Kif18a inhibitor compounds, pharmaceutical compositions, and methods of making and using the same

Abstract

The present application provides a compound shown in formula (I), a pharmaceutical composition and a preparation method and application thereof. The compound has good KIF18A inhibition effect, can be combined with microtubules to form a complex to regulate KIF18A protein, is used for treating KIF18A-mediated diseases and / or diseases, such as tumor diseases, and is used for preparing medicines for such diseases or diseases.

Description

[0001] This invention claims the following:

[0002] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on September 8, 2022, with patent application number 2022110982256 and title "KIF18A inhibitor compound, pharmaceutical composition and preparation method and application thereof".

[0003] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on November 16, 2022, with patent application number 2022114366075 and title "KIF18A inhibitor compound, pharmaceutical composition and preparation method and application thereof".

[0004] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on February 10, 2023, with patent application number 2023100987012 and title "KIF18A inhibitor compound, pharmaceutical composition and preparation method and application thereof".

[0005] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on August 30, 2023, with patent application number 2023111078615 and title "KIF18A inhibitor compound, pharmaceutical composition and preparation method and application thereof".

[0006] The entire contents of the prior application are incorporated herein by reference. Technical Field

[0007] This invention belongs to the pharmaceutical field, specifically relating to a KIF18A inhibitor compound, a pharmaceutical composition, its preparation method, and its application. Background Technology

[0008] Cancer is one of the most serious diseases affecting human health, with mortality and morbidity rates often ranking among the highest of all diseases. Although the quality of life for some patients has been greatly improved with the continuous development and progress of medical technology and drug research, there are still many unmet clinical needs in the search for effective treatments or cures for different cancers, and new targets will provide new possibilities for future cancer drug development.

[0009] Cancer cells exhibit unregulated cell proliferation due to damage or loss of one or more genes that regulate the cell cycle. Various kinases and kinesins have been identified as playing key roles in the regulation and progression of cell cycle and mitosis in both normally dividing cells and cancer cells.

[0010] Kinesin molecules are kinetic proteins that use intracellular microtubules as their orbital pathways; also known as molecular motors, they convert ATP energy into mechanical energy and are closely related to eukaryotic cell division, mitosis, meiosis, tissue and organ growth and development, neuronal development, and signal transduction. Kinesin members share a relatively conserved motor domain. Based on the location of the motor domain in the molecule, the kinesin family is broadly divided into three categories: N-type kinesins, where the amino (-NH2) terminal region of the polypeptide chain contains a motor domain; M-type kinesins, where the middle region contains a motor domain; and C-type kinesins, where the carboxyl (-COOH) terminal region contains a motor domain.

[0011] Chromosomal instability is a hallmark of cancer, caused by errors in chromosome segregation 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 play a role in maintaining the integrity of the bipolar spindle and promoting the survival 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 microtubule inhibitors both stabilize microtubules and prevent microtubule assembly. Currently, antimitotic drugs have limitations due to their narrow therapeutic window, and these issues necessitate the development of new targets to address them.

[0012] Although tubulin inhibitors are widely used as standard treatments for various types of human cancer, these drugs can cause collateral damage to normal cells, including myelosuppression and neurotoxicity. Since KIF18A may not be essential in normal diploid somatic cells (KIF18A knockout mice are viable but have reproductive defects, suggesting that KIF18A is not a necessary gene for normal somatic cell division), targeting KIF18A could potentially significantly reduce its toxicity, thus improving the therapeutic safety window of tubulin-targeting drugs in clinical practice.

[0013] KIF18A protein is highly expressed in various tumors, including colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer, and ovarian cancer. KIF18A plays a crucial role in the occurrence, development, and metastasis of breast cancer, and its high expression predicts poor prognosis. KIF18A is essential for the proliferation of chromosomally unstable cells derived from triple-negative breast cancer or colorectal cancer, but is not required in diploid cells. Knockout of the KIF18A gene leads to infertility in male mice, but female mice are unaffected. KIF18A mRNA expression is significantly associated with higher tumor grade and larger tumors in breast cancer patients, and KIF18A is an independent predictor of lymph node metastasis in breast cancer, with a risk factor of 3.2. Furthermore, inhibiting KIF18A expression not only affects its key function in cell mitosis but also reduces cancer cell migration by stabilizing leading-edge microtubules, ultimately leading to inactivation of the PI3K-AKT signaling pathway and inducing apoptosis.

[0014] Therefore, the development of KIF18A protein inhibitors may be a new breakthrough in cancer drugs. Summary of the Invention

[0015] To address the aforementioned technical problems, the present invention provides a compound of formula (I), its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound:

[0016]

[0017] Wherein, A is selected from unsubstituted or arbitrarily substituted by one, two or more Rs. a Substituted fused-ring groups; said fused-ring groups comprise two, three, or four C groups independently selected from saturated or partially unsaturated C groups. 3-14 Carbon ring, C 6-14 Aromatic rings, 5-14 bivalent heterocyclic aromatic rings, and 3-14 bivalent heterocyclic rings;

[0018] Each R a They may be identical or different, and are independently selected from H, OH, halogens, cyano groups, NH2, and NO2, without substitution or optionally by one, two, or more R groups. a1 The following groups are substituted: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl; or, two R atoms attached to the same carbon atom in a ring. a Together with the carbon atoms it is attached to, they form saturated or partially unsaturated C atoms. 3-14 Carbon rings; or, two non-adjacent Rs a Connected by their end groups, they together form C 1-3Alkylene; each R a1 They may be the same or different, and are independently selected from H, OH, halogens, cyano groups, NH2, NO2, and C. 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 cycloalkyl;

[0019] E is selected from unsubstituted or optionally by one, two or more R. e The following groups are substituted: -NH-S(=O)2-R e1 -S(=O)2-NH-R e2 -S(=O)(=NH)-R e3 -N(R) e4 (R) e5 ), 3-14 membered heterocyclic groups; each R e They may be the same or different, and are independently selected from OH, halogen, cyano, and C groups. 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, Halogenated C 1-12 Alkoxy, cyano C 1-12 Alkyl, cyano C 1-12 Alkoxy, -N(R) e6 (R) e7 );

[0020] Each R e1 R e2 R e3 R e4 R e5 R e6 R e7 Whether the two are the same or different, they are selected independently from H and C. 1-12 Alkyl, hydroxyl C 1-12 Alkyl, Halogenated C 1-12 Alkyl, Halogenated C 1-12 Alkoxy, cyano C 1-12 Alkyl, cyano C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 1-12 Alkoxy-C 1-12 alkyl;

[0021] M is selected from unsubstituted or optionally by one, two or more Rs. m Replacement C 3-12 cycloalkyl, C 3-12 Cycloalkenyl or nitrogen-containing 3-14 membered heterocyclic groups; each R m They may be the same or different, and are independently selected from H, halogen, cyano, and C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, cyano C1-12 Alkyl, C 1-12 Alkoxy, cyano C 1-12 alkoxy group; or, two R groups attached to the same carbon atom in a ring. m Together with the carbon atoms it is attached to, they form saturated or partially unsaturated C atoms. 3-14 Carbon rings;

[0022] Y1, Y2, and Y3 may be the same or different, and are independently selected from N or CH.

[0023] According to some implementation schemes, A is selected from unsubstituted or optionally by one, two or more R. a Substituted fused-ring groups; said fused-ring groups comprise two, three, or four C groups independently selected from saturated or partially unsaturated C groups. 3-8 Carbon ring, C 6-10 Aromatic rings, 5-10 degree heterocyclic aromatic rings, and 3-8 degree heterocyclic rings;

[0024] Each R a They may be the same or different, and are independently selected from H, OH, halogens, cyano groups, NH2, NO2, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, cyano C 1-6 Alkyl, cyano C 1-6 Alkoxy, C 3-8 cycloalkyl-C 1-6 alkoxy group; or, two R groups attached to the same carbon atom in a ring. a Together with the carbon atoms it is attached to, they form saturated or partially unsaturated C atoms. 3-8 Carbon rings; or, two non-adjacent Rs a Connected by their end groups, they together form C 1-3 Alkylene;

[0025] According to some implementation schemes, A is selected from unsubstituted or optionally by one, two or more R. a Substituted fused-ring groups; said fused-ring groups are selected from,

[0026] Wherein, T is selected from CH2, CH, NH, NR a Or O;

[0027] Z is selected from CH2, CH, NH, NR a Or O;

[0028] X is selected from N or CH;

[0029] p and q are independently selected from 0, 1, 2, and 3, and p and q are not both 0 at the same time;

[0030] r and s are independently selected from 0, 1, 2, and 3, and r and s are not both 0 at the same time.

[0031] According to some implementation schemes, A is selected from unsubstituted or optionally by one, two or more R. a Substituted fused-ring groups; said fused-ring groups are selected from

[0032] Z is selected from CH2, CH, NH, and NR. a Or O;

[0033] X is selected from N or CH;

[0034] r and s are independently selected from 0, 1, 2, and 3, and r and s are not both 0 at the same time.

[0035] According to some implementation schemes, A is selected from...

[0036] Wherein, T is selected from CH2, CH, NH, NR a Or O;

[0037] Z is selected from CH2, CH, NH, NR a Or O;

[0038] X is selected from N or CH;

[0039] n is selected from 0, 1, 2, 3, 4 or 5;

[0040] p and q are independently selected from 0, 1, 2, and 3, and p and q are not both 0 at the same time;

[0041] r and s are independently selected from 0, 1, 2, and 3, and r and s are not both 0 at the same time.

[0042] According to some implementation schemes, A is selected from unsubstituted or optionally by one, two or more R. a The substituted fused ring group; said fused ring group is formed by the fusion of two, three, four or more rings selected from benzene ring, pyridine ring, imidazole ring, piperazine ring, piperidine ring, tetrahydropyrrole ring, tetrahydropyran ring, tetrahydrofuran ring, furan ring, morpholine ring, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, and cycloheximine ring.

[0043] According to some implementation schemes, A is selected from unsubstituted or optionally by one, two or more R. a Replacement

[0044] According to some implementation schemes, each Ra The same or different, independently selected from H, OH, F, Cl, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclopropylmethoxy; or, two R atoms attached to the same carbon atom of a ring. a Together with the carbon atoms it is attached to, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane rings; or, two non-adjacent R atoms... a They are connected by their terminal groups to form methylene or ethylene.

[0045] According to some implementation schemes, A is selected from...

[0046] According to some implementation schemes, E is selected from unsubstituted or optionally replaced by one or two R. e The following groups are substituted: -NH-S(=O)2-R e1 -S(=O)2-NH-R e2 -S(=O)(=NH)-R e3 ; Each R e1 R e2 R e3 Whether the two are the same or different, they are selected independently from H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, cyano C 1-6 Alkyl, cyano C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 1-6 Alkoxy-C 1-6 Alkyl; each R e They may be the same or different, and are independently selected from OH, halogen, cyano, and C groups. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, cyano C 1-6 Alkyl, cyano C 1-6 Alkyl group.

[0047] According to some implementation schemes, E is selected from...

[0048] According to some implementation schemes, M is selected from unsubstituted or optionally replaced by one, two or more R. m Replacement C 3-8 cycloalkyl, C 3-8 Cycloalkenyl or nitrogen-containing 3-8 membered heterocyclic groups; each Rm They may be the same or different, and are independently selected from H, halogen, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, cyano C 1-6 alkoxy group; or, two R groups attached to the same carbon atom in a ring. m Together with the carbon atoms it is attached to, they form saturated or partially unsaturated C atoms. 3-8 Carbon rings;

[0049] According to some implementation schemes, M is selected from...

[0050] According to some implementation schemes, Y1, Y2, and Y3 are not all N at the same time;

[0051] According to some implementation schemes, 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.

[0052] According to some embodiments, the compound represented by formula (I) has the following structure:

[0053]

[0054] Among them, A, M, E, Y1, Y2, and Y3 have the definitions described in this paper independently of each other.

[0055] According to some embodiments, the compound represented by formula (I) has the following structure:

[0056]

[0057] Among them, M, E, Y1, Y2, Y3, R a X, Z, T, n, p, q, r, and s each have their own definitions as described herein.

[0058] According to some embodiments, the compound represented by formula (I) has the following structure:

[0059]

[0060] Among them, A, Y1, Y2, and Y3 independently have the definitions described in this paper.

[0061] According to some embodiments, the compound represented by formula (I) has the following structure:

[0062]

[0063] Among them, Y1, Y2, Y3, R a X, Z, T, n, p, q, r, and s each have their own definitions as described herein.

[0064] According to some embodiments, the compound represented by formula (I) has the following structure:

[0065]

[0066] Among them, Y1, Y2, Y3, R a X, Z, n, r, and s each have their own independent definitions as described in this paper.

[0067] According to some embodiments, the compound shown in formula (I) is selected from the following structures:

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081] The present invention also provides a method for preparing the compound shown in formula (I), comprising the following steps:

[0082]

[0083] (1) Compound a reacts with compound A-NH2 to give compound b;

[0084] (2) Compound b reacts with compound EH to give the compound shown in formula (I);

[0085] Among them, A, E, M, Y1, Y2, and Y3 independently have the definitions described above; L is selected from halogens, such as Cl, Br, and I.

[0086] The present invention also provides a pharmaceutical composition comprising at least one of the following: a compound of formula (I), a racemic mixture, a stereoisomer, a tautomer, an isotope label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof, in a therapeutically effective amount.

[0087] According to embodiments of the present invention, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0088] According to embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0089] The present invention also provides a method for treating tumor diseases, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the following: a compound of formula (I), its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound.

[0090] The present invention also provides a method for treating tumor diseases, comprising administering to a patient a preventive or therapeutically effective amount of the above-described pharmaceutical composition.

[0091] The cancers mentioned include colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer, and ovarian cancer.

[0092] In some implementations, the patient includes mammals, preferably humans.

[0093] The present invention also provides at least one of the following: a compound of formula (I) for treating tumor diseases, a racemic mixture, a stereoisomer, a tautomer, an isotope label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof, or a pharmaceutical composition thereof.

[0094] The present invention also provides the use of at least one of the compounds of formula (I), racemates, stereoisomers, tautomers, isotope labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof in the preparation of pharmaceuticals.

[0095] According to embodiments of the present invention, the use may be in the preparation of medicaments for treating KIF18A-mediated conditions and / or diseases, such as in the preparation of KIF18A inhibitor medicaments.

[0096] According to embodiments of the present invention, the disease is, for example, cancer, including colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer, or ovarian cancer.

[0097] Beneficial effects

[0098] This invention, through structural optimization, creatively yields a class of novel compounds that not only exhibit excellent KIF18A inhibitory activity and OVCAR-3 in vitro cellular activity, but also significantly improved physicochemical properties (solubility, permeability), significantly enhanced in vivo OVCAR-3 efficacy, and good safety profile. These compounds can be used to treat KIF18A-mediated conditions and / or diseases, such as cancer, and to prepare drugs for treating such conditions or diseases.

[0099] Terminology Definitions and Explanations

[0100] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0101] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-14" is equivalent to describing each integer value in the numerical range "1-14", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14.

[0102] The term “optional” (or “optionally”, “optionally”) in the general formula definition of this application means the case of being substituted by zero or one or more substituents. For example, “optionally substituted by one, two or more R” means that it may not be substituted by R (no substitution) or may be substituted by one, two or more R.

[0103] "More than three" means three or more.

[0104] Term "C" 1-12 "alkyl" should be understood to refer to straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6"Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0105] Term "C" 3-12 "Cycloalkyl" should be understood to refer to saturated monovalent monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) hydrocarbon rings or tricyclic alkanes, having 3 to 12 carbon atoms, preferably "C". 3-10 "Cycloalkyl", more preferably "C" 3-8 cycloalkyl. The term "C" 3-12 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. The C... 3-12 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0106] Term "C" 3-12 "Cycloalkenyl" should be understood as referring to monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring), or tricyclic olefins containing carbon-carbon double bonds, having 3 to 12 carbon atoms, preferably "C". 3-10 "Cycloalkenyl", more preferably "C" 3-8 "Cycloalkenyl" can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. The C 3-12 Cycloalkenyl groups can be monocyclic hydrocarbon groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, or dicyclic hydrocarbon groups such as spiro[2.5]oct-5-enyl, spiro[3.5]non-6-enyl, spiro[4.5]dec-7-enyl.

[0107] Term "C"6-14 "Aryl" should preferably be understood to represent a monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 14 carbon atoms and possessing monovalent aromaticity or partial aromaticity. It can be a monoaromatic ring or a polyaromatic ring fused together, preferably "C". 6-10 Aryl. The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0108] The term "5-14-membered heteroaryl" should be understood to include monocyclic, bicyclic (e.g., fused, bridged, spirocyclic), or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, for example, "5-10-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzo[a]fused. "Hyperaryl" also refers to a group in which the heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein the root or point of the connection is on the heteroaryl ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indazinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purineyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinazinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4- 5, 6, 7 or 8-isoquinolinyl, 1, 4, 5, 6, 7 or 8-phthalazinyl, 2, 3, 4, 5 or 6-naphthidyl, 2, 3, 5, 6, 7 or 8-quinazolinyl, 3, 4, 5, 6, 7 or 8-cenolinyl, 2, 4, 6 or 7-pteridyl, 1, 2, 3, 4, 5, 6, 7 or 8-4aH carbazole, 1, 2, 3, 4, 5, 6, 7 - or 8-carbazolylcarbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbazolyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinel, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenanthrolinel -Phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenthiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzisoquinolinyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazin[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furano[3,2-b]-pyranolyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-azinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]-azolel, 2-, 4- or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazolo[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furano[3,4-c]cenolinyl, 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]thiopheneyl, 2-, 4-, 5-, 6- or 7-benzozolyl, 2-, 4-, 5-, 6- or 7-benzimidazinyl, 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, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-4H-pyrrolo[1,2-b][2]benzozapinyl. Typical fused heteroaryl groups include, but are not limited to, 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]thiophene, 2-, 4-, 5-, 6-, or 7-benzozozolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14-membered heteroaryl group is linked to other groups to form the compounds of the present invention, the carbon atom on the 5-14-membered heteroaryl ring may be linked to other groups, or the heteroatom on the 5-14-membered heteroaryl ring may be linked to other groups. When the 5-14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution sites; for example, hydrogen atoms bonded to carbon atoms on the heteroaryl ring can be substituted, or hydrogen atoms bonded to heteroatoms on the heteroaryl ring can be substituted.

[0109] Unless otherwise defined, the term "3-14 membered heterocyclic 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 (such as a fused ring, bridged ring, or spirocyclic ring), or a 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and contains at least one, for example, 1, 2, 3, 4, 5, or more heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrides, -S(O)-, or -S(O)2- states. Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic groups". The term "3-10 membered heterocyclic group" means a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl or oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolealkyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazineyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group can be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, like a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the carbon atom on the 3-14-membered heterocyclic group can be linked to other groups, or the heterocyclic atom on the 3-14-membered heterocyclic ring can be linked to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazine, the nitrogen atom on the piperazine group can be attached to other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinium, the nitrogen atom on the piperidinium ring and the carbon atom at its para position can be attached to other groups.

[0110] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0111] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0112] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0113] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0114] "Halogenation" refers to the replacement of a substance by one or more halogens.

[0115] Unless otherwise stated, R as described herein a A substituent on the fused ring group A, that is, representing R a Substitution can optionally occur at any position of the fused ring group A, as shown in the structural formula. R represents a It can be in the ring The substitution of the N-containing heterocycle on the left also indicates R. a It can be in the ring Substitution on the ring containing X on the right, R a The total number of substitutions on the fused ring group A is n.

[0116] Unless otherwise stated, the definitions of terms in this document also apply to groups containing the term, such as C. 1-12 The definition of alkyl also applies to C 1-12 Alkyloxy (i.e., C) 1-12 Alkyl groups).

[0117] The term "alkylene" refers to a divalent group as defined above. For example, the term "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above. Preferably, the alkylene group has 1 to 12 carbon atoms (i.e., C12). 1-12 Alkylenes, more preferably alkylenes containing 1 to 6 carbon atoms (i.e., C16-64 ... 1-6 (alkylene).

[0118] Term "C" 3-14 "Carbon ring" refers to a saturated or unsaturated aliphatic hydrocarbon ring with 3 to 14 carbon atoms, including cycloalkanes with 3 to 14 carbon atoms. 3-14 Cycloalkanes (cycloalkane rings) and cycloalkenes (C14-14 carbon atoms) 3-12 Cyclic olefin rings (C1-C1) or cyclic alkyne rings (C1-C2) with 3 to 14 carbon atoms 3-12 Cyclic alkynes (ring).

[0119] Those skilled in the art will understand that the compounds shown in formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds 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.

[0120] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0121] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers of each chiral carbon in the R or S configuration, or mixtures thereof, and racemates. The compounds of the present invention or their intermediates can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in both R and S forms, 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 separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0122] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0123] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0124] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Detailed Implementation

[0125] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0126] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0127] Example 1

[0128] 2-{6-azaspiro[2.5]octane-6-yl}-4-(2-hydroxyethanesulfonamide)-N-(6-methoxynaphth-1-yl)benzamide (Compound 1)

[0129]

[0130]

[0131] The first step is the synthesis of 6-methoxynaphthalene-1-amine (compounds 1-2):

[0132] Under nitrogen protection, hydroxylamine hydrochloride (206.2 mg, 2.967 mmol, 1.5 eq) was added to a polyphosphoric acid (2 mL) solution of 6-methoxynaphthalene-1-carboxylic acid (400 mg, 1.978 mmol, 1 eq) at room temperature and the mixture was 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 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 to give 6-methoxynaphthalene-1-amine (compounds 1-2, 300 mg, 87.55%).

[0133] MS(ESI, m / z): 174.35 [M+H] + RT(min): 0.760

[0134] The second step is the synthesis of 2-{6-azaspiro[2.5]octane-6-yl}-4-iodo-N-(6-methoxynaphth-1-yl)benzamide (compounds 1-4):

[0135] Under nitrogen protection, 2-{6-azaspiro[2.5]octane-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) were added to a solution of 6-methoxynaphthyl-1-amine (150 mg, 0.866 mmol, 1 eq) in dichloromethane (3 mL) at room temperature, and the mixture was stirred for 2 h; the target 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 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 residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (5:1) to give 2-{6-azaspiro[2.5]octane-6-yl}-4-iodo-N-(6-methoxynaphth-1-yl)benzamide (compounds 1-4, 300 mg, 67.61%).

[0136] MS(ESI, m / z): 513.35 [M+H] + RT(min): 1.499

[0137] Step 3: Synthesis of 2-{6-azaspiro[2.5]octane-6-yl}-4-(2-hydroxyethanesulfonamide)-N-(6-methoxynaphth-1-yl)benzamide (compound 1)

[0138] Under nitrogen protection and at 120°C, 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) were added to a solution of 2-{6-azaspiro[2.5]octane-6-yl}-4-iodo-N-(6-methoxynaphth-1-yl)benzamide (80 mg, 0.156 mmol, 1 eq) in N,N-dimethylformamide (0.5 mL), and the mixture was stirred overnight. The solution was diluted with 10 mL of water and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were backwashed with saturated brine (3 × 10 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography under the following conditions (column specifications: XBridge Prep OBD C18 Column, 30X150mm, 5μm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile (0.1% diethylamine) --HPLC--merk; flow rate: 60mL / min; elution gradient: 40%B to 58%B, 10min, 58%B; detection wavelength: UV 220nm; retention time (min): 8.23), yielding 2-{6-azaspiro[2.5]octane-6-yl}-4-(2-hydroxyethanesulfonylamino)-N-(6-methoxynaphth-1-yl)benzamide (compound 1, 30.32mg, 38.11%).

[0139] MS(ESI, m / z): 509.90 [M+H] + RT(min):1.572

[0140] 1 H NMR: (400MHz, DMSO-d6) δ11.84(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).

[0141] The compounds listed in the table below were prepared using conditions similar to those in Example 1.

[0142]

[0143]

[0144] Example 2

[0145] 2-{6-azaspiro[2.5]octane-6-yl}-4-(2-hydroxyethanesulfonylamino)-N-(6-methoxynaphth-1-yl)benzamide (Compound 21)

[0146]

[0147]

[0148] The first step is the synthesis of 4-(4-bromo-1H-benzimidazol-2-yl)butane-1-ol (compound 21-3):

[0149] Under nitrogen protection and at 100°C, a solution of 3-bromophenyl-1,2-diamine (2 g, 10.693 mmol, 1 eq) in hydrochloric acid (4 M, 20 mL) was stirred for 2 hours. The reaction mixture was cooled to room temperature and alkalized to pH 11 with saturated potassium carbonate solution. 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.

[0150] MS(ESI, m / z): 269.20 [M+H] + RT(min): 0.527

[0151] The second step is the synthesis of 9-bromo-benzo[4,5]imidazo[1,2-a]piperidine (compound 21-4):

[0152] Under nitrogen protection and in an ice bath, di-tert-butyl azodicarbonate (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)but-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 heated to 85°C and stirred overnight. The reaction mixture was quenched with water (60 mL) at room temperature. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were 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) and 9-bromo-benzo[4,5]imidazo[1,2-a]piperidine (compound 21-4, 1 g, 53.59%).

[0153] MS(ESI, m / z): 250.90 [M+H] + RT(min): 0.746

[0154] The third step involves the synthesis of benzo[4,5]imidazo[1,2-a]piperidin-9-ylcarbamate tert-butyl ester (compound 21-6):

[0155] Under nitrogen protection, at room temperature, a solution of 9-bromo-benzo[4,5]imidazo[1,2-a]piperidine (500 mg, 1.991 mmol, 1 eq) and tert-butyl carbamate (466.49 mg, 3.982 mmol, 2 eq) in 1,4-dioxane (5 mL) was added to dicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphonane (159.72 mg, 0.299 mmol, 0.15 eq), (methanesulfonic acid {dicyclohexyl(3-isopropoxy-2',4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphonane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (106). 48 mg (0.199 mmol, 0.1 eq) and cesium carbonate (1946.14 mg, 5.973 mmol, 3 eq) were added. After the addition was complete, the system was stirred at 90°C for 4 hours. The reaction mixture was cooled to room temperature and diluted with water (30 mL) at room temperature. The reaction mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, backwashed with saturated brine (1 × 40 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (3:1) to give benzo[4,5]imidazo[1,2-a]piperidin-9-ylcarbamate tert-butyl ester (compound 21-6, 400 mg, 69.91%).

[0156] MS(ESI, m / z): 288.40 [M+H] + RT(min): 0.728

[0157] The fourth step is the synthesis of benzo[4,5]imidazo[1,2-a]piperidine-9-amine (compound 21-7):

[0158] Under nitrogen protection, a solution of 1,4-dioxane in hydrochloric acid (4 mL) was added to a 4 mL solution of benzo[4,5]imidazo[1,2-a]piperidin-9-ylcarbamate tert-butyl ester (400 mg, 1.392 mmol, 1 eq) in dichloromethane at room temperature. After the addition was complete, the system was stirred at room temperature for 2 hours. The target 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.

[0159] MS(ESI, m / z): 188.05 [M+H] + RT(min): 0.602

[0160] Step 5: Synthesis of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-9-yl)benzamide (compound 21-9):

[0161] Under nitrogen protection, potassium phosphate (340.08 mg, 1.602 mmol, 3 eq) was added to a 2 mL solution of benzo[4,5]imidazo[1,2-a]piperidine-9-amine (240.73 mg, 0.641 mmol, 1.2 eq) in dichloromethane at room temperature. After stirring for 1 minute, a 1 mL solution of 4-iodo-2-(6-azaspiro[2.5]octane-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 was added at room temperature. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) at room temperature. The reaction mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phases were 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.

[0162] MS(ESI, m / z): 526.80 [M+H] + RT(min): 1.178

[0163] Step 6: Synthesis of 4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-9-yl)benzamide (compound 21):

[0164] Under nitrogen protection, at room temperature, 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) were added to a solution of 4-iodo-2-(6-azaspiro[2.5]octane-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), along with 2-hydroxyethanesulfonamide (28.53 mg, 0.228 mmol, 1.5 eq), 63.01 mg, 0.456 mmol, 3 eq), 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 hours. The reaction mixture was cooled to room temperature. It was diluted with water (5 mL) and extracted with ethyl acetate (3 × 10 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 crude product was purified by high-performance liquid chromatography (HPLC) under the following conditions (column specifications: Kinetex EVOC18 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)sulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(benzo[4.5]imidazo[1.2-a]piperidin-9-yl)benzamide (compound 21, 14.1 mg, 17.63%).

[0165] MS(ESI, m / z): 523.85 [M+H] + RT(min): 1.157

[0166] 1H NMR: (400MHz, DMSO-d6) δ11.41(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,1 H),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).

[0167] Example 3

[0168] 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-6-yl)benzamide (compound 22)

[0169]

[0170] The first step was the synthesis of (Z)-N-(2,6-dibromophenyl)piperidine-2-imine (compound 22-3):

[0171] Under nitrogen protection, phosphorus oxychloride (611.03 mg, 3.985 mmol, 1 eq) was added to a toluene solution of 2-piperidinone (790.15 mg, 7.971 mmol, 2.0 eq) at 0°C. After stirring at 0°C for 2 hours, 2,6-dibromoaniline (1 g, 3.985 mmol, 1 eq) was added, 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 the reaction mixture was quenched with 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), the organic phases were combined, backwashed with saturated brine (1 × 80 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was recrystallized from dichloromethane / petroleum ether (1:100) to give (Z)-N-(2,6-dibromophenyl)piperidine-2-imine (compound 22-3, 900 mg, 68.01%) as a white solid.

[0172] MS(ESI, m / z): 332.75 [M+H] + RT(min): 0.731

[0173] The second step involves the synthesis of 6-bromo-benzo[4,5]imidazo[1,2-a]piperidine (compound 22-4):

[0174] Under nitrogen protection, 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) were added to a 10 mL acetonitrile solution of (Z)-N-(2,6-dibromophenyl)piperidine-2-imine (850 mg, 2.560 mmol, 1 eq) at room temperature. The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, backwashed with saturated brine (2 × 40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was also concentrated under reduced pressure. The residue was purified by silica gel column chromatography in 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%).

[0175] MS(ESI, m / z): 250.85 [M+H] + RT(min): 0.646

[0176] The third step is the synthesis of tert-butyl carbamate (compound 22-5):

[0177] Under nitrogen protection, at room temperature, cesium carbonate (1946.14 mg, 5.973 mmol, 3 eq), tert-butyl carbamate (466.49 mg, 3.982 mmol, 2 eq), (182.78 mg, 0.199 mmol, 0.1 eq) and dicyclohexyl (3-ethylpropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (182.78 mg, 0.199 mmol, 0.1 eq) were added to 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) were added. 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), the reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The reaction mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, backwashed with saturated brine (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (2:1) to give tert-butyl (benzo[4,5]imidazo[1,2-a]piperidin-6-yl)carbamate (compound 22-5, 490 mg, 85.64%).

[0178] MS(ESI, m / z): 288.35 [M+H] + RT(min): 0.768

[0179] The fourth step is the synthesis of benzo[4,5]imidazo[1,2-a]piperidine-6-amine (compound 22-6):

[0180] Under nitrogen protection, at room temperature, hydrogen chloride (gas) dissolved in 1,4-dioxane (5 mL) was added to a solution of (benzo[4,5]imidazo[1,2-a]piperidin-6-yl)carbamate tert-butyl ester (400 mg, 1.392 mmol, 1 eq) in dichloromethane (5 mL), and the mixture was stirred for 1 hour. The resulting residue was concentrated under reduced pressure to obtain crude benzo[4,5]imidazo[1,2-a]piperidin-6-amine, which was directly added to the next step without further purification.

[0181] MS(ESI, m / z): 188.35 [M+H] + RT(min): 0.450

[0182] Step 5: Synthesis of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-6-yl)benzamide (compound 22-7):

[0183] Under nitrogen protection, thionyl chloride (279.54 mg, 2.350 mmol, 2 eq) was added to an 8 mL solution of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid (629.51 mg, 1.763 mmol, 1.5 eq) in dichloromethane at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting residue was concentrated under reduced pressure. The residue was dissolved in dichloromethane (4 mL). Potassium phosphate (498.79 mg, 2.350 mmol, 2 eq) was added to the system at room temperature, and the mixture was stirred for 5 minutes. Then, a dichloromethane solution (4 mL) of benzo[4,5]imidazo[1,2-a]piperidine-6-amine (20 mg, 0.107 mmol, 1 eq) and N,N-diisopropylethylamine (455.57 mg, 3.525 mmol, 3 eq) was added. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 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 residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (5:1) to give 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)-N-(benzo[4.5]imidazo[1.2-a]piperidin-6-yl)benzamide (compound 22-7, 530 mg, 85.69%).

[0184] MS(ESI, m / z): 527.35 [M+H] + RT(min): 1.078

[0185] Step 6: Synthesis of 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(benzo[4,5]imidazo[1,2-a]piperidin-6-yl)benzamide (compound 22):

[0186] Under nitrogen protection, 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) were added to a solution of 4-iodo-2-(6-azaspiro[2.5]octane-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) at room temperature. The reaction mixture was stirred at 120 °C for 1.5 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The reaction mixture was extracted with ethyl acetate (3 × 10 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 crude product was purified by high-performance liquid chromatography (HPLC) under the following conditions (column specifications: Xselect CSH C18OBD Column 30*150mm 5μm,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; number of runs: 0). 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(benzo[4.5]imidazo[1.2-a]piperidin-6-yl)benzamide (compound 22, 30.7 mg, 27.69%) was obtained.

[0187] MS(ESI, m / z): 523.90 [M+H] + RT(min):1.530

[0188] 1 H NMR (400MHz, DMSO-d6) δ12.44(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).

[0189] Example 4

[0190] N-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (compound 36)

[0191]

[0192] The first step was the synthesis of (2Z)-N-(2,6-dibromophenyl)pyrrolidine-2-imine (compound 36-2):

[0193] Under nitrogen protection, phosphorus oxychloride (1.22 g, 85.106 mmol, 2 eq) was added to a toluene (10 mL) solution of pyrrolidone (1.36 g, 15.942 mmol, 2 eq) at 0 °C. The reaction mixture was reacted at 0 °C for 2 hours, followed by the addition of 2,6-dibromoaniline (2 g, 7.971 mmol, 1 eq). The reaction mixture was heated to 110 °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), and the pH was adjusted to 10 with saturated sodium bicarbonate solution. The mixture was 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. The residue was purified by preparative chromatography using ethyl acetate / petroleum ether (1:10) to give (2Z)-N-(2,6-dibromophenyl)pyrrolidine-2-imine (2.7 g, 27.65%).

[0194] MS(ESI, m / z): 317.10 [M+H] + RT(min): 0.919

[0195] The second step is the synthesis of 5-bromo-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (compound 36-3):

[0196] Under nitrogen 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)pyrrolidine-2-imine (2.7 g, 8.490 mmol, 1 eq) in acetonitrile (3 mL) at room temperature. The reaction mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (80 mL), and 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. 5-Bromo-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (2 g, 74.07%) was obtained.

[0197] MS(ESI, m / z): 237.15 [M+H] + RT(min): 0.657

[0198] The third step is the synthesis of tert-butyl carbamate (compound 36-5):

[0199] Under nitrogen protection, dicyclohexyl (3-isopropyl-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl) was added to a solution of 5-bromo-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (2 g, 8.436 mmol, 1 eq) and tert-butyl carbamate (1.99 g, 16.87 mmol, 2 eq) in N,N-dimethylformamide (10 mL) at room temperature. Phosphine (451.12 mg, 0.844 mmol, 0.1 eq), (methanesulfonic acid {bicycloethyl(3-isopropyl-2,4,6-triisopropyl-(1,1-biphenyl)-2-yl)phosphonane})(2-methylamino-1,1-biphenyl-2-yl)palladium(II) (1.549 g, 1.688 mmol, 0.2 eq), and cesium carbonate (8.245 g, 25.308 mmol, 3 eq). The reaction mixture was heated to 100 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature and quenched with water (80 mL). It was then 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 residue was purified by preparative chromatography 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%).

[0200] MS(ESI, m / z): 274.35 [M+H] + RT(min): 0.592

[0201] Step 4: Synthesis of 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (compound 36-6):

[0202] The reaction mixture of tert-butyl carbamate (300 mg, 1.098 mmol, 1 eq), 1,4-dioxane hydrochloride (2 mL), and dichloromethanol (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to obtain 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (300 mg, 57.87%), which was directly added to the next step.

[0203] MS(ESI, m / z): 174.35 [M+H] + RT(min): 0.602

[0204] Step 5: Synthesis of 2-{6-azaspiro[2.5]octane-6-yl}-N-{2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl}-4-iodobenzamide (compounds 36-7):

[0205] Under nitrogen protection, tetramethylchlorourea hexafluorophosphate (1.62 g, 5.772 mmol, 4 eq) and N-methylimidazole (1.18 g, 14.430 mmol, 10 eq) were added to a solution of 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (250 mg, 1.443 mmol, 1 eq), 2-{6-azaspiro[2.5]octane-6-yl}-4-iodobenzoic acid (618.62 mg, 1.732 mmol, 1.2 eq) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and 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 mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative chromatography (ethyl acetate: petroleum ether = 1:5) to give 2-{6-azaspiro[2.5]octane-6-yl}-N-{2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl}-4-iodobenzamide (100 mg, 40.00%).

[0206] MS(ESI, m / z): 513.35 [M+H] + RT(min):1.406

[0207] Step 6: Synthesis of N-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (compound 36):

[0208] Under nitrogen protection, at room temperature, 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]octane-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). The reaction mixture was heated to 120 °C and stirred for 1.5 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated saline solution (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 preparative high-performance liquid chromatography (HPLC) under the following conditions: 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: 30% B to 65% B in 8 min, 60% B; detection wavelength: UV 220 nm; retention time (min): 6.12, yielding N-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (4.22 mg, 6.60%).

[0209] MS(ESI, m / z): 510.15 [M+H] + RT(min):1.143

[0210] 1H NMR: (400MHz, DMSO-d6) δ12.34(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).

[0211] The compounds listed in the table below were prepared using conditions similar to those in Example 4.

[0212]

[0213]

[0214] Example 5

[0215] 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-yl}-4-(2-hydroxyethanesulfonylamino)benzamide (Compound 51)

[0216]

[0217] The first step is the synthesis of 5'-bromo-3',4'-dihydrospiro[cyclopentane-1,2'-naphthalene]-1'-one (compound 51-3):

[0218] Under nitrogen protection, sodium hydride (0.71 g, 29.586 mmol, 3.33 eq) was added to a tetrahydrofuran (20 mL) solution of 5-bromo-3,4-dihydro-2H-naphth-1-one (2 g, 8.886 mmol, 1 eq) at 0 °C. After stirring for 1 hour, 1,4-diiodobutane (4.13 g, 13.329 mmol, 1.5 e) was added dropwise at 0 °C. The reaction mixture was heated to room temperature and stirred for 16 hours. The reaction mixture was quenched with ice water at room temperature. The reaction mixture was extracted with ethyl acetate (3 × 80 mL). The combined organic phases were backwashed with saturated saline solution (1 × 100 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (10:1) to give 5'-bromo-3',4'-dihydrospiro[cyclopentan-1,2'-naphthalene]-1'-one (2.37 g, 80.56%).

[0219] MS:(ESI,m / z):278.55[M+H] +RT(min): 1.325

[0220] The second step is the synthesis of 5'-bromo-3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene] (compound 51-4):

[0221] Under nitrogen protection, triethylsilane (5.0 mL, 30.94 mmol, 4.35 eq) was added to a solution of 5'-bromo-3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-1'-one (2 g, 7.11 mmol, 1 eq) in 15 mL of trifluoroacetic acid at 0 °C. The reaction mixture was heated to 50 °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 saline solution (1 × 80 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in 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%).

[0222] MS(EI,m / z):264.1[M],RT(min):8.694

[0223] The third step is the synthesis of tert-butyl carbamate (compound 51-5):

[0224] Under nitrogen protection, cesium carbonate (3.7 g, 12.75 mmol, 1 eq), palladium acetate (84.5 mg, 0.35 mmol, 0.1 eq), and 2-dicyclohexylphosphine-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), tert-butyl carbamate (883.5 mg, 7.5 mmol, 2 eq), and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (359.5 mg, 0.75 mmol, 0.2 eq) in 1,4-dioxane (10 mL) at room temperature. The reaction mixture was heated to 100 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature and quenched with water. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were backwashed with saturated saline solution (1 × 80 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (10:1) to give tert-butyl {3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-yl}carbamate (800 mg, 70.79%).

[0225] MS(EI,m / z):201.1[M-100],RT(min):9.866

[0226] Step 4: Synthesis of 3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-amine (compounds 51-6):

[0227] A solution of 1,4-dioxane in hydrochloric acid (2 mL) was added to a dichloromethane solution (2 mL) of {3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-yl}carbamate (200 mg, 0.66 mmol, 1 eq) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain 3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-amine (60 mg, 46.78%). The crude product was not further purified and was directly added to the next step.

[0228] MS:(ESI,m / z):202.45[M+H] + RT(min):1.041

[0229] Step 5: Synthesis of 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-yl}-4-iodobenzamide (compound 51-7):

[0230] Under nitrogen protection, at room temperature, N,N,N,N-tetramethylchloromethane hexafluorophosphate (334.5 mg, 1.12 mmol, 4 eq), N-methylimidazolium (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) were added to a solution of 2-{6-azaspiro[2.5]octane-6-yl}-4-iodobenzoic acid (127.74 mg, 0.36 mmol, 1.2 eq) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were backwashed with saturated saline solution (1 × 20 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (10:1) to give 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-yl}-4-iodobenzamide (100 mg, 90.34%).

[0231] MS(ESI, m / z): 541.35 [M+H] + RT(min):1.728

[0232] Step 6: Synthesis of 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentan-1,2'-naphthalene]-5'-yl}-4-(2-hydroxyethanesulfonylamino)benzamide (compound 51):

[0233] Under nitrogen protection, at room temperature, 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) were added to a solution of 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-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). The reaction mixture was heated to 120 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated saline solution (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 preparative high-performance liquid chromatography (HPLC) under the following conditions: 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: 45% B to 96% B in 8 min, 96% B; detection wavelength: UV 220 nm; retention time (min): 7.62, yielding 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-5'-yl}-4-(2-hydroxyethanesulfonylamino)benzamide (10 mg, 20.06%).

[0234] MS(ESI, m / z): 538.10 [M+H] + RT(min):1.383

[0235] 1H NMR: (400MHz, DMSO-d6) δ10.87(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).

[0236] Example 6

[0237] 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-yl}-4-(2-hydroxyethanesulfonylamino)benzamide (compound 56)

[0238]

[0239] The first step in the synthesis of (2-chloroethyl)dimethylthionium iodide (compound 56-2):

[0240] 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 hours. A solid precipitated in the mixture. The mixture was filtered, the filter cake was washed with acetone (3 × 30 mL), and the solid was dried to give (2-chloroethyl)dimethylthionium iodide (9.5 g, 52.01%).

[0241] MS(ESI, m / z): 125.02 [M] + .RT(min):0.19.

[0242] The second step is the synthesis of 5'-bromo-3',4'-dihydrospiro[cyclopropane-1,2'-naphthalene]-1'-one (compound 56-4):

[0243] At 0 °C, sodium iodide (0.27 g, 1.777 mmol, 0.2 eq) and sodium hydride (0.71 g, 60%, dispersed in kerosene, 17.77 mmol, 2 eq) were added to a solution of 5-bromo-3,4-dihydro-2H-naphthyl-1-one (2 g, 10.461 mmol, 1.00 eq) in tert-butanol (30 mL). The mixture was stirred at room temperature for 20 min, and then (2-chloroethyl)dimethylthionium iodide (2.47 g, 9.775 mmol, 1.1 eq) was added in portions. The reaction mixture was stirred for 16 h. The reaction solution was quenched with water and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated brine (2 × 50 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (5:1) to give 5'-bromo-3',4'-dihydrospiro[cyclopropane-1,2'-naphthalene]-1'-one (1.8 g, 80.67%).

[0244] MS(EI, m / z): 250.1 [M] + .RT(min):8.46.

[0245] The third step is the synthesis of 5'-bromo-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene] (compound 56-5):

[0246] Under nitrogen protection, triethylsilane (2.57 mL, 15.930 mmol, 5 eq) was added to a solution of 5'-bromo-3',4'-dihydrospiro[cyclopropane-1,2'-naphthyl]-1'-one (800 mg, 3.186 mmol, 1 eq) in dichloromethane (30 mL) at 0 °C, followed by the dropwise addition of boron trifluoride diethyl ether solution (2.02 mL, 15.930 mmol, 5 eq). The reaction mixture was stirred at 0 °C for 4 hours, then brought to room temperature and stirred for 16 hours. The reaction solution was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3 × 50 mL). The combined organic phases were backwashed with saturated brine (1 × 60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (10:1) to give 5'-bromo-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene] (550 mg, crude).

[0247] Step 4: Synthesis of N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-yl}-1,1-diphenylmethyleneimine (compounds 56-7):

[0248] Under nitrogen protection, at room temperature, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (131.29 mg, 0.211 mmol, 0.1 eq) and tris(dibenzylacetone)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'-naphthyl] (500 mg, 2.108 mmol, 1 eq), benzophenone imine (458.56 mg, 2.530 mmol, 1.2 eq), sodium tert-butoxide (303.95 mg, 3.162 mmol, 1.5 eq) in toluene (20 mL). The reaction solution was heated to 90 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and 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. The crude product N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-yl}-1,1-diphenylmethyleneimine (1.1 g, crude product) was not further purified and was directly added to the next step.

[0249] MS(ESI, m / z): 338.50 [M+H] + .RT(min):1.524.

[0250] Step 5: Synthesis of 3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-amine (compound 56-8):

[0251] N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-yl}-1,1-diphenylmethyleneimine (1.1 g, crude) was stirred in 1M hydrochloric acid (10 mL) at room temperature for 16 hours. The reaction mixture was alkalized to pH 8 with saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted with dichloromethane (3 × 50 mL). The combined organic phases were 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 residue was purified by silica gel column chromatography in dichloromethane / methanol (20:1) to give 3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-amine (100 mg).

[0252] MS(ESI, m / z): 174.45 [M+H] + .RT(min):0.892.

[0253] Step 6: Synthesis of 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-yl}-4-iodobenzamide (compound 56-9):

[0254] Under nitrogen protection, at room temperature, 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]octane-6-yl}-4-iodobenzoic acid (247.39 mg, 0.692 mmol, 1.2 eq), and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (647.77 mg, 2.308 mmol, 4 eq) in dichloromethane (4 mL). The reaction solution was heated to 80 °C and reacted for 2 hours. The reaction mixture was cooled to room temperature and extracted with dichloromethane (3 × 20 mL). The organic phases were combined, backwashed with saturated brine (1 × 30 mL), dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (3:1) to give 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-yl}-4-iodobenzamide (56 mg, 18.93%).

[0255] MS(ESI, m / z): 513.05 [M+H] + .RT(min):1.262.

[0256] Step 7: Synthesis of 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-yl}-4-(2-hydroxyethanesulfonylamino)benzamide (compound 56):

[0257] Under nitrogen protection, at room temperature, cuprous iodide (1.86 mg, 0.010 mmol, 0.1 eq) and sarcosine (1.74 mg, 0.020 mmol, 0.2 eq) were added to a solution of 2-{6-azaspiro[2.5]octane-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). The reaction solution was heated to 120 °C and reacted for 1 hour. The reaction solution was cooled to room temperature and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, backwashed with saturated brine (3 × 10 mL), dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) under the following conditions (column specifications: Xselect CSH C18 OBD column, 30*150 mm 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 45% B to 75% B in 8 min; detection wavelength: UV 220 nm; retention time (min): 7.4), yielding 2-{6-azaspiro[2.5]octane-6-yl}-N-{3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-naphthalene]-5'-yl}-4-(2-hydroxyethanesulfonylamino)benzamide (12 mg, 24.01%).

[0258] MS(ESI, m / z): 510.55 [M+H] + .RT(min):1.926.

[0259] 1 H NMR(400MHz,DMSO-d6)δ10.93(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).

[0260] Example 7

[0261] N-(8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (compound 64)

[0262]

[0263]

[0264] The first step was the synthesis of 5,5-difluoro-1-(4-methyl-3-nitropyridin-2-yl)piperidin-2-one (compound 64-3):

[0265] Under nitrogen protection, palladium acetate (156.12 mg, 0.695 mmol, 0.05 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (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 1,4-dioxane (50 mL) solution of 2-chloro-4-methyl-3-nitropyridine (2.4 g, 13.907 mmol, 1 eq), 5,5-difluoropiperidin-2-one (2.25 g, 16.688 mmol, 1.2 eq) at room temperature. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography in 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%).

[0266] MS(ESI, m / z): 272.30 [M+H] + .RT(min):0.786

[0267] The second step involves the synthesis of 8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidine (compound 64-4):

[0268] 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 an ethanol and aqueous solution (10 mL: 1 mL) of 5,5-difluoro-1-(4-methyl-3-nitropyridin-2-yl)piperidin-2-one (1.06 g, 3.908 mmol, 1 eq) 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 by silica gel column chromatography and distilled into petroleum ether / ethyl acetate (4:1) to give 8,8-difluoro-4-methylpyridano[2,3-d]imidazo[1,2-a]piperidine (compound 64-4, 550 mg, 63.04%).

[0269] MS(ESI, m / z): 224.30 [M+H] + .RT(min):0.666

[0270] Step 3: Synthesis of 8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidine-1-oxide (compound 64-5):

[0271] To a 5 mL solution of 8,8-difluoro-4-methylpyridano[2,3-d]imidazo[1,2-a]piperidine (500 mg, 1.843 mmol, 1 eq) in dichloromethane, m-chloroperoxybenzoic acid (561.38 mg, 2.764 mmol, 1.5 eq, 85%) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was directly concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and petroleum ether / ethyl acetate (1:3) to give 8,8-difluoro-4-methylpyridano[2,3-d]imidazo[1,2-a]piperidine-1-oxide (compound 64-5, 220 mg, 53.46%).

[0272] MS(ESI, m / z): 240.30 [M+H] + .RT(min):0.585

[0273] Step 4: Synthesis of 1-(8,8-difluoro-4-methyl-pyrido[2,3-d]imidazo[1,2-a]piperidin-2-yl)pyridine-1-trifluoroacetate (compound 64-6):

[0274] Pyridine (0.37 mL, 4.600 mmol, 5 eq) was added to a dichloromethane solution (4 mL) of 220 mg (0.920 mmol, 1 eq) of 8,8-difluoro-4-methylpyridano[2,3-d]imidazo[1,2-a]piperidine-1-oxide (4 mL). Trifluoroacetic anhydride (0.38 mL, 2.760 mmol, 3 eq) was added dropwise at 0 °C. The reaction mixture was then heated to room temperature and stirred for 16 hours. The resulting mixture was used directly without further purification.

[0275] MS(ESI, m / z): 301.30 [M-CF3COO] - ] + .RT(min):0.501

[0276] Step 5: Synthesis of 8,8-difluoro-4-methylpyrido[2,3-d]imidazo[1,2-a]piperidine-2-amine (compound 64-7):

[0277] Ethanolamine (0.32 mL, 5.310 mmol, 10 eq) was added to an ethanolic solution (3 mL) of 1-(8,8-difluoro-4-methylpyridino[2,3-d]imidazo[1,2-a]piperidin-2-yl)pyridine-1-trifluoroacetate (220 mg, 0.53 mmol, 1 eq) at room temperature. The reaction solution was heated to 80 °C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The petroleum ether / ethyl acetate (2:1) solution was used to give 8,8-difluoro-4-methylpyridino[2,3-d]imidazo[1,2-a]piperidin-2-amine (compounds 64-7, 75 mg).

[0278] MS(ESI, m / z): 239.35 [M+H] + .RT(min):0.475.

[0279] Step 6: Synthesis of N-(8,8-difluoro-4-methylpyridino[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-iodo-2-(6-azaspiro[2,5]octane-6-yl)benzamide (compound 64-8):

[0280] Under nitrogen protection, N-methylimidazole (0.25 mL, 3.150 mmol, 10 eq) was added to a solution of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid (112.45 mg, 0.315 mmol, 1.00 eq), 8,8-difluoro-4-methylpyridico[2,3-d]imidazo[1,2-a]piperidine-2-amine (75 mg, 0.315 mmol, 1.00 eq), and tetramethylchloromethanedihydrazine hexafluorophosphate (353.31 mg, 1.260 mmol, 4 eq) in dichloromethane (4 mL) at room temperature. The reaction solution was heated to 60°C and reacted for 2 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative chromatography using petroleum ether / ethyl acetate (6:1) to give N-(8,8-difluoro-4-methyl-pyridano[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (compound 64-8, 30 mg, 16.50%).

[0281] MS(ESI, m / z): 578.30 [M+H] + .RT(min):1.432

[0282] Step 7: Synthesis of N-(8,8-difluoro-4-methylpyridino[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2,5]octane-6-yl)benzamide (compound 64):

[0283] Under nitrogen protection, at room temperature, cuprous iodide (0.99 mg, 0.005 mmol, 0.1 eq) was added to a solution of N-(8,8-difluoro-4-methylpyridino[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (30 mg, 0.052 mmol, 1 eq), 2-hydroxyethylsulfonamide (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). The reaction solution was heated to 120°C and reacted for 1 hour. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography under the following conditions: 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-methylpyridino[2,3-d]imidazo[1,2-a]piperidin-2-yl)-4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (compound 64, 2.24 mg, 7.46%) was obtained.

[0284] MS(ESI, m / z): 575.35 [M+H] + .RT(min):2.150

[0285] 1 H NMR(400MHz,DMSO-d6)δ13.57(s,1H),8.11–8.02(m,2H),7.25(s,1H),7.11(d,1H),4.47(t,2H),3.7 6(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).

[0286] Example 8

[0287] N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (compound 94)

[0288]

[0289] The first step was the synthesis of (2Z)-N-(2,6-dibromophenyl)-3,3-difluoropyrrolidine-2-imine (compound 94-2):

[0290] Under nitrogen protection, POCl3 (837.11 mg, 5.460 mmol, 1 eq) was added to an ultra-dry toluene (15 mL) solution of 3,3-difluoropyrrolidone-2-one (0.99 g, 8.176 mmol, 1.50 eq) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. A toluene (5 mL) solution of 2,6-dibromoaniline (1.37 g, 5.460 mmol, 1 eq) was added to the above solution, and the reaction mixture was heated to 110 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched with water. The reaction mixture was extracted with dichloromethane (3 × 60 mL). The combined organic phases were backwashed with saturated sodium chloride solution (1 × 80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from petroleum ether / dichloromethane (100:1) to give (2Z)-N-(2,6-dibromophenyl)-3,3-difluoropyrrolidine-2-imine (1.2 g, 62.09%).

[0291] MS(ESI, m / z): 352.85 [M+H] + RT(min): 0.674

[0292] The second step is the synthesis of 5-bromo-3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (compound 94-3):

[0293] Under nitrogen protection, at room temperature, 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) were added to (2Z)-N-(2,6-dibromophenyl)-3,3-difluoropyrrolidine-2-imine (500 mg, 1.412 mmol, 1 eq) and N,N-dimethylformamide (10.00 mL). The reaction mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, quenched with water, and the reaction mixture was extracted with dichloromethane (3 × 50 mL). The organic phases were combined, backwashed with saturated saline solution (1 × 50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in 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%).

[0294] MS(ESI, m / z): 272.90 [M+H] + RT(min): 0.837

[0295] The third step is the synthesis of tert-butyl carbamate (compound 94-4):

[0296] Under nitrogen protection, at room temperature, tert-butyl carbamate (197.33 mg, 1.684 mmol, 2 eq), (methanesulfonic acid {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (154.73 mg, 0.168 mmol, 0.20 eq), and dicyclohexyl(3-isopropyl-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonane were added to 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). 1'-Biphenyl]-2-yl)phosphine (45.04 mg, 0.084 mmol, 0.10 eq), cesium carbonate (823.25 mg, 2.526 mmol, 3.00 eq), the reaction mixture was heated to 100 °C and stirred for 1 h. Liquid chromatography-mass spectrometry (LC-MS) was used to monitor the reaction until complete. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were backwashed with saturated sodium chloride solution (1 × 50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in 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%).

[0297] MS(ESI, m / z): 310.05 [M+H] + RT(min):1.004

[0298] Step 4: Synthesis of 3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (compound 94-5):

[0299] Under nitrogen protection, a solution of 1,4-dioxane hydrochloric acid (2 mL) was added to a dichloromethane solution of (3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)carbamate (189 mg, 0.611 mmol, 1 eq) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain 3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (127 mg, 99.35%).

[0300] MS(ESI, m / z): 210.10 [M+H] + RT(min): 0.193

[0301] 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]octane-6-yl)benzamide (compound 94-6):

[0302] Under nitrogen protection, 3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-amine (100 mg, 0.478 mmol, 1 eq), tetramethylchloroformamidine hexafluorophosphate (536.48 mg, 1.912 mmol, 4 eq), and N-methylimidazolium (392.48 mg, 4.780 mmol, 10 eq) were added to a dichloromethane solution (10.00 mL) of 2-{6-azaspiro[2.5]octane-6-yl}-4-iodobenzoic acid (204.89 mg, 0.574 mmol, 1.2 eq) at room temperature. The reaction solution was heated to 50 °C and stirred for 1 hour. The reaction solution was cooled to room temperature and diluted with water. The reaction mixture was 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 residue was purified by silica gel column chromatography in 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]octane-6-yl)benzamide (150 mg, 57.22%).

[0303] MS(ESI, m / z): 549.05 [M+H] + RT(min):1.311

[0304] Step 6: Synthesis of N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2,5]octane-6-yl)benzamide (compound 94):

[0305] Under nitrogen protection, at room temperature, 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) were added to 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]octane-6-yl)benzamide (100 mg, 0.182 mmol, 1 eq) in N,N-dimethylformamide (20.00 mL), at room temperature. The reaction mixture was heated to 140 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined and backwashed with saturated saline solution (1×30 mL), then 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 (HPLC) under the following conditions: 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 in 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-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (23.00 mg, 23.12%).

[0306] MS(ESI, m / z): 546.30 [M+H] + RT(min):1.621

[0307] 1 H NMR (400MHz, DMSO-d6) δ12.55(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,1 H),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).

[0308] The compounds listed in the table below were prepared using conditions similar to those in Example 8.

[0309]

[0310] Example 9

[0311] 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (compound 96)

[0312]

[0313] The first step was the synthesis of (3Z)-N-(2,6-dibromophenyl)-2-azabicyclo[2.2.1]heptane-3-imine (compound 96-2):

[0314] Under nitrogen protection, phosphorus oxychloride (1833.09 mg, 11.955 mmol, 3 eq) was added to an anhydrous toluene (15 mL) solution of 2-azabicyclo[2.2.1]heptan-3-one (885.89 mg, 7.970 mmol, 2 eq) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. A toluene (5 mL) solution of 2,6-dibromoaniline (1 g, 3.985 mmol, 1 eq) was added to the above solution, and the reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched with water (30 mL). The reaction mixture was extracted with ethyl acetate (3 × 80 mL). The combined organic phases were backwashed with saturated sodium chloride solution (1 × 80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (3:1) to give (3Z)-N-(2,6-dibromophenyl)-2-azabicyclo[2.2.1]heptane-3-imine (190 mg, 13.86%).

[0315] MS(ESI, m / z): 344.80 [M+H] + ,RT(min):0.592.

[0316] The second step is the synthesis of 6-bromo-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (compound 96-3):

[0317] Under nitrogen 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]heptane-3-imine (190 mg, 0.553 mmol, 1 eq) in acetonitrile (5.0 mL) at room temperature. The reaction mixture was heated to 100 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature, quenched with water, and the reaction mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated saline solution (1 × 50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 6-Bromo-1,2,3,4-Tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (140 mg, 96.55%) was obtained.

[0318] MS(ESI,m / z):263.00[M+H] + ,RT(min):0.602.

[0319] The third step is the synthesis of tert-butyl carbamate (compound 96-4):

[0320] Under nitrogen protection, at room temperature, tert-butyl carbamate (115.75 mg, 0.988 mmol, 2 eq), (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (45.38 mg, 0.049 mmol, 0.1 eq), and (3-isopropyl-2',4',6'-triisopropyl-2',4'-triisopropyl-2'-dimethylformamide (5.0 mL) 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) were added to 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). [1,1'-Biphenyl]-2-yl)phosphine (52.84 mg, 0.099 mmol, 0.2 eq), cesium carbonate (482.9 mg, 1.482 mmol, 3 eq), the reaction solution was heated to 100 °C and stirred for 1 hour. The reaction solution 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. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (5:4) to give tert-butyl (1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (94 mg, 63.56%).

[0321] MS(ESI, m / z): 300.10 [M+H] + ,RT(min):0.730.

[0322] Step 4: Synthesis of 1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine-6-amine (compound 96-5):

[0323] A solution of 1,4-dioxane in hydrochloric acid was added to a 2 mL solution of dichloromethane containing (94 mg, 0.314 mmol, 1 eq) of (1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate tert-butyl ester (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain 1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-amine (62 mg, 99.10%).

[0324] MS(ESI,m / z):200.00[M+H] + RT(min): 0.166

[0325] Step 5: Synthesis of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)-N-(1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (compound 96-6):

[0326] Under nitrogen protection, tetramethylchloroformamidine hexafluorophosphate (337.95 mg, 1.204 mmol, 4 eq) and N-methylimidazole (247.24 mg, 3.010 mmol, 10 eq) were added to a dichloromethane solution (10.0 mL) of 1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine-6-amine (60 mg, 0.301 mmol, 1 eq), 2-{6-azaspiro[2,5]octane-6-yl}-4-iodobenzoic acid (129.07 mg, 0.361 mmol, 1.20 eq) for 1 hour at room temperature. The reaction mixture was stirred at room temperature. The reaction mixture was 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 residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (5:2) to give 4-iodo-2-(6-azaspiro[2.5]octane-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%).

[0327] MS(ESI, m / z): 539.35 [M+H] + ,RT(min):1.495.

[0328] Step 6: Synthesis of 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (compound 96):

[0329] Under nitrogen protection, at room temperature, 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]octane-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). The reaction mixture was heated to 120 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3 × 30 mL). Combine the organic phases, backwash with saturated saline solution (1×30 mL), and dry with anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography (HPLC) under the following conditions (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 in 8 min, 65% B; detection wavelength: UV 220 nm; retention time (min): 7.45). 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-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.

[0330] MS(ESI, m / z): 536.00 [M+H] + ,RT(min):1.488.

[0331] 1 H NMR (400MHz, DMSO-d6) δ12.32(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).

[0332] The compounds listed in the table below were prepared using conditions similar to those in Example 9.

[0333]

[0334] Example 10

[0335] 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azaspiro-4-yl)benzamide (compound 97)

[0336]

[0337]

[0338] The first step was the synthesis of (2Z)-N-(2,6-dibromoaniline)azapyro-2-imine (compound 97-2):

[0339] Under nitrogen protection, phosphorus oxychloride (6.1 g, 39.85 mmol, 5 eq) was added dropwise to a toluene (10 mL) solution of caprolactam (1.36 g, 15.94 mmol, 2 eq) at 0 °C, and the reaction was carried out at 0 °C for 2 hours. Then, 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 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, quenched with ice water (50 mL), and the pH was adjusted to 10 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3 × 60 mL). 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 residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (10:1) to give (2Z)-N-(2,6-dibromoaniline)azapyro-2-imine (2.7 g, 27.65%).

[0340] MS:(ESI,m / z):345.10[M+H] + ,RT(min):0.595.

[0341] The second step is the synthesis of 4-bromo-7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azapyridine (compound 97-3):

[0342] Under nitrogen 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)azapyro-2-imine (500 mg, 1.445 mmol, 1 eq) in acetonitrile (3 mL) at room temperature. The reaction solution was heated to 100 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (3 × 30 mL). The organic phases 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. 4-Bromo-7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azapyridine (250 mg, 65.26%) was obtained.

[0343] MS:(ESI,m / z):264.90[M+H] + ,RT(min):1.151.

[0344] The third step is the synthesis of tert-butyl carbamate (7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azaphen-4-yl)carbamate (compound 97-4):

[0345] Under nitrogen protection, at room temperature, tert-butyl carbamate (220.91 mg, 1.886 mmol, 2 eq) and dicyclohexyl (3-isopropyl-2',4',6'-triisopropyl-[1,1'-biphenyl) were added to N,N-dimethylformamide (10 mL) containing 4-bromo-7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azapyridine (250 mg, 0.943 mmol, 1 eq) at room temperature. 1,2-yl)phosphine (50.42 mg, 0.094 mmol, 0.1 eq), (methanesulfonic acid {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). 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 × 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 residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (5:1) to give tert-butyl (7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azaphen-4-yl)carbamate (150 mg, 52.79%).

[0346] MS:(ESI,m / z):302.35[M+H] + ,RT(min):1.106.

[0347] Step 4: Synthesis of 7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azapyro-4-amine (compound 97-5):

[0348] At room temperature, a solution of 1,4-dioxane in hydrochloric acid (4M, 2 mL) was added to a solution of (7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azaphen-4-yl)carbamate tert-butyl ester (150 mg, 0.498 mmol, 1 eq) in dichloromethane (2 mL). 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]azaphen-4-amine (150 mg, 66.67%). This unpurified solution was directly added to the next reaction step.

[0349] MS:(ESI,m / z):202.40[M+H] + ,RT(min):0.544.

[0350] Step 5: Synthesis of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azapheno-4-yl)benzamide (compound 97-6):

[0351] Under nitrogen protection, at room temperature, N-methylimidazole (611.90 mg, 7.450 mmol, 10 eq) was added to a solution of 7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azapyro-4-amine (150 mg, 1.443 mmol, 1 eq), 2-{6-azaspiro[2.5]octane-6-yl}-4-iodobenzoic acid (319.44 mg, 0.894 mmol, 1.2 eq), and N,N,N,N-tetramethylchloromethanesulfonyl hexafluorophosphate (836.42 mg, 2.980 mmol, 4 eq) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 2 hours. Extraction was performed 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 mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (5:1) to give 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azapheno-4-yl)benzamide (60 mg, 14.90%).

[0352] MS:(ESI,m / z):541.35[M+H] + ,RT(min):1.398.

[0353] Step 6: Synthesis of 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azapheno-4-yl)benzamide (compound 97):

[0354] Under nitrogen protection, at room temperature, 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 sequentially to a solution of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azapheno-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). The reaction mixture was heated to 120 °C and stirred for 1 hour. The reaction mixture was then cooled to room temperature and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and backwashed with saturated saline solution (1 × 10 mL), then 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 to give 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azapheno-4-yl)benzamide (12.53 mg, 22.81%).

[0355] MS:(ESI,m / z):538.00[M+H] + ,RT(min):1.588.

[0356] 1H NMR(400MHz,DMSO-d6)δ12.47(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,1 H),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).

[0357] Example 11

[0358] 4-(2-hydroxyethanesulfonamide)-N-(4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide (Compound 98)

[0359]

[0360] The first step was the synthesis of (2Z)-N-(2,6-dibromophenyl)-3-methylpiperidine-2-imine (compound 98-2):

[0361] Under nitrogen protection, at 0°C, phosphorus oxychloride (3.67 g, 23.912 mmol, 2 eq) was added to a toluene solution (20 mL) of 3-methylpiperidin-2-one (1.62 g, 14.347 mmol, 1.2 eq). After the addition was complete, the reaction mixture was stirred at 0°C for 2 hours. Then, 2,6-dibromoaniline (3 g, 11.956 mmol, 1 eq) was added, and the reaction mixture was stirred at 110°C for 1 hour. 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 residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (5:1) to give (2Z)-N-(2,6-dibromophenyl)-3-methylpiperidine-2-imine (2.3 g, 55.59%).

[0362] MS(ESI, m / z): 346.85 [M+H] + RT(min): 0.620

[0363] The second step is the synthesis of 6-bromo-4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine (compound 98-3):

[0364] Under nitrogen 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 2 mL 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 at room temperature. After the addition was complete, the reaction mixture was heated to 100 °C and stirred for 1 hour. 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 organic phases were combined, backwashed with saturated sodium chloride solution (1 × 20 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product / the resulting mixture was not further purified and was directly added to the next step.

[0365] MS(ESI, m / z): 264.90 [M+H] + RT(min): 0.561

[0366] The third step is the synthesis of tert-butyl carbamate (compound 98-4):

[0367] Under nitrogen protection, at room temperature, cesium carbonate (3.50 g, 10.749 mmol, 3 eq) and bicyclohexyl (3-isopropoxy-2′,4′,6′-) were added to 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 tert-butyl carbamate (503.66 mg, 4.300 mmol, 1.2 eq) in N,N-dimethylformamide (10 mL). Triisopropyl-[1,1′-biphenyl]-2-yl)phosphonane (383.23 mg, 0.717 mmol, 0.2 eq) and methanesulfonic acid {dicyclohexyl(3-isopropoxy-2',4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphonane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (329.11 mg, 0.358 mmol, 0.1 eq) were added. The reaction mixture was then heated to 100 °C and stirred for 1 hour. The reaction solution was cooled 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 residue was purified by silica gel column chromatography in 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%).

[0368] MS(ESI, m / z): 302.30 [M+H] + RT(min):1.128

[0369] Step 4: Synthesis of 4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-6-amine (compound 98-5):

[0370] Under nitrogen protection, at room temperature, a solution of 1,4-dioxane (7.5 mL, 4 mol / L) of hydrogen chloride was added to a dichloromethane solution (700 mg, 2.323 mmol, 1 eq) of (4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate tert-butyl (700 mg, 2.323 mmol, 1 eq) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was then concentrated under reduced pressure. The resulting residue was not further purified and was directly added to the next step.

[0371] MS(ESI, m / z): 202.25 [M+H] + RT(min): 0.777

[0372] 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]octane-6-yl)benzamide (compound 98-6):

[0373] Under nitrogen protection, at room temperature, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (2.90 g, 10.336 mmol, 4 eq) and N-methylimidazole (2.12 g, 25.840 mmol, 10 eq) were added to a dichloromethane solution (10 mL) of 4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-6-amine (520 mg, 2.584 mmol, 1 eq) and 2-(6-azaspiro[2.5]octane-6-yl-4-iodobenzoic acid (1.11 g, 3.101 mmol, 1.2 eq) and added to the solution. After the addition was complete, the reaction system was stirred for 1 hour at room temperature. The reaction mixture was extracted with ethyl acetate (3 × 40 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 residue was purified by silica gel column chromatography in 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]octane-6-yl)benzamide (620 mg, 44.40%).

[0374] MS(ESI, m / z): 541.25 [M+H] + RT(min):1.585

[0375] Step 6: Synthesis of 4-(2-hydroxyethanesulfonamide)-N-(4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide (compound 98):

[0376] Under nitrogen protection, at room temperature, 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) were added to 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]octane-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). After the addition was complete, the reaction system was heated to 120 °C and stirred for 1.5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 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 (HPLC) under the following conditions: column specifications: Kinetex 5μm EVO C18, 30mm*150mm; mobile phase A: water (10mmol / L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60ml / min; elution gradient: 10% B to 37% B in 10min; detection wavelength: 254nm / 220nm; retention time (min): 9.03, yielding 4-(2-hydroxyethanesulfonamide)-N-(4-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2,5]octane-6-yl)benzamide (35.6mg, 35.39%).

[0377] MS(ESI, m / z): 538.40 [M+H] + RT(min):1.536

[0378] 1H NMR(400MHz,DMSO-d6)δ12.07(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).

[0379] The compounds listed in the table below were prepared using conditions similar to those in Example 11.

[0380]

[0381]

[0382]

[0383] Example 12

[0384] 4-(2-hydroxyethanesulfonamide)-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]octane-6-yl)benzamide (Compound 99)

[0385]

[0386] The first step was the synthesis of (1S,4R)-2-(3-chloro-5-methyl-2-nitrophenyl)-2-azabicyclo[2.2.1]hepta-3-one (compound 99-3):

[0387] Under nitrogen protection, 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 (1,3-dichloro-5-methyl-2-nitrobenzene, 1 g, 4.854 mmol, 1 eq) of potassium phosphate (3.09 g, 14.562 mmol, 3 eq) and (1S,4R)-2-azabicyclo[2.2.1]hepta-3-one (539.48 mg, 4.854 mmol, 1 eq) in 1,4-dioxane (10 mL) at room temperature. The reaction mixture was heated to 100 °C and 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 and backwashed with saturated brine (2 × 50 mL), then dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (1:1) to give (1S,4R)-2-(3-chloro-5-methyl-2-nitrophenyl)-2-azabicyclo[2.2.1]hepta-3-one (800 mg, 58.71%).

[0388] MS:(ESI,m / z):281.30[M+H] + RT(min):1.079

[0389] The second step involves the 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):

[0390] Under nitrogen protection, at room temperature, reduced iron powder (785.82 mg, 14.070 mmol, 5 eq) and acetic acid (4 mL) were added to an ethanol (10 mL) solution of (1S,4R)-2-(3-chloro-5-methyl-2-nitrophenyl)-2-azabicyclo[2.2.1]hepta-3-one (790 mg, 2.814 mmol, 1 eq). The reaction mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was diluted with water (50 mL), and 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 residue was purified by silica gel column chromatography in 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%).

[0391] MS:(ESI,m / z):233.35[M+H] + RT(min): 0.814

[0392] The third step is the synthesis of tert-butyl carbamate (compound 99-5) of ((1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate:

[0393] Under nitrogen protection, at room temperature, (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 tert-butyl carbamate (553.75 mg, 4.726 mmol, 2 eq) were added to a solution of N,N-dimethylformamide (6 mL) containing methanesulfonic acid {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)4 (217.10 mg, 0.236 mmol, 0.1 eq), bicyclohexyl... Hexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (252.80 mg, 0.473 mmol, 0.2 eq) was reacted with the solution heated to 100 °C and stirred for 16 hours. The reaction solution 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 residue was purified by silica gel column chromatography with 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%).

[0394] MS:(ESI,m / z):314.45[M+H] + RT(min): 0.871

[0395] Step 4: Synthesis of (1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine-6-amine (compound 99-6):

[0396] At room temperature, a solution of 1,4-dioxane in hydrogen chloride (10 mL) 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-yl)carbamate tert-butyl ester (650 mg, 2.074 mmol, 1 eq) in dichloromethane (10 mL), and the mixture was stirred for 1 hour. The reaction was monitored by liquid chromatography-mass spectrometry until complete. The mixture was then concentrated under vacuum to obtain (1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-amine, crude product (700 mg). The crude product was not further purified and was directly added to the next step.

[0397] MS:(ESI,m / z):214.40[M+H] + RT(min): 0.230

[0398] 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]octane-6-yl)benzamide (compound 99-7):

[0399] Under nitrogen protection, at room temperature, N-methylimidazole (344.80 mg, 4.200 mmol, 10 eq) was added to a dichloromethane solution (5 mL) of (1S,4R)-8-methyl-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine-6-amine (107.48 mg, 0.504 mmol, 1.2 eq), 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid (150 mg, 0.420 mmol, 1.0 eq), and N,N,N',N'-tetramethylchloromethanesulfonamide hexafluorophosphate (471.31 mg, 1.680 mmol, 4 eq). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then extracted with dichloromethane (3 × 30 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 residue was purified by silica gel column chromatography in 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]octane-6-yl)benzamide (110 mg, 47.41%).

[0400] MS:(ESI,m / z):553.10[M+H] + RT(min):1.118

[0401] Step 6: Synthesis of 4-(2-hydroxyethanesulfonamide)-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]octane-6-yl)benzamide (compound 99):

[0402] Under nitrogen protection, at room temperature, cuprous iodide (3.45 mg, 0.018 mmol, 0.1 eq) and sarcosine (3.23 mg, 0.036 mmol, 0.2 eq) were added to 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]octane-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. The reaction solution was heated to 120 °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 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 crude product was purified by preparative high-performance liquid chromatography (HPLC) under the following conditions (column specifications: Kinetex 5μm EVO C18, 30mm×150mm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60ml / min; elution gradient: 27% B to 62% B in 8min; detection wavelength: 254nm / 220nm; retention time (min): 7.92), yielding 4-(2-hydroxyethanesulfonamide)-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]octane-6-yl)benzamide (38.29mg, 38.33%).

[0403] MS:(ESI,m / z):550.45[M+H] + RT(min):1.525

[0404] 1H NMR(400MHz,DMSO-d6)δ12.22(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).

[0405] The compounds listed in the table below were prepared using conditions similar to those in Example 12.

[0406]

[0407] Example 13

[0408] 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (compound 100)

[0409]

[0410] The first step was the synthesis of 2-(3-bromo-2-nitrophenyl)-2-azabicyclo[2.2.2]octane-3-one (compound 100-3):

[0411] Under nitrogen protection, at room temperature, tris(dibenzylacetone)dipalladium (326 mg, 0.356 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (412 mg, 0.712 mmol, 0.2 eq) were added to a 1,4-dioxane solution (1,3-dibromo-2-nitrobenzene, 1 g, 3.5 mmol, 1 eq), 2-azabicyclo[2.2.2]octane-3-one (534 mg, 4.3 mmol, 1.2 eq), and cesium carbonate (3.5 g, 10.7 mmol, 3 eq) in 1,4-dioxane (10 mL). After the addition was complete, the reaction solution was heated to 80 °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 phases were combined, and backwashed with saturated brine (2 × 50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (1:1) to give 2-(3-bromo-2-nitrophenyl)-2-azabicyclo[2.2.2]octane-3-one (603 mg, 52%).

[0412] MS:(ESI,m / z):325.30[M+H] + RT(min):1.021

[0413] The second step is the synthesis of 6-bromo-1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridine (compound 100-4):

[0414] Under nitrogen protection, tetrahydroxydiboron (480 mg, 5.4 mmol, 3 eq) and 4,4'-bipyridine (1.4 mg, 0.009 mmol, 0.005 eq) were added to a solution of 2-(3-bromo-2-nitrophenyl)-2-azabicyclo[2.2.2]octane-3-one (580 mg, 1.8 mmol, 1 eq) in N,N-dimethylformamide (1 mL) at room temperature. After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with water (10 mL) at room temperature, and the mixture was extracted with ethyl acetate (3 × 40 mL). The organic phases were combined and backwashed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The 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%).

[0415] MS:(ESI,m / z):277.20[M+H] + RT(min): 0.683

[0416] The third step is the synthesis of tert-butyl carbamate (compound 100-5):

[0417] Under nitrogen protection, at room temperature, tert-butyl carbamate (51 mg, 0.43 mmol, 1.2 eq), (2 mL of a 1,4-dioxane 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) and (33 mg, 0.036 mmol, 0.1 eq) were added to a 1,4-dioxane 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) and (3,1'-biphenyl]-2-(2,4-dioxane)palladium(II)4 (2'-methylamino-1,1'-biphenyl-2- ... Phosphine (39 mg, 0.072 mmol, 0.2 eq) and cesium carbonate (588 mg, 1.8 mmol, 5 eq) were added, and the mixture was heated to 100 °C and stirred for 16 hours. The reaction solution 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, and backwashed with saturated brine (2 × 30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the petroleum ether / ethyl acetate (1:1) yielded tert-butyl (1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate (90 mg, 79%).

[0418] MS:(ESI,m / z):314.40[M+H] + RT(min): 0.768

[0419] Step 4: Synthesis of 1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridine-6-amine (compound 100-6):

[0420] Under nitrogen protection, at room temperature, a solution of 1,4-dioxane containing hydrogen chloride (1 mL) was added to a dichloromethane solution (85 mg, 0.27 mmol, 1 eq) of (1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)carbamate tert-butyl ester (1 mL). After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-amine (57 mg, 98%).

[0421] MS:(ESI,m / z):214.4[M+H] + RT(min): 0.196

[0422] Step 5: Synthesis of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (compound 100-7):

[0423] Under nitrogen protection, at room temperature, 2-{6-azaspiro[4,5]imidazo[1,2-a]pyridine-6-amine (52 mg, 0.24 mmol, 1 eq) was added to a dichloromethane solution (1 mL) containing 1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridine-6-amine (104 mg, 0.23 mmol, 1.2 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (342 mg, 1.2 mmol, 5 eq), and N-methylimidazolium (200 mg, 2.4 mmol, 10 eq). After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction solution 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 filtrate was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (3:1) to give 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (110 mg, 82%).

[0424] MS:(ESI,m / z):553.5[M+H] + RT(min):1.235

[0425] Step 6: Synthesis of 4-(2-hydroxyethanesulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (compound 100):

[0426] Under nitrogen protection, at room temperature, 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]octane-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), under stirring at 120 °C for 1.5 h. The reaction solution 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 (3×30 mL). The organic phases were combined and backwashed with saturated brine (2×20 mL). The mixture was dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) under the following conditions: column specifications: Kinetex 5μm EVO C18, 30mm×150mm; mobile phase A: water (10mmol / L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60ml / min; elution gradient: 30%B to 60%B in 8min; detection wavelength: 254nm / 220nm; retention time (min): 7.65, yielding 4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)-N-(1,2,3,4-tetrahydro-1,4-ethylbenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (28.84mg, 28%).

[0427] MS:(ESI,m / z):550.10[M+H] + RT(min):1.548

[0428] 1 H NMR: (400MHz, CDCl3) δ12.28(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).

[0429] Example 14

[0430] N-(3,3-difluoro-2,3-dihydro-1H-benzopyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonylamino)-2-spiro[2,5]oct-5-en-6-yl)benzamide (compound 90)

[0431]

[0432]

[0433] The first step was the synthesis of methyl 4-bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoate (compound 90-3):

[0434] Under nitrogen protection, at room temperature, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (167.25 mg, 0.205 mmol, 0.1 eq) was added to 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-dioxoborhexacyclopentane (480.74 mg, 2.053 mmol, 1 eq) in 1,4-dioxane (8 mL) and water (1.6 mL). The reaction mixture was heated to 80 °C and stirred for 1 hour. The reaction mixture was then cooled 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 organic phases were combined and 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 residue was purified by reverse-phase column chromatography under the following conditions: column size, C18; mobile phase: acetonitrile in water, gradient 10% to 70% in 10 min; detection wavelength: UV 254 nm. Methyl 4-bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoate (320 mg, 48.52%) was obtained.

[0435] MS:(ESI,m / z):320.95[M+H] + RT(min):1.942

[0436] The second step is the synthesis of 4-bromo-2-{spiro[2.5]oct-5-en-6-yl}benzoic acid (compound 90-4):

[0437] At room temperature, lithium hydroxide (111.84 mg, 4.670 mmol, 5 eq) was added 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). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (15 mL), and the mixture was extracted with ethyl acetate (2 × 20 mL). 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 and backwashed with saturated brine (2 × 20 mL). The mixture was dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to give 4-bromo-2-{spiro[2.5]oct-5-en-6-yl}benzoic acid (250 mg, 87.14%).

[0438] MS:(ESI,m / z):308.90[M+H] + RT(min):1.323

[0439] The third step is the 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):

[0440] Under nitrogen protection and at room temperature, 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'-tetramethylchloromethanemida 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). After the addition was complete, the system was stirred at 60 °C for 2 hours. The reaction solution was cooled to room temperature and 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 resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in 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%).

[0441] MS:(ESI,m / z):498.40[M+H] +RT(min): 1.449

[0442] 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):

[0443] Under nitrogen protection, at room temperature, add (methanesulfonic acid {bicyclohexyl(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) to a solution of N,N-dimethylformamide (2 mL)) to (2,3-dimethylformamide). The reaction mixture of methylamino-1,1'-biphenyl-2-yl)palladium(II) (9.22 mg, 0.010 mmol, 0.1 eq) and bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonane (10.73 mg, 0.020 mmol, 0.2 eq) 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 organic phases 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 crude product was purified by high-performance liquid chromatography (HPLC) under the following conditions (Kinetex column). 5m EVO C18, 30mm*150mm; 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 in 8 min; Detection wavelength: UV 254nm / 220nm; Retention time (min): 7.6). N-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-4-(2-hydroxyethanesulfonylamino)-2-(spiro[2.5]oct-5-en-6-yl)benzamide (10.84 mg, 19.83%) was obtained.

[0444] MS:(ESI,m / z):543.50[M+H] + RT(min): 1.650

[0445] 1H NMR(400MHz,DMSO-d6)δ9.92(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).

[0446] The compounds listed in the table below were prepared using conditions similar to those in Example 14.

[0447]

[0448] Example 15

[0449] N-(dibenzo[b,d]furan-4-yl)-4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (compound 111)

[0450]

[0451] The first step was the synthesis of N-(dibenzo[b,d]furan-4-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (compound 111-2):

[0452] Under nitrogen protection, 4-aminofluorene (61.55 mg, 0.336 mmol, 1.2 eq), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (314.21 mg, 1.120 mmol, 4 eq), and N-methylimidazolium (229.87 mg, 2.800 mmol, 10 eq) were added to a solution of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid (100 mg, 0.280 mmol, 1 eq) in dichloromethane (2 mL) at room temperature. The reaction mixture was heated to 80 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature, and the reaction mixture was quenched with 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 residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (10:1) to give N-(dibenzo[b,d]furan-4-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (140 mg, 95.73%).

[0453] MS:(ESI,m / z):523.30[M+H] + RT(min):1.722

[0454] The second step was the synthesis of N-(dibenzo[b,d]furan-4-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2,5]octane-6-yl)benzamide (compound 111):

[0455] Under nitrogen protection, at room temperature, 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) were added to a solution of N-(dibenzo[b,d]furan-4-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzamide (90 mg, 0.172 mmol, 1 eq) in N,N-dimethylformamide (2 mL). The reaction mixture was heated to 120 °C and stirred for 1 hour. The reaction mixture was then cooled to room temperature and quenched with water. The reaction mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, 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 (HPLC) under the following conditions: 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 in 8 min; detection wavelength: UV 220 nm; retention time (min): 7.03. N-(dibenzo[b,d]furan-4-yl)-4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (25.9 mg, 27.89%) was obtained.

[0456] MS + :(ESI,m / z):519.90[M+H] + ,RT(min):1.784.

[0457] 1H NMR: (400MHz, DMSO-d6) δ12.85(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),3.8 4–3.72(m,2H),3.40–3.35(m,2H),3.14–2.97(m,4H),1.83(s,4H),0.43(d,4H).

[0458] Example 16

[0459] 2-{6-azaspiro[2.5]octane-6-yl}-N-(7-cyclopropylquinolin-4-yl)-4-(2-hydroxyethanesulfonylamino)benzamide (compound 112)

[0460]

[0461]

[0462] The first step is the synthesis of N-(7-bromoquinoline-4-yl)carbamate tert-butyl ester (compound 112-2):

[0463] At room temperature, triethylamine (1.36 g, 13.449 mmol, 3 eq) and di-tert-butyl dicarbonate (978.37 mg, 4.483 mmol, 1 eq) were added to a solution of 7-bromoquinoline-4-amine (1.0 g, 4.483 mmol, 1 eq) in dichloromethane (15.0 mL). The reaction mixture was stirred at room temperature for 17 hours. With reactants remaining, 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 organic phases were combined, 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 residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (5:1) to give N-(7-bromoquinoline-4-yl)carbamate tert-butyl ester (1.16 g, 80.07%).

[0464] MS:(ESI,m / z):323.05[M+H] + RT(min):1.427

[0465] The second step is the synthesis of N-(7-bromoquinoline-4-yl)carbamate tert-butyl ester (compound 112-4):

[0466] Under nitrogen protection, at room temperature, cyclopropylboronic acid (558.15 mg, 6.498 mmol, 3 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (176.44 mg, 0.217 mmol, 0.1 eq), and cesium carbonate (2117.08 mg, 6.498 mmol, 3 eq) were added to a mixture of 2 mL of 1,4-dioxane solution and 0.5 mL of water (700 mg, 2.166 mmol, 1 eq) at room temperature. The reaction mixture was heated to 80 °C and stirred for one 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 brine (2 × 40 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether / ethyl acetate (1:1) to give N-(7-cyclopropylquinoline-4-yl)carbamate tert-butyl ester (530 mg, 86.05%).

[0467] MS:(ESI,m / z):285.30[M+H] + RT(min):1.054

[0468] Step 3: Synthesis of 7-cyclopropylquinoline-4-amine (compound 112-5):

[0469] At room temperature, 2.5 mL of 1,4-dioxane with 4 mol / L hydrogen chloride was added to a solution of N-(7-cyclopropylquinoline-4-yl)carbamate tert-butyl ester (500 mg, 1.758 mmol, 1 eq) in dichloromethane (5 mL), and the mixture was stirred for 30 min. The resulting residue was concentrated under reduced pressure to give the product 7-cyclopropylquinoline-4-amine (240 mg, 74.08%).

[0470] MS:(ESI,m / z):185.20[M+H] + RT(min): 0.672

[0471] Step 4: Synthesis of 2-(6-azaspiro[2.5]octane-6-yl-N-(7-cyclopropylquinoline-4-yl)-4-iodobenzamide (compound 112-6):

[0472] Under nitrogen protection, at room temperature, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (609.16 mg, 2.172 mmol, 4 eq) and N-methylimidazolium (445.64 mg, 5.430 mmol, 10 eq) were added to a solution of 7-cyclopropylquinoline-4-amine (100 mg, 0.543 mmol, 1 eq) and 2-(6-azaspiro[2.5]octane-6-yl-4-iodobenzoic acid (290.81 mg, 0.815 mmol, 1.5 eq) in dichloromethane (4 mL). q). The reaction mixture was stirred at room temperature for one hour. The reaction mixture was quenched with water (3 mL). The reaction mixture was extracted with dichloromethane (2 × 40 mL). The organic phases were combined, 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 in petroleum ether / ethyl acetate (5:1) to give 2-(6-azaspiro[2.5]octane-6-yl-N-(7-cyclopropylquinoline-4-yl)-4-iodobenzamide (70 mg, 24.64%).

[0473] MS:(ESI,m / z):524.45[M+H] + RT(min):1.029

[0474] Step 5: Synthesis of 2-{6-azaspiro[2.5]octane-6-yl}-N-(7-cyclopropylquinoline-4-yl)-4-(2-hydroxyethanesulfonylamino)benzamide (compound 112):

[0475] Under nitrogen protection, at room temperature, 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) were added to a solution of 2-{6-azaspiro[2.5]octane-6-yl}-N-(7-cyclopropylquinoline-4-yl)-4-iodobenzamide (60 mg, 0.115 mmol, 1 eq) in N,N-dimethylformamide (1 mL). The reaction mixture was heated to 120 °C and stirred for 1.5 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 × 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 crude product was purified by high performance liquid chromatography to obtain 2-{6-azaspiro[2.5]octane-6-yl}-N-(7-cyclopropylquinolin-4-yl)-4-(2-hydroxyethanesulfonylamino)benzamide (18.96 mg, 31.55%).

[0476] MS:(ESI,m / z):521.40[M+H] + RT(min):1.352

[0477] 1 H NMR(400MHz,DMSO-d6)δ11.99(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).

[0478] Biological evaluation

[0479] Test Example 1

[0480] Test Name: Imaging-Based Nuclear Counting Analysis (NCA) in OVCAR-3 Cells

[0481] Day 0: Compound dilution and treatment

[0482] a) The final test concentrations of AM-5308 were: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, and 0.5 nM.

[0483] b) The test compounds were finally tested at the following concentrations: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, and 0.5 nM.

[0484] c) The cells were cultured for 4 days in an incubator at 37°C and 5% CO2.

[0485] d) The DMSO concentration is 0.1%.

[0486] On day 1, cells were seeded into 384-well cell culture plates.

[0487] a) When the cell confluence reaches 80%-90%, process the cells.

[0488] b) Resuspend the cells in the culture medium, and then count and dilute the cells at the desired density.

[0489] c) Add 30 μL / well of cell suspension containing appropriate cells to a 384-well plate: 600 cells / well.

[0490] Day 4 testing

[0491] a) Add 30 μL of 8% fixative (final concentration 4%) and incubate the plate at room temperature for 30 minutes.

[0492] b) Centrifuge plate, 1000 RPM, 30 s.

[0493] c) Wash twice with 60 μl / well of PBS.

[0494] d) After fixation, the cells were permeabilized and stained in 60 μL of wash buffer containing 2 μg / mL Hoechst 33342 DNA dye (1% BSA, 0.2% Triton X-100, 1X PBS).

[0495] e) Seal the plate and incubate it at room temperature in the dark for 1 hour.

[0496] f) Wash 3 times with PBS.

[0497] g) Add 50 μL PBS per well and scan the plate using HCS.

[0498] h) Data Acquisition and Detection

[0499] Data Analysis

[0500] Inhibition rate (%) = 100 - (Compound well reading - Low reading control well reading) / (High reading control well reading - Low reading control well reading) * 100

[0501] High reading control wells: cells with 30 nL DMSO; Low reading control wells: 10 μM AM-5308 wells.

[0502] Calculate IC using GraphPad Prism 8 software 50 (nM) and plot the effect-dose curve of the compound.

[0503] Table 1. Biological activity data of the compounds in this application.

[0504]

[0505]

[0506] Test Example 2

[0507] Test Name: KIF18A Enzyme Activity Assay

[0508] Operating steps:

[0509] 1) Compound dilution and treatment: The final test concentrations of AM-5308 were: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, and 0.5 nM. The final test concentrations of the test compounds were: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, and 0.5 nM.

[0510] 2) Transfer 100 nmL of the diluted compound stock solution to each well of the reaction plate using an Echo 655. The final concentration of DMSO is 1%.

[0511] 3) Seal the reaction plate with a sealing film and centrifuge at 1000g for 1 minute.

[0512] 4) Prepare 2× enzyme solution using 1× reaction buffer.

[0513] 5) Add 5 μL of 2× enzyme solution to each well of the reaction plate. Seal the plate with sealing film, centrifuge at 1000g for 1 minute, and incubate at room temperature for 15 minutes.

[0514] 6) Prepare a 2×ATP solution using 1× reaction buffer.

[0515] 7) Add 5 μL of 2×ATP solution to the reaction plate, centrifuge at 1000g for 1 minute to start the reaction.

[0516] 8) React at room temperature for 60 minutes.

[0517] 9) Add 10 μL of ADP Glo reagent. Centrifuge at 1000g for 1 minute and incubate at room temperature for 60 minutes.

[0518] 10) Add 20 μL of kinase detection reagent. Centrifuge at 1000g for 1 minute and incubate at room temperature for 60 minutes.

[0519] 11) Centrifuge at 1000g for 1 minute.

[0520] 12) Read the light emission signal on Envision 2104.

[0521] Data Analysis:

[0522] The inhibition percentage is calculated as follows:

[0523] %inhibition = 100 - (Signal) cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC )×100

[0524] Signal cmpd: The average value of the compounds tested on the reaction plate.

[0525] Signal Ave_PC : The average value of the positive control (AM-5308) on the reaction plate.

[0526] Signal Ave_VC : The mean value of the negative control (DMSO) on the reaction plate.

[0527] Computing IC 50 And the dose-response curve of the fitted compound:

[0528] Using GraphPad 8.0, the IC of the compound is obtained using a nonlinear fitting formula. 50 .

[0529] 3) Quality Control

[0530] Z factor > 0.5; S / B > 2.

[0531] Table 2 Enzyme activity data of the compounds in this application

[0532]

[0533] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. A compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof: （I） in, A is selected from ; Z is selected from CH2; r and s are independently selected from 1 or 2; X is selected from N or CH; n is selected from 0, 1, or 2; Each R a They may be the same or different, and are independently selected from halogens or C. 1-6 Alkyl group; or, two non-adjacent R groups. a They are connected by their terminal groups to form methylene or ethylene; E is selected from ; M is selected from or ; Y1, Y2, and Y3 are the same, and are selected from CH.

2. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to claim 1, wherein, A is selected from unsubstituted or arbitrarily assigned to one or two R. a Replacement , , .

3. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts, wherein, A is selected from unsubstituted or arbitrarily assigned to one or two R. a Replacement , .

4. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts, wherein, Each R a They may be the same or different, and are independently selected from F, Cl, methyl, ethyl or isopropyl.

5. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts, wherein, A is selected from , , , , , , , , , , , , , , , , , .

6. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts, wherein, A is selected from , .

7. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts, wherein, A is selected from , , , , .

8. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts, wherein, A is selected from , , , , , , , .

9. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein, The compound shown in formula (I) has the following structure: ID-3 Among them, Y1, Y2, Y3, R a , n, X, Z, r, s are each independently defined by any one of claims 1-8.

10. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 11. The following compounds, their stereoisomers, or pharmaceutically acceptable salts: 、 、 、 。 12. The following compounds, their stereoisomers, or pharmaceutically acceptable salts: 、 、 。 13. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 14. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: 、 。 15. A method for preparing the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein, Includes the following steps: (1) Compound a reacts with compound A-NH2 to give compound b; (2) Compound b reacts with compound EH to give the compound shown in formula (I); Wherein, A, E, M, Y1, Y2, and Y3 independently have the definition of any one of claims 1-9; L is selected from halogens.

16. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of any one of claims 1-14, their stereoisomers, or their pharmaceutically acceptable salts.

17. Use of at least one of the compounds of any one of claims 1-14, their stereoisomers, or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating KIF18A-mediated symptoms and / or diseases.

18. The use according to claim 17, wherein, The intended use is in the preparation of KIF18A inhibitors.

19. The use according to claim 17, wherein, The disease in question is cancer.

20. The use according to claim 19, wherein, The diseases mentioned include colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer, or ovarian cancer.

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