Spiro KIF18a inhibitor

Abstract

Disclosed is a compound of formula (IA) or a pharmaceutically acceptable salt thereof. The compound is a KIF18A inhibitor. Also disclosed are a pharmaceutical composition comprising the compound and a use of the compound in the preparation of drugs for treating cell proliferative diseases such as cancer.

Description

Spirocyclic KIF18A inhibitors

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on February 6, 2024, with application number CN202410172236.7 and the invention name “Spirocyclic KIF18A inhibitors”, the Chinese patent application filed with the China Patent Office on April 29, 2024, with application number CN202410533572.X and the invention name “Spirocyclic KIF18A inhibitors”, the Chinese patent application filed with the China Patent Office on June 19, 2024, with application number CN202410798931.4 and the invention name “Spirocyclic KIF18A inhibitors”, and the Chinese patent application filed with the China Patent Office on January 22, 2025, with application number CN202510103965.1 and the invention name “Spirocyclic KIF18A inhibitors”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and specifically relates to a KIF18A inhibitor, a pharmaceutical composition containing the compound, and a method for treating cell proliferative diseases such as cancer using the compound of the present invention. Background Art

[0003] KIF18A is a mitotic motor protein that regulates chromosome arrangement during cell mitosis, avoids errors in the mitotic process, and ensures the normal progress of mitosis.

[0004] The vast majority of human cells are diploid, and there are multiple cell cycle checkpoints to ensure that the genome remains stable during continuous cell division. The inactivation of some key proteins related to cell cycle checkpoints can lead to abnormal mitosis and the doubling of the entire genome, thereby converting a natural diploid cell into a chromosomally unstable tetraploid cell. Whole-genome doubling (WGD) events (at least one WGD has occurred) are widely present in clinical tumor samples and are an important feature of chromosomally unstable tumors. The results showed that relative to diploid cells, KIF18A expression levels were significantly increased in WGD cells. + KIF18A knockout in all 10 cell lines revealed that the expression of KIF18A in the WT cells was significantly increased compared to that in the WGD cells. - Cell line, WGD + Cell viability was significantly reduced, and live cell imaging showed that WGD occurred after KIF18A loss. + Compared with WGD- cells, breast cancer cells showed increased spindle length and chromosome hyperoscillation, which triggered abnormal events such as chromosome shedding and mitosis prolongation. The above data revealed that the loss of KIF18A would cause WGD +Abnormal mitosis of tumor cells inhibits WGD + Therefore, KIF18A is an attractive therapeutic target and its inhibition may help to specifically target cells with WGD. + characteristic tumors without affecting the normal diploid cells of human tissues. Summary of the Invention

[0005] The first aspect of the present disclosure provides a compound represented by formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0006] wherein X is selected from O, -C(=O)- or -NR x1 -;

[0007] Y is selected from -CH2-, -C(=O)- or -NR y1 -;

[0008] R x1 and R y1 Each independently selected from H, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 1-4 alkoxy;

[0009] M is selected from N or CH;

[0010] Q is selected from N or CH;

[0011] Ring A is selected from C 3-8 Cycloalkyl or C 3-8 cycloalkenyl;

[0012] R 1 is selected from H or halogen; a is selected from 0, 1, 2 or 3;

[0013] R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Each independently selected from H, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0014] Or, R 2 、R 3 Together with the carbon atom it is connected to, it forms C 3-6 Cycloalkyl or C 2-4 alkenyl, and the C 3-6 Cycloalkyl or C 2-4 The alkenyl group may be optionally further substituted with one or more halogens;

[0015] Or, R4 、R 6 The carbon atom connected to it can form C 3-6 Cycloalkyl;

[0016] Or, R 5 、R 7 The carbon atom connected to it can form C 3-6 Cycloalkyl;

[0017] R 8 Selected from -NHSO2-R 8b , the R 8b C 1-4 Alkyl, and the C 1-4 The alkyl group is optionally further substituted with OH or halogen;

[0018] R 9 Selected from H, halogen or C 1-4 alkyl.

[0019] In some embodiments, the compound represented by formula (IA), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0020] X is selected from O, -C(=O)- or -NR x1 -;

[0021] Y is selected from -CH2- or -C(=O)- or -NR y1 -;

[0022] R x1 and R y1 Each independently selected from H or C 1-4 alkyl;

[0023] M is selected from N or CH;

[0024] Ring A is selected from C 3-8 Cycloalkyl or C 3-8 cycloalkenyl;

[0025] R 1 is selected from H or halogen; a is selected from 0, 1, 2 or 3;

[0026] R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Each is independently H;

[0027] Or, R 2 、R 3 Together with the carbon atom it is connected to, it forms C 3-6 Cycloalkyl or C2-4 alkenyl, and the C 3-6 Cycloalkyl or C 2-4 The alkenyl group may be optionally further substituted with one or more halogens;

[0028] Or, R 4 、R 6 The carbon atom connected to it can form C 3-6 Cycloalkyl;

[0029] Or, R 5 、R 7 The carbon atom connected to it can form C 3-6 Cycloalkyl;

[0030] R 8 Selected from -NHSO2-R 8b , the R 8b C 1-4 Alkyl, and the C 1-4 The alkyl group is optionally further substituted with OH or halogen.

[0031] In some embodiments, X is selected from O, -C(=O)-, or -N(CH3)-.

[0032] In some embodiments, X is selected from -N(CH2CH3)-, -N(OCH3)-, or -N(CHF2)-.

[0033] In some embodiments, Y is selected from -CH2-, -C(=O)-, or -N(CH3)-.

[0034] In some embodiments, M is selected from N or CH; preferably, M is N.

[0035] In some embodiments, Q is selected from N or CH; preferably, Q is CH.

[0036] In some embodiments, the ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl.

[0037] In some embodiments, the R 1 is selected from H or F; a is selected from 0, 1, 2 or 3.

[0038] In some embodiments, the structural unit Selected from

[0039] In some embodiments, the structural unit Selected from

[0040] In some embodiments, the structural unit Selected from

[0041] In some embodiments, the structural unit Selected from

[0042] In some embodiments, the structural unit Selected from

[0043] In some embodiments, the structural unit Selected from

[0044] In some embodiments, the R 2 、R 3 Together with the carbon atom it is connected to, it forms C 3-6 Cycloalkyl; R 4 、R 5 、R 6 and R 7 Each is independently H;

[0045] Preferably, R 2 、R 3 Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

[0046] In some embodiments, the R 2 、R 3 Together with the carbon atom it is connected to, it forms C 2-4 alkenyl, and the C 2-4 The alkenyl group is optionally further substituted with one or more halogens; R 4 、R 5 、R 6 and R 7 Each is independently H;

[0047] Preferably, R 2 、R 3 Together with the carbon atoms to which it is attached,

[0048] In some embodiments, the R 2 、R 3 、R 5 and R 7 Each is independently H;

[0049] R 4 、R 6The carbon atom connected to it can form C 3-6 Cycloalkyl;

[0050] Preferably, R 4 、R 6 Together with the carbon atom to which it is attached, it forms a cyclopentyl group.

[0051] In some embodiments, the R 2 、R 3 、R 4 and R 6 Each is independently H;

[0052] R 5 、R 7 The carbon atom connected to it can form C 3-6 Cycloalkyl;

[0053] Preferably, R 5 、R 7 Together with the carbon atom to which it is attached, it forms a cyclopentyl group.

[0054] In some embodiments, the R 2 Selected from -CHF2 or -CF3; R 3 、R 4 、R 5 、R 6 and R 7 Each is independently H.

[0055] In some embodiments, the structural unit Selected from

[0056] In some embodiments, the structural unit Selected from

[0057] In some embodiments, the R 8 Selected from

[0058] In some embodiments, the R 9 Selected from H or F.

[0059] In some embodiments, the compound of Formula (I) or Formula (IA), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0060] Among them, X, Y, ring A, R 1 、R 2 、R 3 、R 8 、R 9 and a are as defined in the compound of formula (I) or formula (IA).

[0061] In some embodiments, the compound of Formula (I) or Formula (IA), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0062] Among them, X, Y, ring A, R 1 、R 8 、R 9 and a are as defined for the compound of formula (I) or formula (IA).

[0063] In some embodiments, the compound of Formula (I) or Formula (IA), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0064] wherein X is selected from -N(CH3)-, -N(CH2CH3)-, -N(OCH3)- or -N(CHF2)-;

[0065] Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl;

[0066] R 1 is F; a is selected from 0, 1, 2 or 3;

[0067] Structural unit Selected from

[0068] R 8 Selected from

[0069] R 9 Selected from H or F.

[0070] The second aspect of the present disclosure also provides a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0071] The third aspect of the present disclosure also relates to a pharmaceutical composition, which comprises the compound described in the first aspect or the second aspect of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0072] In some embodiments, in the pharmaceutical composition, the content of the compound, its stereoisomer or pharmaceutically acceptable salt thereof is selected from 0.1 mg to 1000 mg.

[0073] In some embodiments, the content of the compound, its stereoisomer or pharmaceutically acceptable salt thereof in the pharmaceutical composition is 1%-95%.

[0074] In some embodiments, in the pharmaceutical composition, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0075] The fourth aspect of the present disclosure also relates to the use of the compound described in the first aspect or the second aspect of the present application, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition described in the third aspect of the present application in the preparation of a drug for treating diseases mediated by KIF18A.

[0076] In some embodiments, the disease is a tumor.

[0077] In some embodiments, the tumor is a chromosomally unstable tumor.

[0078] In some embodiments, the tumor is selected from breast cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, or head and neck cancer.

[0079] In some embodiments, the lung cancer is selected from squamous cell lung cancer, adenocarcinoma of the lung, large cell lung cancer, or small cell lung cancer.

[0080] The fifth aspect of the present disclosure also provides a method for treating or preventing KIF18A-mediated diseases, which comprises administering to a subject in need thereof a therapeutically effective amount of the compound described in the first aspect or the second aspect of the present application, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition described in the third aspect of the present application.

[0081] In some embodiments, the tumor is a chromosomally unstable tumor.

[0082] In some embodiments, the tumor is selected from breast cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, head and neck cancer, gastric cancer, esophageal cancer, or skin cancer.

[0083] In some embodiments, the lung cancer is selected from squamous cell lung cancer, adenocarcinoma of the lung, large cell lung cancer, or small cell lung cancer. DETAILED DESCRIPTION

[0084] Explanation of terms

[0085] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0086] The compounds of the present disclosure also include isotopic derivatives, solvates, N-oxides or prodrug forms thereof.

[0087] The hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine involved in the groups and compounds described in the present disclosure include their isotopic derivatives, such as 2H (deuterium, D), 3H (tritium, T), 11C, 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 125I, 129I and 131I, etc., preferably deuterium. Compared to non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the deuterium replacement may be partial or complete, wherein partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0088] The compounds of the present disclosure also include solvate forms thereof, such as hydrates, and the present disclosure includes various solvates and mixtures thereof.

[0089] The compounds disclosed herein also include their nitrogen oxide or N-oxide forms. Such nitrogen oxides or N-oxides are derivatives formed by further oxidation of the nitrogen atom in a nitrogen-containing group. Common N-oxides include N-oxides of tertiary amines or N-oxides of the nitrogen atom in a nitrogen-containing heterocycle. The synthesis of N-oxides is well known to those skilled in the art and includes oxidation of heterocycles and tertiary amines using peroxyacids such as peracetic acid and m-chloroperbenzoic acid, hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.

[0090] The compounds of the present disclosure also include their prodrug forms, which refer to certain derivatives of the compounds of the present disclosure that have little or no pharmacological activity themselves, and which have cleavable groups and decompose into the compounds of the present disclosure through solvent decomposition or under physiological conditions. The types of prodrugs include but are not limited to amides, esters, acid anhydrides, salts, etc. The "ester" refers to the derivatives formed with suitable alcohols when the compounds of the present disclosure contain acidic groups (such as carboxylic acids); when the compounds of the present disclosure contain hydroxyl groups, they are derivatives formed with suitable acids (including organic acids or inorganic acids). The preparation methods of prodrugs are well known to those skilled in the art. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0091] The term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present invention prepared with a relatively non-toxic acid or base. These salts can be prepared during compound synthesis, separation, and purification, or by reacting the purified free form of the compound with a suitable acid or base. When the compound contains a relatively acidic functional group (e.g., -COOH, -OH, -SO3H, etc.), it reacts with an appropriate inorganic or organic cation (base) to form a base addition salt, including salts formed with alkali metals or alkaline earth metals, ammonium salts formed with amines or their derivatives, and salts formed with amino acids. When the compound contains a relatively basic functional group (e.g., -NH2, etc.), it reacts with an appropriate inorganic or organic anion (acid) to form an acid addition salt, including salts formed with an inorganic acid or organic acid (e.g., carboxylic acid, etc.).

[0092] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of those skilled in the art based on a wide range of factors. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers include a variety of different ingredients and additives, and the inclusion of such additional ingredients in a formulation for various reasons (e.g., to stabilize the active agent, binders, etc.) is well known to those skilled in the art.

[0093] The term "effective prophylactic or therapeutic amount" refers to a sufficient amount of the compound of the present disclosure, its pharmaceutically acceptable salt, or its isomer to treat the disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prevention. However, it should be recognized that the total daily dosage of the compound of Formula I or its pharmaceutically acceptable salt and composition of the present disclosure must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the administration time, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field.

[0094] The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes in the disclosed compounds include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically labeled reagent in place of the unlabeled reagent.

[0095] The term "prodrug" refers to certain derivatives of the compounds of the present invention that have little or no pharmacological activity themselves, which have a cleavable group and decompose into the compounds of the present invention through solvent decomposition or under physiological conditions. The types of prodrugs include, but are not limited to, amides, esters, anhydrides, salts, etc. The "ester" refers to a derivative formed with a suitable alcohol when the compound of the present invention contains an acidic group (such as a carboxylic acid); when the compound of the present invention contains a hydroxyl group, it is formed with a suitable acid (including an organic acid or an inorganic acid). The preparation method of prodrugs is well known to those skilled in the art.

[0096] The term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. The term "hydrate" may be used when the solvent is water. The solvent molecules may be present in stoichiometric or non-stoichiometric amounts. Methods for preparing solvates are known in the art.

[0097] The term "nitrogen oxide" or "N-oxide" refers to a derivative formed by further oxidation of the nitrogen atom in a nitrogen-containing group. Common N-oxides include N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. Synthesis methods of N-oxides are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines using peroxyacids such as peracetic acid and m-chloroperbenzoic acid, hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.

[0098] The compounds of the present disclosure and their salts may exist as isotopic derivatives, and the compounds of the present disclosure include various isotopic derivatives and mixtures thereof.

[0099] The compounds of the present disclosure and their salts may exist in the form of solvates, such as hydrates, and the compounds of the present disclosure include various solvates and mixtures thereof.

[0100] The compounds of the present disclosure and their salts may exist in the form of "N-oxides", and the compounds of the present disclosure include various N-oxides and mixtures thereof.

[0101] The disclosed compounds and their salts may exist in "prodrug" form, and the disclosed compounds include various prodrugs and mixtures thereof.

[0102] The compounds described in the present disclosure, their pharmaceutically acceptable salts, isotopic derivatives, solvates, N-oxides, and prodrugs have the same or similar biological activities and are all included within the scope of the present disclosure.

[0103] The “isomers” described in the present disclosure include geometric isomers and stereoisomers, such as atropisomers, cis-trans isomers, enantiomers, diastereomers, tautomers, and racemic mixtures and other mixtures thereof, all of which fall within the scope of the present disclosure. The term “enantiomer” refers to stereoisomers that are mirror images of each other. The term “tautomer” refers to a type of functional group isomer that has different hydrogen attachment points due to one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers. The term “diastereomer” refers to a stereoisomer in which a molecule has two or more chiral centers and is not a mirror image between the molecules. The term “cis-trans isomer” refers to different spatial configurations in which double bonds or single bonds of ring carbon atoms in a molecule cannot rotate freely. The term “atropisomer” refers to stereoisomers that can be separated because single bond rotation is hindered or rotates very slowly. Stereoisomers of the compounds disclosed herein can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. For example, one enantiomer of a compound disclosed herein can be prepared by asymmetric catalysis or chiral auxiliary derivatization techniques. Alternatively, a single stereoisomer of the compound can be obtained from a mixture using chiral resolution techniques. Alternatively, the enantiomer can be prepared directly using chiral starting materials. Separation of optically pure compounds disclosed herein is typically accomplished using preparative chromatography, employing chiral chromatographic columns to achieve the purpose of separating chiral compounds.

[0104] The absolute stereo configuration of a compound can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction can be used. Alternatively, the absolute configuration of a compound can be confirmed based on the chiral structure of the starting materials and the reaction mechanism of asymmetric synthesis. Alternatively, after resolution, the stereo configuration can be determined by comparison with a product with a known absolute configuration. Compounds labeled "absolute configuration unknown / undetermined" herein are typically resolved from racemic compounds into individual isomers by chiral preparative SFC, followed by characterization and testing.

[0105] In some compound structures disclosed herein, only one bond connecting the same stereocenter C is drawn. For example:

[0106] Its essence and Represents the same structure;

[0107] Its essence and Represent the same structure.

[0108] The compounds disclosed herein can exist in unsolvated and solvated forms, including hydrate forms. Generally speaking, the solvated form is equivalent to the unsolvated form and is also included in the scope of the present invention. It is known to those skilled in the art that when a cyclic compound has a coplanar delocalized system and the number of π electrons is 4n+2, the ring has aromaticity. The expression of the aromatic structure in the compound can be expressed by using a dotted line to represent electron delocalization or by alternating single and double bonds. For example, the benzene ring can be drawn as Can also be

[0109] The term "optionally substituted" as used herein refers to two situations in which one or more hydrogen atoms of the substituted group may be "substituted" or "unsubstituted" by one or more substituents.

[0110] The term "substituted" means that one or more hydrogen atoms in a group are independently replaced by a corresponding number of substituents, e.g. Indicates that a hydrogen on ring A is replaced by a R 1 When a is 0, all the groups connected to ring A are hydrogen.

[0111] When the substituent appears in the structure Indicates that the atom is a bonding atom, for example Indicates that the C atom on the pyrimidine ring is a bonding atom. A dash "-" in a substituent structure indicates the point of attachment for the substituent, for example, -CH3 is attached through a C atom. Indicates the absolute configuration of a stereocenter, i.e., R or S configuration. It represents cis or trans configuration. Double real bonds or double imaginary bonds both represent cis configuration, and one real and one imaginary bond represent trans configuration.

[0112] When a substituent's bond can cross-link to a ring, it means that the substituent can be bonded to any atom on the ring. The substituent R can be substituted at any position on the benzene ring.

[0113] When a substituent is listed without indicating the atom via which the substituent is attached to a given group or a given formula, then the substituent may be attached via any bondable atom thereof.

[0114] When any variable (such as R d ) appears more than once in a compound's composition or structure, its definition is independent in each instance. For example, Indicates that the cyclopentyl group is surrounded by 3 R d is replaced, and each R d There are independent options.

[0115] Unless otherwise specified, the term "halogen" means a fluorine, chlorine, bromine or iodine atom.

[0116] Unless otherwise specified, the term "alkyl" refers to a group derived from a branched or straight chain saturated aliphatic alkane having the specified number of carbon atoms by removing one hydrogen. For example, "C 1-10 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 Alkyl, "C 1-6 Alkyl", "C 1-4 Alkyl", "C 1-3 "alkyl"; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0117] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. 1-6 Alkyl, more preferably halogenated C 1-4 Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. Alkyl groups are as defined above.

[0118] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein attached to another group through an oxygen atom, i.e., "alkyl-O-". 1-6 Alkoxy" (structure is C 1-6 Alkyl-O-), "C 1-4"alkoxy", specific examples include but are not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" described in the present disclosure is preferably C 1-4 Alkoxy, more preferably C 1-3 Alkoxy.

[0119] Unless otherwise specified, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms in an alkoxy group are replaced by halogen. Preferably, the "haloalkoxy" described in the present disclosure is preferably a "haloC 1-6 Alkoxy", "halogenated C 1-4 Alkoxy". Specific examples of the present disclosure include: fluoromethoxy (including monofluoromethoxy, difluoromethoxy, trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkoxy is as defined above.

[0120] Unless otherwise specified, the term "alkenyl" refers to a radical derived from a straight-chain or branched alkene (containing at least one carbon-carbon double bond) by removing a hydrogen atom, including "C 2-6 Alkenyl", "C 2-5 Alkenyl", "C 2-4 Alkenyl", "C 2-3 "Alkenyl", specific examples include but are not limited to: -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, etc.

[0121] Unless otherwise specified, the term "alkynyl" refers to a radical derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing a hydrogen atom, including "C 2-5 Alkynyl", "C 2-4 Alkynyl", "C 2-3 "Alkynyl", specific examples include but are not limited to: -C≡CH, -C≡CHCH3, HC≡CHCH2-, HC≡CC≡C-, etc.

[0122] Unless otherwise specified, the term "ring" refers to saturated, partially saturated or unsaturated monocycles and polycycles, and "polycycles" include spirocycles, condensed rings or bridged rings. The group derived from the ring by removing hydrogen atoms is called a "cyclic group", which includes a monovalent ring, a divalent ring (commonly referred to as a subring), a trivalent ring, a tetravalent ring, etc., and the specific valence depends on the number of substituents connected to the ring. The description of "cyclic group" in this disclosure no longer specifically distinguishes the valence of the ring. Representative "cyclic groups" include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The term "hetero" refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms (also known as heteroatoms), wherein the heteroatoms are generally selected from N, O, S, and P, and the oxidized forms generally include NO, SO, S(O)2, and P(O). The nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined herein); the number of atoms in the ring is generally defined as the number of ring members, for example, "3-6 membered heterocycloalkyl" refers to a ring of 3-6 atoms arranged around, each ring optionally containing 1-3 heteroatoms and / or heteroatoms, i.e., N, O, S, NO, SO, S(O)2, P(O) or NR, each ring optionally substituted by an R group, where R is a group defined herein.

[0123] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl derived from a cycloalkane by removing a hydrogen atom, including a monocyclic or polycyclic saturated hydrocarbon group; the polycyclic saturated hydrocarbon group refers to a polycyclic group formed by two or more cyclic alkyl structures connected by spiro, bridge, condensation, etc. The carbon atoms in the cycloalkyl group can be further oxidized to form C(O). Unless otherwise specified, the "monocyclic cycloalkyl" described herein can be understood as a monocyclic cycloalkyl group. When it is polycyclic, it will be specifically specified as a spiro, condensation or bridged ring group. The cycloalkyl group includes "C 3-8 Cycloalkyl", "C 3-6 Cycloalkyl", "C 3-5 Preferably, the cycloalkyl group is a monocyclic, saturated structure; specific examples include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0124] Unless otherwise specified, "cycloalkenyl" means a cycloalkyl group in which one or more of the ring bonds is a double bond and the cycloalkenyl group is not aromatic. The carbon atoms in the cycloalkenyl group may be further oxidized, i.e., to form C(O). The cycloalkenyl group includes "3-8 membered cycloalkenyl", "3-6 membered cycloalkenyl", "3-5 membered cycloalkenyl", and "5-6 membered cycloalkenyl". Specific examples include, but are not limited to,

[0125] Unless otherwise specified, the term "heterocyclyl" refers to a saturated cyclic group derived from a cycloalkyl group in which one or more ring carbon atoms are replaced by heteroatoms and / or heteroatomic groups. The heteroatoms and / or heteroatomic groups are generally selected from N, O, S, NO, SO, S(O)2, P(O) and NR, wherein the carbon atoms in the heterocyclic ring are optionally oxoed, i.e., forming -C(O); preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heterocyclyl group includes "3-8 membered heterocyclyl", "3-6 membered heterocyclyl", "3-5 membered heterocyclyl", "4-6 membered heterocyclyl", and "5-6 membered heterocyclyl". Specific examples include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and the like.

[0126] Unless otherwise specified, the term "heterocycloalkenyl" refers to a "heterocyclic group" in which one or more of the ring bonds is a double bond and the heterocycle is not aromatic. Preferably, the heteroatoms are independently selected from 1-3 nitrogen atoms and / or oxygen atoms. The heterocyclic group includes "3-8 membered heterocycloalkenyl," "3-6 membered heterocycloalkenyl," "3-5 membered heterocycloalkenyl," and "5-6 membered heterocycloalkenyl." Specific examples include, but are not limited to: wait.

[0127] Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic, hydrocarbon radical which may be a single ring or multiple rings fused together. 5-10 Aryl, more preferably C 5-8 Aryl, most preferably monocyclic C 5-6 Aryl; examples of aryl include, but are not limited to, phenyl, naphthyl.

[0128] Unless otherwise specified, the term "fused ring aromatic group" refers to a fused ring group formed by two or more aromatic rings sharing two adjacent carbon atoms, including naphthyl, anthracenyl and phenanthrenyl.

[0129] The "heteroaryl" described in the present disclosure refers to a monocyclic group with aromatic properties in which at least one ring atom is a heteroatom and / or a heteroatom group, wherein the heteroatom and / or heteroatom group is generally selected from N, O, S, P, NO, SO, S(O)2, P(O) and NR, R is H or any substituent group, wherein the carbon atoms in the heterocyclic ring are optionally oxidized, i.e., forming -C(O); preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heteroaryl includes "5-6 membered heteroaryl"; specific examples include but are not limited to pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyrimidinyl.

[0130] The term "heteroaryl" as used herein refers to a monocyclic or polycyclic aromatic group containing one or more heteroatoms in the ring. These heteroatoms are generally selected from N, O, and S. Preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms. Furthermore, the N and S atoms may be optionally oxidized, and the N atoms may be optionally quaternized. The term "heteroaryl" includes "monocyclic heteroaryl" and "fused-ring heteroaryl." A fused-ring heteroaryl refers to a group containing one or more heteroatoms and possessing aromatic properties, formed by two or more cyclic structures sharing two adjacent atoms. Unless otherwise specified, the term "heteroaryl" herein generally refers to a "monocyclic heteroaryl." For example, the term "5-6 membered heteroaryl" does not have the potential to form a fused-ring heteroaryl. When referring to a fused-ring heteroaryl, it will be specifically indicated as a fused heteroaryl structure, such as an 8-10 membered fused-ring heteroaryl. The heteroaryl group described in the present invention is preferably a "nitrogen-containing heteroaryl group", preferably a "5-6-membered nitrogen-containing aryl group". The heteroatom in the "nitrogen-containing heteroaryl group" contains at least one nitrogen atom, for example, only 1, 2 or 3 nitrogen atoms, or, contains one nitrogen atom and 1 or 2 other heteroatoms (such as S and / or O atoms), or, contains 2 nitrogen atoms and 1 or 2 other heteroatoms. Specific examples of the heteroaryl group include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, and the like.

[0131] Unless otherwise specified, the term "fused cyclic group" refers to a saturated or partially saturated non-aromatic cyclic group formed by two or more carbon rings sharing two adjacent atoms, wherein the ring carbon atoms may be further oxidized, i.e., to form C(O). The fused cyclic groups include "5-14 membered fused cyclic groups", "8-12 membered fused cyclic groups", "9-10 membered fused cyclic groups", etc.; the condensation modes include but are not limited to 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl and 5-6 membered cycloalkyl, etc. Specific examples of the fused cyclic groups include but are not limited to

[0132] Unless otherwise specified, the term "fused heterocyclic group" refers to a saturated or partially saturated non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent atoms, containing at least one ring atom as a heteroatom; the heteroatom is generally selected from N, O, and S; the ring carbon atoms and heteroatoms in the fused heterocyclic ring can be further oxidized to form a cyclic group containing C(O), NO, SO, or S(O)2 groups, which is also included in the definition of the heterocyclic group of the present invention. The 11-14 membered fused heterocyclic group of the present invention includes "11-14 membered saturated fused heterocyclic group" and "11-14 membered partially saturated fused heterocyclic group"; the fusion mode can be 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, 5-6 membered heterocyclic group and 5-6 membered cycloalkyl group, benzo 5-6 membered heterocyclic group, benzo 5-6 membered saturated heterocyclic group, 5-6 membered heteroaryl and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered saturated heterocyclic group, benzo 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, benzo 5-6 membered cycloalkyl and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered cycloalkyl and 5-6 membered heterocyclic group; specific examples of the fused heterocyclic group include but are not limited to:

[0133] Unless otherwise specified, the term "spirocyclyl" refers to a cyclic structure formed by two or more cyclic structures sharing one carbon atom. Optionally, the carbon atoms in the cyclic structure can be oxo-substituted. Specifically including "5-15 membered spirocyclyl", "4-11 membered spirocyclyl", "6-11 membered spirocyclyl", "5-10 membered spirocyclyl", "7-10 membered spirocyclyl", "6-9 membered spirocyclyl", "7-8 membered spirocyclyl", "9-10 membered spirocyclyl" and the like. Specific examples include but are not limited to:

[0134] Unless otherwise specified, the term "spiroheterocyclyl" refers to a cyclic structure derived from the replacement of at least one carbon atom in a "spiroheterocyclyl" by a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from N, O, S, P, NO, SO, S(O)2, P(O) and NR, R is H or any substituent group that may exist, and the "spiroheterocyclyl" is as defined above. It includes, but is not limited to, a cyclic structure formed by a heterocyclic spiroheterocycle and a heterocyclic spiroheteroalkane. The spiroheterocycle preferably contains 1-2 heteroatoms selected from NR and / or O, more preferably 1 NR and 0-1 NR or O heteroatoms. The spiroheterocycle is preferably a "nitrogen-containing spiroheterocycle", which refers to a spiroheterocycle in which at least one ring atom is NR. The spiroheterocycle includes a 7-11-membered spiroheterocycle, a 7-9-membered spiroheterocycle, a 7-11-membered nitrogen-containing spiroheterocycle, and a 7-9-membered nitrogen-containing spiroheterocycle. Specific examples include, but are not limited to: wait.

[0135] Unless otherwise specified, the term "bridged cyclic group" refers to a cyclic structure containing 5-15 ring carbon atoms formed by two or more cyclic structures sharing two non-adjacent carbon atoms. Optionally, the carbon atoms in the cyclic structure can be oxoed. "5-15 membered bridged cyclic groups" include, for example, "5-11 membered bridged cyclic groups", "6-11 membered bridged cyclic groups", "5-10 membered bridged cyclic groups", "7-10 membered bridged cyclic groups", "6-9 membered bridged cyclic groups", "7-8 membered bridged cyclic groups", "9-10 membered bridged cyclic groups" and the like. Specific examples include, but are not limited to: wait.

[0136] Unless otherwise specified, the term "bridged heterocyclic group" refers to a cyclic structure derived from a "bridged heterocyclic group" in which at least one carbon atom is replaced by a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from N, O, S, P, NO, SO, S(O)2, P(O) and NR, R is H or any substituent group that may be present, and the "bridged cycloalkyl" is as defined above. The bridged heterocycle is preferably a "nitrogen-containing bridged heterocycle", which refers to a heterocycle in which at least one ring atom is NR. The bridged heterocycle includes "6-10 membered bridged heterocycle", "6-8 membered bridged heterocycle", etc. Specific examples include, but are not limited to: wait.

[0137] Combinations of substituents and / or variables described herein are permissible only if these combinations result in stable compounds or useful synthetic intermediates. A stable compound or structure is one that is sufficiently robust to withstand chemical reactions, to be isolated to a useful degree of purity, and to be formulated into an efficacious therapeutic agent.

[0138] In the embodiments disclosed herein, the naming of the title compound is converted from the compound structure with the aid of Chemdraw. If there is an inconsistency between the compound name and the compound structure, it can be determined by integrating relevant information and reaction routes; if it cannot be confirmed by other means, the given compound structure shall prevail. The preparation method of some compounds in the present invention refers to the preparation method of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation method cited, the feed ratio of the reactants, the reaction solvent, the reaction temperature, etc. can be appropriately adjusted according to the different reactants.

[0139] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0140] Summary of experimental instruments:

[0141] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and heavy water (D2O) as the internal standard, with tetramethylsilane (TMS) as the internal standard.

[0142] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-6125B single quadrupole mass spectrometer with a Welch Biomate column (C18, 2.7 μm, 4.6 × 50 mm) or a Waters H-Class SQD2 with a Welch Ultimate column (XB-C18, 1.8 μm, 2.1 × 50 mm) mass spectrometer (electrospray ionization as the ion source).

[0143] Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class SQD mass spectrometer (electrospray ionization as the ion source).

[0144] HPLC analysis was performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0145] Preparative HPLC used a Waters 2555-2489 (10 μm, ODS 250 cm×5 cm) or a GILSON Trilution LC, and a Welch XB-C18 column (5 μm, 21.2×150 mm).

[0146] Thin layer chromatography silica gel plates use GF254 silica gel plates from Yantai Jiangyou Silica Gel Development Co., Ltd. or GF254 silica gel plates from Rushan Shangbang New Materials Co., Ltd. The specifications used for TLC are 0.15mm-0.20mm, and the preparative type is 20×20cm. Column chromatography generally uses 200-300 mesh silica gel from Chenghua as a carrier.

[0147] The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art. Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, with dry solvents, and reaction temperatures in degrees Celsius or °C. The percentages referred to herein, unless otherwise specified, refer to mass percentages for solid-liquid mixtures and solid-solid mixtures, and to volume percentages for liquid-liquid mixtures.

[0148] The abbreviations and corresponding names used in the examples are as follows:

[0149] Example 1

[0150] 4-((2-Hydroxyethyl)sulfonamido)-N-(1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0151] Reaction route:

[0152] Steps:

[0153] Step A: Dissolve 5'-chloro-1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-2'-one (0.25 g, 1.20 mmol) in tetrahydrofuran (10 mL) in a 50 mL single-necked flask and replace with nitrogen. Cool the reaction mixture to 0°C and add diisobutylaluminum hydride (3.6 mL, 3.6 mmol, 1 M in tetrahydrofuran) via syringe. Incubate the mixture in an ice bath for 2 hours.

[0154] Water (2 mL) was added to quench the mixture, followed by sodium hydroxide solution (15%, 2 mL). After stirring for ten minutes, the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by normal phase column chromatography (ethyl acetate / petroleum ether = 8%) to give 5'-chloro-1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (0.14 g). MS (ESI) M / Z: 195.0 [M+H] + .

[0155] Step B: In a dry 10 ml single-necked bottle, 5'-chloro-1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (0.1 g, 0.51 mmol), cesium carbonate (0.33 g, 1.02 mmol), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (0.049 g, 0.10 mmol), tert-butyl carbamate (0.090 g, 0.77 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.043 g, 0.051 mmol) were added, followed by the addition of 1,4-dioxane (4 ml). The atmosphere was replaced with nitrogen three times, and the reaction was carried out at 100°C for 2 hours.

[0156] After cooling to room temperature, the reaction system was concentrated and purified by normal phase column chromatography (ethyl acetate / petroleum ether = 25%) to obtain tert-butyl (1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamate (0.092 g) as a pale yellow solid. MS (ESI) M / Z: 276.1 [M+H] + .

[0157] Step C: To a 10 mL single-necked flask, add tert-butyl (1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamate (0.085 g, 0.31 mmol) and dichloromethane (3 mL). Trifluoroacetic acid (1 mL) is then added dropwise to the reaction system. Stir at room temperature for one hour. The reaction solution is concentrated and dried to give 1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-5'-amine (0.043 g) as a light brown oil. The crude product is used directly in the next step without further purification. MS (ESI) M / Z: 176.2 [M+H] + .

[0158] Step D: To a 25 ml single-necked flask, reactants 1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-5'-amine (0.045 g, 0.26 mmol), 2-(6-azaspiro[2.5]octane-6-yl)-4-(2-hydroxyethanesulfonamido)benzoic acid (0.092 g, 0.26 mmol), ethyldiisopropylamine (0.17 g, 1.3 mmol) and solvent N,N-dimethylformamide (2 mL) were added at room temperature. After stirring for 5 minutes, N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (0.15 g, 0.39 mmol) was added to the reaction system and stirred at room temperature for 1 hour.

[0159] The reaction solution was directly purified by preparative high pressure liquid chromatography to give 4-((2-hydroxyethyl)sulfonamido)-N-(1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.0315 g).

[0160] MS (ESI) M / Z: 512.2 [M+H] + .

[0161] 1 H NMR (400MHz, DMSO-d6) δ12.99(s,1H),10.14(s,1H),8.03(d,J=8.6Hz,1H),7.86(d,J =8.4Hz,1H),7.24(d,J=2.2Hz,1H),7.10(dd,J=8.6,2.2Hz,1H),6.85(d,J=8.4Hz,1H ),4.93(s,1H),3.75(t,J=6.6Hz,2H),3.43(s,2H),3.35(t,J=6.6Hz,2H),2.95-2.93 (m,4H),2.77(s,3H),1.70(s,4H),1.14-1.05(m,2H),1.05-0.96(m,2H),0.38(s,4H).

[0162] Example 2

[0163] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2H-spiro[benzofuran-3,1'-cyclopropane]-5-yl)benzamide

[0164] Reaction route:

[0165] Steps:

[0166] Step A: Concentrated sulfuric acid (2 mL) was added dropwise to a toluene (100 mL) solution of 2-(5-bromo-2-hydroxyphenyl)acetic acid (10 g, 43.5 mmol) at room temperature, and then the mixture was moved into an oil bath and stirred at 100°C for 6 h.

[0167] After cooling to room temperature, the reaction solution was added dropwise to ice water for quenching, extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with saturated brine (100 mL × 3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the target compound 5-bromobenzofuran-2(3H)-one (7 g).

[0168] MS (ESI) M / Z: 213.0 [M+H] + .

[0169] 1 H NMR (400MHz, DMSO-d6) δ7.59-7.56 (m, 1H), 7.52-7.48 (m, 1H), 7.16 (d, J = 8.5Hz, 1H), 3.95 (s, 2H).

[0170] Step B: To a solution of 5-bromobenzofuran-2(3H)-one (7 g, 32.9 mmol) in N,N-dimethylformamide (80 mL) were added triethylamine (10 g, 98.6 mmol) and (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (17.5 g, 39.4 mmol) at room temperature, and the reaction was stirred at room temperature for 2 h.

[0171] The mixture was quenched with ice water (100 mL), extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (100 mL × 3), the filtrates were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 5-bromo-2H-spiro[benzofuran-3,1'-cyclopropane]-2-one (3.5 g). MS (ESI) M / Z: 239.0 [M+H] + .

[0172] Step C: To a solution of 5-bromo-2H-spiro[benzofuran-3,1'-cyclopropane]-2-one (1 g, 4.2 mmol) in tetrahydrofuran (10 mL) was added dropwise lithium borohydride (8.4 mL, 8.4 mmol, 1 M tetrahydrofuran solution) under ice-cooling, and the mixture was stirred at 0°C for 1 h.

[0173] The product was quenched with ice water (30 mL), the pH was adjusted to weak acidity with dilute hydrochloric acid (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 4-bromo-2-(1-(hydroxymethyl)cyclopropyl)phenol (0.6 g). MS (ESI) M / Z: 243.0 [M+H] + .1H NMR (400MHz, DMSO-d6) δ9.57(s,1H),7.22(d,J=2.6Hz,1H),7.19(dd,J=8.5,2.6Hz,1H),6.73(d, J=8.5Hz,1H),4.93(t,J=5.4Hz,1H),3.45(d,J=5.4Hz,2H),0.80-0.77(m,2H),0.63-0.61(m,2H).

[0174] Step D: To a solution of 4-bromo-2-(1-(hydroxymethyl)cyclopropyl)phenol (0.6 g, 2.5 mmol) in N,N-dimethylformamide (5 mL) was added a solution of potassium tert-butoxide in tetrahydrofuran (3.75 mL, 3.75 mmol, 1 M tetrahydrofuran solution) at room temperature, and the mixture was moved into an oil bath and stirred at 85°C for 10 h.

[0175] After the reaction, the mixture was cooled to room temperature, quenched with ice water, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 5-bromo-2H-spiro[benzofuran-3,1'-cyclopropane] (0.3 g). MS (ESI) M / Z: 225.0 [M+H] + .

[0176] Step E: To a solution of 5-bromo-2H-spiro[benzofuran-3,1'-cyclopropane] (0.3 g, 1.3 mmol) in 1,4-dioxane (5 mL) were added tris(dibenzylideneacetone)dipalladium (0.12 g, 0.13 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.12 g, 0.2 mmol), cesium carbonate (1.3 g, 0.42 mmol) and benzophenone imine (0.48 g, 2.6 mmol) in sequence at room temperature. The atmosphere was replaced with nitrogen three times, and the mixture was moved into an oil bath and stirred at 100 °C for 16 h.

[0177] The mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound, 1,1-diphenyl-N-(2H-spiro[benzofuran-3,1'-cyclopropane]-5-yl)methanimine (0.15 g). MS (ESI) M / Z: 326.2 [M+H] + .

[0178] Step F: 1,1-Diphenyl-N-(2H-spiro[benzofuran-3,1'-cyclopropane]-5-yl)methanimine (150 mg, 0.46 mmol) was dissolved in 1,4-dioxane hydrochloride (4 mL, 4 M) and stirred at room temperature for 2 h.

[0179] After the reaction, the reaction solution was directly concentrated to obtain a residue, which was dissolved in dichloromethane (2 mL x 3) and the solvent was removed by rotary evaporation to obtain the target compound 2H-spiro[benzofuran-3,1'-cyclopropane]-5-amine hydrochloride (163 mg). MS (ESI) M / Z: 162.1 [M+H] + .

[0180] Step G: To a solution of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (45 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) at room temperature were added triethylamine (39 mg, 0.39 mmol) and HATU (99 mg, 0.26 mmol) in sequence. The mixture was stirred at room temperature for 5 minutes, followed by the addition of 2H-spiro[benzofuran-3,1'-cyclopropane]-5-amine hydrochloride (20 mg, 0.13 mmol). The reaction system was stirred at room temperature for 16 hours.

[0181] After the reaction, the reaction solution was filtered and the filtrate was directly sent to HPLC to obtain the target product 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2H-spiro[benzofuran-3,1'-cyclopropane]-5-yl)benzamide (14 mg).

[0182] MS (ESI) M / Z: 498.2 [M+H] + .

[0183] 1H NMR (400MHz, DMSO-d6) δ11.44(s,1H),7.79(d,J=8.5Hz,1H),7.33(d,J=2.2Hz,1H), 7.26(dd,J=8.5,2.2Hz,1H),7.13(d,J=2.0Hz,1H),7.00(dd,J=8.5,2.1Hz,1H),6.7 8(d,J=8.5Hz,1H),4.48(s,2H),3.75(t,J=6.6Hz,2H),3.30(t,J=6.6Hz,2H),2.98- 2.93(m,4H),1.56-1.45(m,4H),1.10-1.09(m,2H),1.01-1.00(m,2H),0.35(s,4H).

[0184] Example 3

[0185] 4-((2-Hydroxyethyl)sulfonamido)-N-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0186] Reaction route:

[0187] Steps:

[0188] Step A: To a solution of 5-nitroindole-2-one (1 g, 5.6 mmol) in N,N-dimethylformamide (10 mL) were added triethylamine (1.7 g, 16.8 mmol) and (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (3.7 g, 8.4 mmol) in sequence at room temperature, and the reaction was stirred at room temperature for 16 h.

[0189] After the reaction, the mixture was quenched with ice water and extracted with triethylamine (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 5'-nitrospiro[cyclopropane-1,3'-indolin]-2'-one (0.7 g). MS (ESI) M / Z: 205.1 [M+H] + .

[0190] Step B: To a solution of 5'-nitrospiro[cyclopropane-1,3'-indolin]-2'-one (0.7 g, 3.4 mmol) in N,N-dimethylformamide (10 mL) were added sodium hydride (0.27 g, 6.8 mmol, 60%) and iodomethane (0.58 g, 4 mmol) at room temperature, and the mixture was stirred at room temperature for 1 h.

[0191] The mixture was quenched with ice water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 1'-methyl-5'-nitrospiro[cyclopropane-1,3'-indolin]-2'-one (0.5 g). MS (ESI) M / Z: 219.1 [M+H] + .

[0192] Step C: Under ice bath, add 4,4'-bipyridine (36 mg, 0.23 mmol) to a solution of 1'-methyl-5'-nitrospiro[cyclopropane-1,3'-indolin]-2'-one (500 mg, 2.3 mmol) in N,N-dimethylformamide (5 mL). After complete dissolution, add B2(OH)4 (1 g, 11.5 mmol) to the system in small batches. The reaction solution changes from light yellow to dark brown and then back to light yellow within 10 minutes, and the reaction is completed.

[0193] The reaction solution was directly concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography to obtain the target compound 5'-amino-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (0.25 g). MS (ESI) M / Z: 189.0 [M+H] + .

[0194] Step D: To a solution of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (100 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL) were added triethylamine (91 mg, 0.9 mmol) and HATU (228 mg, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h, and then a solution of 5'-amino-1'-methylspiro[cyclopropane-1,3'-indoline]-2'-one (60 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL) was added and the reaction was continued to stir at room temperature for 16 h.

[0195] The reaction mixture was quenched with ice water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the target compound 4-((2-hydroxyethyl)sulfonamido)-N-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (32.6 mg).

[0196] MS (ESI) M / Z: 525.2 [M+H] + .

[0197] 1H NMR (400MHz, DMSO-d6) δ11.47(s,1H),7.80(d,J=8.5Hz,1H),7.62(d,J=2.0Hz,1H),7.42(dd,J=8.4,2.0Hz,1H),7.15(d,J=2.0Hz,1H),7.10(d,J=8. 4Hz, 1H), 7.02 (dd, J=8.5, 2.0Hz, 1H), 3.76 (t, J=6.6Hz, 2H), 3.32 (t, J=6. 6Hz,2H),3.21(s,3H),2.98-2.94(m,4H),1.55-1.52(m,8H),0.35(s,4H).

[0198] Example 4

[0199] 4-((2-Hydroxyethyl)sulfonamido)-N-(2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-6'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0200] Reaction route:

[0201] Steps:

[0202] Step A: To a solution of 6'-bromospiro[cyclopropane-1,1'-isoindolin]-3'-one (250 mg, 1 mmol) in N,N-dimethylformamide (5 mL) were added NaH (40 mg, 2 mmol) and iodomethane (213 mg, 1.5 mmol) at room temperature, and the mixture was stirred at room temperature for 1 h.

[0203] The mixture was quenched with ice (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 6'-bromo-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (218 mg). MS (ESI) M / Z: 252.0 [M+H] + .

[0204] Step B: To a solution of 6'-bromo-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (210 mg, 0.84 mmol) in 1,4-dioxane (5 mL) were added tris(dibenzylideneacetone)dipalladium (77 mg, 0.08 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (73 mg, 1.26 mmol), cesium carbonate (0.82 g, 2.52 mmol) and tert-butyl carbamate (196 mg, 1.68 mmol) at room temperature. The atmosphere was replaced with nitrogen three times and then moved into an oil bath and stirred at 100°C for 2 h.

[0205] The mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound (2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-6'-yl)carbamic acid tert-butyl ester (132 mg). MS (ESI) M / Z: 289.2 [M+H] + .1H NMR (400MHz, DMSO-d6) δ9.70 (s, 1H), 7.58 (d, J = 8.3Hz, 1H), 7.48 (s, 1H), 7.34 (d ,J=1.7Hz,1H),2.75(s,3H),1.71-1.66(m,2H),1.48(s,9H),1.27-1.23(m,2H).

[0206] Step C: To a solution of tert-butyl (2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-6'-yl)carbamate (130 mg, 0.45 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at room temperature, and the reaction was stirred at room temperature for 1 h.

[0207] After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the target compound 6'-amino-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one trifluoroacetate (142 mg). MS (ESI) M / Z: 189.0 [M+H] + .

[0208] Step D: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (132 mg, 0.37 mmol) in acetonitrile (3 mL) were added N-methylimidazole (91 mg, 1.11 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (207 mg, 0.74 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h, and then a solution of 6'-amino-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one trifluoroacetate (70 mg, 0.37 mmol) in acetonitrile (2 mL) was added, and the reaction was continued to stir at room temperature for 2 h.

[0209] The product was quenched with ice water (30 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 4-iodo-N-(2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-6'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (85 mg). MS (ESI) M / Z: 528.1 [M+H] + .

[0210] Step E: To a solution of 4-iodo-N-(2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-6'-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (80 mg, 0.15 mmol) in N,N-dimethylformamide (4 mL) were added cuprous iodide (29 mg, 0.15 mmol), potassium phosphate (127 mg, 0.6 mmol), sarcosine (13 mg, 0.15 mmol) and 2-hydroxyethane-1-sulfonamide (38 mg, 0.3 mmol) in sequence at room temperature. After nitrogen substitution, the reaction system was moved into an oil bath and stirred at 120°C for 16 h.

[0211] After cooling to room temperature, the reaction mixture was filtered and the filtrate was purified by HPLC to give the target compound 4-((2-hydroxyethyl)sulfonamido)-N-(2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-6'-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (46.53 mg).

[0212] MS (ESI) M / Z: 525.2 [M+H] + .

[0213] 1H NMR (400MHz, DMSO-d6) δ11.77(s,1H),7.88(s,1H),7.80(d,J=8.5Hz,1H),7.72(d ,J=8.2Hz,1H),7.59(dd,J=8.3,1.4Hz,1H),7.14(d,J=1.8Hz,1H),7.01(dd,J=8.5 ,1.9Hz,1H),3.76(t,J=6.5Hz,2H),3.33-3.30(m,1H),2.99-2.94(m,4H),2.78(s, 3H),1.74(t,J=6.6Hz,2H),1.56-1.47(m,4H),1.31(t,J=6.8Hz,2H),0.34(s,4H).

[0214] Example 5

[0215] 4-((2-Hydroxyethyl)sulfonamido)-N-(1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0216] Reaction route:

[0217] Steps:

[0218] Step A: To a 50 ml three-necked flask filled with nitrogen, add the reactants 5-chloro-1H,2H,3H-pyrrolo[3,2-b]pyridin-2-one (1 g, 5.93 mmol), zinc trifluoromethanesulfonate (2.16 g, 5.93 mmol), 2-bromoethyl(diphenyl)sulfonium trifluoromethanesulfonate (3.15 g, 7.12 mmol) and solvent N,N-dimethylformamide (10 mL), and stir under ice bath. Subsequently, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.71 g, 17.79 mmol) was added dropwise to the reaction system, and the reaction was stirred at room temperature for 2 hours.

[0219] 30 mL of water was added for dilution, followed by extraction with ethyl acetate three times (20 mL / times). The organic phases were combined, dried, concentrated, and purified by normal phase purification (ethyl acetate / petroleum ether = 22%) to give 5'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-2'-one (0.82 g) as a white solid. MS (ESI) M / Z: 195.0 [M+H] + .

[0220] Step B: Under ice bath, add reactant 5'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-2'-one (0.82 g, 4.21 mmol) and solvent N,N-dimethylformamide (10 mL) to a 50 mL single-necked flask, then add sodium hydride (0.15 g, 6.31 mmol) to the reaction system, stir under ice bath for 30 minutes, then add iodomethane (0.72 g, 5.05 mmol) dropwise to the reaction system, and stir at room temperature for 2 hours.

[0221] Ethyl acetate (25 mL) was added to dilute the mixture, and ice water (10 mL) was added to quench the reaction. The mixed solution was extracted three times with ethyl acetate, and the combined organic phases were dried and concentrated. The product was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 50%) to give 5'-chloro-1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-2'-one (0.79 g). MS (ESI) M / Z: 209.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.50(d,J=8.2Hz,1H),7.36(d,J=8.2Hz,1H),3.24(s,3H),1.78-1.73(m,2H),1.67-1.61(m,2H).

[0222] Step C: To a 25 mL single-necked bottle filled with nitrogen was added the reactants 5'-chloro-1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-2'-one (0.45 g, 2.16 mmol), tert-butyl carbamate (0.38 g, 3.24 mmol), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (0.21 g, 0.43 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.18 g, 0.22 mmol), cesium carbonate (1.41 g, 4.32 mmol) and solvent 1,4-dioxane (8 mL). The atmosphere was replaced with nitrogen three times, and the reaction was carried out at 100°C for 2 hours.

[0223] After cooling to room temperature, ethyl acetate / water (15 mL / 10 mL) was added, and the mixed solution was extracted three times with ethyl acetate. The organic phases were combined, dried, and concentrated. Purification by forward column chromatography (ethyl acetate / petroleum ether = 25%) gave tert-butyl N-(1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamate (0.35 g). MS (ESI) M / Z: 290.1 ​​[M+H]+ .

[0224] Step D: To a 10 mL single-necked vial, add tert-butyl N-(1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamate (0.1 g, 0.35 mmol) and dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was then added dropwise. The reaction was stirred at room temperature for 2 h.

[0225] The reaction solution was concentrated and dried to give crude 5'-amino-1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-2'-one (0.065 g). The crude product was not further purified and was directly used in the next step. MS (ESI) M / Z: 190.2 [M+H] + .

[0226] Step E: To a 15 mL single-necked bottle, reactants 5'-amino-1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-2'-one (0.07 g, 0.37 mmol), 2-(6-azaspiro[2.5]octane-6-yl)-4-(2-hydroxyethanesulfonamido)benzoic acid (0.13 g, 0.37 mmol), ethyldiisopropylamine (0.24 g, 1.85 mmol) and solvent N,N-dimethylformamide (2 mL) were added. After stirring at room temperature for 5 minutes, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.21 g, 0.55 mmol) was added to the reaction system.

[0227] The reaction solution was directly separated and purified by preparative HPLC to give 4-((2-hydroxyethyl)sulfonamido)-N-(1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (0.0598 g).

[0228] MS (ESI) M / Z: 526.2 [M+H] + .

[0229] 1H NMR (400MHz, DMSO-d6) δ13.38(s,1H),8.14(d,J=8.6Hz,1H),8.06(d,J=8.6Hz,1H),7.49(d,J=8.6Hz,1H),7.26(d,J=2.2Hz,1H),7.12 (dd,J=8.6,2.2Hz,1H),3.76(t,J=6.4Hz,2H),3.35(t,J=6.4Hz,2H),3.25(s,3H),2.99-2.95(m,4H),1.67-1.63(m,8H),0.39(s,4H).

[0230] Example 6

[0231] N-(3,3-Difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0232] Reaction route:

[0233] Steps:

[0234] Step A: To a solution of 6-bromo-2-fluoronicotinic acid (1 g, 4.6 mmol) and tert-butyl 3,3-difluorocyclobutane-1-carboxylate (0.88 g, 4.6 mmol) in THF (10 mL) was added dropwise LiHMDS (9.2 mL, 9.2 mmol, 1 M in THF) at -70°C, and the reaction was stirred at -70°C for 2 h.

[0235] After the reaction was completed, the mixture was quenched with ice water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound, 6-bromo-2-(1-(tert-butyloxycarbonyl)-3,3-difluorocyclobutyl)nicotinic acid (0.7 g). MS (ESI) M / Z: 336.0 [Mt-Bu] + .

[0236] Step B: To a solution of 6-bromo-2-(1-(tert-butoxycarbonyl)-3,3-difluorocyclobutyl)nicotinic acid (0.7 g, 1.8 mmol) in N,N-dimethylformamide (10 mL) were added N,N-diisopropylethylamine (0.9 g, 7.2 mmol) and diphenylphosphoryl azide (0.75 g, 2.7 mmol) at room temperature. The mixture was moved into an oil bath and stirred at 90°C for 5 min. Water (0.16 g, 9 mmol) was then added and the reaction was continued with stirring at this temperature for 2 h.

[0237] After cooling to room temperature, the mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound, tert-butyl 1-(3-amino-6-bromopyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylate (0.4 g). MS (ESI) M / Z: 363.0 [M+H] + .

[0238] Step C: Dissolve tert-butyl 1-(3-amino-6-bromopyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylate (0.4 g, 1.2 mmol) in trifluoroacetic acid (3 mL) at room temperature. Seal the reaction system and move into an oil bath for stirring at 100°C for 16 h.

[0239] After cooling to room temperature, the pH was adjusted to 8-9 with aqueous ammonia, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 5'-bromo-3,3-difluorospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (0.2 g). MS (ESI) M / Z: 289.0 [M+H] + .

[0240] Step D: To a solution of 5'-bromo-3,3-difluorospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.2 g, 0.69 mmol) in N,N-dimethylformamide (3 mL) was added NaH (56 mg, 1.39 mmol) at room temperature, stirred for 5 min, and then iodomethane (118 mg, 0.83 mmol) was added dropwise, and the reaction was stirred at room temperature for 1 h.

[0241] The mixture was quenched with ice water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 5'-bromo-3,3-difluoro-1'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (0.16 g). MS (ESI) M / Z: 303.0 [M+H] + .

[0242] Step E: To a solution of 5'-bromo-3,3-difluoro-1'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (160 mg, 0.53 mmol) in Dioxane (3 mL) were added methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (45 mg, 0.05 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (38 mg, 0.08 mmol), cesium carbonate (516 mg, 1.59 mmol) and tert-butyl carbamate (124 mg, 1.06 mmol) at room temperature. After nitrogen substitution, the reaction was continued with stirring at 100°C for 16 h.

[0243] The mixture was quenched with ice water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL × 3). The filtrates were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound (tert-butyl 3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamate (134 mg). MS (ESI) M / Z: 340.2 [M+H] + .

[0244] Step F: To a solution of tert-butyl (3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamate (130 mg, 0.3 mmol) in DCM (3 mL) was added TFA (2 mL) at room temperature and the reaction was stirred at room temperature for 1 h.

[0245] After the reaction, the reaction solution was directly spun to remove the solvent to obtain the target compound 5'-amino-3,3-difluoro-1'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one trifluoroacetate (139 mg). MS (ESI) M / Z: 240.0 [M+H]+ .

[0246] Step G: To a solution of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (191 mg, 0.54 mmol) in N,N-dimethylformamide (5 mL) were added triethylamine (164 mg, 1.62 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (410 mg, 1.08 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h, and then 5'-amino-3,3-difluoro-1'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one trifluoroacetate (130 mg, 0.54 mmol) in N,N-dimethylformamide (2 mL) was added and the reaction was continued to stir at room temperature for 16 h.

[0247] The reaction mixture was quenched with ice water (30 mL), extracted with ethyl acetate (30 mL×3), and the organic phases were combined, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the target compound N-(3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (138.17 mg).

[0248] MS (ESI) M / Z: 576.2 [M+H] + .

[0249] 1 H NMR (400MHz, DMSO-d6) δ13.27(s,1H),8.27(d,J=8.5Hz,1H),8.05(d,J=8.6Hz,1H),7.48(d,J=8.6Hz,1H),7.25(d,J=1.9Hz,1H),7.11(dd,J=8. 6,2.0Hz,1H),3.76(t,J=6.5Hz,2H),3.35(t,J=6.5Hz,2H),3.17(s,3H) ,3.15-3.01(m,4H),2.98-2.96(m,4H),1.97-1.36(m,4H),0.36(s,4H).

[0250] Example 7

[0251] N-(3,3-Difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0252] Reaction route:

[0253] Steps:

[0254] Step A: To a solution of benzyl 3-oxocyclopentane-1-carboxylate (5 g, 22.8 mmol) in 1,2-dichloroethane (50 mL) was added dropwise bis(2-methoxyethyl)aminosulfur trifluoride (10 g, 45.6 mmol) at room temperature, and then the mixture was moved into an oil bath and stirred at 50°C for 24 h.

[0255] After cooling to room temperature, the mixture was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the target compound, 3,3-difluorocyclopentane-1-carboxylic acid benzyl ester (2 g). 1 H NMR (400MHz, DMSO-d6) δ7.42-7.31(m,5H),5.13(s,2H),3.21-3.10(m,1H),2.42-2.29(m,2H),2.21-1.88(m,4H).

[0256] Step B: To a nitrogen-protected solution of benzyl 3,3-difluorocyclopentane-1-carboxylate (2 g, 8.3 mmol) and 6-bromo-2-fluoronicotinic acid (1.8 g, 8.3 mmol) in THF (30 mL) was added lithium bis(trimethylsilylamide) (16.6 mL, 16.6 mmol, 1 M in THF) at -70°C, and the reaction was stirred at this temperature for 2 h.

[0257] After the reaction, the mixture was quenched with ice water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound, 2-(1-(benzyloxy)carbonyl)-3,3-difluorocyclopentyl)-6-bromonicotinic acid (1.5 g). MS (ESI) M / Z: 440.0 [M+H] + .

[0258] Step C: To a solution of 2-(1-(benzyloxy)carbonyl)-3,3-difluorocyclopentyl)-6-bromonicotinic acid (1.5 g, 3.4 mmol) in N,N-dimethylformamide (20 mL) were added N,N-diisopropylethylamine (0.9 g, 6.8 mmol) and diphenylphosphoryl azide (1.4 g, 5.1 mmol) at room temperature. The mixture was moved into an oil bath and stirred at 90°C for 5 minutes. Water (0.3 g, 17 mmol) was then added and the reaction was continued with stirring at this temperature for 2 hours.

[0259] After cooling to room temperature, the mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 5'-bromo-3,3-difluorospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (0.8 g). MS (ESI) M / Z: 303.0 [M+H] + .

[0260] Step D: To a solution of 5'-bromo-3,3-difluorospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.8 g, 2.64 mmol) in N,N-dimethylformamide (10 mL) was added NaH (0.2 g, 5.28 mmol) at room temperature. The mixture was stirred for 5 minutes, and iodomethane (0.45 g, 3.17 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour.

[0261] The mixture was quenched with ice water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the target compound 5'-bromo-3,3-difluoro-1'-methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (0.6 g). MS (ESI) M / Z: 317.0 [M+H] + .

[0262] Step E: To a solution of 5'-bromo-3,3-difluoro-1'-methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (0.6 g, 1.9 mmol) in 1,4-dioxane (10 mL) were added methanesulfonic acid(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (160 mg, 0.19 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (164 mg, 0.28 mmol), cesium carbonate (1.85 g, 5.7 mmol) and tert-butyl carbamate (0.45 g, 3.8 mmol) at room temperature. The atmosphere was replaced with nitrogen and the reaction was stirred at 100°C for 16 h.

[0263] The mixture was quenched with ice water (30 mL), extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated brine (30 mL×3), the filtrates were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the target compound (3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)carbamic acid tert-butyl ester (0.4 g).

[0264] MS (ESI) M / Z: 354.2 [M+H] + .

[0265] Step F: To a solution of tert-butyl (3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)carbamate (0.4 g, 1.1 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3 mL) at room temperature, and the reaction was stirred at room temperature for 1 h.

[0266] After the reaction, the reaction solution was directly vortexed to remove the solvent to obtain the target compound 5'-amino-3,3-difluoro-1'-methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one trifluoroacetate (0.2 g). MS (ESI) M / Z: 254.0 [M+H] + .

[0267] Step G: To a solution of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.28 g, 0.79 mmol) in N,N-dimethylformamide (5 mL) were added triethylamine (0.32 g, 3.16 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.6 g, 1.58 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h, and then a solution of 5'-amino-3,3-difluoro-1'-methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one trifluoroacetate (0.2 g, 0.79 mmol) in N,N-dimethylformamide (2 mL) was added, and the reaction was continued to stir at room temperature for 16 h.

[0268] The reaction mixture was quenched with ice water (30 mL), extracted with ethyl acetate (30 mL×3), and the organic phases were combined, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the target compound N-(3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (47.54 mg).

[0269] MS (ESI) M / Z: 590.2 [M+H] + .

[0270] 1 H NMR (400MHz, DMSO-d6) δ13.23(s,1H),8.29(d,J=8.6Hz,1H),8.07(d,J=8.6Hz,1H),7.50(d,J=8.6Hz,1H),7.27(d,J=1.8Hz,1H),7.12(dd,J=8.7,1.8H z,1H),3.76(t,J=6.5Hz,2H),3.35-3.32(m,2H),3.17(s,3H),2.99-2.97(m ,4H),2.75-2.53(m,2H),2.47-1.97(m,4H),1.94-1.30(m,4H),0.38(s,4H).

[0271] Example 8

[0272] 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]octan-6-yl)benzamide

[0273] Reaction route:

[0274] Steps:

[0275] Step A: Add the reactant 5-chloro-1H,2H,3H-pyrrolo[3,2-b]pyridin-2-one (1 g, 5.93 mmol) and the solvent dimethyl sulfoxide (20 mL) to a 100 mL single-necked bottle and heat to 45°C. Then, potassium tert-butoxide (6 mL, 5.93 mmol, 1 M tetrahydrofuran solution) was added. Methyl acrylate (1.53 g, 17.79 mmol) was then added dropwise to the reaction system over 20 minutes. The temperature was then raised to 50°C. Potassium tert-butoxide (18 mL, 17.79 mmol, 1 M tetrahydrofuran solution) was then added to the reaction system over 15 minutes. The temperature was then raised to 100°C and stirred for 2 hours. Water (10 mL) was added to the reaction system and the reaction was continued at 80°C for 1 hour.

[0276] The mixture was cooled to room temperature and diluted with ethyl acetate / water (30 mL / 40 mL). The mixed solution was extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by forward column chromatography (ethyl acetate / petroleum ether = 40%) to give 5'-chloro-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2',4-dione (0.82 g) as a light yellow solid. MS (ESI) M / Z: 251.1 [M+H] + .

[0277] Step B: At room temperature, the reactants 5'-chloro-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2',4-dione (0.8 g, 3.19 mmol), 4-dimethylaminopyridine (0.39 g, 3.19 mmol) and solvent dichloromethane (10 mL) were added to a 50 mL three-necked flask. Then, tert-butoxycarbonyl anhydride (0.84 g, 3.83 mmol) was added dropwise to the reaction system and stirred at room temperature for 1 hour.

[0278] Dichloromethane (10 mL) and water (15 mL) were added to quench the reaction. The mixed solution was extracted three times with dichloromethane, and the organic phases were combined, dried, and concentrated. Purification by normal phase column (ethyl acetate / petroleum ether = 11%) gave tert-butyl 5'-chloro-2',4-dioxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-1'-carboxylate (0.93 g). MS (ESI) M / Z: 351.1 [M+H] + .

[0279] Step C: To a 25 mL single-necked flask, add the reactant 5'-chloro-2',4-dioxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-1'-carboxylic acid tert-butyl ester (0.93 g, 2.65 mmol) and solvent dichloromethane (10 mL). Diethylaminosulfur trifluoride (1.28 g, 7.95 mmol) was added dropwise to the reaction system under ice bath, and the mixture was reacted under ice bath for 4 hours.

[0280] The reaction was quenched with saturated sodium bicarbonate solution (15 mL), extracted three times with dichloromethane, and the organic phases were combined, dried, concentrated, and purified by forward column chromatography (ethyl acetate / petroleum ether = 18%) to give tert-butyl 5'-chloro-4,4-difluoro-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-1'-carboxylate (0.55 g) as a white solid. MS (ESI) M / Z: 373.0 [M+H] + .

[0281] Step D: To a 25 mL single-necked flask, add the reactant 5'-chloro-4,4-difluoro-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-1'-carboxylic acid tert-butyl ester (0.55 g, 1.48 mmol) and solvent dichloromethane (5 mL), and then add trifluoroacetic acid (0.17 g, 1.48 mmol) dropwise to the reaction system and stir at room temperature for 1 hour.

[0282] The reaction mixture was concentrated, and then saturated sodium bicarbonate solution was added. Extraction with ethyl acetate yielded 5'-chloro-4,4-difluoro-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-2'-one (0.36 g) as a white solid. The resulting compound was used directly in the next step for further purification. MS (ESI) M / Z: 273.1 [M+H] + .

[0283] Step E: To a 25 mL single-necked flask, reactant 5'-chloro-4,4-difluoro-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'-one (0.36 g, 1.32 mmol) and solvent N,N-dimethylformamide (8 mL) were added, the reaction system was cooled to 0°C, sodium hydride (0.063 g, 2.64 mmol) was added, and the reaction was stirred at this temperature for 20 minutes. Subsequently, iodomethane (0.22 g, 1.58 mmol) was added dropwise to the reaction system, and the reaction was stirred at room temperature for 2 hours.

[0284] Ethyl acetate (20 mL) was then added to dilute the mixture, and water (10 mL) was added to quench the reaction. The mixed solution was extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by forward column chromatography (ethyl acetate / petroleum ether = 28%) to obtain 5'-chloro-4,4-difluoro-1'-methyl-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-2'-one (0.35 g) as a white solid. MS (ESI) M / Z: 287.1 [M+H] + .

[0285] Step F: Add the reactants 5'-chloro-4,4-difluoro-1'-methyl-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'-one (0.35 g, 0.85 mmol), tert-butyl carbamate (0.15 g, 1.27 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1' -biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.036 g, 0.043 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.041 g, 0.085 mmol), cesium carbonate (0.55 g, 1.7 mmol) and solvent 1,4-dioxane (5 mL), nitrogen replacement three times, followed by reaction at 90 degrees Celsius for 2 hours.

[0286] After cooling to room temperature, the reaction solution was directly concentrated and mixed, and purified by forward column chromatography (ethyl acetate / petroleum ether = 25%) to obtain tert-butyl N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo]3,2-b]pyridin]-5'-yl)carbamate (0.36 g). MS (ESI) M / Z: 368.1 [M+H] + .

[0287] Step G: To a 15 mL single-necked flask, add reactant tert-butyl N-(4,4-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo]3,2-b]pyridin]-5'-yl)carbamate (0.35 g, 0.95 mmol) and solvent dichloromethane (3 mL). Trifluoroacetic acid (3.07 g, 26.93 mmol) was added dropwise to the reaction system and the reaction was stirred at room temperature for 1 h.

[0288] The reaction mixture was concentrated under reduced pressure to yield 5'-amino-4,4-difluoro-1'-methyl-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo]3,2-b]pyridin-2'-one (0.20 g) as a light brown solid. The crude product was further purified and directly used in the next reaction. MS (ESI) M / Z: 268.2 [M+H] + .

[0289] Step H: To a 15 mL single-necked bottle, reactants 2-(6-azaspiro]2.5]octane-6-yl)-4-(2-hydroxyethanesulfonamido)benzoic acid (0.1 g, 0.28 mmol), 5'-amino-4,4-difluoro-1'-methyl-1',2'-dihydrospiro]cyclohexane-1,3'-pyrrolo]3,2-b]pyridin]-2'-one (0.075 g, 0.28 mmol), ethyldiisopropylamine (0.18 g, 1.40 mmol) and solvent dimethylformamide (3 mL) were added. After stirring at room temperature for 5 minutes, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.16 g, 0.42 mmol) was added to the reaction system and stirred at room temperature overnight.

[0290] The reaction solution was directly separated and purified by high pressure preparative chromatography to obtain 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 (0.0477 g).

[0291] MS (ESI) M / Z: 604.3 [M+H] + .

[0292] 1H NMR (400MHz, DMSO-d6) δ12.89(s,1H),8.35(d,J=8.6Hz,1H),8.04(d,J=8.6Hz,1H),7 .55(d,J=8.6Hz,1H),7.24(d,J=2.2Hz,1H),7.09(dd,J=8.6,2.1Hz,1H),3.75(t,J=6 .5Hz,2H),3.35-3.33(m,2H),3.18(s,3H),2.99-2.97(m,4H),2.48-2.39(m,2H),2.3 1-2.17(m,2H),1.99-1.91(m,2H),1.89-1.81(m,2H),1.67-1.65(m,4H),0.37(s,4H).

[0293] Example 9

[0294] N-(4-Fluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin-3-en-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0295] Reaction route:

[0296] Steps:

[0297] Step A: To a 25 mL single-necked flask, add tert-butyl 5'-chloro-2',4-dioxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-1'-carboxylate (0.93 g, 2.65 mmol) and dichloromethane (10 mL). Add diethylaminosulfur trifluoride (1.28 g, 7.95 mmol) dropwise to the reaction system under ice-bath and react under ice-bath for 4 hours.

[0298] The reaction was quenched with saturated sodium bicarbonate solution (15 mL), extracted three times with dichloromethane, and the organic phases were combined, dried, concentrated, and purified by forward column chromatography (ethyl acetate / petroleum ether = 18%) to give tert-butyl 5'-chloro-4-fluoro-2'-oxospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-3-ene-1'(2'H)-carboxylate (0.55 g) as a white solid. MS (ESI) M / Z: 353.0 [M+H] + .

[0299] Step B: To a 25 mL single-necked flask, add the reactant 5'-chloro-4-fluoro-2'-oxospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-3-ene-1'(2'H)-carboxylic acid tert-butyl ester (0.55 g, 1.48 mmol) and solvent dichloromethane (5 mL). Then, trifluoroacetic acid (0.17 g, 1.48 mmol) was added dropwise to the reaction system and stirred at room temperature for 1 hour.

[0300] The reaction mixture was concentrated, and then saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate to yield 5'-chloro-4-fluorospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-3-ene-2'(1'H)-one (0.36 g). The resulting compound was used directly in the next step for further purification. MS (ESI) M / Z: 253.1 [M+H] + .

[0301] Step C: To a 25 mL single-necked flask, the reactant 5'-chloro-4-fluorospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-3-ene-2'(1'H)-one (0.36 g, 1.32 mmol) and the solvent N,N-dimethylformamide (8 mL) were added, the reaction system was cooled to 0°C, sodium hydride (0.063 g, 2.64 mmol) was added, and the reaction was stirred at this temperature for 20 minutes. Subsequently, iodomethane (0.22 g, 1.58 mmol) was added dropwise to the reaction system, and the reaction was stirred at room temperature for 2 hours.

[0302] The mixture was diluted with 20 mL of ethyl acetate and quenched with 10 mL of water. The mixed solution was extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by forward column chromatography (ethyl acetate / petroleum ether = 28%) to give 5'-chloro-4-fluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-3-ene-2'(1'H)-one (0.35 g). MS (ESI) M / Z: 267.1 [M+H] + .

[0303] Step D: To a 10 mL single-necked bottle, reactants 5'-chloro-4-fluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-3-ene-2'(1'H)-one (0.35 g, 0.85 mmol), tert-butyl carbamate (0.15 g, 1.27 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- Biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (0.036 g, 0.043 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.041 g, 0.085 mmol), cesium carbonate (0.55 g, 1.7 mmol) and solvent 1,4-dioxane (5 mL), nitrogen replacement three times, and then reacted at 90 ° C for 2 hours.

[0304] After cooling to room temperature, the reaction mixture was concentrated and mixed directly, and purified by forward column chromatography (ethyl acetate / petroleum ether = 25%) to obtain tert-butyl (4-fluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-3-en-5'-yl)carbamate (0.36 g). MS (ESI) M / Z: 348.1 [M+H] + .

[0305] Step E: To a 15 mL single-necked bottle, tert-butyl (4-fluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-3-ene-5'-yl)carbamate (0.35 g, 0.95 mmol) and dichloromethane (3 mL) were added. Trifluoroacetic acid (3.07 g, 26.93 mmol) was added dropwise to the reaction system and the reaction was stirred at room temperature for 1 h.

[0306] The reaction mixture was concentrated under reduced pressure to yield 5'-amino-4-fluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-3-ene-2'(1'H)-one (0.20 g) as a light brown solid. The crude product was further purified and directly used in the next reaction. MS (ESI) M / Z: 248.2 [M+H] + .

[0307] Step F: To a 15 mL single-necked bottle, reactants 2-(6-azaspiro]2.5]octane-6-yl)-4-(2-hydroxyethanesulfonamido)benzoic acid (0.1 g, 0.28 mmol), 5'-amino-4-fluoro-1'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-3-ene-2'(1'H)-one (0.075 g, 0.28 mmol), ethyldiisopropylamine (0.18 g, 1.40 mmol) and solvent dimethylformamide (3 mL) were added. After stirring at room temperature for 5 minutes, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.16 g, 0.42 mmol) was added to the reaction system and stirred at room temperature overnight.

[0308] The reaction solution was directly separated and purified by high pressure preparative chromatography to obtain N-(4-fluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-3-en-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (0.0477 g).

[0309] MS (ESI) M / Z: 584.2 [M+H] + .

[0310] 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.31(d,J=8.6Hz,1H),8.02(d,J=8.6Hz,1H),7.51(d,J=8 .6Hz,1H),7.22(d,J=2.2Hz,1H),7.08(dd,J=8.6,2.0Hz,1H),5.32-5.38(m,1H),3.75(t,J=6.5 Hz,2H),3.32(t,J=6.5Hz,2H),3.17(s,3H),3.06-2.84(m,4H),2.69-2.66(m,1H),2.46-2.34(m ,2H),2.20-2.16(m,1H),2.05-1.95(m,1H),1.87-1.85(m,1H),1.67-1.61(m,4H),0.36(s,4H).

[0311] Example 10

[0312] 2-(3-Azabicyclo[3.2.1]octan-3-yl)-N-(3,3-difluoro-1'-methyl-2'-oxo-1'-,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0313] Reaction route:

[0314] Steps:

[0315] Step A: To a solution of 2-(3-azabicyclo[3.2.1]octan-3-yl)-4-bromobenzoic acid (0.1 g, 0.32 mmol) in dimethylformamide (2 mL) were added triethylamine (0.1 g, 0.96 mmol) and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.24 g, 0.64 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h, and then a solution of 5'-amino-3,3-difluoro-1'-methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one trifluoroacetate (0.08 g, 0.32 mmol) in dimethylformamide (1 mL) was added, and the reaction was continued to stir at room temperature for 16 h.

[0316] The reaction mixture was quenched with ice water (30 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate = 5 / 1 to obtain the target compound, 2-(3-azabicyclo[3.2.1]octan-3-yl)-4-bromo-N-(3,3-difluoro-1'-methyl-2'-oxo-1'-,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)benzamide (124 mg). MS (ESI) M / Z: 545.2 [M+H] + .

[0317] Step B: To a solution of 2-(3-azabicyclo[3.2.1]octan-3-yl)-4-bromo-N-(3,3-difluoro-1'-methyl-2'-oxo-1'-, 2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)benzamide (0.12 g, 0.22 mmol) in dimethylformamide (2 mL) was added 2-hydroxyethane-1-sulfonamide (55 mg, 0.44 mmol), cuprous iodide (42 mg, 0.22 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (16 mg, 0.11 mmol) and potassium phosphate (233 mg, 1.1 mmol) at room temperature. After nitrogen substitution, the reaction system was placed under microwave at 150 ° C for 3 h.

[0318] The system was cooled to room temperature, and the reaction solution was directly purified by high pressure preparative chromatography to obtain the target product, 2-(3-azabicyclo[3.2.1]octan-3-yl)-N-(3,3-difluoro-1'-methyl-2'-oxo-1'-,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridinyl]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (49.24 mg). MS (ESI) M / Z: 590.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),8.30(d,J=8.6Hz,1H),7.85(d,J=8.5Hz,1H), 7.50(d,J=8.6Hz,1H),7.25(s,1H),7.04(d,J=8.4Hz,1H),3.75(t,J=6.5Hz,2H),3.3 4-3.28(m,2H),3.17(s,3H),2.98-2.95(m,2H),2.87-2.81(m,2H),2.56-2.41(m,4H ),2.28-2.26-2.23(m,2H),2.16-2.05(m,2H),2.03-1.98(m,2H),1.63-1.52(m,4H).

[0319] Example 11

[0320] 2-(3-Azabicyclo[3.2.1]octan-3-yl)-N-(3,3-difluoro-1'-methyl-2'-oxo-1'-,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-4-(methylsulfonamido)benzamide

[0321] Reaction route:

[0322] Steps:

[0323] Step A: To a solution of 2-(3-azabicyclo[3.2.1]octan-3-yl)-4-bromo-N-(3,3-difluoro-1'-methyl-2'-oxo-1'-,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin]-5'-yl)benzamide (60 mg, 0.11 mmol) in dimethylformamide (1 mL) was added methylsulfonamide (20 mg, 0.22 mmol), cuprous iodide (21 mg, 0.11 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (7 mg, 0.05 mmol) and potassium phosphate (117 mg, 0.55 mmol) at room temperature. After nitrogen substitution, the reaction system was placed under microwave at 150 ° C for 3 h.

[0324] The system was cooled to room temperature, and the reaction solution was directly purified by high pressure preparative chromatography to obtain the target product, 2-(3-azabicyclo[3.2.1]octan-3-yl)-N-(3,3-difluoro-1'-methyl-2'-oxo-1'-,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridinyl]-5'-yl)-4-(methylsulfonamido)benzamide (29.99 mg). MS (ESI) M / Z: 560.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ11.53(s,1H),10.26(s,1H),8.30(d,J=8.6Hz,1H),7.86( d,J=8.5Hz,1H),7.50(d,J=8.6Hz,1H),7.23(s,1H),7.05(d,J=8.5Hz,1H),3.1 7(s,3H),3.06(s,3H),2.98-2.95(m,2H),2.89-2.81(m,2H),2.60-2.52(m,2H ),2.49-2.39(m,2H),2.28-2.25(m,2H),2.15-1.96(m,4H),1.65-1.51(m,4H).

[0325] Example 12

[0326] N-(3,3-Difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro(cyclopentane-1,3'-pyrrolo(3,2-b)pyridine)-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0327] Reaction route:

[0328] Steps:

[0329] Step A: In a 50 mL three-necked flask, reactants 2-(difluoromethylsulfonyl)pyridine (1 g, 5.18 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (2.06 g, 10.36 mmol) and ultra-dry solvent tetrahydrofuran (15 mL) were added and cooled to -65 ° C. Then, a tetrahydrofuran solution of lithium bistrimethylsilylamide (10.3 mL, 10.3 mmol, 1 M) was added dropwise to the reaction system, and the temperature was naturally raised to room temperature for 1 hour. The reaction was then cooled to -65 ° C. 6N dilute hydrochloric acid was added dropwise to the reaction system, the pH was adjusted to about 6, and then the temperature was raised to room temperature for 2 hours.

[0330] The reaction of the raw material was monitored by potassium permanganate color development. Ethyl acetate / water (100 mL / 50 mL) was then added for dilution, and the mixed solution was extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by forward column chromatography (ethyl acetate / petroleum ether = 1%) to give tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate (1.03 g). 1 H NMR (400MHz, DMSO-d6) δ3.43-3.40(m,4H),2.20-2.09(m,4H),1.47(s,9H).

[0331] Step B: Add the reactant tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate (1 g, 4.29 mmol) and solvent dichloromethane (10 mL) to a 15 mL single-necked bottle, then add trifluoroacetic acid (3 mL) dropwise to the reaction system and stir at room temperature for 2 hours.

[0332] The reaction solution was directly concentrated under reduced pressure to obtain 4-difluoromethylenepiperidine (0.54 g), which was used directly in the next step without further purification.

[0333] Step C: To a 50 mL single-necked flask, reactants 4-difluoromethylenepiperidine (0.53 g, 3.98 mmol), methyl 4-bromo-2-fluorobenzoate (0.83 g, 3.58 mmol), N,N-diisopropylethylamine (2.57 g, 19.9 mmol) and solvent N-methylpyrrolidone (10 mL) were added, and the atmosphere was replaced with nitrogen. The reaction was then placed in an oil bath at 120°C for 12 hours.

[0334] The mixture was cooled to room temperature, and ethyl acetate / water (15 mL / 25 mL) was added to dilute it. The mixed solution was extracted with ethyl acetate. The combined organic phases were dried and concentrated, and purified by C-18 column (acetonitrile / water = 80%) to give methyl 4-bromo-2-(4-(difluoromethylene)piperidin-1-yl)benzoate (0.45 g) as a light brown oil. 1H NMR (400MHz, DMSO-d6) δ7.56(d,J=8.3Hz,1H),7.22(d,J=1.9Hz,1H),7.19(dd,J=8.3,1.9Hz,1H),3.81(s,3H),3.01(t,J=5.6Hz,4H),2.30-2.20(m,4H).

[0335] Step D: To a 10 mL single-necked bottle was added reactant 4-bromo-2-(4-(difluoromethylene)piperidin-1-yl)benzoic acid methyl ester (0.45 g, 1.30 mmol), anhydrous lithium hydroxide (0.16 g, 6.5 mmol) and solvents methanol (5 mL) and water (0.5 mL).

[0336] 15 mL of water was then added to dilute the mixture, and the pH was adjusted to 5 with 2N dilute hydrochloric acid. A large amount of white solid precipitated. The mixture was then filtered, rinsed twice with 4 mL of water, and the filter cake was collected and dried to yield 4-bromo-2-(4-(difluoromethylene)piperidin-1-yl)benzoic acid (0.39 g). MS (ESI) M / Z: 332.0 [M+H] + .

[0337] Step E: 5'-amino-3,3-difluoro-1'-methylspiro(cyclopentane-1,3'-pyrrolo(3,2-b)pyridine)-2'(1'H)-one trifluoroacetate is diluted with ethyl acetate, and the pH is adjusted to about 8 with saturated sodium bicarbonate. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined, washed with saturated brine, dried, and concentrated to obtain its free base form, i.e., 5'-amino-3,3-difluoro-1'-methylspiro(cyclopentane-1,3'-pyrrolo(3,2-b)pyridine)-2'(1'H)-one.

[0338] To a 25 mL single-necked bottle, reactants 5'-amino-3,3-difluoro-1'-methylspiro(cyclopentane-1,3'-pyrrolo(3,2-b)pyridine)-2'(1'H)-one (0.15 g, 0.59 mmol), 4-bromo-2-(4-(difluoromethylene)piperidin-1-yl)benzoic acid (0.20 g, 0.59 mmol), N,N-diisopropylethylamine (0.38 g, 2.95 mmol) and solvent N,N-dimethylformamide (5 mL) were added, and then 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.34 g, 0.89 mmol) was added to the reaction system and stirred at room temperature for 2 hours.

[0339] Water / ethyl acetate (20 mL / 10 mL) was then added for dilution. The mixed solution was extracted three times with ethyl acetate, the combined organic phases were dried and concentrated, and purified by normal phase column (ethyl acetate / petroleum ether = 45%) to give 4-bromo-N-(3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro(cyclopentane-1,3,-pyrrolo(3,2-b)pyridine)-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)benzamide (0.16 g).

[0340] MS (ESI) M / Z: 567.1 [M+H] + .

[0341] Step F: To a 10 mL microwave tube were added reactants 4-bromo-N-(3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro(cyclopentane-1,3,-pyrrolo(3,2-b)pyridine)-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)benzamide (0.053 g, 0.42 mmol), cuprous iodide (0.053 g, 0.28 mmol), potassium phosphate (0.059 g, 0.28 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.040 g, 0.28 mmol) and solvent dimethyl sulfoxide (2 mL), the atmosphere was replaced with nitrogen three times, and the reaction was then microwaved at 150°C for 1 hour.

[0342] The mixture was cooled to room temperature. The filtrate was filtered and the filtrate was directly purified by high pressure preparative chromatography to obtain N-(3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro(cyclopentane-1,3'-pyrrolo(3,2-b)pyridine)-5'-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (0.0161 g). MS (ESI) M / Z: 612.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),8.26(d,J=8.6Hz,1H),8.07(d,J=8.6H z,1H),7.51(d,J=8.5Hz,1H),7.17(d,J=2.2Hz,1H),7.12(dd,J=8.6,2.1Hz,1 H),3.75(t,J=6.5Hz,2H),3.35-3.32(m,2H),3.17(s,3H),3.01-2.97(m,4H) ,2.61-2.51(m,6H),2.43-2.31(m,2H),2.18-2.11(m,1H),2.02-1.95(m,1H).

[0343] The following target compounds were prepared by referring to the synthesis methods of the above examples:

[0344] Example 28

[0345] N-(3,3-Difluoro-1'-methyl-2'-oxo-1'-,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin-5'-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0346] Reaction route:

[0347] Steps:

[0348] Step A: Heat a solution of methyl 4-bromo-2,5-difluorobenzoate (5 g, 19.92 mmol), 6-azaspiro[2.5]octane hydrochloride (3.24 g, 21.91 mmol) and N,N-diisopropylethylamine (12.87 g, 99.60 mmol) in dimethyl sulfoxide (50 mL) to 120°C and stir for 5 hours.

[0349] The mixture was cooled to room temperature and diluted with ethyl acetate / water (100 mL / 50 mL). The mixed solution was extracted three times with ethyl acetate, and the organic phases were combined, dried, and concentrated. The residue was purified by flash silica gel column chromatography (2% ethyl acetate / petroleum ether) to obtain methyl 2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-5-fluorobenzoate (4 g). MS (ESI) M / Z: 342.0 [M+H] + .

[0350] Step B: To a mixed solvent of tetrahydrofuran (28 mL) and water (7 mL) containing methyl 2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-5-fluorobenzoate (4 g, 11.69 mmol) was added sodium hydroxide (2.34 g, 58.45 mmol), and the reaction solution was heated to 70°C and stirred for 3 hours.

[0351] After cooling to room temperature, the reaction solution was concentrated under reduced pressure and adjusted to pH 5-6 with HCl (2M). A white solid precipitated, which was filtered and the filter cake dried to give 2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-5-fluorobenzoic acid (3.2 g). MS (ESI) M / Z: 328.0 [M+H] + .

[0352] Step C:

[0353] Chiral separation: 5'-amino-3,3-difluoro-1'-methylspiro(cyclopentane-1,3'-pyrrolo(3,2-b)pyridine)-2'(1'H)-one was separated by chiral SFC (column: Daicel Chiralpak AS (250 mm × 50 mm, 10 μm); mobile phase: [carbon dioxide-isopropanol (0.1% ammonia water)]; B%: 20%, isocratic elution). The product corresponding to the first elution peak (retention time 1.163 min) was collected, concentrated under reduced pressure, and put into the reaction.

[0354] Condensation reaction: To a pyridine (5 mL) solution of 2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-5-fluorobenzoic acid (0.36 g, 1.09 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.28 g, 1.48 mmol) was added the product collected by chiral separation (250 mg, 0.99 mmol), and the reaction solution was heated to 60°C and stirred for 4 hours. After the reaction solution was cooled to room temperature, it was poured into water (100 mL). A white solid precipitated, which was filtered and the filter cake dried to give 2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-N-[3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl]-5-fluorobenzamide (500 mg). MS (ESI) M / Z: 563.1 [M+H] + .

[0355] Step D: To a solution of 2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-N-[3,3-difluoro-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl]-5-fluorobenzamide (500 mg, 0.89 mmol) and 2-hydroxyethane-1-sulfonamide (334.15 mg, 2.67 mmol) in dimethyl sulfoxide (15 mL) were added cuprous iodide (339 mg, 1.78 mmol), potassium phosphate (378 mg, 1.78 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (253.19 mg, 1.78 mmol) in sequence, and the reaction solution was heated to 150 ° C under nitrogen protection and microwave for 1 hour.

[0356] The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL), and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified and separated by preparative high-performance liquid chromatography (formic acid) to obtain N-(3,3-difluoro-1'-methyl-2'-oxo-1'-,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (120 mg), which was structurally identified as having the S configuration.

[0357] MS (ESI) M / Z: 608.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.57(s,1H),10.05(s,1H),8.28(d,J=8.6Hz,1H),7.88( d,J=11.7Hz,1H),7.57(d,J=7.3Hz,1H),7.52(d,J=8.6Hz,1H),5.01(s,1H),3.80 (t,J=6.4Hz,2H),3.39(t,J=6.4Hz,2H),3.18(s,3H),3.01-2.98(m,4H),2.75-2. 53(m,2H),2.45-2.43(m,2H),2.22-1.95(m,3H),1.73-1.71(m,3H),0.38(s,4H).

[0358] Biological test evaluation:

[0359] Test Example 1: Evaluation of the inhibitory effect of the disclosed compounds on human KIF18A actin activity

[0360] This study used the ADP-Glo ​​method to test the inhibitory effect of compounds on human KIF18A actin and obtained the half-maximal concentration IC of the compound to inhibit protein activity. 50 .

[0361] Yangshen molecule: AMG-650, its structure is as follows:

[0362] The abbreviations used in the test examples and their corresponding names are as follows:

[0363] 1. Experimental Materials

[0364] 1) MgCl2, KCl, EGTA, DTT, BSA, Tween-20, and PIPES pH 6.9 were purchased from Sigma and used to prepare assay buffer;

[0365] 2) KIF18A was purchased from CP;

[0366] 3) MT was purchased from Cytoskeleton;

[0367] 4) Paclitaxel was purchased from MCE;

[0368] 5) ADP-Glo ​​reagent, purchased from Promega.

[0369] Assay buffer specifically includes: 50mM PIPES, pH 6.9; 50mM KCl; 0.5mM EGTA; 5mM MgCl2; 1mM DTT; 0.01% BSA; 0.005% Tween-20; 5μM Paclitaxel.

[0370] 2. Experimental Methods

[0371] a) Add 50 nL of test compound or DMSO to a 384-well microplate;

[0372] b) Add 2.5 μL of KIF18A diluted in Assay buffer and incubate at room temperature for 30 minutes;

[0373] c) Add 2.5 μL of substrate mixture (a mixture of MT and ATP, where ATP is derived from ADP-Glo ​​reagent) diluted in assay buffer and incubate at room temperature for 60 minutes;

[0374] d) Add 5 μL of ADP-Glo ​​R1, centrifuge briefly, and incubate at room temperature for 2 hours;

[0375] e) Add 10 μL of ADP-Glo ​​R2, centrifuge briefly, and incubate at room temperature for 1 hour;

[0376] f) Chemiluminescent signals were detected using Envision microplate reader (PerkinElmer).

[0377] g) GraphPad Prism 6 software was used for data analysis to obtain the IC values ​​of the compounds. 50 .

[0378] 3. Experimental Results

[0379] The results of the inhibition of the human KIF18A protein activity by the disclosed compounds are shown in Table 1.

[0380] Table 1 KIF18A protein activity inhibition

[0381] Conclusion: The above results indicate that the disclosed compounds have strong inhibitory activity against human KIF18A protein.

[0382] Test Example 2: Evaluation of the inhibitory effect of the disclosed compounds on the proliferation of ovarian cancer cells NCIOVCAR3

[0383] This study used the CellTiter-Glo (CTG) method to test the inhibitory effect of compounds on NCIOVCAR3 cell proliferation and to obtain the half-maximal concentration IC of the compounds that inhibited cell growth. 50 .

[0384] 1. Experimental Materials

[0385] a) 1640 culture medium, fetal bovine serum (FBS), and Penicillin-Streptomycin were purchased from GIBCO.

[0386] b) CellTiter-Glo reagent, purchased from Promega.

[0387] 2. Experimental Methods

[0388] a) Day 0: NCIOVCAR3 cells were seeded into a 384-well plate at a density of 500 cells per well, with 50 μL per well.

[0389] b) Day 1: Add the test compound to the culture plate using TECAN at a final DMSO concentration of 0.5%. Add DMSO to the blank control wells at a final concentration of 0.5%. Incubate the culture plate in a cell culture incubator for 120 hours (37°C, 5% CO2).

[0390] c) Day 6: Add 20 μL of Cell Titer-Glo reagent to each well, shake at 500 rpm for 2 minutes, and incubate at room temperature in the dark for 10 minutes to stabilize the luminescence signal.

[0391] d) Chemiluminescent signals were detected using Envision microplate reader (PerkinElmer).

[0392] e) GraphPad Prism 6 software was used for data analysis to obtain the IC values ​​of the compounds. 50 .

[0393] 3. Experimental Results

[0394] The results of the inhibition of proliferation of ovarian cancer cells NCIOVCAR3 by the disclosed compounds are shown in Table 2.

[0395] Table 2 NCIOVCAR3 cell proliferation inhibition results

[0396] Conclusion: The above results indicate that the disclosed compounds have a strong inhibitory effect on the proliferation of ovarian cancer cells NCIOVCAR3.

[0397] Test Example 3: Evaluation of the inhibitory effect of the disclosed compounds on the proliferation of chromosomally unstable tumor cells

[0398] The inhibitory activity of the disclosed compounds on the proliferation of chromosomally unstable tumors such as OVCAR8, HT29, MDAMB157, BT549, NCIH23, and Calu6 was tested using methods well known to those skilled in the art, such as the CTG method.

[0399] 3.1 Experimental Materials

[0400] 3.2 Experimental steps

[0401] 1) Cell Culture: All cell culture procedures were performed according to the manufacturer's instructions. Specifically, HT29 cells were cultured in RPMI1640 medium supplemented with 10% FBS and passaged every 3-4 days. Passaging: Thoroughly disperse the cells, collect the cell suspension, and centrifuge at 800 rpm for 3 minutes. Discard the supernatant and resuspend the cells in fresh medium. Subculture was performed at a ratio of approximately 1:4.

[0402] 2) HT29 cells were harvested, resuspended in culture medium, counted, and seeded into 96-well white clear-bottom plates, with 800 cells per well in 100 μL of culture medium.

[0403] 3) Using an Echo 650, transfer the disclosed compounds to the 96-well plate at a top concentration of 2 μM, with 3-fold dilutions for a total of 9 concentration points. The total DMSO content was 0.5%. The plate was incubated at 37°C in a 5% CO2 incubator for 7 days.

[0404] 4) After incubation, add 50 μL of CTG to each well, shake for 10 minutes, and then read the chemiluminescence value using Envision.

[0405] GI 50 Calculation: The reading of the well containing only DMSO before drug addition on the day of drug addition is the low control, and the reading of the well containing only DMSO is the high control. Compound inhibition rate = 100% × ((RLU high control -RLU low control )-(RLU compound -RLU low control )) / (RLU high control -RLU low control ); see Table 3 for experimental results.

[0406] Table 3 Inhibitory activity of the disclosed compounds on chromosomally unstable tumor growth

[0407] The above results show that the disclosed compounds have a significant inhibitory effect on the proliferation of chromosomally unstable tumors.

[0408] Test Example 4: In vivo pharmacodynamic study evaluating the disclosed compounds in an OVCAR3 transplant tumor model

[0409] 4.1 Experimental animals and breeding environment

[0410] Species: Mouse;

[0411] Strain: BALB / c Nude mice;

[0412] Arrival age: 6-8 weeks old;

[0413] Gender: female;

[0414] Weight: 19-24 g;

[0415] Supplier: Zhejiang Weitonglihua Laboratory Animal Technology Co., Ltd.;

[0416] Animal Certificate: SCXK(Zhejiang)2024-0001 20240603Ab220619000250.

[0417] 4.2 Experimental methods and steps

[0418] 1) Cell culture

[0419] Human ovarian cancer OVCAR3 cells (Ovarian Carcinoma, ATCC, Cat No. HTB-161, Lot No. 4470175) were cultured as monolayers in RPMI high-glucose 1640 medium supplemented with 20% heat-inactivated fetal bovine serum, 10 μg / mL insulin, 100 U / mL penicillin, and 100 U / mL streptomycin at 37°C in 5% CO2. Cells were passaged two to three times weekly. When cells reached the exponential growth phase, they were harvested, counted, and plated.

[0420] 2) Tumor cell inoculation and grouping

[0421] will contain 10×10 6 100 μL PBS of 100 OVCAR3 cells and 100 μL Matrigel (1:1) were mixed in equal volumes and inoculated subcutaneously on the back of the right forelimb of each mouse. On the 31st day after inoculation, the average tumor volume reached 132 mm 3 At 4 pm, the mice were randomly divided into groups and drug administration began. Each group consisted of 6 mice, and the drug was administered orally (QD) once a day for 28 days (28 days). The specific groupings are shown in Table 4.

[0422] Table 4. Experimental animal groups

[0423] Note: The vehicle group consisted of 5% DMSO + 10% Solutol (solubilizer) + 85% Saline (normal saline).

[0424] 3) Tumor measurement and experimental indicators

[0425] Tumor diameter was measured twice a week using a vernier caliper. Tumor volume was calculated using the formula: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.

[0426] The tumor inhibition efficacy of the compound was evaluated using the tumor inhibition rate (TGI) (%). TGI (%) was calculated as follows: TGI (%) = [1 - (mean tumor volume of a treatment group at the end of dosing - mean tumor volume of the treatment group at the start of dosing) / (mean tumor volume of the solvent control group at the end of treatment - mean tumor volume of the solvent control group at the start of treatment)] × 100%.

[0427] 4) Statistical analysis

[0428] Statistical analysis was performed using GraphPad Prism 8.3.0 software based on the mean and standard error (SEM) of tumor volume at the end of the experiment. The tumor inhibition effect of each experimental group is shown in Table 5.

[0429] Table 5 Inhibition results of OVCAR3 subcutaneous xenograft tumor proliferation

[0430] Note: - represents not tested. The p value was analyzed based on the tumor volume of different groups with the AMG-650 10 mg / kg group as the control using the Mann-Whitney non-parametric test. A p < 0.05 was considered to be significantly different.

[0431] The experimental results showed that at a dose of 3 mg / kg, the compound provided in Example 28 had a significantly higher OVCAR3 tumor inhibition rate than AMG-650 (98% vs. 58%). At a dose of 10 mg / kg, the compound provided in Example 28 exhibited a statistically significant inhibitory effect on the proliferation of OVCAR3 subcutaneous xenografts compared to the AMG-650 group, with a p-value of 0.0022. This indicates that the compound provided in Example 28 is more effective than AMG-650 in the OVCAR3 xenograft model in vivo.

[0432] Test Example 5: Evaluation of the inhibitory effect of the disclosed compounds on human KIF18A actin

[0433] Comparative activity tests were performed using the compound provided by the present disclosure and the KIF18A inhibitor compound described in Example 3 of WO2024125488A (comparative molecule 1), the structures of which are as follows:

[0434] This study used the ADP-Glo ​​method to test the inhibitory effect of compounds on human KIF18A actin and obtained the half-maximal concentration IC of the compound to inhibit protein activity. 50 .

[0435] 1. Experimental Materials

[0436] 1) MgCl2, KCl, EGTA, DTT, BSA, and Tween-20 were purchased from Sigma and used to prepare assay buffer (the ratio was the same as in Test Example 1);

[0437] 2) KIF18A was purchased from CP;

[0438] 3) MT (tubulin) was purchased from Cytoskeleton, Lot#031;

[0439] 4) Paclitaxel was purchased from MCE;

[0440] 5) ADP-Glo ​​reagent, purchased from Promega.

[0441] 2. Experimental Methods

[0442] a) Add 50 nL of test compound or DMSO to a 384-well microplate;

[0443] b) Add 2.5 μL of KIF18A diluted in Assay buffer and incubate at room temperature for 15 minutes;

[0444] c) Add 2.5 μL of substrate mixture (a mixture of MT and ATP, where ATP is derived from ADP-Glo ​​reagent) diluted in assay buffer and incubate at room temperature for 60 minutes;

[0445] d) Add 5 μL of ADP-Glo ​​R1, centrifuge briefly, and incubate at room temperature for 2 hours;

[0446] e) Add 10 μL of ADP-Glo ​​R2, centrifuge briefly, and incubate at room temperature for 1 hour;

[0447] f) Chemiluminescent signals were detected using Envision microplate reader (PerkinElmer).

[0448] g) GraphPad Prism 6 software was used for data analysis to obtain the IC values ​​of the compounds. 50 .

[0449] 3. Experimental Results

[0450] The results of the inhibition of human KIF18A protein activity by the disclosed compounds are shown in Table 6.

[0451] Table 6 KIF18A protein activity inhibition

[0452] Conclusion: As can be seen from Table 6, the compounds disclosed herein have stronger inhibitory activity against KIF18A protein.

[0453] Test Example 6: DMPK test to evaluate the pharmacokinetics of the disclosed compounds in mice

[0454] Mice were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in plasma at a dose of 1 mg / kg intravenously injected and 10 mg / kg orally administered.

[0455] 1. Experimental Plan

[0456] 1.1 Investigational Drugs:

[0457] The compound disclosed herein and the compound of Example 3 of WO2024125488A.

[0458] 1.2 Experimental animals

[0459] Twelve male CD-1 mice (3 mice / group) were obtained from Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0460] 1.3 Administration:

[0461] Twelve male CD-1 mice were administered IV with free feeding and PO on an empty stomach. The IV dose was 1 mg / kg in a 5 mL / kg volume, and the PO dose was 10 mg / kg in a 10 mL / kg volume.

[0462] 1.4 Experimental Equipment

[0463] Centrifuge (5810R) was purchased from Eppendorf, pipettes were purchased from Eppendorf, and vortexer was purchased from Scientific Industries.

[0464] 1.5 Sample collection

[0465] After administration, 0.1 mL of blood was collected from the saphenous vein of mice at 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8 and 24 hours, placed in EDTA-K2 tubes, centrifuged at 4600 rpm for 5 minutes at 4°C, and plasma was separated and stored at -80°C.

[0466] 1.6 Sample processing

[0467] 1) 50 μL of plasma sample was precipitated by adding 200 μL of methanol:acetonitrile (volume ratio of 1:1), mixed, and centrifuged at 2773 × g for 15 minutes.

[0468] 2) 50 μL of the supernatant solution after treatment was dissolved in diluent (methanol:water volume ratio of 1:1, containing 0.1% formic acid) and analyzed by LC / MS / MS to determine the concentration of the test compound.

[0469] 1.7 Liquid phase analysis

[0470] Liquid phase: Shimadzu LC-30AD or LC-40D XS;

[0471] Mass spectrometry: AB Sciex 5500;

[0472] Chromatographic column: Phenomenex Kinetex C18 (2.6 μm, 5 mm × 3.0 mm) or ACE C4 (50 mm × 2.1 mm) or Waters HSS T3 (2.5 μm, 50 mm × 2.1 mm) or C18 1.8μm column (50mm×2.1mm);

[0473] Mobile phase: A: 5 mM ammonium acetate solution containing 0.05% formic acid, B: 0.05% formic acid in acetonitrile;

[0474] Flow rate: 0.6 mL / min;

[0475] Gradient: Gradient elution 0-3 minutes.

[0476] 2. Experimental Results and Analysis

[0477] The main pharmacokinetic parameters were calculated using WinNonlin software. The pharmacokinetic parameters of the drug after intravenous injection and oral administration in mice are shown in Tables 7 and 8 below.

[0478] Table 7 Pharmacokinetic parameters of some compounds of the present disclosure injected intravenously into mice

[0479] Table 8 Pharmacokinetic parameters of some compounds of the present disclosure in mice after oral administration

[0480] The above experimental results show that compared with the compound in Example 3 of WO2024125488A, the drug exposure (AUC) and half-life (T 1 / 2 ), bioavailability (F), etc., and exhibited good pharmacokinetic properties in animals.

Claims

1. A compound represented by formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, X is selected from O, -C(=O)- or -NR x1 -; Y is selected from -CH2-, -C(=O)- or -NR y1- ; R x1 and R y1 Each independently selected from H, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 1-4 alkoxy; M is selected from N or CH; Q is selected from N or CH; Ring A is selected from C 3-8 Cycloalkyl or C 3-8 cycloalkenyl; R 1 is selected from H or halogen; a is selected from 0, 1, 2 or 3; R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Each independently selected from H, C 1-4 Alkyl or halogenated C 1-4 alkyl; Or, R 2 、R 3 Together with the carbon atom it is connected to, it forms C 3-6 Cycloalkyl or C 2-4 alkenyl, and the C 3-6 Cycloalkyl or C 2-4 The alkenyl group may be optionally further substituted with one or more halogens; Or, R 4 、R 6 Together with the carbon atom it is connected to, it forms C 3-6 Cycloalkyl; Or, R 5 、R 7 Together with the carbon atom it is connected to, it forms C 3-6 Cycloalkyl; R 8 Selected from -NHSO2-R 8b , the R 8b C 1-4 Alkyl, and the C 1-4 The alkyl group is optionally further substituted with OH or halogen; R 9 Selected from H, halogen or C 1-4 alkyl.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein The compound is selected from: wherein X is selected from O, -C(=O)- or -NR x1 -; Y is selected from -CH2- or -C(=O)- or -NR y1 -; R x1 and R y1 Each independently selected from H or C 1-4 alkyl; M is selected from N or CH; Ring A is selected from C 3-8 Cycloalkyl or C 3-8 cycloalkenyl; R 1 is selected from H or halogen; a is selected from 0, 1, 2 or 3; R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Each is independently H; Or, R 2 、R 3 Together with the carbon atom it is connected to, it forms C 3-6 Cycloalkyl or C 2-4 alkenyl, and the C 3-6 Cycloalkyl or C 2-4 The alkenyl group may be optionally further substituted with one or more halogens; Or, R 4 、R 6 Together with the carbon atom it is connected to, it forms C 3-6 Cycloalkyl; Or, R 5 、R 7 Together with the carbon atom it is connected to, it forms C 3-6 Cycloalkyl; R 8 Selected from -NHSO2-R 8b , the R 8b C 1-4 Alkyl, and the C 1-4 The alkyl group is optionally further substituted with OH or halogen.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The X is selected from O, -C(=O)-, -N(CH3)-, -N(CH2CH3)-, -N(OCH3)- or -N(CHF2)-.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The Y is selected from -CH2-, -C(=O)-, -NH- or -N(CH3)-.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The M is selected from N or CH; preferably, M is N.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Said Q is selected from N or CH; preferably, Q is CH.

7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The R 1 is selected from H or F; a is selected from 0, 1, 2 or 3.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The structural unit Selected from 10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 11. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The R 2 、R 3 Together with the carbon atom it is connected to, it forms C 3-6 Cycloalkyl; R 4 、R 5 、R 6 and R 7 Each is independently H; Preferably, R 2 、R 3 Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

12. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The R 2 、R 3 Together with the carbon atom it is connected to, it forms C 2-4 alkenyl, and the C 2-4 The alkenyl group is optionally further substituted with one or more halogens; R 4 、R 5 、R 6 and R 7 Each is independently H; Preferably, R 2 、R 3 Together with the carbon atoms to which it is attached, 13. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The R 2 、R 3 、R 5 and R 7 Each is independently H; R 4 、R 6 The carbon atom connected to it can form C 3-6 Cycloalkyl; Preferably, R 4 、R 6 Together with the carbon atom to which it is attached, it forms a cyclopentyl group.

14. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The R 2 、R 3 、R 4 and R 6 Each is independently H; R 5 、R 7 The carbon atom connected to it can form C 3-6 Cycloalkyl; Preferably, R 5 、R 7 Together with the carbon atom to which it is attached, it forms a cyclopentyl group.

15. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The R 2 Selected from -CHF2 or -CF3; R 3 、R 4 、R 5 、R 6 and R 7 Each is independently H.

16. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 17. The compound according to any one of claims 1 to 16, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The R 8 Selected from 18. The compound according to any one of claims 1 to 17, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The R 9 Selected from H or F.

19. The compound according to any one of claims 1 to 18, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from: Among them, X, Y, ring A, R 1 、R 2 、R 3 、R 8 、R 9 and a as defined in any one of claims 1-18.

20. The compound according to any one of claims 1 to 19, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from: Among them, X, Y, ring A, R 1 、R 2 、R 3 、R 8 、R 9 and a as defined in any one of claims 1-19.

21. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein The compound is selected from: wherein X is selected from -N(CH3)-, -N(CH2CH3)-, -N(OCH3)- or -N(CHF2)-; Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl; R 1 is F; a is selected from 0, 1, 2 or 3; Structural unit Selected from R 8 Selected from R 9 Selected from H or F.

22. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

23. A pharmaceutical composition comprising the compound according to any one of claims 1 to 22, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. Use of the compound according to any one of claims 1 to 22, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 in the preparation of a medicament for treating a disease mediated by KIF18A.

25. The use according to claim 24, wherein The disease is a tumor.

26. The use according to claim 25, wherein The tumor is a chromosomally unstable tumor.

27. The use according to claim 25 or 26, wherein The tumor is selected from breast cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, head and neck cancer, gastric cancer, esophageal cancer or skin cancer.

28. The use according to claim 27, wherein The lung cancer is selected from lung squamous cell carcinoma, lung adenocarcinoma, large cell lung cancer or small cell lung cancer.

29. A method for treating or preventing a KIF18A-mediated disease, wherein: The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 22, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23; preferably, the tumor is a chromosomally unstable tumor; further preferably, the tumor is selected from breast cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, head and neck cancer, gastric cancer, esophageal cancer, or skin cancer.

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