Pyrazolo[1,5-a]pyrimidine derivatives, their preparation methods and uses

Abstract

This invention relates to the pyrazolo[1,5-a]pyrimidine derivative of Formula I, its preparation method, and its uses. It can be used as a PI3Kα inhibitor to treat cancers caused by dysregulation of the PI3Kα signaling pathway, such as breast cancer, lung cancer, or rectal cancer. Furthermore, the preparation method of this compound is simple and it has certain application prospects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to pyrazolo[1,5-a]pyrimidine derivatives, their preparation methods, and uses. Background Technology

[0002] Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates the lipid signaling PIP2 to PIP3. The PIP3 signaling molecule recruits proteins with PIP3 homology (PH) domains to the plasma membrane, such as Akt in the PI3K / Akt / mTOR signaling pathway. The PI3K signaling pathway is one of the most frequently activated pathways in human cancer, affecting nearly 50% of malignancies. The PI3Kα, β, and δ subtypes in class IA are closely associated with cancer, playing important roles in regulating various physiological activities such as cell growth, proliferation, migration, differentiation, metabolism, and apoptosis by influencing numerous downstream effectors. Mutations activating the PIK3CA gene, including those encoding the p110a catalytic subunit of the PI3Kα gene and those inhibiting the tumor suppressor PTEN (a lipid phosphatase that dephosphorylates PIP3, thereby antagonizing PI3Kα), are the second and third most common mutations in cancer. Furthermore, dysregulation of the PI3Kα signaling pathway is often associated with tumorigenesis and drug resistance, making PI3Kα a crucial target in drug development. However, despite extensive research on this target over the past two decades, clinical outcomes for solid tumor treatments based on PI3K inhibitors have so far fallen far short of expectations. The main reasons include drug resistance, such as PTEN inhibition, and intolerable toxicity due to lack of specificity. Encouragingly, in May 2019, the FDA approved the first PI3Kα-targeted therapy for breast cancer (Novartis' Alpelisib). The successful launch of this drug clinically demonstrates the vital role of the PI3Kα target in tumor development and progression. Therefore, PI3Kα has become a highly promising anti-tumor target, and finding highly effective, novel, and selective PI3Kα inhibitors is a crucial strategy in current targeted cancer drug development. Summary of the Invention

[0003] To solve the above-mentioned technical problems, the present invention first provides pyrazolo[1,5-a]pyrimidine derivatives of Formula I, including their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof:

[0004]

[0005] R1 is selected from H, halogen, or C. 1-12 alkyl;

[0006] A is selected from unsubstituted or arbitrarily assigned to one, two or more R.A The following groups are substituted: C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 3-20 cycloalkyl, C 6-20 aryl 3-20 membered heterocyclic groups or C 6-20 Aryl benzo[C] 3-20 cycloalkyl;

[0007] R A Independently selected from =O, halogen, hydroxyl, cyano, amino, and unsubstituted or optionally surrounded by one, two or more R groups. B The following groups are substituted: C 1-12 Alkyl, Halogenated C 1-12 Alkyl, -NH-C 1-12 Alkyl, -N(C) 1-12 Alkyl)2, C 1-12 Alkoxy, C 3-12 cycloalkyl groups, 3-12 membered heterocyclic groups;

[0008] R B Independently selected from: =O, halogen, hydroxyl, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, -NH-C 1-12 Alkyl, -N(C) 1-12 Alkyl)2;

[0009] B is a 3-12 membered heterocyclic group substituted with -CO-NH2, -OC 1-6 Alkyl-CO-NH2.

[0010] According to an embodiment of the present invention, R1 is selected from H, F, Cl or C. 1-6 alkyl;

[0011] In some embodiments of the present invention, B may be... (For example ), -O-CH2-CO-NH2, -O-CH2-CH2-CO-NH2, -O-CH(CH3)-CO-NH2.

[0012] In some embodiments of the present invention, A is selected from unsubstituted or optionally replaced by one, two or more R. A The following groups are substituted: C6- 12 Aryl, 5-12 heteroaryl, C 6-12 aryl 3-6 membered heterocyclic group or C 6-12 Aryl benzo[C] 3-6 cycloalkyl;

[0013] In some embodiments of the present invention, R AIndependently selected from =O, halogen, hydroxyl, cyano, amino, and unsubstituted or optionally surrounded by one, two or more R groups. B The following groups are substituted: C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NH-C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups;

[0014] R B Independently selected from =O, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkyl group.

[0015] In some embodiments of the present invention, R1 is selected from H or methyl; in some embodiments of the present invention,

[0016] A is selected from the following groups: For example Wherein, X is CR7 or N, Y is CH or N, and Z is -CH2-, O, or -NH-; R2, R3, R4, R5, R6, and R7 may be the same or different, and are independently selected from: hydrogen, halogen, hydroxyl, cyano, amino, unsubstituted, or optionally replaced by one, two, or more R groups. C The following groups are substituted: C 1-12 Alkyl, Halogenated C 1-12 Alkyl, -NH-C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups; R C Independently selected from: =O, halogen, hydroxyl, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, -NH-C 1-12 Alkyl, -N(C) 1-12 Alkyl group 2; or, R5 and R6 together form =O;

[0017] In some embodiments of the present invention, A is selected from unsubstituted or optionally replaced by one, two or more R. A The following groups are substituted: phenyl, pyridyl, pyrimidinyl, isoindolinyl, indanyl;

[0018] In some embodiments of the present invention, R A Selected from =O, methyl, hydroxy, tert-butyl, methoxy, trifluoromethyl, 2-trifluoromethylpropyl, 2-cyanopropyl, 1-cyanocyclopropyl, 2-pyrrolidone, 2-oxazolidinone, 2-hydroxyethylamino, 2-hydroxypropyl, 2-methoxypropyl, N-heterocyclic butyl, N-heterocyclic pentyl The asterisk (*) indicates a connection point.

[0019] As an example, the compound is selected from the following:

[0020]

[0021]

[0022]

[0023] The present invention also provides a method for preparing the pyrazolo[1,5-a]pyrimidine derivative as shown in Formula I above, comprising the following steps:

[0024]

[0025] The reaction of compound Ia with compound Ib yields the compound shown in formula I;

[0026] Among them, R1, A, and B groups have the above definitions; X is a leaving group.

[0027] The present invention also provides the use of pyrazolo[1,5-a]pyrimidine derivatives of Formula I, their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof as PI3Kα inhibitors.

[0028] The present invention also provides the use of pyrazolo[1,5-a]pyrimidine derivatives of Formula I or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating cancer.

[0029] According to an embodiment of the present invention, the cancer is selected from cancers caused by dysregulation of the PI3Kα signaling pathway, such as breast cancer, lung cancer, or rectal cancer.

[0030] The present invention also provides a pharmaceutical composition comprising a pyrazolo[1,5-a]pyrimidine derivative of Formula I as described above, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

[0031] According to embodiments of the present invention, the pharmaceutical composition is used to treat cancers caused by dysregulation of the PI3Kα signaling pathway, such as breast cancer, lung cancer, or rectal cancer.

[0032] According to embodiments of the present invention, the pharmaceutical composition may optionally include one, two or more pharmaceutically acceptable excipients; said excipients include one, two or more of fillers, binders, disintegrants, lubricants, flavoring agents, enteric coatings or sustained-release materials.

[0033] Beneficial effects

[0034] This invention provides a novel pyrazolo[1,5-a]pyrimidine derivative, its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, which can be used as PI3Kα inhibitors to treat cancers caused by dysregulation of the PI3Kα signaling pathway, such as breast cancer, lung cancer, or rectal cancer. Furthermore, the compound is simple to prepare and has promising applications.

[0035] Terms and Definitions

[0036] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of protection of this application.

[0037] "More than three" means three or more types.

[0038] Term "C" 1-12 "alkyl" should be understood to refer to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably C12. 1-10 Alkyl group. "C" 1-10 "Alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc., or isomers thereof. In particular, the group has 1, 2, 3, 4, 5, 6, or 10 carbon atoms ("C"). 1-6 Alkyl groups, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, and more particularly, the groups having 1, 2, or 3 carbon atoms (“C”). 1-3 Alkyl), such as methyl, ethyl, n-propyl or isopropyl.

[0039] Term "C" 3-20 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic, bicyclic, or polycyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C". 3-10 cycloalkyl. The term "C" 3-10"Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as decahydronaphthalene ring.

[0040] The term "3-20 membered heterocyclic group" should be understood to refer to a saturated monovalent monocyclic, bicyclic, or polycyclic hydrocarbon or bridged cyclic alkane containing 1-5 heteroatoms independently selected from N, O, and S, forming a non-aromatic cyclic group with a total number of ring atoms of 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.), preferably "3-10 membered heterocyclic group". The term "3-12 membered heterocyclic group" refers to a saturated monovalent monocyclic, bicyclic, or bridged cyclic alkane containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S, for example, 1, 2, or 3 heteroatoms independently selected from N, O, and S. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). Specifically, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azirrobutyl and oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The nitrogen-containing ring can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic group is non-aromatic. When the 3-20 membered heterocyclic group is linked to other groups to form the compounds of the invention, the carbon atom on the 3-20 membered heterocyclic group can be linked to other groups, or the heterocyclic atom on the 3-20 membered heterocyclic ring can be linked to other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazine, the nitrogen atom on the piperazine group can be linked to other groups. Or when the 3-20 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and its para-carbon atom can be linked to other groups.

[0041] Term "C" 6-20 "Aryl" should be understood as representing a monocyclic, bicyclic, or tricyclic hydrocarbon ring with 6 to 20 carbon atoms that is monovalent and partially aromatic, preferably "C".6-14 "Aromatic". The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene.

[0042] The term "5-20-membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, including aromatic or partially aromatic systems. For example, "5-14-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O, and S, and in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylinyl, inazinyl, purinyl, and their benzo[derivatives]; or terpenolyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, etc. When the 5-20 membered heteroaryl group is linked with other groups to form the compound of the present invention, the carbon atom on the 5-20 membered heteroaryl ring may be linked with other groups, or the heteroatom on the 5-20 membered heteroaryl ring may be linked with other groups. When the 5-20 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, the hydrogen atom linked to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen atom linked to the heteroatom on the heteroaryl ring may be substituted.

[0043] Unless otherwise stated, heterocyclic, heteroaryl, or heteroaryl groups include all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, they may include forms in which one, two, or more of their positions (if present) are substituted or bonded to other groups, such as pyridyl or pyridylene groups including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophenyl or thiopheneyl groups including thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; and pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0044] “C 1-12 "Alkoxy" indicates -OC 1-12 Alkyl, wherein C 1-12 Alkyl groups have the definition described above.

[0045] -NH-C 1-12 C in "alkyl" 1-12 Alkyl groups have the definition described above.

[0046] The term "halogen" refers to F, Cl, Br, and I.

[0047] The term "halogenated" refers to substitution by F, Cl, Br, and I. Detailed Implementation

[0048] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0049] Unless otherwise stated, the compounds and reagents used in the following examples are commercially available or can be prepared by known methods.

[0050] EA: Ethyl acetate

[0051] PE: Petroleum ether

[0052] DCM: Dichloromethane

[0053] NBS: N-bromosuccinimide

[0054] Pd(dppf)Cl2: 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride

[0055] Example 1

[0056]

[0057] Step 1: Compound A1 (1.65 g, 10 mmol) and Compound A2 (1.51 g, 10 mmol) were placed in a reaction flask, and dioxane (20 mL) and N,N-diisopropylethylamine (1.29 g, 10 mmol) were added. The mixture was stirred overnight at ambient temperature. Acetic acid (1.2 g, 20 mmol) and Compound A3 (970 mg, 10 mmol) were added. After the addition was complete, the mixture was stirred overnight at 80 °C. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 70:30) to obtain a pale yellow oil, which was Compound A4 (100 mg, 4%).

[0058] Step 2: Compound A4 (100 mg, 0.44 mmol) was placed in a reaction flask, DCM (3 mL) was added, and NBS (78 mg, 0.44 mmol) was added at 0 °C. After the addition was complete, the mixture was stirred at this temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 80:20) to obtain a yellow oily substance, which was compound A5 (96 mg, 65%).

[0059] Step 3: Compound A5 (96 mg, 0.3 mmol), phenylboronic acid A1-1 (73 mg, 0.36 mmol), potassium carbonate (138 mg, 1 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg) were placed in a reaction flask, and dioxane (5 mL) and water (0.5 mL) were added. The mixture was stirred in a microwave at 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A1-2 (90 mg, 93%).

[0060] Step 4: Place compound A1-2 (90 mg) in a sealed tube, add 5 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 91:9) to obtain a yellow solid, which is the target compound (35 mg, 45%). 1H NMR (500MHz, DMSO-d6) δ8.48(s,1H),8.36(d,J=2.4Hz,1H),8.10(dd,J=11.3,5.0Hz,3H),7.57(d,J=17.8Hz,1H),7.40(t,J=7.6Hz,2H),7.24–7. 17(m,2H),4.17(d,J=7.5Hz,1H),3.64–3.57(m,1H),3.30(dd,J=15.5,7 .6Hz,1H),2.26(dt,J=11.6,8.5Hz,1H),2.05–1.94(m,3H);MS:m / z[M+1] + =308.14.

[0061] Example 2

[0062]

[0063] Step 1: Compound A1 (82.5 g, 0.5 mol) and Compound A2 (75.5 g, 0.5 mol) were placed in a reaction flask, and dioxane (1.2 L) and N,N-diisopropylethylamine (174 mL, 1 mol) were added. The mixture was stirred overnight at ambient temperature. Acetic acid (60 mL, 1 mol) and Compound A3 (41.5 g, 0.5 mol) were added. After the addition was complete, the mixture was stirred overnight at 80 °C. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with EA (1 L * 3) / H2O (1 L), and the organic phases were combined. The mixture was washed with saturated NaHCO3 solution and saturated brine, dried, filtered, and purified by column chromatography (PE:EA = 70:30) to obtain a yellow solid, which was Compound A4 (12.3 g, 10%).

[0064] Step 2: Compound A4 (12.3 g, 50 mmol) was placed in a reaction flask, DCM (300 mL) was added, and NBS (10.7 g, 60 mmol) was added at 0 °C. After the addition was complete, the mixture was stirred at this temperature for 3 h. After the reaction was completed, the mixture was extracted with DCM (500 mL * 3) / H2O (500 mL), the organic phases were combined, washed with saturated NaHCO3 solution, washed with saturated brine, dried, filtered, and purified by column chromatography (PE:EA = 80:3 = 20) to obtain a yellow solid, which was compound A5 (10.5 g, 65%).

[0065] Step 3: Compound A5 (97 mg, 0.3 mmol), compound A2-1 (73 mg, 0.36 mmol), potassium carbonate (138 mg, 1 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg) were placed in a reaction flask, and dioxane (5 mL) and water (0.5 mL) were added. The mixture was stirred in a microwave at 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A2-2 (90 mg, 93%).

[0066] Step 4: Place compound A2-2 (90 mg) in a sealed tube, add 5 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 91:9) to obtain a yellow solid, which is the target compound (35 mg, 45%). 1 H NMR(500MHz,DMSO-d6)δ8.68(s,1H),8.53(s,1H),8.52(s,1H),8.41(d,J=2.6Hz,1H),8.19(d,J=2.5Hz,1H),8.06(s,1H),8.05(s,1H),7.60(s,1H ),7.22(s,1H),4.23–4.17(m,1H),3.63–3.57(m,1H),3.32–3.28(m,1H), 2.26(tt,J=16.3,8.2Hz,1H),2.01(td,J=14.0,6.1Hz,3H); MS:m / z[M+1] + =309.15.

[0067] Example 3

[0068]

[0069] Step 1: Compound A5 (97 mg, 0.3 mmol), compound A3-1 (73 mg, 0.36 mmol), potassium carbonate (138 mg, 1 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg) were placed in a reaction flask, and dioxane (5 mL) and water (0.5 mL) were added. The mixture was stirred in a microwave at 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A3-2 (90 mg, 93%).

[0070] Step 2: Place compound A3-2 (90 mg) in a sealed tube, add 5 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 91:9) to obtain a yellow solid, which is the target compound (35 mg, 45%). 1 H NMR(500MHz,DMSO-d6)δ9.28(d,J=1.5Hz,1H),8.58(s,1H),8.43–8.40(m,1H),8.40–8. 38(m,1H),8.37(d,J=2.6Hz,1H),8.15(d,J=2.5Hz,1H),7.60(s,1H),7.41(dd,J=7.8,4 .8Hz,1H),7.22(s,1H),4.21–4.16(m,1H),3.60(dt,J=7.9,5.4Hz,1H),3.30(dd,J=15. 7,7.6Hz,1H),2.26(tt,J=15.5,7.8Hz,1H),2.07–1.94(m,3H); MS: m / z[M+1]+=309.15.

[0071] Example 4

[0072]

[0073] Step 1: Place compound A4-1 (424 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add 1,4-dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0074] Step 2: Compound A5 (324 mg, 1 mmol), compound A4-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A4-3 (151 mg, 40%).

[0075] Step 3: Place compound A4-3 (151 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (72 mg, 50%).1 H NMR(500MHz,DMSO-d6)δ8.49(s,1H),8.37(d,J=2.4Hz,1H),8.15(s,1H),8.11(d, J=2.3Hz,1H),7.87(d,J=7.6Hz,1H),7.59(s,1H),7.32(t,J=7.7Hz,1H),7.25–7.1 9(m,2H),4.20–4.14(m,1H),3.63–3.57(m,1H),3.33–3.28(m,1H),2.27(dd,J=18 .2, 9.8Hz, 1H), 2.00 (dd, J = 14.4, 7.9Hz, 3H), 1.34 (s, 9H); MS: m / z [M+1]+ = 364.21.

[0076] Example 5

[0077]

[0078] Step 1: Place compound A5-1 (374 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0079] Step 2: Compound A5 (324 mg, 1 mmol), compound A5-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A5-3 (140 mg, 40%).

[0080] Step 3: Place compound A5-3 (140 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (67 mg, 50%). 1H NMR (500MHz, DMSO-d6) δ8.65(s,1H),8.40(s,1H),8.16(s,1H),8.12(d,J=5. 4Hz,1H),7.66(d,J=5.3Hz,1H),7.60(s,1H),7.54(s,1H),7.22(s,1H),4.19 (d,J=7.8Hz,1H),3.86(s,3H),3.60(dd,J=8.7,5.0Hz,1H),3.30(dd,J=15.6 ,7.7Hz,1H),2.30–2.22(m,1H),2.01(dd,J=16.0,10.7Hz,3H);MS:m / z[M+1] + =339.15.

[0081] Example 6

[0082]

[0083] Step 1: Place compound A6-1 (426 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0084] Step 2: Compound A5 (324 mg, 1 mmol), compound A6-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A6-3 (151 mg, 39%).

[0085] Step 3: Place compound A6-3 (151 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (75 mg, 52%). 1H NMR(500MHz,DMSO-d6)δ8.70(s,1H),8.46(d,J=5.2Hz,1H),8.43(d,J=2.6Hz ,1H),8.18(d,J=2.5Hz,1H),8.14(s,1H),7.86(dd,J=5.1,1.3Hz,1H),7.60(s ,1H),7.21(s,1H),4.22–4.19(m,1H),3.62–3.58(m,1H),3.30(d,J=6.2Hz,1H ),2.26(tt,J=16.8,8.4Hz,1H),2.07–1.96(m,3H),1.36(s,9H); MS:m / z[M+1] + =365.21.

[0086] Example 7

[0087]

[0088] Step 1: Place compound A7-1 (1.1 g, 4 mmol), pinacol diboronate (1.2 g, 4.8 mmol), KOAc (784 mg, 8 mmol), and Pd(dppf)Cl2 (500 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0089] Step 2: Compound A5 (324 mg, 1 mmol), compound A7-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A7-3 (134 mg, 30%).

[0090] Step 3: Place compound A7-3 (134 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (70 mg, 56%). 1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.55(d,J=5.2Hz,1H),8.45(d,J=2.6H z,1H),8.36(s,1H),8.21(d,J=2.5Hz,1H),8.03(d,J=5.2Hz,1H),7.59(s,1H ),7.22(s,1H),4.25–4.20(m,1H),3.64–3.58(m,1H),3.31(d,J=7.9Hz,1H) ,2.27(tt,J=16.6,8.4Hz,1H),2.07–1.97(m,3H),1.64(s,6H);MS:m / z[M+1] + =419.18.

[0091] Example 8

[0092]

[0093] Step 1: Compound A1 (82.5 g, 0.5 mol) and compound A2 (75.5 g, 0.5 mol) were placed in a reaction flask, and dioxane (1.2 L) and N,N-diisopropylethylamine (174 mL, 1 mol) were added. The mixture was stirred overnight at ambient temperature. Acetic acid (60 mL, 1 mol) and compound B3 (48.5 g, 0.5 mol) were added. After the addition was complete, the mixture was stirred overnight at 80 °C. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with EA (1 L * 3) / H2O (1 L), the organic phases were combined, washed with saturated NaHCO3 solution and saturated brine, dried, filtered, and purified by column chromatography (PE:EA = 70:30) to obtain a yellow solid, which was compound B4 (13.1 g, 10%).

[0094] Step 2: Compound B4 (13g, 50mmol) was placed in a reaction flask, DCM (300mL) was added, and NBS (10.7g, 60mmol) was added at 0℃. After the addition was complete, the mixture was stirred at this temperature for 3 hours. After the reaction was completed, the mixture was extracted with DCM (500mL*3) / H2O (500mL), the organic phases were combined, washed with saturated NaHCO3 solution, washed with saturated brine, dried, filtered, and purified by column chromatography (PE:EA = 80:3 = 20) to obtain a yellow solid, which was compound B5 (13.2g, 78%).

[0095] Step 3: Compound B5 (338 mg, 1 mmol), compound A7-2, potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask, and dioxane (5 mL) and water (1.5 mL) were added. The mixture was stirred in a microwave at 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A8-1 (138 mg, 31%).

[0096] Step 4: Place compound A8-1 (138 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (82 mg, 60%). 1 H NMR (500MHz, DMSO-d6) δ8.58(d,J=5.2Hz,1H),8.34(d,J=2.7Hz,1H),8.11(d,J= 2.6Hz,1H),8.10(s,1H),7.77(dd,J=5.2,1.3Hz,1H),7.59(s,1H),7.21(s,1H),4 .18–4.14(m,1H),3.58(dd,J=13.7,5.4Hz,1H),3.31–3.26(m,1H),2.59(s,3H),2 .29–2.22(m,1H),2.01(ddd,J=18.0,12.0,7.3Hz,3H),1.63(s,6H);MS:m / z[M+1] + =433.19.

[0097] Example 9

[0098]

[0099] Step 1: Place compound A9-1 (450 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0100] Step 2: Compound A5 (324 mg, 1 mmol), compound A9-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A9-3 (131 mg, 33%).

[0101] Step 3: Place compound A9-3 (131 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (80 mg, 64%). 1 H NMR (500MHz, DMSO-d6) δ8.83(s,1H),8.67(d,J=5.2Hz,1H),8.57(s,1H),8.48(d,J=2.6Hz,1H),8.30(d,J=5.0Hz,1H),8.22(d,J=2.6Hz,1H),7.60(s ,1H),7.23(s,1H),4.24–4.20(m,1H),3.63–3.57(m,1H),3.33–3.29(m,1H ),2.27(tt,J=16.5,8.4Hz,1H),2.02(td,J=14.3,6.2Hz,3H); MS:m / z[M+1] + =377.13.

[0102] Example 10

[0103]

[0104] Step 1: Compound A10-1 (1.06 g, 6 mmol) and isobutyronitrile (0.54 mL, 6 mmol) were placed in a reaction flask, and anhydrous THF (15 mL) was added. LiHMDS (6 mL, 6 mmol) was added at 0 °C, and the mixture was stirred at this temperature for 2 h. The reaction was quenched with saturated NH4Cl solution, followed by extraction with H2O (50 mL) / EA (50 mL * 3), washing with saturated brine, and drying. Column chromatography (PE:EA = 90:10) yielded a colorless oil, which was compound A10-2 (500 mg, 37%).

[0105] Step 2: Place compound A10-2 (450 mg, 2 mmol), pinacol diboronate (600 mg, 2.4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100°C. Cool and proceed directly to the next step.

[0106] Step 3: Compound A5 (324 mg, 1 mmol), compound A10-3 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A10-4 (140 mg, 36%).

[0107] Step 4: Place compound A10-4 (140 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (70 mg, 52%). 1 H NMR(500MHz,DMSO-d6)δ8.75(s,1H),8.54(d,J=5.2Hz,1H),8.43(d,J=2.6Hz,1 H),8.30(s,1H),8.21(d,J=2.5Hz,1H),8.03(dd,J=5.2,1.1Hz,1H),7.60(s,1H ),7.22(s,1H),4.24–4.20(m,1H),3.63–3.57(m,1H),3.34–3.28(m,1H),2.27( tt,J=16.1,8.2Hz,1H),2.02(td,J=13.9,6.1Hz,3H),1.75(s,6H);MS:m / z[M+1] + =376.18.

[0108] Example 11

[0109]

[0110] Step 1: Compound A11-1 (1.75 g, 10 mmol) and propionitrile (670 mg, 10 mmol) were placed in a reaction flask, and anhydrous THF (20 mL) was added. LiHMDS (10 mL, 10 mmol) was added at 0 °C, and the mixture was stirred at this temperature for 2 h. The reaction was quenched with saturated NH4Cl solution, extracted with H2O (90 mL) / EA (90 mL * 3), washed with saturated brine, and dried. Column chromatography (PE:EA = 90:10) yielded a white solid, which was compound A11-2 (600 mg, 27%).

[0111] Step 2: Place compound A11-2 (444 mg, 2 mmol), pinacol diboronate (600 mg, 2.4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100°C. Cool and proceed directly to the next step.

[0112] Step 3: Compound A5 (324 mg, 1 mmol), compound A11-3 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A11-4 (155 mg, 40%).

[0113] Step 4: Place compound A11-4 (155 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (75 mg, 50%). 1 H NMR(500MHz,DMSO-d6)δ8.71(s,1H),8.44–8.40(m,2H),8.33(s,1H),8.20( d,J=2.2Hz,1H),7.90(d,J=5.2Hz,1H),7.62(s,1H),7.22(s,1H),4.23(d,J= 8.0Hz,1H),3.63–3.58(m,1H),3.31(d,J=7.3Hz,1H),2.30–2.21(m,1H),2.0 7–1.97(m,3H),1.79(dd,J=7.0,4.3Hz,2H),1.74–1.68(m,2H);MS:m / z[M+1] + =374.17.

[0114] Example 12

[0115]

[0116] Step 1: Place 2-pyrrolidone (850 mg, 10 mmol) in a reaction flask, add 20 mL of dry THF, and add 288 mg, 12 mmol of NaH at 0 °C. After the addition is complete, stir at this temperature for 1 h. Add compound A12-1 (1.75 g, 10 mmol), and stir overnight at ambient temperature. Quench with NH4Cl solution, extract with EA (30 mL * 3) / H2O (30 mL), combine the organic phases, wash with saturated brine, dry, and column chromatography (PE:EA = 60:40) to obtain a white solid, which is compound A12-2 (468 mg, 21%).

[0117] Step 2: Place compound A12-2 (468 mg, 2 mmol), pinacol diboronate (600 mg, 2.4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100°C. Cool and proceed directly to the next step.

[0118] Step 3: Compound A5 (324 mg, 1 mmol), compound A12-3 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A12-4 (175 mg, 43%).

[0119] Step 4: Place compound A12-4 (175 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (70 mg, 41%). 1H NMR(500MHz,DMSO-d6)δ9.00(s,1H),8.56(s,1H),8.40(d,J=2.5Hz,1H),8.32(d ,J=5.3Hz,1H),8.19(d,J=2.4Hz,1H),7.76(d,J=5.2Hz,1H),7.61(s,1H),7.22( s,1H),4.26–4.19(m,1H),4.00(t,J=7.1Hz,2H),3.64–3.56(m,1H),3.34–3.27( m,1H),2.58(t,J=8.0Hz,2H),2.30–2.22(m,1H),2.09–1.96(m,5H); MS:m / z[M+1] + =392.18.

[0120] Example 13

[0121]

[0122] Step 1: Place 2-oxazolidinone (870 mg, 10 mmol) in a reaction flask, add 20 mL of dry THF, and add 288 mg, 12 mmol of NaH at 0 °C. After the addition is complete, stir at this temperature for 1 h. Add compound A13-1 (1.75 g, 10 mmol), and stir at this temperature overnight. Quench with NH4Cl solution, extract with EA (30 mL * 3) / H2O (30 mL), combine the organic phases, wash with brine, dry, and perform column chromatography (PE:EA = 50:50) to obtain a white solid (200 mg, 8%), which is compound A13-2 (487 mg, 22%).

[0123] Step 2: Place compound A13-2 (487 mg, 2 mmol), pinacol diboronate (600 mg, 2.4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100°C. Cool and proceed directly to the next step.

[0124] Step 3: Compound A5 (324 mg, 1 mmol), compound A13-3 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A13-4 (175 mg, 42%).

[0125] Step 4: Place compound A13-4 (175 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (70 mg, 41%). 1 H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.58(s,1H),8.41(d,J=2.1Hz,1H),8.30 (d,J=5.3Hz,1H),8.19(s,1H),7.75(d,J=5.2Hz,1H),7.61(s,1H),7.22(s,1H ),4.46(t,J=8.0Hz,2H),4.20(dd,J=15.2,7.5Hz,3H),3.64–3.57(m,1H),3.3 3–3.29(m,1H),2.30–2.22(m,1H),2.02(dd,J=14.4,10.2Hz,3H);MS:m / z[M+1] + =394.15.

[0126] Example 14

[0127]

[0128] Step 1: Compound A14-1 (8.8 g, 50 mol) and ethyl isobutyrate (6.5 g, 55 mmol) were placed in a reaction flask, and toluene (100 mL) was added. Lithium di(trimethylsilyl)amino(LiHMDS) (110 mL, 110 mmol) was added at 0 °C, and the mixture was stirred overnight at ambient temperature. The mixture was quenched with saturated NH4Cl solution, and extracted with H2O (300 mL) / EA (300 mL * 3). The extract was washed with saturated brine and dried. Column chromatography (PE:EA = 96:4) yielded a yellowish-brown oil, which was compound A14-2 (6 g, 43%).

[0129] Step 2: Compound A14-2 (6g, 22.2mmol) was placed in a reaction flask, and dried DCM (90mL) was added. The mixture was cooled to -20℃, and diisobutylaluminum hydride (DIBAL-H) ​​(66mL, 66mmol) was slowly added. After the addition was complete, the temperature was slowly raised to 0℃, and stirring was continued for 4 hours. The mixture was quenched with saturated NH4Cl solution, and extracted with H2O (500mL) / EA (500mL*3). The extract was washed with saturated brine and dried. Column chromatography (PE:EA = 60:40) yielded a colorless oil, which was compound A14-3 (2g, 38%).

[0130] Step 3: Compound A14-3 (920 mg, 4 mmol) was placed in a reaction flask, DCM (9 mL) was added, and diethylaminotrifluoride DAST (964 mg, 6 mmol) was added. After the addition was complete, the mixture was stirred overnight at this temperature. The reaction was quenched with saturated NaHCO3 solution, and extracted with DCM (30 mL * 3) / H2O (30 mL). The organic phases were combined, washed with saturated brine, dried, and subjected to column chromatography (PE:EA = 80:20) to obtain a colorless oil, which was compound A14-4 (275 mg, 24%).

[0131] Step 4: Place compound A14-4 (275 mg, 1.2 mmol), pinacol diboronate (375 mg, 1.5 mmol), KOAc (352 mg, 3.6 mmol), and Pd(dppf)Cl2 (100 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0132] Step 5: Compound B5 (324 mg, 1 mmol), compound A14-5 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A14-6 (175 mg, 43%).

[0133] Step 6: Place compound A14-6 (175 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (70 mg, 41%). 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=5.2Hz,1H),8.34(d,J=2.6Hz,1H),8.11(d,J=2 .5Hz,1H),7.91(s,1H),7.69–7.65(m,1H),7.58(s,1H),7.19(s,1H),4.69(s,1H) ,4.57(s,1H),4.19–4.12(m,1H),3.59(dd,J=14.0,5.6Hz,1H),3.28(d,J=7.1Hz, 1H),2.60(s,3H),2.33–2.21(m,1H),2.05–1.96(m,3H),1.37(s,6H); MS:m / z[M+1] + =397.21.

[0134] Example 15

[0135]

[0136] Step 1: Compound A15-1 (430 mg, 2 mmol) was placed in a reaction flask, and DCM (15 mL), dihexyl phthalate (DHP) (840 mg, 10 mmol), and pyridine p-toluenesulfonate (PPTS) (10 mg, 0.4 mmol) were added. After the addition was complete, the mixture was stirred overnight at ambient temperature. The reaction was quenched with NaHCO3 solution, and extracted with DCM (40 mL * 3) / H2O (40 mL). The organic phases were combined, washed with saturated brine, dried, and subjected to column chromatography (PE:EA = 80:20) to obtain a colorless oily substance, which was compound A15-2 (400 mg, 67%).

[0137] Step 2: Place compound A15-2 (400 mg, 1.3 mmol), pinacol diboronate (390 mg, 1.6 mmol), KOAc (382 mg, 3.9 mmol), and Pd(dppf)Cl2 (100 mg) in a reaction flask, add dioxane (15 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0138] Step 3: Compound A5 (324 mg, 1 mmol), compound A15-3 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (100 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A15-4 (150 mg, 21%).

[0139] Step 4: Compound A15-4 (100 mg, 0.22 mmol) was added to EtOH (3 mL) and PPTS (5 mg, 0.02 mmol), and refluxed for 1 h. Saturated NaHCO3 solution was added, and the mixture was extracted with DCM (10 mL * 3) / H2O (10 mL). The organic phases were combined, washed with saturated brine, dried, and subjected to column chromatography (DCM:MeOH = 97:3) to obtain a yellow solid, which was compound A15-5 (50 mg, 66%).

[0140] Step 5: Place compound A15-5 (50 mg) in a sealed tube, add 5 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (30 mg, 61%).1 H NMR (500MHz, DMSO-d6) δ8.64(s,1H),8.44(t,J=3.8Hz,2H),8.39(s,1H),8.18(d,J=2.6Hz,1H),7.88(dd,J=5.2,1.5Hz,1H),7.62(s,1H),7.22 (s,1H),5.24(s,1H),4.24–4.19(m,1H),3.63–3.58(m,1H),3.34–3.29( m,1H),2.32–2.21(m,1H),2.07–1.96(m,3H),1.47(s,6H); MS:m / z[M+1] + =367.18.

[0141] Example 16

[0142]

[0143] Step 1: Compound B5 (338 mg, 1 mmol), compound A15-3, potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (100 mg) were placed in a reaction flask, and dioxane (5 mL) and water (1.5 mL) were added. The mixture was stirred in a microwave at 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A16-1 (170 mg, 35%).

[0144] Step 2: Compound A16-1 (170 mg, 0.35 mmol) was added to EtOH (3 mL) and PPTS (5 mg, 0.02 mmol), and refluxed for 1 h. Saturated NaHCO3 solution was added, and the mixture was extracted with DCM (10 mL * 3) / H2O (10 mL). The organic phases were combined, washed with saturated brine, dried, and subjected to column chromatography (DCM:MeOH = 97:3) to obtain a yellow solid, which was compound A16-2 (100 mg, 60%).

[0145] Step 3: Place compound A16-2 (100 mg) in a sealed tube, add 6 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (40 mg, 41%). 1H NMR (500MHz, DMSO-d6) δ8.47(d,J=5.2Hz,1H),8.34(d,J=2.7Hz,1H),8.13(t,J=5.1 Hz,1H),8.10(d,J=2.6Hz,1H),7.67(dd,J=5.2,1.6Hz,1H),7.59(s,1H),7.20(s,1H) ,5.22(s,1H),4.19–4.15(m,1H),3.59(dd,J=8.4,4.8Hz,1H),3.29(dd,J=15.5,7.2H z,1H),2.60(s,3H),2.29–2.22(m,1H),2.05–1.95(m,3H),1.48(s,6H); MS:m / z[M+1] + =381.20.

[0146] Example 17

[0147]

[0148] Step 1: Place compound A17-1 (426 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0149] Step 2: Compound B5 (324 mg, 1 mmol), compound A17-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A17-3 (129 mg, 33%).

[0150] Step 3: Compound A17-3 (129 mg) was placed in a sealed tube, and an ammonia-methanol solution (8 mL) was added. The mixture was stirred at 80 °C for 48 h. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which was the target compound (80 mg, 64%). 1H NMR (400MHz, DMSO-d6) δ8.50(d,J=5.2Hz,1H),8.34(d,J=2.6Hz,1H),8.11(d,J =2.5Hz,1H),7.89(s,1H),7.62–7.59(m,1H),7.57(s,1H),7.18(s,1H),4.18–4. 14(m,1H),3.59(dt,J=10.6,5.4Hz,1H),3.31–3.25(m,1H),2.59(s,3H),2.30– 2.20 (m, 1H), 2.00 (dd, J = 11.0, 5.9Hz, 3H), 1.36 (s, 9H); MS: m / z [M+1]+ = 379.22.

[0151] Example 18

[0152]

[0153] Step 1: Compound A18-1 (1.06 g, 6 mmol) and isobutyronitrile (0.54 mL, 6 mmol) were placed in a reaction flask, and anhydrous THF (15 mL) was added. LiHMDS (6 mL, 6 mmol) was added at 0 °C, and the mixture was stirred at this temperature for 2 h. The reaction was quenched with saturated NH4Cl solution, followed by extraction with H2O (50 mL) / EA (50 mL * 3), washing with saturated brine, and drying. Column chromatography (PE:EA = 90:10) yielded a colorless oil, which was compound A18-2 (500 mg, 37%).

[0154] Step 2: Place compound A18-2 (450 mg, 2 mmol), pinacol diboronate (600 mg, 2.4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100°C. Cool and proceed directly to the next step.

[0155] Step 3: Compound B5 (338 mg, 1 mmol), compound A18-3 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A18-4 (140 mg, 35%).

[0156] Step 4: Place compound A18-4 (140 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (75 mg, 53%). 1 H NMR(500MHz,DMSO-d6)δ8.58(d,J=5.1Hz,1H),8.35(d,J=1.9Hz,1H),8.13(d, J=1.6Hz,1H),8.09(s,1H),7.81(d,J=4.9Hz,1H),7.59(s,1H),7.21(s,1H),4. 17(d,J=7.7Hz,1H),3.59(d,J=7.5Hz,1H),3.29(d,J=7.8Hz,1H),2.62(s,3H), 2.26(dd,J=18.0,9.6Hz,1H),2.00(d,J=6.5Hz,3H),1.75(s,6H);MS:m / z[M+1] + =390.2.

[0157] Example 19

[0158]

[0159] Step 1: Compound A19-1 (215 mg, 1 mmol) was placed in a reaction flask, THF (3 mL) was added, and the mixture was cooled to 0 °C. Then, NaH (31 mg, 1.3 mmol), methyl iodide (168 mg, 1.2 mmol) / THF (0.5 mL) were added, and the mixture was stirred overnight at ambient temperature. The next day, the mixture was quenched with NH4Cl solution, concentrated, and subjected to column chromatography (PE:EA = 70:30) to obtain a colorless oily substance, which was compound A19-2 (130 mg, 58%).

[0160] Step 2: Place compound A19-2 (250 mg, 1.1 mmol), pinacol diboronate (332 mg, 1.3 mmol), KOAc (323 mg, 3.3 mmol), and Pd(dppf)Cl2 (130 mg) in a reaction flask, add dioxane (12 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0161] Step 3: Compound B5 (338 mg, 1 mmol), compound A19-3 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (100 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A19-4 (70 mg, 18%).

[0162] Step 4: Place compound A19-4 (70 mg) in a sealed tube, add 5 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (30 mg, 47%). 1 H NMR(500MHz,DMSO-d6)δ8.51(d,J=5.2Hz,1H),8.35(d,J=2.5Hz,1H),8.11(d,J =2.4Hz,1H),8.00(s,1H),7.69(d,J=5.1Hz,1H),7.59(s,1H),7.20(s,1H),4.1 7(d,J=7.7Hz,1H),3.62–3.57(m,1H),3.32–3.27(m,1H),3.13(s,3H),2.59(s, 3H),2.30–2.21(m,1H),2.00(dd,J=15.3,9.1Hz,3H),1.50(s,6H);MS:m / z[M+1] + =395.21.

[0163] Example 20

[0164]

[0165] Step 1: Compound B5 (339 mg, 1 mmol), compound A20-1 (282 mg, 2 mmol), Na2CO3 (252 mg, 3 mmol), and Pd(dppf)Cl2 (120 mg) were placed in a reaction flask, and dioxane (6 mL) and H2O (0.2 mL) were added. The mixture was stirred in a microwave at 90 °C for 2 h. After concentration, column chromatography (PE:EA = 60:40) yielded a yellow solid, which was compound A20-2 (150 mg, 40%).

[0166] Step 2: Compound A20-2 (90 mg, 0.24 mmol) was placed in a reaction flask, and acetonitrile (3 mL), N,N-diisopropylethylamine (258 mg, 2 mmol), and aziridine (23 mg, 0.4 mmol) were added. After the addition was complete, the mixture was stirred overnight at 90 °C. The solution was concentrated and subjected to column chromatography (DCM:MeOH = 96:4) to obtain a yellow solid, which was compound A20-3 (42 mg, 45%).

[0167] Step 3: Place compound A20-3 (45 mg) in a sealed tube, add 5 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (25 mg, 64%). 1 H NMR(500MHz,DMSO-d6)δ8.29(s,1H),8.08(s,1H),8.05(d,J=5.2Hz,1H),7.58(s,1H ),7.20(s,1H),7.09(d,J=5.0Hz,1H),6.76(s,1H),4.14(d,J=7.9Hz,1H),3.95(t,J =7.2Hz,4H),3.58(d,J=6.7Hz,1H),3.28(d,J=7.7Hz,1H),2.55(s,3H),2.31(dd,J= 14.3, 7.1Hz, 2H), 2.24 (dd, J=18.6, 12.1Hz, 1H), 1.99 (d, J=5.7Hz, 3H); MS: m / z[M+1] + =378.2.

[0168] Example 21

[0169]

[0170] Step 1: Compound B5 (339 mg, 1 mmol), compound A21-1 (282 mg, 2 mmol), Na2CO3 (252 mg, 3 mmol), and Pd(dppf)Cl2 (120 mg) were placed in a reaction flask, and dioxane (6 mL) and H2O (0.2 mL) were added. The mixture was stirred in a microwave at 90 °C for 2 h. After concentration, column chromatography (PE:EA = 60:40) yielded a yellow solid, which was compound A21-2 (150 mg, 40%).

[0171] Step 2: Compound A21-2 (90 mg, 0.24 mmol) was placed in a reaction flask, and acetonitrile (3 mL), DIEA (258 mg, 2 mmol), and tetrahydropyrrole (28 mg, 0.4 mmol) were added. After the addition was complete, the mixture was stirred overnight at 90 °C. The solution was concentrated and subjected to column chromatography (DCM:MeOH = 96:4) to obtain a yellow solid, which was compound A21-3 (40 mg, 43%).

[0172] Step 3: Place compound A21-3 (40 mg) in a sealed tube, add 5 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (25 mg, 63%). 1 H NMR(500MHz,DMSO-d6)δ8.30(d,J=2.3Hz,1H),8.09(d,J=2.1Hz,1H),8.03(d ,J=5.5Hz,1H),7.60(s,1H),7.20(s,1H),7.08(d,J=5.2Hz,1H),6.92(s,1H), 4.15(d,J=7.7Hz,1H),3.58(d,J=7.2Hz,1H),3.43(s,4H),3.31–3.26(m,1H), 2.58(s,3H),2.29–2.23(m,1H),2.06–1.98(m,3H),1.96(s,4H); MS:m / z[M+1] + =392.21.

[0173] Example 22

[0174]

[0175] Step 1: Compound A22-1 (8.8 g, 50 mol) and ethyl isobutyrate (6.5 g, 55 mmol) were placed in a reaction flask, and toluene (100 mL) was added. LiHMDS (110 mL, 110 mmol) was added at 80 °C. After the addition was complete, the mixture was stirred overnight at ambient temperature. The mixture was quenched with saturated NH4Cl solution, followed by extraction with H2O (300 mL) / EA (300 mL * 3), washed with saturated brine, and dried. Column chromatography (PE:EA = 96:4) yielded a yellowish-brown oil, which was compound A22-2 (6 g, 43%).

[0176] Step 2: Compound A22-2 (6g, 22.2mmol) was placed in a reaction flask, and dried DCM (90mL) was added. The mixture was cooled to -20℃, and DIBAL-H (66mL, 66mmol) was slowly added. After the addition was complete, the temperature was slowly raised to 0℃, and stirring was continued for 4 hours. The mixture was quenched with saturated NH4Cl solution, and extracted with H2O (500mL) / EA (500mL*3). The extract was washed with saturated brine and dried. Column chromatography (PE:EA = 60:40) yielded a colorless oil, which was compound A22-3 (2g, 38%).

[0177] Step 3: Compound A22-3 (460 mg, 2 mmol) was placed in a reaction flask, and DCM (15 mL), DHP (840 mg, 10 mmol), and PPTS (10 mg, 0.4 mmol) were added. After the addition was complete, the mixture was stirred overnight at ambient temperature. The reaction was quenched with NaHCO3 solution, and extracted with DCM (40 mL * 3) / H2O (40 mL). The organic phases were combined, washed with saturated brine, dried, and subjected to column chromatography (PE:EA = 80:20) to obtain a colorless oily substance, which was compound A22-4 (407 mg, 65%).

[0178] Step 4: Place compound A22-4 (407 mg, 1.3 mmol), pinacol diboronate (390 mg, 1.6 mmol), KOAc (382 mg, 3.9 mmol), and Pd(dppf)Cl2 (100 mg) in a reaction flask, add dioxane (15 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0179] Step 5: Compound B5 (339 mg, 1 mmol), compound A22-5 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (100 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A22-6 (190 mg, 38%).

[0180] Step 6: Compound A22-6 (190 mg, 0.38 mmol) was added to EtOH (5 mL) and PPTS (5 mg, 0.02 mmol), and refluxed for 1 h. Saturated NaHCO3 solution was added, and the mixture was extracted with DCM (10 mL * 3) / H2O (10 mL). The organic phases were combined, washed with saturated brine, dried, and subjected to column chromatography (DCM:MeOH = 97:3) to obtain a yellow solid, which was compound A22-7 (80 mg, 51%).

[0181] Step 7: Place compound A22-7 (80 mg) in a sealed tube, add 6 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (35 mg, 43%). 1 H NMR(500MHz,DMSO-d6)δ8.50(d,J=5.1Hz,1H),8.33(d,J=2.0Hz,1H),8.10(s, 1H),7.86(s,1H),7.63(d,J=4.8Hz,1H),7.59(s,1H),7.21(s,1H),4.73(s,1H) ,4.15(d,J=7.8Hz,1H),3.59(s,2H),3.59–3.55(m,1H),3.31–3.23(m,1H),2. 59(s,3H),2.30–2.21(m,1H),2.00(d,J=6.2Hz,3H),1.30(s,6H);MS:m / z[M+1] + =395.21.

[0182] Example 23

[0183]

[0184] Step 1: Place compound A23-1 (428 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0185] Step 2: Compound A5 (324 mg, 1 mmol), compound A23-2 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A23-3 (130 mg, 33%).

[0186] Step 3: Place compound A23-3 (130 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (75 mg, 58%). 1 H NMR (500MHz, DMSO-d6) δ8.67(d,J=4.9Hz,2H),8.44(d,J=2.2Hz,1H),8.25(d,J=1.9Hz,1H),8.08(d,J=5.2Hz,1H),7.62(s,1H),7.23(s,1H),4. 22(d,J=7.3Hz,1H),3.61(dd,J=8.7,5.2Hz,1H),3.33–3.27(m,1H),2.30–2.21(m,1H),2.02(dd,J=17.0,10.5Hz,3H),1.39(s,9H); MS:m / z[M+1] + =366.20.

[0187] Example 24

[0188]

[0189] Step 1: Place compound A24-1 (428 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0190] Step 2: Compound B5 (339 mg, 1 mmol), compound A24-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A24-3 (131 mg, 32%).

[0191] Step 3: Place compound A24-3 (131 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (70 mg, 53%). 1 H NMR (500MHz, DMSO-d6) δ8.62(d,J=5.4Hz,1H),8.37(d,J=2.7Hz,1H),8.21(d,J=5.4Hz,1H),8.16(d,J=2.6Hz,1H),7.60(s,1H),7.22(s,1H),4.21–4 .14(m,1H),3.62–3.54(m,1H),3.29(dd,J=15.7,7.6Hz,1H),2.78(s,3H), 2.26(tt,J=15.7,8.0Hz,1H),2.05–1.96(m,3H),1.39(s,9H); MS:m / z[M+1] + =380.21.

[0192] Example 25

[0193]

[0194] Step 1: Place compound A25-1 (422 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0195] Step 2: Compound A5 (324 mg, 1 mmol), compound A25-2 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A25-3 (121 mg, 32%).

[0196] Step 3: Place compound A25-3 (131 mg) in a sealed tube, add ammonia-methanol solution (8 mL), and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (50 mg, 38%). 1 H NMR (500MHz, DMSO-d6) δ8.57(s,1H),8.46(s,1H),8.37(s,1H),8.29(s,1H),8.18(d,J=6.3Hz,1H),8.12(s,1H),7.66(d,J=7.1Hz,1 H),7.61(s,1H),7.22(s,1H),4.41(s,2H),4.17(d,J=6.5Hz,1H),3.59(s,1H),3.31(s,1H),2.26(s,1H),2.01(s,3H); MS:m / z[M+1] + =363.15.

[0197] Example 26

[0198]

[0199] Step 1: Place compound A26-1 (422 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0200] Step 2: Compound A26-3 (4g, 20.2mmol) was placed in a reaction flask, and MeOH (100mL) and KOH (6.8g, 120mmol) were added. After the addition was complete, the mixture was stirred at 65℃ for 2 hours. The reaction mixtures were combined, concentrated to dryness, and the pH was adjusted to 6 with dilute hydrochloric acid. The mixture was extracted with EA (80mL*3) / H2O (80mL). The organic phases were combined, washed with saturated brine, dried, and subjected to column chromatography (DCM:MeOH = 95:5) to obtain an orange-yellow solid, which was compound A26-4 (2.2g, 65%).

[0201] Step 3: Place compound A26-4 (2.2 g, 16.2 mmol) in a reaction flask, add THF (50 mL), and add NBS (2.9 g, 16.2 mmol) at 0 °C. After the addition is complete, stir at ambient temperature for 1 h. Concentrate, filter, and concentrate the filter cake to dryness to obtain a yellow solid, which is compound A26-5 (3.2 g, 85%).

[0202] Step 4: Compound A26-5 (1.07 mg, 5 mmol), ethyl 2-bromoacetate (830 mg, 5 mmol), and Cs₂CO₃ (3.26 g, 10 mmol) were placed in a reaction flask, and DMF (15 mL) was added. The mixture was stirred overnight at ambient temperature. Water (30 mL) / EA (30 mL * 3) was added, and the mixture was extracted. The organic phases were combined, washed with saturated brine, dried, and subjected to chromatography (PE:EA-70:30) to obtain a pale yellow solid, which was compound A26-6 (1 g, 63%).

[0203] Step 5: Compound A26-6 (299 mg, 1 mmol), compound A26-2, potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A26-7 (21 mg, 5%).

[0204] Step 6: Place compound A26-7 (21 mg) in a sealed tube, add 3 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by thin-layer chromatography (DCM:MeOH = 93:7) to obtain a yellow solid, which is the target compound (6 mg, 28%). 1H NMR (500MHz, DMSO-d6) δ8.78(d,J=2.1Hz,1H),8.65(s,1H),8.53(d,J=2.2Hz,1H),8.01(s,1H),7.94(d,J=7.8Hz,1H),7.72( s,1H),7.62(d,J=7.9Hz,1H),7.42(s,1H),4.87(q,J=6.4Hz,1H),4.43(s,2H),1.55(d,J=6.5Hz,3H); MS: m / z[M+1]+=338.12.

[0205] Example 27

[0206]

[0207] Step 1: Place compound A27-1 (844 mg, 4 mmol), pinacol diboronate (2 g, 8 mmol), KOAc (1.17 g, 12 mmol), and Pd(dppf)Cl2 (400 mg) in a reaction flask, add dioxane (20 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0208] Step 2: Compound A26-6 (299 mg, 1 mmol), compound A27-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A27-3 (15 mg, 3%).

[0209] Step 3: Place compound A27-3 (15 mg) in a sealed tube, add 3 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by thin-layer chromatography (DCM:MeOH = 93:7) to obtain a yellow solid, which is the target compound (5 mg, 33%). 1 H NMR (500MHz, DMSO-d6) δ8.74(d,J=2.1Hz,1H),8.61(s,1H),8.55(d,J=2.2Hz,1H),8.01(s,1H),7.94(d,J=7.8Hz,1H),7 .72(s,1H),7.66(d,J=7.9Hz,1H),7.42(s,1H),4.83(q,J=6.4Hz,1H),4.43(s,2H),1.51(d,J=6.5Hz,3H); MS:m / z[M+1]+ =338.12.

[0210] Example 28

[0211]

[0212] Step 1: Compound A28-1 (1.07 g, 5 mmol), ethyl 2-bromoacetate (905 mg, 5 mmol), and Cs₂CO₃ (3.26 g, 10 mmol) were placed in a reaction flask, and DMF (15 mL) was added. The mixture was stirred overnight at ambient temperature. Water (30 mL) / EA (30 mL * 3) was added, and the mixture was extracted. The organic phases were combined, washed with saturated brine, dried, and subjected to chromatography (PE:EA-70:30) to obtain a pale yellow solid, which was compound A28-2 (1 g, 62%).

[0213] Step 2: Compound A28-2 (313 mg, 1 mmol), compound A27-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A28-3 (41 mg, 11%).

[0214] Step 3: Compound A28-3 (41 mg) was placed in a sealed tube, and a methanol solution of ammonia (3 mL) was added. The mixture was stirred at 80 °C for 48 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by thin-layer chromatography (DCM:MeOH = 93:7) to obtain a yellow solid, which was the target compound (15 mg, 36%). 1 H NMR (500MHz, DMSO-d6) δ8.73(d,J=2.1Hz,1H),8.60(s,1H),8.56(d,J=2.2Hz,1H),8.03(s,1H),7.94(d,J=7.8Hz,1H),7.71(s ,1H),7.65(d,J=7.9Hz,1H),7.42(s,1H),4.82(q,J=6.4Hz,1H),4.41(s,2H),2.56(s,3H),1.50(d,J=6.5Hz,3H); MS:m / z[M+1] + =352.13.

[0215] Example 29

[0216]

[0217] Step 1: Place compound A29-1 (422 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0218] Step 2: Compound A5 (324 mg, 1 mmol), compound A29-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A29-3 (15 mg, 4%).

[0219] Step 3: Place compound A29-3 (15 mg) in a sealed tube, add 3 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (5 mg, 33%). 1 H NMR (500MHz, DMSO-d6) δ8.54(s,1H),8.48(s,1H),8.37(s,1H),8.29(s,1H),8.18(d,J=6.3Hz,1H),8.12(s,1H),7.66(d,J=7.1Hz,1 H),7.61(s,1H),7.22(s,1H),4.43(s,2H),4.17(d,J=6.5Hz,1H),3.59(s,1H),3.32(s,1H),2.26(s,1H),2.01(s,3H); MS:m / z[M+1] + =363.15.

[0220] Example 30

[0221]

[0222] Step 1: Place compound A30-1 (900 mg, 4 mmol), pinacol diboronate (1.5 g, 6 mmol), KOAc (1.2 g, 12 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (20 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0223] Step 2: Compound A26-6 (299 mg, 1 mmol), compound A30-2 (from the previous reaction solution), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A30-3 (70 mg, 19%).

[0224] Step 3: Place compound A30-3 (70 mg) in a sealed tube, add ammonia in methanol solution (7 mL), and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by thin-layer chromatography (DCM:MeOH = 93:7) to obtain a yellow solid, which is the target compound (40 mg, 57%). 1 H NMR(500MHz,DMSO-d6)δ8.93(d,J=2.4Hz,1H),8.75(s,1H),8.70(d,J=2.4Hz,1H),8.58(s,1H),8.26(d,J=10.6Hz,2H), 7.72(s,1H),7.68(d,J=7.9Hz,1H),7.54(s,1H),4.68(q,J=6.6Hz,1H),4.64(s,2H),1.42(d,J=6.7Hz,3H); MS:m / z[M+1] + =352.13.

[0225] Example 31

[0226]

[0227] Step 1: Compound A5 (324 mg, 1 mmol), compound A30-2 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A31-1 (75 mg, 19%).

[0228] Step 2: Compound A31-1 (75 mg) was placed in a sealed tube, and a methanol solution of ammonia (7 mL) was added. The mixture was stirred at 80 °C for 48 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by thin-layer chromatography (DCM:MeOH = 93:7) to obtain a yellow solid, which was the target compound (45 mg, 61%). 1H NMR(500MHz,DMSO-d6)δ8.60(s,1H),8.54(s,1H),8.41(s,1H),8.28(s,1H),8 .23(d,J=7.8Hz,1H),8.15(s,1H),7.64(d,J=7.9Hz,1H),7.61(s,1H),7.22(s ,1H),4.66(d,J=6.3Hz,1H),4.19(d,J=7.9Hz,1H),3.60(s,1H),3.33–3.29(m ,1H),2.26(d,J=6.7Hz,1H),2.01(s,3H),1.42(d,J=6.4Hz,3H); MS:m / z[M+1] + =377.16.

[0229] Example 32

[0230]

[0231] Step 1: Place compound A32-1 (418 mg, 1.5 mmol), pinacol diboronate (500 mg, 2 mmol), KOAc (441 mg, 4.5 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (20 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0232] Step 2: Compound A5 (324 mg, 1 mmol), compound A32-2 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography and thin-layer chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A32-3 (12 mg, 3%).

[0233] Step 3: Place compound A32-3 (12 mg) in a sealed tube, add ammonia in methanol solution (4 mL), and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by thin-layer chromatography (DCM:MeOH = 93:7) to obtain a yellow solid, which is the target compound (4 mg, 33%). 1H NMR (500MHz, DMSO-d6) δ8.60(s,1H),8.55(s,1H),8.41(s,1H),8.28(s,1H),8.24(d,J=7.8Hz,1H),8.15(s,1H),7.63(d,J=7.9Hz,1H),7.61(s, 1H),7.22(s,1H),4.66(d,J=6.3Hz,1H),4.19(d,J=7.9Hz,1H),3.62(s, 1H),3.33–3.29(m,1H),2.27(d,J=6.7Hz,1H),2.03(s,3H);MS:m / z[M+1] + =431.14.

[0234] Example 33

[0235]

[0236] Step 1: Place compound A33-1 (422 mg, 2 mmol), pinacol diboronate (1 g, 4 mmol), KOAc (588 mg, 6 mmol), and Pd(dppf)Cl2 (200 mg) in a reaction flask, add dioxane (10 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0237] Step 2: Compound A5 (324 mg, 1 mmol), compound A33-2 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (5 mL) and water (1.5 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A33-3 (125 mg, 31%).

[0238] Step 3: Place compound A33-3 (125 mg) in a sealed tube, add 8 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (40 mg, 32%). 1H NMR (500MHz, DMSO-d6) δ8.48(s,1H),8.30(s,1H),8.09(s,1H),7.96(s,1H),7.88(d,J=7.8Hz,1H),7.72(d,J=7.9Hz,1H),7.59(s,1H),7.20( s,1H),4.42(s,2H),4.15(d,J=8.0Hz,1H),3.58(s,1H),3.29(d,J=7.1Hz,1H),2.57(s,3H),2.25(d,J=6.2Hz,1H),2.00(s,3H); MS:m / z[M+1] + =377.16.

[0239] Example 34

[0240]

[0241] Step 1: Compound A34-1 (10 mL, 71 mmol) and morpholine (53 mL, 610 mmol) were placed in a reaction flask, and n-hexane (100 mL) was added. After the addition was complete, TiCl4 (71 mL, 71 mmol, 1 M toluene solution) was slowly added at 0 °C. After the addition was complete, the mixture was stirred overnight at 50 °C. The mixture was filtered, and the filtrate was concentrated. Trifluoroethyl ketone (5.6 mL, 71 mmol) was added to the reaction mixture, and the mixture was stirred at this temperature for 4 h. Then, 10% hydrochloric acid solution was added, and the mixture was stirred for 1 h. The mixture was extracted with EA (500 mL * 2) / H2O (500 mL), the organic phases were combined, washed with saturated NaHCO3 solution, washed with saturated brine, dried, and subjected to column chromatography (PE:EA = 93:7) to obtain a colorless oil, which was compound A34-2 (9 g, 51%).

[0242] Step 2: Compound A34-2 (9g, 42mmol) was placed in a reaction flask, and trifluoromethanesulfonic acid (100mL) was added. The mixture was stirred overnight at 100°C. The mixture was then added to ice water and extracted with EA (500mL*2) / H2O (500mL). The organic phases were combined, washed with saturated NaHCO3 and saturated brine, dried, and subjected to column chromatography (PE:EA = 95:5) to obtain a pale yellow solid, which was compound A34-3 (3.5g, 38%).

[0243] Step 3: Place compound A34-3 (2.48 g, 10 mmol), pinacol diboronate (3 g, 12 mmol), KOAc (2.95 g, 30 mmol), and Pd(dppf)Cl2 (700 mg) in a reaction flask, add dioxane (60 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0244] Step 4: Compound A5 (975 mg, 3 mmol), compound A34-4 (reaction solution from the previous step), potassium carbonate (1.3 g, 9 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (400 mg) were placed in a reaction flask. Dioxane (15 mL) and water (3 mL) were added, and the mixture was stirred at 100 °C for 5 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A34-5 (300 mg, 25%).

[0245] Step 5: Place compound A34-5 (300 mg) in a sealed tube, add 20 mL of ammonia in methanol, and stir at 80 °C for 48 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, and then purify by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which is the target compound (200 mg, 66%). 1 H NMR(500MHz,DMSO-d6)δ8.76(d,J=1.2Hz,1H),8.54(d,J=5.6Hz,1H),8.46(d,J=2.7Hz,1H), 8.38(ddd,J=8.0,5.1,1.2Hz,1H),8.22(d,J=2.6Hz,1H),7.74(d,J=8.1Hz,1H),7.59(s,1H) ,7.21(s,1H),4.26–4.19(m,1H),3.64–3.58(m,1H),3.38–3.33(m,1H),2.96(d,J=18.8Hz,1 H),2.80(d,J=18.8Hz,1H),2.30–2.22(m,1H),2.07–1.96(m,3H),1.72(s,3H); MS:m / z[M+1] + =444.16.

[0246] Compound A34 was chirally resolved to obtain compounds A34-1 and A34-2.

[0247] Example 35

[0248]

[0249] Step 1: Compound B5 (1.1 g, 3 mmol), compound A34-4, potassium carbonate (1.3 g, 9 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (400 mg) were placed in a reaction flask, and dioxane (15 mL) and water (3 mL) were added. The mixture was stirred at 100 °C for 5 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A35-1 (320 mg, 23%).

[0250] Step 2: Compound A35-1 (320 mg) was placed in a sealed tube, and a methanol solution of ammonia (20 mL) was added. The mixture was stirred at 80 °C for 48 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which was the target compound (210 mg, 65%). 1 H NMR (500MHz, DMSO-d6) δ8.35(s,1H),8.17(s,1H),8.13(s,1H),8.07(d,J=5.7Hz,1H),7.78(d,J=7.1Hz,1H),7.59(s,1H),7.21(s,1H),4.17(s,1H) ,3.59(s,1H),3.31–3.24(m,1H),2.98(d,J=18.8Hz,1H),2.82(d,J=18.6 Hz,1H),2.60(s,3H),2.26(s,1H),2.01(s,3H),1.71(s,3H); MS:m / z[M+1] + =458.17.

[0251] Compound A35 was chirally resolved to obtain compounds A35-1 and A35-2.

[0252] Example 36

[0253]

[0254] Step 1: Place compound A36-1 (956 mg, 4 mmol), pinacol diboronate (1.2 g, 4.8 mmol), KOAc (1.2 g, 12 mmol), and Pd(dppf)Cl2 (400 mg) in a reaction flask, add dioxane (30 mL), and stir overnight at 100 °C. Cool and proceed directly to the next step.

[0255] Step 2: Compound A5 (324 mg, 1 mmol), compound A36-2 (reaction solution from the previous step), potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask. Dioxane (8 mL) and water (3 mL) were added, and the mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A36-3 (100 mg, 21%).

[0256] Step 3: Compound A36-3 (100 mg) was placed in a sealed tube, and an ammonia-methanol solution (8 mL) was added. The mixture was stirred at 80 °C for 48 h. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which was the target compound (40 mg, 26%). 1H NMR (500MHz, DMSO-d6) δ8.26(d,J=2.6Hz,1H),8.10–8.04(m,2H),7.93(s,1H),7.74(d,J=8.1Hz,1H),7.62(s,1H),7.21(s,1H),4.17–4.11(m ,1H),3.59(d,J=7.6Hz,1H),3.28(m,1H),2.59(s,2H),2.28–2.17(m,1H),2.05(dd,J=14.1,8.9Hz,3H),1.43(s,6H); MS: m / z[M+1]+=390.19.

[0257] Example 37

[0258]

[0259] Step 1: Compound B5 (338 mg, 1 mmol), compound A36-2, potassium carbonate (414 mg, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (200 mg) were placed in a reaction flask, and dioxane (8 mL) and water (3 mL) were added. The mixture was stirred in a microwave at 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain a yellow solid, which was compound A37-1 (130 mg, 28%).

[0260] Step 2: Compound A37-1 (130 mg) was placed in a sealed tube, and a methanol solution of ammonia (8 mL) was added. The mixture was stirred at 80 °C for 48 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by column chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which was the target compound (50 mg, 26%). 1H NMR(500MHz,DMSO-d6)δ8.29(d,J=2.6Hz,1H),8.10–8.02(m,2H),7.93(s,1 H),7.74(d,J=8.1Hz,1H),7.61(s,1H),7.20(s,1H),4.17–4.11(m,1H),3.5 9(d,J=7.6Hz,1H),3.28(dd,J=15.2,7.3Hz,1H),2.59(s,2H),2.54(s,3H), 2.29–2.19(m,1H),2.00(dd,J=14.1,8.9Hz,3H),1.41(s,6H);MS:m / z[M+1] + =404.2.

[0261] Example 38

[0262]

[0263] Step 1: Compound A34 (50 mg, 0.1 mmol) was placed in a reaction flask, and methanol (3 mL) and NaBH4 (11 mg, 0.3 mmol) were added. The mixture was stirred at ambient temperature for 2 h. After concentration under reduced pressure, it was purified by thin-layer chromatography (DCM:MeOH = 92:8) to obtain a yellow solid, which was the target compound (30 mg, 60%). 1 H NMR (500MHz, DMSO-d6) δ8.27(d,J=2.3Hz,1H),8.04(s,1H),7.73(d,J=7.8Hz,1H),7.68(s, 1H),7.58(s,1H),7.47(d,J=7.9Hz,1H),7.19(s,1H),5.59(d,J=5.8Hz,1H),4.16–4.09(m,1 H),3.57(t,J=17.1Hz,1H),3.32–3.23(m,1H),2.60(s,3H),2.41(dd,J=13.0,7.4Hz,1H),2. 29–2.21(m,1H),2.12(dt,J=15.6,7.7Hz,1H),2.04–1.95(m,3H),1.44(s,3H); MS:m / z[M+1] + =460.19.

[0264] Test Example 1: Determination of the inhibitory effect of the compounds in this invention on the activity of PI3Kα / β / γ / δ kinases.

[0265] Experimental instruments: Centrifuge purchased from Eppendorf, pipettes purchased from Eppendorf Gilson, and microplate reader purchased from Thermo Fisher Scientific, USA, model Varioskan LUX multi-functional microplate reader.

[0266] Experimental materials:

[0267]

[0268]

[0269] Experimental Methods: The ADP-Glo ​​lipid kinase assay from Promega was used. The lipid kinase PI3Kα / β / γ / δ reacts with a mixture of substrate phosphoinositol-4,5-bisphosphate (PIP2) and apoliposide phosphatidylserine (PS) at a volume ratio of 1:3 (PIP2:3PS) in the presence of ATP. ATP is converted to ADP. The activity of the lipid kinase is characterized by measuring the ADP content in the reaction, and the half-maximal inhibitory concentration (IC50) of the compound inhibiting the activity of PI3Kα / β / γ / δ kinases is determined. 50 .

[0270] The specific experimental procedure is as follows:

[0271] The kinase reaction was carried out in a white 96-well plate. 2 μL of compounds of different concentrations from the present invention, diluted with ddH2O containing 1% DMSO, was added to each well. For positive control wells, 2 μL of ddH2O containing 1% DMSO was added, followed by 2 μL of 0.1–2 nM PI3K kinase solution diluted with 5× kinase buffer (HEPES 250 mM, MgCl2 15 mM, NaCl 250 mM, BSA 0.05%). For negative control wells, 2 μL of 5× kinase buffer was added. All wells were then treated with 4 μL of 50 μM substrate PIP2:3PS prepared with 10× dilution buffer and ddH2O. Finally, 2 μL of 50–100 μM ATP solution diluted with water was added to initiate the reaction. After reacting at room temperature for 90–120 min, 10 μL of ADP-Glo ​​Reagent (containing 10 mM MgCl2) was added to each well. The chemiluminescence value was measured using a Varioskan LUX microplate reader after reacting with MgCl2 at room temperature for 60 min to remove excess ATP. Then, 20 μL of kinase detection reagent was added to each well, and the reaction was carried out at room temperature in the dark for 20 min.

[0272] Experimental data processing methods:

[0273] The percentage inhibition rate of the wells treated with the compounds synthesized in this invention was calculated by comparing the luminescence difference between the positive control wells (DMSO control wells) and the negative control wells (without added kinase) on a control plate, using the following formula:

[0274] Inhibition rate % = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100.

[0275] The IC was calculated using a four-parameter nonlinear logic formula by fitting data of different concentrations and corresponding percentage inhibition rates to GraphPad Prism. 50 value.

[0276] Experimental conclusion:

[0277] Based on the above scheme, the compounds of the present invention and the positive control Alpelisib showed the following biological activities in the PI3Kα / β / γ / δ kinase activity assay, as shown in Table 1 below.

[0278] Test Example 2: Determination of the inhibitory effect of the compounds in the present invention on the proliferation of breast cancer cells.

[0279] Experimental objective:

[0280] The inhibitory activity of the compound of the present invention and the positive control Alpelisib on the proliferation of three breast cancer cell lines, BT474, MDA-MB-453 and T47D, was tested.

[0281] Experimental apparatus:

[0282] The centrifuge and pipettes were purchased from Eppendorf, the CO2 incubator from Thermo, and the microplate reader was purchased from BioTek Instruments, Inc., specifically the Cytation 5 multi-functional microplate reader.

[0283] Experimental methods:

[0284] The inhibitory effects of the compounds in this invention on the proliferation of three breast cancer cell lines—BT474, MDA-MB-453, and T47D—were detected using the CCK8 assay. The specific experimental methods are as follows:

[0285] Cell lines to be tested were seeded at 5000-10000 cells / well in 96-well plates and incubated overnight at 37°C with 5% CO2. Different concentrations of prepared compound solutions were added as needed, along with solvent controls (DMSO) and negative controls, with three replicates per group. The plates were then incubated at 37°C with 5% CO2 for another 72 hours. After incubation, the cells were analyzed using the CCK-8 assay kit according to the manufacturer's instructions. 10 μL of CCK-8 reagent was added to each well, and after incubation for a specified time, the cells were analyzed using a microplate reader.

[0286] Experimental data processing:

[0287] After subtracting the background value of the negative control, the relative cell viability (%) was calculated as: (OD value of test wells / OD value of solvent control wells) × 100%. Curve fitting was performed using Graphpad Prism software to calculate the IC50. 50 .

[0288] The above methods yielded the inhibitory activity of the compounds in the embodiments of the present invention against PI3Kα kinase and the inhibitory activity against the proliferation of three breast cancer cell lines: BT474, MDA-MB-453, and T47D. The experimental results are shown in Table 2.

[0289] Table 1 PI3K kinase activity data

[0290]

[0291]

[0292] Table 2 Inhibitory activity against cancer cell proliferation

[0293]

[0294] Note: "-" indicates that it was not detected.

[0295] Activity Summary: As shown in Tables 1 and 2, the compounds of this invention exhibit excellent inhibitory activity against PI3Kα kinase and high selectivity for PI3Kα. They also demonstrate excellent inhibitory activity against three breast cancer cell lines: BT474, MDA-MB-453, and T47D. Among these, the compounds in Examples 17, 18, and 34-1 are significantly superior to the positive control Alpelisib in terms of PI3Kα activity and selectivity, as well as inhibitory activity against the three breast cancer cell lines (T47D, BT474, and MDA-MB-453).

[0296] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The pyrazolo[1,5-a]pyrimidine derivative of Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof: in, R1 is selected from H, halogen, or C. 1-6 alkyl; A is selected from unsubstituted or arbitrarily assigned to one, two or more R. A The following groups are substituted: phenyl, pyridyl, pyrimidinyl, C6 aryl 3-6 membered heterocyclic group, C6 aryl 3-6 membered heterocyclic group. 3-6 cycloalkyl; R A Independently selected from =O, halogen, hydroxyl, cyano, amino, and unsubstituted or optionally surrounded by one, two or more R groups. B The following groups are substituted: C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkoxy, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R B Independently selected from =O, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy; B is or -OC 1-6 Alkyl-CO-NH2.

2. The pyrazolo[1,5-a]pyrimidine derivative according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from H, F, Cl or C. 1-3 alkyl.

3. The pyrazolo[1,5-a]pyrimidine derivative according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, B is -O-CH2-CO-NH2, -O-CH2-CH2-CO-NH2, -O-CH(CH3)-CO-NH 2; Alternatively, R1 may be selected from H or methyl; or, A is selected from the following groups: Where Z is -CH2-, O, or -NH-; R2, R3, R4, R5, and R6 may be the same or different, and are independently selected from: hydrogen, halogen, hydroxyl, cyano, amino, unsubstituted, or optionally replaced by one, two, or more R groups. C The following groups are substituted: C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NH-C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups; R C Independently selected from: =O, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkyl group; or, R5 and R6 together form =O.

4. The pyrazolo[1,5-a]pyrimidine derivative according to claim 1 or 2, wherein, A is selected from unsubstituted or arbitrarily assigned to one, two or more R. A The following groups are substituted: pyridinyl, pyrimidinyl, isoindolinyl, indanyl; R A Selected from =O, methyl, hydroxy, tert-butyl, methoxy, trifluoromethyl, 2-trifluoromethylpropyl, 2-cyanopropyl, 1-cyanocyclopropyl, 2-pyrrolidone, 2-oxazolidinone, 2-hydroxyethylamino, 2-hydroxypropyl, 2-methoxypropyl, N-heterocyclic butyl, N-heterocyclic pentyl The asterisk (*) indicates a connection point.

5. The pyrazolo[1,5-a]pyrimidine derivative according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, The pyrazolo[1,5-a]pyrimidine derivatives are selected from the following compounds:

6. The use of the pyrazolo[1,5-a]pyrimidine derivative according to any one of claims 1-5, its stereoisomer or a pharmaceutically acceptable salt thereof as a PI3Kα inhibitor; When used as a PI3Kα inhibitor, it is used for non-disease diagnostic and therapeutic purposes.

7. Use of the pyrazolo[1,5-a]pyrimidine derivative of any one of claims 1-5, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancers caused by dysregulation of the PI3Kα signaling pathway.

8. The use according to claim 7, wherein, The cancer is selected from breast cancer, lung cancer, or rectal cancer.

9. A pharmaceutical composition comprising a pyrazolo[1,5-a]pyrimidine derivative as described in any one of claims 1-5, its stereoisomer, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9, wherein, The pharmaceutical composition is used to treat cancers caused by dysregulation of the PI3Kα signaling pathway.

11. The pharmaceutical composition according to claim 9 or 10, wherein, The pharmaceutical composition also includes pharmaceutically acceptable excipients.

12. The pharmaceutical composition according to claim 11, wherein, The excipients include one, or a mixture of two or more, of fillers, binders, disintegrants, lubricants, flavoring agents, enteric coatings, or sustained-release materials.

Images