5-(substituted aryl)-1,2,5-thiadiazolin-3-one compounds that inhibit protein tyrosine phosphatase

Abstract

This invention relates to a class of compounds with protein tyrosine phosphatase inhibitory activity or pharmaceutically acceptable salts thereof, and their use in the preparation of medicaments for treating diseases related to abnormal expression of protein tyrosine phosphatase. Specifically, it relates to compounds of formula (I) and pharmaceutically acceptable salts thereof.

Description

Technical Field

[0001] This invention relates to a class of compounds with protein tyrosine phosphatase inhibitory activity or pharmaceutically acceptable salts thereof, and their use in the preparation of medicaments for treating diseases related to abnormal expression of protein tyrosine phosphatase. Background Technology

[0002] Protein tyrosine phosphatase non-receptor type 2 (PTPN2) is a member of the protein tyrosine phosphatase (PTP) family. The classic PTP family has 17 subtypes: nine non-transmembrane phosphatases and eight receptor phosphatases. PTPs participate in regulating various cellular processes, including cell growth, differentiation, mitotic cycle, and oncogenic transformation, by catalyzing protein dephosphorylation. PTPN2 and PTPN1 share high homology. PTPN2 is expressed in immune cells and plays a crucial role in immune system homeostasis. PTPN2 inhibits the phosphorylation of signaling factors such as JAK and STAT family members, blocking cytokine-mediated signaling pathways (e.g., IFN-γ, IL-2, IL-6), thereby inhibiting the secretion of downstream pro-inflammatory factors such as IFN, IL-6, TNF, and CXCL9 / 10 / 11, and suppressing immune cell proliferation, differentiation, and 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 against cytosolic cytokines such as IFNγ. Furthermore, PTPN1 can regulate the leptin and insulin signaling pathways. The dephosphorylation of PTPN1 negatively regulates leptin and insulin metabolic signal transduction, leading to diseases such as obesity and diabetes. PTPN1 inhibition can improve insulin resistance and glucose tolerance in diseased mice, thereby controlling blood glucose levels. Summary of the Invention

[0003] This invention provides compounds of formula I or pharmaceutically acceptable salts thereof, selected from:

[0004]

[0005] in,

[0006] R x For ring A or structural unit The R x It can be further replaced by R2 1 to 3 times; the R x The hydrogen atoms in the hydrogen can be substituted by protecting groups under conditions where the valence allows;

[0007] X1, X2, and X3 are each independently selected from CH, N, or C;

[0008] L1 is selected from single bonds, C 1～6 Alkylene, C 2～6 imidene group, C 2～6 Alkynylene, -O-, -C(O)-, -NH-, -C(O)-NH-, -NH-C(O)-NH-, -S(O) 0-2 -、-NH-S(O) 1-2 -、-NH-P(O)(R c )-、-P(O)(R c )-、-CO-C 1～5 Alkylene-, -CO-C 2～5 imidene-, -CO-C 2～5 α-, -((R) d )N)C-, wherein the alkyl, alkenyl, alkynyl, and amino groups may optionally be replaced by R a Replace 1 to 3 times;

[0009] Ring A is a monocyclic or bicyclic ring system. The monocyclic ring is selected from 4-7 membered carbon rings, 4-7 membered heterocyclic rings, 5-7 membered aromatic heterocyclic rings, and 5-7 membered aromatic rings. The bicyclic ring is selected from 4-7 membered carbon rings, 4-7 membered heterocyclic rings, 5-7 membered aromatic heterocyclic rings, or 7-12 membered fused rings, fused heterocyclic rings, spirocyclic rings, or spirocyclic rings formed independently of any two of the 5-7 membered aromatic rings. Ring A can optionally be divided by R. a Replace 1 to 3 times;

[0010] Structural unit In this context, --- indicates the presence or absence of a key; structural unit. Can be optionally R a Replace 1 to 3 times;

[0011] Z1 and Z2 are independently selected from -CH2-, -O-, -NH-, -C(O)-, and -S(O), respectively. 0～2 -、-P(O)R a -、-((R d )N)C-;

[0012] R1 is selected from H, CN, OH, halogens, NH2, SH, and C. 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl; the C 1～6 Any carbon atom in the alkyl group may optionally be replaced by a nitrogen or sulfur atom, provided the valence allows; the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl and amino groups may optionally be R a Replace 1 to 3 times;

[0013] R2 is selected from H, NH2, OH, halogen, SH, CN, oxo, and C. 1～6 Alkyl, C 2～6 alkenyl, C 2～6 alkynyl group, C 1～6 Alkoxy, NH-C 1～6 Alkyl, NH-C 2～6 alkenyl, NH-3~6-membered cycloalkyl, NH-5~6-membered heteroaryl, NH-CH2-3~6-membered cycloalkyl, C 1～3 Alkyl-3 to 6-membered cycloalkyl, C 2～4 Alkenyl-3-6 membered cycloalkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-7 membered aryl, 5-7 membered heteroaryl, wherein the C 1～6 Alkyl, C 2～6 alkenyl, C 2～6 alkynyl group, C 1～6 Alkoxy, amino, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-7 membered aryl, 5-7 membered heteroaryl can optionally be R b Replaced 1 to 3 times; the C 1～6 Any carbon atom in an alkyl group may be optionally replaced by a nitrogen atom or a sulfur atom, provided that the valence allows it;

[0014] n is selected from 1, 2, and 3;

[0015] When n is greater than 1, any two R2s can be further cyclically transformed into 3- to 7-membered rings, which can be arbitrarily divided by R. a The 3-7 membered ring can be a carbon ring, a heterocyclic ring, an aromatic ring, or a heteroaromatic ring, after being replaced 1 to 3 times.

[0016] R a Independently selected from H, F, Cl, CN, OH, C 1～3 Alkyl and C 1～3 Alkoxy;

[0017] R b Independently selected from F, Cl, Br, I, NH2, OH, SH, C 1-6 Alkyl, C 1-3 Alkoxy and CN, the C 1～6 Alkyl and C 1～3 The alkoxy group may be substituted with a halogen 1 to 3 times; the C 1～6 Any carbon atom in an alkyl group may be optionally replaced by a nitrogen atom or a sulfur atom, provided that the valence allows it;

[0018] R c Selected from C 1～6 Alkyl, C 2～6 alkenyl, C 2～6 alkynyl group, C 1～6Alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-7 membered aryl, 5-7 membered heteroaryl, wherein the C 1～6 Alkyl, C 2～6 alkenyl, C 2～6 alkynyl group, C 1～6 Alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-7 membered aryl, 5-7 membered heteroaryl, optionally R b Replaced 1 to 3 times; the C 1～6 Alkyl, C 2～6 alkenyl, C 2～6 Any carbon atom in the alkynyl group may be optionally replaced by a nitrogen atom or a sulfur atom, provided that the valence allows it;

[0019] R d Selected from C 1～6 Alkoxy, sulfonyl, phosphonoyl, carbonyl.

[0020] In some embodiments of the present invention, the above-mentioned compounds or their pharmaceutically acceptable salts have structures as shown in formulas (II) and (III):

[0021]

[0022] The definitions of X1, X2, X3, L1, ring A, Z1, Z2, R1, R2, n, ---- are the same as before.

[0023] In some embodiments of the present invention, when ring A is a single ring, ring A can be selected from...

[0024] Wherein, ring A can be optionally divided by R a Replace 1 to 3 times.

[0025] In some embodiments of the present invention, when ring A is a double ring, ring A can be selected from...

[0026] Wherein, ring A can be optionally divided by R a Replace 1 to 3 times.

[0027] In some embodiments of the present invention, ring A is selected from... The ring A may optionally be substituted with halogens 1 to 3 times.

[0028] In some embodiments of the present invention, ring A is selected from... The ring A may optionally be substituted with halogens 1 to 3 times.

[0029] In some embodiments of the present invention, structural units Optional

[0030] Among them, the structural unit Can be optionally R a Replace 1 to 3 times.

[0031] In some embodiments of the present invention, R1 is selected from -H, -F, -Cl, -CH3, -CH2CH3, -CH(CH3)CH3, -OCH3, -cyclopropyl; R1 may optionally be replaced by R a Replace 1 to 3 times.

[0032] In some embodiments of the present invention, R1 is selected from hydrogen, methyl, ethyl, and cyclopropyl.

[0033] In some embodiments of the present invention, R2 is selected from H, NH2, and NH-C. 1～3 Alkyl, C 1～6 Alkyl, C 1～3 Alkoxy, C 2～6 alkenyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl, wherein C 1～6 Alkyl, C 2～6 alkenyl, C 1～3 Alkoxy, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl can optionally be R b Replace 1 to 3 times.

[0034] In some embodiments of the present invention, R2 is selected from -H, -CH3, -CH=CH2, -CH2CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -C(CH3)3, -CH(CH3)2, -CH2CH2CH3, -CH2CH2CH(CH3)2, -CH=CH2CH(CH3)2, -CH2CH=CH2, -CH2C(CH3)2CH2OH, -CH2C(CH3)2OH, -OCH(CH3)2, -NHCH(CH3)2, -OCH3, -NHCH3, -OCH2CH3, -NHCH2CH3,

[0035] In some embodiments of the present invention, R2 is selected from...

[0036] In some embodiments of the present invention, L1 is selected from single bonds, -CH2-, -NH-, -CH2CH2-, -CH=, -CH2CH=, -CH=CH-CH2-, -CH=CH-, -CH2-CH=CH-, -C≡C-, -C≡CCH2-, -C(CH3)=CH-, -C(O)-, -C(O)-NH-, -NH-C(O)-, -NH-CH2-, -CH=N-, -C(O)-CH=, -S(O) 0-2 -, -S(O)2-NH-, -C(CH3)=N-, -C(OCH3)=N-, -C≡CC(O)-, -CH=CH-C(O)-, -CH2CH=CH-C(O)-, -CH2CH2-C(O)-, -CH2-C(O)-, -C≡CCH2-C(O)-.

[0037] In some embodiments of the present invention, L1 is selected from single bonds, -CH2-, -C≡C-, -C≡CCH2-, -CH=CH-CH2-, -C(O)-CH=, and -NH-C(O)-.

[0038] In some embodiments of the present invention, structural units Selected from

[0039] In some embodiments of the present invention, structural units Selected from

[0040] In some embodiments of the present invention, structural units Selected from

[0041]

[0042] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:

[0043]

[0044] Among them, rings A, X1, R1, R2, and R a Z1, Z2, L1, and n are defined as before.

[0045] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from: Among them, rings A, X1, R1, R2, and n are defined as before.

[0046] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from: Where R1, R2, n, Rx Same as the previous definition.

[0047] Some solutions in this invention are derived from arbitrary combinations of the above-mentioned variables.

[0048] This invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0049] This invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0050]

[0051] This invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0052] Or its pharmaceutically acceptable salt.

[0053] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of drugs related to protein tyrosine phosphatase inhibitors.

[0054] In some embodiments of the present invention, the above-described application is characterized in that the protein tyrosine phosphatase inhibitor-related drug is a drug for treating and / or preventing tumors and / or cancer.

[0055] The compounds provided by this invention are protein tyrosine phosphatase inhibitors, wherein the compounds of formula I and formula "" and their pharmaceutically acceptable salts 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.

[0056] The compounds of Formula I provided by this invention and their pharmaceutically acceptable salts can be used alone or in combination with at least one other therapeutic agent in treatment.

[0057] The present invention also provides pharmaceutical compositions comprising a compound of formula I as described above or a pharmaceutically acceptable salt thereof, and one or more other therapeutically active ingredients.

[0058] The present invention also provides pharmaceutical compositions comprising a compound of formula I as described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0059] The pharmaceutically acceptable salts described in this article include acid addition salts and base salts.

[0060] The pharmaceutically acceptable salts described in this article can exist in both non-solvated and solvated forms.

[0061] The present invention also provides compounds of Formula I as described above and pharmaceutically acceptable salts thereof for the preparation of treatments and / or preventions of protein tyrosine phosphatase-related diseases or conditions and related diseases or conditions.

[0062] The present invention also provides a treatment for a disease or condition comprising administering to a patient in need a therapeutically effective amount of a compound of formula I as described above and a pharmaceutically acceptable salt thereof, wherein the disease or condition is a protein tyrosine phosphatase-related disease or condition and related diseases or conditions.

[0063] In some embodiments, the disease or condition mediated by the protein tyrosine phosphatase is a tumor and / or cancer. In some embodiments, the tumor and / or cancer includes, but is not limited to: melanoma, thyroid adenoma, head and neck cancer, cervical 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, esophageal cancer, colorectal cancer, pancreatic cancer, small bowel cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma, and germ cell tumor.

[0064] In some implementations, the diseases or conditions mediated by the protein tyrosine phosphatase and related diseases or conditions include, but are not limited to: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell tumor, Wilms' tumor, and hepatocellular carcinoma.

[0065] In some embodiments, the protein tyrosine phosphatase-mediated diseases or conditions are metabolic diseases. In some embodiments, the metabolic diseases include, but are not limited to: diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia / hyperinsulinemia, metabolic syndrome, phenylketonuria, atherosclerosis, non-alcoholic steatohepatitis, and liver fibrosis.

[0066] The present invention also provides the use of the above-described compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of medicaments related to protein tyrosine phosphatase inhibitors.

[0067] In some implementations, the protein tyrosine phosphatase inhibitor-related drugs are used to treat tumors and / or cancer.

[0068] Definitions and Explanations

[0069] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0070] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0071] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or 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 this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or 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, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0072] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. 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 thereof.

[0073] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereo isomers, enantiomers, optical isomers, diastereomers and tautomers.

[0074] The term "protecting group" refers to a molecule containing two or more functional groups. To protect one of the functional groups from being destroyed by a reaction, a certain reagent is often used to protect it first. The "protecting group" is selected from methyl ethers, tert-butyl ethers, and benzyl ethers. In some embodiments of the present invention, an example of the "protecting group" is tert-butyloxycarbonyl.

[0075] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0076] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0077] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0078] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0079] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0080] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0081] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0082] Unless otherwise stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0083] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, 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 desired enantiomer in pure form. 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 salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0084] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting 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, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0085] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0086] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that 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 or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0087] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0088] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0089] 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.

[0090] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0091] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0092] When a substituent can be cross-bonded to two or more atoms on a ring, this substituent can bond with any atom on that ring, for example, structural units. This indicates that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridyl group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0093] When the linking groups listed do not specify their linking direction, the linking direction is arbitrary.

[0094] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line express.

[0095] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “5-7 elemental ring” refers to a “ring” with 5-7 atoms arranged around it.

[0096] In this invention, the terms "halogenated," "halogen," and "halogen atom" refer to fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc. Preferably, the halogen atoms used as substituents for the aryl groups in this invention are fluorine atoms and chlorine atoms.

[0097] The term "C" in this invention 1～6 "Alkyl" refers to a straight-chain or branched 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-chain or branched alkyl group having 1 to 3 carbon atoms, including but not limited to methyl, ethyl, n-propyl and isopropyl.

[0098] The term "C" in this invention 1～6 "Alkoxy" refers to the carbon group. 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" refers to the carbon group. 1-3 Alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy and isopropoxy.

[0099] In this invention, the term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) 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, heterocyclic, or cycloalkyl ring, including benzo3- to 8-membered cycloalkyl and benzo3- to 8-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1-3 heterocyclic atoms independently selected from N, O, and S; or may further comprise a three-membered nitrogen-containing fused ring containing a benzene ring.

[0100] The term "heteroaryl" or "heteroaryl ring" in this invention refers to a heteroaryl system having 5 to 14 ring atoms, wherein the heteroaryl group has 1 to 4 heterocyclic atoms independently selected from N, O, and S. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc.

[0101] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaryl" in this invention are used interchangeably. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). 5-6-membered heteroaryl groups can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-6-membered heteroaryl groups include both 5-membered and 6-membered heteroaryl groups.

[0102] The term "halogenated alkyl" in this invention refers to an alkyl group that has been substituted with one or more halogens.

[0103] The term "3- to 8-membered heterocyclic group" in this invention refers to a non-aromatic cyclic group having 3 to 8 ring atoms, comprising one or more heterocyclic atoms independently selected from N, O, and S, and may be fully saturated (i.e., 3- to 8-membered heterocyclic alkyl) or partially unsaturated. The heterocycle may be a 3- to 8-membered monocyclic, bicyclic, or spirocyclic ring. The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclic group.

[0104] The term "C" in this invention 3～8 "Cycloalkyl" refers to a monovalent group obtained by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 8 carbons, i.e., a cycloalkyl group with 3 to 8 carbons.

[0105] The term "fused ring" in this invention refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. The carbon atoms in the fused ring may optionally be replaced by heteroatoms of O, S, or N, i.e., "fused heterocyclic rings" are also included.

[0106] The term "fused heterocyclic ring" in this invention refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of 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.

[0107] The term "spirocyclic" in this invention refers to a 5- to 20-membered polycyclic group, wherein the monocyclic rings share a carbon atom (called a spiro atom). The spirocyclic ring may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The spirocyclic ring is preferably 6- to 14-membered, for example 6- to 10-membered, more preferably 7- to 10-membered. Spirocyclic alkyl groups are classified as monospirocyclic alkyl, bispirocyclic alkyl, or polyspirocyclic alkyl groups according to the number of shared spiro atoms between the rings, with monospirocyclic alkyl and bispirocyclic alkyl groups being preferred. More preferably, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic alkyl groups are preferred. The carbon atom in the spirocyclic ring may optionally be replaced by a heteroatom of O, S, or N, i.e., "spiroheterocyclic" groups are also included.

[0108] In this invention, the term "spiroheterocycle" refers to a 5- to 20-membered polycyclic heterocyclic group, wherein the monocyclic rings share a common atom (called a spiro atom), and one or more ring atoms are selected from nitrogen, oxygen, or S(O). m (Where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Spiroheterocyclic rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Spiroheterocyclic rings are preferably 6 to 14-membered, for example 6 to 10-membered, more preferably 7 to 10-membered. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiroatoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic groups are preferred.

[0109] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0110] The compounds described in this invention are named according to their chemical structural formulas. If the name of a compound representing the same compound does not match its chemical structural formula, the chemical structural formula shall prevail.

[0111] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0112] The solvent used in this invention is commercially available.

[0113] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names.

[0114] Technical effect

[0115] As a novel protein tyrosine phosphatase inhibitor, the compound of this invention has strong inhibitory activity against protein tyrosine phosphatase. Detailed Implementation

[0116] The present invention will be described in detail below through embodiments, but this does not imply any adverse limitations on the invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof. Intermediate int1:

[0117]

[0118] (1) Compound int1-1 (1 g, 5.85 mmol) was added to acetic acid (10 mL), cooled to 0 °C, and liquid bromine (1.3 mL, 23.4 mmol) was added. The mixture was stirred at 55 °C for 4 h. After the reaction was complete, the mixture was quenched with saturated sodium thiosulfate solution, diluted with ethyl acetate, and the pH was adjusted to 13-14 with sodium hydroxide solution. Water was then added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined. The organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound int1-2 (1.2 g).

[0119] (2) Compound int1-2 (2 g, 8.00 mmol) was dissolved in dichloromethane (20 mL), and then boron tribromide (24 mL, 24.00 mmol) was added to the solution at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the mixture was diluted with dichloromethane, then water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound int1-3 (1.7 g).

[0120] (3) Compound int1-3 (2 g, 8.47 mmol) was dissolved in N,N-dimethylformamide (20 mL), and then potassium carbonate (1.4 g, 10.16 mmol) and benzyl bromide (1.45 g, 8.47 mmol) were added. The reaction mixture was stirred at 60 °C for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then water was added. The mixture was extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated, and purified by column chromatography to obtain compound int1-4 (2.7 g).

[0121] (4) Compound int1-4 (2.7 g, 8.28 mmol) was dissolved in a mixed solvent of ethanol (30 mL) and water (10 mL), and then ammonium chloride (4.43 g, 82.8 mmol) and iron powder (2.32 g, 41.4 mmol) were added sequentially. The reaction solution was stirred at 80 °C for 1 h. After the reaction was completed, the solution was diluted with ethyl acetate, then water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by column chromatography to obtain compound int1-5 (2.1 g).

[0122] (5) Compound int1-5 (1.7 g, 5.74 mmol) was dissolved in N,N-dimethylformamide (17 mL), and then potassium carbonate (1.98 g, 14.35 mmol) and methyl bromoacetate (3.51 g, 22.96 mmol) were added. The reaction mixture was stirred at 60 °C for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by column chromatography to obtain compound int1-6 (1.5 g).

[0123] (6) Chlorosulfonic acid isocyanate (1.09 g, 7.74 mmol) was dissolved in dichloromethane (10 mL), and tert-butanol (574 mg, 7.74 mmol) was added. The mixture was stirred at 0 °C for 0.5 h. Then, a mixture of compound int1-6 (1.9 g, 5.16 mmol) and triethylamine (1.04 g, 10.32 mmol) dissolved in dichloromethane (10 mL) was added. The mixture was stirred at 0 °C for 0.5 h, and then heated to room temperature and stirred for 1 h. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum and purified by column chromatography to obtain compound int1-7 (2.4 g).

[0124] (7) Compound int1-7 (1.5 g, 2.74 mmol) was dissolved in dichloromethane (18 mL), and trifluoroacetic acid (2 mL) was added. 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). This process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum and purified by column chromatography to obtain compound int1-8 (800 mg).

[0125] (8) Compound int1-8 (1.2 g, 2.68 mmol) was dissolved in tetrahydrofuran (14 mL), and a methanol solution of sodium methoxide (0.74 mL, 4.02 mmol) was added. The mixture was stirred at room temperature for 20 min. The reaction was monitored by LCMS. The solution was diluted with ethyl acetate (100 mL) and extracted with water (500 mL), and the process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum and purified by column chromatography to obtain compound int1 (1 g).

[0126] intermediate int2:

[0127]

[0128] (1) Compound int2-1 (2 g, 12.73 mmol) and benzyl bromide (2.11 g, 15.28 mmol) were added to the solvent N,N-dimethylformamide (20 mL), and potassium carbonate (2.11 g, 15.28 mmol) was added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound int2-2 (3 g).

[0129] (2) Compound int2-2 (100 mg, 0.40 mmol) was dissolved in a mixed solvent of ethanol (4 mL) and water (2 mL), followed by the sequential addition of ammonium chloride (214 mg, 4.00 mmol) and reduced iron powder (112 mg, 2.00 mmol). The reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction mixture was filtered through dichloromethane, and the filtrate was concentrated under vacuum. The filtrate was extracted with dichloromethane, and the organic phases were combined. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography to obtain compound int2-3 (80 mg).

[0130] (3) Compound int2-3 (1 g, 4.60 mmol) was added to a mixed solvent of acetic acid (9 mL) and methanol (3 mL), and the temperature was lowered to 0 °C. Liquid bromine (0.33 mL, 5.98 mmol) was then added. The mixture was stirred at 0 °C for 1 h. After the reaction was complete, the mixture was quenched with a saturated sodium thiosulfate solution, diluted with ethyl acetate, and the pH was adjusted to 13–14 with sodium hydroxide solution. Water was then added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound int2-4 (800 mg).

[0131] (4) Compound int2-4 (3 g, 10.13 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then potassium carbonate (3.5 g, 25.33 mmol) and methyl bromoacetate (4.65 g, 30.39 mmol) were added. The reaction mixture was stirred at 60 °C for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography to obtain compound int2-5 (2.5 g).

[0132] (5) Chlorosulfonic acid isocyanate (1.20 g, 8.55 mmol) was dissolved in dichloromethane (12 mL), and tert-butanol (634 mg, 8.55 mmol) was added. The mixture was stirred at 0 °C for 0.5 h. Then, a mixture of compound int2-5 (2.1 g, 5.70 mmol) and triethylamine (1.15 g, 11.40 mmol) dissolved in dichloromethane (10 mL) was added. The mixture was stirred at 0 °C for 0.5 h, and then heated to room temperature and stirred for 1 h. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (200 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum and purified by silica gel column chromatography to obtain compound int2-6 (2.7 g).

[0133] (6) Compound int2-6 (2.3 g, 4.20 mmol) was dissolved in dichloromethane (23.4 mL), and trifluoroacetic acid (2.6 mL) was added. 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). This process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum and purified by silica gel column chromatography to obtain compound int2-7 (1.8 g).

[0134] (7) Compound int2-7 (1.87 g, 4.18 mmol) was dissolved in tetrahydrofuran (20 mL), and a methanol solution of sodium methoxide (1.2 mL, 6.27 mmol) was added. The mixture was stirred at room temperature for 20 min. The reaction was monitored by LCMS. The solution was diluted with ethyl acetate (100 mL) and extracted with water (500 mL), and the process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum and purified by silica gel column chromatography to obtain compound int2 (1.7 g).

[0135] intermediate int3:

[0136]

[0137] (1) Dissolve int3-1 (5 g, 21.01 mmol) in methanol (50 mL) and add potassium hydroxide (1.30 g, 23.11 mmol). Stir the mixture at 90 °C for 4 h and monitor the reaction by TLC. Dilute the reaction solution with ethyl acetate (50 mL) and extract with water (200 mL), repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under vacuum, and purify the concentrate by silica gel column chromatography. Elute with petroleum ether:ethyl acetate = 8:1 to give compound int3-2 (5.1 g).

[0138] (2) Dissolve int3-2 (5.75 g, 23.00 mmol) in N,N-dimethylformamide (60 mL), add trimethylcyclotriboroxane (3.18 g, 25.30 mmol), then add cesium carbonate (22.48 g, 69.00 mmol) and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (1.86 g, 2.30 mmol). Stir the mixture at 115 °C for 16 h under nitrogen protection, and monitor the reaction completion by TLC. Dilute the reaction solution with ethyl acetate (50 mL) and extract with water (200 mL), repeating three times. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under vacuum, and purify the concentrate by silica gel column chromatography, eluting with petroleum ether:ethyl acetate = 8:1 to obtain compound int3-3 (2 g).

[0139] (3) int3-3 (1.8 g, 9.72 mmol) was added to acetic acid (20 mL), the temperature was lowered to 0 °C, and liquid bromine (2.13 mL, 38.88 mmol) was added. The mixture was stirred at 55 °C for 4 h. After the reaction was complete, the mixture was quenched with saturated sodium thiosulfate solution, diluted with ethyl acetate, and the pH was adjusted to 13-14 with sodium hydroxide solution. Water was then added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined. The organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The residue was eluted with petroleum ether:ethyl acetate = 8:1 to give compound int3-4 (2.4 g).

[0140] (4) Dissolve int3-4 (3.6 g, 13.63 mmol) in dichloromethane (40 mL), and then add boron tribromide (3.94 mL, 40.89 mmol) to the solution at 0 °C. Stir the reaction mixture at room temperature for 0.5 h. After the reaction is complete, dilute with dichloromethane, add water, and extract three times with dichloromethane. Combine the organic phases, wash twice with saturated brine, dry the organic phase with sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography, and elute with petroleum ether:ethyl acetate = 8:1 to give compound int3-5 (2.3 g).

[0141] (5) Dissolve int3-5 (2.3 g, 9.20 mmol) in N,N-dimethylformamide (25 mL), then add potassium carbonate (1.53 g, 11.04 mmol) and benzyl bromide (1.57 g, 9.20 mmol). Stir the reaction mixture at 60 °C for 1 h. After the reaction is complete, cool the reaction mixture to room temperature, dilute with ethyl acetate, add water, extract three times with ethyl acetate, combine the organic phases, wash twice with saturated brine, dry the organic phase with sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography, eluting with petroleum ether:ethyl acetate = 8:1 to give compound int3-6 (3.0 g).

[0142] (6) Dissolve int3-6 (4.4 g, 12.94 mmol) in a mixed solvent of ethanol (42 mL) and water (14 mL), then add ammonium chloride (6.92 g, 129.40 mmol) and iron powder (3.62 g, 64.70 mmol) sequentially. Stir the reaction mixture at 80 °C for 1 h. After the reaction is complete, dilute with ethyl acetate, add water, and extract three times with ethyl acetate. Combine the organic phases, wash with brine, dry with anhydrous sodium sulfate, concentrate under vacuum, and purify the residue by silica gel column chromatography. Elute with petroleum ether:ethyl acetate = 8:1 to obtain compound int3-7 (2.6 g).

[0143] (7) Dissolve int3-7 (2.1 g, 6.77 mmol) in N,N-dimethylformamide (24 mL), then add potassium carbonate (2.34 g, 16.93 mmol) and methyl bromoacetate (4.14 g, 27.08 mmol). The reaction mixture was stirred at 60 °C for 16 h. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate = 8:1 to give compound int3-8 (1.9 g).

[0144] (8) Dissolve int3-8 (1.06 g, 7.46 mmol) in dichloromethane (10 mL), add tert-butanol (553 mg, 7.46 mmol), and stir the mixture at 0 °C for 0.5 h. Then add a mixture of 6-benzyloxy-3-bromo-2-fluoro-4-methylphenylglycine methyl ester (1.9 g, 4.97 mmol) and triethylamine (1.01 g, 9.94 mmol) dissolved in dichloromethane (10 mL). Stir at 0 °C for 0.5 h, then raise to room temperature and stir for 1 h. Monitor the reaction completion by LCMS. Dilute the reaction solution with ethyl acetate (50 mL) and extract with water (200 mL), repeating three times. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under vacuum, and purify the concentrate by silica gel column chromatography, eluting with petroleum ether:ethyl acetate = 6:1 to give compound int3-9 (2.4 g).

[0145] (9) Dissolve int3-9 (6.6 g, 11.76 mmol) in dichloromethane (118.8 mL) and add trifluoroacetic acid (13.2 mL). Stir the mixture at room temperature for 1 h. Monitor the reaction progress by LCMS. Adjust the pH of the reaction solution to 8 with saturated sodium bicarbonate, dilute with ethyl acetate (50 mL), and extract with water (200 mL). Repeat three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under vacuum. Purify the concentrate by silica gel column chromatography and elute with petroleum ether:ethyl acetate = 3:1 to give compound int3-10 (4.2 g).

[0146] (10) Dissolve int3-10 (4.1 g, 8.89 mmol) in tetrahydrofuran (45 mL) and add potassium tert-butoxide (998 mg, 8.89 mmol). Stir the mixture at room temperature for 20 min. Monitor the reaction progress by LCMS. Dilute with ethyl acetate (100 mL) and extract with water (500 mL), repeating three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under vacuum. Purify the concentrate by silica gel column chromatography, eluting with dichloromethane:methanol = 7:1 to give compound int3 (1.2 g).

[0147] Example 1

[0148]

[0149] Synthesis route:

[0150]

[0151] (1) Compound int1 (300 mg, 0.72 mmol) was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL), and 2-(2-methylpropyl-1-en-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (560 mg, 2.16 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (59 mg, 0.072 mmol) and cesium carbonate (704 mg, 2.16 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (1000 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum and purified by silica gel column chromatography to obtain compound 3a (170 mg).

[0152] (2) Compound 3a (160 mg, 0.34 mmol) was dissolved in dichloromethane (6 mL), and pentamethylbenzene (101 mg, 0.68 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (2.04 mL, 2.04 mmol) was slowly added. The mixture was stirred at -78 °C for 15 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum, and the concentrate was purified by reverse-phase column chromatography to give compound 3 (37.68 mg).

[0153] Example 2

[0154]

[0155] Synthesis route:

[0156]

[0157] Compound 3 (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (4 mL), and palladium on carbon (60 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum, and the concentrate was purified by reverse-phase column chromatography to give compound 4 (1 mg).

[0158] Example 3

[0159]

[0160] Synthesis route:

[0161]

[0162] (1) Compound int1 (300 mg, 0.72 mmol) was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL), and 2-(4-isobutylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (562 mg, 2.16 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (59 mg, 0.072 mmol) and cesium carbonate (704 mg, 2.16 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (1000 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum and purified by silica gel column chromatography to obtain compound 5a (170 mg).

[0163] (2) Compound 5a (100 mg, 0.21 mmol) was dissolved in tetrahydrofuran (4 mL), and palladium on carbon (100 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum, and the concentrate was purified by reverse-phase column chromatography to obtain product 5 (17 mg).

[0164] Example 4

[0165]

[0166] Synthesis route:

[0167]

[0168] (1) Compound int1 (400 mg, 0.97 mmol) was dissolved in diisopropylamine (5 mL), and 6b (437 mg, 1.94 mmol), bis(triphenylphosphine)palladium dichloride (68 mg, 0.097 mmol), and cuprous iodide (19 mg, 0.097 mmol) were added. The mixture was stirred at 100 °C for 16 h. The reaction was monitored by TLC. The reaction solution was concentrated under vacuum and purified by silica gel column chromatography to obtain compound 6a (250 mg).

[0169] (2) Compound 6a (200 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL), and pentamethylbenzene (107 mg, 0.72 mmol) and boron trichloride (2.2 mL, 2.16 mmol) were added. The mixture was stirred at -78 °C for 15 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum, and the concentrate was sent for preparative purification to obtain product 6 (13 mg).

[0170] Example 5

[0171]

[0172] Synthesis route:

[0173]

[0174] (1) Compound int1 (400 mg, 0.97 mmol) was dissolved in diisopropylamine (5 mL), and tert-butyl isopentyl (prop-2-yn-1-yl)carbamate (437 mg, 1.94 mmol), bis(triphenylphosphine)palladium dichloride (68 mg, 0.097 mmol), and cuprous iodide (19 mg, 0.097 mmol) were added. The mixture was stirred at 100 °C for 16 h. The reaction was monitored by TLC. The reaction solution was concentrated under vacuum and purified by silica gel column chromatography to obtain product 7a (250 mg).

[0175] (2) Compound 7a (200 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL), and pentamethylbenzene (107 mg, 0.72 mmol) and boron trichloride (2.2 mL, 2.16 mmol) were added. The mixture was stirred at -78 °C for 15 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum, and the concentrate was sent for preparative purification to obtain product 7 (13 mg).

[0176] Example 6

[0177]

[0178] Synthesis route:

[0179]

[0180] (1) Compound 7a (200 mg, 0.3 mmol) was dissolved in methanol (20 mL), and palladium-calcium carbonate-lead acetate (200 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to obtain product 8a (188 mg).

[0181] (2) Compound 8a (345 mg, 0.61 mmol) was dissolved in anhydrous dichloromethane (10 mL), and pentamethylbenzene (182 mg, 1.22 mmol) was added. The reaction solution was cooled to -78 °C, and 1 M boron trichloride (3.68 mL, 3.68 mmol) was added dropwise while maintaining this temperature. The mixture was stirred at this temperature for 10 min. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with dichloromethane, and silica gel powder was added and stirred while heating. The resulting mixture was purified by silica gel column chromatography using dichloromethane:methanol (10:1) to obtain the crude product. The crude product was then purified by reverse-phase column chromatography to obtain product 8 (10.3 mg).

[0182] Example 7

[0183]

[0184] Synthesis route:

[0185]

[0186] (1) Int1 (200 mg, 0.48 mmol) was dissolved in diisopropylamine (4 mL), and 5-ethynyl-2-isopropylpyridine (139 mg, 0.96 mmol), palladium dichloride bis(triphenylphosphine) (34 mg, 0.048 mmol), and cuprous iodide (9 mg, 0.048 mmol) were added. The mixture was stirred at 100 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (1000 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrated solution was purified by silica gel column chromatography to give compound 9a.

[0187] (2) Compound 9a (150 mg, 0.31 mmol) was dissolved in dichloromethane (4 mL), and pentamethylbenzene (92 mg, 0.62 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (1.86 mL, 1.86 mmol) was slowly added. The mixture was stirred at -78 °C for 15 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by reverse-phase column chromatography to obtain compound 9.

[0188] Example 8

[0189]

[0190] Synthesis route:

[0191]

[0192] (1) 10a (156 mg, 0.518 mmol) was dissolved in 1,4-dioxane (30 mL) and water (3 mL), and int1 (179 mg, 0.432 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (36 mg, 0.0432 mmol) and cesium carbonate (422 mg, 1.3 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated solution was purified by TLC (methanol:dichloromethane = 1:10) to obtain 10b (120 mg, mixture).

[0193] (2) Mixture 10b (120 mg, 0.236 mmol) was dissolved in tetrahydrofuran (12 mL), and palladium on carbon (120 mg) was added. The mixture was stirred for 16 h at room temperature under a hydrogen atmosphere. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified using a reverse-phase ammonia system to give compounds 10 (2.08 mg) and 44 (15.5 mg).

[0194] Example 9

[0195]

[0196] Synthesis route:

[0197]

[0198] (1) Compound int1 (200 mg, 0.48 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL), and 11a (267 mg, 0.96 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (39 mg, 0.04 mmol), and cesium carbonate (314 mg, 0.96 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrated solution was purified by TLC (methanol:dichloromethane = 1:10) to obtain compound 11b (100 mg).

[0199] (2) Compound 11b (100 mg, 0.2 mmol) was dissolved in tetrahydrofuran (20 mL), and palladium on carbon (100 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified using a reverse-phase formic acid system to obtain compound 11 (1 mg).

[0200] Example 10

[0201]

[0202] Synthesis route:

[0203]

[0204] (1) Int1 (197 mg, 0.47 mmol) was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL), and 12a (150 mg, 0.57 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (39 mg, 0.048 mmol), and cesium carbonate (466 mg, 1.43 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (100 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography, and eluted with dichloromethane:methanol = 15:1 to give compound 12b (200 mg).

[0205] (2) Compound 12b (100 mg, 0.21 mmol) was dissolved in tetrahydrofuran (4 mL), and palladium on carbon (100 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified by alkaline reversed-phase column chromatography to obtain compound 12 (3.39 mg).

[0206] Example 11

[0207]

[0208] Synthesis route:

[0209]

[0210] (1) Compound int1 (200 mg, 0.48 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL), and 13a (264 mg, 0.96 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (39 mg, 0.04 mmol), and cesium carbonate (314 mg, 0.96 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrated solution was purified by TLC (methanol:dichloromethane = 1:10) to obtain 13b (64 mg).

[0211] (2) Compound 13b (64 mg, 0.13 mmol) was dissolved in tetrahydrofuran (10 mL), and palladium on carbon (70 mg) was added. The mixture was stirred for 16 h at room temperature under a hydrogen atmosphere. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified using a reverse-phase formic acid system to obtain compound 13 (5.50 mg).

[0212] Example 12

[0213]

[0214] Synthesis route:

[0215]

[0216] (1) 14a (300 mg, 1.07 mmol) was dissolved in 1,4-dioxane (5 mL), water (1 mL), and int1 (224 mg, 0.54 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (90 mg, 0.11 mmol), and cesium carbonate (698 mg, 2.14 mmol) were added. The mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under vacuum. The concentrated solution was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give compound 14b (120 mg).

[0217] (2) 14b (100 mg, 0.21 mmol) was dissolved in tetrahydrofuran (5 mL), and palladium on carbon (100 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under vacuum. The resulting concentrate was sent for preparative purification to obtain compound 14 (19 mg).

[0218] Example 13

[0219]

[0220] Synthesis route:

[0221]

[0222] (1) Compound 15a (240 mg, 0.916 mmol) was dissolved in 1,4-dioxane (10 mL), and int1 (316 mg, 0.763 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride, DPPFpalladium dichloride (56 mg, 0.076 mmol), cesium carbonate (746 mg, 2.289 mmol), and water (1 mL) were added. The mixture was heated to 90 °C and stirred for 16 h. The reaction solution was diluted with ethyl acetate (100 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 under vacuum. The resulting concentrate was purified by silica gel column chromatography and eluted with dichloromethane:methanol = 10:1 to give compound 15b (100 mg).

[0223] (2) 15b (100 mg) was dissolved in tetrahydrofuran (5 mL), and palladium on carbon (100 mg) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 16 h, and the reaction was monitored by LCMS. The reaction solution was filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by reverse-phase preparation to obtain compound 15 (1.85 mg).

[0224] Example 14

[0225]

[0226] Synthesis route:

[0227]

[0228] (1) Dissolve 16a (100 mg, 0.5 mmol) in 1,4-dioxane (2 mL), water (0.2 mL), and add int1 (166 mg, 0.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (41 mg, 0.05 mmol), and cesium carbonate (489 mg, 1.5 mmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain product 16b (100 mg).

[0229] (2) Dissolve 16b (100 mg, 0.2 mmol) in dichloromethane (2 mL), add pentamethylbenzene (59 mg, 0.4 mmol) and boron trichloride (1.2 mL, 1.2 mmol). Stir the mixture at -78 °C for 10 min. Monitor the reaction completion by LCMS. Concentrate the filtrate under vacuum. Send the concentrate for preparative purification to obtain product 16 (7.9 mg).

[0230] (3) Dissolve 16b (100 mg, 0.21 mmol) in tetrahydrofuran (5 mL) and add palladium on carbon (200 mg). Stir the mixture at room temperature under a hydrogen atmosphere for 16 h. Monitor the reaction completion by LCMS. Concentrate the filtrate under vacuum. Purify the resulting concentrate by reverse-phase column chromatography to obtain product 25 (14 mg).

[0231] Example 15

[0232]

[0233] Synthesis route:

[0234]

[0235] (1) The crude product 17a (300 mg, 0.99 mmol) was dissolved in 1,4-dioxane (60 mL) and water (6 mL), and int1 (347 mg, 0.834 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (69 mg, 0.0834 mmol) and cesium carbonate (815 mg, 2.52 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated solution was purified by TLC (methanol:dichloromethane = 1:10) to give compound 17b (140 mg).

[0236] (2) Compound 17b (70 mg, 0.138 mmol) was dissolved in dichloromethane (4 mL), and pentamethylbenzene (41 mg, 0.276 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (1.655 mL, 1.62 mmol) was slowly added. The mixture was stirred at -78 °C for 20 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by reverse-phase column chromatography to give compound 17 (5.67 mg).

[0237] (3) 17b (140 mg, 0.28 mmol) was dissolved in tetrahydrofuran (10 mL), and palladium on carbon (280 mg) was added. The mixture was stirred at 50 °C under a hydrogen atmosphere for 48 h. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under vacuum. The resulting concentrate was purified by reverse-phase preparation with ammonium bicarbonate to give compound 20 (29.97 mg).

[0238] Example 16

[0239]

[0240] Synthesis route:

[0241]

[0242] (1) Compound int1 (91 mg, 0.22 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL), and 18a (120 mg, 0.44 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (18 mg, 0.02 mmol) and cesium carbonate (143 mg, 0.43 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrated solution was purified by TLC (methanol:dichloromethane = 1:10) to give compound 18b (30 mg).

[0243] (2) Compound 18b (43 mg, 0.07 mmol) was dissolved in anhydrous dichloromethane (5 mL), and pentamethylbenzene (23 mg, 0.15 mmol) was added. The reaction solution was cooled to -78 °C, and 1 M boron trichloride (0.45 mL, 0.45 mmol) was added dropwise while maintaining this temperature. The mixture was stirred at this temperature for 10 min. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with dichloromethane and concentrated under vacuum to obtain a crude product, which was purified by reverse-phase column chromatography to obtain compound 18 (1.73 mg).

[0244] (3) Compound 18b (30 mg, 0.1 mmol) was dissolved in tetrahydrofuran (10 mL), and palladium on carbon (50 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified using a reverse-phase ammonium bicarbonate system to give compound 19 (8.9 mg).

[0245] Example 17

[0246]

[0247] Synthesis route:

[0248]

[0249] (1) Compound int1 (200 mg, 0.48 mmol) was dissolved in 1,4-dioxane (16 mL) and water (4 mL), and 21a (361 mg, 1.3 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (117 mg, 0.14 mmol) and cesium carbonate (471 mg, 1.44 mmol) were added. The mixture was stirred at 95 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrated solution was purified by TLC (methanol:dichloromethane = 1:10) to obtain compound 21b (60 mg).

[0250] (2) Compound 21b (60 mg, 0.12 mmol) was dissolved in anhydrous dichloromethane (5 mL), and pentamethylbenzene (37 mg, 0.24 mmol) was added. The reaction solution was cooled to -78 °C, and 1 M boron trichloride (0.74 mL, 0.74 mmol) was added dropwise while maintaining this temperature. The mixture was stirred at this temperature for 10 min. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with dichloromethane and concentrated under vacuum to obtain a crude product. The crude product was purified by reverse-phase extraction with ammonium bicarbonate to obtain product 21 (9.6 mg).

[0251] Example 18

[0252]

[0253] Synthesis route:

[0254]

[0255] (1) Compound int1 (86 mg, 0.2 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL), and 22a (120 mg, 0.41 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (17 mg, 0.02 mmol), and cesium carbonate (202 mg, 0.62 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrated solution was purified by TLC (methanol:dichloromethane = 1:10) to give compound 22b (53 mg).

[0256] (2) Compound 22b (53 mg, 0.1 mmol) was dissolved in tetrahydrofuran (10 mL), and palladium on carbon (100 mg) was added. The mixture was stirred for 16 h at room temperature under a hydrogen atmosphere. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified using a reverse-phase ammonium bicarbonate system to obtain compound 22 (5.92 mg).

[0257] Example 19

[0258]

[0259] Synthesis route:

[0260]

[0261] (1) Compound 23a (200 mg, 0.48 mmol) was dissolved in 1,4-dioxane (6 mL), water (0.6 mL), and 5-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (128 mg, 0.58 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (35 mg, 0.048 mmol), and cesium carbonate (469 mg, 144 mmol) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under vacuum. The concentrated solution was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give compound 23b (100 mg).

[0262] (2) Compound 23b (100 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and palladium on carbon (100 mg) was added. The mixture was stirred at 50 °C under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS to ensure completion. The reaction solution was filtered and concentrated under vacuum. The resulting concentrate was sent for preparative purification to obtain product 23 (12.6 mg).

[0263] Example 20

[0264]

[0265] Synthesis route:

[0266]

[0267] (1) Compound 24a (200 mg, 0.69 mmol) was dissolved in 1,4-dioxane (40 mL) and water (4 mL), and int1 (239 mg, 0.574 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (47 mg, 0.0574 mmol) and cesium carbonate (561 mg, 1.722 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (100 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography and eluted with dichloromethane:methanol = 10:1 to give compound 24b (45 mg).

[0268] (2) Compound 24b (45 mg, 0.09 mmol) was dissolved in tetrahydrofuran (4 mL), and palladium on carbon (90 mg) was added. The mixture was stirred for 16 h at room temperature under a hydrogen atmosphere. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified by alkaline reversed-phase column chromatography to give compound 24 (6.19 mg).

[0269] Example 21

[0270]

[0271] Synthesis route:

[0272]

[0273] (1) Compound 26a (230 mg, 0.75 mmol) was dissolved in 1,4-dioxane (16 mL) and water (4 mL), and int1 (156 mg, 0.37 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (30 mg, 0.037 mmol) and cesium carbonate (368 mg, 1.12 mmol) were added. The mixture was stirred at 90 °C for 12 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by TLC (methanol:dichloromethane = 1:10) to give compound 26b (30 mg).

[0274] (2) Compound 26b (30 mg, 0.05 mmol) was dissolved in tetrahydrofuran (4 mL) and methanol (4 mL), and palladium on carbon (30 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 12 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified using a reverse-phase ammonium bicarbonate system to give compound 26 (5.25 mg).

[0275] Example 22

[0276]

[0277] Synthesis route:

[0278]

[0279] (1) Compound 27a (400 mg, 1.39 mmol) was dissolved in 1,4-dioxane (8 mL) and water (0.8 mL), and int1 (191 mg, 0.46 mmol), cesium carbonate (450 mg, 1.38 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (38 mg, 0.046 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (100 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography and eluted with dichloromethane:methanol = 6:1 to give compound 27b (160 mg).

[0280] (2) Compound 27b (120 mg, 0.24 mmol) was dissolved in tetrahydrofuran (8 mL), and palladium on carbon (120 mg) was added. The mixture was stirred at 50 °C under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified by alkaline reversed-phase column chromatography to obtain compound 27 (9.01 mg).

[0281] Example 23

[0282]

[0283] Synthesis route:

[0284]

[0285] (1) Compound 28a (156 mg, 0.54 mmol) was dissolved in 1,4-dioxane (3 mL), water (0.5 mL), and int1 (150 mg, 0.36 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (29 mg, 0.036 mmol), and cesium carbonate (352 mg, 1.08 mmol) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain product 28b (100 mg).

[0286] (2) Compound 28b (100 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and palladium on carbon (100 mg) was added. The mixture was stirred at 50 °C under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The reaction solution was filtered and concentrated under vacuum. The resulting concentrate was sent for preparative purification to obtain product 28 (35 mg).

[0287] Example 24

[0288]

[0289] Synthesis route:

[0290]

[0291] (1) Compound 29a (100 mg, 0.33 mmol) was dissolved in 1,4-dioxane (20 mL) and water (2 mL), and int1 (108 mg, 0.26 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (19 mg, 0.026 mmol) and cesium carbonate (268 mg, 0.83 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (100 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography and eluted with dichloromethane:methanol = 10:1 to give compound 29b (45 mg).

[0292] (2) Compound 29b (34 mg, 0.08 mmol) was dissolved in tetrahydrofuran (4 mL), and palladium on carbon (34 mg) was added. The mixture was stirred at 50 °C under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified by alkaline reversed-phase column chromatography to obtain compound 29 (3.95 mg).

[0293] Example 25

[0294]

[0295] Synthesis route:

[0296]

[0297] (1) Compound 30a (166 mg, 0.54 mmol) was dissolved in 1,4-dioxane (3 mL), water (0.5 mL), and int1 (150 mg, 0.36 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (29 mg, 0.036 mmol), and cesium carbonate (352 mg, 1.08 mmol) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under vacuum. The concentrated solution was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain product 30b (100 mg).

[0298] (2) Compound 30b (100 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and palladium on carbon (100 mg) was added. The mixture was stirred at 50 °C under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The reaction solution was filtered and concentrated under vacuum. The resulting concentrate was sent for preparative purification to obtain product 30 (39 mg).

[0299] Example 26

[0300]

[0301] Synthesis route:

[0302]

[0303] (1) Compound 31a (350 mg, 1.15 mmol) was dissolved in 1,4-dioxane (20 mL) and water (5 mL), and int1 (241 mg, 0.58 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (47 mg, 0.058 mmol) and cesium carbonate (564 mg, 1.73 mmol) were added. The mixture was stirred at 95 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrated solution was purified by TLC (methanol:dichloromethane = 1:10) to obtain compound 31b (75 mg).

[0304] (2) Compound 31b (75 mg, 0.15 mmol) was dissolved in tetrahydrofuran (4 mL), and palladium on carbon (150 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was sent for preparative purification to obtain compound 31 (17.21 mg).

[0305] Example 27

[0306]

[0307] Synthesis route:

[0308]

[0309] (1) Int1 (116 mg, 0.28 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), and 32a (100 mg, 0.34 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (20 mg, 0.088 mmol) and cesium carbonate (274 mg, 0.84 mmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (1000 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by TLC and eluted with dichloromethane:methanol = 15:1 to give compound 32b (42 mg).

[0310] (2) Compound 32b (42 mg, 0.08 mmol) was dissolved in tetrahydrofuran (10 mL), and palladium on carbon (40 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified by reverse-phase column chromatography to obtain compound 32 (1.17 mg).

[0311] Example 28

[0312]

[0313] Synthesis route:

[0314]

[0315] (1) Int1 (144 mg, 0.35 mmol) was dissolved in triethylamine (3 mL), and 4-isopropylphenylacetylene 33a (100 mg, 0.69 mmol), bis(triphenylphosphine) palladium dichloride (25 mg, 0.035 mmol), and cuprous iodide (7 mg, 0.035 mmol) were added. The mixture was stirred at 105 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (50 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by TLC (dichloromethane:methanol = 10:1) to give compound 33b (60 mg).

[0316] (2) Compound 33b (90 mg, 0.188 mmol) was dissolved in dichloromethane (6 mL), and pentamethylbenzene (56 mg, 0.377 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (1.2 mL, 1.13 mmol) was slowly added. The mixture was stirred at -78 °C for 30 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was sent for preparative purification to obtain compound 33 (1.46 mg).

[0317] Example 29

[0318]

[0319] Synthesis route:

[0320]

[0321] (1) Dissolve int1 (150 mg, 0.8 mmol) in triethylamine (10 mL), and add 2-(cyclopentylmethyl)-5-ethynylpyridine 34a (224 mg, 0.53 mmol), bis(triphenylphosphine) palladium dichloride (38 mg, 0.05 mmol), and cuprous iodide (10 mg, 0.05 mmol). The mixture is sealed under nitrogen protection and reacted at 100 °C for 12 h. The reaction is monitored by LCMS until completion. The mixture is neutralized with water, then extracted three times with dichloromethane. The organic phase is concentrated, and the concentrate is purified by TLC with dichloromethane:methanol (10:1) to obtain product 34b (216 mg).

[0322] (2) Compound 34b (200 mg, 0.38 mmol) was dissolved in anhydrous dichloromethane (10 mL), and pentamethylbenzene (114 mg, 0.76 mmol) was added. The reaction solution was cooled to -78 °C, and 1 M boron trichloride (2.3 mL, 2.3 mmol) was added dropwise while maintaining this temperature. The mixture was stirred at this temperature for 10 min. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with dichloromethane and concentrated to dryness to obtain a crude product. The crude product was purified by ammonium bicarbonate reverse-phase column chromatography to obtain product 34 (7.82 mg).

[0323] Example 30

[0324]

[0325] Synthesis route:

[0326]

[0327] (1) Dissolve INT3 (100 mg, 0.21 mmol) in N,N-dimethylformamide (2 mL), and add 2-(cyclopentylmethyl)-5-ethynylpyridine 34a (46 mg, 0.25 mmol), bis(triphenylphosphine) palladium dichloride (15 mg, 0.021 mmol), cuprous iodide (4 mg, 0.021 mmol), and triethylamine (64 mg, 0.63 mmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under vacuum. The concentrated solution was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain product 35b (100 mg).

[0328] (2) Compound 35b (100 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), and pentamethylbenzene (56 mg, 0.38 mmol) was added. Boron trichloride (1.2 mL, 1.2 mmol) was added at -78 °C. The mixture was stirred at -78 °C for 15 min. The reaction was monitored by LCMS. The resulting concentrate was sent for preparative purification to obtain product 35 (10 mg).

[0329] Example 31

[0330]

[0331] Synthesis route:

[0332]

[0333] (1) int3 (50 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 4-isopropylphenylacetylene 33a (84 mg, 0.58 mmol), palladium dichloride (8 mg, 0.012 mmol), cuprous iodide (2 mg, 0.012 mmol), and potassium carbonate (32 mg, 0.23 mmol) were added. The mixture was stirred at 100 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (50 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrated solution was purified by TLC (dichloromethane:methanol = 10:1) to give compound 36b (40 mg).

[0334] (2) Compound 36b (40 mg, 0.081 mmol) was dissolved in dichloromethane (3 mL), and pentamethylbenzene (24 mg, 0.163 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (0.5 mL, 0.49 mmol) was slowly added. The mixture was stirred at -78 °C for 30 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by ammonium bicarbonate to obtain compound 36 (8.33 mg).

[0335] Example 32

[0336]

[0337] Synthesis route:

[0338]

[0339] (1) 2-(tert-butyl)-5-ethylpyridine 37a (50 mg, 0.31 mmol) was dissolved in tetrahydrofuran (2 mL). The reaction solution was cooled to -78 °C, and n-butyllithium (2.5 M, 0.31 mL) was added to the reaction solution. The reaction was maintained at -78 °C for 30 min, and then at 0 °C for 30 min. The reaction solution was cooled to -78 °C again, and tri-n-butylhydrochloride (0.21 mL, 0.78 mmol) was added. The mixture was stirred overnight at room temperature. The reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate, extracted with water, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give compound 37b (145 mg).

[0340] (2) Dissolve int3 (67 mg, 0.15 mmol) in N,N-dimethylformamide (2 mL), and add 37b (145 mg, 0.31 mmol) and tetraphenylphosphine (17 mg, 0.01 mmol). The mixture is then sealed under nitrogen protection and reacted at 120 °C for 12 h. The reaction is monitored by LCMS until completion. The mixture is neutralized with water, then extracted three times with dichloromethane. The organic phase is concentrated, and the concentrate is purified by TLC using dichloromethane:methanol (10:1) to obtain product 37c (62 mg).

[0341] (3) Compound 37c (62 mg, 0.12 mmol) was dissolved in anhydrous dichloromethane (2 mL), and pentamethylbenzene (36 mg, 0.24 mmol) was added. The reaction solution was cooled to -78 °C, and 1 M boron trichloride (0.73 mL, 0.73 mmol) was added dropwise while maintaining this temperature. The mixture was stirred at this temperature for 10 min. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with dichloromethane and concentrated to dryness to obtain the crude product. The crude product was purified by ammonium bicarbonate reverse-phase column chromatography to obtain product 37 (1.1 mg).

[0342] Example 33

[0343]

[0344] Synthesis route:

[0345]

[0346] (1) Dissolve 38a (100 mg, 0.21 mmol) in N,N-dimethylformamide (2 mL), and add 3-(cyclopentylmethyl)-5-ethynylpyridine 38b (46 mg, 0.25 mmol), bis(triphenylphosphine) palladium dichloride (15 mg, 0.021 mmol), cuprous iodide (4 mg, 0.021 mmol), and triethylamine (64 mg, 0.63 mmol). The mixture was stirred at 60 °C under a nitrogen atmosphere for 16 h. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under vacuum. The concentrated solution was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain product 38c (100 mg).

[0347] (2) Compound 38c (100 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), and pentamethylbenzene (56 mg, 0.38 mmol) was added. Boron trichloride (1.2 mL, 1.2 mmol) was added at -78 °C. The mixture was stirred at -78 °C for 15 min. The reaction was monitored by LCMS. The resulting concentrate was sent for preparative purification to obtain product 38 (10 mg).

[0348] Example 34

[0349]

[0350] Synthesis route:

[0351]

[0352] (1) 38a (100 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-ethyl-5-isopropylpyridine 39a (92 mg, 0.62 mmol), bis(triphenylphosphine) palladium dichloride (14 mg, 0.02 mmol), cuprous iodide (4 mg, 0.02 mmol), and triethylamine (0.2 mL) were added. The mixture was stirred at 60 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (50 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by TLC (dichloromethane:methanol = 10:1) to give compound 39b (133 mg).

[0353] (2) Compound 39b (133 mg, 0.26 mmol) was dissolved in anhydrous dichloromethane (10 mL), and pentamethylbenzene (80 mg, 0.53 mmol) was added. The reaction solution was cooled to -78 °C, and 1 M boron trichloride (1.61 mL, 1.61 mmol) was added dropwise while maintaining this temperature. The mixture was stirred at this temperature for 10 min. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with dichloromethane and concentrated to dryness to obtain a crude product. The crude product was purified by ammonium bicarbonate reverse-phase column chromatography to obtain product 39 (6.53 mg).

[0354] Example 35

[0355]

[0356] Synthesis route:

[0357]

[0358] (1) Compound int1 (175 mg, 0.42 mmol) was dissolved in 1,4-dioxane (16 mL) and water (4 mL), and 40a (240 mg, 0.84 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (34 mg, 0.04 mmol), and cesium carbonate (412 mg, 1.26 mmol) were added. The mixture was stirred at 95 °C for 16 h under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrated solution was purified by TLC (methanol:dichloromethane = 1:10) to obtain compound 40b (75 mg).

[0359] (2) Compound 40b (50 mg, 0.1 mmol) was dissolved in tetrahydrofuran (10 mL), and palladium on carbon (50 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified using a reverse-phase formic acid system to obtain compound 40 (13.66 mg).

[0360] Example 36

[0361]

[0362] Synthesis route:

[0363]

[0364] (1) 41a (100 mg, 0.57 mmol) was dissolved in triethylamine (8 mL), and int1 (216 mg, 0.52 mmol), bis(triphenylphosphine)palladium dichloride (9 mg, 0.013 mmol), and cuprous iodide (10 mg, 0.052 mmol) were added. The mixture was stirred at 105 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (1000 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography, and eluted with dichloromethane:methanol = 8:1 to give compound 41b (70 mg).

[0365] (2) 41b (70 mg, 0.14 mmol) was dissolved in dichloromethane (4 mL), and pentamethylbenzene (42 mg, 0.28 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (0.84 mL, 0.84 mmol) was slowly added. The mixture was stirred at -78 °C for 20 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified by alkaline reverse-phase method to give compound 41 (15.73 mg).

[0366] Example 37

[0367]

[0368] Synthesis route:

[0369]

[0370] (1) 38a (50 mg, 0.11 mmol) was dissolved in dimethylformamide (2 mL), and 4-acetylene-2-isopropylpyridine 42a (18 mg, 0.13 mmol), bis(triphenylphosphine) palladium dichloride (7 mg, 0.01 mmol), cuprous iodide (2 mg, 0.01 mmol), and triethylamine (31 mg, 0.32 mmol) were added. The mixture was stirred at 100 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (50 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by TLC (dichloromethane:methanol = 10:1) to give compound 42b (40 mg).

[0371] (2) Compound 42b (40 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), and pentamethylbenzene (27 mg, 0.18 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (0.54 mL, 0.54 mmol) was slowly added. The mixture was stirred at -78 °C for 30 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was sent for preparative purification to obtain compound 42 (7.45 mg).

[0372] Example 38

[0373]

[0374] Synthesis route:

[0375]

[0376] (1) 38a (62 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-ethynyl-4-isopropylcyclohexyl-1-amine 43a (26 mg, 0.16 mmol), bis(triphenylphosphine) palladium dichloride (9 mg, 0.01 mmol), cuprous iodide (3 mg, 0.01 mmol), and triethylamine (40 mg, 0.39 mmol) were added. The mixture was stirred at 100 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (50 mL), repeated three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by TLC (dichloromethane:methanol = 9:1) to give compound 43b (35 mg).

[0377] (2) Dissolve 43b (30 mg, 0.06 mmol) in ultradry dichloromethane (10 mL) and add pentamethylbenzene (18 mg, 0.12 mmol). Cool the reaction solution to -78 °C and maintain this temperature while adding 1 M boron trichloride (0.35 mL, 0.35 mmol). Stir the mixture at this temperature for 30 min. Monitor the reaction completion by LCMS. Dilute the reaction solution with dichloromethane and concentrate to dryness to obtain the crude product. Purify the crude product using an ammonium bicarbonate reverse-phase column to obtain product 43 (5.25 mg).

[0378] Example 39

[0379]

[0380] Synthesis route:

[0381]

[0382] (1) 5-Bromo-1,3-difluoro-2-nitrobenzene int3-1 (20 g, 84.04 mmol) was dissolved in methanol (200 mL), and potassium hydroxide (5.19 g, 92.44 mmol) was added. The mixture was stirred at 90 °C for 4 h, and the reaction was monitored by TLC. The reaction solution was diluted with dichloromethane (250 mL) and extracted with water (400 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain compound 5-bromo-3-methoxynitrobenzene int3-2 (20.2 g).

[0383] (2) 5-Bromo-1-fluoro-3-methoxy-2-nitrobenzene int3-2 (17.3 g, 69.19 mmol) was dissolved in 1,4-dioxane (300 mL) and water (30 mL), and ethylboric acid (6.4 g, 86.49 mmol), cesium carbonate (84.6 g, 259.5 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (6.3 g, 8.65 mmol) were added. The mixture was stirred at 100 °C for 16 h under nitrogen protection, and the reaction was monitored by TLC. The reaction solution was filtered, diluted with ethyl acetate (100 mL), and extracted with water (200 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrate was purified by silica gel column chromatography, and eluted with petroleum ether:ethyl acetate = 10:1 to give compound 45a (9.4 g).

[0384] (3) 45a (3 g, 15.06 mmol) was dissolved in acetonitrile (30 mL), and N-iodosuccinimide (10.2 g, 45.19 mmol) and trifluoroacetic acid (0.34 mL) were added. The mixture was stirred at 80 °C for 16 h. After the reaction was completed, the mixture was quenched with a saturated sodium thiosulfate solution, diluted with ethyl acetate, and then water was added. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The residue was eluted with petroleum ether:ethyl acetate = 10:1 to give compound 45b (3.9 g).

[0385] (4) 45b (1.7 g, 5.35 mmol) was dissolved in dichloromethane (100 mL), and then boron tribromide (1.55 mL, 16.06 mmol) was added dropwise to the solution at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. After the reaction was complete, the mixture was diluted with dichloromethane, then water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography, and eluted with petroleum ether:ethyl acetate = 10:1 to give compound 45c (1.4 g).

[0386] (5) 45c (1.4 g, 4.50 mmol) was dissolved in N,N-dimethylformamide (70 mL), and then potassium carbonate (1.24 g, 9.00 mmol) and benzyl bromide (770 mg, 4.50 mmol) were added. The reaction mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then water was added. The mixture was extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate = 10:1 to give compound 45d (1.9 g).

[0387] (6) 45d (1.9 g, 4.74 mmol) was dissolved in a mixed solvent of ethanol (21 mL) and water (7 mL), and then ammonium chloride (2.53 g, 47.36 mmol) and iron powder (1.33 g, 23.68 mmol) were added sequentially. The reaction solution was stirred at 80 °C for 2 h. After the reaction was completed, the solution was diluted with ethyl acetate, and then water was added. The solution was extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate = 10:1 to give compound 45e (1.9 g).

[0388] (7) 45e (1.8 g, 4.74 mmol) was dissolved in N,N-dimethylformamide (20 mL), and then potassium carbonate (1.64 g, 11.85 mmol) and methyl bromoacetate (2.9 g, 18.96 mmol) were added. The reaction mixture was stirred at 60 °C under a N2 atmosphere for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate = 10:1 to give compound 45f (0.9 g).

[0389] (8) Chlorosulfonic acid isocyanate (431 mg, 3.05 mmol) was dissolved in dichloromethane (5 mL), and tert-butanol (226 mg, 3.05 mmol) was added. The mixture was stirred at 0 °C for 0.5 h. Then, a mixture of 45f (900 mg, 2.03 mmol) and triethylamine (411 mg, 4.06 mmol) dissolved in dichloromethane (5 mL) was added. The mixture was stirred at 0 °C for 0.5 h, and then heated to room temperature and stirred for 1 h. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (100 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrate was purified by silica gel column chromatography, and eluted with petroleum ether:ethyl acetate = 6:1 to give 45 g (900 mg) of the compound.

[0390] (9) Dissolve 45 g (900 mg, 2.03 mmol) in dichloromethane (10 mL) and add trifluoroacetic acid (3 mL). Stir the mixture at room temperature for 0.5 h. Monitor the reaction progress by LCMS. Adjust the pH of the reaction solution to 8 with saturated sodium bicarbonate, dilute with ethyl acetate (50 mL), and extract with water (100 mL). Repeat three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under vacuum. Purify the concentrate by silica gel column chromatography, eluting with petroleum ether:ethyl acetate = 4:1 to give compound 45 h (830 mg).

[0391] (10) 45h (300 mg, 0.57 mmol) was dissolved in tetrahydrofuran (5 mL), and potassium tert-butoxide (97 mg, 0.86 mmol) was added. The mixture was stirred at room temperature for 20 min. The reaction was monitored by LCMS. The mixture was diluted with ethyl acetate (50 mL) and extracted with water (50 mL), and the process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography, and eluted with dichloromethane:methanol = 9:1 to give compound 45i (150 mg).

[0392] (11) 45i (50 mg, 0.102 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 5-ethynyl-2-isopropylpyridine (18 mg, 0.122 mmol), bis(triphenylphosphine) palladium dichloride (7 mg, 0.01 mmol), and cuprous iodide (2 mg, 0.01 mmol) were added. The mixture was stirred at 100 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (100 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by TLC, and eluted with dichloromethane:methanol = 10:1 to give compound 45j (40 mg).

[0393] (12) 45 J (40 mg, 0.079 mmol) was dissolved in dichloromethane (2 mL), and pentamethylbenzene (23 mg, 0.158 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (0.5 mL, 0.5 mmol) was slowly added. The mixture was stirred at -78 °C for 20 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by reverse-phase column chromatography to give compound 45 (11.1 mg).

[0394] Example 40

[0395]

[0396] Synthesis route:

[0397]

[0398] (1) int3 (200 mg, 0.468 mmol) was dissolved in N,N-dimethylformamide (4 mL), and cyclohexyethynyl 46a (101 mg, 0.936 mmol), bis(triphenylphosphine)palladium dichloride (32.8 mg, 0.047 mmol), potassium carbonate (129 mg, 0.936 mmol), and cuprous iodide (8.8 mg, 0.047 mmol) were added. The mixture was stirred at 105 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (150 mL) and extracted with water (50 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by thin-layer chromatography, and eluted with dichloromethane:methanol = 10:1 to give compound 46b (100 mg).

[0399] (2) 46b (100 mg, 0.220 mmol) was dissolved in dichloromethane (5 mL), and pentamethylbenzene (65 mg, 0.440 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (1.32 mL, 1.32 mmol) was slowly added. The mixture was stirred at -78 °C for 20 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by reverse-phase extraction with ammonia to give compound 46 (4.57 mg).

[0400] Example 41

[0401]

[0402] Synthesis route:

[0403]

[0404] (1) 5-Bromo-1,3-difluoro-2-nitrobenzene int3-1 (15 g, 63 mmol) was dissolved in ultradry tetrahydrofuran (150 mL), and benzyl alcohol (6.8 g, 63 mmol) was added. The mixture was stirred at –50 °C under nitrogen protection with potassium tert-butoxide / tetrahydrofuran (1 mol / L, 69.3 mmol) for 1 h, and the reaction was monitored by TLC. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (20 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrate was purified by silica gel column chromatography, eluted with petroleum ether:ethyl acetate = 8:1, to give compound 47a (16.5 g).

[0405] (2) 47a (200 mg, 0.7 mmol) was dissolved in toluene / water (20 / 1, 2.5 mL), and tricycloethylphosphide (20 mg, 0.07 mmol) was added, followed by potassium phosphate (445 mg, 2.1 mmol), cyclopropionic acid (90 mg, 1.05 mmol), and palladium acetate (8 mg, 0.035 mmol). The mixture was stirred at 110 °C for 16 h under nitrogen protection, and the reaction was monitored by TLC. The reaction solution was diluted with ethyl acetate (200 mL) and extracted with water (50 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrate was purified by silica gel column chromatography, eluted with petroleum ether:ethyl acetate = 8:1, to give compound 47b (160 mg).

[0406] (3) 47b (2 g, 7 mmol) was dissolved in acetonitrile (20 mL), and trifluoroacetic acid (0.718 g, 6.3 mmol) and N-iodosuccinimide (3.9 g, 17.5 mmol) were added. The mixture was stirred at 80 °C for 20 h. The reaction was monitored by LCMS. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (200 mL), repeated three times, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The residue was eluted with petroleum ether:ethyl acetate = 8:1 to give compound 47c (1 g).

[0407] (4) 47c (2.2 g, 5.3 mmol) was dissolved in a mixed solvent of ethanol (20 mL) and water (7 mL), and then ammonium chloride (2.8 g, 53 mmol) and iron powder (1.5 g, 26.6 mmol) were added sequentially. The reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was diluted with ethyl acetate, and then water was added. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by silica gel column chromatography. The residue was eluted with petroleum ether:ethyl acetate = 8:1 to give compound 47d (2 g).

[0408] (5) 47d (2.0 g, 5.2 mmol) was dissolved in N,N-dimethylformamide (20 mL), and then potassium carbonate (1.8 g, 13 mmol) and methyl bromoacetate (2.38 g, 15.6 mmol) were added. The reaction mixture was stirred at 60 °C for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate = 8:1 to give compound 47e (1.3 g).

[0409] (6) Chlorosulfonic acid isocyanate (2.51 g, 3.6 mmol) was dissolved in dichloromethane (10 mL), and tert-butanol (0.27 g, 3.6 mmol) was added. The mixture was stirred at 0 °C for 0.5 h. Then, a mixture of 47f (1.1 g, 2.4 mmol) and triethylamine (0.48 g, 4.8 mmol) dissolved in dichloromethane (5 mL) was added. The mixture was stirred at 0 °C for 0.5 h, and then heated to room temperature and stirred for 1 h. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (200 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrate was purified by silica gel column chromatography, and eluted with petroleum ether:ethyl acetate = 6:1 to give compound 47f (2.4 g).

[0410] (7) 47f (2.5 g, 4 mmol) was dissolved in dichloromethane (25 mL), and trifluoroacetic acid (2.5 mL) was added. 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 dichloromethane (200 mL), and extracted with water (50 mL). This process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate = 3:1 to give compound 47 g (1 g).

[0411] (8) Dissolve 47 g (1 g, 1.8 mmol) in tetrahydrofuran (10 mL) and add sodium methoxide / methanol (2.55 mmol, 5.4 mmol / L). Stir the mixture at room temperature for 20 min. Monitor the reaction progress by LCMS. Dilute with ethyl acetate (500 mL) and extract with water (100 mL), repeating three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under vacuum. Purify the concentrate by silica gel column chromatography, eluting with dichloromethane:methanol = 7:1 to give compound 47 h (0.5 g).

[0412] (9) 47i (200 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide (4 mL), and cyclohexylethynylene (64 mg, 0.6 mmol), bis(triphenylphosphine)palladium dichloride (28 mg, 0.04 mmol), triethylamine (0.6 mL), and cuprous iodide (8 mg, 0.04 mmol) were added. The mixture was stirred at 105 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (150 mL) and extracted with water (50 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by thin-layer chromatography, eluted with dichloromethane:methanol = 10:1 to give compound 47i (150 mg).

[0413] (10) 47i (150 mg, 0.311 mmol) was dissolved in dichloromethane (10 mL), and pentamethylbenzene (0.92 mg, 0.622 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (1.86 mL, 1.86 mmol) was slowly added. The mixture was stirred at -78 °C for 20 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by reverse-phase column chromatography to give compound 47 (33.33 mg).

[0414] Example 42

[0415]

[0416] Synthesis route:

[0417]

[0418] (1) 5-Bromo-1,3-difluoro-2-nitrobenzene int3-1 (15 g, 63 mmol) was dissolved in ultradry tetrahydrofuran (150 mL), and benzyl alcohol (6.8 g, 63 mmol) was added. The mixture was stirred at –50 °C under nitrogen protection with potassium tert-butoxide / tetrahydrofuran (1 mol / L, 69.3 mmol) for 1 h, and the reaction was monitored by TLC. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (20 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrate was purified by silica gel column chromatography, eluted with petroleum ether:ethyl acetate = 8:1, to give compound 47a (16.5 g).

[0419] (2) 47a (200 mg, 0.7 mmol) was dissolved in toluene / water (20 / 1, 2.5 mL), and tricycloethylphosphide (20 mg, 0.07 mmol) was added, followed by potassium phosphate (445 mg, 2.1 mmol), cyclopropionic acid (90 mg, 1.05 mmol), and palladium acetate (8 mg, 0.035 mmol). The mixture was stirred at 110 °C for 16 h under nitrogen protection, and the reaction was monitored by TLC. The reaction solution was diluted with ethyl acetate (200 mL) and extracted with water (50 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrate was purified by silica gel column chromatography, eluted with petroleum ether:ethyl acetate = 8:1, to give compound 47b (160 mg).

[0420] (3) 47b (2 g, 7 mmol) was dissolved in acetonitrile (20 mL), and trifluoroacetic acid (0.718 g, 6.3 mmol) and N-iodosuccinimide (3.9 g, 17.5 mmol) were added. The mixture was stirred at 80 °C for 20 h. The reaction was monitored by LCMS. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (200 mL), repeated three times, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The residue was eluted with petroleum ether:ethyl acetate = 8:1 to give compound 47c (1 g).

[0421] (4) 47c (2.2 g, 5.3 mmol) was dissolved in a mixed solvent of ethanol (20 mL) and water (7 mL), and then ammonium chloride (2.8 g, 53 mmol) and iron powder (1.5 g, 26.6 mmol) were added sequentially. The reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was diluted with ethyl acetate, and then water was added. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by silica gel column chromatography. The residue was eluted with petroleum ether:ethyl acetate = 8:1 to give compound 47d (2 g).

[0422] (5) 47d (2.0 g, 5.2 mmol) was dissolved in N,N-dimethylformamide (20 mL), and then potassium carbonate (1.8 g, 13 mmol) and methyl bromoacetate (2.38 g, 15.6 mmol) were added. The reaction mixture was stirred at 60 °C for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate = 8:1 to give compound 47e (1.3 g).

[0423] (6) Chlorosulfonic acid isocyanate (2.51 g, 3.6 mmol) was dissolved in dichloromethane (10 mL), and tert-butanol (0.27 g, 3.6 mmol) was added. The mixture was stirred at 0 °C for 0.5 h. Then, a mixture of 47f (1.1 g, 2.4 mmol) and triethylamine (0.48 g, 4.8 mmol) dissolved in dichloromethane (5 mL) was added. The mixture was stirred at 0 °C for 0.5 h, and then heated to room temperature and stirred for 1 h. The reaction was monitored by LCMS to indicate completion. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (200 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The concentrate was purified by silica gel column chromatography, and eluted with petroleum ether:ethyl acetate = 6:1 to give compound 47f (2.4 g).

[0424] (7) 47f (2.5 g, 4 mmol) was dissolved in dichloromethane (25 mL), and trifluoroacetic acid (2.5 mL) was added. 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 dichloromethane (200 mL), and extracted with water (50 mL). This process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate = 3:1 to give compound 47 g (1 g).

[0425] (8) Dissolve 47 g (1 g, 1.8 mmol) in tetrahydrofuran (10 mL) and add sodium methoxide / methanol (2.55 mmol, 5.4 mmol / L). Stir the mixture at room temperature for 20 min. Monitor the reaction progress by LCMS. Dilute with ethyl acetate (500 mL) and extract with water (100 mL), repeating three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under vacuum. Purify the concentrate by silica gel column chromatography, eluting with dichloromethane:methanol = 7:1 to give compound 47 h (0.5 g).

[0426] (9) 47i (200 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide (4 mL), and cyclohexylethynylene (64 mg, 0.6 mmol), bis(triphenylphosphine)palladium dichloride (28 mg, 0.04 mmol), triethylamine (0.6 mL), and cuprous iodide (8 mg, 0.04 mmol) were added. The mixture was stirred at 105 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (150 mL) and extracted with water (50 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by thin-layer chromatography, eluted with dichloromethane:methanol = 10:1 to give compound 47i (150 mg).

[0427] (10) 47i (150 mg, 0.311 mmol) was dissolved in dichloromethane (10 mL), and pentamethylbenzene (0.92 mg, 0.622 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (1.86 mL, 1.86 mmol) was slowly added. The mixture was stirred at -78 °C for 20 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by reverse-phase column chromatography to give compound 47 (33.33 mg).

[0428] Example 43

[0429]

[0430] Synthesis route:

[0431]

[0432] (1) Compound 2-ethynyl-2-methylcyclohexane-1-ol 48a (100 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide (8 mL) and triethylamine (1.2 mL), and 38a (286 mg, 0.60 mmol), bis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol) and cuprous iodide (11 mg, 0.06 mmol) were added. The mixture was stirred at 60 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (200 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography, and eluted with dichloromethane:methanol = 6:1 to give compound 48b (140 mg).

[0433] (2) Compound 48b (40 mg, 0.082 mmol) was dissolved in dichloromethane (5 mL), and pentamethylbenzene (24 mg, 0.164 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (0.49 mL, 0.49 mmol) was slowly added. The mixture was stirred at -78 °C for 40 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by alkaline reverse-phase method to give compound 48 (9.45 mg).

[0434] Example 44

[0435]

[0436] Synthesis route:

[0437]

[0438] (1) int3 (500 mg, 1.16 mmol) was dissolved in diisopropylamine (10 mL), and 5-ethynyl-2-isopropylpyridine 9b (505 mg, 3.48 mmol), bis(triphenylphosphine) palladium dichloride (81 mg, 0.116 mmol), and cuprous iodide (22 mg, 0.116 mmol) were added. The mixture was stirred at 100 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (1000 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography, and eluted with dichloromethane:methanol = 15:1 to give compound 49a (130 mg).

[0439] (2) 49a (230 mg, 0.47 mmol) was dissolved in dichloromethane (5 mL), and pentamethylbenzene (139 mg, 0.94 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (2.82 mL, 2.82 mmol) was slowly added. The mixture was stirred at -78 °C for 15 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by reverse-phase column chromatography to give compound 49 (2.85 mg).

[0440] Example 45

[0441]

[0442] Synthesis route:

[0443]

[0444] (1) Compound 50a (40 mg, 0.158 mmol) was dissolved in N,N-dimethylformamide (4 mL) and triethylamine (0.6 mL), and 38a (50 mg, 0.105 mmol), bis(triphenylphosphine)palladium dichloride (7 mg, 0.0105 mmol) and cuprous iodide (2 mg, 0.0105 mmol) were added. The mixture was stirred at 100 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (200 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography, and eluted with dichloromethane:methanol = 8:1 to give compound 50b (30 mg).

[0445] (2) 50b (180 mg, 0.3 mmol) was dissolved in dichloromethane (10 mL), and pentamethylbenzene (90 mg, 0.6 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (1.8 mL, 1.8 mmol) was slowly added. The mixture was stirred at -78 °C for 40 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by reverse-phase column chromatography to give compound 50 (9.38 mg).

[0446] Example 46

[0447]

[0448] Synthesis route:

[0449]

[0450] (1) 38a (50 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1 mL), and cyclohexylacetylene (16 mg, 0.15 mmol), bis(triphenylphosphine)palladium dichloride (7 mg, 0.01 mmol), ultra-dry triethylamine (31 mg, 0.30 mmol), and cuprous iodide (2 mg, 0.01 mmol) were added. The mixture was stirred at 100 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (100 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by TLC, and eluted with dichloromethane:methanol = 10:1 to give compound 51a (40 mg).

[0451] (2) 51a (40 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL), and pentamethylbenzene (12 mg, 0.08 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (0.38 mL, 0.38 mmol) was slowly added. The mixture was stirred at -78 °C for 20 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by reverse-phase column chromatography to give compound 51 (6.04 mg).

[0452] Example 47

[0453]

[0454] Synthesis route:

[0455]

[0456] (1) Compound 2-ethynyl-5-isopropylpiperidine-1-carboxylic acid tert-butyl ester (540 mg, 2.15 mmol) was dissolved in N,N-dimethylformamide (6 mL) and triethylamine (0.9 mL), and 38a (233 mg, 1.43 mmol), bis(triphenylphosphine) palladium dichloride (56 mg, 0.14 mmol) and cuprous iodide (15 mg, 0.14 mmol) were added. The mixture was stirred at 60 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (200 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography, and eluted with dichloromethane (8:1) to give compound 52a (140 mg).

[0457] (2) Compound 52a (140 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL), and pentamethylbenzene (69.3 mg, 0.47 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (1.4 mL, 1.38 mmol) was slowly added. The mixture was stirred at -78 °C for 20 minutes. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The concentrate was purified by alkaline reverse-phase method to give compound 52 (13 mg).

[0458] Example 48

[0459]

[0460] Synthesis route:

[0461]

[0462] (1) Compound 4-ethynyl-2-isopropylpiperidine-1-carboxylic acid tert-butyl ester 53a (160 mg, 0.64 mmol) was dissolved in N,N-dimethylformamide (6 mL) and triethylamine (0.9 mL), and 38a (233 mg, 0.49 mmol), bis(triphenylphosphine) palladium dichloride (34 mg, 0.049 mmol) and cuprous iodide (9 mg, 0.049 mmol) were added. The mixture was stirred at 60 °C for 16 h under nitrogen protection in a sealed tube, and the reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (200 mL), repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting concentrate was purified by silica gel column chromatography, and eluted with dichloromethane (8:1) to give compound 53b (300 mg).

[0463] (2) Compound 53b (340 mg, 0.57 mmol) was dissolved in dichloromethane (7 mL), and pentamethylbenzene (169 mg, 1.14 mmol) was added. The mixture was cooled to -78 °C, and then boron trichloride (3.4 mL, 3.42 mmol) was slowly added. The mixture was stirred at -78 °C for 20 min. The reaction was monitored by LCMS. The filtrate was concentrated under vacuum. The resulting concentrate was purified by alkaline reverse-phase method to obtain compound 53 (9.96 mg).

[0464] Various embodiments 1 The H NMR and MS data are shown in the table below:

[0465] Table 1: 1 H NMR and MS data

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475] Biological test data

[0476] In vitro PTPN2 enzymatic experiment

[0477] A. Main materials and reagents: Human PTPN2 protein (10570-HNCB, Sino Biological), Phosphatase Assay Kit (E12020, Invitrogen), DMSO (D8418, Sigma)

[0478] Consumables: 96-well polypropylene microplates (249944, Nunc), 384-well microplates (784075, Greiner); Instruments: Microplate shaker (QB-9002, Qilinbeier), centrifuge (5804R, Eppendorf), Vivtor Nivo 35 multi-plate reader (PerkinElmer), vortex mixer (MS3 digital, IKA).

[0479] B. Method Principle: This method aims to evaluate the ability of compounds to inhibit PTPN2 phosphatase activity. The assay is based on the fact that PTPN2 phosphatase can remove the phosphate group from the substrate DIFMUP, generating the fluorescent product DIFMU; the enzyme activity of PTPN2 is then determined by measuring the change in fluorescence intensity of the system. Under the action of the compound, the weaker the fluorescence signal, the lower the PTPN2 phosphatase activity, indicating a higher inhibitory activity of the compound against PTPN2 tyrosine phosphatase.

[0480] Test Procedure: The compound was dissolved in DMSO to obtain a 10 mM stock solution. The stock solution was diluted with DMSO in a 96-well plate to a final initial concentration of 10 μM, resulting in 10 concentration points. The diluted compound was transferred to a 384-well plate using an Echo 550 (100 nmL per well). The plate was then sealed and centrifuged at 1000 rpm for 1 min. A 2X PTPN2 solution was prepared using analysis buffer and added to each well (10 μL), and centrifuged at 1000 rpm for 1 min. A 2X DIFMUP solution was prepared using analysis buffer and added to each well to initiate the reaction (10 μL per well). After 1 h of reaction, the fluorescence signal was read using a Vivtor Nivo 35 multi-plate reader. The signal intensity was used to characterize the phosphatase activity.

[0481] Data Analysis: Phosphatase activity data are expressed as a comparison between the enzyme activity containing the test compound and the enzyme activity of the blank group (containing only DMSO). IC50 values ​​were obtained by curve fitting using Prism software (GraphPad 8.0). The experimental results are shown below. Experimental Results:

[0482] Table 2 Results of in vitro activity assays for protein tyrosine phosphatase

[0483]

[0484]

[0485] Conclusion: The compounds of this invention have strong inhibitory activity against protein tyrosine phosphatase.

[0486] This document uses examples to illustrate the principles and implementation methods of the present invention. These examples are merely illustrative and not intended to limit the scope of the invention. It should be noted that those skilled in the art can make various improvements and modifications to the invention without departing from its principles, and these improvements and modifications also fall within the scope of the claims.

Claims

1. A compound of the formula: ###0001### or a pharmaceutically acceptable salt thereof. wherein Ring A is selected from , , , , , , , ; said ring A is optionally substituted 1 to 3 times with R a ; R1is selected from the group consisting of -H, -F, -Cl, -CH3, -CH2CH3, -CH(CH3)CH3, -OCH3, -cyclopropyl; said R1may be optionally substituted 1 to 3 times with R a substituents; R2is selected from H, NH2, OH, halogen, SH, CN, oxo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, NH-C 1~6 alkyl, NH-C 2~6 alkenyl, NH-3-6 membered cycloalkyl, NH-5-6 membered heteroaryl, NH-CH2-3-6 membered cycloalkyl, C 1~3 alkyl-3-6 membered cycloalkyl, C 2~4 alkenyl-3-6 membered cycloalkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-7 membered aryl, 5-7 membered heteroaryl, said C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, amine, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-7 membered aryl, 5-7 membered heteroaryl, optionally substituted 1-3 times with R b ; any carbon atom in said C 1~6 alkyl can optionally be replaced with a nitrogen or a sulfur atom, where valency permits; n is selected from 1, 2 and 3; R a independently selected from H, F, CI, CN, OH, C 1~3 alkyl and C 1~3 alkoxy; R b independently selected from F, Cl, Br, I, NH2, OH, SH, C 1-6 alkyl, C 1-3 alkoxy and CN, said C 1~6 alkyl and C 1~3 alkoxy is optionally substituted 1 to 3 times with halogen; and any carbon atom in said C 1~6 alkyl is optionally replaced with a nitrogen atom or a sulfur atom, where valence permits.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R2is selected from -H, -NH2, -OH, -CH3, -CH2CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -C(CH3)3, -CH(CH3)2, -CH2CH2CH3, -CH2CH2CH(CH3)2, -CH2C(CH3)2CH2OH, -CH2C(CH3)2OH, -OCH(CH3)2, -NHCH(CH3)2, -OCH3, -NHCH3, -OCH2CH3, -NHCH2CH3, , , , .

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

4. A compound or pharmaceutically acceptable salt thereof: , , , , , , , , , , , , , .

5. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the inhibition of a protein tyrosine phosphatase.

6. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of a disease or condition mediated by a protein tyrosine phosphatase and related diseases or conditions.

7. Use according to claims 5 to 6, wherein the disease or condition mediated by a protein tyrosine phosphatase is a cancer or a tumor selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor and hepatocellular carcinoma.

8. Use according to claims 5 to 6, wherein the disease or condition mediated by a protein tyrosine phosphatase is a metabolic disease selected from the group consisting of diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, metabolic syndrome, phenylketonuria, atherosclerosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease and liver fibrosis.

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