A condensed ring compound, preparation and use thereof

Abstract

The present application provides a kind of fused ring compound and its preparation and use. Specifically, the structure of the compound is as shown in formula (I), the compound of formula (I) or its pharmaceutically acceptable salt, for increasing the activity of liver-type phosphofructokinase, can be used for treating diseases related to liver-type phosphofructokinase activity, such as cancer, diabetes, sepsis and septic shock.I.

Description

A condensed ring compound and its preparation and application Technical Field

[0001] The present invention belongs to the field of medical technology. Specifically, the present invention provides a compound of a liver-type phosphofructokinase (PFKL) activator, the structure of which is shown in formula (I). Background Art

[0002] Reactive oxygen species (ROS) with bactericidal activity are produced within the phagosomes of phagocytes. Neutrophils are a crucial phagocyte that helps defend the body against pathogenic microorganisms and are the predominant white blood cell type in the blood (comprising approximately 50%-70%). Neutrophils have multiple functions, including phagocytosis, degranulation, ROS production, and the formation of neutrophil extracellular traps (NETs). Although neutrophils are crucial for innate immunity, overactivation can be detrimental. NETs-induced local tissue damage, inflammation, and autoantigen formation exacerbate the pathology of chronic diseases such as atherosclerosis, gout, and lupus. Targeting excessive ROS production may have therapeutic potential, but reducing ROS levels by inhibiting NOX2 or enzymes in the pentose phosphate pathway may pose safety concerns, including effects due to suppression of innate immunity or other general toxicities.

[0003] In response to external stimuli such as infection, NOX2 is a major enzyme that rapidly catalyzes the production of ROS in cells. It is a key enzyme in oxidative stress and inflammatory responses and is widely distributed throughout the body, including in multiple organs and tissues such as blood vessels, liver, pancreas, colon, and prostate. The NOX2-catalyzed ROS production reaction requires NADPH, produced by the pentose phosphate metabolic pathway of glucose, as a reducing donor.

[0004] The process of neutrophil secretion of NETs is called NETosis, an inflammatory cell death mode of neutrophils. NETosis is crucial for the body's microbial eradication, but its underlying molecular mechanisms remain largely unknown. Most physiological stimuli, including bacteria, fungi, and crystalline particles, trigger NOX2-dependent NETosis, but some bacterial toxins that act as potassium and calcium ion carriers can trigger NOX2-independent NETosis. The mechanism of NOX2-dependent NETosis can be divided into two stages. In the first stage, an active signaling cascade triggers a NOX2-induced burst of reactive oxygen species, such as elastase (NE) and histone-modifying enzymes such as peptidyl-arginine deaminase 4 (PAD4), which enter the cell nucleus. The second stage involves chromatin decondensation, cell membrane disruption, and the rapid extracellular release of decondensed DNA structures along with highly hydrolytic enzyme granules, including various antimicrobial peptides, following nuclear membrane rupture, forming a glue-like network.

[0005] It is reported that liver-type phosphofructokinase (PFKL) is a key enzyme in glycolysis that negatively regulates the generation of reactive oxygen species bursts. By activating PFKL, glucose metabolism through the pentose phosphate pathway is inhibited, thereby limiting the production of NADPH, and thus reducing the generation of reactive oxygen species bursts that NOX2 depends on. Therefore, PFKL activators can maintain the production of NADPH at the basal level without damaging normal cellular redox activity. Therefore, it can block but not completely inhibit the production of ROS in neutrophils induced by phorbol-12-pyrimidinic acid-13-acetate (PMA). PFKL activators prevent PMA-induced apoptosis in activated neutrophils, but it does not block the spontaneous apoptosis of neutrophils in the resting state (Vishva M.Dixit et al., Cell, 184, 4480-4494, 2021).

[0006] Currently, there are no marketed drugs targeting this target. To meet the enormous clinical demand in the future, compounds and methods for activating liver-type phosphofructokinase (PFKL) are needed. Compounds that can inhibit NOX2-dependent reactive oxygen species (ROS) production are also needed. Such compounds and methods could be used to treat diseases including diabetes and cancer.

[0007] Summary of the Invention

[0008] The purpose of the present invention is to provide a liver-type phosphofructokinase (PFKL) activator compound, and a preparation method and application thereof.

[0009] The first aspect of the present invention provides a fused ring compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof:

[0010] in:

[0011] Y is N or CH;

[0012] R 2 Selected from the group consisting of: -L-NHC(=O)R c 、-L-NH-C(=N-CN)R c , -L-NH-C(=N-CN)NH2, -L-NHC(=O)NHR c 、-L-NHC(=O)NH 2、 -L-NHC(=S)NH 2、 And R 2 Can be further replaced by one or more R p replace;

[0013] L is -(CH2)-;

[0014] R c Independently selected from the group consisting of: C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, cyano substituted C 1-6 alkyl;

[0015] R 5 Select from the following group: C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR j R k 、-C(=O)NR j R k 、-NR j C(=O)R k ; and said R 5 Can be further replaced by one or more R g or R h replace;

[0016] R g Selected from the group consisting of hydrogen, halogen, cyano, oxo (=O), =CH2;

[0017] R h Selected from the group consisting of: hydroxyl, -NR h1 R h2 、-C(=O)NR h1 R h2 、-C(=O)OC 1-6 Alkyl, NR h1 Rh2 、-S(O)2NR h1 R h2 、-S(O)2R h2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkanoyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, C 1-4 Alkyl C 3-10 Cycloalkyl; and said R h Can be further replaced by one or more R r replace;

[0018] R j , R k , R h1 , R h2 are independently selected from the group consisting of hydrogen, C 1-6 alkyl;

[0019] R 6 Selected from the group consisting of hydrogen, deuterium, cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 2-4 Alkenyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 2-4 Alkenyl, 3-6 membered partially saturated carbocyclic group, -C 1-4 Alkyl-OH; halogen is arbitrarily selected from: F, Cl, Br, I;

[0020] The R p , R r Each independently selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl;

[0021] The carbocyclic or heterocyclic group may be a saturated or partially saturated ring, including a monocyclic, bridged, spirocyclic, and polycyclic structure, but does not include an aromatic structure. Unless otherwise specified, the heterocyclic or heteroaryl group includes 1, 2, or 3 heteroatoms selected from N, S, or O.

[0022] In another preferred embodiment, the Y is N or CH.

[0023] In another preferred embodiment, the Y is CH.

[0024] In another preferred embodiment, the compound of formula I has the following structure:

[0025] Among them, R d C 1-4 Alkyl, -NH2, -OH, -SH, R d Can be further C 1-4 Alkyl substitution.

[0026] In another preferred embodiment, the R 2 Selected from the following structures,

[0027] In another preferred embodiment, the R 6 Selected from the group consisting of hydrogen, deuterium, cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 2-4 Alkenyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 2-4 Alkenyl, 3-6 membered partially saturated carbocyclic group, -C 1-4 Alkyl-OH; halogen is arbitrarily selected from: F, Cl, Br, I.

[0028] In another preferred embodiment, the R 6 Selected from the group consisting of hydrogen, deuterium, cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 3-6 Cycloalkyl; halogen is arbitrarily selected from: F, Cl, Br, I.

[0029] In another preferred embodiment, the R 6 C 1-4 Alkyl, halogenated C 1-4 alkyl.

[0030] In another preferred embodiment, the R 6 It is trifluoromethyl.

[0031] In another preferred embodiment, the R 6 It is a methyl group.

[0032] In another preferred embodiment, the R 6 It is a halogen.

[0033] In another preferred embodiment, the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, is selected from the following structures:

[0034] Among them, R 5 Select from the following group: C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group; and said R 5 Can be further replaced by one or more R g or R h replace.

[0035] In another preferred embodiment, the compound or its pharmaceutically acceptable salt is selected from the following formula:

[0036] R 6 Selected from the group consisting of F, Cl, Br, I, methyl, trifluoromethyl, and ethyl.

[0037] In another preferred embodiment, in the compound of formula I, R 5 is a benzene ring, and the R 5 Can be further replaced by one or more R g or R h replace.

[0038] In another preferred embodiment, in the compound of formula I, R 5 is a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, S or O, and the R 5 Can be further replaced by one or more R g or R h In another preferred embodiment, in the compound of formula I, R 5 is a 3-7 membered monocyclic heterocyclic ring, a 7-12 membered saturated or partially saturated heterospirocyclic ring or, containing any 1, 2 or 3 heteroatoms selected from N or O, and said R 5 Can be further replaced by one or more R g or R h replace.

[0039] In another preferred embodiment, in the compound of formula I, R 5 is a 7-12 membered saturated or partially saturated carbon spiro ring, a 3-7 membered saturated or partially saturated carbon ring, and the R 5 Can be further replaced by one or more R g or R h In another preferred embodiment, in the compound of formula I, R 5To arbitrarily replace C 2-6 Alkynyl, substituents are selected from 3-6 membered cycloalkyl, benzene ring, 5-6 membered heteroaryl, and said R 5 Can be further replaced by one or more R g or R h replace.

[0040] In another preferred embodiment, in the compound of formula I, R 5 Select from the following groups:

[0041] And the R 5 Can be further replaced by one or more R g or R h replace, Represents R 5 Connection.

[0042] In another preferred embodiment, in the compound of formula I, R 5 Select from the following groups:

[0043] n is arbitrarily selected from 0, 1, 2, 3 or 4, Represents R 5 Connection.

[0044] In another preferred embodiment, the compound of formula I is selected from the following group:

[0045] The second aspect of the present invention provides a pharmaceutical composition comprising (1) a compound as described in the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; and (2) a pharmaceutically acceptable carrier.

[0046] The third aspect of the present invention provides a use of the compound according to the first aspect of the present invention or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, prodrug, hydrate or solvate, or the pharmaceutical composition according to the second aspect of the present invention, characterized in that it is used to prepare a pharmaceutical composition for preventing and / or treating diseases related to the activity of PFKL.

[0047] In another preferred embodiment, the disease is selected from the following group: lung disease, thrombosis, sepsis, autoimmune disease, inflammatory disease, metabolic disease, and cancer.

[0048] In another preferred embodiment, the lung disease is selected from the group consisting of pneumonia, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary fibrosis, asthma, acute lung injury, and idiopathic pulmonary fibrosis (IPF).

[0049] In another preferred embodiment, the thrombotic disease is selected from the group consisting of cerebral thrombosis, myocardial infarction, heart failure, coronary heart disease, atherosclerosis, and retinal vascular embolism.

[0050] In another preferred embodiment, the sepsis is selected from the group consisting of systemic inflammatory response syndrome, sepsis, severe sepsis, septic shock, systemic inflammation caused by viral infection, and multiple organ failure.

[0051] In another preferred embodiment, the autoimmune disease is selected from the group consisting of psoriasis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and systemic sclerosis.

[0052] In another preferred embodiment, the inflammatory disease is selected from the group consisting of inflammatory bowel disease, encephalitis, eye inflammation, nephritis, pancreatitis, dermatitis, Alzheimer's disease, and Parkinson's disease.

[0053] In another preferred embodiment, the metabolic disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, gout, obesity and its complications.

[0054] In another preferred embodiment, the cancer is selected from the group consisting of brain cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, skin cancer, oral cancer, pharyngeal cancer, colon cancer, liver cancer, cecal cancer, stomach cancer, pancreatic cancer, prostate cancer, esophageal cancer, blood cancer, thyroid cancer, uterine cancer and head and neck cancer.

[0055] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0056] After long and in-depth research, the inventors designed and synthesized a new type of PFKL activator, on the basis of which the inventors completed the present invention.

[0057] the term

[0058] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0059] As used herein, the term "about" when used in reference to a specific recited value means that the value may vary by no more than 5% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 95 and 105 (e.g., 95.1, 95.2, 95.3, 95.4, etc.).

[0060] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0061] definition

[0062] As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example, C 1-6 The alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.

[0063] As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. For example, C 2-6 The alkenyl group refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

[0064] As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. 2-6 Alkynyl refers to a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

[0065] As used herein, the term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be a bicyclic ring, such as a bridged ring or a spiro ring.

[0066] As used herein, the term "C 1-6 The term "alkoxy" refers to a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.

[0067] As used herein, the term "3-8 membered heterocyclic group having 1-3 heteroatoms selected from the group consisting of N, S, and O" refers to a saturated or partially saturated cyclic group having 3-8 atoms, 1-3 of which are heteroatoms selected from the group consisting of N, S, and O. It may be a monocyclic or polycyclic ring, such as a bridged ring, a spirocyclic ring, or a fused ring. Specific examples include oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, and pyrrolidinyl.

[0068] As used herein, the term "C 6-10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.

[0069] As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S, and O" refers to a cyclic aromatic group having 5-10 atoms, 1-3 of which are heteroatoms selected from the group consisting of N, S, and O. It may be a monocyclic or condensed ring. Specific examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, and oxazolyl.

[0070] Unless otherwise specified, all groups of the present invention may be substituted by substituents selected from the group consisting of halogen, nitrile, nitro, hydroxyl, amino, C 1-6 Alkyl-amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, halo C 1-6 Alkoxy, allyl, benzyl, C 6-12 Aryl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-carbonyl, phenoxycarbonyl, C 2-6 Alkynyl-carbonyl, C 2-6 Alkenyl-carbonyl, C 3-6 Cycloalkyl-carbonyl, C 1-6 Alkyl-sulfonyl, etc.

[0071] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl, and Br. "Halogenated" means substituted with one or more atoms selected from F, Cl, Br, and I.

[0072] Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or configurational isomers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, etc. Therefore, individual stereochemical isomers of the compounds of the present invention, or mixtures of such enantiomers, diastereomers, or geometric isomers (or configurational isomers), are within the scope of the present invention. Unless otherwise specified, the absolute stereo configuration of the compounds herein is undetermined and is determined by chiral resolution of racemic compounds. The stereo configurations indicated in the structural formulas and compound names are arbitrarily assigned.

[0073] As used herein, the term "tautomer" refers to structural isomers of different energies that can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropy) include interconversion via proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion via reorganization of some of the bonding electrons.

[0074] As used herein, the term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0075] Pharmaceutical compositions and methods of administration

[0076] Since the compounds of the present invention have excellent activation properties for liver-type phosphofructokinase, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, prodrugs, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat diseases related to PFKL kinase activity.

[0077] The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0078] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0079] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral (intravenous, intramuscular or subcutaneous) injection, and the like.

[0080] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0081] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0082] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0083] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0084] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0085] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0086] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0087] When administered in combination, the pharmaceutical composition may further comprise one or more other pharmaceutically acceptable compounds. One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with the compound of the present invention.

[0088] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0089] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. The experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified, or can be synthesized using or according to methods known in the art.

[0090] Unless otherwise stated, abbreviations used in the specification and claims have the same meanings as commonly used in the art.

[0091] Synthesis Example

[0092] Intermediate A: Synthesis of 2-bromo-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile

[0093] Step 1: Synthesis of 5-cyano-2-fluorobenzoyl chloride (A-1)

[0094] To a reaction flask containing compound A-0 (10 g, 0.06 mol) was added SOCl2 (72.1 g, 0.61 mmol) at room temperature. The reaction mixture was stirred at 90°C for 2 hours. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.4) indicated complete conversion of the starting material. After completion of the reaction, the reaction mixture was concentrated to afford the title compound A-1 (11 g, quantitative yield).

[0095] Step 2: Synthesis of 4-fluoro-3-(hydroxymethyl)benzene-1-carbonitrile (A-2)

[0096] At 0°C, NaBH4 (6.8 g, 180.30 mmol) was slowly added to a solution of compound A-1 (11 g, 60.11 mmol) in anhydrous tetrahydrofuran (100 mL). The reaction mixture was stirred at 0°C for 2 hours. TLC (petroleum ether:ethyl acetate = 6:1, Rf = 0.5) showed complete conversion of the starting material. Water (100 mL) was slowly added to the reaction solution to quench the reaction, and then extracted three times with ethyl acetate (100 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound A-2 (5.7 g, yield: 60.5%) as a colorless oil.

[0097] Step 3: Synthesis of methyl 5-bromo-2-[(5-cyano-2-fluorophenyl)methyl]pyrazole-3-carboxylate (A-3)

[0098] Under nitrogen protection, a solution of compound A-2 (5.7 g, 36.42 mmol), 5-bromo-2H-pyrazole-3-carboxylic acid methyl ester (7.7 g, 36.42 mmol) and PPh3 (19.8 g, 72.85 mmol) in tetrahydrofuran (60 mL) was cooled to 0 ° C, and then DIAD (15 mL, 72.85 mmol) was slowly added dropwise to the solution. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred at 25 ° C for 2 hours. LC-MS showed that the starting material was completely converted. The reaction solution was quenched with water (50 mL) and extracted three times with ethyl acetate (100 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-15:85) to obtain the title compound A-3 (10 g, yield: 81.0%) as a yellow solid. MS (ESI): m / z = 338.0, 340.0 [M+H] + .

[0099] Step 4: Synthesis of 5-bromo-2-[(5-cyano-2-fluorophenyl)methyl]pyrazole-3-carboxylic acid (A-4)

[0100] At room temperature, a solution of LiOH.H2O (1.4 g, 74.19 mmol) in water (52 mL) was added to a solution of compound A-3 (10 g, 37.09 mmol) in methanol (105 mL). The reaction mixture was stirred at 25 ° C for 2 hours. The reaction was detected by LCMS. After the reaction was completed, the reaction solution was cooled to 0 ° C, and then an aqueous hydrochloric acid solution (1N) was added to adjust the reaction solution to pH = 4, and then extracted three times with ethyl acetate (50 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound A-4 (12.4 g, quantitative yield), which was a pink oil. The crude product was used directly in the next reaction. MS (ESI): m / z = 324.0, 326.0 [M+H] + .

[0101] Step 5: Synthesis of 5-bromo-2-[(5-cyano-2-fluorophenyl)methyl]pyrazole-3-carbonyl chloride (A-5)

[0102] At room temperature, SOCl2 (46 g, 337.49 mmol) was added to a reaction flask containing compound A-4 (12.4 g, 33.75 mmol). The reaction mixture was stirred at 90°C for 2 hours. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.4) indicated complete conversion of the starting material. After completion of the reaction, the reaction mixture was concentrated to give the title compound A-5 (13.4 g, crude product). The crude product was used directly in the next reaction.

[0103] Step 6: Synthesis of 3-{[3-bromo-5-(hydroxymethyl)pyrazol-1-yl]methyl}-4-fluorobenzene-1-carbonitrile (A-6)

[0104] At 0°C, NaBH4 (4.5 g, 114.4 mmol) was slowly added to a solution of compound A-5 (13.4 g, 38.13 mmol) in anhydrous tetrahydrofuran (130 mL). The reaction mixture was stirred at 0°C for 2 hours. TLC (petroleum ether: ethyl acetate = 6:1, Rf = 0.5) showed that the starting material was completely converted. After the reaction was completed, water (40 mL) was slowly added to the reaction solution to quench the reaction, and then extracted three times with ethyl acetate (400 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound A-6 (6.3 g, yield: 53%) as a white solid. MS (ESI): m / z = 310.0, 312.0 [M+H] + .

[0105] Step 7: Synthesis of 2-bromo-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (A)

[0106] Under nitrogen protection, compound A-6 (6.3 g, 20.39 mmol) was added to a mixture of sodium hydride (1.20 g, 30.58 mmol, 60%) in tetrahydrofuran (60 mL) at room temperature. The reaction mixture was then placed in a 95°C oil bath and stirred for 2 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride solution (40 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:99-10:90) to obtain intermediate A (2.4 g, yield: 41%) as a white solid. MS (ESI): m / z = 290.0, 292.0 [M+H] + .

[0107] 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J=2.0Hz,1H),7.69(dd,J=8.8,2.0Hz,1H),7.03(d,J=8.8Hz,1H),6.58(s,1H),5.71(s,2H),5.47(s,2H).

[0108] Intermediate F: Synthesis of N-{[2-bromo-3-(trifluoromethyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide

[0109] Step 1: Synthesis of ethyl 5-bromo-4-(trifluoromethyl)-2H-pyrazole-3-carboxylate (F-1)

[0110] At room temperature, NBS (117 g, 657.3 mmol) and glacial acetic acid (37 mL, 657.3 mmol) were added to a solution of compound F-0 (68.4 g, 328.6 mmol) in acetonitrile (500 mL). The reaction mixture was heated to 90°C and stirred overnight under argon. LCMS indicated complete conversion of the starting material. After cooling to room temperature, water (400 mL) was added to quench the reaction, followed by extraction with ethyl acetate (400 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:99-40:60) to obtain a crude product. The crude product was purified by slurrying with water (200 mL) to obtain the title compound F-1 (83.0 g, yield: 88.0%) as a white solid. MS (ESI): m / z = 288.8 [M+H] + .

[0111] 1 H NMR (400MHz, DMSO-d6) δ15.16(s,1H),4.36-4.27(m,2H),1.32 -1.26(m,3H).

[0112] Step 2: Synthesis of ethyl 5-bromo-2-[(5-cyano-2-fluorophenyl)methyl]-4-(trifluoromethyl)pyrazole-3-carboxylate (F-2) (

[0113] To a solution of compound F-1 (40.0 g, 139.4 mmol), A-2 (21.1 g, 139.4 mmol), and PPh3 (43.9 g, 167.2 mmol) in tetrahydrofuran (400 mL) at 0°C was slowly added dropwise DIAD (33.8 g, 167.2 mmol). After the addition was complete, the reaction solution was stirred at 0°C for 30 minutes, then slowly warmed to room temperature and stirred for half an hour. LCMS indicated complete conversion of the starting material. The reaction solution was quenched with water (500 mL) and extracted three times with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-15:85) to obtain the title compound F-2 (43.0 g, yield: 73.4%) as a white solid. MS(ESI):m / z=419.9,421.9[M+H] + .

[0114] 1 H NMR (400MHz, CDCl3) δ7.65(m,1H),7.46(dd,J=6.8,2.0Hz,1H),7.22(t,J=8.8Hz,1H),5.71(s,2H),4.41(q,J=7.2Hz,2H),1.37(t,J=7.2Hz,3H).

[0115] Step 3: Synthesis of 3-{[3-bromo-5-(hydroxymethyl)-4-(trifluoromethyl)pyrazol-1-yl]methyl}-4-fluorobenzene-1-carbonitrile (F-3)

[0116] Under nitrogen, a mixture of compound F-2 (10.0 g, 23.8 mmol), anhydrous calcium chloride (2.64 g, 23.8 mmol) in anhydrous tetrahydrofuran (100 mL), and anhydrous methanol (50 mL) was cooled to 0°C. NaBH4 (18.0 g, 47.6 mmol) was then added portionwise to the solution. After the addition was complete, the reaction mixture was stirred at 25°C for 30 minutes. LCMS indicated complete conversion of the starting material. After cooling to 0°C, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound F-3 (8.1 g, yield: 90.0%) as a white solid. MS (ESI): m / z = 378.1, 380.1 [M+H] + .

[0117] Step 4: Synthesis of 2-bromo-3-(trifluoromethyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (F-4)

[0118] Under argon protection, a solution of compound F-3 (724 mg, 2.34 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to 0°C, and t-BuONa (113.8 mg, 2.33 mmol) was slowly added. The reaction mixture was then slowly warmed to room temperature and stirred for 1 hour. LCMS showed complete conversion of the starting material. After cooling to 0°C, the reaction solution was quenched with water (10 mL) and extracted three times with ethyl acetate (15 mL). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound F-4 (696 mg, yield: 100%) as a white solid. MS (ESI): m / z = 357.9, 359.8 [M+H] + .

[0119] Step 5: Synthesis of [2-bromo-3-(trifluoromethyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methanamine (F)

[0120] Under argon, compound F-4 (696 mg, 1.94 mmol) was added to a pre-dried round-bottom flask. After the reaction flask was cooled to 0°C, BH3-THF (9.7 mL, 9.7 mmol, 1 M) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred for 1 hour. LCMS indicated complete conversion of the starting material. After cooling to 0°C, the reaction solution was quenched with methanol (1 mL) and concentrated under reduced pressure to obtain a residue. Ethyl acetate (20 mL) and saturated ammonium chloride solution (10 mL) were added to the residue, stirred at room temperature for 10 minutes, and then separated and extracted. The aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate F (687 mg, yield: 97.6%) as a white solid. MS (ESI): m / z = 362.9, 364.9 [M+H] + .

[0121] Intermediate G: Synthesis of N-{[2-bromo-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}-2,2,2-trifluoroacetamide

[0122] Under argon protection, a mixed solution of compound F (1.52 g, 4.20 mmol) and triethylamine (1.7 g, 16.79 mmol) in tetrahydrofuran (30 mL) was cooled to 0°C, and trifluoroacetic anhydride (1.8 g, 8.39 mmol) was then added dropwise to the solution. The reaction mixture was stirred at room temperature for 2 hours under argon protection. LCMS indicated complete conversion of the starting material. The reaction solution was quenched with water (30 mL) and extracted three times with ethyl acetate (60 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0:100-5:95) to obtain intermediate G (1.13 g, yield: 58.8%) as a white solid. MS (ESI): m / z = 457.9, 459.9 [M+H] + .

[0123] Intermediate H: Synthesis of N-[(2-bromo-3-methyl-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methyl]acetamide

[0124] Step 1: Synthesis of ethyl 5-bromo-2-[(5-cyano-2-fluorophenyl)methyl]-4-methylpyrazole-3-carboxylate (H-1)

[0125] At 0°C, DIAD (5.20 g, 25.72 mmol) was slowly added dropwise to a solution of compound H-0 (4.97 g, 21.44 mmol), A-2 (3.24 g, 21.44 mmol), and PPh3 (6.75 g, 25.72 mmol) in tetrahydrofuran (50 mL). After the addition was complete, the reaction solution was stirred at 0°C for 30 minutes, then slowly warmed to room temperature and continued stirring for half an hour. LCMS indicated complete conversion of the starting material. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-40:60) to obtain the title compound H-1 (5.19 g, yield: 66.1%) as a white solid. MS (ESI): m / z = 366.0, 368.0 [M+H] + .

[0126] 1 H NMR (400MHz, CDCl3) δ7.58(m,1H),7.19(d,J=9.2Hz,1H),7.15(dd,J=6.8,2.0H z,1H),5.77(s,2H),4.34(q,J=7.2Hz,2H),2.28(s,3H),1.35(t,J=7.2Hz,3H).

[0127] Step 2: Synthesis of 3-{[3-bromo-5-(hydroxymethyl)-4-methylpyrazol-1-yl]methyl}-4-fluorobenzene-1-carbonitrile (H-2)

[0128] Under nitrogen, a mixture of compound H-1 (5.29 g, 14.45 mmol), anhydrous calcium chloride (1.60 g, 14.45 mmol) in anhydrous tetrahydrofuran (50 mL), and anhydrous methanol (25 mL) was cooled to 0°C, and then NaBH4 (1.09 g, 28.89 mmol) was added portionwise to the solution. After the addition was complete, the reaction mixture was stirred at 25°C for 30 minutes. LCMS indicated complete conversion of the starting material. After cooling to 0°C, the reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound H-2 (4.75 g, yield: 101%) as a white solid. MS (ESI): m / z = 323.9, 325.9 [M+H] + .

[0129] Step 3: Synthesis of 2-bromo-3-methyl-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (H-3)

[0130] Under argon protection, a solution of compound H-2 (4.75 g, 14.65 mmol) in anhydrous tetrahydrofuran (60 mL) was cooled to 0°C, and t-BuONa (1.69 g, 17.58 mmol) was added in portions. The reaction mixture was then slowly warmed to room temperature and stirred for 1 hour. LCMS indicated complete conversion of the starting material. After cooling to 0°C, the reaction solution was quenched with dilute hydrochloric acid and diluted with water (30 mL). It was then extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound H-3 (4.45 g, yield: 99.8%) as a white solid. The product was used directly in the next reaction. MS (ESI): m / z = 303.9, 305.9 [M+H] + .

[0131] Step 4: Synthesis of 2-bromo-3-methyl-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (H-4)

[0132] Under argon, compound H-3 (4.45 g, 14.63 mmol) was added to a pre-dried round-bottom flask. After the reaction flask was cooled to 0°C, BH3-THF (73.1 mL, 73.1 mmol, 1 M) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred for 1 hour. LCMS indicated complete conversion of the starting material. After cooling to 0°C, the reaction solution was quenched with methanol (10 mL) and concentrated under reduced pressure to obtain a residue. Ethyl acetate (80 mL) and saturated sodium carbonate solution (20 mL, 5%) were added to the residual material, stirred at room temperature for 10 minutes, and then separated by extraction. The aqueous phase was extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound H-4 (4.26 g, yield: 94.4%) as a white solid. MS(ESI):m / z=290.9,292.9.[M+H] + .

[0133] Step 5: Synthesis of N-[(2-bromo-3-methyl-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methyl]acetamide (H)

[0134] Compound H-4 (3.21 g, 10.4 mmol) and triethylamine (4.21 g, 41.6 mmol) in anhydrous tetrahydrofuran (40 mL) were stirred in an ice bath for 10 minutes, followed by the dropwise addition of acetyl chloride (1.63 g, 20.8 mmol). The reaction mixture was stirred at 0°C for 1 hour. LCMS indicated complete conversion of the starting material. The reaction mixture was quenched with ice-water (30 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-99:1) to obtain the title compound H (1.42 g, yield: 39.0%) as a white solid. MS (ESI): m / z = 350.0, 352.0 [M+H] + .

[0135] 1 H NMR (400MHz, DMSO) δ8.27(t,J=5.6Hz,1H),7.21(d,J=2.0Hz,1H),7.14(dd,J=8.4,2.0Hz,1H),6.91(d,J= 8.4Hz,1H),5.48(d,J=7.6Hz,2H),5.27(d,J=6.8Hz,2H),4.16(d,J=6.0Hz,2H),1.92(s,3H),1.85(s,3H).

[0136] Using a similar method to compound H, replacing the corresponding starting materials, the compounds shown in the following table were obtained:

[0137] Intermediate L: Synthesis of [2-bromo-3-(trifluoromethyl)-4,10-dihydropyrido[3,2-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methanamine

[0138] Step 1: Synthesis of ethyl 5-bromo-2-[(5-bromo-2-chloropyridin-3-yl)methyl]-4-(trifluoromethyl)pyrazole-3-carboxylate (L-1)

[0139] At 0°C, DIAD (785 mg, 3.88 mmol) was slowly added dropwise to a solution of L-0 (720 mg, 3.24 mmol), ethyl 5-bromo-4-(trifluoromethyl)-2H-pyrazole-3-carboxylate (929 mg, 3.24 mmol), and PPh3 (1019 mg, 3.88 mmol) in anhydrous tetrahydrofuran (8 mL). After the addition was complete, the reaction solution was stirred at 0°C for 0.5 hours, then warmed to room temperature and stirred for 2 hours. LCMS indicated complete conversion of the starting material. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0:100-25:75) to obtain the title compound L-1 (1200 mg, yield: 75.4%) as a white solid. MS (ESI): m / z = 491.8, 493.8 [M+H] + .

[0140] Step 2: Synthesis of {5-bromo-2-[(5-bromo-2-chloropyridin-3-yl)methyl]-4-(trifluoromethyl)pyrazol-3-yl}methanol (L-2)

[0141] At 0°C, NaBH4 (239 mg, 6.31 mmol) was slowly added to a solution of compound L-1 (1.55 g, 3.15 mmol) and anhydrous calcium chloride (350 mg, 3.15 mmol) in anhydrous tetrahydrofuran (10 mL) and methanol (5 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. LCMS showed that a large amount of starting material remained. The reaction mixture was heated to 50°C and stirred for 2 hours. LCMS showed that the starting material was completely converted. The reaction solution was cooled to 0°C and saturated ammonium chloride solution (20 mL) was slowly added to quench the reaction. The mixture was then extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound L-2 (1.15 g, yield: 80.8%) as a white solid. MS (ESI): m / z = 449.8, 451.8 [M+H] + .

[0142] Step 3: Synthesis of 2,8-dibromo-3-(trifluoromethyl)-4,10-dihydropyrido[3,2-f]pyrazolo[5,1-c][1,4]oxazepine (L-3)

[0143] Under argon protection, a solution of compound L-2 (1.15 g, 2.55 mmol) in anhydrous tetrahydrofuran (10 mL) was cooled to 0°C, and then sodium tert-butoxide (294 mg, 3.06 mmol) was slowly added. The reaction mixture was slowly warmed to 25°C and stirred for 1 hour. LCMS showed that the starting material was completely converted. After cooling to 0°C, the reaction solution was quenched with dilute hydrochloric acid, diluted with water (30 mL), and extracted three times with ethyl acetate (40 mL). The combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0:100-26:74) to obtain the title compound L-3 (1.10 g, yield: 94.1%) as a white solid. MS (ESI): m / z = 413.8, 415.8 [M+H] + .

[0144] Step 4: Synthesis of 2-bromo-3-(trifluoromethyl)-4,10-dihydropyrido[3,2-f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (L-4)

[0145] Under argon, anhydrous DMF (6 mL) was added to a mixture of compound L-3 (1.10 mg, 2.66 mmol), zinc cyanide (156 mg, 1.33 mmol), Pd2(dba)3 (244 mg, 0.27 mmol), DPPF (295 mg, 0.53 mmol), and zinc powder (35 mg, 0.533 mmol). The reaction solution was purged with argon three times and stirred at 100°C for 2 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0:100-30:70) to obtain the title compound L-4 (635 mg, yield: 66.4%) as a light yellow solid. MS(ESI):m / z=358.9,360.9[M+H] + .

[0146] 1 H NMR (400MHz, CD3OD) δ8.58(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),5.77(s,2H),5.70(s,2H).

[0147] Step 5: Synthesis of [2-bromo-3-(trifluoromethyl)-4,10-dihydropyrido[3,2-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methanamine (L)

[0148] To a solution of compound L-4 (600 mg, 1.67 mmol) in tetrahydrofuran (2 mL) at 0°C, BH3-THF (5.0 mL, 5.0 mmol, 1 M) was slowly added dropwise. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 4 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was cooled to 0°C and quenched by the slow addition of methanol (20 mL). The mixture was concentrated under reduced pressure to afford intermediate L (300 mg, yield: 49.5%) as a white solid.

[0149] Example 1: Synthesis of 2,2,2-trifluoro-N-{[2-(2-fluorophenyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide

[0150] Step 1: Synthesis of 2-(2-fluorophenyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (1-1)

[0151] Under argon, to a dry, sealed tube equipped with a stirrer were added Intermediate A (200 mg, 0.689 mmol), 2-fluorophenylboronic acid (106 mg, 0.758 mmol), XPhos Pd G3 (70 mg, 0.083 mmol), anhydrous potassium phosphate (293 mg, 1.38 mmol), anhydrous 1,4-dioxane (2.0 mL), and water (0.6 mL). The reaction mixture was purged with argon three times and then heated to 100°C with stirring for 2 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (10 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-50:50) and further purified by reverse phase column chromatography (acetonitrile:water = 10:90-90:10, the aqueous solution containing 0.1% formic acid) to obtain the title compound 1-1 (120 mg, yield: 57.0%) as a light yellow solid. MS (ESI): m / z = 306.1 [M+H] + .

[0152] Step 2: Synthesis of [2-(2-fluorophenyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methanamine (1-2)

[0153] Under argon protection, compound 1-1 (450 mg, 1.54 mmol) and anhydrous tetrahydrofuran (3.0 mL) were added sequentially to a pre-dried round-bottom flask. After the reaction solution was cooled to 0°C, BH3-THF (1.38 mL, 1.38 mmol, 1 M) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred for 1 hour. LCMS indicated complete conversion of the starting material. After cooling to 0°C, the reaction solution was quenched with methanol (5 mL) and concentrated under reduced pressure to obtain a residue. The residue was purified using a reverse phase column (acetonitrile:water = 10:90-90:10, the aqueous solution containing 0.1% ammonium bicarbonate) to obtain the title compound 1-2 (82 mg, yield: 50.6%) as a white solid. MS (ESI): m / z = 310.1 [M+H] + .

[0154] Step 3: Synthesis of 2,2,2-trifluoro-N-{[2-(2-fluorophenyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (1)

[0155] Under argon protection, a mixed solution of compound 1-2 (96 mg, 0.31 mmol) and triethylamine (188 mg, 1.86 mmol) in dichloromethane (2 mL) was cooled to 0°C, and trifluoroacetic anhydride (78.2 mg, 0.37 mmol) was then added dropwise to the solution. The reaction mixture was stirred at room temperature under argon protection for 2 hours. LCMS indicated complete conversion of the starting material. The reaction solution was quenched with water (10 mL) and extracted three times with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 100:1-35:65) to obtain the title compound 1 (82 mg, yield: 65.2%) as an off-white solid. MS (ESI): m / z = 406.1 [M+H] + .

[0156] 1 H NMR (400MHz, DMSO-d6) δ9.92(s,1H),7.90(t,J=7.8Hz,1H),7.34(t,J=6.8Hz,1H),7.31-7.20(m,3H),7.16(dd,J =8.4,2.0Hz,1H),6.93(d,J=8.4Hz,1H),6.71(d,J=4.0Hz,1H),5.66(s,2H),5.38(s,2H),4.30(d,J=5.6Hz,2H).

[0157] Example 2: Synthesis of 2,2,2-trifluoro-N-{[2-(2-fluorophenyl)-3-iodo-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (2)

[0158] To a solution of compound 1 (82 mg, 0.202 mmol) in acetonitrile (1 mL) at room temperature was added NIS (50 mg, 0.223 mmol). The reaction mixture was heated to 80°C and stirred for 6 hours under argon. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 100:1-40:60) to obtain the title compound 2 (102 mg, yield: 94.9%) as a white solid. MS (ESI): m / z = 532.0 [M+H] + .

[0159] 1H NMR (400MHz, DMSO-d6) δ9.94 (t, J=5.6Hz, 1H), 7.53-7.41 (m, 2H), 7.36 -7.19(m,3H),7.22(dd,J=8.4,2.2Hz,1H),7.03(d,J=8.4Hz,1H),5.69(s,2H),5.31(s,2H),4.33(d,J=5.6Hz,2H).

[0160] Example 3: Synthesis of 2,2,2-trifluoro-N-{[2-(2-fluorophenyl)-3-methyl-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (3)

[0161] Under argon protection, a mixture of compound 2 (33 mg, 0.062 mmol), MeB(OH)2 (5.6 mg, 0.093 mmol), XPhos Pd G3 (9.1 mg, 0.11 mmol), potassium phosphate (39.6 mg, 0.186 mmol), 1,4-dioxane (0.6 mL), and water (0.2 mL) was added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C with stirring for 2 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 3 (12 mg, yield: 46.1%) as a white solid. MS (ESI): m / z = 420.1 [M+H] + .

[0162] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.50-7.40 (m, 2H), 7.32-7.22 (m, 3H), 7.17 (dd, J = 8.4, 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 5.61 (s, 2H), 5.35 (s, 2H), 4.31 (s, 2H), 1.97 (d, J = 2.0 Hz, 3H). A method similar to that of Example 3 was used, substituting the corresponding starting materials, to give the compounds shown in the following table:

[0163] Example 4: Synthesis of 2,2,2-trifluoro-N-{[2-(2-fluorophenyl)-3-(trifluoromethyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (4)

[0164] Under argon protection, compound 4-1 (89 mg, 0.467 mmol) was slowly added to a mixture of compound 2 (62 mg, 0.117 mmol), cuprous iodide (45 mg, 0.233 mmol), HMPA (84 mg, 1.467 mmol) and DMF (0.5 mL). The mixture was stirred at 100°C under argon protection for 72 hours. LCMS showed complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (10 mL) and extracted three times with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 4 (17.4 mg, yield: 31.5%) as a white solid. MS (ESI): m / z = 420.1 [M+H] + .

[0165] 1 H NMR(400MHz,DMSO-d6)δ9.90(brs,1H),7.57-7.42(m,2H),7.40-7.21(m,4H) ,7.10-7.03(m,1H),5.80-5.70(m,2H),5.53-5.44(m,2H),4.40-4.29(m,2H).

[0166] Example 5: Synthesis of N-[(2-cyclohexyl-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methyl]acetamide (5)

[0167] Step 1: Synthesis of 2-(cyclohex-1-enyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (5-1)

[0168] Under argon, to a mixture of Intermediate A (450 mg, 1.55 mmol), B2 (348 mg, 1.71 mmol), Xphos Pd G3 (131 mg, 0.155 mmol), and potassium phosphate (659 mg, 3.10 mmol) were added 1,4-dioxane (4.5 mL) and water (1.1 mL). The mixture was replaced with argon three times and then heated to 100°C with stirring for 2 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (30 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99 to 50:50) to obtain 5-1 (450 mg, yield: 97.6%) as a light yellow foamy solid. MS (ESI): m / z = 292.1 [M+H] + .

[0169] Step 2: Synthesis of [2-(cyclohex-1-enyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methanamine (5-2)

[0170] Under argon protection, BH3-THF (4.6 mL, 4.6 mmol, 1 M) was added dropwise to a solution of compound 5-1 (450 mg, 1.55 mmol) in tetrahydrofuran at 0°C. The mixture was then slowly warmed to room temperature and stirred for 1 hour. LCMS indicated complete conversion of the starting material. The reaction solution was quenched with methanol (30 mL), diluted with water (30 mL), and extracted three times with methanol / dichloromethane (v / v, 1 / 10, 50 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:99-10:90) to obtain the title compound 5-2 (252 mg, yield: 51.4%) as a white solid. MS (ESI): m / z = 296.1 [M+H] + .

[0171] Step 3: Synthesis of (2-cyclohexyl-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methanamine (5-3)

[0172] Under argon, Pd / C (10%, 70 mg, 0.66 mmol) was added to a solution of compound 5-2 (125 mg, 0.42 mmol) in methanol (3 mL). The mixture was stirred at room temperature under hydrogen (15 psi) for 2 hours. LCMS indicated complete conversion of the starting material. The reaction solution was quenched with methanol (20 mL), diluted with water (20 mL), and extracted three times with methanol / dichloromethane (v / v, 1:10, 50 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 5-3 (126 mg, yield: 95.1%) as a light yellow foamy solid. MS (ESI): m / z = 298.1 [M+H] + .

[0173] Step 4: Synthesis of N-[(2-cyclohexyl-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methyl]acetamide (5)

[0174] To a solution of compound 5-3 (126 mg, 0.42 mmol) in dichloromethane (3 mL) were added sodium carbonate (90 mg, 0.85 mmol) and acetic anhydride (0.060 mL, 0.64 mmol). The reaction mixture was purged with argon and allowed to react at room temperature for 2 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was quenched with water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-99:1) to obtain the title compound 5 (98 mg, yield: 66.8%) as a yellow solid. MS (ESI): m / z = 340.2 [M+H] + .

[0175] Example 6: Synthesis of N-[(2-cyclohexyl-3-iodo-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methyl]acetamide (6)

[0176] To a solution of compound 5 (98 mg, 0.29 mmol) in dichloromethane (2 mL) was added N-iodosuccinimide (117 mg, 0.52 mmol). The reaction mixture was stirred at 80°C under argon for 18 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:99-5:95) to obtain the title compound 6 (120 mg, yield: 81.3%) as a white solid. MS (ESI): m / z = 466.1 [M+H] + .

[0177] 1 H NMR (400MHz, CD3OD) δ7.17-7.33(m,2H),6.99-7.12(m,2H),5.44(s,2H),5.14(s,2H),4.30(s, 2H),2.55-2.63(m,1H),1.97(s,3H),1.79-1.87(m,4H),1.48-1.58(m,2H),1.25-1.46(m,4H).

[0178] Example 7: Synthesis of N-{[2-cyclohexyl-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepine (7)

[0179] Under argon protection, 4-1 (301.8 mg, 1.57 mmol) was slowly added to a mixture of compound 6 (75 mg, 0.16 mmol), cuprous iodide (30.7 mg, 0.16 mmol), HMPA (206 mg, 1.15 mmol), and DMF (0.1 mL). The mixture was stirred at 85°C for 48 hours under argon protection. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:99-5:95) to obtain the title compound 7 (16.6 mg, yield: 24.3%) as a white solid. MS (ESI): m / z = 408.2 [M+H] + .

[0180] 1H NMR (400MHz, CD3OD) δ7.16-7.44(m,2H),7.06(d,J=8.0Hz,1H),5.47(s,2H),5.30(d,J=1.2Hz,2H),4.3 1(s,2H),2.65-2.77(m,1H),1.97(s,3H),1.85(t,J=13.2Hz,4H),1.49-1.60(m,2H),1.31-1.46(m,4H).

[0181] Using a method similar to Examples 1 to 6, replacing the corresponding starting materials, the compounds shown in the following table were obtained:

[0182] Example 10: Synthesis of N-{[2-cyclohexyl-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}-2,2,2-trifluoroacetamide (10)

[0183] Step 1: Synthesis of N-[(2-cyclohexyl-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methyl]-2,2,2-trifluoroacetamide (8)

[0184] Under argon protection, trifluoroacetic anhydride (150 mg, 0.71 mmol) was added to a mixture of compound 8-1 (106 mg, 0.36 mmol) and sodium carbonate (113 mg, 1.07 mmol) in dichloromethane (2 mL). The reaction mixture was purged with argon three times and stirred at room temperature for 2 hours. LCMS indicated complete conversion of the starting material. The reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:99-10:90) to obtain the title compound 8 (88 mg, yield: 61.5%) as a light yellow foamy solid. MS (ESI): m / z = 394.1 [M+H] + .

[0185] Step 2: Synthesis of N-[(2-cyclohexyl-3-iodo-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methyl]-2,2,2-trifluoroacetamide (9)

[0186] To a solution of compound 8 (88 mg, 0.22 mmol) in dichloromethane (1 mL) was added NIS (90.6 mg, 0.40 mmol). The reaction mixture was stirred at 80°C under argon for 18 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:99-5:95) to obtain the title compound 9 (70 mg, yield: 56.0%) as a white solid. MS (ESI): m / z = 520.1 [M+H] + .

[0187] 1 H NMR(400MHz,CD3OD)δ7.24-7.27(m,2H),6.95-7.17(m,1H),5.45(s,2H),5.16 (s,2H),4.41(s,2H),2.56-2.63(m,1H),1.80-1.88(m,4H),1.25-1.60(m,6H).

[0188] Step 3: Synthesis of N-{[2-cyclohexyl-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}-2,2,2-trifluoroacetamide (10)

[0189] Under argon, to a mixture of compound 9 (70 mg, 0.14 mmol), cuprous iodide (51 mg, 0.27 mmol), HMPA (206 mg, 1.15 mmol), and DMF (0.2 mL) was slowly added 4-1 (302 mg, 1.57 mmol). The mixture was heated to 130°C in a microwave oven under argon and stirred for 10 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:99-5:95) to obtain the title compound 10 (19.5 mg, yield: 31.4%) as a light yellow solid. MS (ESI): m / z = 462.1 [M+H] + .

[0190] 1H NMR (400MHz, CD3OD) δ7.27(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,1H),5.48(s,2H),5.31(s,2H),4.41( s,2H),2.72(t,J=12.0Hz,1H),1.80-1.89(m,4H),1.54(dd,J=24.0,12.0Hz,2H),1.31-1.44(m,4H).

[0191] Example 45-2: Synthesis of 5-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pent-4-yn-1-ol

[0192] Step 1: Synthesis of 5-(2-bromophenyl)pent-4-yn-1-ol (45-1)

[0193] Under nitrogen, to a mixture of compound 45-0 (10.0 g, 35.35 mmol) and pent-4-yn-1-ol (3.8 g, 45.95 mmol) in triethylamine (100 mL) were added cuprous iodide (269 mg, 1.41 mmol) and Pd(PPh3)4 (817 mg, 0.71 mmol). The mixture was stirred at 25°C for 16 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (100 mL) and extracted three times with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-25:75) to obtain the title compound 45-1 (4.05 g, yield: 48%) as a yellow oil.

[0194] 1 H NMR (400MHz, CDCl3) δ7.55 (dd, J=8.0, 1.0Hz, 1H), 7.41 (dd, J=7.7, 1.6Hz, 1H), 7.22 (td, J=7.6, 1.2H z,1H),7.11(td,J=7.8,1.7Hz,1H),3.85(q,J=6.2Hz,2H),2.59(t,J=6.9Hz,2H),1.93-1.84(m,2H).

[0195] Step 2: Synthesis of 5-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]pent-4-yn-1-ol (45-2)

[0196] Under nitrogen, to a mixture of compound 45-1 (4.2 g, 17.71 mmol), (Bpin)2 (6.7 g, 26.57 mmol), and potassium acetate (5.2 g, 53.13 mmol) in DMSO (200 mL) was added Pd(dppf)Cl2 (1.3 g, 1.77 mmol). The mixture was stirred at 80°C for 16 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (100 mL) and extracted three times with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-20:80) to obtain the title compound 45-2 (2.17 g, yield: 42.8%) as an orange-red oil. MS (ESI): m / z = 287.2 [M+H] + .

[0197] 1 H NMR(400MHz, DMSO-d6)δ7.59(d,J=7.2Hz,1H),7.39(dt,J=12.0,3.8Hz,2H),7.32-7.27(m,1H),4.48(t, J=5.2Hz,1H),3.56(dd,J=11.6,6.2Hz,2H),2.45(t,J=7.2Hz,2H),1.71(t,J=6.8Hz,2H),1.30(s,12H).

[0198] Example 46: N-({2-[2-(5-hydroxypent-1-ynyl)phenyl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide

[0199] Step 1: Synthesis of 2-[2-(5-hydroxypent-1-ynyl)phenyl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (46-1)

[0200] Under argon, intermediate A (110 mg, 0.38 mmol), compound 45-2 (163 mg, 0.57 mmol), Xphos Pd G3 (32 mg, 0.038 mmol), and potassium phosphate (161 mg, 0.76 mmol) were mixed thoroughly. 1,4-dioxane (1.2 mL) and water (0.3 mL) were added. The mixture was heated to 100°C under argon for 2 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99 to 50:50) to obtain the title compound 46-1 (85 mg, 54.6% yield) as a pale yellow foamy solid. MS (ESI): m / z = 370.2 [M+H] + .

[0201] Step 2: Synthesis of 5-{2-[8-(aminomethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-2-yl]phenyl}pent-4-yn-1-ol (46-2)

[0202] Under argon protection, a tetrahydrofuran solution of compound 46-1 (85 mg, 0.23 mmol) was added dropwise with a tetrahydrofuran solution of lithium aluminum tetrahydride (0.92 mL, 0.92 mmol, 1.0 M) at 0°C. The mixture was reacted at 0°C under argon protection for 2 hours. LCMS showed that the starting material had been completely converted. The reaction solution was quenched with water (20 mL) and extracted three times with methanol / dichloromethane (v / v, 1 / 10, 50 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 46-2, which was used directly in the next step. MS (ESI): m / z = 374.3 [M+H] + .

[0203] Step 3: Synthesis of N-({2-[2-(5-hydroxypent-1-ynyl)phenyl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide (46)

[0204] Compound 46-2 (83 mg, 0.22 mmol) and sodium carbonate (71 mg, 0.67 mmol) were mixed thoroughly, followed by the addition of dichloromethane (2 mL) and acetic anhydride (0.042 mL, 0.44 mmol). The reaction mixture was allowed to react at room temperature under an argon atmosphere for 2 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 46 (1.7 mg, 1.9% yield) as a white solid. MS (ESI): m / z = 416.2 [M+H] + .

[0205] 1 H NMR (400MHz, CD3OD) δ7.70(d,J=8.0Hz,1H),7.44(d,J=8.0Hz,1H),7.30-7.36(m,1H),7.21-7.29(m,3H),7.00(d,J=8.0Hz,1H),6 .89(s,1H),5.56(s,2H),5.33(s,2H),4.31(s,2H),3.63(t,J=8.0Hz,2H),2.51(t,J=8.0Hz,2H),1.98(s,3H),1.73-1.80(m,2H).

[0206] A similar method to Example 46 was used, substituting the corresponding starting materials to obtain the compounds shown in the following table:

[0207] Example 60: Synthesis of 2-(2-fluorophenyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (60)

[0208] Step 1: Synthesis of N-{[2-bromo-3-(trifluoromethyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (59)

[0209] Intermediate F (687 mg, 1.90 mmol) and triethylamine (768 mg, 7.59 mmol) in anhydrous tetrahydrofuran (10 mL) were stirred in an ice bath for 10 minutes, followed by the dropwise addition of acetyl chloride (298 mg, 3.79 mmol). The reaction mixture was purged with argon and stirred at 0°C for 1 hour. LCMS indicated complete conversion of the starting material. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-99:1) to obtain the title compound 59 (400 mg, yield: 52.2%) as a white solid. MS (ESI): m / z = 404.0, 406.0 [M+H] + .

[0210] 1 H NMR(400MHz, DMSO-d6)δ8.33-8.26(m,1H),7.31(d,J=2.0Hz,1H),7.22(dd,J=8.4,2.0Hz,1H), 7.05(d,J=8.4Hz,1H),5.61(s,2H),5.41(d,J=0.8Hz,2H),4.19(d,J=6.0Hz,2H),1.86(s,3H).

[0211] Step 2: Synthesis of 2-(2-fluorophenyl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (60)

[0212] Under argon, compound 59 (35 mg, 0.087 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)pyrazole (29.5 mg, 0.113 mmol), XPhos Pd G3 (15.7 mg, 0.019 mmol), anhydrous potassium phosphate (73.5 mg, 0.346 mmol), anhydrous 1,4-dioxane (0.3 mL), and water (0.1 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C with stirring for 3 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (10 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-99:1) to obtain the title compound 60 (35 mg, yield: 88.0%) as a white solid. MS (ESI): m / z = 460.1 [M+H] + .

[0213] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.30(t,J=5.6Hz,1H),8.16(s,1H),7.31(d,J=2.0Hz,1H),7.21(dd ,J=8.4,2.0Hz,1H),7.04(d,J=8.4Hz,1H),5.68(s,2H),5.47(s,2H),4.19(d,J=6.0Hz,2H),1.85(s,3H).

[0214] Using a method similar to Example 60, replacing the corresponding starting materials, the compounds shown in the following table were obtained:

[0215] Synthesis of Examples 109 and 110: N-({2-[(1s,4s)-4-(hydroxymethyl)cyclohexyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide or N-({2-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide Synthesis of N-({2-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide or N-({2-[(1s,4s)-4-(hydroxymethyl)cyclohexyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide

[0216] Step 1: Example 107: Synthesis of methyl 4-{8-[(acetylamino)methyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-2-yl}cyclohex-3-ene-1-carboxylate (107)

[0217] Under argon protection, 1,4-dioxane (1.5 mL) and water (0.5 mL) were added to a mixture of intermediate C (130 mg, 0.32 mmol), 107-0 (100 mg, 0.38 mmol), Xphos Pd G3 (27.2 mg, 0.032 mmol) and potassium phosphate (136.5 mg, 0.64 mmol). The mixture was replaced with argon three times and then heated to 100°C and stirred for 2 hours. LCMS showed complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (30 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase silica gel column chromatography to obtain the title compound 107 (123 mg, yield: 72.0%) as a white solid. MS (ESI): m / z = 464.3 [M+H] + .

[0218] 1 H NMR (400MHz, CD3OD) δ7.27(d,J=8.0Hz,2H),7.07(d,J=12.0Hz,1H),6.00(s,1H),5.49(s,2H),5.33(s,2H),4.3 1(s,2H),3.70(s,3H),2.72-2.59(m,1H),2.53-2.31(m,4H),2.17-2.06(m,1H),1.97(s,3H),1.82-1.73(m,1H).

[0219] Step 2: Example 108: Synthesis of N-({2-[4-(hydroxymethyl)cyclohex-1-enyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide (108)

[0220] Under argon protection, a tetrahydrofuran solution of compound 107 (78 mg, 0.17 mmol) was cooled to 0°C, and a tetrahydrofuran solution of lithium aluminum hydroxide (0.4 mL, 1.00 mmol, 1.0 M) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 2 hours. LCMS indicated that the starting material had been completely converted. The reaction solution was quenched with ammonium chloride solution (20 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 108 (32.4 mg, yield: 44.3%) as a white solid. MS (ESI): m / z = 436.1 [M+H] + .

[0221] 1 H NMR (400MHz, CD3OD) δ7.35-7.21(m,2H),7.07(d,J=8.0Hz,1H),5.98(s,1H),5.49(s,2H),5.33(d,J=1.2Hz, 2H),4.31(s,2H),3.53-3.45(m,2H),2.46-2.27(m,3H),1.97(s,3H),1.95-1.76(m,3H),1.51-1.31(m,1H).

[0222] Step 3: Synthesis of 109 and 110: N-({2-[(1s,4s)-4-(hydroxymethyl)cyclohexyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide or N-({2-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide Synthesis of amine and N-({2-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide or N-({2-[(1s,4s)-4-(hydroxymethyl)cyclohexyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide (109, 110)

[0223] Under argon, Pd / C (10%, 24 mg, 0.02 mmol) was added to a solution of compound 108 (24 mg, 0.055 mmol) in methanol (2 mL). The mixture was stirred at room temperature under hydrogen (15 psi) for 8 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compounds 109 (9.1 mg, yield: 37.0%) and 110 (2.9 mg, yield: 11.8%) as white solids.

[0224] Example 109: MS (ESI): m / z=438.1 [M+H] + .

[0225] 1H NMR (400MHz, CD3OD) δ7.26(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,1H),5.48(s,2H),5.31(s,2H),4.31(s,2H),3.68-3.56(m, 1H),3.40(d,J=4.0Hz,2H),2.69(t,J=12.0Hz,1H),1.97(s,3H),1.95-1.89(m,4H),1.72-1.40(m,3H),1.12-1.02(m,2H);

[0226] Example 110: MS (ESI): m / z=438.1 [M+H] + .

[0227] 1 H NMR(400MHz,CD3OD)δ7.45-7.21(m,2H),7.06(d,J=8.0Hz,1H),5.49(s,2H),5.31(s,2H),4.3 1(s,2H),3.72-3.51(m,3H),2.86(s,1H),1.98(s,3H),1.81-1.72(m,5H),1.76-1.53(m,3H).

[0228] Example 112: Synthesis of N-({2-[1-(cyclopropylmethyl)pyrazol-3-yl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide (112)

[0229] Step 1: Synthesis of 4-bromo-3-cyclopropyl-1-methylpyrazole (112-1)

[0230] Under nitrogen, a solution of 4-bromo-3-cyclopropyl-1H-pyrazole (500 mg, 2.67 mmol) in anhydrous THF (8 mL) was cooled to 0°C, and sodium hydride (160 mg, 4.01 mmol, 60%) was added portionwise to the solution. The reaction mixture was stirred at 0°C for 30 minutes, and then MeI (759 mg, 5.75 mmol) was added dropwise. The reaction mixture was stirred at room temperature over the weekend. LCMS indicated complete conversion of the starting material. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted three times with ethyl acetate (10 mL). The combined organic phases were washed sequentially with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99 to 40:60) to obtain the title compound 112-1 (209 mg, yield: 38.9%) as a colorless oil. MS(ESI):m / z=200.9,202.9[M+H] + .

[0231] Step 2: Synthesis of 3-cyclopropyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (112-2)

[0232] Under argon, compound 112-1 (209 mg, 1.04 mmol), bispinacol boronate (396 mg, 1.56 mmol), Pd2(dba)3 (47.6 mg, 0.052 mmol), Xphos (44.1 mg, 0.104 mmol), anhydrous KOAc (204 mg, 2.08 mmol), and anhydrous 1,4-dioxane (2 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C and stirred overnight. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (20 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99 to 40:60) to obtain the title compound 112-2 (109 mg, yield: 42.3%) as a light yellow oil. MS (ESI): m / z = 249.1 [M+H] + .

[0233] Step 3: Synthesis of N-({2-[1-(cyclopropylmethyl)pyrazol-3-yl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide (112)

[0234] Under argon, compound 59 (30 mg, 0.074 mmol), 112-2 (36.7 mg, 0.148 mmol), XPhos Pd G3 (6.3 mg, 0.007 mmol), K2CO3 (21 mg, 0.148 mmol), 1,4-dioxane (0.3 mL), and water (0.1 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times, heated to 100°C, and stirred for 3 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was extracted twice with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 10:90-90:10, aqueous solution containing 0.08% HCOOH) to obtain the title compound 112 (15.6 mg, yield: 47.3%) as a white solid. MS (ESI): m / z = 446.1 [M+H] + .

[0235] 1 H NMR (400MHz, DMSO-d6) δ8.30(t,J=5.6Hz,1H),7.66(s,1H),7.32(d,J=2.0Hz,1H),7.20(dd,J=8.4,2.0Hz,1H),7.03(d,J=8.4Hz,1H) ,5.65(s,2H),5.43(s,2H),4.18(d,J=6.0Hz,2H),3.75(s,3H),2.17-2.08(m,1H),1.85(s,3H),0.82-0.76(m,2H),0.75-0.70(m,2H).

[0236] A similar method to Example 112 was used to replace the corresponding starting materials to obtain the compounds shown in the following table:

[0237] Example 113: Synthesis of N-{[3-(trifluoromethyl)-2-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (113)

[0238] Under argon, compound 59 (30 mg, 0.074 mmol), 4,4,5,5-tetramethyl-2-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,3,2-dioxaborolane (23.3 mg, 0.089 mmol), cataCXium A (5.3 mg, 0.015 mmol), Pd(OAc)2 (1.7 mg, 0.007 mmol), Cu2O (14.1 mg, 0.074 mmol), Cs2CO3 (72.3 mg, 0.222 mmol), and anhydrous cyclopentyl methyl ether (0.3 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 120°C with stirring for 24 h. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was diluted with methanol (3 mL) and filtered. The solution was purified by prep-HPLC (acetonitrile:water = 10:90 to 90:10, the aqueous solution containing 0.08% HCOOH) to obtain the title compound 113 (17.5 mg, yield: 51.5%) as a white solid. MS (ESI): m / z = 460.1 [M+H] + .

[0239] 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H),7.33-7.26(m,1H),7.18(dd,J=8.4,2.0Hz,1H),7.00(t,J=7.6Hz,1H ),5.61(d,J=6.0Hz,2H),5.47(s,2H),5.39(d,J=9.2Hz,2H),4.20-4.12(m,2H),2.30(s,4H),1.85(s,3H).

[0240] Using a method similar to Example 113, replacing the corresponding starting materials, the compounds shown in the following table were obtained:

[0241] Example 115: Synthesis of N-{[2-(5-cyclopropyl-1,3-thiazeolan-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide

[0242] Step 1: N-{[3-(trifluoromethyl)-2-(trimethyl-λ 4 Synthesis of 4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (115-1)

[0243] Under argon protection, compound 59 (500 mg, 1.23 mmol), hexamethyltin (527 mg, 1.61 mmol), Pd(PPh3)4 (143 mg, 0.124 mmol) and toluene (5 mL) were added in sequence to a dry sealed tube equipped with a stirrer. The reaction mixture was replaced with argon three times and then heated to 110°C and stirred for 48 hours. LCMS showed that the starting material was completely converted. After cooling to room temperature, a saturated aqueous KF solution (10 mL) was added to quench the reaction. After stirring at room temperature for 1 hour, the mixture was filtered to remove insoluble matter. The filtrate was extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 50:90-90:10, the aqueous solution containing 0.08% NH4HCO3) to afford the title compound 115-1 (215 mg, yield: 35.6%) as a white solid. MS (ESI): m / z = 488.0, 490.0 [M+H] + .

[0244] 1 H NMR (400MHz, CD3OD) δ7.27(s,1H),7.26-7.22(m,1H),7.05(d,J=8.4Hz,1H),5.57(s,2H),5.35(s,2H),4.30(s,2H),1.96(s,3H),0.40-0.23(m,9H).

[0245] Step 2: Synthesis of N-{[2-(5-cyclopropyl-1,3-thiazolin-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (115)

[0246] Under argon, 115-1 (70 mg, 0.14 mmol), 2-bromo-5-cyclopropylthiazole (38 mg, 0.19 mmol), CuI (3 mg, 0.014 mmol), Pd(PPh3)4 (17 mg, 0.014 mmol), and toluene (0.5 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C and stirred for 16 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0:100-5:95) to obtain a crude product. The crude product was further purified by prep-HPLC to obtain the title compound 115 (48 mg, yield: 74.8%) as a white solid. MS (ESI): m / z = 449.2 [M+H]+ .

[0247] 1 H NMR(400MHz,CD3OD)δ7.55(s,1H),7.34-7.31(m,1H),7.31-7.26(m,1H),7.14-7.09(m,1H),5.59(s,2H), 5.40(d,J=1.2Hz,2H),4.32(s,2H),2.21-2.12(m,1H),1.97(s,3H),1.15-1.06(m,2H),0.81-0.74(m,2H).

[0248] Using a method similar to that of Example 115 above, replacing the corresponding starting materials, the compounds shown in the following table were obtained:

[0249] Example 118: Synthesis of N-{[2-(4-cyclopropylpyridin-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (118)

[0250] Step 1: 4-cyclopropyl-2-(trimethyl-λ 4 Synthesis of (118-1)-tin-pyridine

[0251] Under argon protection, anhydrous 1,4-dioxane (0.8 mL) was added to a mixture of compound 118-0 (40 mg, 0.26 mmol), hexamethyltin (128 mg, 0.39 mmol), and tetrakistriphenylphosphine palladium (30 mg, 0.026 mmol). The mixture was replaced with argon three times and then heated to 100°C and stirred for 6 hours. LCMS showed complete conversion of the starting material. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure to obtain crude product 118-1. The crude product was used directly in the next reaction without purification. MS (ESI): m / z = 284.2 [M+H] + .

[0252] Step 2: Synthesis of N-{[2-(4-cyclopropylpyridin-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (118)

[0253] Under argon protection, Pd(PPh3)2Cl2 (6.9 mg, 0.010 mmol) was added to a mixture of compound 59 (40 mg, 0.099 mmol), 118-1 (55.8 mg, 0.198 mmol) and 1,4-dioxane (1 mL). The reaction mixture was replaced with argon three times, heated to 100°C and stirred for 12 hours. LCMS showed complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 118 (5.4 mg, yield: 12.3%) as a white solid. MS (ESI): m / z = 443.1 [M+H] + .

[0254] 1 H NMR (400MHz, CD3OD) δ8.40(d,J=8.0Hz,1H),7.38(d,J=1.6Hz,1H),7.32-7.27(m,2H),7.17-7.08(m,2H),5.63(s ,2H),5.42(d,J=1.2Hz,2H),4.33(s,2H),2.04-1.99(m,1H),1.98(s,3H),1.21-1.12(m,2H),0.91-0.83(m,2H).

[0255] Example 119: Synthesis of N-{[2-(5-cyclopropylthiophen-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (119)

[0256] Step 1: Synthesis of 2-cyclopropylthiophene (119-1)

[0257] Under argon protection, compound 119-0 (1200 mg, 7.36 mmol), cyclopropylboronic acid (822 mg, 9.57 mmol), XPhos Pd G3 (623 mg, 0.74 mmol), potassium phosphate (3.12 g, 14.72 mmol), a mixed solvent of 1,4-dioxane (12 mL) and water (2 mL) were added in sequence to a dry sealed tube equipped with a stirrer. The reaction mixture was replaced with argon three times, heated to 100°C and stirred for 3 hours. LCMS showed that the starting material was completely converted. After cooling to room temperature, the reaction solution was quenched with water (30 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane:petroleum ether = 0:100-20:80) to obtain the title compound 119-1 (360 mg, yield: 39.4%) as a colorless oil. MS (ESI): m / z = 125.1 [M+H] + .

[0258] Step 2: Synthesis of 2-bromo-5-cyclopropylthiophene (119-2)

[0259] At room temperature, NBS (516 mg, 2.90 mmol) and acetic acid (3 mL) were added sequentially to a solution of compound 119-1 (360 mg, 2.90 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 3 hours under argon protection. LCMS showed complete conversion of the starting material. The reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane: petroleum ether = 1:99-99:1) to obtain the title compound 119-2 (440 mg, yield: 74.7%) as a light yellow oil. MS (ESI): m / z = 203.1, 205.1 [M+H] + .

[0260] Step 3: Synthesis of 2-(5-cyclopropylthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (119-3)

[0261] Under argon protection, intermediate 119-2 (140 mg, 0.69 mmol), bis-pinacol boronate (350 mg, 1.38 mmol), Pd (dppf) Cl2 .To a mixture of CH2Cl2 (56.3 mg, 0.069 mmol) and potassium acetate (203 mg, 2.07 mmol) was added 1,4-dioxane (3 mL). The mixture was replaced with argon three times and then heated to 90°C and stirred for 12 hours. LCMS showed that the starting material was completely converted. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 119-3. The crude product was used directly in the next reaction without purification. MS (ESI): m / z = 251.3 [M+H] + .

[0262] Step 4: Synthesis of N-{[2-(5-cyclopropylthiophen-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (119)

[0263] Under argon, a mixture of compound 59 (100 mg, 0.25 mmol), 119-3 (160.9 mg, 0.64 mmol), XPhos Pd G3 (20.9 mg, 0.025 mmol), potassium phosphate (105 mg, 0.50 mmol), 1,4-dioxane (2.5 mL), and water (0.5 mL) was added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C and stirred for 3 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 119 (12.2 mg, yield: 11.0%) as a white solid. MS (ESI): m / z = 448.2 [M+H] + .

[0264] 1 H NMR (400MHz, CD3OD) δ7.31-2.27(m,2H),7.18-6.97(m,2H),6.74(d,J=4.0Hz,1H),5.54(s,2H),5.37 (d,J=4.0Hz,2H),4.32(s,2H),2.22-2.06(m,1H),1.98(s,3H),1.11-0.96(m,2H),0.78-0.70(m,2H).

[0265] Example 120: Synthesis of N-{[2-(spiro[3.5]non-6-en-7-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide:

[0266] Step 1: Synthesis of spiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (120-1)

[0267] Under nitrogen, a solution of compound 120-0 (200 mg, 1.45 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (569 mg, 1.59 mmol) in anhydrous tetrahydrofuran (2.0 mL) was cooled to -70°C, and LiHMDS (1.8 mL, 1.0 M, 1.8 mmol) was then added dropwise. After the addition was complete, the reaction was stirred at -70°C for 1 hour, then slowly warmed to 0°C and stirred for 20 minutes. TLC confirmed the reaction was complete. The reaction was cooled to -20°C, quenched with saturated ammonium chloride solution (2 mL), and extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-10:90) to afford the title compound 120-1 (315 mg, yield: 80.5%) as a colorless oil.

[0268] 1 H NMR (400MHz, CDCl3) δ5.68-5.61(m,1H),2.37-2.29(m,2H),2.26-2.20(s,2H),1.97-1.86(m,2H),1.85-1.72(m,6H).

[0269] Step 2: Synthesis of 4,4,5,5-tetramethyl-2-(spiro[3.5]non-6-en-7-yl)-1,3,2-dioxaborolane (120-2)

[0270] Under argon, compound 120-1 (270 mg, 1.00 mmol), bis(pinacol boronate) (380 mg, 1.50 mmol), Pd(dppf)Cl2·CH2Cl2 (81.6 mg, 0.10 mmol), anhydrous KOAc (294 mg, 3.00 mmol), and anhydrous 1,4-dioxane (3.0 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C and stirred for 6 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (20 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-10:90) to obtain the title compound 120-2 (159 mg, yield: 64.1%) as a colorless oil. MS (ESI): m / z = 249.1 [M+H] + .

[0271] Step 3: Synthesis of N-{[2-(spiro[3.5]non-6-en-7-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (120)

[0272] Under argon, compound 59 (40 mg, 0.099 mmol), 120-2 (34.4 mg, 0.139 mmol), XPhos Pd G3 (8.4 mg, 0.010 mmol), K2CO3 (27.4 mg, 0.198 mmol), 1,4-dioxane (0.4 mL), and water (0.13 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times, heated to 100°C, and stirred for 3 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was extracted three times with ethyl acetate (5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 50:90-90:10, the aqueous solution containing 0.08% NH4HCO3) to afford the title compound 120 (30 mg, yield: 68.0%) as a white solid. MS (ESI): m / z = 446.1 [M+H] + .

[0273] 1H NMR (400MHz, DMSO-d6) δ8.28(t,J=5.6Hz,1H),7.28(d,J=2.0Hz,1H),7.19(dd,J=8.4,2.0Hz,1H),7.00(d,J=8.4Hz,1H), 5.85(br,1H),5.57(s,2H),5.37(s,2H),4.17(d,J=6.0Hz,2H),2.35-2.27(m,2H),2.23-2.16(m,2H),1.94-1.63(m,11H).

[0274] A similar method to Example 120 was used, replacing the corresponding reagents, to obtain the compounds shown in the following table:

[0275] Example 123: Synthesis of N-{[2-(spiro[3.5]nonan-7-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide

[0276] Under argon, to a solution of compound 120 (30 mg, 0.067 mmol) in methanol (5 mL) was added Pd / C (10%, 35 mg, 0.33 mmol). The mixture was stirred at room temperature under hydrogen (15 psi) for 2 hours. LCMS indicated complete conversion of the starting material. The reaction solution was diluted with methanol (20 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 50:90-90:10, aqueous solution containing 0.08% NH4HCO3) to obtain the title compound 123 (20.1 mg, yield: 66.8%) as a white solid. MS (ESI): m / z = 448.2 [M+H] + .

[0277] 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),7.28(s,1H),7.18(d,J=8.4Hz,1H),6.98(d,J=8.4Hz,1H),5.57(s,2H) ,5.35(s,2H),4.17(d,J=6.0Hz,2H),2.54(m,1H),1.85(s,3H),1.84-1.60(m,10H),1.57-1.45(m,2H),1.34 -1.25(m,2H).

[0278] A similar method to Example 123 was used, replacing the corresponding reagents, to obtain the compounds shown in the following table:

[0279] Example 129: Synthesis of N-{[2-(Spiro[3.5]non-1-en-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide and Example 130: Synthesis of N-{[2-(Spiro[3.5]non-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide

[0280] Step 1: Spiro[3.5]non-1-en-2-yl trifluoromethanesulfonate (129-1)

[0281] Using compound 129-0 (250 mg, 1.81 mmol) as starting material and referring to the synthesis method of compound 120-1, the title compound 129-1 (3.81 g, yield: 77.7%) was obtained as a colorless oil.

[0282] 1 H NMR (400MHz, CDCl3) δ: 5.60 (s, 1H), 2.53 (s, 2H), 1.53 (m, 6H), 1.50-1.33 (m, 4H).

[0283] Step 2: 4,4,5,5-tetramethyl-2-(spiro[3.5]non-1-en-2-yl)-1,3,2-dioxaborolane (129-2)

[0284] Compound 129-1 (370 mg, 1.37 mmol) was used as the starting material, and the synthetic method of compound 120-2 was followed to obtain the title compound 129-2 (124 mg, yield: 36.5%) as a light yellow solid. MS (ESI): m / z = 248.9 [M+H] + .

[0285] Step 3: Synthesis of N-{[2-(spiro[3.5]non-1-en-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (129)

[0286] Compound 59 (50 mg, 0.124 mmol) and compound 129-2 (36.8 mg, 0.148 mmol) were used as starting materials, and the synthetic method of compound 120 was followed to obtain the title compound 129 (40 mg, yield: 72.6%) as a white solid. MS (ESI): m / z = 446.2 [M+H]+ .

[0287] 1 H NMR (400MHz, DMSO-d6) δ8.29(t,J=5.6Hz,1H),7.29(d,J=2.0Hz,1H),7.19(dd,J=8.4,2.0Hz,1H),7.00(d,J=8.4Hz ,1H),6.46(s,1H),5.60(s,2H),5.40(s,2H),4.17(d,J=6.0Hz,2H),2.41(s,2H),1.85(s,3H),1.56-1.29(m,10H).

[0288] Step 4: Synthesis of N-{[2-(spiro[3.5]nonan-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (130)

[0289] Compound 129 (36 mg, 0.081 mmol) was used as the starting material, and the synthetic method of compound 123 was followed to obtain the title compound 130 (28 mg, yield: 77.4%) as a white solid. MS (ESI): m / z = 448.2 [M+H] + .

[0290] 1 H NMR (400MHz, DMSO) δ8.29(t,J=5.6Hz,1H),7.29(d,J=2.0Hz,1H),7.18(dd,J=8.4,2.0Hz,1H),6.98(d,J=8.4Hz,1H),5.59(s,2H),5.3 4(s,2H),4.17(d,J=6.0Hz,2H),3.48-3.37(m,2H),2.12-2.01(m,2H),2.00-1.91(m,2H),1.86(s,3H),1.54(m,2H),1.47-1.25(m,8H).

[0291] Example 132: Synthesis of N-{[2-(spiro[3.5]nonan-6-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide

[0292] Step 1: Synthesis of spiro[3.5]non-6-en-6-yl trifluoromethanesulfonate (132-1)

[0293] Under nitrogen, a solution of compound 132-0 (138 mg, 1.00 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (392 mg, 1.10 mmol) in anhydrous tetrahydrofuran (2 mL) was cooled to -78°C, and a solution of LiHMDS (1.2 mL, 1.20 mmol, 1 M) was slowly added dropwise to the solution. After the addition was complete, the reaction mixture was slowly warmed to 0°C and stirred for 1 hour. TLC indicated complete conversion of the starting material. The reaction mixture was slowly diluted with ethyl acetate (20 mL) at 0°C and quenched with saturated ammonium chloride solution (10 mL). The organic phase was separated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=10:90-15:85) to obtain the title compound 132-1 (175 mg, yield: 64.8%) as a transparent oil.

[0294] Step 2: Synthesis of 4,4,5,5-tetramethyl-2-(spiro[3.5]non-5-en-6-yl)-1,3,2-dioxaborolane (132-2)

[0295] Under argon, to a dry, sealed tube equipped with a stirrer were added 132-1 (165 mg, 0.61 mmol), bis(pinacol boronate) (233 mg, 0.92 mmol), Pd(dppf)Cl2·CH2Cl2 (50 mg, 0.061 mmol), anhydrous potassium acetate (180 mg, 1.83 mmol), and 1,4-dioxane (2 mL). The reaction mixture was purged with argon three times and then heated to 100°C with stirring for 6 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (20 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0:100 to 15:85) to obtain the title compound 132-2 (135 mg, yield: 89.1%) as a clear oil. MS (ESI): m / z = 248.9 [M+H] + .

[0296] Step 3: Synthesis of N-{[2-(spiro[3.5]non-5-en-6-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (132-3)

[0297] Under argon, compound 132-2 (83 mg, 0.33 mmol), compound 59 (135 mg, 0.33 mmol), XPhos Pd G3 (28 mg, 0.033 mmol), anhydrous potassium carbonate (142 mg, 0.67 mmol), 1,4-dioxane (0.6 mL), and water (0.2 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times, then heated to 100°C and stirred for 2 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0:100-3:97) to obtain the title compound 132-3 (134 mg, yield: 90.0%) as a light yellow solid. MS (ESI): m / z = 446.2 [M+H] + .

[0298] Step 4: Synthesis of N-{[2-(spiro[3.5]nonan-6-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (132)

[0299] To a solution of compound 132-3 (134 mg, 0.30 mmol) in methanol (5 mL) was added Pd / C (10%, 366 mg, 0.30 mmol) at room temperature. The mixture was stirred at room temperature for 2 days under a hydrogen atmosphere (15 psi). LCMS indicated complete conversion of the starting material. The reaction solution was diluted with methanol (20 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 132 (38 mg, yield: 28.2%) as a white solid. MS (ESI): m / z = 448.1 [M+H] + .

[0300] 1 H NMR (400MHz, CD3OD) δ7.28-7.23(m,2H),7.08-7.04(m,1H),5.47(s,2H),5.31(s,2H),4.31(s,2H),2.78 -2.69(m,1H),1.97(s,3H),1.93-1.79(m,6H),1.77-1.64(m,4H),1.51-1.40(m,3H),1.29-1.22(m,1H).

[0301] Example 133: Synthesis of N-{[3-(trifluoromethyl)-2-(5-oxaspiro[3.5]non-1-en-2-yl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (133)

[0302] Step 1: Synthesis of 3-(benzyloxy)-1-(prop-2-enyl)cyclobutan-1-ol (133-1)

[0303] Under nitrogen, a solution of 3-(benzyloxy)cyclobutan-1-one (11.00 g, 62.4 mmol) in anhydrous tetrahydrofuran (110 mL) was cooled to 0°C, and allylmagnesium chloride (34.3 mL, 68.6 mmol, 2 M) was then added dropwise to the solution. After the addition was complete, the reaction mixture was stirred at 0°C for 60 minutes. TLC indicated complete conversion of the starting material. The reaction solution was quenched with saturated ammonium chloride solution (30 mL), then extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-20:80) to obtain the title compound 133-1 (8.10 g, yield: 59.4%) as a colorless oil.

[0304] 1 H NMR (400MHz, CDCl3) δ7.38-7.27(m,5H),5.90-5.76(m,1H),5.22-5.13(m,2H),4.42 (s,2H),3.76-3.68(m,1H),2.54-2.41(m,2H),2.34-2.24(m,2H),2.14-2.06(m,2H).

[0305] Step 2: Synthesis of ({[3-(prop-2-enyl)-3-(prop-2-enyloxy)cyclobutyl]oxy}methyl)benzene (133-2)

[0306] Under nitrogen, a suspension of NaH (3.08 g, 77.0 mmol, 60%) in anhydrous tetrahydrofuran (150 mL) was cooled to 0°C, and a solution of compound 133-1 (8.40 g, 38.5 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise to the solution. After the addition was complete, the reaction mixture was stirred at 70°C for 1 hour. The reaction solution was cooled to room temperature, and allyl bromide (6.98 g, 57.7 mmol) was added dropwise. The reaction solution was stirred and refluxed at 70°C for 24 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride solution (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:99-10:90) to obtain the title compound 133-2 (8.00 g, yield: 80.5%) as a colorless oil.

[0307] 1 H NMR (400MHz, CDCl3) δ7.37-7.27(m,5H),5.97-5.74(m,2H),5.32 5.20(m,1H),5.16-5.06(m,3H),4.41(s,2H),3.87(m,2H),3.73(q,J=6.8Hz,1H),2.44-2.35(m,2H),2.31(d,J=6.8Hz,2H),2.20-2.11(m,2H).

[0308] Step 3: Synthesis of 2-(benzyloxy)-5-oxaspiro[3.5]non-7-ene (133-3)

[0309] Under nitrogen, Hoveyda-Grubbs Catalyst 2nd (121 mg, 0.194 mmol, 2 M) was added to a solution of compound 133-2 (1000 mg, 3.87 mmol) in anhydrous dichloromethane (80 mL). The reaction mixture was stirred at room temperature overnight. LCMS indicated complete conversion of the starting material. Ethylene glycol dimethyl ether (2 mL) was added to quench the reaction. The product was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-20:80) to obtain the title compound 133-3 (566 mg, yield: 63.5%) as a colorless oil. MS (ESI): m / z = 231.1 [M+H] + .

[0310] 1H NMR (400MHz, CDCl3) δ7.36-7.32(m,4H),7.32-7.26(m,1H),5.75-5.66(m,2H),4.43 (s,2H),4.18-4.12(m,2H),3.87-3.80(m,1H),2.38-2.30(m,2H),2.37-2.30(m,4H).

[0311] Step 4: Synthesis of 5-oxaspiro[3.5]nonan-2-ol (133-4)

[0312] Under argon, to a solution of compound 133-3 (5.80 g, 25.2 mmol) in methanol (240 mL) was added Pd / C (10%, 2.68 g). The mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere (15 psi). LCMS indicated complete conversion of the starting material. The product was filtered and concentrated under reduced pressure to afford the title compound 133-4 (3.77 g, yield: 105%) as a colorless oil. MS (ESI): m / z = 143.1 [M+H] + .

[0313] Step 5: Synthesis of 5-oxaspiro[3.5]nonan-2-one (133-5)

[0314] A solution of compound 133-4 (3.77 g, 26.5 mmol) in anhydrous dichloromethane (60 mL) was cooled to 0°C, and DESS-MARTIN reagent (13.49 g, 31.8 mmol) was added portionwise to the solution. The reaction mixture was stirred at room temperature for 2 hours. TLC indicated complete conversion of the starting material. The product was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99 to 25:75) to obtain the title compound 133-5 (2.67 g, yield: 71.8%) as a colorless oil.

[0315] 1 H NMR (400MHz, CDCl3) δ3.71-3.65(m,2H),3.16-3.06(m,2H),2.96-2.86(m,2H),1.80-1.73 (m,2H),1.72-1.64(m,2H),1.71-1.55(m,2H).

[0316] Step 6: Synthesis of 5-oxaspiro[3.5]non-1-en-2-yl trifluoromethanesulfonate (133-6)

[0317] Using compound 133-5 (2.00 g, 14.27 mmol) as starting material and referring to the synthesis method of compound 120-1, the title compound 133-6 (1.98 g, yield: 51.0%) was obtained as a colorless oil.

[0318] 1 H NMR (400MHz, CDCl3) δ5.68 (d, J = 0.8Hz, 1H), 3.82-3.74 (m, 1H), 3.63-3.54 (m, 1H), .80 (q, J = 12.8Hz, 2H), 1.83-1.52 (m, 6H).

[0319] Step 7: Synthesis of 4,4,5,5-tetramethyl-2-(5-oxaspiro[3.5]non-1-en-2-yl)-1,3,2-dioxaborolane (133-7)

[0320] Compound 133-6 (238 mg, 0.94 mmol) was used as the starting material and the synthetic method of compound 120-2 was followed to obtain the title compound 133-7 (124 mg) as a pale yellow crude product. MS (ESI): m / z = 251.4 [M+H] + .

[0321] Step 8: Synthesis of N-{[3-(trifluoromethyl)-2-(5-oxaspiro[3.5]non-1-en-2-yl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (133)

[0322] Compound 59 (150 mg, 0.37 mmol) and compound 133-7 (121 mg, 0.482 mmol) were used as starting materials, and the synthetic method of compound 120 was followed to obtain the title compound 133 (10 mg, yield: 6.0%) as a white solid. MS (ESI): m / z = 448.3 [M+H] + .

[0323] 1 H NMR (400MHz, DMSO-d6) δ8.31(t,J=5.6Hz,1H),7.58-7.44(m,1H),7.31(m,1H),7.21(m,1H),7.03(m,1H),6.49(s,1H),5.75-5.58(m,2H),5.50 -5.38(m,2H),4.24-4.15(m,2H),3.73-3.50(m,2H),2.70-2.58(m,2H),1.86(s,3H),1.75-1.56(m,4H),1.53-1.41(m,2H).

[0324] Example 134: Synthesis of N-{[2-(cyclohexylethynyl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide

[0325] Under argon, compound 59 (40 mg, 0.099 mmol), ethynylcyclohexane (21 mg, 0.20 mmol), cuprous iodide (4 mg, 0.020 mmol), Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol), triethylamine (40 mg, 0.40 mmol), and DMF (0.5 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 135°C and stirred for 40 hours. LCMS indicated that most of the starting material was converted. After cooling to room temperature, the mixture was diluted with dichloromethane (10 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to afford the title compound 134 (3 mg, yield: 7.0%) as a white solid. MS (ESI): m / z = 432.1 [M+H] + .

[0326] 1 H NMR (400MHz, CD3OD) δ7.33-7.27(m,2H),7.14-7.08(m,1H),5.52(s,2H),5.34(s,2H),4.34(s, 2H),2.71-2.63(m,1H),2.00(s,3H),1.92-1.73(m,4H),1.63-1.51(m,3H),1.48-1.38(m,3H).

[0327] Example 137: Synthesis of N-{[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}-2,2,2-trifluoroacetamide (137)

[0328] Under argon, to a dry, sealed tube equipped with a stirrer were added Intermediate G (40 mg, 0.087 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (24 mg, 0.10 mmol), XPhos Pd G3 (7 mg, 0.009 mmol), anhydrous potassium phosphate (37 mg, 0.18 mmol), 1,4-dioxane (0.6 mL), and water (0.2 mL). The reaction mixture was purged with argon three times and then heated to 100°C with stirring for 2 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0:100-3:97) and further purified by prep-HPLC to obtain the title compound 137 (14 mg, yield: 33.0%) as a white solid. MS (ESI): m / z = 486.1 [M+H] + .

[0329] 1 H NMR(400MHz,CD3OD)δ7.91(s,1H),7.71(s,1H),7.34-7.28(m,2H),7.13-7.09(m, 1H),5.55(s,2H),5.39(s,2H),4.42(s,2H),3.76-3.62(m,1H),1.15-1.02(m,4H).

[0330] A similar method to Example 137 was used, substituting the corresponding reagents to obtain the compounds shown in the following table:

[0331] Example 146: Synthesis of N-{[2-(hexahydropyridin-1-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (146)

[0332] Under argon, compound 59 (20 mg, 0.049 mmol), hexahydropyridine (8 mg, 0.098 mmol), Pd2(dba)3 (5 mg, 0.005 mmol), BINAP (6 mg, 0.010 mmol), anhydrous cesium carbonate (32 mg, 0.098 mmol), and 1,4-dioxane (0.5 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C with stirring for 16 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was diluted with methanol (10 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 146 (5 mg, yield: 24.8%) as a white solid. MS (ESI): m / z = 409.1 [M+H] + .

[0333] 1 H NMR(400MHz,CD3OD)δ7.27-7.22(m,2H),7.08-7.03(m,1H),5.37(s,2H),5.25(s,2H) ,4.31(s,2H),3.09-3.00(m,4H),1.97(s,3H),1.69-1.61(m,4H),1.60-1.52(m,2H).

[0334] Using a method similar to that of Example 146 above, replacing the corresponding starting materials, the compounds shown in the following table were obtained:

[0335] Example 160: Synthesis of N-{[3-(Trifluoromethyl)-2-(3,6-diazabicyclo[3.1.1]hept-3-yl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide and 161: Synthesis of N-{[2-(6-methyl-3,6-diazabicyclo[3.1.1]hept-3-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide

[0336] Step 1: Synthesis of N-{[3-(trifluoromethyl)-2-(3,6-diazabicyclo[3.1.1]hept-3-yl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (160)

[0337] To a solution of compound 152 (25 mg, 0.048 mmol) in anhydrous dichloromethane (2 mL) at 0°C was added trifluoroacetic acid (0.5 mL). The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in DMF and adjusted to neutrality with saturated aqueous ammonia. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was further purified by pre-HPLC to obtain the title compound 160 (15 mg, yield: 74.3%) as a white solid. MS (ESI): m / z = 422.2 [M+H] + .

[0338] 1 H NMR (400MHz, CD3OD) δ7.27-7.22(m,2H),7.08-7.04(m,1H),5.37(s,2H),5.28(s,2H),4.31(s, 2H),3.76(d,J=5.6Hz,2H),3.66(s,4H),2.71-2.63(m,1H),1.97(s,3H),1.79(d,J=8.8Hz,1H).

[0339] Step 2: Synthesis of N-{[2-(6-methyl-3,6-diazabicyclo[3.1.1]hept-3-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (161)

[0340] To a solution of compound 160 (12 mg, 0.028 mmol) in methanol (1 mL) was added aqueous formaldehyde solution (7 mg, 0.085 mmol, 40%) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of sodium cyanoborohydride (4 mg, 0.057 mmol). The final reaction mixture was stirred at room temperature for 1 hour. LCMS indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was further purified by pre-HPLC to obtain the title compound 161 (8 mg, yield: 64.5%) as a white solid. MS (ESI): m / z = 436.3 [M+H] + .

[0341] 1H NMR (400MHz, CD3OD) δ7.31-7.25(m,2H),7.12-7.06(m,1H),5.40(s,2H),5.31(s,2H),4.33(s,2H),3.77(d,J=11.6Hz ,2H),3.64(d,J=5.6Hz,2H),3.57-3.44(m,2H),2.65-2.53(m,1H),2.32-2.13(m,3H),1.99(s,3H),1.82-1.72(m,1H).

[0342] Example 162: Synthesis of N-{[3-(trifluoromethyl)-2-(6-azaspiro[3.5]nonan-6-yl)-4,10-dihydrobenzo[2,1-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (162)

[0343] Under argon, compound 59 (40 mg, 0.099 mmol), 6-azaspiro[3.5]nonane hydrochloride (24 mg, 0.15 mmol), Pd2(dba)3 (9 mg, 0.010 mmol), 2-[bis(3,5-trifluoromethylphenylphosphine)-3,6-dimethoxy]-2',6'-dimethylamino-1,1'-biphenyl (15 mg, 0.20 mmol), sodium tert-butoxide (38 mg, 0.40 mmol), and toluene (0.5 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C with stirring for 12 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was diluted with methanol (10 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0:100-5:95) and prep-HPLC to obtain the title compound 162 (8 mg, yield: 18.0%) as a white solid. MS (ESI): m / z = 449.2 [M+H] + .

[0344] 1 H NMR (400MHz, CD3OD) δ7.27-7.23(m,2H),7.07-7.03(m,1H),5.38(s,2H),5.26(s,2H),4.31(s, 2H),2.99-2.92(m,4H),1.97(s,3H),1.93-1.79(m,4H),1.79-1.69(m,2H),1.62-1.50(m,4H).

[0345] Using a method similar to that of Example 162 above, replacing the corresponding starting materials, the compounds shown in the following table were obtained:

[0346] Example 173: Synthesis of 2,2,2-trifluoro-N-{[3-(trifluoromethyl)-2-(2-azaspiro[3.3]hept-2-yl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (173)

[0347] Step 1: Synthesis of [3-(trifluoromethyl)-2-(2-azaspiro[3.3]hept-2-yl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methanamine (173-1)

[0348] Under argon, to a dry, sealed tube equipped with a stirrer were added intermediate G (46 mg, 0.10 mmol), 2-azaspiro[3.3]heptaneethanedioic acid (38 mg, 0.20 mmol), Pd2(dba)3 (9 mg, 0.010 mmol), BINAP (13 mg, 0.020 mmol), anhydrous cesium carbonate (98 mg, 0.30 mmol), and 1,4-dioxane (0.6 mL). The reaction mixture was purged with argon three times and then heated to 120°C and stirred for 20 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was diluted with methanol (10 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0:100 to 6:94) to obtain the title compound 173-1 (21 mg, yield: 55.6%) as a pale yellow solid. MS (ESI): m / z = 379.1 [M+H] + .

[0349] Step 2: Synthesis of 2,2,2-trifluoro-N-{[3-(trifluoromethyl)-2-(2-azaspiro[3.3]hept-2-yl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (173)

[0350] To a solution of compound 173-1 (21 mg, 0.055 mmol) and sodium carbonate (12 mg, 0.11 mmol) in dichloromethane (2 mL) was added trifluoroacetic anhydride (14 mg, 0.067 mmol). The reaction mixture was reacted at room temperature for 1 hour. LCMS indicated complete conversion of the starting material. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 173 (11 mg, yield: 39.7%) as a white solid. MS (ESI): m / z = 475.1 [M+H] + .

[0351] 1 H NMR(400MHz,CD3OD)δ7.33-7.26(m,2H),7.14-7.05(m,1H),5.36(s,2H),5.2 7(s,2H),4.43(s,2H),3.89(s,4H),2.21(t,J=7.6Hz,4H),1.93-1.83(m,2H).

[0352] Using a method similar to that of Example 173 above, replacing the corresponding starting materials, the compounds shown in the following table were obtained:

[0353] Example 176: Synthesis of N-{[2-(spiro[3.5]non-1-en-2-yl)-3-(trifluoromethyl)-4,10-dihydropyrido[3,2-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide

[0354] Step 1: Synthesis of N-{[2-bromo-3-(trifluoromethyl)-4,10-dihydropyrido[3,2-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (176-1)

[0355] To a mixture of intermediate L (300 mg, 0.83 mmol), sodium carbonate (175 mg, 1.65 mmol), and dichloromethane (5 mL) was slowly added acetic anhydride (126 mg, 1.24 mmol) at 0°C. The reaction mixture was allowed to react at room temperature for 16 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0:100-5:95) to obtain the title compound 176-1 (174 mg, yield: 52.0%) as a white solid. MS (ESI): m / z = 404.9, 406.9 [M+H] + .

[0356] Step 2: Synthesis of N-{[2-(spiro[3.5]non-1-en-2-yl)-3-(trifluoromethyl)-4,10-dihydropyrido[3,2-f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (176)

[0357] Under argon, compound 176-1 (60 mg, 0.15 mmol), 4,4,5,5-tetramethyl-2-(spiro[3.5]non-1-en-2-yl)-1,3,2-dioxaborolane (40 mg, 0.16 mmol), XPhos Pd G3 (13 mg, 0.015 mmol), anhydrous potassium phosphate (63 mg, 0.30 mmol), 1,4-dioxane (0.6 mL), and water (0.2 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C with stirring for 2 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified sequentially by silica gel column chromatography (methanol:dichloromethane = 0:100-3:97) and prep-HPLC to obtain the title compound 176 (23 mg, yield: 34.8%) as a white solid. MS (ESI): m / z = 447.3 [M+H] + .

[0358] 1 H NMR (400MHz, CD3OD) δ8.13(d,J=2.4Hz,1H),7.80(d,J=2.4Hz,1H),6.54(s,1H),5. 65(s,2H),5.56(s,2H),4.35(s,2H),2.49(s,2H),2.00(s,3H),1.66-1.35(m,10H).

[0359] Example 183: Synthesis of 1-(ethylamino)-N-{[3-(trifluoromethyl)-2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}methaneamide (183)

[0360] Step 1: Synthesis of 3-(trifluoromethyl)-2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (183-1)

[0361] Using compound F-4 (250 mg, 0.70 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)pyrazole (220 mg, 0.84 mmol) as starting materials, following the synthesis method of compound 177-1, the title compound 183-1 (244 mg, yield: 84.6%) was obtained as a white solid. MS (ESI): m / z = 414.1 [M+H] + .

[0362] Step 2: Synthesis of 3[3-(trifluoromethyl)-2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methanamine (183-2)

[0363] Compound 183-1 (188 mg, 0.57 mmol) and BH3-THF (3.0 mL) were used as starting materials, and the synthetic method of compound F was followed to obtain the title compound 183-2 (202 mg, yield: 82.0%) as a white solid. MS (ESI): m / z = 401.1 [M+H] + .

[0364] Step 2: Synthesis of 1-(ethylamino)-N-{[3-(trifluoromethyl)-2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}methaneamide (183)

[0365] To a solution of compound 183-2 (50 mg, 0.12 mmol) in anhydrous tetrahydrofuran (0.5 mL) was added ethyl isocyanate (17 mg, 0.24 mmol). The reaction mixture was purged with argon three times and stirred at room temperature for 1 hour. LCMS indicated complete conversion of the starting material. The product was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 10:90-90:10, aqueous solution containing 0.08% NH4HCO3) to afford the title compound 183 (20 mg, yield: 34.2%) as a white solid. MS (ESI): m / z = 489.3 [M+H] + .

[0366] 1H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.16(s,1H),7.30(d,J=2.0Hz,1H),7.21(dd,J=8.4,2.0Hz,1H),7.04(d,J=8.4Hz,1H),6.27( t,J=6.0Hz,1H),5.86(t,J=5.6Hz,1H),5.66(s,2H),5.46(s,2H),4.13(d,J=6.0Hz,2H),3.06-2.96(m,2H),0.98(t,J=7.2Hz,3H).

[0367] A similar method to Example 183 was used, replacing the corresponding reagents, to obtain the compounds shown in the following table:

[0368] Example 197: Synthesis of [(1E)-1-({[3-(trifluoromethyl)-2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}amino)ethylidene]azanecarbonitrile (197)

[0369] To a solution of compound 183-2 (75 mg, 0.18 mmol) in anhydrous tetrahydrofuran (0.8 mL) was added ethyl (E)-N-cyanoethylimidate (20 mg, 0.18 mmol). The reaction mixture was purged with argon three times and stirred at room temperature for 4 hours. LCMS indicated complete conversion of the starting material. The product was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 20:90-90:10, aqueous solution containing 0.08% NH4HCO3) to afford the title compound 197 (9.2 mg, yield: 10.6%) as a white solid. MS (ESI): m / z = 484.2 [M+H] + .

[0370] 1 H NMR (400MHz, DMSO-d6) δ9.23-9.17(br,1H),8.65(s,1H),8.18-8.14(m,1H),7.36(d,J=2.0Hz,1H),7. 25(dd,J=8.0Hz,1H),7.06(d,J=2.0Hz,1H),5.71(s,2H),5.48(s,2H),4.36-4.31(m,2H),2.25(s,3H).

[0371] Example 198: Synthesis of [sulfylidene({[3-(trifluoromethyl)-2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}amino)methyl]azanecarbonitrile

[0372] A solution of compound 183-2 (40 mg, 0.096 mmol) in anhydrous dichloromethane (1.0 mL) was cooled to 0°C, and di-2-pyridinethiocarbonate (26.7 mg, 0.115 mmol) was added. The reaction mixture was purged with argon three times and stirred at room temperature for 1 hour. LCMS indicated complete conversion of the starting material. Cyanamide (40.4 mg, 0.96 mmol) was then added to the reaction solution, and stirring was continued at room temperature over the weekend. LCMS indicated complete conversion of the starting material. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 30:70-90:10, aqueous solution containing 0.08% NH4HCO3) to obtain the title compound 198 (17.2 mg, yield: 35.8%) as a white solid. MS (ESI): m / z = 502.2 [M+H] + .

[0373] 1 H NMR(400MHz, DMSO-d6)δ8.68(s,1H),8.49-8.36(br,1H),8.16(s,1H),7.49-7.42(m,1H),7.35-7. 29(m,1H),7.24(s,1H),7.03(s,1H),5.64(m,2H),5.45(s,2H),4.58(d,J=5.2Hz,1H),4.19(s,1H).

[0374] Example 200: Synthesis of 2-cyano-N-{[3-(trifluoromethyl)-2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (200)

[0375] To a solution of compound 183-2 (60 mg, 0.144 mmol) in anhydrous tetrahydrofuran (0.6 mL) was added ethyl cyanoacetate (326 mg, 2.88 mmol). The reaction mixture was purged with argon three times and stirred at 100°C overnight. LCMS indicated that most of the starting material had been converted. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 10:90-90:10, aqueous solution containing 0.08% NH4HCO3) to obtain the title compound 200 (29 mg, yield: 41.7%) as a white solid. MS (ESI): m / z = 458.2 [M+H] + .

[0376] 1 H NMR (400MHz, DMSO-d6) δ8.70(t,J=5.6Hz,1H),8.65(s,1H),8.16(s,1H),7.33(d,J=1.6Hz,1H),7.23(dd ,J=8.4,2.0Hz,1H),7.05(d,J=8.4Hz,1H),5.69(s,2H),5.47(s,2H),4.24(d,J=5.6Hz,2H),3.69(s,2H).

[0377] A similar method to Example 200 was used, replacing the corresponding reagents, to obtain the compounds shown in the following table:

[0378] Example 201: Synthesis of [(2E)-5-[3-(trifluoromethyl)-2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]-2,4-diazapent-2-en-3-yl]azanecarbonitrile (201)

[0379] To a solution of compound 183-2 (80 mg, 0.19 mmol) in anhydrous pyridine (0.8 mL) was added 183-0 (74.3 mg, 0.58 mmol). The reaction mixture was purged with argon three times and stirred at 110°C overnight. LCMS indicated that most of the starting material had been converted. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 10:90-90:10, aqueous solution containing 0.08% NH4HCO3) to obtain the title compound 201 (12 mg, yield: 12.6%) as a white solid. MS (ESI): m / z = 499.3 [M+H] + .

[0380] 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.14(s,1H),7.47(t,J=6.4Hz,1H),7.31(s,1H),7.25-7.19( m,1H),7.05-7.03(m,2H),5.68(s,2H),5.46(s,2H),4.25(d,J=5.6Hz,2H),2.68(d,J=4.4Hz,3H).

[0381] Example 204: Synthesis of N-{[2-(5-cyclopropyl-4-methylthiophen-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (204)

[0382] Step 1: Synthesis of N-{[2-(4-methylthiophen-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (202)

[0383] Compound 59 (150 mg, 0.37 mmol) and (4-methylthiophen-2-yl)boranediol (63 mg, 0.45 mmol) were used as starting materials, and the synthetic method of compound 177-1 was followed to obtain the title compound 202 (110 mg, yield: 70.3%) as a white solid. MS (ESI): m / z = 422.1 [M+H] + .

[0384] 1 H NMR(400MHz,DMSO-d6)δ8.28(m,1H),7.32(s,1H),7.23-7.16(m,2H),7.11(s,1H),7.02(d ,J=8.4Hz,1H),5.64(s,2H),5.43(s,2H),4.17(d,J=6.0Hz,2H),2.21(s,3H),1.84(s,3H).

[0385] Step 2: Synthesis of N-{[2-(5-bromo-4-methylthiophen-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (203)

[0386] To a solution of compound 202 (74 mg, 0.176 mmol) in dichloromethane (1.5 mL) at room temperature was added NBS (34.4 mg, 0.193 mmol). The reaction mixture was stirred at room temperature for 16 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was cooled to 0°C, diluted with dichloromethane (10 mL), and quenched by the addition of a 10% aqueous solution of Na2SO3 (1 mL). The layers were separated, the organic phase collected, and the aqueous phase extracted twice with dichloromethane (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 30:70-90:10, aqueous solution containing 0.08% NH4HCO3) to afford the title compound 203 (73 mg, yield: 81.1%) as a white solid. MS(ESI):m / z=500.1,502.1[M+H] + .

[0387] 1 H NMR (400MHz, DMSO-d6) δ8.33-8.27(m,1H),7.34(s,1H),7.22(d,J=8.4Hz,1H),7.09(s,1H),7. 04(d,J=8.4Hz,1H),5.65(s,2H),5.44(s,2H),4.18(d,J=6.0Hz,2H),2.17(s,3H),1.86(s,3H).

[0388] Step 3: Synthesis of N-{[2-(5-cyclopropyl-4-methylthiophen-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (204)

[0389] Compound 203 (56 mg, 0.11 mmol) and cyclopropylboronic acid (14.4 mg, 0.17 mmol) were used as starting materials, and the synthetic method of compound 177-1 was followed to obtain the title compound 204 (31 mg, yield: 60.0%) as a white solid. MS (ESI): m / z = 462.2 [M+H] + .

[0390] 1H NMR (400MHz, DMSO-d6) δ8.30(m,1H),7.31(s,1H),7.21(d,J=8.0Hz,1H),7.03(d,J=8.4Hz,1H),6.98(s,1H),5.61(s,2H), 5.42(s,2H),4.18(d,J=6.0Hz,2H),2.20(s,3H),2.04-2.02(m,1H),1.85(s,3H),1.06-0.97(m,2H),0.62(t,J=5.4Hz,2H).

[0391] Example 205: Synthesis of N-{[2-(5-cyclopropyl-4-methylthiophen-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (205)

[0392] Step 1: Synthesis of 2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (205-1)

[0393] Under argon, to a dry, sealed tube equipped with a stirrer were added Intermediate A (500 mg, 1.72 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)pyrazole (497 mg, 1.90 mmol), XPhos Pd G3 (73 mg, 0.086 mmol), K2CO3 (476 mg, 3.45 mmol), 1,4-dioxane (2.0 mL), and water (0.7 mL). The reaction mixture was purged with argon three times, then heated to 100°C and stirred for 3 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-40:60) to obtain the title compound 205-1 (463 mg, yield: 77.8%) as a light yellow solid. MS (ESI): m / z = 346.1 [M+H] + .

[0394] Step 2: Synthesis of {2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methanamine (205-2)

[0395] Compound 205-1 (198 mg, 0.57 mmol) and BH3-THF (3.0 mL) were used as starting materials, and the synthetic method of Intermediate F was followed to obtain the title compound 205-2 (220 mg, yield: 99.9%) as a white solid. MS (ESI): m / z = 333.1 [M-NH2] + .

[0396] Step 3: Synthesis of N-({2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide (205-3)

[0397] Compound 205-2 (220 mg, 0.63 mmol) was used as the starting material, and the synthetic method of compound 59 was followed to obtain the title compound 205-3 (109 mg, yield: 44.2%) as a white solid. MS (ESI): m / z = 392.2 [M+H] + .

[0398] Step 4: Synthesis of N-({2-[1-(trifluoromethyl)pyrazol-4-yl]-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide (205-4)

[0399] To a solution of compound 205-3 (109 mg, 0.279 mmol) in DMF (2.0 mL) at room temperature was added NBS (54.5 mg, 0.306 mmol). The reaction mixture was stirred at room temperature for 2 hours. LCMS indicated complete conversion of the starting material. LCMS indicated the reaction was complete. The reaction mixture was cooled to 0°C, quenched by the addition of water (10 mL), and stirred at room temperature for 30 minutes. The mixture was filtered and the filter cake was dried to afford the title compound 205-4 (120 mg, yield: 91.6%) as a white solid. MS (ESI): m / z = 470.1, 472.1 [M+H] + .

[0400] Step 5: Synthesis of N-{[2-(5-cyclopropyl-4-methylthiophen-2-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}acetamide (205)

[0401] Under argon, compound 205-4 (60 mg, 0.148 mmol), 2-butoxy-1,2-oxaborolane (27.1 mg, 0.178 mmol), XPhos Pd G3 (12.6 mg, 0.015 mmol), K2CO3 (128 mg, 0.927 mmol), 1,4-dioxane (1.2 mL), and water (0.4 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C and stirred for 4 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (acetonitrile:water = 5:95-90:10, the aqueous solution containing 0.08% NH4HCO3) to afford the title compound 205 (8.0 mg, yield: 7.7%) as a white solid. MS (ESI): m / z = 450.3 [M+H] + .

[0402] 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.26(d,J=5.6Hz,1H),8.20(s,1H),7.19(s,1H),7.10(dd,J=8.4,2.0Hz,1H),6.86(d,J=8.4H z,1H),5.55(s,2H),5.31(s,2H),4.59(t,J=4.8Hz,1H),4.14(d,J=5.6Hz,2H),2.65-2.58(m,2H),1.83(s,3H),1.59-1.50(m,2H).

[0403] Example 207: Synthesis of N-{[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}cyclopropanecarboxamide (207)

[0404] Under argon protection, a mixed solution of compound 206-2 (40 mg, 0.10 mmol) and potassium carbonate (28.4 mg, 0.21 mmol) in acetonitrile (2 mL) was cooled to 0°C, and cyclopropylcarbonyl chloride (10.8 mg, 0.10 mmol) was then added dropwise to the solution. The reaction mixture was stirred at room temperature under argon protection for 10 hours. LCMS indicated complete conversion of the starting material. The reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 207 (13.8 mg, yield: 26.6%) as a white solid. MS (ESI): m / z = 458.3 [M+H] + .

[0405] 1 H NMR (400MHz, DMSO-d6) δ8.51(s,1H),8.00(s,1H),7.63(s,1H),7.30(s,1H),7.21(d,J=8.0Hz,1H),7.03(d,J=8.0Hz,1H),5.63(s,2H ),5.43(s,2H),4.21(d,J=8.0Hz,2H),3.88-3.75(m,1H),1.61-1.52(m,1H),1.11-1.04(m,2H),1.03-0.94(m,2H),0.74-0.59(m,4H).

[0406] A similar method to Example 207 was used, replacing the corresponding reagents, to obtain the compounds shown in the following table:

[0407] Example 210: Synthesis of {1-[(E)-{[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}azinedione]ethyl}azanecarbonitrile (210)

[0408] Under argon, 206-2 (40 mg, 0.10 mmol), tetrahydrofuran (0.4 mL), and ethyl (E)-N-cyanoethylimidate (11.5 mg, 0.10 mmol) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was stirred at room temperature under argon for 4 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 210 (7.9 mg, yield: 16.5%) as a white solid. MS (ESI): m / z = 456.2 [M+H] + .

[0409] 1 H NMR (400MHz, DMSO-d6) δ9.19(s,1H),8.00(s,1H),7.63(s,1H),7.35(s,1H),7.24(d,J=12.0Hz,1H),7.04(d,J= 8.0Hz,1H),5.65(s,2H),5.45(s,2H),4.33(d,J=4.0Hz,2H),3.69-3.94(m,1H),2.24(s,3H),0.87-1.14(m,4H).

[0410] Example 211: Synthesis of N-{[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}-2-hydroxyacetamide (211)

[0411] Step 1: Synthesis of 2-({[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}amino)-2-oxyylideneethyl acetate (211-1)

[0412] Under argon, a mixed solution of compound 206-2 (40 mg, 0.10 mmol) and DIEA (0.029 mL, 0.21 mmol) in dichloromethane (2 mL) was cooled to 0°C, and acetoxyacetyl chloride (14.1 mg, 0.10 mmol) was then added dropwise. The reaction mixture was stirred at room temperature under argon for 2 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0:100-10:90) to obtain the title compound 211-1 (30 mg, yield: 59.5%) as a white solid. MS (ESI): m / z = 490.3 [M+H] + .

[0413] Step 2: Synthesis of N-{[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}-2-hydroxyacetamide (211)

[0414] Under argon protection, a mixed solution of compound 211-1 (30 mg, 0.061 mmol), tetrahydrofuran (2 mL, 0.10 mmol), methanol (1 mL), and water (0.5 mL) was cooled to 0°C, and then lithium hydroxide monohydrate (3.9 mg, 0.092 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed complete conversion of the starting material. The reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 211 (17.7 mg, yield: 64.6%) as a white solid. MS (ESI): m / z = 448.2 [M+H] + .

[0415] 1 H NMR (400MHz, DMSO-d6) δ8.26(s,1H),8.00(s,1H),7.62(s,1H),7.31(s,1H),7.23(d,J=8.0Hz,1H),7.02(d,J=8.0Hz ,1H),5.61(s,2H),5.48(t,J=8.0Hz,1H),5.42(s,2H),4.24(d,J=8.0Hz,2H),3.90-3.74(m,3H),1.26-0.83(m,4H).

[0416] Example 213: Synthesis of 2-({[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}amino)-2-oxoacetamide (213)

[0417] Under argon, a mixed solution of compound 206-2 (40 mg, 0.10 mmol), DMF (2 mL), and DIEA (0.034 mL, 0.21 mmol) in dichloromethane (2 mL) was cooled to 0°C, and 2,2-difluoropropionic acid (14.7 mg, 0.13 mmol) and HATU (58.6 mg, 0.15 mmol) were added to the solution. The reaction mixture was stirred at room temperature under argon for 2 hours. LCMS indicated complete conversion of the starting material. The reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 213 (15.5 mg, yield: 31.3%) as a white solid. MS (ESI): m / z = 482.3 [M+H] + .

[0418] 1 H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.00(s,1H),7.62(s,1H),7.30(s,1H),7.21(dd,J=8.0,4.0Hz,1H),7.04(d,J=8.0 Hz,1H),5.64(s,2H),5.44(s,2H),4.27(d,J=8.0Hz,2H),3.84-3.78(m,1H),1.76(t,J=20.0Hz,3H),1.21-0.77(m,4H).

[0419] Example 214: Synthesis of {amino[(E)-{[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}azolylidene]methyl}azanecarbonitrile

[0420] Step 1: Synthesis of 4-({[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}amino)-3-ethoxycyclobut-3-ene-1,2-dione (214-1)

[0421] Under argon protection, a mixed solution of compound 206-2 (21 mg, 0.12 mmol) and TEA (0.021 mL, 0.15 mmol) in ethanol (1 mL) was cooled to 0°C, and diethyl squarate (40 mg, 0.10 mmol) was then added dropwise to the solution. The reaction mixture was stirred at room temperature for 24 hours under argon protection. LCMS indicated complete conversion of the starting material. The reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0:100-10:90) to obtain the title compound 214-1 (46 mg, yield: 87.0%) as a light yellow oil. MS (ESI): m / z = 514.3 [M+H] + .

[0422] Step 2: Synthesis of {amino[(E)-{[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}azine ylidene]methyl}azanecarbonitrile (214)

[0423] Under argon, a methanolic ammonia solution (7 M, 0.038 mL, 0.27 mmol) was added dropwise to a solution of compound 214-1 (46 mg, 0.090 mmol) in ethanol (2 mL). The reaction mixture was stirred at room temperature under argon for 24 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was quenched with water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to obtain the title compound 214 (22.2 mg, yield: 51.2%) as a white solid. MS (ESI): m / z = 485.3 [M+H] + .

[0424] 1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.79-7.70(br,3H),7.62(s,1H),7.39(s,1H),7.28(d,J=8.0Hz,1 H),7.07(d,J=8.0Hz,1H),5.65(s,2H),5.45(s,2H),4.64(s,2H),4.01-3.62(m,1H),1.07-0.94(m,4H).

[0425] Example 215: Synthesis of {amino[(E)-{[2-(1-cyclopropylpyrazol-4-yl)-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl]methyl}azinedione]methyl}azanecarbonitrile (215)

[0426] Under argon, 206-2 (40 mg, 0.10 mmol), 215-0 (11.9 mg, 0.13 mmol), and n-butanol (0.3 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 120°C and stirred for 24 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC to afford the title compound 215 (2.0 mg, yield: 4.3%) as a white solid. MS (ESI): m / z = 457.2 [M+H] + .

[0427] 1 H NMR (400MHz, DMSO-d6) δ8.00(s,1H),7.63(s,1H),7.30(s,1H),7.22(d,J=8.0Hz,1H),7.04(d,J=8.0Hz,1 H),6.75(brs,3H),5.63(s,2H),5.44(s,2H),4.21(d,J=4.0Hz,2H),3.94-3.72(m,1H),1.15-0.87(m,4H).

[0428] A similar method to Example 215 was used, replacing the corresponding reagents, to obtain the compounds shown in the following table:

[0429] Example 221: Synthesis of N-[(2-bromo-3-methyl-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methyl]acetamide

[0430] Step 1: Synthesis of 3-methyl-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepane-8-carbonitrile (221-1)

[0431] Under argon, Intermediate B (1520 mg, 4.51 mmol), methylboronic acid (810 mg, 13.52 mmol), Xphos Pd G3 (382 mg, 0.451 mmol), and potassium phosphate (1.91 g, 9.02 mmol) were mixed, and 1,4-dioxane (15 mL) and water (3 mL) were added. The mixture was heated to 70°C and stirred under argon for 6 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99 to 30:70) to obtain the title compound 221-1 (930 mg, 91.6% yield) as a light yellow solid. MS (ESI): m / z = 226.0 [M+H] + .

[0432] Step 2: Synthesis of (3-methyl-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methanamine (221-2)

[0433] Under argon, a tetrahydrofuran solution of compound 221-1 (930 mg, 4.13 mmol) was cooled to 0°C, and BH3-THF (10 mL, 10.0 mmol, 1 M) was then added dropwise to the reaction mixture. After the addition was complete, the mixture was slowly warmed to room temperature and stirred for 1 hour. LCMS indicated complete conversion of the starting material. The reaction mixture was quenched with methanol (30 mL), diluted with water (30 mL), and extracted three times with methanol / dichloromethane (v / v, 1 / 10, 50 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:99-10:90) to obtain the title compound 221-2 (860 mg, yield: 90.9%) as a white foamy solid. MS (ESI): m / z = 230.1 [M+H] + .

[0434] Step 3: Synthesis of N-[(3-methyl-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methyl]acetamide (221-3)

[0435] To a solution of compound 221-2 (860 mg, 3.75 mmol) in dichloromethane (9 mL) were added sodium carbonate (1.19 g, 11.3 mmol) and acetic anhydride (1.40 mL, 15.0 mmol). The reaction mixture was purged with argon and allowed to react at room temperature for 2 hours. LCMS indicated complete conversion of the starting material. The reaction mixture was quenched with water (30 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse-phase silica gel column chromatography to obtain the title compound 221-3 (253 mg, yield: 24.9%) as a yellow solid. MS (ESI): m / z = 272.0 [M+H] + .

[0436] Step 4: Synthesis of N-[(2-bromo-3-methyl-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl)methyl]acetamide (221)

[0437] To a solution of compound 221-3 (253 mg, 0.93 mmol) in acetonitrile (2 mL) was added NBS (199 mg, 1.12 mmol) at room temperature. The reaction mixture was heated to 55°C and stirred for 4 hours under argon. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:99-10:90) to obtain the title compound 221 (246 mg, yield: 73.8%) as a white solid. MS (ESI): m / z = 350.0, 352.0 [M+H] + .

[0438] 1 H NMR (400MHz, CD3OD) δ7.21(d,J=4.0Hz,2H),6.99(d,J=8.0Hz,1H),5.41(s,2H),5.21(s,2H),4.29(s,2H),1.97(s,3H),1.95(s,3H).

[0439] Using a method similar to Example 46 and using 221 as the corresponding starting material, the compounds shown in the following table were obtained:

[0440] Example 243: Synthesis of N-({2-[4-(cyclopropylethynyl)phenyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide (243)

[0441] Step 1: Synthesis of 1-bromo-4-(cyclopropylethynyl)benzene (243-1)

[0442] Under argon, compound 243-0 (849 mg, 3.00 mmol), ethynylcyclopropane (198 mg, 3.00 mmol), Pd(dppf)Cl2·CH2Cl2 (245 mg, 0.30 mmol), cuprous iodide (229 mg, 1.20 mmol), triethylamine (911 mg, 9.00 mmol), and anhydrous 1,4-dioxane (10.0 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C and stirred for 1 hour. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 3:97) to obtain the title compound 243-1 (660 mg, yield: 99.5%) as a white solid.

[0443] Step 2: Synthesis of 2-[4-(cyclopropylethynyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (243-2)

[0444] Under argon, compound 243-1 (221 mg, 1.00 mmol), bis(pinacol boronate) (380 mg, 1.50 mmol), Pd(dppf)Cl2·CH2Cl2 (81.6 mg, 0.10 mmol), anhydrous methyl acetate (294 mg, 3.00 mmol), and anhydrous 1,4-dioxane (5.0 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 90°C and stirred for 16 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (20 mL), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:99-3:97) to obtain the title compound 243-2 (120 mg, yield: 44.8%) as a white solid. MS (ESI): m / z = 269.0 [M+H] + .

[0445] Step 3: Synthesis of N-({2-[4-(cyclopropylethynyl)phenyl]-3-(trifluoromethyl)-4,10-dihydrobenzo[f]pyrazolo[5,1-c][1,4]oxazepan-8-yl}methyl)acetamide (243)

[0446] Under argon, compound 59 (40 mg, 0.10 mmol), compound 243-2 (27 mg, 0.10 mmol), XPhos Pd G3 (4 mg, 0.005 mmol), anhydrous potassium phosphate (42 mg, 0.120 mmol), 1,4-dioxane (0.6 mL), and water (0.2 mL) were added sequentially to a dry, sealed tube equipped with a stirrer. The reaction mixture was purged with argon three times and then heated to 100°C with stirring for 2 hours. LCMS indicated complete conversion of the starting material. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:99-3:97) and then by prep-HPLC to obtain the title compound 243 (10 mg, yield: 21.7%) as a white solid. MS (ESI): m / z = 466.1 [M+H] + .

[0447] 1 H NMR (400MHz, CD3OD) δ7.55-7.48(m,2H),7.44-7.38(m,2H),7.36-7.29(m,2H),7.13(d,J=8.4Hz,1H),5.6 1(s,2H),5.43(s,2H),4.35(s,2H),2.00(s,3H),1.55-1.46(m,1H),0.95-0.88(m,2H),0.81-0.74(m,2H).

[0448] Biological test example 1: Human PFKL in vitro enzyme activity test

[0449] Experimental Materials

[0450] Recombinant human PFKL protein (NP_002617) was obtained using a baculovirus protein expression system. Other reaction components included aldolase, triosephosphate isomerase, glycerolphosphate dehydrogenase, adenosine triphosphate (ATP), dithiothreitol (DTT), magnesium chloride solution, dimethyl sulfoxide (DMSO), fructose-6-phosphate disodium salt, 4-hydroxyethylpiperazineethanesulfonic acid (HEPES), NADH disodium salt, and potassium chloride.

[0451] Experimental methods

[0452] Test compounds were dissolved in DMSO to a 10 mM stock solution. The stock solution was diluted with DMSO to 100-fold the final concentration of the highest point in the reaction. A three-fold serial dilution series was then performed with DMSO, with nine concentration points for each compound. Enzyme reaction buffer (50 mM HEPES, 100 mM KCl, 5 mM MgCl2, 1 mM DTT, pH 7.5) was prepared. A 2.5x reaction mixture was prepared by adding the substrate, auxiliary enzyme, and PFKL protein, excluding fructose-6-phosphate, to the reaction buffer. The reaction mixture contained the following components at the final concentrations: 3.1 mM ATP, 0.5 mM NADH, 0.45 U / mL aldolase, 4.5 U / mL triosephosphate isomerase, 1.5 U / mL glycerolphosphate dehydrogenase, and the appropriate concentration of PFKL. 8 μL of the reaction mixture was added to each well of a 384-well plate.

[0453] Prepare a 10-fold serial dilution of compound DMSO in enzyme reaction buffer and add 2 μL to the corresponding wells of a 384-well plate. Each concentration should be tested in duplicate. Add the same diluted DMSO to the negative control wells and background control wells as a control dilution. Incubate at 25°C for 10 minutes. Prepare a 2× reaction by diluting fructose-6-phosphate in enzyme reaction buffer. Add 10 μL of this to the 384-well plate for a final reaction concentration of 4 mM. For background control wells, add only 10 μL of enzyme reaction buffer.

[0454] The plate was read using a BioTek microplate reader Synergy Neo 2 in kinetic mode, and the OD340 absorbance was read at 2-minute intervals for 30 minutes at 25°C.

[0455] Data Analysis

[0456] Data analysis was performed within the time period during which the signal showed a linear change. The decrease in OD340 during this time period represents the enzyme reaction rate for that well. EC50 values ​​were calculated using a four-parameter curve fit using Prism software after subtracting the mean value of the background control wells from the values ​​in the test compound wells and negative control wells. See Table 1 for details.

[0457] Table 1: Human PFKL in vitro enzyme activity

[0458] Where A represents EC 50 Value ≤ 20nM; B means 20nM<EC 50 Value ≤ 100nM; C means 100nM<EC 50 Value ≤500nM.

[0459] The results showed that the compounds of the present invention have excellent PFKL activation properties.

[0460] Biological Test Example 2 In vitro study of metabolic stability in mouse, rat and human liver microsomes

[0461] Experimental Materials

[0462] Liver microsomes were stored at -80°C. The information of liver microsomes is shown in Table 2.

[0463] Table 2: Liver microparticle information

[0464] Experimental design

[0465] Prepare the incubation solution according to Table 3.

[0466] Table 3: Incubation solution preparation

[0467] Incubate the cells according to the following two methods: a) With NADPH: Add 40 μL of 10 mM NADPH to a final concentration of 0.5 mg / mL for liver microsomes and 1 mM for NADPH. b) Without NADPH: Add 40 μL of 100 mM phosphate buffer to a final concentration of 0.5 mg / mL for liver microsomes. Mix and preincubate at 37°C for 10 minutes.

[0468] 4 μL of 100 μM test compound or positive control solution was added and the reaction was started at 37°C. The final concentration of the compound was 1 μM.

[0469] At 0, 5, 10, 20, 40, and 60 minutes, remove 50 μL of the reaction solution and immediately terminate the reaction by adding 4 volumes of cold acetonitrile (containing the internal standard: 40 ng / mL Glipizide). Centrifuge at 4400 g for 15 minutes. Remove 100 μL of the supernatant, add 100 μL of ultrapure water, and analyze by LC-MS / MS.

[0470] Data Analysis

[0471] Using a semi-quantitative method, the ratio of the peak area of ​​the analyte to the peak area of ​​the internal standard represents the residual amount of the compound (R). The logarithm of the residual percentage of the prototype compound at time T relative to time T0 is linearly regressed against the reaction time T to calculate the slope (Slope), which is the elimination rate constant (Ke). Then T 1 / 2 =Ln(2) / Ke.

[0472] Table 4: Metabolic stability in human, mouse and rat liver microsomes

[0473] The results showed that the compounds of the present invention have excellent metabolic stability.

[0474] Biological Test Example 3: Human Neutrophil NETosis Test in Vitro

[0475] Experimental Materials

[0476] Neutrophils from healthy volunteers were collected and isolated on the day of the experiment. Other reagents included: RPMI 1640 medium, dimethyl sulfoxide (DMSO), phorbol 12-myristate 13-acetate (PMA), SYTOX TM Green nucleic acid dye, Nuclear Red TM LCS1 live cell dye.

[0477] Experimental methods

[0478] Dissolve the test compound in DMSO to a 10 mM stock solution. Dilute the compound stock solution with DMSO to 500-fold the highest final concentration. Perform a 4-fold serial dilution with DMSO, with eight concentration points for each compound. Dilute the serial compound dilutions in RPMI 1640 medium to 10-fold the final concentration, and add 10 μL to the corresponding wells of the cell culture plate. Dilute compound-free DMSO with RPMI 1640 medium, and add the resulting dilutions as compound blanks to the positive and negative control wells.

[0479] Centrifuge the neutrophil suspension, resuspend the cells in RPMI1640 medium, measure the cell density and adjust the cell density to 3×10 5 / ml, add SYTOX TM Green nucleic acid dye to a final concentration of 400nM, add Nuclear Red TM Add 50 μL of cell suspension to each well of the cell culture plate. Place the plate in a 37°C incubator and preincubate the cells with the compound for 30 minutes. Dilute PMA to 125 nM in RPMI 1640 medium and add 40 μL to each well, except for the negative control wells. For the negative control wells, add 40 μL of RPMI 1640 medium.

[0480] Place the plate in Using a live cell imaging system with a 10x objective, two sets of images were taken at different locations in each well at different time points to document NETosis after PMA stimulation. Phase contrast images demonstrate cell morphology, while green fluorescence indicates extracellular DNA released by cells following NETosis, and red fluorescence indicates both live cell DNA accumulated in the nucleus and extracellular DNA released.

[0481] Data Analysis

[0482] Adjust software parameters and count the number of cells undergoing NETosis and the number of live cells in each group of images. Calculate the proportion of cells undergoing NETosis in each well after 3 hours of PMA stimulation. Use GraphPad Prism software to fit the NETosis proportion and compound concentration into a dose-effect curve to calculate the compound IC. 50 See Table 5 for details.

[0483] Table 5: NETosis activity of human neutrophils in vitro

[0484] Where A represents IC 50 Value ≤ 20nM; B means 20nM < IC 50 Value ≤ 200nM; C means 200nM < IC 50 ≤2000nM value.

[0485] The results showed that the compounds of the present invention have excellent NETosis inhibitory activity.

[0486] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A fused ring compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof: in: Y is N or CH; R 2 Selected from the group consisting of: -L-NHC(=O)R c 、-L-NH-C(=N-CN)R c , -L-NH-C(=N-CN)NH2, -L-NHC(=O)NHR c 、-L-NHC(=O)NH 2、 -L-NHC(=S)NH 2、 And R 2 can be further represented by one or more R p replace; L is -(CH2)-; R c Independently selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, cyano substituted C 1-6 alkyl; R 5 Select from the following group: C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR j R k 、-C(=O)NR j R k 、-NR j C(=O)R k ; and said R 5 can be further represented by one or more R g or R h replace; R g Selected from the group consisting of hydrogen, halogen, cyano, oxo (=O), =CH2; R h Selected from the group consisting of hydroxyl, -NR h1 R h2 、-C(=O)NR h1 R h2 、-C(=O)OC 1-6 Alkyl, NR h1 R h2 、-S(O)2NR h1 R h2 、-S(O)2R h2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkanoyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, C 1-4 Alkyl C 3-10 Cycloalkyl; and said R h can be further represented by one or more R r replace; R j , R k , R h1 , R h2 are independently selected from the group consisting of hydrogen, C 1-6 alkyl; R 6 Selected from the group consisting of hydrogen, deuterium, cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 2-4 Alkenyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 2-4 alkenyl, 3-6 membered partially saturated carbocyclic group, -C 1-4 Alkyl-OH; wherein the halogen is arbitrarily selected from: F, Cl, Br, I; The R p , R r Each independently selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl; Wherein, the carbocyclic group or heterocyclic group can be a saturated or partially saturated ring, including a monocyclic ring, a bridged ring, a spirocyclic ring, and a ring structure, but does not include an aromatic structure. Unless otherwise specified, the heterocyclic group or heteroaryl group includes 1, 2 or 3 heteroatoms selected from N, S or O.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that Y is CH.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from the following formula, Among them, R d C 1-4 Alkyl, -NH2, -OH, -SH, R d Can be further C 1-4 Alkyl substitution.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The R 2 Select from the following formula, 5. The compound according to claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that: R 6 Selected from the group consisting of hydrogen, deuterium, cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 3-6 Cycloalkyl; halogen is arbitrarily selected from: F, Cl, Br, I.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The compound is selected from the following formula: Among them, R 5 Select from the following group: C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 carbocyclic group, 3-12 membered heterocyclic group; and said R 5 can be further represented by one or more R g or R h replace.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The compound is selected from the following formula, Among them, R 6 Selected from the group consisting of F, Cl, Br, I, methyl, trifluoromethyl, ethyl.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following structures, 9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises (1) the compound according to claim 1 or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, prodrug, hydrate or solvate; and (2) a pharmaceutically acceptable carrier.

10. Use of the compound according to claim 1 or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, prodrug, hydrate or solvate, or the pharmaceutical composition according to claim 9, characterized in that: Used for preparing a pharmaceutical composition for preventing and / or treating diseases associated with the activity of PFKL.

11. The use according to claim 10, characterized in that The disease is selected from the group consisting of lung disease, thrombosis, sepsis, autoimmune disease, inflammatory disease, metabolic disease, and cancer.

12. The use according to claim 11, characterized in that The disease is selected from the group consisting of: (1) The pulmonary disease is selected from the group consisting of pneumonia, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary fibrosis, asthma, acute lung injury, and idiopathic pulmonary fibrosis (IPF); (2) The thrombotic disease is selected from the group consisting of cerebral thrombosis, myocardial infarction, heart failure, coronary heart disease, atherosclerosis, and retinal vascular embolism; (3) The sepsis is selected from the group consisting of systemic inflammatory response syndrome, sepsis, severe sepsis, septic shock, systemic inflammation caused by viral infection, and multiple organ failure; (4) The autoimmune disease is selected from the group consisting of psoriasis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and systemic sclerosis; (5) The inflammatory disease is selected from the group consisting of inflammatory bowel disease, encephalitis, eye inflammation, nephritis, pancreatitis, dermatitis, Alzheimer's disease, and Parkinson's disease; (6) The metabolic disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, gout, obesity and its complications; (7) The cancer is selected from the group consisting of brain cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, skin cancer, oral cancer, pharyngeal cancer, colon cancer, liver cancer, cecum cancer, stomach cancer, pancreatic cancer, prostate cancer, esophageal cancer, blood cancer, thyroid cancer, uterine cancer and head and neck cancer.

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