optionally substituted 1 to 2 times by R2, and X2 is selected from S, O, CH2, CH and C, wherein said CH2 and CH may be optionally substituted 1 to 2 times by R2; or It is a compound as shown in formula II-2 or a pharmaceutically acceptable salt thereof: in: X1 is selected from CH, C and N, wherein said CH may be optionally substituted once by R2, and X2 is selected from CH and C, wherein said CH may be optionally substituted once by R2.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: The ring A is selected from wherein the ring A may be optionally substituted n times by R2; Preferably, the ring A is selected from More preferred The ring A may be optionally substituted n times by R2.

6. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound or a pharmaceutically acceptable salt thereof as shown in Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, and more preferably Formula II-G:

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: The L1 is selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH(CH3)2-, -O- and -O-CH2-, preferably selected from -CH2-, -CH2CH2-, -CH2CH2CH2- and -O-, more preferably -CH2-.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: The L2 is selected from -NH-(CH2) p2 -, the L2 may optionally be R a Replace 1 to 3 times, Preferably, L2 is selected from -NHCH2-, -NHCH2CH2-, -NHCH2CH2CH2- and -NHCH2CH2CH2CH2-, and L2 may be optionally replaced by R a Replaced 1 to 3 times, where R a Preferably independently selected from hydrogen, halogen (preferably F) and C 1～4 Alkyl, the C 1～4 The alkyl group may be optionally substituted 1 to 3 times by halogen (preferably F), More preferably, L2 is selected from -NHCH2-, -NHCH2CH2-, -NHCH2CF2-, -NHCH(CH3)CH2-, -NHCH2CH2CH2-, -NHCH2CF2CH2-, -NHCH2CH2CF2-, -NHCH2CH2CH(CHF2)-, -NHCH2CH(CHF2)CH2-, -NHCH2CH2CH2CH2-, -NHCH2CH2C(CH3)2-, -NHCH2CH(CH3)CH2-, -NHCH2CH2CH(CHF2)CH2-, -NHCH2CH2CH2CF2-; and / or When L2 is optionally replaced by R a When replacing 2 or more times, two independent R a It can form a 3-membered or 4-membered carbon ring, and the 3-membered or 4-membered carbon ring can be optionally substituted 1 to 3 times by halogen. Preferably, the 3-membered or 4-membered carbon ring is selected from Preferably, the R1 is -O-NH-(CH2) p2 -R x , or more preferably -(CH2) 1-3 -NH-(CH2) p2 -R x , or further more preferably -CH2-NH-(CH2) p2 -R x , where -NH-(CH2) p2 - denotes L2 as defined above.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: The R x Selected from hydrogen, halogen, C 1～3 Alkyl, C 3～6 Cycloalkyl and phenyl, any of the R x Optionally R b Replace 1 to 3 times; Preferably, the R x Selected from H, F, Cl, -CH3, -CH2CH3, -CH(CH3)CH2CH3, -CH(CH3)2, The arbitrary R x Optionally R b Replace 1 to 3 times; More preferably, wherein R b Independently selected from H, F, Cl and C 1-3 Alkyl, wherein the C 1～3 The alkyl group may be optionally substituted 1 to 3 times by F or Cl; More preferably, R x Selected from H, F, Cl, -CH3, -CH2CH3, -CH(CH3)2, Even more preferably, said R1 is selected from and / or The R2 is selected from -H, -Cl, -F, -CH3, -OCH3, wherein the -CH3 or -OCH3 may be optionally substituted 1 to 3 times by halogen; and / or When n is greater than or equal to 2, any two R2 can form the ring B together with the ring atoms of the ring A to which they are connected, and the ring B is selected from a 3-6 membered carbon ring (preferably cyclopropane, cyclobutane, cyclopentane or cyclohexane), or a 3-6 membered carbon heterocycle having 1-3 heteroatoms independently selected from N, O and S (preferably azetidine, oxetane, azopentane or oxolan), and the ring B can be optionally substituted by halogen, C 1～3 Alkyl, C 1～3 The ring B and the ring A together form a structural unit selected from a spiro ring, more preferably The structural unit may be optionally replaced by R a Replaced 1 to 3 times, where R a Preferably, they are independently halogen, C 1～3 Alkyl or C 1～3 Haloalkyl; and / or The R3 is selected from -H, -Cl, -F, -CH3, -CF3 and -OCH3.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

12. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the preparation of a medicament related to a protein tyrosine phosphatase inhibitor, or in the preparation of a medicament for treating and / or preventing a disease or condition mediated by protein tyrosine phosphatase and related diseases or conditions.

13. A method for preventing and / or treating a protein tyrosine phosphatase-mediated disease or condition and related diseases or conditions in an individual, comprising administering to the individual a therapeutically effective amount of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11.

14. The method of claim 12, wherein the protein tyrosine phosphatase mediated disease or condition is a cancer or tumor selected from the group consisting of melanoma, thyroid tumor, head and neck cancer, cervical cancer, lung cancer, bronchial cancer, brain cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small intestine cancer, kidney cancer, liver cancer, hepatocellular carcinoma, malignant mesothelioma, bile duct cancer, cholangiocarcinoma, renal cell carcinoma, pancreatic cancer, uterine cancer, bladder cancer, bone cancer, myeloma, glioma, mesothelioma, adenocarcinoma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, neuroblastoma, Wilms tumor, retinoblastoma and germ cell tumor.

15. The use of claim 12 or the method of claim 13, wherein the protein tyrosine phosphatase mediated disease or disorder is a metabolic disease, and the metabolic disease is preferably selected from diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, metabolic syndrome, phenylketonuria, atherosclerosis, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis and liver fibrosis.

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