KIF18A inhibitor compound, pharmaceutical composition, and method for producing the same and application thereof

Abstract

The present invention provides a compound represented by formula (I), a pharmaceutical composition, and methods for preparing and using the same. The compound has good KIF18A inhibitory activity and can regulate KIF18A protein either alone or by forming a binding complex with microtubules, thereby treating KIF18A-mediated disorders and / or diseases, such as neoplastic diseases, and can be used to prepare drugs for such disorders or diseases. [Formula 1] JPEG2025533411000090.jpg30169

Description

[Technical Field]

[0001] The present invention provides Priority of the earlier application filed with the State Intellectual Property Office of China on September 8, 2022, with patent application number 2022110982256 and title "KIF18A inhibitor compounds, pharmaceutical compositions and their preparation methods and applications"; Priority of the earlier application filed with the State Intellectual Property Office of China on November 16, 2022, with patent application number 2022114366075 and title "KIF18A inhibitor compounds, pharmaceutical compositions and their preparation methods and applications"; Priority of the earlier application filed with the State Intellectual Property Office of China on February 10, 2023, with patent application number 2023100987012 and title "KIF18A inhibitor compounds, pharmaceutical compositions, and their preparation methods and applications"; The company claims priority from a patent application filed with the State Intellectual Property Office of China on August 30, 2023, with the patent application number 2023111078615 and the title "KIF18A inhibitor compounds, pharmaceutical compositions, and their manufacturing methods and applications." The above prior application is incorporated herein by reference in its entirety.

[0002] The present invention relates to the pharmaceutical field, specifically to KIF18A inhibitor compounds, pharmaceutical compositions, and preparation methods and applications thereof. [Background technology]

[0003] Cancer is one of the most serious diseases that affect human health, and its mortality and morbidity rate always take the lead among various diseases.With the continuous development and progress of medical technology and drug development, the quality of life of some patients has been greatly improved, but there are still many unmet clinical needs in the approach to seek drugs that can effectively treat or cure different cancers, while more and more new targets provide new possibilities for future cancer drug development.

[0004] Cancer cells undergo uncontrolled cell proliferation due to damage or deletion of one or more genes that regulate the cell cycle. Various kinases and kinesins have been identified that play important roles in the regulation and progression of the cell cycle and mitosis in both normally dividing and cancer cells.

[0005] Kinesin molecules, also known as molecular motors, are dyneins that track intracellular microtubules. They can convert ATP energy into mechanical energy. In eukaryotic cells, they are closely related to cell mitosis and meiosis, tissue and organ growth, and neuronal growth and signal transduction. Kinesin members share a relatively conserved motor domain. Depending on the location of the motor domain within the molecule, the kinesin family is broadly classified into three types: N-type kinesins, which have one motor domain in the amino-terminal (-NH2) region of the protein polypeptide chain; M-type kinesins, which have one motor domain in the middle region; and C-type kinesins, which have one motor domain in the carboxyl-terminal (-COOH) region.

[0006] Chromosomal instability, a hallmark of cancer, is caused by chromosome segregation errors during mitosis. Targeting chromosomal instability is an emerging therapeutic strategy in drug development. KIF18A, a member of the N-type Kinesin-8 kinesin family, has been shown to help maintain bipolar spindle stability and promote the viability of chromosomally unstable cancer cells. Mitosis is an effective intervention point, and many antimitotic drugs are used clinically to treat human cancers. The most widely used tubulin inhibitors can either stabilize microtubules or prevent microtubule assembly. Currently, antimitotic drugs are limited by a relatively narrow therapeutic window, making it necessary to develop new targets to address these issues.

[0007] Although tubulin inhibitors are widely used as standard treatments for multiple human cancer types, these drugs cause collateral damage to normal cells, including myelosuppression and neurotoxicity. Because KIF18A may not be essential in normal diploid cells (KIF18A gene knockout mice are viable but have reproductive defects, indicating that KIF18A is not essential for normal somatic cell division), targeting KIF18A may significantly reduce its toxicity and be advantageous for improving the therapeutic safety window of tubulin-targeting drugs in the clinic.

[0008] The KIF18A protein is highly expressed in various tumors, including colon, breast, lung, pancreatic, prostate, bladder, head and neck, cervical, and ovarian cancers. KIF18A plays an important role in the development, progression, and metastasis of breast cancer, and its high expression predicts poor patient prognosis. KIF18A is required for the proliferation of chromosomally unstable cells derived from triple-negative breast or colorectal cancer, but diploid cells do not require KIF18A. KIF18A gene knockout causes infertility in male mice, but not in female mice. KIF18A mRNA expression is significantly associated with high tumor grade and large tumor size in breast cancer patients, and KIF18A is an independent predictor of breast cancer lymph node metastasis, with a risk factor of 3.2. Furthermore, inhibition of KIF18A expression not only affects the important function of KIF18A in cell mitosis, but also reduces the migration of cancer cells by stabilizing apical microtubules, ultimately leading to the inactivation of the PI3K-AKT signaling pathway and the induction of apoptosis.

[0009] Therefore, the development of a KIF18A protein inhibitor could be a new breakthrough in anticancer drugs. Summary of the Invention

[0010] In order to solve the above technical problems, the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope marker, solvate, polytype, pharmaceutically acceptable salt or prodrug compound thereof, [ka]

[0011] where A is unsubstituted or contains one, two or more R a and optionally substituted fused ring groups, wherein the fused ring groups are selected from saturated or partially unsaturated C 3-14 carbocycle, C 6-14 comprising two, three or four rings independently selected from an aryl ring, a 5- to 14-membered heteroaryl ring, and a 3- to 14-membered heterocycle;

[0012] Each R a are the same or different and may be H, OH, halogen, cyano group, NH2, NO2, unsubstituted or one, two or more R a1 the following groups optionally substituted with: 1-12 Alkyl group, C 1-12 Alkoxy group, C 3-12 cycloalkyl groups, or two R a together with the carbon atoms to which they are attached, form saturated or partially unsaturated C 3-14 Form a carbocyclic ring or two non-adjacent R a are linked together at their end groups to form C 1-3 and each R a1 are the same or different and are H, OH, halogen, cyano group, NH2, NO2, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 3-12 are independently selected from cycloalkyl groups,

[0013] E is unsubstituted or one, two or more R c the following groups optionally substituted with: -NH-S(=O)2-Rc1 , -S(=O)2-NH-R c2 , -S(=O)(=NH)-R e3 , -N(R e4 )(R e5 ), and a 3- to 14-membered heterocyclyl group, and each R e are the same or different and may be OH, halogen, cyano group, C 1-12 Alkyl group, C 1-12 Alkoxy group, halogenated C 1-12 Alkyl groups, halogenated C 1-12 Alkoxy group, cyano C 1-12 Alkyl group, cyano C 1-12 Alkoxy group, -N(R e6 )(R e7 ), selected independently from

[0014] Each R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 are the same or different, and H, C 1-12 Alkyl group, hydroxy C 1-12 Alkyl groups, halogenated C 1-12 Alkyl groups, halogenated C 1-12 Alkoxy group, cyano C 1-12 Alkyl group, cyano C 1-12 Alkoxy group, C 3-12 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 1-12 Alkoxy-C 1-12 are independently selected from alkyl groups,

[0015] M is unsubstituted or one, two or more R m C optionally substituted with 3-12 Cycloalkyl groups, C 3-12 cycloalkenyl groups or nitrogen-containing 3- to 14-membered heterocyclyl groups, and each R m are the same or different and may be H, halogen, cyano group, C 1-12 Alkyl groups, halogenated C 1-12Alkyl group, cyano C 1-12 Alkyl group, C 1-12 Alkoxy group, cyano C 1-12 or two R alkoxy groups independently selected from the group consisting of alkoxy groups and alkoxy groups linked to the same ring carbon atom. m together with the carbon atoms to which they are attached, form saturated or partially unsaturated C 3-14 forming a carbocyclic ring,

[0016] Y1, Y2, Y3 are the same or different and are independently selected from N or CH.

[0017] According to some embodiments, A is unsubstituted or contains one, two or more R a and optionally substituted fused ring groups, wherein the fused ring groups are selected from saturated or partially unsaturated C 3-8 carbocycle, C 6-10 Contains two, three or four rings independently selected from an aryl ring, a 5- to 10-membered heteroaryl ring and a 3- to 8-membered heterocycle;

[0018] Each R a are the same or different and are H, OH, halogen, cyano group, NH2, NO2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-8 Cycloalkyl groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, cyano C 1-6 Alkyl group, cyano C 1-6 Alkoxy group, C 3-8 Cycloalkyl-C 1-6 or two R alkoxy groups independently selected from the group consisting of alkoxy groups and alkoxy groups linked to the same ring carbon atom. a together with the carbon atoms to which they are attached, form saturated or partially unsaturated C 3-8 Form a carbocyclic ring or two non-adjacent R a are linked together at their end groups to form C 1-3 and forming an alkylene group of the formula:

[0019] According to some embodiments, A is unsubstituted or contains one, two or more R a wherein the fused ring group is selected from a fused ring group optionally substituted with [ka] is selected from

[0020] where T is CH2, CH, NH, NR a or O,

[0021] Z is CH2, CH, NH, NR a or O,

[0022] X is selected from N or CH;

[0023] p and q are independently selected from 0, 1, 2, and 3, and p and q cannot be 0 at the same time;

[0024] r and s are independently selected from 0, 1, 2, and 3, and r and s cannot be 0 at the same time.

[0025] According to some embodiments, A is unsubstituted or contains one, two or more R a wherein the fused ring group is selected from a fused ring group optionally substituted with [ka] is selected from

[0026] where Z is CH, CH, NH, NR a or O,

[0027] X is selected from N or CH;

[0028] r and s are independently selected from 0, 1, 2, and 3, and r and s cannot be 0 at the same time.

[0029] According to some embodiments, A is [ka] is selected from

[0030] where T is CH2, CH, NH, NR a or O,

[0031] Z is CH2, CH, NH, NR a or O,

[0032] X is selected from N or CH;

[0033] n is selected from 0, 1, 2, 3, 4 or 5;

[0034] p and q are independently selected from 0, 1, 2, and 3, and p and q cannot be 0 at the same time;

[0035] r and s are independently selected from 0, 1, 2, and 3, and r and s cannot be 0 at the same time.

[0036] According to some embodiments, A is unsubstituted or contains one, two or more R a The fused ring group is selected from a fused ring group optionally substituted with a benzene ring, a pyridine ring, an imidazole ring, a piperazine ring, a piperidine ring, a tetrahydropyrrole ring, a tetrahydropyran ring, a tetrahydrofuran ring, a furan ring, a morpholine ring, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, and a cycloheximine ring.

[0037] According to some embodiments, A is unsubstituted or contains one, two or more R a is optionally replaced by [ka] is selected from

[0038] According to some embodiments, each R a are the same or different and are independently selected from H, OH, F, Cl, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, and cyclopropylmethoxy, or two R linked to the same ring carbon atom. a together with the carbon atoms to which they are attached form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring, or two non-adjacent R a are linked at their end groups and together form a methylene or ethylene group.

[0039] According to some embodiments, A is [ka] JPEG2025533411000008.jpg244169 JPEG2025533411000009.jpg84169 is selected from.

[0040] According to some embodiments, E is unsubstituted or has one or two R c the following groups optionally substituted with: -NH-S(=O)2-R c1 , -S(=O)2-NH-R c2 , -S(=O)(=NH)-R c3 Each R c1 , R c2 , R c3 are the same or different, and H, C 1-6 Alkyl group, hydroxy C 1-6 Alkyl groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, cyano C 1-6 Alkyl group, cyano C1-6 Alkoxy group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 1-6 Alkoxy-C 1-6 alkyl groups, each R e are the same or different and may be OH, halogen, cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, cyano C 1-6 Alkyl group, cyano C 1-6 are independently selected from alkoxy groups.

[0041] According to some embodiments, E is [ka] is selected from.

[0042] According to some embodiments, M is unsubstituted or contains one, two or more R m C optionally substituted with 3-8 Cycloalkyl groups, C 3-8 a cycloalkenyl group or a nitrogen-containing 3- to 8-membered heterocyclyl group, and each R m are the same or different and may be H, halogen, cyano group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, cyano C 1-6 Alkyl group, C 1-6 Alkoxy group, cyano C 1-6 or two R alkoxy groups independently selected from the group consisting of alkoxy groups and alkoxy groups linked to the same ring carbon atom. m together with the carbon atoms to which they are attached, form saturated or partially unsaturated C 3-8 forming a carbocyclic ring,

[0043] According to some embodiments, M is [ka] is selected from.

[0044] According to some embodiments, Y1, Y2, Y3 cannot be N at the same time;

[0045] According to some embodiments, when Y1 is CH, Y2 is CH and Y3 is N or CH; when Y1 is CH, Y2 is N and Y3 is N or CH; when Y1 is N, Y2 is CH and Y3 is N or CH; when Y1 is N, Y2 is N and Y3 is CH.

[0046] According to some embodiments, the compound of formula (I) has the structure: [ka]

[0047] wherein A, M, E, Y1, Y2, and Y3, independently of one another, have the definitions set forth herein.

[0048] According to some embodiments, the compound of formula (I) has the structure: [ka]

[0049] where M, E, Y1, Y2, Y3, R a , X, Z, T, n, p, q, r, s independently have the definitions set forth herein.

[0050] According to some embodiments, the compound of formula (I) has the structure: [ka]

[0051] wherein A, Y1, Y2, and Y3 independently have the definitions described herein.

[0052] According to some embodiments, the compound of formula (I) has the structure: [ka]

[0053] where Y1, Y2, Y3, R a , X, Z, T, n, p, q, r, s independently have the definitions set forth herein.

[0054] According to some embodiments, the compound of formula (I) has the structure: [ka]

[0055] where Y1, Y2, Y3, R a , X, Z, n, r, s independently of each other have the definitions set forth herein.

[0056] According to some embodiments, the compound of formula (I) is [ka] JPEG2025533411000018.jpg208169 JPEG2025533411000019.jpg210169 JPEG2025533411000020.jpg217169 JPEG2025533411000021.jpg219169 JPEG2025533411000022.jpg212169 JPEG2025533411000023.jpg212169 JPEG2025533411000024.jpg228169 JPEG2025533411000025.jpg215169 JPEG2025533411000026.jpg224169 JPEG2025533411000027.jpg218169 JPEG2025533411000028.jpg164169 It has the following structure.

[0057] The present invention further provides a method for preparing a compound of formula (I), [ka] (1) reacting compound a with compound A-NH2 to obtain compound b; (2) reacting compound b with compound EH to obtain the compound of formula (I),

[0058] wherein A, E, M, Y1, Y2, Y3, independently of one another, have the definitions given above, and L is selected from halogen, for example Cl, Br, I.

[0059] The present invention further provides pharmaceutical compositions, which comprise a therapeutically effective amount of at least one of a compound of formula (I), its racemate, stereoisomer, tautomer, isotopic marker, solvate, polytype, pharmaceutically acceptable salt, or prodrug compound thereof.

[0060] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0061] According to embodiments of the present invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

[0062] The present invention further provides a method for treating a neoplastic disease, which comprises administering to a patient a prophylactically or therapeutically effective amount of at least one of a compound of formula (I), its racemate, stereoisomer, tautomer, isotopic marker, solvate, polytype, pharmaceutically acceptable salt or prodrug compound thereof.

[0063] The present invention further provides a method for treating a neoplastic disease, which comprises administering to a patient a prophylactically or therapeutically effective amount of the above-described pharmaceutical composition.

[0064] The neoplastic diseases include intestinal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer and ovarian cancer.

[0065] In some embodiments, the patient comprises a mammal, preferably a human.

[0066] The present invention further provides at least one of the compounds of formula (I), its racemates, stereoisomers, tautomers, isotopic markers, solvates, polytypes, pharmaceutically acceptable salts or prodrug compounds thereof, or pharmaceutical compositions thereof for treating tumor diseases.

[0067] The present invention further provides the use of at least one of the compounds of formula (I), its racemates, stereoisomers, tautomers, isotopic markers, solvates, polytypes, pharmaceutically acceptable salts or prodrug compounds thereof in the manufacture of a medicament.

[0068] According to an embodiment of the present invention, the use may be in the manufacture of a medicament for treating a KIF18A-mediated disorder and / or disease, for example, in the manufacture of a KIF18A inhibitor medicament.

[0069] According to an embodiment of the invention, the disease is cancer, including, for example, bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.

[0070] [Beneficial Effects] By optimizing the structure, the present invention has uniquely obtained a class of compounds with novel structures, which not only have good KIF18A inhibitory activity and in vitro cellular activity of OVCAR-3, but also have significantly improved physicochemical properties (solubility, permeability), significantly improved in vivo pharmacological activity of OVCAR-3, and high safety. Such compounds can be used for the treatment of KIF18A-mediated disorders and / or diseases, such as neoplastic diseases, and for the manufacture of drugs for treating such disorders or diseases.

[0071] [Definitions and explanations of terms] Unless otherwise stated, the radical and term definitions described in the specification and claims of this application, including their exemplary definitions, exemplary definitions, preferred definitions, definitions set forth in tables, definitions of specific compounds in the examples, etc., may be combined with each other in any combination, and it should be understood that such combined radical definitions and compound structures are within the scope of the description and / or claims of this application.

[0072] Unless otherwise specified, the numerical ranges described in this specification and claims are equivalent to at least describing each specific integer value. For example, the numerical range "1 to 14" is equivalent to describing each integer value in the numerical range "1 to 14," i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

[0073] The term "optionally" (or "optionally", "optionally") in the definition of the general formula of the present application means a situation where there is substitution with zero, one or more substituents, for example, "optionally substituted with one, two or more R" means that there may be no substitution with R (it may be unsubstituted), or there may be substituted with one, two or more R.

[0074] "More" means three or more than three.

[0075] "C 1-12The term "alkyl group" should be understood to represent straight and branched chain alkyl groups having 1 to 12 carbon atoms, and "C 1-8 "Alkyl group" refers to straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; 1-6 The term "alkyl group" refers to straight-chain and branched-chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, and 1,2-dimethylbutyl, and isomers thereof.

[0076] "C 3-12 The term "cycloalkyl group" should be understood to represent a saturated monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) hydrocarbon ring or tricyclic alkane, having 3 to 12 carbon atoms, preferably "C 3-10 cycloalkyl group," and more preferably, "C 3-8 "Cycloalkyl group". 3-12 The term "cycloalkyl group" should be understood to represent a saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring or tricyclic alkane, which has 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12The cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, or a cyclodecyl group; or a bicyclic hydrocarbon group such as a bornyl group, an indolyl group, a hexahydroindolyl group, a tetrahydronaphthyl group, a decahydronaphthyl group, a bicyclo[2.1.1]hexyl, a bicyclo[2.2.1]heptyl, a bicyclo[2.2.1]heptenyl, a 6,6-dimethylbicyclo[3.1.1]heptyl, a 2,6,6-trimethylbicyclo[3.1.1]heptyl, a bicyclo[2.2.2]octyl, a 2,7-diazaspiro[3.5]nonyl, a 2,6-diazaspiro[3,4]octanyl; or a tricyclic hydrocarbon group such as an adamantyl group.

[0077] "C 3-12 The term "cycloalkenyl group" should be understood to represent a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic alkene containing a carbon-carbon double bond, which has 3 to 12 carbon atoms, preferably "C 3-10 cycloalkenyl group," and more preferably, "C 3-8 A cycloalkenyl group is a "cycloalkenyl group," which may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 3-12 The cycloalkenyl group may be a monocyclic hydrocarbon group such as a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, a cyclononenyl group or a cyclodecenyl group, or a bicyclic hydrocarbon group such as spiro[2.5]oct-5-enyl, spiro[3.5]non-6-enyl or spiro[4.5]dec-7-enyl.

[0078] "C 6-14 It is to be understood that the term "aryl group" preferably denotes a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a monocyclic aromatic ring or polycyclic aromatic rings fused together, and preferably denotes a "C 6-10 "C" is an aryl group. 6-14The term "aryl group" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14 aryl groups"), in particular rings having 6 carbon atoms ("C6 aryl groups"), such as phenyl or biphenyl groups, or rings having 9 carbon atoms ("C9 aryl groups"), such as indanyl or indenyl groups, or rings having 10 carbon atoms ("C 10 aryl group"), such as a tetralinyl group, a dihydronaphthyl group or a naphthyl group, or a ring having 13 carbon atoms ("C 13 aryl group), such as a fluorenyl group, or a ring having 14 carbon atoms ("C 14 It should be understood that it is preferable that the C represents an aryl group, for example, an anthryl group. 6-20 When substituted, the aryl group may be mono- or polysubstituted, and there is no limitation on the substitution site, for example, it may be ortho-, para-, or meta-substituted.

[0079] A "5- to 14-membered heteroaryl group" should be understood to include a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring system containing 5 to 14 ring atoms and 1 to 5 heteroatoms independently selected from N, O and S, such as a "5- to 10-membered heteroaryl group." The term "5- to 14-membered heteroaryl group" should be understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and which in each case may be benzo-fused. A "heteroaryl group" also refers to a group in which the heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, where the base or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl groups, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl groups, 2-, 3-, 4-, 5-, 6- or 7-indolyl groups, 2-, 3-, 4-, 5-, 6- or 7-indazolyl groups, 2-, 4-, 5-, 6-, 7- or 8-purinyl groups, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolidinyl group, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl group, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl group, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl group, 2-, 3-, 4-, 5- or 6-naphthyridinyl group, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3- , 4-, 5-, 6-, 7-, 8- or 9-carbolinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl group, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl group, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-dinyl group, 2-, 3-, 4-, 5-, 6-, 8-,9- or 10-phenanthrolinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl group, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl group, 2-, 3-, 4- or thieno[2,3-b]furanyl group, pyranyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-azinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]azolyl, 2-, 4- or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3 -d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoazolyl group, 2-, These include 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoazinyl, and 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups are 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl and 2-, 4-, 5-,Examples of the 5- to 14-membered heteroaryl group include, but are not limited to, a 6- or 7-benzothiazolyl group. When the 5- to 14-membered heteroaryl group is linked to another group to form the compound of the present invention, a carbon atom in the 5- to 14-membered heteroaryl ring may be linked to the other group, or a heteroatom in the 5- to 14-membered heteroaryl ring may be linked to the other group. When the 5- to 14-membered heteroaryl group is substituted, it may be mono- or polysubstituted. There is no limitation on the substitution site; for example, a hydrogen atom linked to a carbon atom in the heteroaryl ring may be substituted, or a hydrogen atom linked to a heteroatom in the heteroaryl ring may be substituted.

[0080] Unless otherwise defined, the term "3- to 14-membered heterocyclyl group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (e.g., fused, bridged, spirocyclic ring), or a 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and containing at least one, e.g., 1, 2, 3, 4, 5, or more, heteroatoms selected from O, S, and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)-, or -S(O)2-. Preferably, the heterocyclyl group may be selected from "3- to 10-membered heterocyclyl groups." The term "3- to 10-membered heterocyclyl group" is intended to refer to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclyl group can be linked to the rest of the molecule through any one of the carbon atoms or, if present, a nitrogen atom. The heterocyclyl group may include fused or bridged rings and spiro rings. In particular, the heterocyclyl group may include, but is not limited to, a 4-membered ring such as an azetidinyl group or an oxetanyl group, a 5-membered ring such as a tetrahydrofuranyl group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a pyrrolinyl group, a 6-membered ring such as a tetrahydropyranyl group, a piperidine group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, or a trithianyl group, or a 7-membered ring such as a diazepanyl group. Optionally, the heterocyclyl group may be benzo-fused.The heterocyclyl group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclyl group may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. When the 3- to 14-membered heterocyclyl group is linked to another group to form the compound of the present invention, a carbon atom in the 3- to 14-membered heterocyclyl group may be linked to the other group, or a heterocyclic atom in the 3- to 14-membered heterocyclyl ring may be linked to the other group. For example, when the 3- to 14-membered heterocyclyl group is selected from a piperazinyl group, a nitrogen atom in the piperazinyl group may be linked to the other group. Or, when the 3- to 14-membered heterocyclyl group is selected from a piperidine group, a nitrogen atom in the piperidine ring and a carbon atom at the para-position thereof may be linked to the other group.

[0081] The term "spirocycle" refers to a ring system in which two rings share one ring-forming atom.

[0082] The term "fused ring" refers to a ring system in which two rings share two ring-forming atoms.

[0083] The term "bridged ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0084] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0085] "Halogenated" refers to substitution with one or more halogens.

[0086] Unless otherwise stated, R a is a substituent on the fused ring group A, i.e., R a represents that the fused ring group A can be optionally substituted at any position, for example, [ka] is R a The ring [ka] represents that the N-containing heterocycle on the left side of R a The ring [ka] represents that the X-containing ring on the right side of R a The total number of substitutions in the fused ring group A is n.

[0087] Unless otherwise stated, the definitions of terms in this specification also apply to groups which contain said terms, e.g., C 1-12 The definition of an alkyl group is C 1-12 Alkyloxy groups (i.e., C 1-12 This also applies to alkoxy groups.

[0088] The term "alkylene group" refers to a divalent group, wherein the group is as defined below, for example, the term "alkylene group" refers to a divalent alkyl group, wherein the alkyl group is as defined below, and the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene groups), more preferably alkylene groups containing 1 to 6 carbon atoms (i.e., C 1-6 alkylene group).

[0089] "C 3-14 The term "carbocycle" refers to a saturated or unsaturated aliphatic hydrocarbon ring having 3 to 14 carbon atoms, and includes cycloalkane rings (C3-14 Cycloalkane ring), cycloalkene ring of 3 to 14 carbon atoms (C 3-12 Cycloalkene ring) or cycloalkyne ring (C 3-12 Contains a cycloalkyne ring.

[0090] As will be appreciated by those skilled in the art, the compounds of formula (I) can exist in a variety of pharmaceutically acceptable salt forms: if they contain a basic center, they can form acid addition salts; if they contain an acidic center, they can form base addition salts; and if they contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0091] The compounds of the present invention can exist in the form of solvates (e.g., hydrates), in which the compounds of the present invention contain a polar solvent, in particular, for example, water, methanol, or ethanol, as a component of the compound's crystal lattice. The amount of polar solvent, in particular water, can be present in a stoichiometric or non-stoichiometric ratio.

[0092] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Therefore, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be isolated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or can be used in synthesis in such forms. In the case of racemic amines, diastereomers were prepared from the mixture by reacting with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can be advantageously carried out with optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives, or chiral derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are water or alcohol-containing solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0093] The corresponding stable isomers can be separated according to known methods, such as extraction, filtration or column chromatography.

[0094] The term "patient" refers to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse or primate, and most preferably a human.

[0095] The term "therapeutically effective amount" refers to an amount of an active compound or drug that elicits the biological or medical response a researcher, veterinarian, physician, or other clinician is looking for in a tissue, system, animal, individual, or human, including one or more of the following: (1) prevention of disease: e.g., preventing a disease, disorder, or disorder in an individual who is susceptible to the disease, disorder, or disorder but has not yet experienced or developed the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibiting a disease, disorder, or disorder (i.e., preventing further progression of the pathology and / or symptoms) in an individual who is experiencing or has developed the pathology or symptoms of the disease, disorder, or disorder; or (3) amelioration of disease: e.g., ameliorating a disease, disorder, or disorder (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or has developed the pathology or symptoms of the disease, disorder, or disorder. DETAILED DESCRIPTION OF THE INVENTION

[0096] The following provides a more detailed description of the technical solutions of the present invention through specific examples. It should be understood that the following examples are merely for illustrative purposes and are not intended to limit the scope of protection of the present invention. Any technology realized based on the above content of the present invention is included within the intended scope of protection of the present invention.

[0097] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0098] Example 1 2-{6-azaspiro[2.5]octan-6-yl}-4-(2-hydroxyethanesulfonamido)-N-(6-methoxynaphthalen-1-yl)benzamide (Compound 1) [ka]

[0099] Step 1. Synthesis of 6-methoxynaphthalen-1-amine (compound 1-2):

[0100] Hydroxylamine hydrochloride (206.2 mg, 2.967 mmol, 1.5 eq) was added to a solution of 6-methoxynaphthalene-1-carboxylic acid (400 mg, 1.978 mmol, 1 eq) in polyphosphoric acid (2 mL) under nitrogen gas protection at room temperature and stirred at 80°C for 2 hours. The reaction mixture was quenched with ice water (30 mL) at 0°C. The aqueous phase was extracted with ethyl acetate (1 × 50 mL). The aqueous phase was then alkalized to pH ~9 with solid sodium hydroxide and extracted with ethyl acetate (3 × 100 mL). The combined organic phase was backwashed with saturated brine (1 × 50 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give 6-methoxynaphthalen-1-amine (compound 1-2, 300 mg, 87.55%). MS (ESI, m / z): 174.35 [M+H] + ,RT(min):0.760

[0101] Step 2. Synthesis of 2-{6-azaspiro[2.5]octan-6-yl}-4-iodo-N-(6-methoxynaphthalen-1-yl)benzamide (compound 1-4):

[0102] A solution of 6-methoxynaphthalen-1-amine (150 mg, 0.866 mmol, 1 eq) in dichloromethane (3 mL) was added with 2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzoic acid (463.98 mg, 1.299 mmol, 1.5 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (971.9 mg, 3.464 mmol, 4 eq), and 1-methylimidazole (711.02 mg, 8.660 mmol, 10 eq) under nitrogen gas protection at room temperature. The reaction mixture was stirred for 2 h and the desired product was detected by liquid chromatography-mass spectrometry. The reaction mixture was quenched with water (50 mL) at room temperature and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was backwashed with saturated brine (1 × 50 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:1) to give 2-{6-azaspiro[2.5]octan-6-yl}-4-iodo-N-(6-methoxynaphthalen-1-yl)benzamide (compound 1-4, 300 mg, 67.61%). MS (ESI, m / z): 513.35 [M+H] + ,RT(min):1.499

[0103] Step 3: Synthesis of 2-{6-azaspiro[2.5]octan-6-yl}-4-(2-hydroxyethanesulfonamido)-N-(6-methoxynaphthalen-1-yl)benzamide (Compound 1)

[0104] A solution of 2-{6-azaspiro[2.5]octan-6-yl}-4-iodo-N-(6-methoxynaphthalen-1-yl)benzamide (80 mg, 0.156 mmol, 1 eq) in N,N-dimethylformamide (0.5 mL) was added with 2-hydroxyethanesulfonamide (23.45 mg, 0.187 mmol, 1.2 eq), cuprous iodide (7.43 mg, 0.039 mmol, 0.25 eq), potassium carbonate (64.73 mg, 0.468 mmol, 3 eq), and sarcosine (5.56 mg, 0.062 mmol, 0.4 eq) under nitrogen gas protection at 120°C overnight. The mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance liquid chromatography under the following conditions (chromatographic column specifications: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate); mobile phase B: acetonitrile (0.1% diethylamine) - HPLC - merck; flow rate: 60 mL / min; elution gradient: 40% B to 58% B, 10 min, 58% B; detection wavelength: UV 220 nm; retention time (min): 8.23) to obtain 2-{6-azaspiro[2.5]octan-6-yl}-4-(2-hydroxyethanesulfonamido)-N-(6-methoxynaphthalen-1-yl)benzamide (compound 1, 30.32 mg, 38.11%). MS (ESI, m / z): 509.90 [M+H] + ,RT(min):1.572 1H NMR: (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.12 (s, 1H), 8.07 (d, 1H), 8.03 - 7.98 (m, 1H), 7.94 (d, 1H), 7.66 (d, 1H), 7.49 (t, 1H), 7.39 (d, 1H), 7.26 (d, 1H), 7.22 - 7.16 (m, 1H), 7.13 - 7.03 (m, 1H), 4.96 (s, 1H), 3.90 (s, 3H), 3.78 (t, 2H), 3.36 (t, 2H), 3.15 - 2.96 (m, 4H), 1.42 (s, 4H), 0.26 (s, 4H).

[0105] Using conditions similar to those in Example 1, the compounds in the following table were prepared.

[0106] [Table 1] JPEG2025533411000035.jpg239169 JPEG2025533411000036.jpg58169

[0107] Example 2 2-{6-azaspiro[2.5]octan-6-yl}-4-(2-hydroxyethanesulfonamido)-N-(6-methoxynaphthalen-1-yl)benzamide (Compound 21) [ka]

[0108] Step 1. Synthesis of 4-(4-bromo-1H-benzimidazol-2-yl)butan-1-ol (compound 21-3):

[0109] A solution of 3-bromobenzene-1,2-diamine (2 g, 10.693 mmol, 1 eq) and δ-valerolactone (4.28 g, 42.772 mmol, 4 eq) in hydrochloric acid (4 M, 20 mL) was stirred under nitrogen gas protection and at 100°C for 2 hours. The reaction mixture was cooled to room temperature, and the mixture was alkalized to pH = 11 with saturated aqueous potassium carbonate. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were backwashed with saturated brine (2 × 50 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was used directly without further purification. MS(ESI, m / z): 269.20 [M+H] + ,RT(min):0.527

[0110] Step 2: Synthesis of 9-bromo-benzo[4,5]imidazo[1,2-a]piperidine (compound 21-4):

[0111] Under nitrogen gas protection and an ice bath, di-t-butyl diazenedicarboxylate (2.57 g, 11.146 mmol, 1.5 eq) was added dropwise to a solution of 4-(4-bromo-1H-1,3-benzodiazol-2-yl)butan-1-ol (2 g, 7.431 mmol, 1 eq) and triphenylphosphine (2.92 g, 11.146 mmol, 1.5 eq) in toluene (20 mL). The reaction mixture was warmed to 85°C and stirred overnight. The reaction mixture was quenched by adding water (60 mL) at room temperature. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phase was backwashed with saturated brine (2 × 80 mL) and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography in dichloromethane / methanol (10:1) to give 9-bromo-benzo[4,5]imidazo[1,2-a]piperidine (compound 21-4, 1 g, 53.59%). MS(ESI, m / z): 250.90 [M+H] + ,RT(min):0.746

[0112] Step 3 Synthesis of t-butyl benzo[4,5]imidazo[1,2-a]piperidin-9-ylcarbamate (compound 21-6):

[0113] A solution of 9-bromo-benzo[4,5]imidazo[1,2-a]piperidine (500 mg, 1.991 mmol, 1 eq) and t-butyl carbamate (466.49 mg, 3.982 mmol, 2 eq) in 1,4-dioxane (5 mL) was added with dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (159.72 mg, 0.299 mmol, 0.15 eq), (bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (106.48 mg, 0.299 mmol, 0.15 eq) at room temperature under nitrogen gas protection. To the mixture was added 1,2-dimethyl-3-(2,4-dimethyl-2,6-dimethyl-1,6 ... MS(ESI, m / z): 288.40 [M+H] + ,RT(min):0.728

[0114] Step 4. Synthesis of benzo[4,5]imidazo[1,2-a]piperidin-9-amine (compound 21-7):

[0115] Under nitrogen gas protection, a solution of t-butyl benzo[4,5]imidazo[1,2-a]piperidin-9-ylcarbamate (400 mg, 1.392 mmol, 1 eq) in dichloromethane (4 mL) was added to a solution of 1,4-dioxane hydrochloric acid (4 mL) at room temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The desired product was detected by liquid chromatography-mass spectrometry. The resulting residue was concentrated under reduced pressure. The resulting mixture was used directly without further purification. MS(ESI, m / z): 188.05 [M+H] + ,RT(min):0.602

[0116] Step 5 Synthesis of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-9-yl)benzamide (compound 21-9):

[0117] Under nitrogen gas protection, potassium phosphate (340.08 mg, 1.602 mmol, 3 eq) was added to a solution of benzo[4,5]imidazo[1,2-a]piperidin-9-amine (240.73 mg, 0.641 mmol, 1.2 eq) in dichloromethane (2 mL) at room temperature. The mixture was stirred for 1 minute, followed by a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (100 mg, 0.534 mmol, 1 eq) and N,N-diisopropylethylamine (207.08 mg, 1.602 mmol, 3 eq) in dichloromethane (1 mL) at room temperature. The reaction mixture was allowed to react for 2 hours at room temperature. The reaction mixture was quenched with water (20 mL) at room temperature. The reaction mixture was extracted with dichloromethane (3 × 20 mL). The organic layers were combined, backwashed with saturated brine (1 × 30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was used directly without further purification. MS(ESI, m / z): 526.80 [M+H] + ,RT(min):1.178

[0118] Step 6. Synthesis of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-9-yl)benzamide (compound 21):

[0119] Under nitrogen gas protection, a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-9-yl)benzamide (80 mg, 0.152 mmol, 1 eq) in N,N-dimethylformamide (2 mL) was added at room temperature with 2-hydroxyethanesulfonamide (28.53 mg, 0.228 mmol, 1.5 eq), potassium carbonate (63.01 mg, 0.456 mmol, 3 eq), cuprous iodide (2.89 mg, 0.015 mmol, 0.1 eq), and 2-(methylamino)acetic acid (2.71 mg, 0.030 mmol, 0.2 eq). After the addition was complete, the mixture was stirred at 120 °C for 2 h. The reaction mixture was then allowed to cool to room temperature. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were backwashed with saturated brine (1 × 10 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: Kinetex EVO C18 Column, 30*150, 5 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: 10% B to 50% B, 8 min, 50% B, detection wavelength: UV 220 nm, retention time (min): 7.47) to give 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-9-yl)benzamide (Compound 21, 14.1 mg, 17.63%). MS(ESI, m / z): 523.85 [M+H] + ,RT(min):1.157 1 H NMR: (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 10.09 (s, 1H), 7.87 (d, 1H), 7.46 (s, 1H), 7.25 - 7.12 (m, 2H), 7.09 - 6.99 (m, 2H), 4.97 (s, 1H), 4.21 (t, 2H), 3.77 (t, 2H), 3.36 - 3.32 (m, 2H), 3.04 (t, 4H), 2.96 (s, 2H), 1.93 (d, 2H), 1.87 (s, 2H), 1.52 (t, 4H), 0.34 (s, 4H).

[0120] Example 3 4-(2-Hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-6-yl)benzamide (Compound 22) [ka]

[0121] Step 1 Synthesis of (Z)-N-(2,6-dibromophenyl)piperidin-2-imine (compound 22-3):

[0122] Under nitrogen gas protection, phosphoryl chloride (611.03 mg, 3.985 mmol, 1 eq) was added to a toluene solution of 2-piperidone (790.15 mg, 7.971 mmol, 2.0 eq) at 0°C. The reaction mixture was stirred at 0°C for 2 hours, followed by the addition of 2,6-dibromoaniline (1 g, 3.985 mmol, 1 eq) and the reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature. The resulting residue was concentrated under reduced pressure and quenched by the addition of water (50 mL) at 0°C. The reaction mixture was alkalized to pH 10 with sodium hydroxide. The aqueous phase was extracted with dichloromethane (3 × 50 mL), and the combined organic phases were backwashed with saturated brine (1 × 80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude material was recrystallized from dichloromethane / petroleum ether (1:100) to give (Z)-N-(2,6-dibromophenyl)piperidin-2-imine (compound 22-3, 900 mg, 68.01%) as a white solid. MS(ESI, m / z): 332.75 [M+H] + ,RT(min):0.731

[0123] Step 2: Synthesis of 6-bromo-benzo[4,5]imidazo[1,2-a]piperidine (compound 22-4):

[0124] Under nitrogen atmosphere, a solution of (Z)-N-(2,6-dibromophenyl)piperidin-2-imine (850 mg, 2.560 mmol, 1 eq) in acetonitrile (10 mL) was added with cuprous iodide (1.43 mg, 0.008 mmol, 0.05 eq), potassium carbonate (20.81 mg, 0.151 mmol, 1 eq), and N,N-dimethylethylenediamine (1.33 mg, 0.015 mmol, 0.1 eq) at room temperature. The reaction mixture was stirred at 100°C for 2 hours. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was backwashed with saturated brine (2 × 40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (6:1) to give 6-bromo-benzo[4,5]imidazo[1,2-a]piperidine (compound 22-4, 360 mg, 56.00%). MS(ESI, m / z): 250.85 [M+H] + ,RT(min):0.646

[0125] Step 3 Synthesis of t-butyl (benzo[4,5]imidazo[1,2-a]piperidin-6-yl)carbamate (compound 22-5):

[0126] Under nitrogen gas, a solution of 6-bromo-benzo[4,5]imidazo[1,2-a]piperidine (500 mg, 1.991 mmol, 1 eq) in N,N-dimethylformamide (15 mL) was added with cesium carbonate (1946.14 mg, 5.973 mmol, 3 eq), t-butyl carbamate (466.49 mg, 3.982 mmol, 2 eq), and (bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (182.78 mg, 0.199 mmol, 0.1 eq) and dicyclohexyl(3-ethylpropoxy-2',4',6'-triisopropyl-[1,1'-diphenyl]-2-yl)phosphine, dicyclohexyl(3-isopropyl-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (212.96 mg, 0.398 mmol, 0.2 eq) were added, and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and the reaction mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and backwashed with saturated brine (1 × 20 mL). The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) to give t-butyl (benzo[4,5]imidazo[1,2-a]piperidin-6-yl)carbamate (Compound 22-5, 490 mg, 85.64%). MS (ESI, m / z): 288.35 [M+H] + , RT(min):0.768

[0127] Step 4. Synthesis of benzo[4,5]imidazo[1,2-a]piperidin-6-amine (compound 22-6):

[0128] Under nitrogen gas protection, a solution of t-butyl (benzo[4,5]imidazo[1,2-a]piperidin-6-yl)carbamate (400 mg, 1.392 mmol, 1 eq) in dichloromethane (5 mL) was dissolved in 1,4-dioxane (5 mL) and stirred for 1 hour. The resulting residue was concentrated under reduced pressure to give crude benzo[4,5]imidazo[1,2-a]piperidin-6-amine, which was directly used in the next step without further purification. MS (ESI, m / z): 188.35 [M+H] + ,RT(min):0.450

[0129] Step 5. Synthesis of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-6-yl)benzamide (compound 22-7):

[0130] Under nitrogen gas, a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (629.51 mg, 1.763 mmol, 1.5 eq) in dichloromethane (8 mL) was added to sulfinyl chloride (279.54 mg, 2.350 mmol, 2 eq), and the reaction mixture was stirred at room temperature for 1 hour. The resulting residue was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (4 mL). Potassium phosphate (498.79 mg, 2.350 mmol, 2 eq) was added to the above system at room temperature and stirred for 5 minutes. A dichloromethane solution (4 mL) of benzo[4,5]imidazo[1,2-a]piperidin-6-amine (20 mg, 0.107 mmol, 1 eq) and N,N-diisopropylethylamine (455.57 mg, 3.525 mmol, 3 eq) was then added to the above system. After the addition was complete, the system was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding water (20 mL), and the reaction mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, backwashed with saturated brine (1 × 20 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:1) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-6-yl)benzamide (compound 22-7, 530 mg, 85.69%). MS (ESI, m / z): 527.35 [M+H] + ,RT(min):1.078

[0131] Step 6. Synthesis of 4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-6-yl)benzamide (compound 22):

[0132] Under nitrogen gas, a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-6-yl)benzamide (100 mg, 0.190 mmol, 1 eq) in N,N-dimethylformamide (2 mL) was added with cuprous iodide (3.62 mg, 0.019 mmol, 0.1 eq), sarcosine (3.39 mg, 0.038 mmol, 0.2 eq), potassium carbonate (78.76 mg, 0.570 mmol, 3 eq), and 2-hydroxyethanesulfonamide (47.54 mg, 0.380 mmol, 2 eq) at room temperature in N,N-dimethylformamide, and the reaction mixture was stirred at 120°C for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were backwashed with saturated brine (1 × 10 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (chromatographic column specifications: Xselect CSH C18 OBD Column 30*150 mm 5 μm, n; mobile phase A: water (0.1% formic acid); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 10% B to 37% B, 10 min, 37% B; detection wavelength: 220 nm; retention time (min): 9.03; run number: 0). 4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-6-yl)benzamide (compound 22, 30.7 mg, 27.69%) was obtained. MS (ESI, m / z): 523.90 [M+H] + ,RT(min):1.530 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.14 (s, 1H), 8.33 (d, 1H), 8.04 (d, 1H), 7.27 (d, 1H), 7.21 - 7.13 (m, 2H), 7.09 (dd, 1H), 4.93 (d, 1H), 4.13 (t, 2H), 3.76 (q, 2H), 3.32 (s, 2H), 3.00 (q, 6H), 2.11 - 2.03 (m, 2H), 2.02 - 1.92 (m, 2H), 1.83 (s, 4H), 0.31 (s, 4H).

[0133] Example 4 N-(2,3-Dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 36) [ka]

[0134] Step 1 Synthesis of (2Z)-N-(2,6-dibromophenyl)pyrrolidin-2-imine (compound 36-2):

[0135] Under nitrogen gas protection, o In C, phosphoryl chloride (1.22 g, 85.106 mmol, 2 eq) was added to a solution of pyrrolidone (1.36 g, 15.942 mmol, 2 eq) in toluene (10 mL), and the reaction mixture was cooled to 0°C. o C for 2 hours, and then 2,6-dibromoaniline (2 g, 7.971 mmol, 1 eq) was added. oThe mixture was heated to 10°C and stirred for 16 hours. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, quenched with ice water (50 mL), adjusted to pH 10 with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 × 50 mL), and the combined organic phases were backwashed with saturated brine (1 × 50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified on a preparative chromatography plate using ethyl acetate / petroleum ether (1:10) to give (2Z)-N-(2,6-dibromophenyl)pyrrolidin-2-imine (2.7 g, 27.65%). MS (ESI, m / z): 317.10 [M+H] + , RT(min):0.919

[0136] Step 2 Synthesis of 5-bromo-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (compound 36-3):

[0137] Under nitrogen gas protection, N,N'-dimethyl-1,2-ethylenediamine (74.84 mg, 0.849 mmol, 0.10 eq), cuprous iodide (80.85 mg, 0.425 mmol, 0.05 eq), and potassium carbonate (1.17 g, 8.490 mmol, 1 eq) were added to a solution of (2Z)-N-(2,6-dibromophenyl)pyrrolidin-2-imine (2.7 g, 8.490 mmol, 1 eq) in acetonitrile (3 mL) at room temperature. o The mixture was warmed to 0°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, quenched by the addition of water (80 mL), and extracted with ethyl acetate (3 × 60 mL). The organic layers were combined, backwashed with saturated brine (1 × 80 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 5-bromo-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (2 g, 74.07%). MS (ESI, m / z): 237.15 [M+H] + , RT(min):0.657

[0138] Step 3 Synthesis of t-butyl (2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)carbamate (compound 36-5):

[0139] Under nitrogen gas protection, a solution of 5-bromo-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (2 g, 8.436 mmol, 1 eq), t-butyl carbamate (1.99 g, 16.87 mmol, 2 eq) in N,N-dimethylformamide (10 mL) was added with dicyclohexyl(3-isopropyl-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (451.12 mg, 0.844 mmol, 0.1 eq), (bicycloethyl(3-isopropyl-2,4,6-triisopropyl-(1,1-biphenyl)-2-yl)phosphine})(2-methylamino-1,1-biphenyl-2-yl)palladium(II) (1.549 g, 1.688 mmol), and 2-methylamino-1,1-biphenyl-2-yl)palladium(II) (1.549 g, 1.688 mmol) at room temperature. The reaction mixture was added with 100 mL of cesium carbonate (8.245 g, 25.308 mmol, 0.2 eq) and cesium carbonate (8.245 g, 25.308 mmol, 3 eq). o The temperature was raised to 0°C and the reaction was stirred for 1 hour. The reaction was cooled to room temperature and quenched by the addition of water (80 mL). The mixture was extracted with ethyl acetate (3 × 60 mL). The organic phases were combined, backwashed with saturated brine (1 × 80 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified on a preparative chromatography plate using ethyl acetate / petroleum ether (1:5) to give tert-butyl (2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)carbamate (700 mg, 35.77%). MS (ESI, m / z): 274.35 [M+H] + , RT(min):0.592

[0140] Step 4 2. Synthesis of 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (compound 36-6):

[0141] A reaction mixture of (2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl) t-butyl carbamate (300 mg, 1.098 mmol, 1 eq), hydrochloric acid in 1,4-dioxane (2 mL), and dichloromethanol (2 mL) was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure to give 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (300 mg, 57.87%), which was carried on directly to the next step. MS (ESI, m / z): 174.35 [M+H] + , RT(min):0.602

[0142] Step 5. Synthesis of 2-{6-azaspiro[2.5]octan-6-yl}-N-{2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl}-4-iodobenzamide (compound 36-7):

[0143] A solution of 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (250 mg, 1.443 mmol, 1 eq) and 2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzoic acid (618.62 mg, 1.732 mmol, 1.2 eq) in dichloromethane (5 mL) was added with tetramethylformamidinium hexafluorophosphate (1.62 g, 5.772 mmol, 4 eq) and N-methylimidazole (1.18 g, 14.430 mmol, 10 eq) under nitrogen gas protection at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was backwashed with saturated brine (1 × 20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative chromatography (ethyl acetate:petroleum ether = 1:5) to give 2-{6-azaspiro[2.5]octan-6-yl}-N-{2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl}-4-iodobenzamide (100 mg, 40.00%). MS (ESI, m / z): 513.35 [M+H] + , RT(min):1.406

[0144] Step 6. Synthesis of N-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 36):

[0145] Under nitrogen gas protection, sarcosine (2.09 mg, 0.023 mmol, 0.2 eq), cuprous iodide (2.23 mg, 0.012 mmol, 0.1 eq), and potassium carbonate (48.55 mg, 0.351 mmol, 3 eq) were added to a solution of N-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (60 mg, 0.117 mmol, 1 eq) and 2-hydroxyethanesulfonamide (17.58 mg, 0.140 mmol, 1.2 eq) in N,N-dimethylformamide (2 mL) at room temperature. oThe temperature was raised to 0°C, and the reaction mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature, quenched by adding water, and the reaction mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated brine solution (1 × 10 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative high pressure liquid chromatography under the following conditions: chromatography column specifications: Kinetex EVO C18 chromatography column, 30*150, 5 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: 30% B to 65% B, 8 min, 60% B, detection wavelength: UV 220 nm, retention time (min): 6.12 to obtain N-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (4.22 mg, 6.60%). MS (ESI, m / z): 510.15 [M+H] + , RT(min):1.143 1 H NMR: (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 10.14 (s, 1H), 8.30 (dd, 1H), 8.01 (d, 1H), 7.25 (d, 1H), 7.19 - 7.10 (m, 2H), 7.09 - 7.04 (m, 1H), 4.96 (s, 1H),4.15 (t, 2H), 3.76 (t, 2H), 3.36 (d, 2H), 2.97 (dt, 6H), 2.67 (q, 2H), 1.78 (s, 4H), 0.30 (s, 4H).

[0146] Using conditions similar to those in Example 4, the compounds in the following table were prepared.

[0147] [Table 2]

[0148] Example 5 2-{6-Azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-5'-yl}-4-(2-hydroxyethanesulfonamido)benzamide (Compound 51) [ka]

[0149] Step 1. Synthesis of 5'-bromo-3',4'-dihydrospiro[cyclopentane-1,2'-naphthalen]-1'-one (compound 51-3):

[0150] Under nitrogen gas protection, o C. Sodium hydride (0.71 g, 29.586 mmol, 3.33 eq) was added to a solution of 5-bromo-3,4-dihydro-2H-naphthalen-1-one (2 g, 8.886 mmol, 1 eq) in tetrahydrofuran (20 mL). The mixture was stirred for 1 hour, and then 0 o 1,4-Diiodobutane (4.13 g, 13.329 mmol, 1.5 e) was added dropwise at C. The reaction mixture was warmed to room temperature and stirred for 16 hours. At room temperature, the reaction mixture was quenched with ice water. The reaction mixture was extracted with ethyl acetate (3 × 80 mL). The combined organic phases were backwashed with saturated brine solution (1 × 100 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1) to give 5'-bromo-3',4'-dihydrospiro[cyclopentane-1,2'-naphthalen]-1'-one (2.37 g, 80.56%). MS: (ESI, m / z): 278.55 [M+H] + , RT(min):1.325

[0151] Step 2 Synthesis of 5'-bromo-3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene] (compound 51-4):

[0152] Under nitrogen gas protection, o C. Triethylsilane (5.0 mL, 30.94 mmol, 4.35 eq) was added to a solution of 5'-bromo-3',4'-dihydrospiro[cyclopentane-1,2'-naphthalen]-1'-one (2 g, 7.11 mmol, 1 eq) in trifluoroacetic acid (15 mL), and the reaction mixture was stirred for 50 minutes. o The mixture was heated to 10°C and stirred for 1 hour. The reaction mixture was cooled to room temperature, and the reaction mixture was extracted with ethyl acetate (3 × 80 mL). The organic phases were combined, backwashed with saturated brine solution (1 × 80 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1) to give 5'-bromo-3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene] (1.43 g, 64.18%). MS (EI, m / z): 264.1 [M], RT(min):8.694

[0153] Step 3 Synthesis of t-butyl {3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-5'-yl}carbamate (compound 51-5):

[0154] Under nitrogen gas protection, cesium carbonate (3.7 g, 12.75 mmol, 3 eq), palladium acetate (84.5 mg, 0.35 mmol, 0.1 eq), and 2-bicyclohexylphosphine-2,4,6-triisopropylbiphenyl (359.5 mg, 0.75 mmol, 0.2 eq) were added to a solution of 5'-bromo-3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene] (1 g, 3.75 mmol, 1 eq) and t-butyl carbamate (883.5 mg, 7.5 mmol, 2 eq) in 1,4-dioxane (10 mL) at room temperature. o The mixture was heated to 1°C and stirred for 1 hour. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated brine (1 × 80 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1) to give t-butyl {3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-5'-yl}carbamate (800 mg, 70.79%). MS (EI, m / z): 201.1 [M-100], RT(min):9.866

[0155] Step 4 Synthesis of 3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-amine (compound 51-6):

[0156] To a solution of t-butyl {3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-5'-yl}carbamate (200 mg, 0.66 mmol, 1 eq) in dichloromethane (2 mL) was added a solution of hydrochloric acid in 1,4-dioxane (2 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give 3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-5'-amine (60 mg, 46.78%). The crude product was carried on directly to the next step without further purification. MS: (ESI, m / z): 202.45 [M+H] + , RT(min):1.041

[0157] Step 5. Synthesis of 2-{6-azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-5'-yl}-4-iodobenzamide (compound 51-7):

[0158] Under nitrogen gas protection, a solution of 2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzoic acid (127.74 mg, 0.36 mmol, 1.2 eq) in dichloromethane (1 mL) was added with N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (334.5 mg, 1.12 mmol, 4 eq), N-methylimidazole (244.71 mg, 2.97 mmol, 10 eq), and 3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-amine (60 mg, 0.300 mmol, 1 eq) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phase was backwashed with saturated brine solution (1 × 20 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1) to give 2-{6-azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-5'-yl}-4-iodobenzamide (100 mg, 90.34%). MS(ESI, m / z): 541.35 [M+H] + , RT(min):1.728

[0159] Step 6. Synthesis of 2-{6-azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-5'-yl}-4-(2-hydroxyethanesulfonamido)benzamide (compound 51):

[0160] Under nitrogen gas protection, a solution of 2-{6-azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-5'-yl}-4-iodobenzamide (50 mg, 0.095 mmol, 1 eq) and 2-hydroxyethanesulfonamide (13.9 mg, 0.115 mmol, 1.2 eq) in N,N-dimethylformamide (1 mL) was added with cuprous iodide (1.75 mg, 0.010 mmol, 0.1 eq), sarcosine (1.65 mg, 0.020 mmol, 0.20 eq), and potassium carbonate (38.35 mg, 0.285 mmol, 3 eq) at room temperature. o The temperature was raised to 0°C and the reaction was stirred for 1 hour. The reaction mixture was cooled to room temperature and quenched by adding water. The reaction mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated brine solution (1 × 10 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative high pressure liquid chromatography under the following conditions: chromatography column specifications: Kinetex EVO C18 chromatography column, 30*150, 5 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: 45% B to 96% B, 8 min, 96% B, detection wavelength: UV 220 nm, retention time (min): 7.62 to obtain 2-{6-azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-yl}-4-(2-hydroxyethanesulfonamido)benzamide (10 mg, 20.06%). MS (ESI, m / z): 538.10 [M+H] + , RT(min):1.383 1H NMR: (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.07 (s, 1H), 7.85 (d, 1H), 7.58 (m, 1H), 7.19 (d, 1H), 7.17 (d, 1H), 7.03 (m, 2H), 4.93 (d, 1H), 3.76 (q, 2H), 2.99 (d, 4H), 2.78 (d, 2H), 2.07 (s, 2H), 1.89 (s, 1H), 1.78 (s, 1H), 1.70 (d, 6H), 1.46 - 1.36 (m, 4H), 1.30 - 1.13 (m, 4H), 0.34 (s, 4H).

[0161] Example 6 2-{6-Azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalen]-5'-yl}-4-(2-hydroxyethanesulfonamido)benzamide (Compound 56) [ka]

[0162] Step 1 Synthesis of (2-chloroethyl)dimethylsulfonium iodide (compound 56-2):

[0163] A solution of 1-chloro-2-(methylthio)ethane (8 g, 72.333 mmol, 1 eq) and iodomethane (27.02 mL, 433.998 mmol, 6 eq) was stirred at room temperature for 65 h. A solid precipitated from the mixture and was filtered. The filter cake was washed with acetone (3 × 30 mL) and the solid was dried to give (2-chloroethyl)dimethylsulfonium iodide (9.5 g, 52.01%). MS (ESI, m / z): 125.02 [M] + . RT (min): 0.19.

[0164] Step 2 Synthesis of 5'-bromo-3',4'-dihydrospiro[cyclopropane-1,2'-naphthalen]-1'-one (compound 56-4):

[0165] 0 o In step C, to a solution of 5-bromo-3,4-dihydro-2H-naphthalen-1-one (2 g, 10.461 mmol, 1.00 eq) in t-butanol (30 mL) was added sodium iodide (0.27 g, 1.777 mmol, 0.2 eq) and sodium hydride (0.71 g, 60%, dispersion in kerosene, 17.77 mmol, 2 eq). The mixture was stirred at room temperature for 20 minutes, and then (2-chloroethyl)dimethylsulfonium iodide (2.47 g, 9.775 mmol, 1.1 eq) was added portionwise. The reaction was stirred for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was backwashed with saturated brine (2 × 50 mL). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:1) to give 5'-bromo-3',4'-dihydrospiro[cyclopropane-1,2'-naphthalen]-1'-one (1.8 g, 80.67%). MS (EI, m / z): 250.1 [M] + . RT (min): 8.46.

[0166] Step 3 Synthesis of 5'-bromo-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene] (compound 56-5):

[0167] Under nitrogen gas protection, o C. To a solution of 5'-bromo-3',4'-dihydrospiro[cyclopropane-1,2'-naphthalen]-1'-one (800 mg, 3.186 mmol, 1 eq) in dichloromethane (30 mL) was added triethylsilane (2.57 mL, 15.930 mmol, 5 eq), and then a solution of boron trifluoride in diethyl ether (2.02 mL, 15.930 mmol, 5 eq) was added dropwise.o The mixture was stirred at RT for 4 hours, then allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3 × 50 mL). The organic phases were combined, backwashed with saturated brine (1 × 60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1) to give 5'-bromo-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene] (550 mg, crude).

[0168] Step 4 Synthesis of N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalen]-5'-yl}-1,1-diphenylmethylamine (compound 56-7):

[0169] Under nitrogen gas protection, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (131.29 mg, 0.211 mmol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium (96.54 mg, 0.105 mmol, 0.05 eq) were added to a solution of 5'-bromo-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene] (500 mg, 2.108 mmol, 1 eq), benzophenone imine (458.56 mg, 2.530 mmol, 1.2 eq), and sodium t-butanol (303.95 mg, 3.162 mmol, 1.5 eq) in toluene (20 mL) at room temperature. o The temperature was raised to C and the reaction was stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate, the mixture was extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, backwashed with saturated brine (1 × 60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalen]-5'-yl}-1,1-diphenylmethylamine (1.1 g, crude), which was carried on directly to the next step without further purification. MS (ESI, m / z): 338.50 [M+H] + . RT (min): 1.524.

[0170] Step 5 Synthesis of 3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-amine (compound 56-8):

[0171] N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-yl}-1,1-diphenylmethamine (1.1 g, crude product) was dissolved in 1 M hydrochloric acid. The reaction solution was made alkaline with saturated aqueous sodium bicarbonate to pH = 8. The reaction mixture was extracted with dichloromethane (3 × 50 mL). The organic phases were combined, backwashed with saturated brine (1 × 50 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol (20:1) to give 3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-amine (100 mg). MS (ESI, m / z): 174.45 [M+H] + . RT (min): 0.892.

[0172] Step 6 Synthesis of 2-{6-azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalen]-5'-yl}-4-iodobenzamide (compound 56-9): Under nitrogen gas protection, N-methylimidazole (473.89 mg, 5.770 mmol, 10 eq) was added to a solution of 3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-amine (100 mg, 0.577 mmol, 1 eq), 2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzoic acid (247.39 mg, 0.692 mmol, 1.2 eq), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (647.77 mg, 2.308 mmol, 4 eq) in dichloromethane (4 mL) at room temperature. o The mixture was heated to 10°C and reacted for 2 hours. The reaction mixture was cooled to room temperature and extracted with dichloromethane (3 × 20 mL). The combined organic phases were backwashed with saturated brine (1 × 30 mL), dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) to give 2-{6-azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalen]-5'-yl}-4-iodobenzamide (56 mg, 18.93%). MS (ESI, m / z): 513.05 [M+H] + . RT (min): 1.262.

[0173] Step 7 Synthesis of 2-{6-azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalen]-5'-yl}-4-(2-hydroxyethanesulfonamido)benzamide (compound 56):

[0174] Under nitrogen gas protection, a solution of 2-{6-azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-yl}-4-iodobenzamide (50 mg, 0.098 mmol, 1 eq), 2-hydroxyethanesulfonamide (14.65 mg, 0.118 mmol, 1.2 eq), and potassium carbonate (40.46 mg, 0.294 mmol, 3 eq) in N,N-dimethylformamide (1 mL) was added with cuprous iodide (1.86 mg, 0.010 mmol, 0.1 eq) and sarcosine (1.74 mg, 0.020 mmol, 0.2 eq) at room temperature. o The temperature was raised to C and reacted for 1 hour. The reaction solution was cooled to room temperature, extracted with ethyl acetate (3 × 20 mL), the organic phases were combined, backwashed with saturated saline (3 × 10 mL), dried over anhydrous sulfuric acid, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified under the following conditions (chromatography column specifications: XselectCSHC18 OBD chromatography column, 30*150mm 5μm, mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: 45% B to 75% B 8 min, detection wavelength: UV 220 nm, retention time (min): 7.4) and purified by preparative high performance liquid chromatography to give 2-{6-azaspiro[2.5]octan-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalen]-5'-yl}-4-(2-hydroxyethanesulfonamido)benzamide (12 mg, 24.01%). MS (ESI, m / z): 510.55 [M+H] + . RT (min): 1.926. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.08 (s, 1H), 7.86 (d, 1H), 7.65 (d, 1H), 7.18 (d, 1H), 7.12 (t, 1H), 7.02 (dd, 1H), 6.88 (d, 1H), 4.95 (s, 1H), 3.76 (t, 2H), 3.36 - 3.30 (m, 2H), 3.00 (t, 4H), 2.79 (t, 2H), 2.66 (s, 2H), 1.57 (t, 2H), 1.47 (s, 4H), 0.39 (s, 4H), 0.33 (s, 4H).

[0175] Example 7 N-(8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 64) [ka]

[0176] Step 1 Synthesis of 5,5-difluoro-1-(4-methyl-3-nitropyridin-2-yl)piperidin-2-one (compound 64-3):

[0177] Palladium acetate (156.12 mg, 0.695 mmol, 0.05 eq), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (804.73 mg, 1.391 mmol, 0.1 eq), and cesium carbonate (6.80 g, 20.861 mmol, 1.5 eq) were added to a solution of 2-chloro-4-methyl-3-nitropyridine (2.4 g, 13.907 mmol, 1 eq) and 5,5-difluoropiperidin-2-one (2.25 g, 16.688 mmol, 1.2 eq) in 1,4-dioxane (50 mL) at room temperature under nitrogen gas protection. The reaction mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (6:1) to give 5,5-difluoro-1-(4-methyl-3-nitropyridin-2-yl)piperidin-2-one (compound 64-3, 980 mg, 25.98%). MS (ESI, m / z): 272.30 [M+H] + . RT(min): 0.786

[0178] Step 2 Synthesis of 8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidine (compound 64-4):

[0179] Iron powder (12.35 mg, 0.222 mmol, 3 eq) and ammonium chloride (0.13 g, 2.345 mmol, 0.6 eq) were added to a solution of 5,5-difluoro-1-(4-methyl-3-nitropyridin-2-yl)piperidin-2-one (1.06 g, 3.908 mmol, 1 eq) in ethanol and water (10 mL:1 mL) at room temperature. The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. The residue was purified on a silica gel column with petroleum ether / ethyl acetate (4:1) to give 8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidine (compound 64-4, 550 mg, 63.04%). MS (ESI, m / z): 224.30 [M+H] + . RT (min): 0.666

[0180] Step 3 Synthesis of 8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidine-1-oxide (compound 64-5):

[0181] At room temperature, 8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidine (500 mg, 1.843 mmol, 1 eq) in dichloromethane (5 mL) was added with metachloroperbenzoic acid (561.38 mg, 2.764 mmol, 1.5 eq, 85%) and stirred at room temperature for 16 hours. The reaction mixture was directly concentrated under reduced pressure, and the resulting residue was chromatographed on a silica gel column to obtain 8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidine-1-oxide (compound 64-5, 220 mg, 53.46%) in petroleum ether / ethyl acetate (1:3). MS (ESI, m / z): 240.30 [M+H] + . RT (min): 0.585

[0182] Step 4 Synthesis of 1-(8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidin-2-yl)pyridine-1-trifluoroacetic acid salt (compound 64-6):

[0183] To a solution of 8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidine-1-oxide (220 mg, 0.920 mmol, 1 eq) in dichloromethane (4 mL) was added pyridine (0.37 mL, 4.600 mmol, 5 eq) at room temperature, and trifluoroacetic anhydride (0.38 mL, 2.760 mmol, 3 eq) was added dropwise at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The resulting mixture was used directly without further purification. MS (ESI, m / z): 301.30 [M-CF3COO- ] + . RT (min): 0.501

[0184] Step 5. Synthesis of 8,8-difluoro-4-methylpyrido[2,3-d]imidazo[1,2-a]piperidin-2-amine (compound 64-7):

[0185] At room temperature, ethanolamine (0.32 mL, 5.310 mmol, 10 eq) was added to an ethanol solution (3 mL) of 1-(8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidin-2-yl)pyridine-1-trifluoroacetic acid salt (220 mg, 0.53 mmol, 1 eq). The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) to obtain 8,8-difluoro-4-methylpyrido[2,3-d]imidazo[1,2-a]piperidin-2-amine (compound 64-7, 75 mg). MS (ESI, m / z): 239.35 [M+H] + . RT (min): 0.475.

[0186] Step 6 Synthesis of N-(8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 64-8):

[0187] Under nitrogen gas protection, a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (112.45 mg, 0.315 mmol, 1.00 eq), 8,8-difluoro-4-methylpyrido[2,3-d]imidazo[1,2-a]piperidin-2-amine (75 mg, 0.315 mmol, 1.00 eq), and tetramethylchloroformamidinium hexafluorophosphate (353.31 mg, 1.260 mmol, 4 eq) in dichloromethane (4 mL) was added with N-methylimidazole (0.25 mL, 3.150 mmol, 10 eq) at room temperature. The reaction mixture was heated to 60°C and reacted for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (3 × 10 mL), the combined organic phases were backwashed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified on a preparative chromatography plate with petroleum ether / ethyl acetate (6:1) to give N-(8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 64-8, 30 mg, 16.50%). MS (ESI, m / z): 578.30 [M+H] + . RT (min): 1.432

[0188] Step 7 Synthesis of N-(8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 64):

[0189] Under nitrogen gas protection, a solution of N-(8,8-difluoro-4-methylpyrido[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (30 mg, 0.052 mmol, 1 eq), 2-hydroxyethanesulfonamide (7.80 mg, 0.062 mmol, 1.2 eq), sarcosine (0.93 mg, 0.010 mmol, 0.2 eq), and potassium carbonate (21.54 mg, 0.156 mmol, 3 eq) in dimethylformamide (0.8 mL) was added with cuprous iodide (0.99 mg, 0.005 mmol, 0.1 eq) at room temperature. The reaction mixture was heated to 120°C and reacted for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were backwashed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography under the following conditions: chromatography column specifications: Kinetex EVO prep C18, 30*150, 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 20% B to 55% B, 8 min, 55% B; detection wavelength: 220 nm; retention time (min): 7.57. N-(8,8-difluoro-4-methylpyrido[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 64, 2.24 mg, 7.46%) was obtained. MS (ESI, m / z): 575.35 [M+H] + . RT (min): 2.150 1H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.11 - 8.02 (m, 2H), 7.25 (s, 1H), 7.11 (d, 1H), 4.47 (t, 2H), 3.76 (m, 4H), 3.33(m, 2H), 3.19 (m, 2H), 2.99 (t, 4H), 2.61 (m, 2H), 2.56 (s, 3H), 1.81 (s, 4H), 0.40 (s, 4H).

[0190] Example 8 N-(3,3-Difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 94) [ka]

[0191] Step 1 Synthesis of (2Z)-N-(2,6-dibromophenyl)-3,3-difluoropyrrolidin-2-imine (compound 94-2):

[0192] Under nitrogen gas protection, o C: POCl3 (837.11 mg, 5.460 mmol, 1 eq) was added to a solution of 3,3-difluoropyrrolidin-2-one (0.99 g, 8.176 mmol, 1.50 eq) in ultra-dehydrated toluene (15 mL), and the reaction mixture was stirred at room temperature for 2 hours. To the above solution, a solution of 2,6-dibromoaniline (1.37 g, 5.460 mmol, 1 eq) in toluene (5 mL) was added, and the reaction mixture was heated to 110°C. oThe mixture was warmed to 0°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched by the addition of water. The reaction mixture was extracted with dichloromethane (3 × 60 mL). The organic layers were combined, backwashed with saturated sodium chloride solution (1 × 80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from petroleum ether / dichloromethane (100:1) to give (2Z)-N-(2,6-dibromophenyl)-3,3-difluoropyrrolidin-2-imine (1.2 g, 62.09%). MS (ESI, m / z): 352.85 [M+H] + , RT(min):0.674

[0193] Step 2 Synthesis of 5-bromo-3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (compound 94-3):

[0194] Under nitrogen gas protection, (2Z)-N-(2,6-dibromophenyl)-3,3-difluoropyrrolidin-2-imine (500 mg, 1.412 mmol, 1 eq) in N,N-dimethylformamide (10.00 mL) was added N,N-dimethylethylenediamine (12.45 mg, 0.141 mmol, 0.1 eq), anhydrous potassium carbonate (195.21 mg, 1.412 mmol, 1 eq), and cuprous iodide (13.45 mg, 0.071 mmol, 0.05 eq) at room temperature. o The temperature was raised to 1°C and the reaction was stirred for 1 h. The reaction mixture was cooled to room temperature and quenched by adding water. The reaction mixture was extracted with dichloromethane (3 × 50 mL). The organic phases were combined, backwashed with saturated brine (1 × 50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) to give 5-bromo-3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (240 mg, 62.22%). MS (ESI, m / z): 272.90 [M+H]+ , RT(min):0.837

[0195] Step 3 Synthesis of t-butyl (3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)carbamate (compound 94-4):

[0196] Under nitrogen gas protection, a solution of 5-bromo-3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (230 mg, 0.842 mmol, 1 eq) in N,N-dimethylformamide (5.00 mL) was added with t-butyl carbamate (197.33 mg, 1.684 mmol, 2 eq), (methanesulfonic acid {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (154.73 mg, 0.168 mmol, 0.20 eq), dicyclohexyl(3-isopropyl-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (45.04 mg, 0.084 mmol, 0.10 eq), and cesium carbonate (823.25 mg, 2.526 mmol, 3.00 eq) were added to the reaction mixture. o The mixture was warmed to 1°C and stirred for 1 h. Complete reaction was monitored by liquid chromatography-mass spectrometry. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated sodium chloride (1 × 50 mL), 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 using petroleum ether / ethyl acetate (2:1) to give tert-butyl (3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)carbamate (189 mg, 72.55%). MS (ESI, m / z): 310.05 [M+H] + ,RT(min):1.004

[0197] Step 4 Synthesis of 3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (compound 94-5):

[0198] Under nitrogen gas protection, a solution of t-butyl (3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)carbamate (189 mg, 0.611 mmol, 1 eq) in dichloromethane (2 mL) was added with a solution of hydrochloric acid in 1,4-dioxane (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (127 mg, 99.35%). MS (ESI, m / z): 210.10 [M+H] + ,RT(min):0.193

[0199] Step 5 Synthesis of N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 94-6):

[0200] Under nitrogen gas protection, 3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (100 mg, 0.478 mmol, 1 eq), tetramethylchloroformamidinium hexafluorophosphate (536.48 mg, 1.912 mmol, 4 eq), and N-methylimidazole (392.48 mg, 4.780 mmol, 10 eq) were added to a dichloromethane solution (10.00 mL) of 2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzoic acid (204.89 mg, 0.574 mmol, 1.2 eq) at room temperature. oThe temperature was raised to 1°C and the reaction was stirred for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with dichloromethane (3 × 50 mL). The organic phases were combined, backwashed with saturated brine (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (4:1) to give N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (150 mg, 57.22%). MS (ESI, m / z): 549.05 [M+H] + ,RT(min):1.311

[0201] Step 6. Synthesis of N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 94):

[0202] Under nitrogen gas protection, a solution of N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.182 mmol, 1 eq) in N,N-dimethylformamide (20.00 mL) was added with 2-hydroxyethanesulfonamide (27.38 mg, 0.218 mmol, 1.2 eq), sarcosine (3.25 mg, 0.036 mmol, 0.2 eq), cuprous iodide (3.47 mg, 0.018 mmol, 0.1 eq), and potassium carbonate (75.61 mg, 0.55 mmol, 3 eq) at room temperature. oThe temperature was raised to 1°C and the reaction was stirred for 1 hour. The reaction mixture was cooled to room temperature and quenched by adding water. The reaction mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, backwashed with saturated brine (1 × 30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography under the following conditions: chromatography column specifications: Kinetex EVO prep C18, 30*150, 5 μm; mobile phase A: water (10 mmol / L sodium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 20% B to 65% B for 8 min, 65% B; detection wavelength: 220 nm; retention time (min): 7.45. N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (23.00 mg, 23.12%) was obtained. MS (ESI, m / z): 546.30 [M+H] + ,RT(min):1.621 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.16 (s, 1H), 8.47 (m, 1H), 8.04 (d, 1H), 7.45 - 7.33 (m, 2H), 7.28 (d, 1H), 7.09 (m, 1H), 4.92 (s, 1H), 4.66 - 4.34 (m, 2H), 3.76 (t, 2H), 3.43 - 3.32 (m, 2H), 3.01 (d, 4H), 1.77 (s, 4H), 1.23 (s, 2H), 0.27 (s, 4H).

[0203] Using conditions similar to those in Example 8, the compounds in the following table were prepared.

[0204] [Table 3]

[0205] Example 9 4-(2-Hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (Compound 96) [ka]

[0206] Step 1 Synthesis of (3Z)-N-(2,6-dibromophenyl)-2-azabicyclo[2.2.1]heptan-3-imine (compound 96-2):

[0207] Under nitrogen gas protection, o In C, phosphoryl chloride (1833.09 mg, 11.955 mmol, 3 eq) was added to a solution of 2-azabicyclo[2.2.1]heptan-3-one (885.89 mg, 7.970 mmol, 2 eq) in anhydrous toluene (15 mL), and the reaction mixture was stirred at room temperature for 2 hours. A solution of 2,6-dibromoaniline (1 g, 3.985 mmol, 1 eq) in toluene (5 mL) was added to the above solution, and the reaction mixture was diluted to 100°C. o The mixture was warmed to 0°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched by the addition of water (30 mL). The reaction mixture was extracted with ethyl acetate (3 × 80 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) to give (3Z)-N-(2,6-dibromophenyl)-2-azabicyclo[2.2.1]heptan-3-imine (190 mg, 13.86%). MS (ESI, m / z): 344.80 [M+H] + , RT(min):0.592.

[0208] Step 2: Synthesis of 6-bromo-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (compound 96-3):

[0209] Under nitrogen gas protection, N,N-dimethylethylenediamine (4.87 mg, 0.055 mmol, 0.1 eq), anhydrous potassium carbonate (76.22 mg, 0.553 mmol, 1 eq), and cuprous iodide (5.26 mg, 0.028 mmol, 0.05 eq) were added to a solution of (3Z)-N-(2,6-dibromophenyl)-2-azabicyclo[2.2.1]heptan-3-imine (190 mg, 0.553 mmol, 1 eq) in acetonitrile (5.0 mL) at room temperature. o The mixture was warmed to 0°C and stirred for 1 hour. The reaction mixture was cooled to room temperature, quenched by adding water, and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated brine (1 × 50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 6-bromo-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (140 mg, 96.55%). MS (ESI, m / z): 263.00 [M+H] + , RT(min):0.602.

[0210] Step 3 Synthesis of t-butyl (1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (compound 96-4):

[0211] Under nitrogen gas protection, a solution of 6-bromo-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (130 mg, 0.494 mmol, 1 eq) in N,N-dimethylformamide (5.0 mL) was added with t-butyl carbamate (115.75 mg, 0.988 mmol, 2 eq), methanesulfonate {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (45.38 mg, 0.049 mmol, 0.1 eq), dicyclohexyl(3-isopropyl-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (52.84 mg, 0.099 mmol, 0.2 eq), and cesium carbonate (482.9 mg, 1.482 mmol, 3 eq) were added to the reaction mixture, and the reaction mixture was diluted to 100°C. o The temperature was raised to 1°C and the reaction was stirred for 1 hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 50 mL), 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 using petroleum ether / ethyl acetate (5:4) to give t-butyl (1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (94 mg, 63.56%). MS (ESI, m / z): 300.10 [M+H] + , RT(min):0.730.

[0212] Step 4 Synthesis of 1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-amine (compound 96-5):

[0213] To a solution of t-butyl (1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (94 mg, 0.314 mmol, 1 eq) in dichloromethane (2 mL) was added a solution of hydrochloric acid in 1,4-dioxane (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-amine (62 mg, 99.10%). MS (ESI, m / z): 200.00 [M+H] + , RT(min):0.166

[0214] Step 5. Synthesis of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (compound 96-6):

[0215] Under nitrogen gas protection, a solution of 1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-amine (60 mg, 0.301 mmol, 1 eq) and 2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzoic acid (129.07 mg, 0.361 mmol, 1.20 eq) in dichloromethane (10.0 mL) was added with tetramethylchloroformamidinium hexafluorophosphate (337.95 mg, 1.204 mmol, 4 eq) and N-methylimidazole (247.24 mg, 3.010 mmol, 10 eq) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with dichloromethane (3 × 50 mL), the combined organic phases were backwashed with saturated brine (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:2) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (70 mg, 43.17%). MS (ESI, m / z): 539.35 [M+H] + , RT (min): 1.495.

[0216] Step 6. Synthesis of 4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (compound 96):

[0217] Under nitrogen gas protection, sarcosine (2.16 mg, 0.024 mmol, 0.2 eq) and cuprous iodide (2.3 mg, 0.012 mmol, 0.1 eq) were added to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (65 mg, 0.121 mmol, 1 eq), 2-hydroxyethanesulfonamide (30.21 mg, 0.242 mmol, 2.0 eq), and potassium carbonate (50.05 mg, 0.363 mmol, 3 eq) in N,N-dimethylformamide (5.0 mL) at room temperature. o The temperature was raised to 1°C and the reaction was stirred for 1 hour. The reaction mixture was cooled to room temperature and quenched by adding water. The reaction mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, backwashed with saturated brine (1 × 30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography under the following conditions: chromatography column specifications: Kinetex EVO prep C18, 30*150, 5 μm; mobile phase A: water (10 mmol / L sodium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 20% B to 65% B for 8 min, 65% B; detection wavelength: UV 220 nm; retention time (min): 7.45. 4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (16.99 mg, 25.96%) was obtained. MS (ESI, m / z): 536.00 [M+H] + , RT(min): 1.488. 1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 10.13 (s, 1H), 8.28 (d, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.31 - 7.18 (m, 2H), 7.12 (t, 1H), 7.06 (m, 1H), 5.15 (s, 1H), 4.94 (s, 1H), 3.76 (t, 2H), 3.59 (d, 1H), 3.35 (d, 2H), 3.08 - 2.83 (m, 4H), 2.25-2.23 (m, 1H), 2.16-2.10 (m, 1H), 2.02-1.95 (m, 2H), 1.75 (s, 4H), 1.19-1.13 (m, 2H), 0.29 (s, 4H).

[0218] Using conditions similar to those in Example 9, the compounds in the following table were prepared.

[0219] [Table 4]

[0220] Example 10 4-(2-Hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-yl)benzamide (Compound 97) [ka]

[0221] Step 1 Synthesis of (2Z)-N-(2,6-dibromoaniline)azepin-2-imine (compound 97-2):

[0222] Under nitrogen gas protection, o In C, phosphoryl chloride (6.1 g, 39.85 mmol, 5 eq) was added dropwise to a solution of caprolactam (1.36 g, 15.94 mmol, 2 eq) in toluene (10 mL), and the reaction mixture was heated to 0°C. oC for 2 hours. After that, a toluene solution (5 mL) of 2,6-dibromoaniline (2 g, 7.97 mmol, 1 eq) was added, and the reaction mixture was heated to 110 o The temperature was raised to 10°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, quenched by the addition of ice water (50 mL), adjusted to pH 10 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (3 × 60 mL). The organic phases were combined, backwashed with saturated brine (1 × 50 mL), 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 using petroleum ether / ethyl acetate (10:1) to give (2Z)-N-(2,6-dibromoaniline)azepin-2-imine (2.7 g, 27.65%). MS: (ESI, m / z): 345.10 [M+H] + , RT(min): 0.595.

[0223] Step 2: Synthesis of 4-bromo-7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepine (compound 97-3):

[0224] Under nitrogen gas protection, N,N-dimethylethylenediamine (25.47 mg, 0.289 mmol, 0.10 eq), cuprous iodide (27.52 mg, 0.145 mmol, 0.05 eq), and potassium carbonate (599.04 mg, 4.335 mmol, 3 eq) were added to a solution of (2Z)-N-(2,6-dibromoaniline)azepin-2-imine (500 mg, 1.445 mmol, 1 eq) in acetonitrile (3 mL) at room temperature. o The temperature was raised to 1°C and the reaction was stirred for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined, backwashed with saturated brine (1 × 40 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4-bromo-7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepine (250 mg, 65.26%). MS: (ESI, m / z): 264.90 [M+H] + , RT(min):1.151.

[0225] Step 3 Synthesis of t-butyl (7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-yl)carbamate (compound 97-4):

[0226] Under nitrogen gas protection, 4-bromo-7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepine (250 mg, 0.943 mmol, 1 eq) in N,N-dimethylformamide (10 mL) was added with t-butyl carbamate (220.91 mg, 1.886 mmol, 2 eq), dicyclohexyl(3-isopropyl-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (50.42 mg, 0.094 mmol, 0.1 eq), (methanesulfonate{bicycloethyl(3-isopropyl-2,4,6-triisopropyl-(1,1-biphenyl)-2-yl)phosphine})(2-methylamino-1,1-biphenyl-2-yl)palladium(II) (173.21 mg, 0.189 mmol, 0.2 eq), and cesium carbonate (921.59 mg, 2.829 mmol, 3 eq) were added to the reaction mixture. o The mixture was warmed to 0°C and stirred for 1 hour. The reaction was cooled to room temperature and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, backwashed with saturated brine (1 × 50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:1) to give tert-butyl (7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-yl)carbamate (150 mg, 52.79%). MS: (ESI, m / z): 302.35 [M+H] + , RT(min):1.106.

[0227] Step 4 Synthesis of 7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-amine (compound 97-5):

[0228] To a solution of t-butyl (7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-yl)carbamate (150 mg, 0.498 mmol, 1 eq) in dichloromethane (2 mL) was added a solution of hydrochloric acid in 1,4-dioxane (4 M, 2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-amine (150 mg, 66.67%). This product was used directly in the next step without further purification. MS: (ESI, m / z): 202.40 [M+H] + , RT(min):0.544.

[0229] Step 5. Synthesis of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-yl)benzamide (compound 97-6):

[0230] Under nitrogen gas protection, a solution of 7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-amine (150 mg, 1.443 mmol, 1 eq), 2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzoic acid (319.44 mg, 0.894 mmol, 1.2 eq), and N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (836.42 mg, 2.980 mmol, 4 eq) in dichloromethane (5 mL) was added with N-methylimidazole (611.90 mg, 7.450 mmol, 10 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phase was backwashed with saturated brine (1 × 20 mL) and dried over anhydrous sodium sulfate. It was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:1) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-yl)benzamide (60 mg, 14.90%). MS: (ESI, m / z): 541.35 [M+H] + , RT(min):1.398.

[0231] Step 6. Synthesis of 4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-yl)benzamide (compound 97):

[0232] Under nitrogen gas protection, sarcosine (2.09 mg, 0.023 mmol, 0.2 eq), cuprous iodide (2.23 mg, 0.012 mmol, 0.1 eq), and potassium carbonate (48.55 mg, 0.351 mmol, 3 eq) were sequentially added to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-yl)benzamide (60 mg, 0.117 mmol, 1 eq) and 2-hydroxyethanesulfonamide (17.58 mg, 0.140 mmol, 1.2 eq) in N,N-dimethylformamide (2 mL) at room temperature. o The temperature was raised to 1°C and the reaction was stirred for 1 hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, backwashed with saturated brine (1 × 10 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by preparative high pressure liquid chromatography to give 4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-4-yl)benzamide (12.53 mg, 22.81%). MS: (ESI, m / z): 538.00 [M+H] + , RT(min): 1.588. 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 10.15 (s, 1H), 8.30 (d, 1H), 8.03 (s, 1H), 7.27 (d, 1H), 7.23 (d, 1H), 7.16 (d, 1H), 7.09 (s, 1H), 4.94 (s, 1H), 4.27 (d, 2H), 3.76 (s, 2H), 3.37 (s, 2H), 3.09 (s, 2H), 3.01-2.93 (m, 4H), 1.90 (s, 4H), 1.73 (s, 6H), 0.30 (s, 4H).

[0233] Example 11 4-(2-Hydroxyethanesulfonamido)-N-(4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 98) [ka]

[0234] Step 1 Synthesis of (2Z)-N-(2,6-dibromophenyl)-3-methylpiperidin-2-imine (compound 98-2):

[0235] Under nitrogen gas protection, phosphoryl chloride (3.67 g, 23.912 mmol, 2 eq) was added to a solution of 3-methylpiperidin-2-one (1.62 g, 14.347 mmol, 1.2 eq) in toluene (20 mL) at 0 °C. After the addition was complete, the reaction was stirred at 0 °C for 2 h. 2,6-Dibromoaniline (3 g, 11.956 mmol, 1 eq) was then added. After the addition was complete, the reaction was stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature and quenched with water (20 mL). The reaction mixture was extracted with ethyl acetate (3 × 60 mL). The combined organic phases were backwashed with saturated sodium chloride solution (1 × 60 mL) and dried over anhydrous sodium sulfate. The resulting mixture was 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 give (2Z)-N-(2,6-dibromophenyl)-3-methylpiperidin-2-imine (2.3 g, 55.59%). MS (ESI, m / z): 346.85 [M+H] + , RT(min):0.620

[0236] Step 2: Synthesis of 6-bromo-4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine (compound 98-3):

[0237] Under nitrogen gas protection, cuprous iodide (71.54 mg, 0.376 mmol, 0.1 eq) and N,N-dimethylethylenediamine (66.23 mg, 0.751 mmol, 0.2 eq) were added to a solution of (2Z)-nitrogen-(2,6-dibromophenyl)-3-methylpiperidin-2-imine (1.3 g, 3.757 mmol, 1 eq) and potassium carbonate (1038.34 mg, 7.514 mmol, 2 eq) in acetonitrile (2 mL) at room temperature. After the addition was complete, the reaction mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL). The reaction mixture was extracted with ethyl acetate (1 × 20 mL). The combined organic phases were backwashed with saturated sodium chloride solution (1 × 20 mL) and dried over anhydrous sodium sulfate. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure. The crude / resulting mixture was carried directly to the next step without further purification. MS(ESI, m / z):264.90 [M+H] + , RT(min):0.561

[0238] Step 3 Synthesis of t-butyl (4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (compound 98-4):

[0239] Under nitrogen gas protection, a solution of 6-bromo-4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine (950 mg, 3.583 mmol, 1 eq) and t-butyl carbamate (503.66 mg, 4.300 mmol, 1.2 eq) in N,N-dimethylformamide (10 mL) was added with cesium carbonate (3.50 g, 10.749 mmol, 3 eq), dicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (383.23 mg, 0.717 mmol, 0.2 eq) and {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (329.11 mg, 0.358 mmol, 0.1 eq) were added. After the addition was complete, the reaction mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were backwashed with saturated sodium chloride solution (1 × 40 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:1) to give tert-butyl (4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (950 mg, 87.98%). MS (ESI, m / z): 302.30 [M+H] + , RT(min):1.128

[0240] Step 4 Synthesis of 4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-amine (compound 98-5):

[0241] Under nitrogen gas protection, a solution of t-butyl (4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (700 mg, 2.323 mmol, 1 eq) in dichloromethane (7 mL) was added with a solution of hydrogen chloride in 1,4-dioxane (7.5 mL, 4 mol / L) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was directly carried on to the next step without further purification. MS (ESI, m / z): 202.25 [M+H] + , RT(min):0.777

[0242] Step 5. Synthesis of 4-iodo-N-(4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 98-6):

[0243] Under nitrogen gas protection, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (2.90 g, 10.336 mmol, 4 eq) and N-methylimidazole (2.12 g, 25.840 mmol, 10 eq) were added to a solution of 4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-amine (520 mg, 2.584 mmol, 1 eq) and 2-(6-azaspiro[2.5]octan-6-yl-4-iodobenzoic acid (1.11 g, 3.101 mmol, 1.2 eq) in dichloromethane (10 mL) at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate (3 × 40 mL). mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 50 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (4:1) to give 4-iodo-N-(4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (620 mg, 44.40%). MS (ESI, m / z): 541.25 [M+H] + , RT(min):1.585

[0244] Step 6. Synthesis of 4-(2-hydroxyethanesulfonamido)-N-(4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 98):

[0245] Under nitrogen gas protection, a solution of 4-iodo-N-(4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.185 mmol, 1 eq) and 2-hydroxyethanesulfonamide (27.79 mg, 0.222 mmol, 1.2 eq) in N,N-dimethylformamide (2 mL) was added with 2-(methylamino)acetic acid (13.19 mg, 0.148 mmol, 0.8 eq), cuprous iodide (14.1 mg, 0.074 mmol, 0.4 eq), and potassium phosphate (117.83 mg, 0.555 mmol, 3 eq) at room temperature. After the addition was complete, the reaction was heated to 120°C and stirred for 1.5 hours. The reaction was cooled to room temperature and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were backwashed with saturated sodium chloride solution (1 x 20 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography under the following conditions: chromatography column specifications: Kinetex 5 μm EVO C18, 30 mm * 150 mm, mobile phase A: water (10 mmol / L sodium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml / min, elution gradient: 10% B to 37% B 10 min, detection wavelength: 254 nm / 220 nm, retention time (min): 9.03 to give 4-(2-hydroxyethanesulfonamido)-N-(4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (35.6 mg, 35.39%). MS (ESI, m / z): 538.40 [M+H] + , RT(min):1.536 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.12 (s, 1H), 8.39 (dd, 1H), 8.01 (d, 1H), 7.25 (d, 1H), 7.21 - 7.10 (m, 2H), 7.07 (dd, 1H), 5.11 (d, 1H), 4.25 - 4.11 (m, 1H), 4.10 - 3.93 (m, 1H), 3.76 (t, 2H), 3.35 (t, 2H), 3.20 - 3.07 (m, 1H), 3.02 (s, 4H), 2.24 - 2.07 (m, 2H), 2.08 - 1.94 (m, 1H), 1.93 - 1.65 (m, 4H), 1.68 - 1.56 (m, 1H), 1.48 (d, 3H), 0.30 (s, 4H).

[0246] Using conditions similar to those in Example 11, the compounds in the following table were prepared.

[0247] [Table 5] JPEG2025533411000051.jpg171169

[0248] Example 12 4-(2-Hydroxyethanesulfonamido)-N-((1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 99) [ka]

[0249] Step 1 Synthesis of (1S,4R)-2-(3-chloro-5-methyl-2-nitrophenyl)-2-azabicyclo[2.2.1]heptan-3-one (compound 99-3):

[0250] Palladium acetate (108.97 mg, 0.485 mmol, 0.1 eq) and 1,1'-bis(diphenylphosphine)ferrocene (536.23 mg, 0.971 mmol, 0.2 eq) were added to a 1,4-dioxane solution (10 mL) of 1,3-dichloro-5-methyl-2-nitrobenzene (1 g, 4.854 mmol, 1 eq), potassium phosphate (3.09 g, 14.562 mmol, 3 eq), and (1S,4R)-2-azabicyclo[2.2.1]heptan-3-one (539.48 mg, 4.854 mmol, 1 eq) at room temperature under nitrogen gas protection. o The temperature was raised to 1°C and the reaction was stirred for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (3 × 10 mL). The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated brine (2 × 50 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1:1) to give (1S,4R)-2-(3-chloro-5-methyl-2-nitrophenyl)-2-azabicyclo[2.2.1]heptan-3-one (800 mg, 58.71%). MS: (ESI, m / z): 281.30 [M+H] + , RT(min): 1.079

[0251] Step 2 Synthesis of (1S,4R)-6-chloro-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (compound 99-4):

[0252] Under nitrogen gas protection, reduced iron powder (785.82 mg, 14.070 mmol, 5 eq) and acetic acid (4 mL) were added to a solution of (1S,4R)-2-(3-chloro-5-methyl-2-nitrophenyl)-2-azabicyclo[2.2.1]heptan-3-one (790 mg, 2.814 mmol, 1 eq) in ethanol (10 mL) at room temperature. oThe mixture was warmed to 0°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. After diluting the crude product with water (50 mL), the mixture was extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, backwashed with saturated brine (2 × 30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1:1) to give (1S,4R)-6-chloro-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (560 mg, 85.51%). MS: (ESI, m / z): 233.35 [M+H] + , RT(min): 0.814

[0253] Step 3 Synthesis of t-butyl ((1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (compound 99-5):

[0254] Under nitrogen gas protection, a solution of (1S,4R)-6-chloro-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (550 mg, 2.363 mmol, 1 eq), cesium carbonate (2.31 g, 7.089 mmol, 3 eq), and t-butyl carbamate (553.75 mg, 4.726 mmol, 2 eq) in N,N-dimethylformamide (6 mL) was added to the reaction mixture (methanesulfonate{bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)4 (217.10 mg, 0.236 mmol, 0.1 mL)). eq), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (252.80 mg, 0.473 mmol, 0.2 eq), and the reaction mixture was diluted to 100°C. oThe mixture was warmed to 0°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, backwashed with saturated brine (2 × 30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1:1) to give tert-butyl ((1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (650 mg, 87.75%). MS: (ESI, m / z): 314.45 [M+H] + , RT(min): 0.871

[0255] Step 4 Synthesis of (1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-amine (compound 99-6):

[0256] A solution of t-butyl ((1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (650 mg, 2.074 mmol, 1 eq) in dichloromethane (10 mL) was added to a solution of hydrogen chloride in 1,4-dioxane (10 mL) and stirred at room temperature for 1 h. After monitoring completeness by liquid chromatography-mass spectrometry, the mixture was concentrated in vacuo to give crude (1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-amine (700 mg), which was carried directly to the next step without further purification. MS: (ESI, m / z): 214.40 [M+H] + , RT(min): 0.230

[0257] Step 5 Synthesis of 4-iodo-N-((1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 99-7):

[0258] Under nitrogen gas protection, N-methylimidazole (344.80 mg, 4.200 mmol, 10 eq) was added to a solution of (1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-amine (107.48 mg, 0.504 mmol, 1.2 eq), 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (150 mg, 0.420 mmol, 1.0 eq), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (471.31 mg, 1.680 mmol, 4 eq) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with dichloromethane (3 × 30 mL). The combined organic phases were backwashed with saturated brine (2 × 30 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) to give 4-iodo-N-((1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (110 mg, 47.41%). MS: (ESI, m / z): 553.10 [M+H] + ,RT(min): 1.118

[0259] Step 6. Synthesis of 4-(2-hydroxyethanesulfonamido)-N-((1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 99):

[0260] Under nitrogen gas protection, a solution of 4-iodo-N-((1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.181 mmol, 1 eq), potassium carbonate (75.05 mg, 0.543 mmol, 3 eq), and 2-hydroxyethane-1-sulfonamide (45.30 mg, 0.362 mmol, 2 eq) in N,N-dimethylformamide (2 mL) was added with cuprous iodide (3.45 mg, 0.018 mmol, 0.1 eq), sarcosine (3.23 mg, 0.036 mmol, 0.2 eq), and 2-hydroxyethane-1-sulfonamide (45.30 mg, 0.362 mmol, 2 eq) at room temperature. eq) was added and the reaction mixture was diluted to 120 oThe mixture was heated to 100°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (3 × 5 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, backwashed with saturated brine (2 × 30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography under the following conditions (chromatographic column specifications: Kinetex 5 μm EVO C18, 30 mm × 150 mm, mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml / min, elution gradient: 27% B to 62% B 8 min, detection wavelength: 254 nm / 220 nm, retention time (min): 7.92) to obtain 4-(2-hydroxyethanesulfonamido)-N-((1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (38.29 mg, 38.33%). MS: (ESI, m / z): 550.45 [M+H] + , RT(min): 1.525 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 10.13 (s, 1H), 8.15 (d, 1H), 7.98 (d, 1H), 7.23 (d, 1H), 7.10 - 7.01 (m, 2H), 5.09 (s, 1H), 4.94 (s, 1H), 3.76 (t, 2H), 3.55 (d, 1H), 3.35 (d, 2H), 2.97 (d, 4H), 2.41 (s, 3H), 2.21 (d, 1H), 2.14 - 2.05 (m, 1H), 2.00 - 1.90 (m, 2H), 1.72 (s, 4H), 1.20 - 1.07 (m, 2H), 0.28 (s, 4H).

[0261] Using conditions similar to those in Example 12, the compounds in the following table were prepared.

[0262] [Table 6]

[0263] Example 13 4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (Compound 100) [ka]

[0264] Step 1. Synthesis of 2-(3-bromo-2-nitrophenyl)-2-azabicyclo[2.2.2]octan-3-one (compound 100-3):

[0265] Under nitrogen gas protection, tris(dibenzylideneacetone)dipalladium (326 mg, 0.356 mmol, 0.1 eq) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (412 mg, 0.712 mmol, 0.2 eq) were added to a 1,4-dioxane solution (10 mL) of 1,3-dibromo-2-nitrobenzene (1 g, 3.56 mmol, 1 eq), 2-azabicyclo[2.2.2]octan-3-one (534 mg, 4.3 mmol, 1.2 eq), and cesium carbonate (3.5 g, 10.7 mmol, 3 eq) at room temperature. oThe mixture was warmed to 0°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (3 × 10 mL). The mixture was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, backwashed with saturated brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1:1) to give 2-(3-bromo-2-nitrophenyl)-2-azabicyclo[2.2.2]octan-3-one (603 mg, 52%). MS: (ESI, m / z): 325.30 [M+H] + , RT(min):1.021

[0266] Step 2: Synthesis of 6-bromo-1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridine (compound 100-4):

[0267] Under nitrogen gas protection, a solution of 2-(3-bromo-2-nitrophenyl)-2-azabicyclo[2.2.2]octan-3-one (580 mg, 1.8 mmol, 1 eq) in N,N-dimethylformamide (1 mL), tetrahydroxydiboron (480 mg, 5.4 mmol, 3 eq), and 4,4'-bipyridine (1.4 mg, 0.009 mmol, 0.005 eq) was added at room temperature. After the addition was complete, the reaction was stirred at room temperature for 16 hours. The reaction was quenched by adding water (10 mL) at room temperature, and the mixture was extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, backwashed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (1:1) to give 6-bromo-1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridine (380 mg, 76%). MS: (ESI, m / z): 277.20 [M+H] + , RT(min):0.683

[0268] Step 3 Synthesis of t-butyl (1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (compound 100-5):

[0269] Under nitrogen gas protection, a solution of 6-bromo-1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridine (100 mg, 0.36 mmol, 1 eq) in 1,4-dioxane (2 mL) was added with t-butyl carbamate (51 mg, 0.43 mmol, 1.2 eq), methanesulfonate {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) 4 (33 mg, 0.036 mmol, 0.1 eq), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (39 mg, 0.072 mmol, 0.2 eq), and cesium carbonate (588 mg, 1.8 mmol, 5 eq) were added. o The mixture was warmed to C and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (3 × 5 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, backwashed with saturated brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1:1) to give tert-butyl (1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (90 mg, 79%). MS: (ESI, m / z): 314.40 [M+H] + , RT(min):0.768

[0270] Step 4 Synthesis of 1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-amine (compound 100-6):

[0271] Under nitrogen gas, a solution of t-butyl (1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (85 mg, 0.27 mmol, 1 eq) in dichloromethane (1 mL) was added with a solution of hydrogen chloride in 1,4-dioxane (1 mL). After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-amine (57 mg, 98%). MS: (ESI, m / z): 214.4 [M+H] + , RT(min):0.196

[0272] Step 5. Synthesis of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (compound 100-7):

[0273] Under nitrogen gas protection, 2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzoic acid (104 mg, 0.23 mmol, 1.2 eq), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (342 mg, 1.2 mmol, 5 eq), and N-methylimidazole (200 mg, 2.4 mmol, 10 eq) were added to a dichloromethane solution (1 mL) of 1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-amine (52 mg, 0.24 mmol, 1 eq) at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate (3 × 30 mL), the combined organic phases were backwashed with saturated brine (2 × 20 mL), 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 using petroleum ether / ethyl acetate (3:1) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (110 mg, 82%). MS: (ESI, m / z): 553.5 [M+H] + , RT(min):1.235

[0274] Step 6. Synthesis of 4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (compound 100):

[0275] Under nitrogen gas protection, 2-hydroxyethanesulfonamide (27 mg, 0.2 mmol, 1.2 eq), cuprous iodide (3.5 mg, 0.018 mmol, 0.1 eq), sarcosine (3.2 mg, 0.036 mmol, 0.2 eq), and potassium carbonate (75 mg, 0.5 mmol, 3 eq) were added to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (100 mg, 0.18 mmol, 1 eq) in N',N'-dimethylformamide (100 mg, 0.18 mmol, 1 eq) at room temperature. o The mixture was stirred at C for 1.5 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (3 × 5 mL), the mixture was extracted with ethyl acetate (3 × 30 mL), the organic phases were combined, backwashed with saturated brine (2 × 20 mL), and dried over anhydrous sodium sulfate. The residue was purified by preparative high-performance liquid chromatography under the following conditions: chromatography column: Kinetex 5 μm EVO C18, 30 mm × 150 mm, mobile phase A: water (10 mmol / L sodium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: 30% B to 60% B for 8 min, detection wavelength: 254 nm / 220 nm, retention time (min): 7.65 to give 4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (28.84 mg, 28%). MS: (ESI, m / z): 550.10 [M+H] + , RT(min):1.548 1H NMR: (400 MHz, CDCl3) δ 12.28 (s, 1H), 8.34 (d, 1H), 8.01 (d, 1H), 7.85 (d, 1H), 7.64 - 7.28 (m, 1H), 7.27 (s, 1H), 7.15 (d, 1H), 6.92 (dd, 1H), 4.83 (s, 1H), 4.05 (t, 2H), 3.52 (s, 2H), 3.27 (t, 2H), 3.08 (t, 4H), 2.02 (dt, 4H), 1.88 - 1.66 (m, 8H), 0.24 (s, 4H).

[0276] Example 14 N-(3,3-difluoro-2,3-dihydro-1H-benzopyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonamido)-2-spiro[2.5]oct-5-en-6-yl)benzamide (Compound 90) [ka]

[0277] Step 1. Synthesis of methyl 4-bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoate (compound 90-3):

[0278] Under nitrogen gas protection, a solution of methyl 4-bromo-2-iodobenzoate (700 mg, 2.053 mmol, 1 eq), sodium carbonate (326.41 mg, 3.079 mmol, 1.5 eq), and 4,4,5,5-tetramethyl-2-{spiro[2.5]oct-5-en-6-yl}-1,3,2-dioxaborolane (480.74 mg, 2.053 mmol, 1 eq) in 1,4-dioxane (8 mL) and water (1.6 mL) was added with [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (167.25 mg, 0.205 mmol, 0.1 eq). The reaction mixture was stirred for 80 minutes. oThe mixture was warmed to 0°C and stirred for 1 hour. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 50 mL). The filtrate was diluted with water (30 mL). The mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phase was backwashed with saturated brine (1 × 50 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The resulting residue was purified using a reverse-phase column chromatography under the following conditions: column specifications, C18, mobile phase: acetonitrile / water, gradient 10% to 70% for 10 min, detection wavelength: UV 254 nm to give methyl 4-bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoate (320 mg, 48.52%). MS: (ESI, m / z): 320.95 [M+H] + ,RT(min):1.942

[0279] Step 2 Synthesis of 4-bromo-2-{spiro[2.5]oct-5-en-6-yl}benzoic acid (compound 90-4): To a solution of methyl 4-bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoate (300 mg, 0.934 mmol, 1 eq) in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL) was added lithium hydroxide (111.84 mg, 4.670 mmol, 5 eq) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (2 × 20 mL), and the aqueous phase was collected and acidified to pH 4–5 with 1 mol / L dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, collected, backwashed with saturated brine (2 × 20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 4-bromo-2-{spiro[2.5]oct-5-en-6-yl}benzoic acid (250 mg, 87.14%). MS: (ESI, m / z): 308.90 [M+H] + , RT(min):1.323

[0280] Step 3 Synthesis of 4-bromo-N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-2-(spiro[2.5]oct-5-en-6-yl)benzamide (compound 90-5): Under nitrogen gas protection, N-methylimidazole (400.93 mg, 4.880 mmol, 10 eq) was added dropwise to a solution of 3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (112.37 mg, 0.537 mmol, 1.1 eq), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (548.03 mg, 1.952 mmol, 4 eq), and 4-bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoic acid (150 mg, 0.488 mmol, 1.00 eq) in dichloromethane (5 mL) at room temperature. After the addition was complete, the mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were backwashed with saturated brine (2 × 20 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) to give 4-bromo-N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-2-(spiro[2.5]oct-5-en-6-yl)benzamide (64 mg, 26.30%). MS: (ESI, m / z): 498.40 [M+H] + , RT(min):1.449

[0281] Step 4. Synthesis of 4-bromo-N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-2-(spiro[2.5]oct-5-en-6-yl)benzamide (compound 90):

[0282] Under nitrogen gas protection, 4-bromo-N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-2-(spiro[2.5]oct-5-en-6-yl)benzamide (50 mg, 0.100 mmol, 1 eq), cesium carbonate (98.06 mg, 0.300 mmol, 3 eq), and 2-hydroxyethane-1-sulfonamide (25.11 mg, 0.200 mmol, 2 eq) were dissolved in N,N-dimethylformamide (2 To the solution of (methanesulfonate {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (9.22 mg, 0.010 mmol, 0.1 eq) and dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (10.73 mg, 0.020 mmol, 0.2 eq) were added, and the reaction mixture was heated to 100 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was backwashed with saturated brine (1 × 30 mL). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (chromatographic column specifications: Kinetex 5 m EVO C18, 30 mm x 150 mm, mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: 23% B to 60% B for 8 min, detection wavelength: UV 254 nm / 220 nm, retention time (min): 7.6). N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonamido)-2-(spiro[2.5]oct-5-en-6-yl)benzamide (10.84 mg, 19.83%) was obtained. MS: (ESI, m / z): 543.50 [M+H] + , RT(min):1.650 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.48 (s, 1H), 8.13 (d, 1H), 7.59 (d, 1H), 7.34 - 7.29 (m, 1H), 7.26 (t, 1H), 7.14 (dd, 1H), 6.99 (d, 1H), 5.88 (s, 1H), 4.84 (s, 1H), 4.34 (d, 2H), 3.66 (t, 2H), 3.16 (d, 4H), 2.16 (s, 2H), 2.08 - 1.98 (m, 2H), 1.16 (t, 2H), 0.00 (d, 4H).

[0283] Using conditions similar to those in Example 14, the compounds in the following table were prepared.

[0284] [Table 7] JPEG2025533411000057.jpg75169

[0285] Example 15 N-(dibenzo[b,d]furan-4-yl)-4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 111) [ka]

[0286] Step 1. Synthesis of N-(dibenzo[b,d]furan-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 111-2):

[0287] Under nitrogen gas protection, a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (100 mg, 0.280 mmol, 1 eq) in dichloromethane (2 mL) was added with 4-aminooxyfluorene (61.55 mg, 0.336 mmol, 1.2 eq), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (314.21 mg, 1.120 mmol, 4 eq), and N-methylimidazole (229.87 mg, 2.800 mmol, 10 eq) at room temperature. The reaction mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (20 mL). The reaction mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, backwashed with saturated brine (3 × 20 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1) to give N-(dibenzo[b,d]furan-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (140 mg, 95.73%). MS: (ESI, m / z): 523.30 [M+H] + , RT(min): 1.722

[0288] Step 2 Synthesis of N-(dibenzo[b,d]furan-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 111):

[0289] Under nitrogen gas protection, a solution of N-(dibenzo[b,d]furan-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (90 mg, 0.172 mmol, 1 eq) in N,N-dimethylformamide (2 mL) was added with 2-hydroxyethane-1-sulfonamide (32.34 mg, 0.258 mmol, 1.5 eq), cuprous iodide (8.2 mg, 0.043 mmol, 0.25 eq), potassium carbonate (71.43 mg, 0.516 mmol, 3 eq), and 2-(methylamino)acetic acid (6.14 mg, 0.069 mmol, 0.4 eq) at room temperature. The reaction mixture was heated to 120 °C and stirred for 1 h. The reaction mixture was cooled to room temperature and quenched with water. The reaction mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were backwashed with saturated brine (2 × 20 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions: chromatography column specifications: Kinetex EVO prep C18, 30*150, 5 μm; mobile phase A: water (10 mmol / mL sodium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 45% B to 70% B for 8 min; detection wavelength: UV 220 nm; retention time (min): 7.03. N-(dibenzo[b,d]furan-4-yl)-4-(2-hydroxyethanesulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (25.9 mg, 27.89%) was obtained. MS + :(ESI, m / z):519.90 [M+H] + , RT(min):1.784. 1H NMR: (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.21 (s, 1H), 8.74 -8.62 (m, 1H), 8.26 - 8.18 (m, 1H), 8.17 - 8.07 (m, 1H), 7.95 -7.84 (m, 1H), 7.73 (d, 1H), 7.67 -7.57 (m, 1H), 7.51 -7.45(m, 1H), 7.44 - 7.35 (m, 2H), 7.23 -7.13 (m, 1H), 4.95 (s, 1H), 3.84 -3.72 (m, 2H), 3.40 -3.35 (m, 2H), 3.14 - 2.97 (m, 4H), 1.83 (s, 4H), 0.43 (d, 4H).

[0290] Example 16 2-{6-Azaspiro[2.5]octan-6-yl}-N-(7-cyclopropylquinolin-4-yl)-4-(2-hydroxyethanesulfonamido)benzamide (Compound 112) [ka]

[0291] Step 1 Synthesis of t-butyl N-(7-bromoquinolin-4-yl)carbamate (compound 112-2):

[0292] To a solution of 7-bromoquinolin-4-amine (1.0 g, 4.483 mmol, 1 eq) in dichloromethane (15.0 mL) at room temperature, triethylamine (1.36 g, 13.449 mmol, 3 eq) and di-t-butyl dicarbonate (978.37 mg, 4.483 mmol, 1 eq) were added. The reaction mixture was stirred at room temperature for 17 hours. Since starting material was still present, the reaction mixture was heated to 50 °C and reacted for 1 hour. The reaction mixture was cooled to room temperature, and the reaction mixture was extracted with dichloromethane (3 × 60 mL). The combined organic phase was backwashed with saturated brine (2 × 60 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:1) to give t-butyl N-(7-bromoquinolin-4-yl)carbamate (1.16 g, 80.07%). MS: (ESI, m / z): 323.05 [M+H] + , RT(min):1.427

[0293] Step 2 Synthesis of t-butyl N-(7-bromoquinolin-4-yl)carbamate (compound 112-4):

[0294] Under nitrogen gas protection, a solution of t-butyl N-(7-bromoquinolin-4-yl)carbamate (700 mg, 2.166 mmol, 1 eq) in 1,4-dioxane (2 mL) and water (0.5 mL) was added with cyclopropylboronic acid (558.15 mg, 6.498 mmol, 3 eq), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (176.44 mg, 0.217 mmol, 0.1 eq), and cesium carbonate (2117.08 mg, 6.498 mmol, 3 eq) at room temperature. The reaction mixture was heated to 80 °C and stirred for 1 h. The mixture was cooled to room temperature and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was backwashed with saturated brine (2 × 40 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1:1) to give t-butyl N-(7-cyclopropylquinolin-4-yl)carbamate (530 mg, 86.05%). MS: (ESI, m / z): 285.30 [M+H] + , RT(min):1.054

[0295] Step 3 Synthesis of 7-cyclopropylquinolin-4-amine (compound 112-5):

[0296] To a solution of t-butyl N-(7-cyclopropylquinolin-4-yl)carbamate (500 mg, 1.758 mmol, 1 eq) in dichloromethane (5 mL), 4 mol / L hydrogen chloride in 1,4-dioxane (2.5 mL) was added at room temperature and stirred for 30 min. The resulting residue was concentrated under reduced pressure to give the product, 7-cyclopropylquinolin-4-amine (240 mg, 74.08%). MS: (ESI, m / z): 185.20 [M+H] + , RT(min):0.672

[0297] Step 4. Synthesis of 2-(6-azaspiro[2.5]octan-6-yl-N-(7-cyclopropylquinolin-4-yl)-4-iodobenzamide (compound 112-6):

[0298] Under nitrogen gas protection, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (609.16 mg, 2.172 mmol, 4 eq) and N-methylimidazole (445.64 mg, 5.430 mmol, 10 eq) were added to a solution of 7-cyclopropylquinolin-4-amine (100 mg, 0.543 mmol, 1 eq) and 2-(6-azaspiro[2.5]octan-6-yl-4-iodobenzoic acid (290.81 mg, 0.815 mmol, 1.5 eq) in dichloromethane (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding water (3 mL). The reaction mixture was extracted with dichloromethane (2 × 40 mL). The combined organic phases were backwashed with saturated brine (2 × 20 mL). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:1) to give 2-(6-azaspiro[2.5]octan-6-yl-N-(7-cyclopropylquinolin-4-yl)-4-iodobenzamide (70 mg, 24.64%). MS: (ESI, m / z): 524.45 [M+H] + , RT(min):1.029

[0299] Step 5. Synthesis of 2-{6-azaspiro[2.5]octan-6-yl}-N-(7-cyclopropylquinolin-4-yl)-4-(2-hydroxyethanesulfonamido)benzamide (compound 112):

[0300] Under nitrogen gas protection, a solution of 2-{6-azaspiro[2.5]octan-6-yl}-N-(7-cyclopropylquinolin-4-yl)-4-iodobenzamide (60 mg, 0.115 mmol, 1 eq) in N,N-dimethylformamide (1 mL) was added with 2-(methylamino)acetic acid (2.04 mg, 0.023 mmol, 0.2 eq), potassium carbonate (47.53 mg, 0.345 mmol, 3 eq), cuprous iodide (2.18 mg, 0.012 mmol, 0.1 eq), and 2-hydroxyethane-1-sulfonamide (17.21 mg, 0.138 mmol, 1.2 eq) at room temperature. The reaction mixture was heated to 120 °C and stirred for 1.5 h. The mixture was cooled to room temperature and extracted with ethyl acetate (2 × 30 mL). The combined organic phase was backwashed with saturated brine (2 × 20 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography to give 2-{6-azaspiro[2.5]octan-6-yl}-N-(7-cyclopropylquinolin-4-yl)-4-(2-hydroxyethanesulfonamido)benzamide (18.96 mg, 31.55%). MS: (ESI, m / z): 521.40 [M+H] +, RT(min):1.352 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.17 (s, 1H), 8.76 (d, , 1H), 8.33 (d, 1H), 8.23 ​​(d, 1H), 7.90 (d, , 1H), 7.69 (d, 1H), 7.39 (dd, , 1H), 7.23 (s, 1H), 7.06 (d, 1H), 4.96 (s, 1H), 3.78 (t, 2H), 3.35 (t, 2H), 3.03 (d, 4H), 2.18 (ddd, 1H), 1.41 (s, 4H), 1.15 - 1.06 (m, 2H), 0.91 - 0.83 (m, 2H), 0.25 (s, 4H).

[0301] Biological evaluation

[0302] Test Example 1

[0303] Test name: Imaging-based Nuclear Count Analysis (NCA) in OVCAR-3 cells Day 0 Compound Dilution and Treatment a) AM-5308 final test concentrations are 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM. b) Final test concentrations of test compounds are 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM. c) 37 cells o C, Cultured in a 5% CO2 incubator for 4 days. d) The DMSO concentration is 0.1%.

[0304] Day 1: Cells were seeded into 384-well cell culture plates. a) Cells were treated when cell confluence reached 80%-90%. b) The cells were resuspended in medium and counted and diluted to the desired concentration. c) 30 μL / well of cell suspension containing the appropriate cells was added to a 384-well plate at 600 cells / well.

[0305] Day 4 Detection a) 30 μL of 8% fixative (final concentration 4%) was added and the plate was incubated at room temperature for 30 minutes. b) The plate was centrifuged at 1000 RPM for 30 s. c) Washed twice with 60 μl / well of PBS. d) After fixation, cells were permeabilized and stained with 60 μL of wash buffer (1% BSA, 0.2% Triton X-100, 1X PBS) containing 2 μg / mL of Hoechst 33342 DNA dye. e) The plate was sealed and incubated at room temperature, protected from light, for 1 hour. f) Washed three times with PBS. g) 50 μL PBS was added per well and the plate was scanned with HCS. h) Data collection and detection

[0306] Data analysis % Inhibition = 100 - (Compound well reading - Low control well reading) / (High control well reading - Low control well reading) * 100 High reading control wells: cells and 30 nL DMSO, low reading control wells: 10 μM AM-5308 wells.

[0307] Using GraphPad Prism 8 software, IC 50 (nM) was calculated and the effect-dose curve of the compound was plotted.

[0308] [Table 8]

[0309] Test Example 2

[0310] Test name: KIF18A enzyme activity detection

[0311] Operation steps: 1) Compound dilution and treatment: The final test concentrations of AM-5308 are 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM, and the final test concentrations of test compounds are 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM. 2) 100 nL / well of diluted compound stock solution was transferred to the reaction plate using Echo 655. The final concentration of DMSO was 1%. 3) The reaction plate was sealed with sealing film and centrifuged at 1000 g for 1 minute. 4) A 2x enzyme solution was prepared with 1x reaction buffer. 5) 5 μL / well of 2× enzyme solution was added to the reaction plate. The plate was sealed with sealing film, centrifuged at 1000 g for 1 minute, and left at room temperature for 15 minutes. 6) Prepare a 2x ATP solution with 1x reaction buffer. 7) 5 μL of 2×ATP solution was added to the reaction plate, and the plate was centrifuged at 1000 g for 1 minute to start the reaction. 8) The reaction was carried out at room temperature for 60 minutes. 9) 10 μL of ADP Glo reagent was added, centrifuged at 1000 g for 1 minute, and incubated at room temperature for 60 minutes. 10) 20 μL of kinase detection reagent was added. The mixture was centrifuged at 1000 g for 1 minute and incubated at room temperature for 60 minutes. 11) Centrifuge at 1000g for 1 time. 12) The luminescence signal was read using Envision 2104.

[0312] Data Analysis: The calculation of the percentage of inhibition is as follows: %inhibition = 100- (Signal cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC ) × 100 Signal cmpd : Mean value of test compound in reaction plate. Signal Ave_PC : Mean value of positive control (AM-5308) in the reaction plate. Signal Ave_VC : Mean value of negative control (DMSO) in the reaction plate. I C 50 Calculation of and fitting of compound dose-effect curves: Using GraphPad 8.0, the IC of the compound was calculated by nonlinear fitting equation. 50 obtained.

[0313] 3) Quality control Z factor > 0.5, S / B > 2.

[0314] [Table 9]

[0315] The above is an illustrative description of the embodiments of the technical solutions of the present invention. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of this application.

Claims

1. A compound of formula (I), its racemate, stereoisomer, tautomer, isotopic marker, solvate, polytype, pharmaceutically acceptable salt or prodrug compound thereof, 【Chemical 1】 where A is unsubstituted or contains one, two or more R a and optionally substituted fused ring groups, wherein the fused ring groups are selected from saturated or partially unsaturated C 3-14 carbocycle, C 6-14 comprising two, three or four rings independently selected from an aryl ring, a 5- to 14-membered heteroaryl ring, and a 3- to 14-membered heterocycle; Each R a are the same or different and are H, OH, halogen, cyano group, NH 2 , NO 2 , unsubstituted or one, two or more R a1 The following groups optionally substituted with: C 1-12 Alkyl group, C 1-12 Alkoxy group, C 3-12 cycloalkyl groups, or two R a together with the carbon atoms to which they are attached form saturated or partially unsaturated C 3-14 Form a carbocyclic ring or two non-adjacent R a are linked together at their end groups to form C 1-3 and each R a1 are the same or different and are H, OH, halogen, cyano group, NH 2 , NO 2 , C 1-12 Alkyl group, C 1-12 Alkoxy group, C 3-12 are independently selected from cycloalkyl groups, E is unsubstituted or one, two or more R ｃ The following groups optionally substituted with: -NH-S(=O) 2 -R ｃ1 , -S(=O) 2 -NH-R ｃ2 , -S(=O)(=NH)-R e3 , -N(R e4 )(R e5 ), and a 3- to 14-membered heterocyclyl group, and each R e are the same or different and may be OH, halogen, cyano group, C 1-12 Alkyl group, C 1-12 Alkoxy group, halogenated C 1-12 Alkyl groups, halogenated C 1-12 Alkoxy group, cyano C 1-12 Alkyl group, cyano C 1-12 Alkoxy group, -N(R e6 )(R e7 ), selected independently from Each R ｃ1 , R ｃ2 , R ｃ3 , R ｃ4 , R ｃ5 , R ｃ6 , R ｃ7 are the same or different, and H, C 1-12 Alkyl group, hydroxy C 1-12 Alkyl groups, halogenated C 1-12 Alkyl groups, halogenated C 1-12 Alkoxy group, cyano C 1-12 Alkyl group, cyano C 1-12 Alkoxy group, C 3-12 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 1-12 Alkoxy-C 1-12 are independently selected from alkyl groups, M is unsubstituted or one, two or more R m C optionally substituted with 3-12 Cycloalkyl groups, C 3-12 a cycloalkenyl group or a nitrogen-containing 3- to 14-membered heterocyclyl group, and each R m are the same or different and may be H, halogen, cyano group, C 1-12 Alkyl groups, halogenated C 1-12 Alkyl group, cyano C 1-12 Alkyl group, C 1-12 Alkoxy group, cyano C 1-12 or two R alkoxy groups independently selected from the group consisting of alkoxy groups and alkoxy groups linked to the same ring carbon atom. m together with the carbon atoms to which they are attached form saturated or partially unsaturated C 3-14 forming a carbocyclic ring, Y 1 , Y 2 , Y 3 are the same or different and are independently selected from N or CH, a compound, its racemate, stereoisomer, tautomer, isotopic marker, solvate, polytype, pharmaceutically acceptable salt or prodrug compound thereof.

2. A is unsubstituted or has one, two or more R a and optionally substituted fused ring groups, wherein the fused ring groups are selected from saturated or partially unsaturated C 3-8 carbocycle, C 6-10 comprising two, three or four rings independently selected from an aryl ring, a 5- to 10-membered heteroaryl ring, and a 3- to 8-membered heterocycle; Each R a are the same or different and are H, OH, halogen, cyano group, NH 2 , NO 2 , C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-8 Cycloalkyl groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, cyano C 1-6 Alkyl group, cyano C 1-6 Alkoxy group, C 3-8 Cycloalkyl-C 1-6 or two R alkoxy groups independently selected from the group consisting of alkoxy groups and alkoxy groups linked to the same ring carbon atom. a together with the carbon atoms to which they are attached form saturated or partially unsaturated C 3-8 Form a carbocyclic ring or two non-adjacent R a are linked together at their end groups to form C 1-3 and forming an alkylene group of the formula: Preferably, A is unsubstituted or contains one, two or more R a wherein the fused ring group is selected from a fused ring group optionally substituted with 【Chemistry 2】 is selected from where T is CH 2 , C.H., N.H., N.R. a or O, Z is CH 2 , C.H., N.H., N.R. a or O, X is selected from N or CH; p and q are independently selected from 0, 1, 2, and 3, and p and q cannot be 0 at the same time; r and s are independently selected from 0, 1, 2, and 3, and r and s cannot be 0 at the same time. Preferably, A is unsubstituted or contains one, two or more R a wherein the fused ring group is selected from a fused ring group optionally substituted with 【Chemistry 3】 is selected from where Z is CH 2 , C.H., N.H., N.R. a or O, X is selected from N or CH; r and s are independently selected from 0, 1, 2, and 3, and r and s cannot be 0 at the same time. Preferably, A is 【Chemistry 4】 is selected from where T is CH 2 , C.H., N.H., N.R. a or O, Z is CH 2 , C.H., N.H., N.R. a or O, X is selected from N or CH; n is selected from 0, 1, 2, 3, 4 or 5; p and q are independently selected from 0, 1, 2, and 3, and p and q cannot be 0 at the same time; r and s are independently selected from 0, 1, 2, and 3, and r and s cannot be 0 at the same time. Preferably, A is unsubstituted or contains one, two or more R a wherein the fused ring group is formed by condensing two, three, four or more rings selected from a benzene ring, a pyridine ring, an imidazole ring, a piperazine ring, a piperidine ring, a tetrahydropyrrole ring, a tetrahydropyran ring, a tetrahydrofuran ring, a furan ring, a morpholine ring, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, and a cycloheximine ring; Preferably, A is unsubstituted or contains one, two or more R a is optionally replaced by 【Chemistry 5】 is selected from Preferably, each R a are the same or different and are independently selected from H, OH, F, Cl, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, and cyclopropylmethoxy, or two R linked to the same ring carbon atom. a together with the carbon atoms to which they are attached form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring, or two non-adjacent R a are linked at their end groups and together form a methylene or ethylene group, Preferably, A is 【Chemistry 6】 【change】 【change】 The compound of claim 1, its racemate, stereoisomer, tautomer, isotopic marker, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, is selected from the group consisting of:

3. E is unsubstituted or has one or two R e The following groups optionally substituted with: -NH-S(=O) 2 -R e1 , -S(=O) 2 -NH-R e2 , -S(=O)(=NH)-R e3 Each R e1 , R e2 , R e3 are the same or different, and H, C 1-6 Alkyl group, hydroxy C 1-6 Alkyl groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, cyano C 1-6 Alkyl group, cyano C 1-6 Alkoxy group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 1-6 Alkoxy-C 1-6 alkyl groups, each R e are the same or different and may be OH, halogen, cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, cyano C 1-6 Alkyl group, cyano C 1-6 are independently selected from alkoxy groups, Preferably, E is 【Chemistry 7】 The compound according to claim 1 or 2, its racemate, stereoisomer, tautomer, isotopic marker, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, is selected from the group consisting of:

4. M is unsubstituted or one, two or more R m C optionally substituted with 3-8 Cycloalkyl groups, C 3-8 a cycloalkenyl group or a nitrogen-containing 3- to 8-membered heterocyclyl group, and each R m are the same or different and may be H, halogen, cyano group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, cyano C 1-6 Alkyl group, C 1-6 Alkoxy group, cyano C 1-6 or two R alkoxy groups independently selected from the group consisting of alkoxy groups and alkoxy groups linked to the same ring carbon atom. m together with the carbon atoms to which they are attached form saturated or partially unsaturated C 3-8 forming a carbocyclic ring, Preferably, M is 【Chemistry 8】 The compound according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotopic marker, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, is selected from the group consisting of:

5. Y 1 , Y 2 , Y 3 cannot be N at the same time, Preferably, Y 1 If CH, then Y 2 is CH and Y 3 is N or CH, and Y 1 If CH, then Y 2 is N and Y 3 is N or CH, and Y 1 If N, then Y 2 is CH and Y 3 is N or CH, and Y 1 If N, then Y 2 is N and Y 3 is CH, or a racemate, stereoisomer, tautomer, isotopic marker, solvate, polytype, pharmaceutically acceptable salt, or prodrug compound thereof according to any one of claims 1 to 4.

6. The compound has the following structure: 【Chemistry 9】 where A, M, E, Y 1 , Y 2 , Y 3 have, independently of one another, the definitions according to any one of claims 1 to 5, Preferably, the compound of formula (I) has the following structure: 【Chemistry 10】 where M, E, Y 1 , Y 2 , Y 3 , R a , X, Z, T, n, p, q, r, s independently of one another have the definitions according to any one of claims 1 to 5, Preferably, the compound of formula (I) has the following structure: 【Chemistry 11】 where A and Y 1 , Y 2 , Y 3 independently have the definitions set forth in any one of claims 1 to 5; Preferably, the compound of formula (I) has the following structure: 【Chemistry 12】 where Y 1 , Y 2 , Y 3 , R a , X, Z, T, n, p, q, r, s independently of one another have the definitions according to any one of claims 1 to 5, Preferably, the compound of formula (I) has the following structure: 【Chemistry 13】 where Y 1 , Y 2 , Y 3 , R a 6. The compound according to any one of claims 1 to 5, characterized in that X, Z, n, r, s have, independently of one another, the definitions according to any one of claims 1 to 5, or a racemate, stereoisomer, tautomer, isotopic marker, solvate, polytype, pharmaceutically acceptable salt or prodrug compound thereof.

7. The compound is 【Chemistry 14】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 The compound according to any one of claims 1 to 6, characterized in that it has the structure:

8. A method for producing the compound according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, isotopic marker, solvate, polytype, pharmaceutically acceptable salt or prodrug compound thereof, comprising: 【Chemistry 15】 (1) Compound a is converted to compound A-NH 2 to obtain compound b; (2) reacting compound b with compound EH to obtain the compound of formula (I), where A, E, M, Y 1 , Y 2 , Y 3 have, independently of one another, the definitions according to any one of claims 1 to 7, and L is selected from halogen, for example Cl, Br, I.

9. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, isotopic marker, solvate, polytype, pharmaceutically acceptable salt or prodrug compound thereof.

10. Use of at least one of the compounds according to any one of claims 1 to 7, their racemates, stereoisomers, tautomers, isotopic markers, solvates, polytypes, pharmaceutically acceptable salts or prodrug compounds thereof in the manufacture of a drug, comprising: Preferably, the use is in the manufacture of a medicament for treating a KIF18A-mediated disorder and / or disease, for example, in the manufacture of a KIF18A inhibitor medicament; Preferably, the disease is cancer, including, for example, bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.

Images