Compound as KIF18A inhibitor and application thereof

Abstract

The invention belongs to the field of medical chemistry, relates to a compound serving as a KIF18A inhibitor and application of the compound, and particularly provides a compound shown in a formula (I) or pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug of the compound, processes for their preparation, pharmaceutical compositions containing these compounds and the use of these compounds or compositions for the treatment of diseases associated with KIF18A.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to compounds as KIF18A inhibitors or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs, methods for their preparation, pharmaceutical compositions containing these compounds, and the use of these compounds or compositions for treating diseases related to KIF18A. Background Technology

[0002] Chromosomal aneuploidy refers to changes in the copy number of an entire chromosome arm or the entire chromosome, and is the most common genetic alteration in human cancer. Since normal cells almost always have euploid chromosomes, while tumor cells are almost always aneuploid, and the aneuploidy of chromosomes increases with the severity of tumor invasion and metastasis, utilizing the aneuploidy of tumor cell chromosomes to develop targeted drugs has been a hot topic in cancer research. Studies have shown that tumor cells containing aneuploid chromosomes are significantly more sensitive to inhibition of mitotic kinin family member 18A (KIF18A) than normal cells containing euploid chromosomes. The main mechanism is that abnormal chromosome binding to mitotic spindle microtubules leads to abnormal chromosome segregation, triggering the spindle assembly checkpoint (SAC), and inducing tumor cell apoptosis.

[0003] KIF18A is a microtubule depolymerase that inhibits the polymerization of microtubule tips without compromising their stability, reducing the overall dynamics of the tips and effectively limiting the distance of growth and contraction. This allows chromosomes to successfully converge during metaphase by inhibiting abnormal chromosome oscillations. KIF18A deficiency leads to abnormal chromosome alignment on the cell plate during metaphase and causes abnormal chromosome segregation. While this usually does not cause abnormal cell division in normal cells, it often triggers spindle checkpoints and induces apoptosis in tumor cells containing aneuploid chromosomes. Extensive omics and literature data indicate that KIF18A is overexpressed in various tumor types, including but not limited to colorectal cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, cervical cancer, cervical cancer, and hematologic malignancies, suggesting a potentially important role in tumorigenesis and development.

[0004] Microtubule inhibitors with similar mechanisms of action to KIF18A inhibitors include paclitaxel and vincristine, which are widely used in clinical anti-tumor treatment. However, they exhibit significant neurotoxicity and myelosuppressive toxicity, and their selective killing effect on tumor cells is poor. In contrast, KIF18A inhibitors demonstrate good tumor cell specificity and low myelosuppressive toxicity. In conclusion, KIF18A inhibitors have a well-defined mechanism of action in treating chromosomal aneuploidy tumors and related diseases, and have great potential to become a new treatment approach in the field of cancer therapy. Therefore, the development of small molecule KIF18A inhibitors has significant clinical implications. Summary of the Invention

[0005] One object of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

[0006]

[0007] Another object of the present invention is to provide compositions comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof and a pharmaceutically acceptable carrier, as well as compositions comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof and one or more other antitumor drugs.

[0008] Another object of the present invention is to provide the use of compounds of general formula (I) of the present invention, or pharmaceutically acceptable salts, isomers, solvates, crystals, prodrugs or pharmaceutical compositions thereof, in the preparation of medicaments for the treatment and / or prevention of KIF18A-mediated diseases.

[0009] To achieve the above objectives, the present invention provides the following technical solution:

[0010] In a first aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs thereof.

[0011]

[0012] in,

[0013] Cycle A and Cycle B are each independently selected from cycloalkyl and heterocyclic groups, and are optionally substituted by 1, 2, 3 or 4 groups selected from halogen, alkyl, alkenyl, haloalkyl, haloalkenyl, hydroxyalkyl, alkoxy, haloalkoxy or oxo groups.

[0014] W either does not exist or is -N(CH3)-;

[0015] Y is selected from CH and N;

[0016] L is selected from -NHSO2-, -SO2NH-, -SO2-,

[0017] R 1 It is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and is optionally substituted by 1, 2, 3 or 4 groups selected from halogen, amino, hydroxy, cyano, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, cycloalkyl, heterocyclol;

[0018] R 2 Selected from halogens, hydroxyl groups, cyano groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, oxo groups, cycloalkyl groups, heterocyclic groups; and

[0019] p is selected from 0, 1, 2, 3, and 4.

[0020] In some embodiments, the compounds of the present invention are compounds of general formula (I) or pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs thereof, wherein ring A is selected from C 3-8 Monocycloalkyl, C 4-12 Fused cycloalkyl, C 5-12 Spirocycloalkyl, C 4-12 Bridged cycloalkyl, 4-8 membered monoheterocyclic, 4-12 membered fused heterocyclic, 5-12 membered spiroheterocyclic, and 4-12 membered bridged heterocyclic, wherein the heteroatom is selected from one or more N, O, P, S, and Si, and the C 3-8 Monocycloalkyl, C 4-12 Fused cycloalkyl, C 5-12 Spirocycloalkyl, C 4-12 Bridged cycloalkyl, 4-8 membered monoheterocyclic group, 4-12 membered fused heterocyclic group, 5-12 membered spirocyclic group, 4-12 membered bridged heterocyclic group are optionally selected by 1, 2, 3 or 4 halogens, C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 1-6 Alkyl, Halogenated C 2-6 alkenyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Group substitutions of alkoxy and oxo groups; and ring B selected from C. 3-8 Cycloalkyl groups, optionally composed of 1, 2, 3, or 4 alkyl groups selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 1-6 Alkyl, Halogenated C 2-6 alkenyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Group substitution of alkoxy and oxo groups.

[0021] In some embodiments, the compound of general formula (I) according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein ring A is selected from... It may be selected from 1, 2, 3 or 4 halogens, C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 1-6 Alkyl, Halogenated C 2-6 alkenyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Group substitution of alkoxy and oxo groups.

[0022] In some specific embodiments, the compound of formula (I) according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein ring A is selected from...

[0023] In some embodiments, the compounds of the present invention are compounds of general formula (I) or pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs thereof, wherein:

[0024] R 1 Selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-12 Aryl and C 6-12 Heteroaryl groups, optionally surrounded by 1, 2, 3, or 4 groups selected from halogens, amino groups, hydroxyl groups, cyano groups, C4 groups, and hydroxyl groups. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Group substitution of the heterocyclic group, wherein the heteroatom is selected from N, O, S; R 2 Selected from halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy group, oxo group, C 3-8 cycloalkyl, C 3-8 Heterocyclic group, wherein the heteroatom is selected from N, O, S; and p is selected from 1, 2, 3, and 4;

[0025] More preferably, R1 Selected from hydrogen, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-12 Aryl and C 6-12 Heteroaryl groups, optionally surrounded by 1, 2, 3, or 4 groups selected from halogens, amino groups, hydroxyl groups, cyano groups, C4 groups, and hydroxyl groups. 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkylamino, amino C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Group substitution of the heterocyclic group, wherein the heteroatom is selected from N, O, S; R 2 Selected from halogens, hydroxyl groups, cyano groups, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 alkoxy group, oxo group, C 3-8 cycloalkyl, C 3-8 Heterocyclic group, wherein the heteroatom is selected from N, O, S; and p is selected from 1, 2, 3, and 4;

[0026] More preferably, R 1 Selected from methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, trifluoroethyl, methoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyethyloxyethyl, 2-Fluoroethyl, dimethylaminoethyl, cyclopropylmethyl, oxetyl, R 2 Selected from fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 alkoxy group, oxo group, C 3-8 cycloalkyl, C 3-8 Heterocyclic group, p is selected from 1, 2, 3 and 4.

[0027] In some embodiments, the compound of formula (I) according to the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein formula (I) has the structure of formula (Ia):

[0028]

[0029] Among them, A, W, Y, L, R 1 As defined in general formula (I) of this invention.

[0030] This invention provides the following specific compounds or their pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs:

[0031]

[0032]

[0033]

[0034] On the other hand, the present invention provides pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof.

[0035] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, and pharmaceutical compositions comprising compounds of the present invention or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, said compounds or pharmaceutical compositions for treating diseases associated with KIF18A.

[0036] In some embodiments, the present invention provides pharmaceutical compositions comprising the compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug and a pharmaceutically acceptable carrier.

[0037] The compounds of the present invention, or pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs thereof, can be mixed with pharmaceutically acceptable carriers, diluents, or excipients to prepare pharmaceutical formulations suitable for oral or parenteral administration. Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations can be administered via any route, such as by infusion or bolus, or by absorption through the epithelium or mucous membranes (e.g., oral mucosa or rectum). Administration can be systemic or local. Examples of oral formulations include solid or liquid dosage forms, specifically including tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The formulations can be prepared by methods known in the art and contain carriers, diluents, or excipients conventionally used in the field of pharmaceutical formulations.

[0038] Thirdly, the present invention provides a method for using compounds of formulas (I) and (Ia) of the present invention, or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, or pharmaceutical compositions comprising thereof, for treating diseases associated with KIF18A, and for use in the preparation of medicaments for treating diseases associated with KIF18A.

[0039] In some preferred embodiments, the present invention provides methods for using compounds of formulas (I) and (Ia) or pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs thereof, or pharmaceutical compositions comprising thereof, for treating diseases associated with KIF18A, and uses in the preparation of medicaments for treating KIF18A-related diseases, wherein said KIF18A-related diseases include, but are not limited to, cancer, proliferative disorders, hematologic disorders, or metabolic disorders. In some embodiments, the KIF18A-related disease of the present invention is cancer.

[0040] In some embodiments, the present invention provides a method for treating KIF18A-mediated diseases using compounds of formulas (I) and (Ia) of the present invention, or pharmaceutically acceptable salts, isomers, solvates, crystals, prodrugs, or pharmaceutical compositions thereof, comprising administering a therapeutically effective amount of the compounds of formulas (I) and (Ia) of the present invention, or pharmaceutically acceptable salts, isomers, solvates, crystals, prodrugs, or pharmaceutical compositions thereof. In some embodiments, the present invention provides a method for treating proliferative diseases, comprising administering a therapeutically effective amount of the compounds of formulas (I) and (Ia) of the present invention, or pharmaceutically acceptable salts, isomers, solvates, crystals, prodrugs, or pharmaceutical compositions thereof. In some embodiments, the present invention provides a method for inhibiting tumor cell growth and / or metastasis, comprising administering a therapeutically effective amount of the compounds of formulas (I) and (Ia) of the present invention, or pharmaceutically acceptable salts, isomers, solvates, crystals, prodrugs, or pharmaceutical compositions thereof.

[0041] In some embodiments, the KIF18A-related diseases described in this invention are tumors or cancers, including but not limited to: pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0042] Terminology Definition

[0043] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0044] In the compounds of this invention, "hydrogen," "carbon," and "oxygen" include all their isotopes. Isotopes should be understood to include those atoms having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, and isotopes of carbon include... 12 C 13 C and 14 C, oxygen isotopes include 16 O and18 O etc.

[0045] In this invention, "isomers" refers to molecules with the same atomic composition and bonding but different three-dimensional spatial arrangements, including but not limited to diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active forms, meaning they are capable of rotating the plane of polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes D, L, or (+), (-) are used to name the symbols for the plane polarization rotation of the compound; (-) or L indicates that the compound is levorotatory, and the prefix (+) or D indicates that the compound is dextrorotatory. These stereoisomers have the same chemical structure but different stereostructures. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomer mixtures. A 50:50 enantiomer mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms “racemic mixture” and “racemate” refer to a mixture of two equimolar enantiomers that lack optical activity.

[0046] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0047] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0048] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine. "Halogenated" in this invention means substituted with fluorine, chlorine, bromine, or iodine.

[0049] In this invention, "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group containing 1 to 6 carbon atoms, and more preferably a straight-chain or branched group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc. The alkyl group can be substituted or unsubstituted, and when substituted, the substituent can be at any usable connection point.

[0050] In this invention, "carbonyl" and "acyl" both refer to -C(O)-.

[0051] In this invention, "sulfonyl" refers to -S(O)2-.

[0052] In this invention, "sulfonamide group" refers to -S(O)2NH-.

[0053] In this invention, "halogenated alkyl" refers to an alkyl group that is substituted with at least one halogen.

[0054] In this invention, "hydroxyalkyl" refers to an alkyl group that is substituted with at least one hydroxyl group.

[0055] In this invention, "alkoxy" refers to -O-alkyl. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, etc. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any usable connection point.

[0056] In this invention, "cycloalkyl" refers to a cyclic saturated or partially unsaturated hydrocarbon group. The cycloalkyl group can be monocyclic ("monocyclic cycloalkyl") or fused, bridged, or spirocyclic systems (e.g., bicyclic cycloalkyl systems, tricyclic cycloalkyl systems, etc.). Suitable cycloalkyl groups can be substituted or unsubstituted monocyclic, bicyclic, bridged, spirocyclic, or tricyclic saturated or partially unsaturated hydrocarbon groups having 3-20 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

[0057] The term "heterocyclic group" in this invention refers to a group ("3- to 20-membered non-aromatic ring system") having one to four cyclic heteroatoms (each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon). In heterocyclic groups containing one or more nitrogen atoms, the connecting point can be a carbon or nitrogen atom, provided the valence permits. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic ring systems (e.g., bicyclic systems (also known as "bicyclic heterocyclic groups"), tricyclic systems (also known as "tricyclic heterocyclic groups")) and can be saturated or partially unsaturated. Suitable heterocyclic groups include, but are not limited to, piperidinyl, aziridine, aziridine propane, tetrahydropyrrolyl, piperazine, dihydroquinazolinyl, oxacyclopropyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, dioxopentacyclic, etc. Dihydrobenzoxycyclohexenyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, and tetrahydroisoquinolinyl, etc. Each instance of the heterocyclic group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any usable connection point.

[0058] In this invention, "aryl" refers to an aromatic system that may comprise a monocyclic, bicyclic, or polycyclic ring, including fused rings, bridged rings, and spirocyclic rings. It may be a partially aromatic system containing 6 to 20 carbon atoms, preferably about 6 to about 10 carbon atoms. "Aryl" also refers to a group in which an aromatic ring is fused, spiro-, or bridged with one or more aryl, cycloalkyl, or heterocyclic rings. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, fluorenyl, and indanyl. Aryl groups may be optionally substituted or unsubstituted; when substituted, the substituent may be at any usable connection point.

[0059] In this invention, "heteroaryl" refers to an aryl group in which at least one carbon atom is replaced by a heteroatom, including monocyclic, bicyclic (such as fused ring, bridged ring, spirocyclic), or tricyclic (containing fused ring, bridged ring, spirocyclic) aromatic ring systems: preferably composed of 5-20 atoms (5-20-membered heteroaryl), more preferably composed of 5-10 atoms (5-10-membered heteroaryl), wherein the heteroatom is O, S, or N. "Heteroaryl" also refers to a group in which the heteroaryl ring is fused, spiro-, or bridged with one or more aryl, cycloalkyl, or heterocyclic rings. The heteroaryl groups include, but are not limited to, imidazolyl, pyrrololyl, furanyl, thiophenel, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzoimidazolyl, benzofuranyl, benzopyranyl, benzothiophenel, benzooxazolyl, benzothiazolyl, benzothiazolyl, benzoisooxazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cenolinyl, quinoxazinyl, benzothiazolyl, imidazopyridyl, pyrimidopyrazolyl, and pyrimidoimidazolyl. The heteroaryl groups can be optionally substituted or unsubstituted; when substituted, the substituents can be at any usable connection point.

[0060] The term "pharmaceutically acceptable salt" in this invention refers to salts of the compounds of this invention that are safe and effective when used in mammals and possess the intended biological activity.

[0061] In the conventional sense, the term "solvent" in this invention refers to a complex formed by a combination of a solute (such as an active compound or a salt of an active compound) and a solvent (such as water). The solvent refers to a solvent known or readily identifiable to those skilled in the art. If water is present, the solvate is typically referred to as a hydrate, such as a hemihydrate, monohydrate, dihydrate, trihydrate, or a substitute thereof.

[0062] The in vivo effects of compounds having chemical formulas (I) and (Ia) can be partially exerted by one or more metabolites formed in the human or animal body after administration of a compound having chemical formula (I). As described above, the in vivo effects of compounds having chemical formula (I) can also be exerted via the metabolism of a prodrug ("prodrug"). The "prodrug" of the present invention refers to a compound that, under physiological conditions in an organism, is converted into a compound of the present invention through reaction with enzymes, gastric acid, etc., i.e., a compound converted into a compound of the present invention through enzymatic oxidation, reduction, hydrolysis, etc., and / or through hydrolytic reactions such as gastric acid, etc.

[0063] The “crystallization” of this invention refers to a solid whose internal structure is formed by the regular repetition of atoms (or groups thereof) in three dimensions, which is different from amorphous solids that do not have such a regular internal structure.

[0064] The term "pharmaceutical composition" as used in this invention refers to a mixture comprising any of the compounds described herein, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or their chemically protected forms, and one or more pharmaceutically acceptable carriers and / or mixtures of other one or more drugs. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism. Such compositions are typically used in the preparation of medicaments for the treatment and / or prevention of diseases mediated by one or more kinases.

[0065] The "pharmaceutical-grade carrier" of this invention refers to a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound. This includes all solvents, diluents or other excipients, dispersants, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., unless any conventional carrier medium is incompatible with the compounds of this invention. Some examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, as well as cellulose and cellulose acetate; malt, gelatin, etc.

[0066] In this invention, "excipient" refers to an inert substance added to a pharmaceutical composition to further promote the delivery of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Detailed Implementation

[0067] The present invention will be further described in detail below with reference to the embodiments, but the present invention is not limited to these embodiments. Unless otherwise specified, all materials used in the following embodiments are commercially available.

[0068] Intermediate: 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0069]

[0070] Step 1: Preparation of N-(2-bromo-6-chloropyridin-3-yl)-4,4-difluorocyclohexane-1-carboxamide

[0071]

[0072] 4,4-Difluorocyclohexane-1-carboxylic acid (3 g, 18.293 mmol), 2-bromo-6-chloropyridin-3-amine (3.789 g, 18.293 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (5.646 g, 20.122 mmol), and 2,4,6-trimethylpyridine (6.650 g, 54.879 mmol) were dissolved in acetonitrile (40 mL) and reacted at 80 °C for 18 h. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography to give 5.1 g of the product. ESI-MS m / z: 353.1 [M+H] +

[0073] Step 2: Preparation of N-(2-bromo-6-chloropyridin-3-yl)-4,4-difluoro-N-methylcyclohexane-1-carboxamide

[0074]

[0075] N-(2-bromo-6-chloropyridin-3-yl)-4,4-difluorocyclohexane-1-carboxamide (5 g, 14.205 mmol) was dissolved in tetrahydrofuran (50 mL). Sodium hydride (0.682 g, 17.046 mmol) and methyl iodoform (0.9 g, 14.205 mmol) were slowly added at 0 °C, and the reaction was carried out at 50 °C for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to give 4.8 g of a white solid. ESI-MS m / z: 367.0 [M+H] +

[0076] Step 3: Preparation of 5'-chloro-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0077]

[0078] N-(2-bromo-6-chloropyridin-3-yl)-4,4-difluoro-N-methylcyclohexane-1-carboxamide (0.6 g, 1.63 mmol) was dissolved in toluene (15 mL), and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ide](3-chloropyridinium)palladium dichloride (0.111 g, 0.16 mmol) and sodium tert-butoxide (0.314 g, 3.26 mmol) were added. The mixture was reacted at 100 °C for 5 h. After the reaction was complete, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to give 0.8 g of a white solid. ESI-MS m / z: 287.1 [M+H] +

[0079] Step 4: Preparation of tert-butyl carbamate (4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamate

[0080]

[0081] 5'-chloro-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.8 g, 2.797 mmol), tert-butyl carbamate (0.655 g, 5.593 mmol), tris(dibenzylideneacetone)palladium (0.256 g, 0.280 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (0.3 g, 0.560 mmol) and cesium carbonate (2.733 g, 8.390 mmol) were dissolved in 1,4-dioxane (8 mL), Ar was substituted, and the reaction was carried out at 100 °C for 4 h. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.7 g of product. ESI-MS m / z: 368.2 [M+H] +

[0082] Step 5: Preparation of 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0083]

[0084] (0.7 g, 1.907 mmol) of tert-butyl carbamate (4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamate was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 0.56 g of the title product. ESI-MS m / z: 268.2 [M+H] +

[0085] Example 1: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6,6-difluoro-2-azaspiro[3,3]heptane-2-yl)-4-((2-hydroxyethyl)sulfonamide)benzamide

[0086]

[0087] Step 1: Preparation of 2-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-4-iodobenzoic acid

[0088]

[0089] Under stirring at room temperature, 6,6-difluoro-2-azaspiro[3.3]heptane (600.7 mg, 4.51 mmol) was added to a DMF (15 mL) solution of 2-fluoro-4-iodobenzoic acid (1 g, 3.76 mmol), followed by K₂CO₃ (1.56 g, 11.28 mmol). The reaction system was stirred at 100 °C for 2.0 h. The reaction was monitored by TLC. After the reaction was complete, water (50 mL) was added to quench the reaction. The mixture was then extracted three times with EA, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 700 mg of brown solid.

[0090] ESI-MS m / z: 379.9 [M+H] + .

[0091] Step 2: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6,6-difluoro-2-azaspiro[3,3]heptane-2-yl)-4-iodobenzamide

[0092]

[0093] Under stirring at room temperature, the intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (300 mg, 1.123 mmol) was added to a DMA (10 mL) solution of 2-(6,6-difluoro-2-azaspiro[3,3]heptan-2-yl)-4-iodobenzoic acid (387 mg, 1.021 mmol), followed by CMPI (391.4 mg, 1.532 mmol) and DIEA (533.5 μL, 3.063 mmol). The reaction system was stirred at room temperature for 2.0 h. The reaction was monitored by TLC. After the reaction was completed, water (50 mL) was added to quench the reaction. The mixture was then extracted three times with EA, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 369 mg of brown solid. ESI-MS m / z: 631.0 [M+H] + .

[0094] Step 3: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(6,6-difluoro-2-azaspiro[3,3]heptane-2-yl)-4-((2-hydroxyethyl)sulfonamide)benzamide

[0095]

[0096] At room temperature, 2-hydroxyethyl-1-sulfonamide (146.8 mg, 1.174 mmol) was added to a DMF (10 mL) solution of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-4-iodobenzamide (369 mg, 0.587 mmol) followed by CuI (111.8 mg, 0.587 mmol), sarcosine (156.9 mg, 1.761 mmol), and K3PO4 (498.4 mg, 2.348 mmol). The reaction system was stirred at 100 °C for 2.0 h. The reaction was monitored by TLC. After the reaction was completed, water (50 mL) was added to quench the reaction. The product was then extracted three times with EA, the organic phases were combined, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 330 mg of a brown liquid. After separation, 130 mg of the title product was obtained. 1HNMR (400MHz, DMSO) δ10.52(s,1H),9.84(s,1H),8.07(d,J=6.0Hz,1H),7.50(d,J=8.6Hz,1H ),7.31(d,J=7.8Hz,1H),6.62(d,J=8.1Hz,1H),6.37(d,J=1.7Hz,1H),4.95(s,1H),3.90(s,4 H),3.74(t,J=6.7Hz,2H),3.28(t,J=6.7Hz,2H),3.17(s,3H),2.82(t,J=12.5Hz,4H),2.62-2 .51(m,2H),2.26-2.12(m,2H),1.97-1.87(m,2H),1.85-1.72(m,2H).ESI-MSm / z:625.9[M+H] +

[0097] Example 2: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(1-oxa-7-azaspiro[3,5]nonane-7-yl)benzamide

[0098]

[0099] Step 1: Preparation of 1-oxa-7-aza-spiro[3,5]nonane

[0100]

[0101] 1-oxa-7-aza-spiro[3,5]nonane-7-carboxylic acid tert-butyl ester was dissolved in dichloromethane, and trifluoroacetic acid was added at 0°C. The mixture was then heated to room temperature and reacted for 3 hours. After the reaction was complete, the solvent was removed under vacuum to obtain the crude product, which was directly used in the next step.

[0102] Step 2: Preparation of 4-iodo-2-(1-oxa-7-azaspiro[3.5]nonane-7-yl)benzoic acid

[0103]

[0104] Under argon protection, 1-oxa-7-aza-spiro[3,5]nonane (1.5 g, 12 mmol), 2-fluoro-4-iodobenzoic acid (2.7 g, 10 mmol), and potassium carbonate (4.1 g, 30 mmol) were dissolved in NMP and reacted at 180 °C for 16 h. After the reaction was completed by LCMs, the reaction solution was cooled to room temperature, extracted with saturated brine and ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to give 2.6 g of the product as a yellow solid. ESI-MS m / z: 373.9 [M+H]+.

[0105] Step 3: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(1-oxa-7-azaspiro[3,5]nonane-7-yl)benzamide

[0106]

[0107] Intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (534 mg, 2 mmol), 4-iodo-2-(1-oxa-7-azaspiro[3.5]nonane-7-yl)benzoic acid (1.1 g, 3 mmol), 2-chloro-1-methylpyridine iodide (1.0 g, 4 mmol), and N,N-diisopropylethylamine (774 mg, 6 mmol) were dissolved in N,N-dimethylacetamide and reacted at 40 °C for 3 h. After the reaction was complete, the mixture was extracted with ethyl acetate and saturated brine, the organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum by column chromatography to give 607 mg of product. ESIMS m / z: 622.8 [M+H]+.

[0108] Step 4: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(1-oxa-7-azaspiro[3,5]nonane-7-yl)benzamide

[0109]

[0110] Under argon protection, N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(1-oxa-7-azaspiro[3.5]nonane-7-yl)benzamide (311 mg, 0.5 mmol), 2-hydroxyethyl-1-sulfonamide (125 mg, 1 mmol), cuprous iodide (48 mg, 0.25 mmol), potassium phosphate (530 mg, 2.5 mmol), and sarcosine (45 mg, 0.5 mmol) were dissolved in DMF and reacted at 100 °C for 1 h. After the reaction was completed by LCM monitoring, the reaction solution was extracted with saturated brine and ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was obtained by column chromatography. HPLC purification yielded 20 mg of the title product. 1 HNMR (400MHz, DMSO) δ12.24(s,1H),8.25(d,J=8.6Hz,1H),7.98(d,J=8.6Hz,1H),7.51(d,J=8. 7Hz,1H),7.22(d,J=1.8Hz,1H),7.09(dd,J=8.6,1.9Hz,1H),4.46(t,J=5.2Hz,1H),3.76(t,J= 6.5Hz,2H),3.50(dd,J=11.9,6.8Hz,2H),3.44(s,2H),3.36(s,4H),3.17(s,3H),3.14(t,J=5. 5Hz,2H),2.41-2.23(m,6H),2.17(t,J=6.7Hz,2H),1.93-1.80(m,4H).ESI-MSm / z:619.9[M+H] + .

[0111] Example 3: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-((3aR,6aS)-hexahydrocyclopentano[c]pyrrolo-2(1H)-yl)-4-((2-hydroxyethyl)sulfonamide)benzamide

[0112]

[0113] Step 1: Preparation of 2-((3aR,6aS)-hexahydrocyclopentano[c]pyrrole-2(1H)-yl)-4-iodobenzoic acid

[0114]

[0115] 2-Fluoro-4-iodobenzoic acid (0.5 g, 1.888 mmol), potassium carbonate (0.78 g, 5.641 mmol), and (3aR,6aS)-octahydrocyclopentano[c]pyrrole (0.36 g, 2.444 mmol) were dissolved in dimethyl sulfoxide (5 mL), and the mixture was purged with argon and reacted at 180 °C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to approximately 2, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.4 g of a brown powder. ESI-MS m / z: 357.8 [M+H] +

[0116] Step 2: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-((3aR,6aS)-hexahydrocyclopentano[c]pyrrolo-2(1H)-yl)-4-iodobenzamide

[0117]

[0118] 2-((3aR,6aS)-hexahydrocyclopentano[c]pyrrolo-2(1H)-yl)-4-iodobenzoic acid (0.241 g, 0.6739 mmol) was dissolved in dichloromethane (3 mL), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.641 g, 1.6846 mmol), the intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.15 g, 0.5615 mmol), and N,N-diisopropylethylamine (0.5 mL, 2.808 mmol) were added. The reaction was carried out at room temperature for 2 h. The product was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give 0.3 g of the product. ESI-MS m / z: 606.9 [M+H] +

[0119] Step 3: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-((3aR,6aS)-hexahydrocyclopentano[c]pyrrolo-2(1H)-yl)-4-((2-hydroxyethyl)sulfonamide)benzamide

[0120]

[0121] N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-((3aR,6aS)-hexahydrocyclopentano[c]pyrrolo-2(1H)-yl)-4-iodobenzamide (300 mg, 0.495 mmol), 2-hydroxyethyl-1-sulfonamide (124 mg, 0.99 mmol), cuprous iodide (47 mg, 0.248 mmol), sarcosine (44 mg, 0.495 mmol), potassium phosphate (525 mg, 2.475 mmol), and N,N-dimethylformamide (2 mL) were added to a reaction flask, Ar was substituted, and the reaction was carried out at 100 °C for 2 h. After the reaction was completed, water was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and 27 mg of the title compound was obtained by HPLC. 1 H NMR (400MHz, DMSO) δ11.48(s,1H),10.00(s,1H),8.23(d,J=8.6Hz,1H),7.69(d,J=8.4Hz,1H) ,7.52(d,J=8.7Hz,1H),6.99(s,1H),6.92(d,J=8.4Hz,1H),3.75(t,J=6.6Hz,2H),3.57-3.35( m,3H),3.35-3.25(m,4H),3.17(s,3H),2.75(d,J=5.9Hz,4H),2.20(dd,J=21.0,13.2Hz,2H), 1.99-1.87(m,2H),1.85-1.73(m,2H),1.65(s,3H),1.57-1.38(m,3H).ESI-MSm / z:603.9[M+H] + .

[0122] Example 4: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0123]

[0124] Step 1: Preparation of 2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-4-iodobenzoic acid

[0125]

[0126] 2-Fluoro-4-iodobenzoic acid (1 g, 3.761 mmol), potassium carbonate (1.559 g, 11.282 mmol), and 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (0.544 g, 4.889 mmol) were dissolved in dimethyl sulfoxide (10 mL), purged with argon, and reacted at 180 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, the pH was adjusted to approximately 2, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.6 g of a brown powder. ESI-MS m / z: 357.8 [M+H] +

[0127] Step 2: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-4-iodobenzamide

[0128]

[0129] 2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-4-iodobenzoic acid (0.27 g, 0.749 mmol) was dissolved in N,N-dimethylformamide (3 mL), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.85 g, 2.246 mmol), the intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.2 g, 0.749 mmol), and N,N-diisopropylethylamine (0.65 mL, 3.744 mmol) were added. The mixture was reacted at 50 °C for 3 days. The product was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give 0.12 g of the product. ESI-MS m / z: 606.8 [M+H] +

[0130] Step 3: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0131]

[0132] N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-4-iodobenzamide (120 mg, 0.198 mmol), 2-hydroxyethyl-1-sulfonamide (50 mg, 0.396 mmol), cuprous iodide (19 mg, 0.099 mmol), sarcosine (18 mg, 0.198 mmol), potassium phosphate (200 mg, 0.99 mmol), and N,N-dimethylformamide (2 mL) were added to a reaction flask, Ar was substituted, and the reaction was carried out at 100 °C for 1 h. After the reaction was completed, water was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and 38 mg of the product was obtained by HPLC. ESI-MS m / z: 603.9 [M+H] + . 1 H NMR (400MHz, DMSO) δ10.78(s,1H),9.83-9.59(m,1H),8.11(d,J=8.6Hz,1H),7.49(d,J=8.6Hz,1H),7.19(d,J=8.6Hz,1H),6.55(d,J=6. 1Hz,2H),5.02-4.88(m,1H),3.74(t,J=6.4Hz,2H),3.44(dd,J=7.5,1.4Hz,2H),3.26(t,J=6.8Hz,2H),3.20(d,J=10.0Hz,2H),3.17(s, 3H), 2.73-2.53 (m, 2H), 2.24-2.09 (m, 2H), 1.99-1.86 (m, 2H), 1.83-1.68 (m, 2H), 1.49-1.43 (m, 2H), 0.99 (d, J = 8.3 Hz, 3H), 0.81 (s, 3H). Example 5: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(1,1-difluoro-5-azaspiro[2.5]octane-5-yl)-4-((2-hydroxyethyl)sulfonamide)benzamide

[0133]

[0134] Step 1: Preparation of 2-(1,1-difluoro-5-azaspiro[2.5]octane-5-yl)-4-iodobenzoic acid

[0135]

[0136] 2-Fluoro-4-iodobenzoic acid (724 mg, 2.7 mmol) was dissolved in 10 mL of dimethyl sulfoxide, and potassium carbonate (2.2 g, 16.2 mmol) and 1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (1.0 g, 5.4 mmol) were added. The mixture was stirred at 180 °C for 4 h, extracted with ethyl acetate, washed thoroughly with water, dried over anhydrous sodium sulfate, and concentrated to obtain 1.3 g of crude compound, which was directly added to the next step. ESI-MS m / z: 393.9 [M+H] +

[0137] Step 2: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(1,1-difluoro-5-azaspiro[2,5]octane-5-yl)-4-iodobenzamide

[0138]

[0139] Weigh 0.1 g (0.254 mmol) of 2-(1,1-difluoro-5-azaspiro[2.5]oct-5-yl)-4-iodobenzoic acid and 0.289 g (0.762 mmol) of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.289 g (0.762 mmol)) into a reaction flask, add 5 mL of N,N-dimethylformamide to dissolve, add N,N-diisopropylethylamine (0.5 mL), stir for 2 min, add intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.067 g (0.254 mmol)), react at room temperature for 2 h, after the reaction is complete, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate to obtain 0.15 g of the target product, and directly add to the next step.

[0140] Step 3: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(1,1-difluoro-5-azaspiro[2,5]octane-5-yl)-4-((2-hydroxyethyl)sulfonamide)benzamide

[0141]

[0142] N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(1,1-difluoro-5-azaspiro[2.5]oct-5-yl)-4-iodobenzamide (200 mg, 0.311 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 2-hydroxyethyl-1-sulfonamide (116 mg, 0.933 mmol), cuprous iodide (60 mg, 0.311 mmol), sarcosine (56 mg, 0.622 mmol), and potassium phosphate (296 mg, 1.4 mmol) were added. The mixture was purged with argon and reacted at 100 °C for 2 h. After the reaction was complete, the mixture was filtered, the residue was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, and the product was prepared by separation and lyophilization to obtain 30 mg of the white powder title product. ESI-MS m / z: 639.9 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.33(s,1H),8.31(s,1H),8.24(d,J=8.6Hz,1H),8.00(d ,J=8.6Hz,1H),7.51(d,J=8.6Hz,1H),7.16(s,1H),7.11-6.98(m,1H),3.75(t, J=6.5Hz,2H),3.31(d,J=6.4Hz,2H),3.17(s,3H),2.96(dt,J=16.5,8.7Hz,4H ),2.44-2.20(m,4H),2.05-1.72(m,7H),1.67-1.47(m,2H),1.33-1.20(m,1H).

[0143] Example 6: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0144]

[0145] Step 1: Preparation of tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate

[0146]

[0147] 4-O-piperidin-1-carboxylic acid tert-butyl ester (2.00 g, 10.038 mmol) was dissolved in N,N-dimethylformamide (50 mL), purged three times with argon, and then slowly added dropwise at -40 °C in a solution of 2-((difluoromethyl)sulfonyl)pyridine (1.937 g, 10.038 mmol) in N,N-dimethylformamide (20 mL) and potassium tert-butoxide (1.69 g, 15.057 mmol) in N,N-dimethylformamide (50 mL). The mixture was stirred at -40 °C for 2 h, and then saturated ammonium chloride (4.8 mL) and 3M hydrochloric acid (12 mL) were added to the reaction solution. The mixture was slowly heated to room temperature. The solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (0-8% gradient of ethyl acetate / petroleum ether) to give 1.5 g of a colorless oil.

[0148] Step 2: Preparation of 4-(difluoromethylene)piperidine hydrochloride

[0149]

[0150] 4-(difluoromethylene)piperidine-1-carboxylic acid tert-butyl ester (2 g, 8.571 mmol) was dissolved in 1,4-dioxane (20 mL), and hydrochloric acid / dioxane (20 mL, 4 M) was added. The mixture was reacted at 25 °C for 16 h. The reaction solution was concentrated and evaporated to dryness to obtain 2.2 g of white solid.

[0151] Step 3: Preparation of 2-(4-(difluoromethylene)piperidin-1-yl)-4-nitrobenzoic acid

[0152]

[0153] 2-Fluoro-4-nitrobenzoic acid (1 g, 5.4 mmol) was dissolved in dimethyl sulfoxide (10 mL), and 4-(difluoromethylene)piperidine hydrochloride (1.2 g, 7.1 mmol) and potassium carbonate (2.2 g, 16.2 mmol) were added. The mixture was purged three times with argon and reacted at 140 °C for 2 days. After the reaction was complete, the solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.5 g of the product. ESI-MS m / z: 299.1 [M+H] +

[0154] Step 4: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-nitrobenzamide

[0155]

[0156] 2-(4-(difluoromethylene)piperidin-1-yl)-4-nitrobenzoic acid (0.223 g, 0.7487 mmol) was dissolved in dichloromethane (2 mL), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.854 g, 2.2462 mmol), the intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.2 g, 0.7487 mmol), and N,N-diisopropylethylamine (0.65 mL, 3.744 mmol) were added. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, the mixture was diluted with water, extracted with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.23 g of the product. ESI-MS m / z: 548.2 [M+H] +

[0157] Step 5: Preparation of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)benzamide

[0158]

[0159] N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-nitrobenzamide (0.2 g, 0.3655 mmol) was dissolved in ethanol (2 mL) and water (0.5 mL). Reduced iron powder (61 mg, 1.0965 mmol) and ammonium chloride (39 mg, 0.731 mmol) were added. The mixture was purged three times with argon gas and reacted at 80 °C for 6 h. After the reaction was complete, the filtrate was collected by filtration and concentrated under reduced pressure to obtain 0.15 g of product. ESI-MS m / z: 518.2 [M+H] +

[0160] Step 6: Preparation of methyl 2-(N-(4-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamoyl)-3-(4-(difluoromethylene)piperidin-1-yl)phenyl)aminosulfonyl)acetate

[0161]

[0162] 230 mg (0.445 mmol) of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin-1-yl)benzamide was dissolved in 2 mL of dichloromethane. Pyridine (0.05 mL, 0.534 mmol) and methyl 2-(chlorosulfonyl)acetate (0.05 mL, 0.445 mmol) were added at 0 °C, and the reaction was carried out at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 150 mg of a yellow solid. ESI-MS m / z: 653.9 [M+H] + .

[0163] Step 7: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0164]

[0165] 150 mg (0.23 mmol) of methyl 2-(N-(4-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamoyl)-3-(4-(difluoromethylene)piperidin-1-yl)phenyl)aminosulfonyl)acetate was dissolved in tetrahydrofuran (2 mL), purged three times with argon, and lithium borohydride (0.23 mL, 0.46 mmol) was added dropwise at 0 °C. The reaction was carried out at 0 °C for 1 hour. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 90 mg of a yellow solid. 42 mg of the title compound was separated by HPLC. ESI-MS m / z: 625.9 [M+H] + . 1H NMR (400MHz, DMSO) δ12.78(s,1H),10.36-10.10(m,1H),8.34(d,J=8.6Hz,1H),8.07(d,J=8.6Hz,1 H),7.56(d,J=8.7Hz,1H),7.19(d,J=2.0Hz,1H),7.13(dd,J=8.6,2.0Hz,1H),5.05-4.83(m,1H),3 .76(t,J=6.4Hz,2H),3.36(t,J=6.5Hz,2H),3.18(s,3H),3.00(t,J=5.3Hz,4H),2.49(d,J=3.7Hz, 4H),2.38(dd,J=31.4,14.9Hz,2H),2.24-2.10(m,2H),2.00-1.89(m,2H),1.77(d,J=13.8Hz,2H).

[0166] Example 7: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(7-azaspiro[3,5]nonane-7-yl)benzamide

[0167]

[0168] Step 1: Preparation of 4-iodo-2-(7-azaspiro[3.5]nonane-7-yl)benzoic acid

[0169]

[0170] 2-Fluoro-4-iodobenzoic acid (3 g, 11.2 mmol) was dissolved in 35 mL of dimethyl sulfoxide, and potassium carbonate (8.1 g, 59 mmol) and 7-azaspiro[3.5]nonane hydrochloride (1.9 g, 11.8 mmol) were added. The mixture was stirred at 180 °C for 14 h, extracted with ethyl acetate, washed thoroughly with water, dried over anhydrous sodium sulfate, and concentrated to obtain 2.0 g of crude compound, which was directly added to the next step. ESI-MS m / z: 370.1 [MH] -

[0171] Step 2: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(7-azaspiro[3,5]nonane-7-yl)benzamide

[0172]

[0173] Weigh 0.14 g (0.375 mmol) of 4-iodo-2-(7-azaspiro[3.5]nonane-7-yl)benzoic acid and 0.37 g (976 mmol) of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.37 g, 976 mmol) into a reaction flask, add 5 mL of N,N-dimethylformamide to dissolve, add N,N-diisopropylethylamine (1.0 mL), stir for 2 min, add intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.13 g, 0.488 mmol), react at room temperature for 2 h, after the reaction is complete, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate to obtain 0.27 g of the target product, and directly add to the next step.

[0174] Step 3: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(7-azaspiro[3.5]nonane-7-yl)benzamide

[0175]

[0176] N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(7-azaspiro[3.5]non-7-yl)benzamide (278 mg, 0.449 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 2-hydroxyethyl-1-sulfonamide (168 mg, 1.35 mmol), cuprous iodide (42 mg, 0.225 mmol), sarcosine (80 mg, 0.898 mmol), and potassium phosphate (475 mg, 2.2 mmol) were added. The mixture was purged with argon and reacted overnight at 100 °C. After the reaction was complete, the mixture was filtered, the residue was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, and the product was prepared by separation and lyophilization to obtain 30 mg of the white powder title product. ESI-MS m / z: 618.2 [M+H] + . 1H NMR (400MHz, DMSO) δ12.68(s,1H),8.31(d,J=8.6Hz,1H),8.01(d,J=8.6Hz,1H),7.52(d,J=8.7Hz,1H),7.17(s,1H),7.08(d, J=8.7Hz,1H),3.75(t,J=6.5Hz,2H),3.32(d,J=6.3Hz,2H),3.17(s,3H),2.84(s,4H),2.41-2.21(m,4H),2.01-1.64(m,14H).

[0177] Example 8: N-(2-(4,4-dimethyl-1,4-azasilane-1-yl)-4-(methylsulfonamido)phenyl)-4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-carboxamide

[0178]

[0179] Step 1: Preparation of 2-(4,4-dimethyl-1,4-azasilane-1-yl)-4-nitrobenzoic acid

[0180]

[0181] The substrate 2-fluoro-4-nitrobenzoic acid (1.43 g, 7.75 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by the addition of cesium carbonate (7.56 g, 23.25 mmol) and 4,4-dimethyl-1,4-azasilane hydrochloride (1.0 g, 7.75 mmol). The mixture was stirred at 120 °C for 14 h, extracted with ethyl acetate, washed thoroughly with water, dried over anhydrous sodium sulfate, and concentrated to obtain 1.5 g of crude compound, which was directly added to the next step. ESI-MS m / z: 293.1 [MH] -

[0182] Step 2: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(4,4-methyl-1,4-azasilane-1-yl)-4-nitrobenzamide

[0183]

[0184] Weigh 0.16 g (0.56 mmol) of 2-(4,4-dimethyl-1,4-azasilane-1-yl)-4-nitrobenzoic acid and 0.425 g (1.12 mmol) of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.425 g, 1.12 mmol) into a reaction flask, add 5 mL of N,N-dimethylformamide to dissolve, add N,N-diisopropylethylamine (1.0 mL), stir for 2 min, add intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.15 g, 0.56 mmol), react at room temperature for 2 h, after the reaction is complete, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain 0.5 g of the target product.

[0185] Step 3: Preparation of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(4,4-methyl-1,4-azasilane-1-yl)benzamide

[0186]

[0187] Weigh 0.5 g (0.92 mmol) of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(4,4-methyl-1,4-azasilane-1-yl)-4-nitrobenzamide into a two-necked flask, dissolve in 20 mL of methanol, add 300 mg of wet palladium on carbon, and react at room temperature for 2 h under hydrogen protection. Filter the reaction solution with diatomaceous earth, collect the filtrate, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 500 mg of crude product. [ESI-MS m / z: 514.2 M+H] +

[0188] Step 4: Preparation of N-(2-(4,4-dimethyl-1,4-azasilane-1-yl)-4-(methylsulfonamido)phenyl)-4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-carboxamide

[0189]

[0190] Weigh 0.5 g (0.97 mmol) of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(4,4-methyl-1,4-azasilane-1-yl)benzamide into a two-necked flask, dissolve in 20 mL of dichloromethane, add 0.5 mL of pyridine, and add 0.2 mL of methanesulfonyl chloride dropwise under ice bath. After the reaction is complete, extract with water, collect the filtrate, dry to anhydrous sodium sulfate, concentrate under reduced pressure to obtain 300 mg of crude product, and prepare the title product by plateau separation and purification. ESI-MS m / z: 592.2 [M+H] + . 1 H NMR(400MHz,DM SO)δ12.49(s,1H),10.13(s,1H),8.26(d,J=8.6Hz,1H),7.99(d,J=8.6Hz,1H),7.52(d,J=8.7Hz,1H),7.22(d,J=1.9Hz,1H),7.08(dd, J=8.6,2.0Hz,1H),3.23-3.17(m,4H),3.16(s,3H),3.09(s,3H),2.42-2.19(m,4H),1.98-1.82(m,4H),1.01-0.89(m,4H),0.13(s,6H).

[0191] Example 9: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-(2-hydroxyethoxy)ethyl)sulfonamide)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0192]

[0193] Step 1: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-nitro-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0194]

[0195] Weigh 0.155 g (0.56 mmol) of 4-nitro-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid and 284 mg (0.748 mmol) of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (284 mg, 0.748 mmol) into a reaction flask. Dissolve the urea in 5 mL of N,N-dimethylformamide, add 1.0 mL of N,N-diisopropylethylamine, stir for 2 min, add the intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.15 g, 0.56 mmol), react at room temperature for 2 h. After the reaction is complete, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain 0.3 g of the target product. ESI-MS m / z: 527.1 [M+H] +

[0196] Step 2: Preparation of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0197]

[0198] Weigh 0.3 g (0.57 mmol) of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-nitro-2-(6-azaspiro[2.5]octane-6-yl)benzamide into a two-necked flask, dissolve it in 20 mL of methanol and 10 mL of ethyl acetate, add 100 mg of wet palladium on carbon, and react at room temperature for 2 h under hydrogen atmosphere. Filter the reaction solution with diatomaceous earth, collect the filtrate, dry it with anhydrous sodium sulfate, and concentrate it under reduced pressure to obtain 350 mg of crude product. ESI-MS m / z: 496.2 [M+H] +

[0199] Step 3: Preparation of methyl 2-(N-(4-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamoyl)-3-(6-azaspiro[2,5]octane-6-yl)phenyl)aminosulfonyl)acetate

[0200]

[0201] Weigh 0.35 g (0.36 mmol) of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide into a two-necked flask, dissolve it in 20 mL of dichloromethane, add 1.0 mL of pyridine, and add 0.5 mL of methyl 2-(chlorosulfonyl)-acetate dropwise under ice bath. After the reaction is complete, extract with water, collect the filtrate, dry it with anhydrous sodium sulfate, and concentrate it under reduced pressure to obtain 300 mg of crude product. ESI-MS m / z: 632.2 [M+H] +

[0202] Step 4: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0203]

[0204] Weigh 0.3 g (0.475 mmol) of methyl 2-(N-(4-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamoyl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)aminosulfonyl)acetate into a two-necked flask, dissolve in 10 mL of tetrahydrofuran, add 1.0 mL of lithium borohydride solution dropwise under ice bath, extract with water after the reaction is complete, collect the filtrate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 200 mg of crude product. ESI-MS m / z: 603.9 [M+H] +

[0205] Step 5: Preparation of 2-(2-(N-(4-((4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamoyl)-3-(6-azaspiro[2,5]octane-6-yl)phenyl)aminosulfonyl)ethoxy)ethyl acetate

[0206]

[0207] Weigh 0.2 g (0.33 mmol) of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide into a two-necked flask, add 0.12 g (0.36 mmol) of ethyl 2-bromoacetate, dissolve in 5 mL of N,N-dimethylformamide, then add potassium carbonate (225 mg, 1.65 mmol), react at room temperature for 1 h, extract with water after reaction, collect the filtrate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 150 mg of crude product. ESI-MS m / z: 690.2 [M+H] +

[0208] Step 6: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-(hydroxyethoxy)ethyl)sulfonamide)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0209]

[0210] 0.15 g (0.21 mmol) of 2-(2-(N-(4-((4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamoyl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)aminosulfonyl)ethoxy)ethyl acetate (0.15 g, 0.21 mmol) was dissolved in 10 mL of tetrahydrofuran. Lithium borohydride (2 mol / L) solution was added dropwise in small batches under ice bath conditions. After the reaction was complete, the mixture was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, and the filtrate was collected, dried over anhydrous sodium sulfate, and sent to a preparative platform to separate 10 mg of the product. ESI-MS m / z: 647.9 [M+H] + . 1H NMR (400MHz, DMSO) δ12.93(s,1H),8.35(d,J=8.6Hz,1H),8.10(d,J=8.5Hz,1H),7.56(d, J=8.7Hz,1H),7.52(d,J=1.9Hz,1H),7.37(dd,J=8.5,2.0Hz,1H),4.84(s,1H),3.78(q,J= 6.1Hz,4H),3.41(dd,J=14.6,8.5Hz,4H),3.19(s,3H),3.04(t,J=5.0Hz,4H),2.45(s,2H) ,2.26(d,J=10.3Hz,2H),2.01-1.93(m,2H),1.90-1.82(m,2H),1.65(s,4H),0.37(s,4H).

[0211] Example 10: Dimethyl(4-((1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)phosphamide

[0212]

[0213] Step 1: Preparation of 5'-bromo-1'-methylspiro[cyclopropane-1,3'-indoline]-2'-one

[0214]

[0215] 1.0 g (4.2 mmol) of 5'-bromospiro[cyclopropane-1,3'-indoline]-2'-one was weighed into a 100 mL reaction flask and placed in an ice bath. It was dissolved in 10 mL of N,N-dimethylformamide, and sodium hydroxide (1.6 g, 42 mmol) was slowly added. The reaction was carried out at room temperature for 1 minute, followed by the addition of 1.3 mL (21 mmol) of iodomethane, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.0 g of a yellow oil. ESI-MS m / z: 251.9 [M+H] +

[0216] Step 2: Preparation of tert-butyl (1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0217]

[0218] 5'-Bromo-1'-methylspiro[cyclopropane-1,3'-indoline]-2'-one (1.0 g, 4 mmol) was added to 1,4-dioxane (20 mL), followed by tert-butyl carbamate (918 mg, 8 mmol), tris(dibenzylacetone)dipalladium (150 mg, 0.163 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tris-1-propyl-11'-biphenyl (200 mg, 0.373 mmol), and cesium carbonate (4.5 g, 3.5 mmol). The mixture was purged three times with argon and reacted at 100 °C for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain 1.5 g of a yellow solid. ESI-MS m / z: 289.1 [M+H] +

[0219] Step 3: Preparation of 5'-amino-1'-methylspiro[cyclopropane-1,3'-indoline]-2'-one

[0220]

[0221] 1.0 g (13.4 mmol) of tert-butyl (1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate was added to 10 mL of dichloromethane, followed by 5 mL of trifluoroacetic acid. The reaction was carried out at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.9 g of a brown oil. ESI-MS m / z: 189.1 [M+H] +

[0222] Step 4: Preparation of 4-iodo-N-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0223]

[0224] Weigh 0.749 g (2.1 mmol) of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid and 1.6 g (4.2 mmol) of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (4.2 mmol) into a reaction flask. Dissolve the urea in 10 mL of N,N-dimethylformamide, add 1.0 mL of N,N-diisopropylethylamine, stir for 2 min, add 0.4 g (2.1 mmol) of 5'-amino-1'-methylspiro[cyclopropane-1,3'-indoline]-2'-one, and react at room temperature for 2 h. After the reaction is complete, wash with saturated brine, dry with anhydrous sodium sulfate, and separate by column chromatography to obtain 0.7 g of the target product. ESI-MS m / z: 529.66 [M+2H]+

[0225] Step 5: Preparation of tert-butyl (4-((1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamoyl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)carbamate

[0226]

[0227] 4-Iodo-N-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide (606 mg, 1 mmol), tert-butyl carbamate (442 mg, 0.84 mmol), tris(dibenzylacetone)dipalladium (76 mg, 0.084 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (97 mg, 0.168 mmol), and cesium carbonate (819 mg, 2.52 mmol) were dissolved in 1,4-dioxane, and the mixture was heated to 100 °C and reacted for 2 h. After the reaction was completed by LCM monitoring, the reaction was cooled to room temperature, extracted with saturated brine and ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain the product. ESIMS m / z: 517.0 [M+H] + .

[0228] Step 6: Preparation of 4-amino-N-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0229]

[0230] (4-((1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)tert-butyl carbamate was dissolved in dichloromethane, and trifluoroacetic acid was added with stirring. After the reaction was complete, the pH was adjusted to weakly alkaline by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (20 ml × 3) and saturated sodium chloride solution. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. ESI-MS m / z: 417.0 [M+H] + .

[0231] Step 7: Preparation of dimethyl(4-((1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)phosphamide

[0232]

[0233] Weigh 0.4 g (0.96 mmol) of 4-amino-N-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide into a two-necked flask, dissolve it in 20 mL of dichloromethane, add 1.0 mL of pyridine, and add 1.0 mL of O,O-dimethylphosphoryl chloride dropwise under ice bath. After the reaction is complete, extract with water, collect the filtrate, dry it with anhydrous sodium sulfate, concentrate it under reduced pressure to obtain 300 mg of crude product, and prepare the title compound by plateau separation and purification. ESI-MS m / z: 525.2 M+H] + . 1 H NMR (400MHz, DMSO) δ11.68(s,1H),8.42(d,J=8.9Hz,1H),7.78(d,J=8.5Hz,1H),7.62(d,J=1.9Hz,1H),7.41(dd,J=8.4,2.0Hz,1H),7.08(t,J=10.5Hz, 1H),7.02(d,J=2.0Hz,1H),6.86(dd,J=8.5,2.0Hz,1H),3.68(s,3H),3.66( s,3H),3.21(s,3H),2.94(t,J=5.0Hz,4H),1.59-1.46(m,8H),0.35(s,4H).

[0234] Example 11: Dimethyl(4-((4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamoyl)-3-(6-azaspiro[2,5]octane-6-yl)phenyl)phosphamide

[0235]

[0236] Step 1: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0237]

[0238] Intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one, 4-iodo-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid, 2-chloro-1-methylpyridine iodide, and N,N-diisopropylethylamine were dissolved in N,N-dimethylacetamide and reacted at 40°C for 3 h. After the reaction was complete, the mixture was extracted with ethyl acetate and saturated brine, the organic layers were combined, dried over anhydrous Na2SO4, and concentrated by vacuum column chromatography to give 684 mg of product. ESIMS m / z: 607.1 [M+H] + .

[0239] Step 2: Preparation of tert-butyl(4-((4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamoyl)-3-(6-azaspiro[2,5]octane-6-yl)phenyl)carbamate

[0240]

[0241] N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (606 mg, 1 mmol), tert-butyl carbamate (234 mg, 2 mmol), tris(dibenzylideneacetone)palladium (91 mg, 0.1 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (57 mg, 0.1 mmol), and cesium carbonate (975 mg, 0.3 mmol) were dissolved in 1,4-dioxane and reacted at 100 °C for 2 h. After the reaction was monitored by LCMs, the reaction was cooled to room temperature, extracted with saturated brine and ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the product. ESIMS m / z: 596.1 [M+H] + .

[0242] Step 3: Preparation of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0243]

[0244] Tert-butyl(4-((4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamoyl)-3-(6-azaspiro[2,5]octane-6-yl)phenyl)carbamate was dissolved in dichloromethane, and trifluoroacetic acid was added with stirring. After the reaction was complete, the pH was adjusted to weakly alkaline by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (20 ml × 3) and saturated sodium chloride solution. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. ESI-MS m / z: 496.2 [M+H] + .

[0245] Step 4: Preparation of dimethyl(4-((4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamoyl)-3-(6-azaspiro[2,5]octane-6-yl)phenyl)phosphamide

[0246]

[0247] Elemental iodine (406 mg, 1.6 mmol) was dissolved in dichloromethane, and a solution of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide and trimethoxyphosphine (199 mg, 1.6 mmol) in dichloromethane was added dropwise. After the reaction was monitored by LCMs, the reaction solution was concentrated under reduced pressure, and 50 mg of the title product was obtained by column chromatography. ESI-MS m / z: 604.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ12.90(s,1H),8.48(d,J=8.2Hz,1H),8.19(d,J=8.4Hz,1H),7.18(d,J=8.6Hz,1H),7.02-6.83(m,2H),6.33(s,1H),3.85(s,3 H),3.82(s,3H),3.25(s,3H),3.07(s,4H),2.68-2.48(m,4H),2.38-2.25 (m,2H),2.19-2.10(m,2H),1.91-1.84(m,2H),1.73(s,2H),0.41(s,4H).

[0248] Example 12: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-methoxyethyl)sulfonamide)benzamide

[0249]

[0250] 4-Amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)benzamide (100 mg, 0.193 mmol) was dissolved in dichloromethane (2 mL), and pyridine (0.07 mL, 0.76 mmol) and 2-methoxy-1-ethylsulfonyl chloride (0.02 mL, 0.193 mmol) were added. The reaction was carried out at 25 °C for 2 hours. Then, pyridine (0.07 mL, 0.76 mmol) and methylsulfonyl chloride (0.02 mL, 0.193 mmol) were added, and the reaction was carried out for 1 hour. This process was repeated twice more until the starting material was completely reacted. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 80 mg of a white solid. HPLC then separated 27 mg of the title compound. ESI-MS m / z: 639.9 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.79(s,1H),10.30(s,1H),8.34(d,J=8.6Hz,1H),8.06(d,J= 8.6Hz,1H),7.55(d,J=8.7Hz,1H),7.17(s,1H),7.15-7.09(m,1H),3.67(t,J=5.8Hz ,2H),3.47(t,J=5.8Hz,2H),3.17(d,J=5.9Hz,6H),2.99(t,J=4.8Hz,4H),2.49-2. 30(m,6H),2.26-2.09(m,2H),1.96(dd,J=17.8,7.2Hz,2H),1.77(d,J=13.7Hz,2H).

[0251] Example 13: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-(N-(2-hydroxyethyl)methylsulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0252]

[0253] Step 1: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0254]

[0255] Weigh 0.14 g (0.38 mmol) of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid, 0.10 g (0.38 mmol) of intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.10 g (0.38 mmol) and 0.4 g (1.1 mmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.4 g (1.1 mmol)) into a reaction flask, dissolve in dichloromethane (2 mL), add N,N-diisopropylethylamine (0.32 mL (1.8 mmol), react at room temperature for 12 h, quench with water after the reaction is complete, extract with ethyl acetate and combine the organic phases, dry with anhydrous sodium sulfate, and vacuum dry to give 0.18 g of product. ESI-MS m / z: 607.2 [M+H] + .

[0256] Step 2: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-(methylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0257]

[0258] Weigh N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (0.10 g, 0.16 mmol), methanesulfonamide (0.018 g, 0.18 mmol), cuprous iodide (0.010 g, 0.05 mmol), sarcosine (0.010 g, 0.1 mmol), and potassium phosphate (0.11 g, 0.48 mmol) into a two-necked flask, purge with argon, dissolve in N,N-dimethylformamide (1.0 mL), and react at 110 °C for 8 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and extracted with water and ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and then dried under vacuum. The mixture was then subjected to silica gel column chromatography at 25%-30% (ethyl acetate: petroleum ether). The target product eluted, collected, and dried under vacuum to give 0.084 g of the product. ESI-MS m / z: 574.2 [M+H] +

[0259] Step 3: Preparation of N-(4-((4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamoyl)-3-(6-azaspiro[2,5]octane-6-yl)phenyl)-N-(methylsulfonyl)glycine methyl ester

[0260]

[0261] Weigh N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-(methylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (0.080 g, 0.14 mmol), methyl 2-bromoacetate (0.035 g, 0.21 mmol), potassium carbonate (0.029 g, 0.21 mmol), and potassium iodide (0.035 g, 0.21 mmol) into a reaction flask, add N,N-dimethylformamide (1 mL), and stir at room temperature for 10 h. After the reaction was complete, the mixture was filtered, water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then dried under vacuum. The mixture was then subjected to silica gel column chromatography at 35%-40% (ethyl acetate: petroleum ether). The target product eluted, collected, and dried under vacuum to give 0.075 g of the product. ESI-MS m / z: 646.3 [M+H] + .

[0262] Step 4: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-(N-(2-hydroxyethyl)methylsulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0263]

[0264] 0.070 g (1.1 mmol) of N-(4-((4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamoyl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)-N-(methylsulfonyl)glycine methyl ester was weighed into a reaction flask, dissolved in tetrahydrofuran (1 mL), cooled to 0 °C in an ice bath, and 2 mL of 2 mol / L sodium borohydride tetrahydrofuran solution was added. The reaction was carried out at 0 °C for 4 h. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and then dried under vacuum. The mixture was sent to a preparative separation platform to obtain 0.012 g of the title product. ESI-MS m / z: 618.0 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.96(s,1H),8.36(d,J=8.6Hz,1H),8.11(d,J=8.5Hz,1H),7.57(d,J=8. 7Hz,1H),7.45(d,J=30.7Hz,1H),7.36(dd,J=8.5,1.9Hz,1H),4.87(s,1H),3.74(t,J=26.8,2 0.8Hz,2H),3.44(t,J=5.9Hz,2H),3.19(s,3H),3.10(s,3H),3.05(t,J=4.9Hz,4H),2.48-2.4 2(m,2H),2.33-2.21(m,2H),2.02-1.94(m,2H),1.90-1.83(m,2H),1.66(s,4H),0.37(s,4H).

[0265] Example 14: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((4-methylpiperazin-1-yl)sulfonyl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0266]

[0267] Step 1: Preparation of 1-(4-bromo-3-fluorophenyl)sulfonyl)-4-methylpiperazine

[0268]

[0269] 4-Bromo-3-fluorobenzenesulfonyl chloride (6 g, 36.57 mmol) was dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (7.5 g, 36.57 mmol) and N-methylpiperazine (11.54 g, 40.425 mmol) were added sequentially. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water, extracted with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 3 g of white solid. ESI-MS m / z: 337.1 [M+H] +

[0270] Step 2: Preparation of methyl 2-fluoro-4-((4-methylpiperazin-1-yl)sulfonyl)benzoate

[0271]

[0272] 1-(4-bromo-3-fluorophenyl)sulfonyl)-4-methylpiperazine (2.6 g, 7.76 mmol), palladium acetate (226 mg, 350 mmol), 1,4-bis(diphenylphosphine)butane (660 mg, 1.55 mmol), and triethylamine (5 mL, 38 mmol) were placed in a 200 mL double-necked flask, dissolved in 10 mL of methanol and 10 mL of dimethyl sulfoxide, and stirred in a 70 °C oil bath for 5 h under carbon monoxide protection. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to 2.3 g. ESI-MS m / z: 317.1 [M+H]+

[0273] Step 3: Preparation of 2-fluoro-4-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid

[0274]

[0275] Methyl 2-fluoro-4-((4-methylpiperazin-1-yl)sulfonyl)benzoate (2.3 g, 7.2 mmol) was dissolved in methanol (15 mL), tetrahydrofuran (15 mg, 0.082 mmol), and lithium hydroxide aqueous solution (10 N, 5 mL). The reaction was carried out under argon protection at room temperature for 6 hours. After the reaction was completed, the pH was adjusted to acidic, the water and solvent were evaporated, and the mixture was directly added to the next step. ESI-MS m / z: 302.1 [M+H] +

[0276] Step 4: Preparation of (4-(4-methylpiperazin-1-yl)sulfonyl)-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid

[0277]

[0278] 300 mg of crude 2-fluoro-4-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid was dissolved in 10 mL of N,N-dimethylformamide. Cesium carbonate (3 g, 8.8 mmol) and 6-azaspiro[2.5]octane hydrochloride (1.0 g, 6.84 mmol) were added. The mixture was stirred at 120 °C for 3 h, filtered, and concentrated to obtain the crude compound. Column chromatography yielded 200 mg of the product. ESI-MS m / z: 394.1 [M+H] +

[0279] Step 5: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((4-methylpiperazin-1-yl)sulfonyl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0280]

[0281] Weigh (4-(4-methylpiperazin-1-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid (0.2 g, 0.508 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (386 mg, 1.0 mmol) into a reaction flask, add 5 mL of N,N-dimethylformamide to dissolve, add N,N-diisopropylethylamine (0.2 mL), stir for 2 min, add intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.135 g, 0.508 mmol), and react at room temperature for 3 h. After the reaction is complete, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to give 0.2 g of the title product. ESI-MS m / z: 643.1 [M+H] + . 1H NMR (400MHz, DMSO) δ12.56(s,1H),8.33(d,J=8.6Hz,1H),8.24(d,J=8.1Hz,1H),7.64-7.54(m,3H),3.18(s,3H),3.09(t,J=5.0Hz,4H),2.94(s ,4H),2.59-2.51(m,2H),2.41-2.32(m,4H),2.24(d,J=8.7Hz,2H),2.13 (s,3H),1.92(ddd,J=44.4,14.1,6.4Hz,4H),1.62(s,4H),0.35(s,4H).

[0282] Example 15: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-fluoroethyl)sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0283]

[0284] Step 1: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0285]

[0286] Intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo|[3,2-b]pyridine]-2'(1'H)-one (0.4 g, 1.5 mmol), 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid (0.589 g, 1.65 mmol), 2-chloro-1-methylpyridine iodide (0.958 g, 3.75 mmol), and N,N-diisopropylethylamine (0.581 g, 4.5 mmol) were dissolved in N,N-dimethylacetamide. The reaction was then carried out at room temperature for 3 h. After the reaction was complete, the mixture was extracted with ethyl acetate and saturated brine. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum by column chromatography to obtain the product. ESIMS m / z: 607.1 [M+H] + .

[0287] Step 2: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0288]

[0289] Under argon protection, N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (0.2 g, 0.33 mmol), 2-hydroxyethyl-1-sulfonamide (82.5 mg, 0.66 mmol), cuprous iodide (9.5 mg, 0.05 mmol), potassium phosphate (0.35 g, 1.65 mmol), and sarcosine (29 mg, 0.33 mmol) were dissolved in DMF and reacted at 100 °C for 2 h. After the reaction was completed by LCM monitoring, the reaction solution was extracted with saturated brine and ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the sample was obtained by column chromatography.

[0290] Step 3: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-fluoroethyl)sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0291]

[0292] N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (0.1 g, 0.166 mmol) was dissolved in dichloromethane, and DAST (0.08 g, 0.498 mmol) was added and stirred. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane (20 ml × 3) and saturated sodium chloride solution. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the title compound. ESI-MS m / z: 606.1 [M+H] + .

[0293] 1H NMR (400MHz, DMSO) δ12.85(s,1H),10.45(s,1H),8.35(d,J=8.6Hz,1H),8.05(d,J=8.6H z,1H),7.55(d,J=8.7Hz,1H),7.24(d,J=1.9Hz,1H),7.11(dd,J=8.6,2.0Hz,1H),4.85- 4.66(m,2H),3.68(dt,J=25.1,5.1Hz,2H),3.18(s,3H),2.98(s,4H),2.49-2.38(m,2H) ,2.25(d,J=9.3Hz,2H),2.01-1.92(m,2H),1.89-1.81(m,2H),1.65(s,4H),0.37(s,4H).

[0294] Example 16: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4((2-(dimethylamino)ethyl)sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0295]

[0296] Step 1: Preparation of 4-nitro-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid

[0297]

[0298] 2-Fluoro-4-nitrobenzoic acid (3 g, 16.2 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by the addition of cesium carbonate (7.56 g, 23.25 mmol) and 6-azaspiro[2.5]octane hydrochloride (2.6 g, 17.8 mmol). The mixture was stirred at 120 °C for 14 h, extracted with ethyl acetate, washed thoroughly with water, dried over anhydrous sodium sulfate, and concentrated to obtain 4.5 g of crude compound, which was directly added to the next step. ESI-MS m / z: 275.1 [MH] -

[0299] Step 2: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-nitro-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0300]

[0301] Weigh 0.13 g (0.488 mmol) of 4-nitro-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid and 0.37 g (976 mmol) of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.37 g, 976 mmol) into a reaction flask, add 5 mL of N,N-dimethylformamide to dissolve, add N,N-diisopropylethylamine (1.0 mL), stir for 2 min, add intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.13 g, 0.488 mmol), react at room temperature for 2 h, after the reaction is complete, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate to obtain 0.4 g of the target product, and directly add to the next step.

[0302] Step 3: Preparation of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0303]

[0304] Weigh 0.4 g (0.76 mmol) of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-nitro-2-(6-azaspiro[2.5]octane-6-yl)benzamide into a two-necked flask, dissolve it in 20 mL of methanol, add 200 mg of wet palladium on carbon, and react under hydrogen protection at room temperature for 2 h. Filter the reaction solution with diatomaceous earth, collect the filtrate, dry it with anhydrous sodium sulfate, and concentrate it under reduced pressure to obtain 350 mg of crude product. [ESI-MS m / z: 496.2 M+H] +

[0305] Step 4: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-(1,3-dioxoisoindoline-2-yl)ethyl)sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0306]

[0307] Weigh 0.4 g (0.8 mmol) of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide into a two-necked flask, dissolve it in 20 mL of dichloromethane, add 0.8 mL of pyridine, and add 0.37 mL of 2-(1,3-dioxoisoindoline-2-yl)ethane-1-sulfonyl chloride dropwise under ice bath. After the reaction is complete, extract with water, collect the filtrate, dry it with anhydrous sodium sulfate, concentrate it under reduced pressure to obtain 300 mg of crude product, and directly add it to the next step. ESI-MS m / z: 733.2.M+H] +

[0308] Step 5: Preparation of 4-((2-aminoethyl)sulfonamido)-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0309]

[0310] Weigh 0.3 g (0.4 mmol) of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-((2-(1,3-dioxoisoindoline-2-yl)ethyl)sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide into a two-necked flask, dissolve in 20 mL of methanol, add 1.0 mL of hydrazine hydrate, and stir in an oil bath at 80 °C for 2 h. A large amount of white solid precipitates. After the reaction is complete, cool and filter, collect the filtrate, concentrate, add a small amount of ethanol, filter again, collect the filtrate, concentrate under reduced pressure to obtain 500 mg of crude product, and directly add to the next step. ESI-MS m / z: 603.2.M+H] +

[0311] Step 6: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-(dimethylamino)ethyl)sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0312]

[0313] Crude 4-((2-aminoethyl)sulfonamido)-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide was dissolved in anhydrous methanol (10 mL). 1 mL of formaldehyde aqueous solution (40%) and 6 drops of acetic acid were slowly added under ice bath conditions. After stirring for 10 min, sodium cyanoborohydride (268 mg, 4.2 mmol) was slowly added, followed by stirring at room temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution under ice bath conditions. The product was washed with water, and methanol was removed by vacuum distillation. The product was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified to obtain the title product. ESI-MS m / z: 631.3 M+H + . 1 H NMR (400MHz, DMSO) δ12.89(s,1H),8.35(d,J=8.6Hz,1H),8.06(d,J=8.6Hz,1H),7 .55(d,J=8.7Hz,1H),7.26(d,J=1.9Hz,1H),7.13(dd,J=8.6,2.0Hz,1H),3.32(s,2 H),3.18(s,3H),2.98(s,4H),2.68-2.60(m,2H),2.49-2.38(m,2H),2.32-2.19(m, 2H),2.08(s,6H),2.01-1.91(m,2H),1.89-1.81(m,2H),1.65(s,4H),0.37(s,4H).

[0314] Example 17: 4-((cyclopropylmethyl)sulfonamido)-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0315]

[0316] Step 1: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0317]

[0318] Weigh 0.067 g (0.19 mmol) of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid, 0.050 g (0.19 mmol) of intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.050 g (0.19 mmol) and 0.2 g (0.57 mmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate in a reaction flask, dissolve in dichloromethane (1 mL), add N,N-diisopropylethylamine (0.16 mL (0.93 mmol), react at room temperature for 12 h, quench with water after the reaction is complete, extract with ethyl acetate and combine the organic phases, dry with anhydrous sodium sulfate, and vacuum dry to give 0.10 g of product. ESI-MS m / z: 607.2 [MH] - .

[0319] Step 2: Preparation of 4-((cyclopropylmethyl)sulfonamido)-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0320]

[0321] N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (0.10 g, 0.16 mmol), cyclopropylmethanesulfonamide (0.025 g, 0.18 mmol), cuprous iodide (0.010 g, 0.05 mmol), sarcosine (0.010 g, 0.1 mmol), and potassium phosphate (0.11 g, 0.48 mmol) were weighed into a two-necked flask, purged with argon, dissolved in N,N-dimethylformamide (1.0 mL), and reacted at 110 °C for 8 h. After the reaction was complete, the mixture was filtered, dried under vacuum, and separated to obtain 0.027 g of the title compound. ESI-MS m / z: 614.2 [M+H] + . 1H NMR (400MHz, DMSO) δ12.87(s,1H),10.25(s,1H),8.35(d,J=8.6Hz,1H),8.04(d,J=8.6Hz,1H ),7.54(d,J=8.7Hz,1H),7.29(d,J=1.8Hz,1H),7.13(dd,J=8.6,1.9Hz,1H),3.18(d,J=6.3Hz ,5H),2.98(s,4H),2.47(s,2H),2.26(d,J=7.6Hz,2H),2.01-1.92(m,2H),1.85(d,J=13.8Hz ,2H),1.65(s,4H),1.03-0.93(m,1H),0.56-0.50(m,2H),0.37(s,4H),0.23(q,J=4.7Hz,2H).

[0322] Example 18: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-(oxecyclobutane-3-sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0323]

[0324] Step 1: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-(oxecyclobutane-3-sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0325]

[0326] N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (200 mg, 0.329 mmol) was dissolved in N,N-dimethylformamide (5 mL), and oxetanesulfonamide (150 mg, 1.094 mmol), cuprous iodide (100 mg, 0.512 mmol), sarcosine (180 mg, 2.02 mmol), and potassium phosphate (174 mg, 0.825 mmol) were added. The mixture was purged with argon and reacted overnight at 100 °C. After the reaction was complete, the mixture was filtered, the residue was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, and the prepared compound was separated and lyophilized to give 30 mg of the title compound. ESI-MS m / z: 616.1 [M+H] +

[0327] 1 H NMR (400MHz, DMSO) δ12.89(s,1H),8.35(d,J=8.6Hz,1H),8.01(d,J=8.6Hz,1H),7.54( d,J=8.7Hz,1H),7.19(s,1H),7.05(dd,J=8.6,1.5Hz,1H),4.83-4.76(m,2H),4.75-4. 71(m,1H),4.71-4.66(m,2H),3.18(s,3H),2.97(s,4H),2.50-2.39(m,2H),2.26(d,J= 8.4Hz,2H),1.97(dd,J=17.2,6.9Hz,2H),1.89-1.80(m,2H),1.64(s,4H),0.36(s,4H).

[0328] Example 19: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-(1,1-dioxoisothiazolidin-2-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0329]

[0330] Step 1: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-(1,1-dioxoisothiazolidin-2-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0331]

[0332] Under argon protection, N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (120 mg, 0.2 mmol), 1,1-dioxoisothiazolium (50 mg, 0.4 mmol), cuprous iodide (19 mg, 0.1 mmol), potassium phosphate (212 mg, 1 mmol), and sarcosine (18 mg, 0.2 mmol) were dissolved in DMF and reacted at 100 °C for 2 h. After the reaction was completed by LCM monitoring, the reaction solution was extracted with saturated brine and ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was obtained by column chromatography. 20 mg of the title compound was then purified by HPLC. ESI-MS m / z: 600.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ12.98(s,1H),8.48(d,J=8.5Hz,1H),8.28(d,J=8.5Hz,1H ),7.30(s,1H),7.18(d,J=8.5Hz,1H),6.99(d,J=7.7Hz,1H),3.86(s,2H),3.44 (t,J=6.9Hz,2H),3.25(s,3H),3.10(s,4H),2.60-2.51(d,J=34.1Hz,4H),2.37 -2.28(m,2H),2.18-2.11(m,2H),1.90-1.87(m,2H),1.59(s,4H),0.41(s,4H).

[0333] Example 20: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0334]

[0335] Step 1: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2,5]octane-6-yl)benzamide

[0336]

[0337] Weigh N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]oct-6-yl)benzamide (0.10 g, 0.16 mmol), 1-methylcyclopropane-1-sulfonamide (0.025 g, 0.18 mmol), cuprous iodide (0.010 g, 0.05 mmol), sarcosine (0.010 g, 0.1 mmol), and potassium phosphate (0.11 g, 0.48 mmol) into a two-necked flask, purge with argon, dissolve in N,N-dimethylformamide (1.0 mL), react at 110 °C for 12 h. After the reaction is complete, filter and dry under vacuum, prepare and separate to obtain 0.010 g of the title product. ESI-MS m / z: 612.2 [MH] - . 1 H NMR (400MHz, DMSO) δ12.97(s,1H),8.34(d,J=8.6Hz,1H),8.03(d,J=8.6Hz,1H),7.52(d,J =14.9,8.7Hz,1H),7.30(d,J=1.9Hz,1H),7.12(dd,J=8.6,1.9Hz,1H),3.24-3.09(m,3H), 2.96(s,4H),2.45-2.37(m,2H),2.28-2.17(m,2H),1.99-1.92(m,2H),1.89-1.79(m,2H), 1.77-1.48(m,4H),1.39(s,3H),1.18(q,J=4.5Hz,2H),0.81(q,J=4.9Hz,2H),0.36(s,4H).

[0338] Example 21: N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane]-8-yl)benzamide

[0339]

[0340] Step 1: Preparation of 4-nitro-2-(-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane]-8-yl)benzoic acid

[0341]

[0342] 2-Fluoro-4-nitrobenzoic acid (0.2 g, 1.081 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane hydrochloride (0.4 g, 2.162 mmol) and potassium carbonate (1.592 g, 11.517 mmol) were added. The mixture was purged with argon three times and reacted at 140 °C for 1 day. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.5 g of the product. ESI-MS m / z: 303.0 [M+H] +

[0343] Step 2: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-nitro-2-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane]-8-yl)benzamide

[0344]

[0345] 4-Nitro-2-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane]-8-yl)benzoic acid (0.226 g, 0.7487 mmol) was dissolved in dichloromethane (2 mL), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.854 g, 2.246 mmol), intermediate 5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.2 g, 0.7487 mmol) and N,N-diisopropylethylamine (0.65 mL, 3.744 mmol) were added. The mixture was reacted at 25 °C for 2 hours. After the reaction was complete, the product was diluted with water, extracted with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.3 g of product. ESI-MS m / z: 551.9 [M+H] +

[0346] Step 3: Preparation of 4-amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane]-8-yl)benzamide

[0347]

[0348] N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)-4-nitro-2-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane]-8-yl)benzamide (0.3 g, 0.5442 mmol) was dissolved in ethanol (5 mL) and water (1 mL). Reduced iron powder (0.304 g, 5.442 mmol) and ammonium chloride (0.203 g, 3.81 mmol) were added. The mixture was purged three times with argon gas and reacted at 80 °C for 6 h. After the reaction was complete, the filtrate was collected by filtration and concentrated under reduced pressure to give 0.31 g of product. ESI-MS m / z: 522.0 [M+H] +

[0349] Step 4: Preparation of methyl 2-(N-(4-((4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamoyl)-3-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane]-8-yl)phenyl)aminosulfonyl)acetate

[0350]

[0351] 4-Amino-N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane]-8-yl)benzamide (0.3 g, 0.576 mmol) was dissolved in dichloromethane (5 mL). Pyridine (0.06 mL, 0.691 mmol) and methyl 2-(chlorosulfonyl)acetate (0.1 mL, 0.576 mmol) were added at 0 °C, and the reaction was carried out at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.32 g of a yellow solid. ESI-MS m / z: 657.9 [M+H] + .

[0352] Step 5: Preparation of N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane]-8-yl)benzamide

[0353]

[0354] Methyl 2-(N-(4-((4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamoyl)-3-(8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane]-8-yl)phenyl)aminosulfonyl)acetate (0.3 g, 0.456 mmol) was dissolved in tetrahydrofuran (2 mL), purged three times with argon, and lithium borohydride (0.5 mL, 0.916 mmol) was added dropwise at 0 °C. The reaction was carried out at 0 °C for 1 hour. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by HPLC to obtain 70 mg of the title compound. ESI-MS m / z: 629.9 [M+H] + . 1 H NMR (400MHz, DMSO) δ11.32(s,1H),10.36-9.80(m,1H),8.31(d,J=8.6Hz,1H),7.80(d,J=8.5Hz ,1H),7.53(d,J=8.7Hz,1H),7.07(s,1H),6.93(dd,J=8.5,1.5Hz,1H),5.29-4.69(m,1H),3.80( s,2H),3.74(t,J=6.5Hz,2H),3.34-3.29(m,4H),3.17(s,3H),2.33(d,J=12.4Hz,2H),2.21(d, J=9.2Hz,2H),2.04-1.73(m,8H),0.93(d,J=11.9Hz,2H),0.64-0.45(m,2H),0.18-0.02(m,2H).

[0355] Referring to the preparation methods of the above embodiments of the present invention, compounds of Example 22 in Table 1 were prepared using different raw materials.

[0356] Table 1

[0357]

[0358] Experimental Example 1: Evaluation of the in vitro KIF18A enzyme activity of the compound

[0359] Test compounds: The compounds of the present invention prepared in the above examples were each prepared with DMSO at 10 μM and then successively diluted 3-fold to 3.3 μM, 1.1 μM, 370 nM, 123 nM, 41 nM, 13 nM, 4.6 nM, 1.5 nM and 0.5 nM.

[0360] 1) Reagents:

[0361] The required reagents, materials, equipment and consumables are shown in Table 2.

[0362] Table 2

[0363]

[0364]

[0365] 2) Operation process:

[0366] a) Add 50 μL of the compound solution to a 384-well dilution plate;

[0367] b) Dilute DMSO three times consecutively to obtain 10 concentration points;

[0368] c) Transfer 0.05 μL of the compound dilution to a 384-well plate, with each concentration divided into two groups;

[0369] d) Add 2.5 μL of enzyme reaction solution (KIF18A final concentration 1 nM), centrifuge at 1000 rpm for 1 min, and react at 25 °C for 10 min;

[0370] e) Add 2.5 μL of ATP reaction solution (final ATP concentration 10 μM) and react at 25 °C for 60 min;

[0371] f) Add 4.0 μL of ADP-Glo ​​reagent and react at 25 °C for 40 min;

[0372] g) Add 8.0 μL of the detection reagent and react at 25 °C for 40 min;

[0373] h) Use Microplate Reader to read fluorescence signals.

[0374] 3) Data Analysis

[0375] 3.1 Inhibition rate of each compound pore (%inh) = 100 × (ave High control - cpd well) / (ave High control - ave Low control);

[0376] 3.2 Use data from the Low Control or High Control to check the robustness of the experimental system.

[0377] 1)S / B=ave High control / ave Low control,

[0378] 2)CV%(Low control)=100X(SD Low control / ave Low control)

[0379] 3) CV% (High control) = 100X (SD High control / ave High control)

[0380] 4)Z'=1-3X(SD Low control+SD High control) / (ave High control-ave Low control)

[0381] 3.3 Calculate IC 50 XLfit 5.5.0 software was used for concentration-response curve fitting and IC50 analysis. 50 Sure.

[0382] 4) KIF18A enzymatic activity

[0383] Experimental results show that the compound of the present invention has good inhibitory activity against KIF18A enzyme.

[0384] Experimental Example 2: Evaluation of the activity of compounds against colorectal cancer cells

[0385] 1. Experimental Materials

[0386] Test compounds: The compounds of the present invention prepared in the above examples were each prepared in 10 mM solution with DMSO and then diluted 5 times in sequence to 20 μM, 4 μM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, 0.26 nM and 0.05 nM.

[0387] The colorectal cancer cell line HT-29 was purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0388] Reagents: RPMI-1640 medium (Gibco, 11875-089); fetal bovine serum (Gibco, 10099-141); trypsin-EDTA (Gibco, 25200-056); penicillin-streptomycin (Gibco, 15140-122); CellCounting-Lite 2.0 Luminescent Cell Viability Assay Luminescent Cell Viability Assay (Invitrogen Vazyme, DD1101-01G7571); 96-well cell culture plate (Costar, 3599).

[0389] Cell culture: HT-29 cells were cultured in PRMI-1640 medium containing 10% fetal bovine serum and placed in an incubator at 37°C and 5% CO2. Only cells in the logarithmic growth phase were used for experiments.

[0390] 2. Experimental Procedure

[0391] Day 1 of the experiment:

[0392] Cells were resuspended in culture medium at their density using trypsin, and the cell suspension was diluted to a density of 4 × 10⁻⁶. 3 The required volume of cells / mL; divide the cells at 4 × 10⁻⁶. 3 Cells were seeded per well in a 96-well plate and incubated at 37°C for 24 hours in a 5% CO2 incubator.

[0393] Day 2 of the experiment:

[0394] HT-29 cells were cultured in the original medium (100 μL) with 100 μL of (2×) drug added, with two replicates for each concentration group. Cells were incubated at 37°C in a 5% CO2 incubator for 3 days. (The compound powder was dissolved in DMSO to prepare a 10 mM stock solution; the compound was serially diluted in microplates).

[0395] Day 7 of the experiment:

[0396] Five days after HT-29 cell treatment, the CellCounting-Lite 2.0 Luminescent CellViability Assay was removed 30 minutes before the scheduled incubation period and allowed to equilibrate to room temperature. 150 μL of a 1:1 diluted Celltiter-Glo reagent working solution was added. The cells were incubated at room temperature for 2 minutes with shaking. After another 10 minutes of incubation at room temperature, 100 μL of cell culture was transferred to a white plate. Chemiluminescence signal was detected, and the plate was shaken. The read sequence was set at 500 ms. Based on the AU values ​​derived from the microplate reader, the inhibition rate of each well relative to the solvent control well was calculated.

[0397] Inhibition (%) = 100 - (AU experimental wells - AU blank wells) / (AU solvent control wells - AU blank wells) × 100.

[0398] Based on different drug concentrations and their corresponding inhibition rates, four-parameter logistic sigmoid curves were fitted using GraghPad Prism 6.0 software. The data were analyzed, and the IC50 was calculated. 50 The values ​​are shown in Table 3.

[0399] Table 3. Activity of the compounds of this invention in inhibiting the proliferation of HT-29 cells.

[0400]

[0401]

[0402] Experimental results show that the compound of the present invention has good inhibitory activity against the proliferation of human colorectal cancer cells HT-29.

[0403] Although the present invention has been described in detail above, those skilled in the art will understand that various modifications and changes can be made to the invention without departing from its spirit and scope. The scope of the invention is not limited to the detailed description above, but should be attributed to the claims.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, in, Cycle A and Cycle B are each independently selected from cycloalkyl and heterocyclic groups, and are optionally substituted by 1, 2, 3 or 4 groups selected from halogen, alkyl, alkenyl, haloalkyl, haloalkenyl, hydroxyalkyl, alkoxy, haloalkoxy or oxo groups. W either does not exist or is -N(CH3)-; Y is selected from CH and N; L is selected from -NHSO2-, -SO2NH-, -SO2-, R 1 It is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and is optionally substituted by 1, 2, 3 or 4 groups selected from halogen, amino, hydroxy, cyano, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, cycloalkyl, heterocyclol; R 2 Selected from halogens, hydroxyl groups, cyano groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, oxo groups, cycloalkyl groups, heterocyclic groups; and p is selected from 0, 1, 2, 3, and 4.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein ring A is selected from C. 3-8 Monocycloalkyl, C 4-12 Fused cycloalkyl, C 5-12 Spirocycloalkyl, C 4-12 Bridged cycloalkyl, 4-8 membered monoheterocyclic, 4-12 membered fused heterocyclic, 5-12 membered spiroheterocyclic, and 4-12 membered bridged heterocyclic, wherein the heteroatom is selected from one or more N, O, P, S, and Si, and the C 3-8 Monocycloalkyl, C 4-12 Fused cycloalkyl, C 5-12 Spirocycloalkyl, C 4-12 Bridged cycloalkyl, 4-8 membered monoheterocyclic group, 4-12 membered fused heterocyclic group, 5-12 membered spirocyclic group, 4-12 membered bridged heterocyclic group are optionally selected by 1, 2, 3 or 4 halogens, C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 1-6 Alkyl, Halogenated C 2-6 alkenyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Group substitutions of alkoxy and oxo groups; and ring B selected from C. 3-8 Cycloalkyl groups, optionally composed of 1, 2, 3, or 4 alkyl groups selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 1-6 Alkyl, Halogenated C 2-6 alkenyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Group substitution of alkoxy and oxo groups.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein the general formula (I) has the structure of the following general formula (Ia): Among them, A, W, Y, L, R 1 As defined by general formula (I) in claim 1 or 2.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein: Ring A is selected from It may be selected from 1, 2, 3 or 4 halogens, C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 1-6 Alkyl, Halogenated C 2-6 alkenyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Group substitution of alkoxy and oxo groups.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein ring A is selected from...

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein R 1 Selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-12 Aryl and C 6-12 Heteroaryl groups, optionally surrounded by 1, 2, 3, or 4 groups selected from halogens, amino groups, hydroxyl groups, cyano groups, C4 groups, and hydroxyl groups. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Group substitution of the heterocyclic group, wherein the heteroatom is selected from N, O, S; R 2 Selected from halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy group, oxo group, C 3-8 cycloalkyl, C 3-8 A heterocyclic group, wherein the heteroatom is selected from N, O, S; and p is selected from 1, 2, 3, and 4.

7. The compound of claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein the compound is selected from the group consisting of:

8. A pharmaceutical composition comprising the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug and a pharmaceutically acceptable carrier thereof.

9. The use of the compound of any one of claims 1-7 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug of the same or the pharmaceutical composition of claim 8 in the preparation of a medicament for treating diseases associated with KIF18A.

10. The application of claim 9, wherein the disease associated with KIF18A is cancer.

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