Heteroaromatic compound, and pharmaceutical composition thereof, preparation method therefor and use thereof

Abstract

The present disclosure provides a heteroaromatic compound as represented by formula I, and a pharmaceutical composition thereof, a preparation method therefor and a use thereof. The compound of formula I has high inhibitory activity on CDK2, CDK4 and / or CDK6. Also provided is a use in the preparation of a drug for treatment and / or related to CDK2 / 4 / 6 activity.

Description

Heterocyclic aromatic compounds, their pharmaceutical compositions, their preparation methods and uses

[0001] Cross-reference to related applications

[0002] This disclosure claims Chinese patent applications filed on April 17, 2025, with application number CN202510486835.0, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof," filed on May 28, 2025; and Chinese patent applications filed on June 23, 2025, with application number CN202510846234.6, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof." Priority is given to Chinese patent applications for “heteroaromatic compounds, pharmaceutical compositions thereof, and uses thereof” filed on July 31, 2025, with application number “CN202511071904.8” and title “heteroaromatic compounds, pharmaceutical compositions thereof, and uses thereof”, and Chinese patent applications for “heteroaromatic compounds, pharmaceutical compositions thereof, and uses thereof” filed on September 26, 2025, with application number “CN202511386730.4” and title “heteroaromatic compounds, pharmaceutical compositions thereof, and uses thereof”, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure pertains to the field of medicinal chemistry, specifically relating to heterocyclic aromatic compounds, pharmaceutical compositions thereof, preparation methods, and uses thereof. Background Technology

[0004] Cyclin-dependent kinases (CDKs) are serine / threonine kinases whose activity depends on the regulatory subunit α-cyclin. Based on the sequence of their kinase domains, CDKs belong to the CMGC kinase group and, like mitogen-activated protein kinase (MAPK) and glycogen synthase kinase 3β (GSK3B), are members of the dual-specificity tyrosine-regulated kinase (DYRK) family and CDK-like kinases. The CDK family of proteins includes CDK1 through CDK20.

[0005] CDK4 / 6 participates in cell cycle regulation through the Cyclin D-CDK4 / 6-RB pathway. CDK6 is a major mediator of estrogen-mediated cell proliferation: estrogen induces Cyclin D1 expression in HR+ breast cancer, thereby promoting CDK4 / 6 activity, leading to RB1 hyperphosphorylation and promoting cell cycle progression from G1 to S phase. CDK4 / 6 inhibitors inhibit tumor proliferation by arresting tumor cells from entering the S phase from G1.

[0006] CDK2 overexpression is associated with abnormal cell cycle regulation, and the CDK2 / Cyclin E complex is involved in the regulation of the cell cycle from G1 to S phase. At the end of G1 phase, the CDK2 / Cyclin E complex can also catalyze Rb phosphorylation, thereby promoting cell cycle progression from G1 to S phase; in S phase, the CDK2 / cyclin A complex can promote DNA replication. Cyclin E, the counterpart to CDK2, is commonly found in tumors. Cyclin E amplification and overexpression are associated with poor prognosis in ovarian cancer, gastric cancer, and breast cancer.

[0007] Activation of upstream signaling pathways (such as Ras / MAPK, ER, and PI3K / mTOR) promotes the formation of the cell cycle cyclin D-CDK4 / 6 complex, phosphorylates retinoblastoma protein (RB), releases transcription factor E2F, activates other cyclin-CDK complexes (including cyclin E-CDK2), and proceeds through the G1, S (DNA synthesis phase), G2, and M (cell division phase) phases, ultimately completing the cell mitosis process.

[0008] Currently, there are five CDK4 / 6 inhibitors available globally. Palbociclib, Ribociclib, Abeciclib, and Darcitabine are used for HR+ / HER2- advanced or metastatic breast cancer, while Trilacizumab is used to alleviate myelosuppression caused by chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). Recent studies have found that the safety and resistance of CDK4 / 6 inhibitors need further improvement; therefore, there is still a need for safer CDK2 / 4 / 6 inhibitors that can overcome resistance. Summary of the Invention

[0009] In a first aspect, this disclosure provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs thereof, wherein said compounds have a structure as shown in Formula I:

[0010] in,

[0011] X 1 Selected from N and CR 1 ;

[0012] (1) When X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C 1-6Alkylene-C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups;

[0013] R 3 Selected from H, C 1-6 Alkyl, -C 1-6 Alkylene-OR c C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 6 replace;

[0014] Or, R 2 R 3 The atoms bonded to it form 3-8 membered heterocyclic groups, said heterocyclic groups optionally bonded by one or more elements selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-OR a3 The alkyl, cycloalkyl, and heterocyclic groups are substituted with groups selected from cyano, -C, and cycloalkyl groups, respectively. 1-6 alkylene-cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-OR a3 Substitution of groups;

[0015] (2) When X 1 For CR 1 At that time, R 2 R 3 The atoms bonded to it form 3-8 membered heterocyclic groups, said heterocyclic groups optionally being bonded by one or more elements selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-OR a4 -OC 1-6The alkyl and 3-8 membered heterocyclic groups are substituted, and the alkyl, cycloalkyl and heterocyclic groups are further replaced by one or more groups selected from cyano, -C 1-6 alkylene-cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-OR a4 Substitution of groups;

[0016] R 1 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0017] R 4 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0018] R 5 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0019] R 6 Each is independently selected from H, deuterium, halogen, cyano, and -OR. d1 C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-OR d2 C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0020] Y is selected from phenyl and 5-10 heteroaryl groups, wherein the phenyl and heteroaryl groups are optionally separated by one or more R groups. 7 replace;

[0021] R 7 Each is independently selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6Halogenated alkyl groups;

[0022] Or, R 7 Formation of 3-10 membered heterocycles fused with Y, wherein the heterocycles are optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0023] L is selected from covalent bonds, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -C 1-6 Alkylene-N(R) e1 )-、-C 1-6 Alkylene-O-, -N(R) e2 )-、-O-、-N(R e3 )-C 1-6 Alkylene-N(R) e4 )-、-N(R e5 )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) e6 )-、-C(=O)-C 1-6 Alkylene -O-, -C(=O)-C 1-6 Alkylene-N(R) e7 - and -S(=O)2-;

[0024] Z is selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 8 replace;

[0025] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo (=O), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(R) g1 )R h1 -C 1-6 Alkylene-N(R) g2 )R h2 -C 1-6 Alkylene-OR g3 -C(=O)-N(R) g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R)g7 )R h4 C 3-10 cycloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -N(R) g8 )R h5 Substitution of groups;

[0026] R a1 R a2 R a3 and R a4 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen;

[0027] R b Selected from H and C 1-6 alkyl;

[0028] R c Selected from H, C 1-6 Alkyl and C 3-8 cycloalkyl;

[0029] R d1 and R d2 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen;

[0030] R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H and C. 1-6 alkyl;

[0031] R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 R h1 R h2 R h3 Rh4 and R h5 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl.

[0032] A second aspect of this disclosure provides a method for preparing the compounds disclosed herein.

[0033] A third aspect of this disclosure provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0034] This disclosure provides a medicine box product comprising:

[0035] a) at least one compound described herein as a first therapeutic agent, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, or a pharmaceutical composition as a first pharmaceutical composition;

[0036] b) At least one other therapeutic agent optionally present as a second therapeutic agent, or a pharmaceutical composition comprising another therapeutic agent as a second pharmaceutical composition; and

[0037] c) Optional packaging and / or instructions.

[0038] The fifth aspect of this disclosure provides the use of the compounds described herein, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs thereof, or pharmaceutical compositions, or kit products, in the preparation of medicaments for the treatment and / or prevention of diseases or symptoms associated with CDK2 / 4 / 6 activity.

[0039] The sixth aspect of this disclosure provides the compounds described herein or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs, or pharmaceutical compositions, or kit products, for the treatment and / or prevention of diseases or conditions associated with CDK2 / 4 / 6 activity.

[0040] The seventh aspect of this disclosure provides a method for treating and / or preventing diseases or symptoms associated with CDK2 / 4 / 6 activity, the method comprising administering to an individual in need an effective amount of the compound described in this disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or pharmaceutical composition, or kit product thereof.

[0041] definition

[0042] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better interpret this disclosure.

[0043] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0044] The term "one or more species" or similar expression "at least one species" refers to, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0045] When the lower and upper limits of a numerical range are disclosed, any value or subrange falling within that range is specifically disclosed. In particular, each numerical range of parameters disclosed herein (e.g., in the form of "about a to b", or equivalently "approximately a to b", or equivalently "about ab") should be understood to encompass every value and subrange therein. For example, "C..." 1-6 "This should be understood as encompassing any subrange and every point value, such as C." 2-5 C 3-4 C 1-2 C 1-3 C 1-4 C 1-5 And so on, as well as C1, C2, C3, C4, C5, C6, etc. For example, "3-10 yuan" should be understood as encompassing any sub-range and each point value, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 3-9 yuan, 4-5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc.

[0046] As used herein, an asterisk (*) in a compound structural formula indicates that the labeled carbon atom is a chiral carbon atom, and this disclosure includes a pair of enantiomers formed from that chiral carbon atom. If a compound contains two different chiral carbon atoms, this disclosure includes four optical isomers formed from that chiral carbon atom.

[0047] As used in this article, This indicates the location where a structural segment connects to other parts of the molecule.

[0048] The term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl), which is optionally substituted by one or more (such as 1, 2, or 3) suitable substituents.

[0049] The term "alkylene" refers to a divalent group formed by losing a hydrogen atom from the same or different carbon atoms of a straight-chain or branched "alkyl" group. For example, the term "C" in this disclosure... 1-6 "Alkylene" refers to an alkylene group having 1-6 carbon atoms, including but not limited to methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), =CH2, =CHCH3, =CHCH2CH3, etc. If the valence requirement is met, an alkylene group can be attached to two atoms, such as methylene (-CH2-), ethylene (-CH2CH2-), and isopropylene (-CH(CH3)CH2-); an alkylene group can also be attached to one atom, such as =CH2, =CHCH3, and =CHCH2CH3.

[0050] The term "hydroxyalkyl" or "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is defined as described above. For example, the term "C" in this disclosure... 1-6 "Hydroxyalkyl" refers to hydroxyalkyl groups having 1-6 carbon atoms. Common hydroxyalkyl groups include (but are not limited to) -CH2OH, -CH2CH2OH, -CH2CH(OH)2, and -(CH2)3OH.

[0051] The term "amine alkyl" refers to an alkyl group substituted with one or more amino groups, wherein the alkyl group is defined as described above. For example, the term "C" in this disclosure... 1-6 "Aminoalkyl" refers to an aminoalkyl group having 1-6 carbon atoms. Common aminoalkyl groups include (but are not limited to) -CH2-NH2, -CH2CH2-NH2, -CH2CH(NH2)2, and -(CH2)3-NH2.

[0052] The term "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C" as used herein... 2-6"Alkenyl" refers to an alkenyl group (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.) having 2-6 carbon atoms and one, two, or three carbon-carbon double bonds, which is optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0053] The term "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C" as used herein... 2-6 "Alynyl" refers to an alkynyl group having 2-6 carbon atoms and one, two or three carbon-carbon triple bonds (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), which is optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0054] The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group; for example, monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene; or bicyclic, including spirocyclic, fused-ring, or bridged rings (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, or decahydronaphthyl, etc.). For example, the term "C 3-12 "Cycloalkyl" refers to a cycloalkyl group having 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) ring carbon atoms. The term "C"... 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 cyclic carbon atoms, such as C10. 3-8 Cycloalkyl groups can be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or they can be bicycloalkyl, such as C10, C20, C30, C40, C50, C60, C7 ... 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl groups.

[0055] The term "heterocyclic group" or "heterocyclic alkyl group" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic cyclic structure whose ring atoms consist of a carbon atom and at least one (e.g., 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. The heterocyclic group can be attached to the rest of the molecule via any one ring atom, provided the valence requirements are met. The term also covers cases where the C or P atom in the ring can be substituted with an oxo group (=O), the S atom in the ring can be substituted with one or two oxo groups (=O), or the N atom on the ring can form a nitride. The ring system in a heterocyclic alkyl group can be a fused ring, a bridged ring, or a spirocyclic system. "Heterocyclic group" or "heterocyclic alkyl group" can be characterized by the number of ring atoms. For example, 3-12 membered heterocyclic groups or heterocyclic alkyl groups can contain 3-12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 3, 4, 5, 6, 7, 8, 9, and 10 ring atoms. If valence requirements are met, heterocyclic alkyl groups can be linked to other groups (or segments) through any carbon atom or heteroatom in the ring. Examples of 3-12, 3-8, 3-6, and 3-5 membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, aziridine, oxobutidine, thiobutidine, tetrahydrofuranyl, dioxacyclopentyl, dioxacyclohexyl, tetrahydrothiophenyl, pyrrolyl, pyrrolidone, piperidinyl, morpholinyl, thiomorpholinyl, and piperazine.

[0056] The term "saturated heterocycle" refers to a completely saturated heterocycle, such as the tetrahydrofuran ring, piperidine ring, tetrahydropyran ring, and piperazine ring. The term "partially saturated heterocycle" refers to a heterocycle that contains both saturated single bonds and unsaturated double bonds, such as 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, and dihydrofuran.

[0057] As used herein, the terms “3-8 membered heterocyclic group” or “3-8 membered heterocyclic alkyl group” mean a heterocyclic group containing 3-8 ring atoms, including but not limited to 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 4-6 membered heterocyclic groups, 5-6 membered heterocyclic groups, 3-7 membered heterocyclic groups, 4-6 membered nitrogen-containing heterocyclic groups, 4-6 membered oxygen-containing heterocyclic groups, 4-6 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups, etc., wherein each of the “nitrogen-containing heterocyclic group”, “oxygen-containing heterocyclic group” and “sulfur-containing heterocyclic group” optionally also contains one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of “4-6 membered heterocyclic group” or “4-6 membered heterocyclic alkyl group” include, but are not limited to, nitrogen heterocyclic butyl, oxoheterocyclic butyl, thioheterocyclic butyl, tetrahydrofuranyl, dioxacyclopentyl, dioxacyclohexyl, tetrahydrothiophenyl, pyrrolyl, pyrrolidone, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, etc.

[0058] The term "oxygen-containing heterocycle" refers to a heterocycle as described above that has one or more (e.g., 1, 2, or 3) ring atoms of oxygen atoms, such as 5-6 membered oxygen-containing heterocycles, five membered oxygen-containing heterocycles, and specific examples include, but are not limited to, ethylene oxide rings, tetrahydrofuran rings, furan rings, tetrahydropyran rings, pyran rings, 1,3-dioxolane rings, etc.

[0059] The term "nitrogen-containing heterocycle" refers to a heterocycle as described above that has one or more (e.g., 1, 2, or 3) ring atoms consisting of nitrogen atoms.

[0060] The term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (e.g., bicyclic) aromatic group having a conjugated π-electron system. As used herein, the term "C" refers to a carbon-based aromatic group. 6-10 "Aryl" refers to an aromatic group containing 6-10 carbon atoms, such as phenyl or naphthyl.

[0061] The term "heteroaryl" or "heteroary ring" refers to an aromatic group, either monocyclic or fused-ring, with a conjugated π-electron system, containing one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms) and one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from N, O, P, and S. Heteroaryls can be characterized by the number of ring atoms. For example, 5-12 membered heteroaryls can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 5, 6, 7, 8, 9, or 10 ring atoms. If valence requirements are met, a heteroaryl group can be attached to the parent molecule via any one of the ring atoms. Examples of heteroaryl groups include thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridine, pyrimidine, pyrazine, pyridazine, etc. The term also covers cases where the heteroaryl group may optionally be further fused to an aryl (e.g., benzene) or heteroaryl ring to form a fused ring system.

[0062] The terms "5-10-membered heteroaryl" or "5-10-membered heteroaryl ring" refer to a heteroaryl group (heteroaryl ring) containing 5 to 10 (e.g., 5, 6, 7, 8, 9, 10) ring atoms, including 5-10-membered nitrogen-containing heteroaryl, 5-10-membered oxygen-containing heteroaryl, 5-10-membered sulfur-containing heteroaryl, 5-6-membered nitrogen-containing heteroaryl, 5-6-membered oxygen-containing heteroaryl, 5-6-membered sulfur-containing heteroaryl, etc. Each of the "nitrogen-containing heteroaryl," "oxygen-containing heteroaryl," and "sulfur-containing heteroaryl" may optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of these groups include, but are not limited to, thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., as well as 5-10 fused cyclic groups containing these groups.

[0063] The term "fused ring system" refers to a polycyclic structure formed by two or more (e.g., 3, 4, or 5) carbon rings or heterocycles sharing a common ring edge, wherein the carbon rings include cycloalkyl and aryl groups, and the heterocycles include heteroaryl and heterocyclic alkyl groups. The fused ring system can be, for example, a fused ring system formed by cycloalkyl groups with cycloalkyl groups, a fused ring system formed by cycloalkyl groups with heterocyclic alkyl groups, a fused ring system formed by cycloalkyl groups with aryl groups, a fused ring system formed by cycloalkyl groups with heterocyclic aryl groups, a fused ring system formed by heterocyclic alkyl groups with aryl groups, a fused ring system formed by heterocyclic aryl groups with heterocyclic aryl groups, a fused ring system formed by heterocyclic aryl groups with heterocyclic aryl groups, or a fused ring system formed by heterocyclic aryl groups with aryl groups.

[0064] The term "fused heteroaryl" refers to an aromatic group with a fused ring having a conjugated π-electron system, containing one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms) and one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from N, O, P, and S. For example, the term "8-10 fused heteroaryl" refers to a fused heteroaryl containing 8-10 (e.g., 8, 9, or 10) ring atoms, which, if valence requirements are met, can be attached to the parent molecule via any one ring atom. Examples of "8-10 fused heteroaryl" include benzopyridyl, thiazopyridyl, oxazolopyridyl, and pyrazolopyrimidinyl.

[0065] The term "halogenated alkyl" or "halogen-substituted alkyl" refers to the alkyl group described above, in which one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 "Halogenated alkyl" or "halogenated C" 1-6 "Alkyl" refers to a C-aryl group that is optionally substituted with one or more (e.g., 1-3) halogens. 1-6 Alkyl group. The term "C" 1-4 "Halogenated alkyl" or "halogenated C" 1-4"Alkyl" refers to a C-aryl group that is optionally substituted with one or more (e.g., 1-3) halogens. 1-4 Alkyl groups. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. Examples of alkyl halogens include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0066] The term "halogenated alkylene" refers to the alkylene group described above, in which one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 "Halogenide" refers to a C-shaped alkyl group substituted with one or more (e.g., 1-3) halogens. 1-6 Alkylene. The term "C" is used to indicate that the alkylene group is alkylene oxide. 1-4 "Halogenide" refers to a C-shaped alkyl group substituted with one or more (e.g., 1-3) halogens. 1-4 Alkylenes. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. Examples of alkyl halides include, for example, -CHF-, -CF2-, =CF2, =CFCH3, =CFCH2CH3, etc.

[0067] The term "alkoxy" refers to a group having an "alkyl-O-" structure, where alkyl is defined as described above. For example, C 1-6 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy or C 1-2 Alkoxy groups, etc. Common alkoxy groups include (but are not limited to) methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, etc. Alkoxy groups in this disclosure may optionally be substituted by one or more substituents described in this disclosure.

[0068] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, or 4) alkoxy groups, wherein alkoxy groups and alkyl groups are defined as described above. For example, the term "C" as used in this disclosure... 1-6 "Alkoxyalkyl" refers to an alkyl group having 1-6 carbon atoms that is substituted with one or more (e.g., 1, 2, 3, or 4) alkoxy groups. Common alkoxyalkyl groups include (but are not limited to) CH3O-CH2-, C2H5-O-CH2-, C2H5-O-CH2CH2-, etc.

[0069] The term "halogenated" or "halogenated" is defined as including F, Cl, Br, or I.

[0070] As used herein, the terms "independently" or "independently" mean that at least two groups (or segments) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, -CN, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, -CN, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, -CN, alkyl, or aryl.

[0071] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more substituents from the list of substituents, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together by independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted by one or more substituents from the list of substituents, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted by independently selected optional substituents.

[0072] If a functional group or structural segment is described as “substituted or unsubstituted”, then the functional group or structural segment may be (1) unsubstituted or (2) substituted.

[0073] The term "substitution" refers to the replacement of one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms on a specified compound or structural segment by a substituent, provided that the substitution does not exceed the normal valence of the specified atom in the present case and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. For example, each substituent may independently consist of one or more of the following structures: -O-, -S-, -NR'-, halogen, -CN, -OH, -NH2, -NO2, -CN, =O, C 1-6 (alkylene) group, C 1-6 Halogenated (alkylene) group, C 1-6 Alkoxy, C 2-6 (imide)alkenyl, C 2-6 (Asyl) ynyl, C 3-8 (Hypo-cycloalkylene), 3-8 membered (hetero-cycloalkylene), C 6-10 (A)aryl and 5-10 (A)heteroaryl, etc. If a substituent is described as being "independently selected" from a group of functional groups, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0074] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0075] It should also be understood that certain compounds of this disclosure may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In this disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of this disclosure or their metabolites or residues. Therefore, when referring to “compounds of this disclosure” herein, it is also intended to cover the various derivative forms of the compounds described above.

[0076] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this disclosure that is substantially non-toxic to organisms. Pharmaceutically acceptable salts of the compounds of this disclosure include their acid addition salts and base addition salts.

[0077] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to organisms and is hydrolyzed in vivo to the disclosed compound or its salts. Additionally, the compounds disclosed herein may themselves be esters.

[0078] The term "isomer" refers to compounds that have the same molecular weight due to having the same number and type of atoms, but different spatial arrangements or configurations of atoms.

[0079] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that, due to having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.), has a perpendicular asymmetric plane, thereby enabling the rotation of plane-polarized light. Because the compounds of this disclosure contain asymmetric centers and other chemical structures that may lead to stereoisomerism, this disclosure also includes these stereoisomers and mixtures thereof. Since the compounds of this disclosure (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, or mixtures of enantiomers and diastereomers. Typically, these compounds can be prepared as racemates. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched with single stereoisomers (purity ≥99%, ≥98%, ≥97%, ≥96%, ≥95%, ≥90%, ≥85%, ≥80%, ≥75%, ≥70%, ≥65%, or ≥60%). As described below, the single stereoisomers of the compounds are prepared from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, for example, by converting to a mixture of diastereomers followed by separation or recrystallization, chromatographic treatment, using chiral resolving reagents, or by direct separation of the enantiomers on a chiral chromatographic column. Starting compounds with specific stereochemistry are commercially available or can be prepared according to the methods described below and then resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Certain individual molecules may also exist as geometric isomers (cis / trans). Unless otherwise stated, all stereoisomers of the compounds disclosed herein are within the scope of the disclosed compounds.

[0080] The term "tautomer" refers to a compound existing in a mixture of two or more structurally different forms in a rapidly equilibrating state; these compound forms are commonly called tautomers. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. For instance, nitroso-oximes can exist in equilibrium in solution in the following tautomeric forms:

[0081] Solid lines may be used in this article. solid wedge Or virtual wedge The carbon-carbon bonds of the compounds of this disclosure are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of this disclosure are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-isomers, and mixtures thereof). The compounds of this disclosure may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0082] This article uses This indicates the double bond form of compounds of this disclosure that does not distinguish between cis-trans isomers (including cis-trans isomers and / or cis-trans isomers resulting from Z / E isomer nomenclature), such as the imine intermediates of this disclosure.

[0083] The term "polymorph" (or "polymorphic form") refers to the solid crystalline form of a compound or complex. This disclosure covers all possible crystalline forms or polymorphs of the compounds disclosed herein, which may be a single polymorph or a mixture of multiple polymorphs in any proportion.

[0084] The term "solvent" refers to a substance formed by the combination of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. The compounds of the present disclosure may exist as solvates, containing a polar solvent as an element of the crystal structure. The amount of polar solvent may be in stoichiometric or non-stoichiometric form.

[0085] The term "isotope-labeled compound" refers to a derivative compound formed by replacing a specific atom in a compound of this disclosure with its isotopic atom. Unless otherwise indicated, the compounds of this disclosure include various isotopes of H, C, N, O, F, P, S, and Cl, such as... 2 H(D), 3 H(T), 13 C 14 C 13 N、 15 N、 17 O、 18 O、 18 F, 31 P, 32P, 34 S, 35 S, 36 S, 37 Cl and 125 I. For example, 12 C can be 13 C or 14 C substitution; 1 H can be 2 H(D, deuterium) or 3 H(T, tritium) substitution; 16 O can be 18 O substitution, etc.

[0086] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming N-oxides. They will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane.

[0087] The term "metabolite" refers to a derivative compound formed after the metabolism of the compounds of this disclosure, such as those produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, or enzymatic hydrolysis. This disclosure covers all possible metabolite forms of the compounds of this disclosure, i.e., substances formed in the body of an individual who has been given the compounds of this disclosure. The metabolites of the compounds can be identified by techniques known in the art, and their activity can be characterized by assays.

[0088] The term "prodrug" refers to a derivative compound that, upon administration to an individual, can directly or indirectly provide the compounds of this disclosure. Particularly preferred derivative compounds or prodrugs are those that, upon administration to an individual, can improve the bioavailability of the compounds of this disclosure (e.g., facilitate absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of this disclosure are within the scope of this disclosure, and various prodrug forms are known in the art. Furthermore, this disclosure also covers compounds of this disclosure containing protecting groups. In any process of preparing the compounds of this disclosure, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of this disclosure. These protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0089] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat one or more symptoms of a target condition or disease.

[0090] As used herein, the term "effective amount" (e.g., "therapeutic effective amount" or "preventive effective amount") refers to the amount of active ingredient that, when administered, will achieve the desired effect to a certain extent, such as relieving one or more symptoms of the treated condition or preventing the occurrence of the condition or its symptoms.

[0091] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or improve the condition or illness to which such term applies, or the progression of one or more symptoms of such condition or illness.

[0092] As used in this article, the term "prevention" includes suppressing and delaying the onset of disease, and includes not only prevention before the development of disease, but also prevention of recurrence of disease after treatment.

[0093] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this disclosure, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0094] In the event that one or more of the accompanying documents, patents and similar materials differ from or contradict this disclosure (including but not limited to defined terms, application of terms, described techniques, etc.), the description and accompanying structural formulas of this disclosure shall prevail. In the event of any discrepancy between the chemical name and the chemical structural formula in this disclosure, the chemical structural formula shall prevail.

[0095] compound

[0096] In a first aspect, this disclosure provides compounds of Formula I or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled substances, metabolites, or prodrugs thereof:

[0097] in,

[0098] X 1 Selected from N and CR 1 ;

[0099] (1) When X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups;

[0100] R 3 Selected from H, C 1-6 Alkyl, -C 1-6 Alkylene-OR c C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 6 replace;

[0101] Or, R 2 R 3 The atoms bonded to it form 3-8 membered heterocyclic groups, said heterocyclic groups optionally being bonded by one or more elements selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-OR a3 The alkyl, cycloalkyl, and heterocyclic groups are substituted with groups selected from cyano, -C, and cycloalkyl groups, respectively. 1-6 alkylene-cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-OR a3 Substitution of groups;

[0102] (2) When X 1 For CR 1 At that time, R 2 R 3 The atoms bonded to it form 3-8 membered heterocyclic groups, said heterocyclic groups optionally being bonded by one or more elements selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C1-6 Alkylene-OR a4 -OC 1-6 The alkyl and 3-8 membered heterocyclic groups are substituted, and the alkyl, cycloalkyl and heterocyclic groups are further replaced by one or more groups selected from cyano, -C 1-6 alkylene-cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-OR a4 Substitution of groups;

[0103] R 1 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0104] R 4 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0105] R 5 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0106] R 6 Each is independently selected from H, deuterium, halogen, cyano, and -OR. d1 C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-OR d2 C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0107] Y is selected from phenyl and 5-10 heteroaryl groups, wherein the phenyl and heteroaryl groups are optionally separated by one or more R groups. 7 replace;

[0108] R 7 Each is independently selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0109] Or, R 7 Formation of 3-10 membered heterocycles fused with Y, wherein the heterocycles are optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0110] L is selected from covalent bonds, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -C 1-6 Alkylene-N(R) e1 )-、-C 1-6 Alkylene-O-, -N(R) e2 )-、-O-、-N(R e3 )-C 1-6 Alkylene-N(R) e4 )-、-N(R e5 )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) e6 )-、-C(=O)-C 1-6 Alkylene -O-, -C(=O)-C 1-6 Alkylene-N(R) e7 - and -S(=O)2-;

[0111] Z is selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 8 replace;

[0112] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo (=O), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(R) g1 )R h1 -C 1-6 Alkylene-N(R) g2 )R h2 -C 1-6 Alkylene-OR g3 -C(=O)-N(R) g4 )R h3-C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4 C 3-10 cycloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -N(R) g8 )R h5 Substitution of groups;

[0113] R a1 R a2 R a3 and R a4 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen;

[0114] R b Selected from H and C 1-6 alkyl;

[0115] R c Selected from H, C 1-6 Alkyl and C 3-8 cycloalkyl;

[0116] R d1 and R d2 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen;

[0117] R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H and C. 1-6 alkyl;

[0118] R g1 R g2 R g3 R g4 R g5 R g6 R g7 Rg8 R h1 R h2 R h3 R h4 and R h5 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl.

[0119] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups.

[0120] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups.

[0121] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-8 cycloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Substitution of cycloalkyl and 3-8 membered heterocyclic groups.

[0122] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Substitution of cycloalkyl and 3-8 membered heterocyclic groups.

[0123] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Substitution of cycloalkyl and 3-8 membered heterocyclic groups.

[0124] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-6 membered heterocyclic groups.

[0125] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally composed of one or more groups selected from deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-6 membered heterocyclic groups.

[0126] In some implementation schemes, when X 1 When R is N, 2 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally composed of one or more groups selected from deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-6 membered heterocyclic groups.

[0127] In some implementation schemes, when X 1 When R is N, 2 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally selected from one or more cyano, -OR a2C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-6 membered heterocyclic groups.

[0128] In some implementation schemes, when X 1 When R is N, 2 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl and cycloalkyl groups are optionally separated by one or more groups selected from cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-6 membered heterocyclic groups.

[0129] In some implementation schemes, when X 1 When R is N, 2 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally selected from one or more cyano and -OR groups. a2 Substitution of groups.

[0130] In some implementation schemes, when X 1 When R is N, 2 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally selected from one or more cyano and -OR groups. a2 Substitution of groups.

[0131] In some implementation schemes, when X 1 When R is N, 2 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, tetrahydropyrrolyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, tetrahydropyrrolyl, Optionally selected by one or more groups selected from cyano and -OR a2 Substitution of groups.

[0132] In some implementation schemes, when X 1 When R is N, 2 The group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, tetrahydropyrrolyl, -CH2-cyclopropyl, -CH2-cyclobutyl, and -CH2-cyclopentyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, and tetrahydropyrrolyl groups are optionally replaced by one or more groups selected from cyano and -OR. a2 Substitution of groups.

[0133] In some implementation schemes, when X 1 When R is N, 2 The group is selected from methyl, isopropyl, cyclopropyl, morpholino, tetrahydropyrrole, -CH2-cyclopropyl, and -CH2-cyclopentyl, wherein the methyl, isopropyl, cyclopropyl, cyclopentyl, morpholino, and tetrahydropyrrole groups are optionally replaced by one or more groups selected from cyano and -OR. a2 Substitution of groups.

[0134] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups.

[0135] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-6 Alkyl, C 1-6Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups.

[0136] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups.

[0137] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Substitution of cycloalkyl and 3-8 membered heterocyclic groups.

[0138] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Substitution of cycloalkyl and 3-8 membered heterocyclic groups.

[0139] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-6 membered heterocyclic groups.

[0140] In some implementation schemes, when X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally composed of one or more groups selected from deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-6 membered heterocyclic groups.

[0141] In some implementation schemes, when X 1 When R is N, 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally composed of one or more groups selected from deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-6 membered heterocyclic groups.

[0142] In some implementation schemes, when X 1 When R is N, 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally selected from one or more cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6Substitution with cycloalkyl and 3-6 membered heterocyclic groups.

[0143] In some implementation schemes, when X 1 When R is N, 2 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl group and the cycloalkyl group are optionally composed of one or more groups selected from cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-6 membered heterocyclic groups.

[0144] In some implementation schemes, when X 1 When R is N, 2 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl and cycloalkyl groups are optionally composed of one or more groups selected from cyano and -OR. a2 Substitution of groups.

[0145] In some implementation schemes, when X 1 When R is N, 2 The group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally replaced by one or more groups selected from cyano and -OR. a2 Substitution of groups.

[0146] In some implementation schemes, when X 1 When R is N, 2 The group selected from methyl, isopropyl, and cyclopropyl, wherein the methyl, isopropyl, and cyclopropyl groups are optionally replaced by one or more groups selected from cyano and -OR. a2 Substitution of groups.

[0147] In some implementation schemes, R a2 Selected from H, C 1-4 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen.

[0148] In some implementation schemes, R a2 The alkyl group is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein the alkyl and cycloalkyl groups are optionally substituted by one or more groups selected from deuterium, cyano, and halogen.

[0149] In some implementation schemes, R a2The alkyl group is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein the alkyl and cycloalkyl groups are optionally substituted by one or more groups selected from deuterium and cyano.

[0150] In some implementation schemes, R a2 It is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF3 and deuterated methyl.

[0151] In some implementation schemes, R a2 Selected from H, methyl, ethyl, cyclopropyl, -CF3 and deuterated methyl.

[0152] In some implementation schemes, R a2 Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CD3 and -CH2CD3.

[0153] In some implementation schemes, R a2 Selected from H, methyl, ethyl, cyclopropyl and -CD3.

[0154] In some implementation schemes, when X 1 When R is N, 2 Selected from methyl, isopropyl, cyclopropyl, morpholino, tetrahydropyrrolyl, -CH2-cyclopropyl, -CH2-cyclopentyl, The methyl, isopropyl, cyclopropyl, morpholino, tetrahydropyrrolyl, and cyclopentyl groups mentioned above... Optionally selected by one or more groups selected from cyano and -OR a2 Group substitution; R a2 Selected from H, methyl, ethyl, cyclopropyl, -CF3 and deuterated methyl.

[0155] In some implementation schemes, when X 1 When R is N, 2 Selected from methyl, isopropyl, cyclopropyl, morpholino, tetrahydropyrrolyl, -CH2-cyclopropyl, -CH2-cyclopentyl, The methyl, isopropyl, cyclopropyl, morpholino, tetrahydropyrrolyl, and cyclopentyl groups mentioned above... Optionally selected by one or more groups selected from cyano and -OR a2 Group substitution; R a2 Selected from H, methyl, ethyl, cyclopropyl and -CD3.

[0156] In some implementation schemes, when X 1 When R is N, 2 Selected from methyl,

[0157] In some implementation schemes, when X 1 When R is N, 2 Selected from methyl,

[0158] In some implementation schemes, when X 1 When R is N, 2 Selected from methyl,

[0159] In some implementation schemes, when X 1 When R is N, 3 Selected from H, C 1-6 Alkyl, -C 1-6 Alkylene-OR c C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 6 replace.

[0160] In some implementation schemes, when X 1 When R is N, 3 Selected from H, C 1-6 Alkyl, -C 1-4 Alkylene-OR c C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 6 replace.

[0161] In some implementation schemes, when X 1 When R is N, 3 Selected from C 1-6 Alkyl and C 3-8 cycloalkyl, wherein the alkyl group, or cycloalkyl group, is optionally surrounded by one or more R 6 replace.

[0162] In some implementation schemes, when X 1 When R is N, 3 Selected from C 1-4 Alkyl and C 3-6 cycloalkyl, wherein the alkyl group, or cycloalkyl group, is optionally surrounded by one or more R 6 replace.

[0163] In some implementation schemes, when X 1 When R is N, 3The group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally separated by one or more R groups. 6 replace.

[0164] In some implementation schemes, when X 1 When R is N, 3 Selected from isopropyl, tert-butyl, and cyclopropyl, wherein the isopropyl, tert-butyl, and cyclopropyl groups are optionally oxidized by one or more R groups. 6 replace.

[0165] In some implementation schemes, R 6 Each is independently selected from H, deuterium, halogen, cyano, and -OR. d1 C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR d2 C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl groups are substituted.

[0166] In some implementation schemes, R 6 Each is independently selected from H, deuterium, halogen, cyano, and -OR. d1 C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR d2 C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl groups are substituted.

[0167] In some implementation schemes, R 6 Each is independently selected from H, deuterium, halogen, cyano, and -OR. d1 C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR d2 C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, cyano, C1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl groups are substituted.

[0168] In some implementation schemes, R 6 Each is independently selected from H, deuterium, halogen, cyano, and -OR. d1 C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR d2 C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-6 cycloalkyl and -OC 1-4 Alkyl groups are substituted.

[0169] In some implementation schemes, R 6 Each is independently selected from cyano, -OR d1 C 1-4 Alkyl, -C 1-4 Alkylene-OR d2 C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-6 cycloalkyl and -OC 1-4 Alkyl groups are substituted.

[0170] In some implementation schemes, R 6 Each is independently selected from cyano, -OR d1 C 1-4 Alkyl, -C 1-4 Alkylene-OR d2 C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally replaced by one or more groups selected from cyano, C 1-4 Alkyl and -OC 1-4 Alkyl groups are substituted.

[0171] In some implementation schemes, R 6 Each is independently selected from cyano, -OR d1 C 1-4 Alkyl, -C 1-4 Alkylene-OR d2 C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl group is optionally substituted with one or more groups selected from cyano.

[0172] In some implementation schemes, R 6 Each is independently selected from cyano, -OR d1 C 1-4 Alkyl and -C 1-4 Alkylene-OR d2 The alkyl group is optionally substituted with one or more groups selected from cyano.

[0173] In some implementation schemes, R 6 Each is independently selected from cyano, -OR d1 -CH2CN, -CH2CH2CN, -CH(CN)CH3 and -C 1-4 Alkylene-OR d2 .

[0174] In some implementation schemes, R 6 Each is independently selected from cyano, -OR d1 -CH2CN and -C 1-4 Alkylene-OR d2 .

[0175] In some implementation schemes, R d1 and R d2 Each is independently selected from H and C. 1-4 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen.

[0176] In some implementation schemes, R d1 and R d2 Each is independently selected from H and C. 1-4 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl group is optionally substituted with one or more groups selected from deuterium and halogens.

[0177] In some implementation schemes, R d1 and R d2 Each is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CD3 and -CH2CD3.

[0178] In some implementation schemes, R d1 and R d2 Each is independently selected from methyl, ethyl, -CF3, -CH2CF3 and -CD3.

[0179] In some implementation schemes, R d1 and R d2 Each is independently selected from methyl, ethyl, -CF3 and -CD3.

[0180] In some implementation schemes, R 6 Each is independently selected from cyano, -OR d1 -CH2CN and -C 1-4 Alkylene-OR d2 ;

[0181] R d1 and R d2 Each is independently selected from H and C. 1-4 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen.

[0182] In some implementation schemes, R 6 Each is independently selected from cyano, -OR d1 -C 1-4 Alkylene-CN and -C 1-4 Alkylene-OR d2 ;

[0183] R d1 and R d2 Each is independently selected from H and C. 1-4 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl group is optionally substituted with one or more groups selected from deuterium and halogens.

[0184] In some implementation schemes, R 6 Each is independently selected from cyano, -OR d1 -C 1-4 Alkylene-CN and -C 1-4 Alkylene-OR d2 ;

[0185] R d1 and R d2 Each is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CD3 and -CH2CD3.

[0186] In some implementation schemes, R 6 Each is independently selected from cyano, -OR d1 -C 1-4 Alkylene-CN and -C 1-4 Alkylene-OR d2 ;

[0187] R d1 and R d2 Each is independently selected from methyl, ethyl, -CF3, -CH2CF3 and -CD3.

[0188] In some implementation schemes, R 6 Each is independently selected from cyano, -CH2CN, -CH2CH2CN, -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH2CH3, -OCH3, -OCH2CH3, -OCF3, -OCH2CF3, -CH2OCF3, -CH2CH2OCF3, -OCD3 and -CH2OCD3.

[0189] In some implementation schemes, R 6 Each is independently selected from cyano, -CH2CN, -CH2OCH3, -CH2OCH2CH3, -OCH3, -OCH2CH3, -OCF3, -CH2OCF3, -OCD3 and -CH2OCD3.

[0190] In some implementation schemes, when X 1 When R is N, 3 Selected from isopropyl, cyclopropyl,

[0191] In some implementation schemes, when X 1 When R is N, 3 Selected from isopropyl,

[0192] In some implementation schemes, when X 1 When R is N, 2 R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, said heterocyclic groups optionally bonded by one or more elements selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-OR a3 The alkyl, cycloalkyl, and heterocyclic groups are substituted with groups selected from cyano, -C, and cycloalkyl groups, respectively. 1-6 alkylene-cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-OR a3 Substitution of groups.

[0193] In some implementation schemes, when X 1 When R is N, 2R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, said heterocyclic groups optionally bonded by one or more elements selected from deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, -OC 1-4 Alkyl and -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-OR a3 The alkyl, cycloalkyl, and heterocyclic groups are substituted with groups selected from cyano, -C, and cycloalkyl groups, respectively. 1-4 alkylene-cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -C 1-4 Alkylene-OR a3 Substitution of groups.

[0194] In some implementation schemes, when X 1 When R is N, 2 R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally bonded by one or more atoms selected from C. 1-4 Alkyl, C 3-6 cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl groups are substituted.

[0195] In some implementation schemes, when X 1 When R is N, 2 R 3 and connected atoms form The Each is optionally selected by one or more of C 1-4 Alkyl, C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 cycloalkyl, 3-6 membered heterocyclic groups Substitution of groups.

[0196] In some implementation schemes, when X 1 When R is N, 2 R 3 and connected atoms form The Each is optionally bound by one or more compounds selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, tetrahydropyranyl, Substitution of groups.

[0197] In some implementation schemes, when X 1 When R is N, 2 R 3 and connected atoms form The Each is optionally bound by one or more compounds selected from methyl, cyclopropyl, -CH2-cyclopropyl, tetrahydropyranyl, Substitution of groups.

[0198] In some implementation schemes, when X 1 When R is N, 2 R 3 and connected atoms form

[0199] In some implementation schemes, when X 1 When R is N, 2 R 3 The atoms bonded to it form 3-8 membered heterocyclic groups, said heterocyclic groups optionally being bonded by one or more elements selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl and -C 1-6 Alkylene-OR a3 Substitution of groups.

[0200] In some implementation schemes, when X 1 When R is N, 2 R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, said heterocyclic groups optionally bonded by one or more elements selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl and -C 1-6 Alkylene-OR a3 Substitution of groups.

[0201] In some implementation schemes, when X 1 When R is N, 2 R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, said heterocyclic groups optionally bonded by one or more elements selected from deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4Haloalkyl, C 3-6 cycloalkyl, -OC 1-4 Alkyl and -C 1-4 Alkylene-C 3-6 cycloalkyl and -C 1-4 Alkylene-OR a3 Substitution of groups.

[0202] In some implementation schemes, when X 1 When R is N, 2 R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally bonded by one or more atoms selected from C. 1-4 Alkyl, C 3-6 cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl groups are substituted.

[0203] In some implementation schemes, when X 1 When R is N, 2 R 3 and connected atoms form The Each is optionally selected by one or more of C 1-4 Alkyl, C 3-6 cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl groups are substituted.

[0204] In some implementation schemes, when X 1 When R is N, 2 R 3 and connected atoms form The Each may optionally be substituted by one or more groups selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl and -CH2-cyclobutyl.

[0205] In some implementation schemes, when X 1 When R is N, 2 R 3 and connected atoms form The Each group may optionally be substituted with one or more groups selected from methyl, cyclopropyl and -CH2-cyclopropyl.

[0206] In some implementation schemes, when X 1 When R is N, 2 R 3 and connected atoms form

[0207] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, each of which is optionally bonded by one or more atoms selected from deuterium, halogens, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-OR a4 -OC 1-6 The alkyl and 3-8 membered heterocyclic groups are substituted, and the alkyl, cycloalkyl and heterocyclic groups are further replaced by one or more groups selected from cyano, -C 1-6 alkylene-cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-OR a4 Substitution of groups.

[0208] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, each of which is optionally bonded by one or more atoms selected from deuterium, halogens, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-OR a4 -OC 1-4 The alkyl group and 3-6 membered heterocyclic groups are substituted, and the alkyl, cycloalkyl and heterocyclic groups are further replaced by one or more groups selected from cyano, -C 1-4 alkylene-cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -C 1-4 Alkylene-OR a4 Substitution of groups.

[0209] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 The atoms attached to it form 3-6 membered heterocyclic groups, each of which is optionally surrounded by one or more atoms selected from C. 1-4Alkyl, C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 cycloalkyl, 3-6 membered heterocyclic groups Substitution of groups.

[0210] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 and connected atoms form The Each is optionally selected by one or more of C 1-4 Alkyl, C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 cycloalkyl, 3-6 membered heterocyclic groups Substitution of groups.

[0211] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 and connected atoms form The Each is optionally bound by one or more compounds selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, tetrahydropyranyl, Substitution of groups.

[0212] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 and connected atoms form The Each is optionally bound by one or more compounds selected from methyl, cyclopropyl, -CH2-cyclopropyl, tetrahydropyranyl, Substitution of groups.

[0213] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 and connected atoms form

[0214] In some implementation schemes, when X 1For CR 1 At that time, R 2 R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, each of which is optionally bonded by one or more atoms selected from deuterium, halogens, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-OR a4 and -OC 1-6 Alkyl groups are substituted.

[0215] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, each of which is optionally bonded by one or more atoms selected from deuterium, halogens, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-OR a4 and -OC 1-4 Alkyl groups are substituted.

[0216] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 The atoms attached to it form 3-6 membered heterocyclic groups, each of which is optionally surrounded by one or more atoms selected from C. 1-4 Alkyl, C 3-6 cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl groups are substituted.

[0217] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 and connected atoms form The Each is optionally selected by one or more of C 1-4 Alkyl, C 3-6 cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl groups are substituted.

[0218] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 and connected atoms form The Each may optionally be substituted by one or more groups selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl and -CH2-cyclobutyl.

[0219] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 and connected atoms form The Each group may optionally be substituted with one or more groups selected from methyl, cyclopropyl and -CH2-cyclopropyl.

[0220] In some implementation schemes, when X 1 For CR 1 At that time, R 2 R 3 and connected atoms form

[0221] In some implementation schemes, when X 1 For CR 1 At that time, R 1 Selected from H, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups.

[0222] In some implementation schemes, when X 1 For CR 1 At that time, R 1 Selected from H, F, Cl, cyano, methyl, ethyl, -CF3, -O-CH3, -O-CH2CH3, -O-CF3 and -O-CH2CF3.

[0223] In some implementation schemes, when X 1 For CR 1 At that time, R 1 Selected from H, F, Cl, cyano, methyl, -CF3, -O-CH3 and -O-CF3.

[0224] In some implementation schemes, when X1 For CR 1 At that time, R 1 Selected from H.

[0225] In some implementation schemes, when X 1 For CR 1 At that time, R 1 Selected from H, R 2 R 3 and connected atoms form The Each is optionally selected by one or more of C 1-4 Alkyl, C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 cycloalkyl, 3-6 membered heterocyclic groups Substitution of groups.

[0226] In some implementation schemes, when X 1 For CR 1 At that time, R 1 Selected from H, R 2 R 3 and connected atoms form The Each is optionally bound by one or more compounds selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, tetrahydropyranyl, Substitution of groups.

[0227] In some implementation schemes, when X 1 For CR 1 At that time, R 1 Selected from H, R 2 R 3 and connected atoms form The Each is optionally bound by one or more compounds selected from methyl, cyclopropyl, -CH2-cyclopropyl, tetrahydropyranyl, Substitution of groups.

[0228] In some implementation schemes, when X 1 For CR 1 At that time, R 1 Selected from H, R 2 R 3 and connected atoms form

[0229] In some implementation schemes, when X 1 For CR 1 At that time, R 1 Selected from H, R 2 R 3 and connected atoms form The Each may optionally be substituted by one or more groups selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl and -CH2-cyclobutyl.

[0230] In some implementation schemes, when X 1 For CR 1 At that time, R 1 Selected from H, R 2 R 3 and connected atoms form The Each group may optionally be substituted with one or more groups selected from methyl, cyclopropyl and -CH2-cyclopropyl.

[0231] In some implementation schemes, when X 1 For CR 1 At that time, R 1 Selected from H, R 2 R 3 and connected atoms form

[0232] In some implementation schemes, R 4 Selected from H, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups.

[0233] In some implementation schemes, R 4 Selected from H, F, Cl, cyano, methyl, ethyl, -CF3, -O-CH3, -O-CH2CH3, -O-CF3 and -O-CH2CF3.

[0234] In some implementation schemes, R 4 Selected from H, F, Cl, cyano, methyl, -CF3, -O-CH3 and -O-CF3.

[0235] In some implementation schemes, R 4 Selected from H.

[0236] In some implementation schemes, R 5 Selected from H, halogen, cyano, C1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups.

[0237] In some implementation schemes, R 5 Selected from H, F, Cl, cyano, methyl, ethyl, -CF3, -O-CH3, -O-CH2CH3, -O-CF3 and -O-CH2CF3.

[0238] In some implementation schemes, R 5 Selected from H, F, Cl, cyano, methyl, -CF3, -O-CH3 and -O-CF3.

[0239] In some implementation schemes, R 5 Selected from H.

[0240] In some embodiments, Y is selected from phenyl and 5-6-membered heteroaryl groups, wherein the phenyl and heteroaryl groups are optionally separated by one or more R groups. 7 replace.

[0241] In some embodiments, Y is selected from phenyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrimidinyl, pyridinyl, pyrazinyl, and pyridazinyl, wherein the phenyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrimidinyl, pyridinyl, and pyridazinyl groups are optionally separated by one or more R groups. 7 replace.

[0242] In some embodiments, Y is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, and pyridazinyl, wherein the phenyl, pyrimidinyl, pyridinyl, and pyridazinyl groups are optionally separated by one or more R groups. 7 replace.

[0243] In some embodiments, Y is selected from pyridyl and pyrazinyl, said pyridyl and pyrazinyl groups optionally being converted by one or more R groups. 7 replace.

[0244] In some embodiments, Y is selected from pyridinyl, said pyridinyl group optionally being reacted with one or more R groups. 7 replace.

[0245] In some implementation schemes, R 7 Each is independently selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0246] Or, R 7 Formation of 3-8 membered heterocycles fused with Y, wherein the heterocycles are optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 Alkyl groups are substituted.

[0247] In some implementation schemes, R 7 Each is independently selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Haloalkyl; or, R 7 Formation of 3-6 membered heterocycles fused with Y, wherein the heterocycles are optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 Alkyl groups are substituted.

[0248] In some implementation schemes, R 7 Each is independently selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups.

[0249] In some implementation schemes, R 7 Each is independently selected from H, F, Cl, hydroxyl, cyano, methyl, ethyl, -CF3, -CH2CF3, methoxy, ethoxy, -O-CF3 and -O-CH2CF3.

[0250] In some implementation schemes, R 7 Each is independently selected from H.

[0251] In some embodiments, Y is selected from pyridyl and pyrazinyl, said pyridyl and pyrazinyl groups optionally being converted by one or more R groups. 7 Replace; R 7 Each is independently selected from H, F, Cl, hydroxyl, cyano, methyl, ethyl, -CF3, -CH2CF3, methoxy, ethoxy, -O-CF3 and -O-CH2CF3.

[0252] In some embodiments, Y is selected from pyridinyl, said pyridinyl group optionally being reacted with one or more R groups. 7 Replace; R 7Each is independently selected from H, F, Cl, hydroxyl, cyano, methyl, ethyl, -CF3, -CH2CF3, methoxy, ethoxy, -O-CF3 and -O-CH2CF3.

[0253] In some implementation schemes, Y is selected from The Optionally by one or more R 7 Replace; R 7 Each is independently selected from H, F, Cl, hydroxyl, cyano, methyl, ethyl, -CF3, -CH2CF3, methoxy, ethoxy, -O-CF3 and -O-CH2CF3.

[0254] In some implementation schemes, Y is selected from The Optionally by one or more R 7 Replace; R 7 Each is independently selected from H, F, Cl, hydroxyl, cyano, methyl, ethyl, -CF3, -CH2CF3, methoxy, ethoxy, -O-CF3 and -O-CH2CF3.

[0255] In some implementation schemes, Y is selected from The Optionally by one or more R 7 Replace; R 7 Each is independently selected from H, F, Cl, hydroxyl, cyano, methyl, ethyl, -CF3, -CH2CF3, methoxy, ethoxy, -O-CF3 and -O-CH2CF3.

[0256] In some implementation schemes, Y is selected from

[0257] In some implementation schemes, Y is selected from

[0258] In some implementation schemes, Y is selected from

[0259] In some embodiments, Y is selected from 5-6-membered heteroaryl groups, said heteroaryl group being substituted by one or more R groups. 7 Replace, and R 7 Formation of 3-8 membered heterocycles fused with Y, wherein the heterocycles are optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl groups are substituted.

[0260] In some embodiments, Y is selected from pyridinyl, said pyridinyl group being reacted with one or more R groups. 7Replace, and R 7 Formation of a 5-8 membered heterocycle fused with Y, wherein the heterocycle is optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl groups are substituted.

[0261] In some embodiments, Y is selected from 5-6-membered heteroaryl groups, said heteroaryl group being substituted by one or more R groups. 7 Replace, and R 7 Formation of 3-6 membered heterocycles fused with Y, wherein the heterocycles are optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl groups are substituted.

[0262] In some embodiments, Y is selected from pyridinyl, said pyridinyl group being reacted with one or more R groups. 7 Replace, and R 7 Formation of a 5-6 membered heterocycle fused with Y, wherein the heterocycle is optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl groups are substituted.

[0263] In some implementation schemes, Y is selected from

[0264] In some implementation schemes, Y is selected from

[0265] In some implementations, L is selected from covalent bonds, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -C 1-4 Alkylene-N(R) e1 )-、-C 1-4 Alkylene-O-, -N(R) e2 )-、-O-、-N(R e3 )-C 1-4 Alkylene-N(R) e4 )-、-N(R e5 )-C 1-4 Alkylene-O-, -C(=O)-, -C(=O)-N(R) e6 )-、-C(=O)-C 1-4 Alkylene -O-, -C(=O)-C 1-4 Alkylene-N(R) e7 )- and -S(=O)2-.

[0266] In some embodiments, L is selected from covalent bonds, methylene, vinylene, ethynylene, -methylene-N(R) e1 )-、-methylene-O-、-N(R e2 )-、-O-、-N(R e3 )-Methylene-N(R e4 )-、-N(R e5 -methylene-O-, -C(=O)-, -C(=O)-N(R) e6 -, -C(=O)-methylene-O-, -C(=O)-methylene-N(R) e7 )- and -S(=O)2-.

[0267] In some implementation schemes, R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0268] In some implementation schemes, R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H and methyl.

[0269] In some embodiments, L is selected from covalent bonds, methylene, vinylene, ethynylene, -methylene-NH-, -methylene-O-, -NH-, -O-, -NH-methylene-NH-, -NH-methylene-O-, -C(=O)-, -C(=O)-NH-, -C(=O)-methylene-O-, -C(=O)-methylene-NH- and -S(=O)2-.

[0270] In some embodiments, L is selected from covalent bonds, methylene, -methylene-NH-, -methylene-O-, -NH-, -O-, -NH-methylene-NH-, -NH-methylene-O-, -C(=O)-, -C(=O)-NH-, -C(=O)-methylene-NH- and -S(=O)2-.

[0271] In some implementations, L is selected from covalent bonds, methylene, -NH-, -O-, -C(=O)-, and -S(=O)2-.

[0272] In some implementations, L is selected from covalent bonds, methylene, -NH-, -O-, and -C(=O)-.

[0273] In some implementations, L is selected from covalent bonds, methylene, -NH-, and -O-.

[0274] In some implementations, L is selected from covalent bonds, -O-, and -C(=O)-.

[0275] In some implementations, L is selected from covalent bonds.

[0276] In some implementation schemes, Z is selected from H and C. 1-4 Alkyl, C 3-6 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 8 replace.

[0277] In some implementation schemes, Z is selected from H and C. 1-4 Alkyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 8 replace.

[0278] In some implementation schemes, Z is selected from H and C. 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 8 replace.

[0279] In some implementations, Z is selected from C. 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 8 replace.

[0280] In some embodiments, Z is selected from 3-6 membered heterocyclic groups, which are optionally surrounded by one or more R groups. 8 replace.

[0281] In some implementation schemes, R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -N(R) g1 )R h1 -C 1-4 Alkylene-N(R) g2 )R h2 -C 1-4 Alkylene-OR g3-C(=O)-N(R) g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4 C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -N(R) g8 )R h5 replace.

[0282] In some implementation schemes, R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -N(R) g1 )R h1 -C 1-4 Alkylene-N(R) g2 )R h2 -C 1-4 Alkylene-OR g3 -C(=O)-N(R) g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4 C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups.

[0283] In some implementation schemes, R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF3, -CH2-CF3, -OCH3, -OCF3, -N(R) g1 )R h1 ,-methylene-N(R) g2 )R h2 ,-methylene-OR g3 -C(=O)-N(R)g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4 Cyclopropyl, azircyclopropane, -CH2-cyclopropyl, ethylene oxide, and oxacyclobutane.

[0284] In some implementation schemes, R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF3, -CH2-CF3, -OCH3, -OCF3, -N(R) g1 )R h1 ,-methylene-N(R) g2 )R h2 ,-methylene-OR g3 -C(=O)-N(R) g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4 Cyclopropyl, azircyclopropane, -CH2-cyclopropyl and ethylene oxide.

[0285] In some implementation schemes, R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo (=O), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(R) g1 )R h1 -C 1-6 Alkylene-N(R) g2 )R h2 -C 1-6 Alkylene-OR g3 -C(=O)-N(R) g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4 C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6Halogenated alkyl groups, -OC 1-6 Alkyl and -N(R) g8 )R h5 Substitution of groups.

[0286] In some implementation schemes, R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -N(R) g1 )R h1 -C 1-4 Alkylene-N(R) g2 )R h2 -C 1-4 Alkylene-OR g3 -C(=O)-N(R) g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4 C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -N(R) g8 )R h5 replace.

[0287] In some implementation schemes, R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -N(R) g1 )R h1 -C 1-4 Alkylene-N(R) g2 )R h2 -C 1-4 Alkylene-OR g3 -C(=O)-N(R) g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups.

[0288] In some implementation schemes, R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF3, -OCH3, -OCF3, -N(R) g1 )R h1 ,-methylene-N(R) g2 )R h2 ,-methylene-OR g3 -C(=O)-N(R) g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4 Cyclopropyl, azircyclopropane, and ethylene oxide.

[0289] In some implementation schemes, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R h1 R h2 R h3 and R h4 Each is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0290] In some implementation schemes, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R h1 R h2 R h3 and R h4 Each is independently selected from H, methyl, ethyl and cyclopropyl.

[0291] In some implementation schemes, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R h1 Rh2 R h3 and R h4 Each is independently selected from methyl and cyclopropyl.

[0292] In some implementation schemes, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R h1 R h2 R h3 and R h4 Each is independently selected from methyl groups.

[0293] In some embodiments, Z is selected from 3-6 membered heterocyclic groups, which are optionally surrounded by one or more R groups. 8 replace;

[0294] R 8 Each is independently selected from oxygen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 cycloalkyl and -N(R) g1 )R h1 .

[0295] In some embodiments, Z is selected from 3-6 membered heterocyclic groups, which are optionally surrounded by one or more R groups. 8 replace;

[0296] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl, -CF3, -CH2-CF3, cyclopropyl, -CH2-cyclopropyl, -N(R) g1 )R h1 and

[0297] In some embodiments, Z is selected from 3-6 membered heterocyclic groups, which are optionally surrounded by one or more R groups. 8 replace;

[0298] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl, -CF3, -CH2-CF3, cyclopropyl, -CH2-cyclopropyl and -N(R) g1 )R h1 .

[0299] In some embodiments, Z is selected from 3-6 membered heterocyclic groups, which are optionally divided by two R groups. 8 replace;

[0300] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl, -CF3, -CH2-CF3, cyclopropyl, -CH2-cyclopropyl, -N(R) g1 )R h1 and

[0301] In some embodiments, Z is selected from 3-6 membered heterocyclic groups, which are optionally divided by two R groups. 8 replace;

[0302] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl, -CF3, -CH2-CF3, cyclopropyl, -CH2-cyclopropyl and -N(R) g1 )R h1 .

[0303] In some embodiments, Z is selected from 3-6 membered heterocyclic groups, which are optionally surrounded by one or more R groups. 8 replace;

[0304] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl and -N(R) g1 )R h1 .

[0305] In some embodiments, Z is selected from 3-6 membered heterocyclic groups, which are optionally divided by two R groups. 8 replace;

[0306] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl and -N(R) g1 )R h1 .

[0307] In some implementation schemes, R g1 and R h1 Each is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0308] In some implementation schemes, R g1 and R h1 Each is independently selected from H, methyl, ethyl and cyclopropyl.

[0309] In some implementation schemes, R g1 and R h1 Each is independently selected from methyl and cyclopropyl.

[0310] In some embodiments, Z is selected from piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrroleyl, morpholinyl, and piperazineyl, wherein the piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrroleyl, morpholinyl, and piperazineyl are optionally separated by two R. 8 replace;

[0311] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl, -CF3, -CH2-CF3, cyclopropyl, -CH2-cyclopropyl and -N(CH3)CH3.

[0312] In some embodiments, Z is selected from piperidinyl, piperazinyl, and morpholinyl, wherein the piperidinyl, piperazinyl, and morpholinyl groups are optionally surrounded by one or two R groups. 8 replace;

[0313] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl, -CF3, -CH2-CF3, cyclopropyl, -CH2-cyclopropyl and -N(CH3)CH3.

[0314] In some implementation schemes, Z is selected from The Optionally by one or two R 8 replace;

[0315] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl, -CF3, -CH2-CF3, cyclopropyl, -CH2-cyclopropyl, -N(CH3)CH3 and

[0316] In some implementation schemes, Z is selected from The Optionally by one or two R 8 replace;

[0317] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl, -CF3, -CH2-CF3, cyclopropyl, -CH2-cyclopropyl and -N(CH3)CH3.

[0318] In some implementation schemes, Z is selected from

[0319] In some implementation schemes, Z is selected from

[0320] In some embodiments, Z is selected from piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrroleyl, morpholinyl, and piperazineyl, wherein the piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrroleyl, morpholinyl, and piperazineyl are optionally separated by two R. 8 replace;

[0321] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl and -N(CH3)CH3.

[0322] In some embodiments, Z is selected from piperidinyl and piperazine, said piperidinyl and piperazine are optionally separated by two R. 8 replace;

[0323] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl and -N(CH3)CH3.

[0324] In some implementation schemes, Z is selected from The Optionally by two R 8 replace;

[0325] R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl and -N(CH3)CH3.

[0326] In some implementation schemes, Z is selected from

[0327] In some embodiments, Y is selected from 5-6-membered heteroaryl groups, said heteroaryl group being substituted by one or more R groups. 7 Replace, and R 7 Formation of 3-6 membered heterocycles fused with Y, wherein the heterocycles are optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0328] L is selected from covalent bonds, methylene, -NH-, -O-, -C(=O)- and -S(=O)2-;

[0329] Z is selected from H and C. 1-4 Alkyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 8 replace.

[0330] In some embodiments, Y is selected from pyridinyl, said pyridinyl group being reacted with one or more R groups. 7 Replace, and R 7Formation of a 5-8 membered heterocycle fused with Y, wherein the heterocycle is optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0331] L is selected from covalent bonds, methylene, -NH-, -O-, and -C(=O)-;

[0332] Z is selected from H and C. 1-4 alkyl.

[0333] In some embodiments, Y is selected from pyridinyl, said pyridinyl group being reacted with one or more R groups. 7 Replace, and R 7 Formation of a 5-6 membered heterocycle fused with Y, wherein the heterocycle is optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0334] L is selected from covalent bonds, methylene, -NH-, -O-, and -C(=O)-;

[0335] Z is selected from H and C. 1-4 alkyl.

[0336] In some implementation schemes, Y is selected from

[0337] L is selected from covalent bonds, methylene, -NH-, -O-, and -C(=O)-;

[0338] Z is selected from H and methyl.

[0339] In some implementation schemes, Y is selected from

[0340] L is selected from covalent bonds, methylene, -NH-, -O-, and -C(=O)-;

[0341] Z is selected from H and methyl.

[0342] In some implementation schemes, Y is selected from

[0343] L is selected from covalent bonds; Z is selected from H and methyl groups.

[0344] In some implementation schemes, R a1 Selected from H, C 1-4 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen.

[0345] In some implementation schemes, R a1 Selected from H, C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0346] In some implementation schemes, R a1 Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0347] In some implementation schemes, R a1 Selected from H, methyl, ethyl and cyclopropyl.

[0348] In some implementation schemes, R a3 R a4 Each is independently selected from H and C. 1-4 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen.

[0349] In some implementation schemes, R a3 R a4 Each group is independently selected from H, methyl, ethyl, and cyclopropyl, wherein the methyl, ethyl, and cyclopropyl groups are optionally substituted by one or more groups selected from deuterium and halogens.

[0350] In some implementation schemes, R a3 R a4 Each is independently selected from H, methyl, ethyl, cyclopropyl, -CF3 and deuterated methyl.

[0351] In some implementation schemes, R a3 R a4 Each is independently selected from H, methyl, ethyl, cyclopropyl, -CF3 and -CD3.

[0352] In some implementation schemes, R b Selected from H and C 1-4 alkyl.

[0353] In some implementation schemes, R b Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

[0354] In some implementation schemes, R b Selected from H and methyl.

[0355] In some implementation schemes, R c Selected from H, C 1-6 Alkyl and C 3-8 Cycloalkyl.

[0356] In some implementation schemes, R cSelected from H, C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0357] In some implementation schemes, R c Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0358] In some implementation schemes, R c Selected from H, methyl and cyclopropyl.

[0359] In some implementation schemes, R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H and C. 1-4 alkyl.

[0360] In some implementation schemes, R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0361] In some implementation schemes, R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H and methyl.

[0362] In some implementation schemes, R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H.

[0363] In some implementation schemes, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 Rh1 R h2 R h3 R h4 and R h5 Each is independently selected from H and C. 1-4 Alkyl and C 3-6 Cycloalkyl.

[0364] In some implementation schemes, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 R h1 R h2 R h3 R h4 and R h5 Each is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0365] In some implementation schemes, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 R h1 R h2 R h3 R h4 and R h5 Each is independently selected from H, methyl, ethyl and cyclopropyl.

[0366] In some implementation schemes, R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 R h1 R h2 R h3 R h4 and R h5 Each is independently selected from methyl and cyclopropyl.

[0367] In some implementation schemes, R g1 R g2 R g3 R g4 R g5 Rg6 R g7 R g8 R h1 R h2 R h3 R h4 and R h5 Each is independently selected from methyl groups.

[0368] In some embodiments, the compounds disclosed herein are selected from:

[0369] The functional groups in all the above-described embodiments of this disclosure can be suitably selected and combined in any way to obtain different general formula ranges or specific schemes, all of which are included in this disclosure.

[0370] This disclosure covers compounds obtained by arbitrarily combining various embodiments.

[0371] The compounds disclosed herein can be optionally substituted at suitable positions with suitable substituents, such as those selected from deuterium, halogens, -OH, -CN, -COOH, -NH2, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, the substituent is selected from deuterium, F, Cl, -OH, -CN, -COOH, -NH2, methyl, ethyl, -CF3, -CHF2, -CH2F.

[0372] Preparation method

[0373] Secondly, this disclosure provides a method for preparing the compound of formula (I):

[0374] Among them, B 1 Selected from halogen, borate group, borate ester group and -Sn(C 1-6 Alkyl)3; B 2 It is a halogen; A 1 Selected from borate groups, borate ester groups, and halogens; X 1 R 2 R 3 R 4 R 5 Y, L, and Z are as defined above.

[0375] In some implementation schemes, B 1 Selected from Cl, Br, I, -B(OH)2, Trimethyltinyl and tributyltinyl; preferably, B 1 Selected from Cl, Br and tributyltin.

[0376] In some implementation schemes, B 2 It is Cl, Br or I, preferably Cl or Br.

[0377] In some implementation schemes, A 1 Selected from -B(OH)2, Cl, Br, and I; preferably -B(OH)2 Cl or Br.

[0378] In some implementation schemes, the method is performed according to the following steps:

[0379] Step A: Compound I-1 and compound I-2 undergo a coupling reaction to give compound I-3.

[0380] Preferably, the coupling reaction is carried out in the presence of a metal catalyst and a base.

[0381] Preferably, the metal catalyst can be a palladium metal catalyst, such as tetra(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, bis(triphenylphosphine)palladium dichloride, preferably [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; the base can be an inorganic base, such as potassium phosphate, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium carbonate; the coupling reaction is carried out in a suitable organic solvent, which may be 1,4-dioxane, N,N-dimethylformamide, methanol, ethanol, toluene, or a mixture of the above organic solvents and water, for example, a mixture of 1,4-dioxane and water; the coupling reaction is preferably carried out under a suitable protective atmosphere (e.g., nitrogen atmosphere); the coupling reaction is preferably carried out at 70-110°C, and the coupling reaction is preferably carried out for 1-24 hours;

[0382] Step B: Compound I-3 and compound I-4 undergo a coupling reaction to give compound I.

[0383] Preferably, the coupling reaction is carried out in the presence of a metal catalyst, a ligand, and a base.

[0384] Preferably, the metal catalyst can be a palladium metal catalyst, such as tetra(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylacetone)palladium, bis(triphenylphosphine)palladium dichloride, preferably tris(dibenzylacetone)palladium; the ligand is, for example, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, and 1,1'-binaphine-2,2'-bisdiphenylphosphine, preferably 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl. Benzene; the base may be an inorganic base, such as potassium phosphate, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably cesium carbonate; the coupling reaction is carried out in a suitable organic solvent, such as 1,4-dioxane, N,N-dimethylformamide, methanol, ethanol, toluene, or a mixture of the above organic solvents and water, for example, 1,4-dioxane; the coupling reaction is preferably carried out under a suitable protective atmosphere (e.g., nitrogen atmosphere); the coupling reaction is preferably carried out at 70-110°C; the coupling reaction is preferably carried out for 1-24 hours.

[0385] Synthetic intermediates

[0386] In some implementations, this disclosure provides the following synthetic intermediates:

[0387] Among them, X 1 R 2 R 3 R 4 R 5 Y, L, Z, A 1 and B 2 As defined above.

[0388] In some embodiments, the synthetic intermediates of this disclosure are selected from:

[0389] Pharmaceutical compositions, formulations and packaging

[0390] Thirdly, this disclosure provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0391] Furthermore, this disclosure provides a method for preparing a pharmaceutical composition of the present disclosure, the method comprising combining a compound of the present disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0392] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions described in this disclosure include, but are not limited to, sterile liquids and pharmaceutical excipients.

[0393] The pharmaceutical compositions described herein can be administered in any form, provided that they achieve the prevention, relief, prevention or cure of symptoms in human or animal patients, and for example, can be formulated into various suitable dosage forms depending on the route of administration.

[0394] When taken orally, the pharmaceutical compositions described in this disclosure can be formulated into any orally acceptable dosage form.

[0395] When applied transdermally or topically, the pharmaceutical compositions described herein can be formulated as suitable ointments, lotions, or liniments, wherein the active ingredient can be suspended or dissolved in one or more carriers.

[0396] The pharmaceutical compositions described in this disclosure can also be administered in injectable form, including injectable solutions, sterile powders for injection, and concentrated solutions for injection.

[0397] This disclosure also relates to a pharmaceutical formulation comprising, as an active ingredient, the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, or a mixture thereof, or a pharmaceutical composition thereof, of the compound described herein or thereof.

[0398] In some embodiments, the pharmaceutical formulations described herein are in the form of solid dosage forms, semi-solid dosage forms, liquid dosage forms, or gaseous dosage forms.

[0399] Fourthly, this disclosure provides an article of manufacture, for example, provided in the form of a medicine box. The article of manufacture as used herein is intended to include, but is not limited to, pharmaceutical compositions and packaging. For example, an article of manufacture of this disclosure comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of this disclosure or a pharmaceutically acceptable form thereof, or a mixture thereof, said pharmaceutically acceptable form being selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs; and (c) optionally present packaging instructions indicating that the pharmaceutical composition may be used to treat diseases or conditions for which CDK2 / 4 / 6 inhibitors are applicable, such as oncological conditions.

[0400] The packaging instructions, such as trademarks, labels, or markings, list information relating to the pharmaceutical composition contained within the first container. The listed information is typically determined by the regulatory authority governing the region where the product is to be sold (e.g., the U.S. Food and Drug Administration). Preferably, the packaging instructions specifically list the approved indications for which the pharmaceutical composition is used. The packaging instructions can be made of any material from which information contained therein or on the material can be read. Preferably, the packaging instructions are made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic) on which the desired information can be formed (e.g., printed or coated).

[0401] Treatment methods and uses

[0402] Fifthly, the use of the compounds described herein or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs, or pharmaceutical compositions described herein, or kit products described herein, in the preparation of medicaments for the treatment and / or prevention of diseases or symptoms associated with CDK2 / 4 / 6 activity.

[0403] Sixthly, another object of this disclosure is to provide the compounds described herein or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs, or the pharmaceutical compositions described herein, or the kit products described herein, for the treatment and / or prevention of diseases or symptoms associated with CDK2 / 4 / 6 activity.

[0404] In a seventh aspect, this disclosure provides a method for treating and / or preventing diseases or symptoms associated with CDK2 / 4 / 6 activity, the method comprising administering to an individual in need an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug of the present disclosure, or a pharmaceutical composition of the present disclosure, or a kit product of the present disclosure.

[0405] Furthermore, this disclosure provides a method for treating and / or preventing tumor-like or cancer-like diseases or symptoms, the method comprising administering to an individual in need an effective amount of the compound described in this disclosure or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug described in this disclosure, or a pharmaceutical composition described in this disclosure, or a kit product described in this disclosure.

[0406] In some embodiments, the diseases or conditions associated with CDK2 / 4 / 6 activity described in this disclosure include (but are not limited to) tumor-related or cancer-related diseases or conditions.

[0407] In some embodiments, the diseases or conditions associated with CDK2 / 4 / 6 activity described in this disclosure are selected from: bladder cancer, breast cancer, colon cancer, kidney cancer, epidermal cancer, liver cancer, lung cancer (including SCLC and NSCLC), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer or skin cancer, lymphoid hematopoietic tumors (e.g., leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma). Multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pilocellular lymphoma or Burkett's lymphoma, myeloid hematopoietic tumors, follicular thyroid carcinoma, mesenchymal tumors, central or peripheral nervous system tumors (e.g., astrocytoma, neuroblastoma, glioma or schwannoma), melanoma, familial melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, Kaposi's sarcoma Squamous cell carcinoma, sarcoma, malignant mesothelioma, non-small cell lung cancer, cholangiocarcinoma, soft tissue sarcoma, glioblastoma, (recurrent) brain tumors, secondary to hormone receptor-positive breast cancer, brain metastases from melanoma (including cyclin D1-expressing positive melanoma), (recurrent or persistent) endometrial cancer, (recurrent or metastatic) head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma, esophageal squamous cell carcinoma (SCC), esophageal adenocarcinoma (ADC), renal cell carcinoma, and urothelial carcinoma. Beneficial effects

[0408] This disclosure provides a novel class of CDK2 / 4 / 6 inhibitors capable of achieving at least one of the following technical effects:

[0409] (1) It has high inhibitory activity against CDK2, CDK4 and CDK6.

[0410] (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability).

[0411] (3) Excellent pharmacokinetic properties (e.g., good bioavailability, appropriate half-life and duration of action).

[0412] (4) Excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc. Detailed Implementation

[0413] The present disclosure will be further illustrated by the following embodiments. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure and are not intended to limit the scope of the present disclosure. Those skilled in the art can make some non-essential improvements and adjustments, which still fall within the protection scope of the present disclosure.

[0414] Unless otherwise specified in the examples, all procedures were performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0415] The structure of the compound was determined by nuclear magnetic resonance (NMR). 1 It was determined by 1H NMR or mass spectrometry (MS). 1 The 1H NMR was performed using a JEOL Eclipse 400 NMR spectrometer. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6). The internal standard was tetramethylsilane (TMS). Chemical shifts (δ) were given in parts per million (ppm).

[0416] The instrument used for MS measurements was an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0417] Preparation method of high performance liquid chromatograph:

[0418] Instrument model: Agilent 1260; Column: Waters SunFire Prep C18 OBD (19mm×150mm×5.0μm); Column temperature: 25℃; Flow rate: 20.0mL / min; Detection wavelength: 214nm; Elution gradient: (0min: 10%A, 90%B; 16.0min: 90%A, 10%B); Mobile phase A: Acetonitrile; Mobile phase B: 0.05% formic acid aqueous solution.

[0419] The thin-layer chromatography silica gel plates (TLC) used were Merck aluminum plates (20×20cm), and the TLC separation and purification used Yantai-made GF 254 (1mm) plates.

[0420] The reaction was monitored using thin-layer chromatography (TLC) or LC-MS. The developing solvent systems used included dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compound or by adding triethylamine, etc.

[0421] Preparation method of reversed-phase column chromatography:

[0422] Preparation method A:

[0423] Instrument model: Biotage rapid medium-pressure preparative chromatography; Column: Agela C18 reversed-phase column (Spherical; 20-35μm; 100A); Column temperature: 25℃; Flow rate: 28.0mL / min; Detection wavelength: 220nm; Mobile phase A: acetonitrile; Mobile phase B: 0.05% formic acid aqueous solution;

[0424] Preparation method B:

[0425] Instrument model: Biotage rapid medium-pressure preparative chromatography; Column: Agela C18 reversed-phase column (Spherical; 20-35μm; 100A); Column temperature: 25℃; Flow rate: 28.0mL / min; Detection wavelength: 220nm; Mobile phase A: acetonitrile; Mobile phase B: 0.05% NH4HCO3 aqueous solution;

[0426] The microwave reaction was performed using a Biotage Initiator+ (400W, RT~300℃) microwave reactor.

[0427] Column chromatography typically uses 200-300 mesh silica gel as the support. Eluent systems include dichloromethane and methanol systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and a small amount of triethylamine can also be added for adjustment.

[0428] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~35℃).

[0429] The reagents used in this disclosure were purchased from Acros Organics, Aldrich Chemical Company, TEB Chemicals, and other companies.

[0430] In the conventional synthesis methods and examples, as well as intermediate synthesis examples, the meanings of the abbreviations are as follows.

[0431] Preparation Example 1: Preparation of 4-(dimethylamino)piperidin-2-one (Int1)

[0432] Step 1: Preparation of 4-(dimethylamino)-5,6-dihydropyridine-2(1H)-one

[0433] Tetraisopropyl titanate (75.4 g, 265 mmol, 78.3 mL) was added to a solution of piperidine-2,4-dione (30.0 g, 265 mmol) in dichloromethane (150 mL). The mixture was stirred at 0 °C for 5 minutes. While maintaining the temperature, a solution of dimethylamine in tetrahydrofuran (2 M, 530 mL) was added dropwise. The mixture was allowed to rise naturally to room temperature for two hours. The reaction was quenched with water, filtered, extracted with dichloromethane, and the combined organic phases were washed with saturated brine. The organic phase was concentrated to give the title compound of this step (6.26 g, yield: 18.2%).

[0434] MS m / z (ESI): 141.1 [M+H] + .

[0435] Step 2: Preparation of 4-(dimethylamino)piperidin-2-one

[0436] Solution 1 (S1): 4-(dimethylamino)-5,6-dihydropyridine-2(1H)-one (7.50 g, 53.5 mmol) was dissolved in methanol (180 mL).

[0437] The fixed bed (named FLR1, volume 5 mL) was completely filled with 5% palladium on carbon (1.1 g, WXC1030) granular catalyst.

[0438] The hydrogen back pressure regulator was adjusted to 1.5 MPa, and the hydrogen flow rate was 30 mL / min.

[0439] Solution 1 (S1) was pumped from pump 1 into the fixed bed {FLR1, PFA, fixed bed, 6.350 (1 / 4) mm, 1 mL, 60 °C}.

[0440] Solution S1 was flowed through {FLR1, 3.3 min}, exiting the reactor zone, and the reaction mixture was then collected from the reactor output. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound of this step (6.45 g, yield: 84.8%).

[0441] MS m / z (ESI): 143.1 [M+H] + .

[0442] 1 H NMR (400MHz, CDCl3): δ6.53(s,1H),3.33-3.45(m,1H),3.18-3.30(m,1H),2 .51-2.65(m,2H),2.25-2.38(m,7H),1.97-2.08(m,1H),1.56-1.71(m,1H).

[0443] Preparation Example 2: Preparation of 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (Int2)

[0444] 4-(dimethylamino)piperidin-2-one (800 mg, 5.63 mmol) was dissolved in 1,4-dioxane (20 mL), and 5-iodopyridin-2-amine (1.61 g, 7.31 mmol) and (1S,2S)-N were added. 1 N 2 The reaction mixture was prepared by reacting 1,2-dimethylcyclohexane-1,2-diamine (320 mg, 1.13 mmol), cuprous iodide (214 mg, 1.13 mmol), and potassium phosphate (3.58 g, 16.9 mmol) under nitrogen purging at 110 °C for 12 hours. The reaction solution was filtered, and the crude product obtained by concentration was purified by high performance liquid chromatography to give the title compound (384 mg, yield: 29.1%).

[0445] MS m / z(ESI): 235.1 [M+H] + .

[0446] 1 H NMR (400MHz, CDCl3): δ7.95(s,1H),7.35(dd,J=8.0,2.0Hz,1H),6.51(d,J=8.0Hz,1H),4.46(s,2H),3.61(dd,J =8.0,4.0Hz,2H),2.66-2.85(m,2H),2.48-2.58(m,1H),2.34(s,6H),2.20(d,J=12.0Hz,1H),1.84-1.92(m,1H).

[0447] Preparation Example 3: Preparation of (3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int3)

[0448] Step 1: Preparation of 5-chloro-3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridine

[0449] 5-Chloro-2-methyl-3H-imidazo[4,5-b]pyridine (100 mg, 596.68 μmol) and 2-bromopropane (366.93 mg, 2.98 mmol) were dissolved in dimethyl sulfoxide (5 mL), and potassium carbonate (412.32 mg, 2.98 mmol) was added. The mixture was reacted at 60 °C for 2 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the crude product obtained by organic phase concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 (v / v)) to give the title compound of this step (70 mg, yield: 47.6%).

[0450] MS m / z(ESI): 210.1 [M+H] + .

[0451] Step 2: Preparation of (3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0452] 5-Chloro-3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridine (60 mg, 286.16 μmol) and pinacol diborate (145.33 mg, 572.31 μmol) were dissolved in 1,4-dioxane (3 mL). Tris(dibenzylacetone)palladium (78.61 mg, 85.85 μmol), tricyclohexylphosphine (48.15 mg, 171.69 μmol), and potassium acetate (56.17 mg, 572.31 μmol) were added. The mixture was purged with nitrogen and reacted at 100 °C for 16 hours. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated to obtain the title compound of this step (55 mg, yield: 87.7%).

[0453] MS m / z(ESI): 220.0 [M+H] + .

[0454] Preparation Example 4: Preparation of 1,1-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium (Int4)

[0455] Step 1: Preparation of N-(4-bromo-2-fluorophenyl)-5,5-dimethylpyrrolidine-2-imine

[0456] 4-Bromo-2-fluoroaniline (1.00 g, 5.26 mmol) was dissolved in toluene (10 mL), and 5,5-dimethylpyrrolidone-2-one (1.19 g, 10.5 mmol), triethylamine (799 mg, 7.89 mmol), and phosphorus oxychloride (1.21 g, 7.89 mmol) were added. The mixture was reacted at 120 °C for 3 hours. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 99 / 1 (v / v)) to give the title compound of this step (1.50 g, yield: 100%).

[0457] MS m / z(ESI): 285.0 [M+H] + .

[0458] Step 2: Preparation of 7-bromo-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

[0459] N-(4-bromo-2-fluorophenyl)-5,5-dimethylpyrrolidine-2-imine (300 mg, 1.05 mmol) and potassium tert-butoxide (295 mg, 2.63 mmol) were added to N-methylpyrrolidone (9 mL), and the mixture was microwaved at 200 °C for 4 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (1.50 g, yield: 80.1%).

[0460] MS m / z(ESI): 265.1 [M+H] + .

[0461] Step 3: Preparation of 1,1-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

[0462] 7-Bromo-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (410 mg, 1.55 mmol) was dissolved in 1,4-dioxane (8 mL), and pinacol diboronate (471 mg, 1.86 mmol), potassium acetate (304 mg, 3.09 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (113 mg, 155 μmol) were added. The mixture was purged with nitrogen and reacted at 85 °C for 2 hours. The reaction mixture was filtered, and the residue obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 97 / 3 (v / v)) to give the title compound of this step (490 mg, yield: 98.0%).

[0463] MS m / z(ESI): 313.1 [M+H] + .

[0464] Preparation Example 5: Preparation of 1,1-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine (Int5)

[0465] Following the synthetic method of compound Int4, 5,5-dimethylpyrrolidone-2-one was replaced with 6,6-dimethylpiperidin-2-one to obtain the title compound (69 mg).

[0466] MS m / z (ESI): 327.1 [M+H] + .

[0467] Preparation Example 6: Preparation of (R)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (Int2A) and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (Int2B)

[0468] 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was purified by chiral separation using SFC (column: CHIRAL-IK-30-daicel CHIRAL IK (250mm*30mm, 10μm); mobile phase: (A: CO2, B: ethanol / acetonitrile = 7 / 3 (0.1% ammonia)), elution gradient: mobile phase B% = 45%, isobaric elution mode; detection wavelength: 220nm), yielding (R)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (4.43g, ee value: 99.7%) and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (4.58g, ee value: 99.1%).

[0469] MS m / z(ESI): 235.1 [M+H] + .

[0470] Preparation Example 7: Preparation of (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid (Int6)

[0471] Step 1: Preparation of N-(2,6-dichloropyridin-3-yl)-5,5-dimethylpyrrolidine-2-imine

[0472] 2,6-Dichloropyridin-3-amine (1.00 g, 6.13 mmol) was dissolved in toluene (10 mL), and 5,5-dimethylpyrrolidone-2-one (1.39 g, 12.3 mmol), triethylamine (931 mg, 9.20 mmol), and phosphorus oxychloride (1.41 g, 9.20 mmol) were added. The mixture was reacted at 120 °C for 3 hours. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 97 / 3 (v / v)) to give the title compound of this step (1.58 g, yield: 99.8%).

[0473] MS m / z(ESI): 258.1 [M+H] + .

[0474] Step 2: Preparation of 2-chloro-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine

[0475] N-(2,6-dichloropyridin-3-yl)-5,5-dimethylpyrrolidine-2-imine (300 mg, 1.16 mmol) and potassium tert-butoxide (326 mg, 2.91 mmol) were added to N-methylpyrrolidone (9.00 mL), and the mixture was microwaved at 200 °C for 4 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 97 / 3 (v / v)) to give the title compound of this step (187 mg, yield: 31.1%).

[0476] MS m / z(ESI): 222.2 [M+H] + .

[0477] Step 3: Preparation of (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid

[0478] 2-Chloro-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine (40 mg, 180.44 μmol) and pinacol diboronate (91.64 mg, 360.87 μmol) were dissolved in 1,4-dioxane (3 mL). Tris(dibenzylacetone)palladium (33.05 mg, 36.09 μmol), tricyclohexylphosphine (30.36 mg, 108.26 μmol), and potassium acetate (35.42 mg, 360.87 μmol) were added. The mixture was purged with nitrogen and reacted at 100 °C for 16 hours. The reaction mixture was filtered through a diatomaceous earth sieve, and the filtrate was concentrated to give the title compound of this step (41 mg, yield: 93.4%).

[0479] MS m / z(ESI): 232.2 [M+H] + .

[0480] Preparation Example 8: Preparation of (9,9-dimethyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']bipyridin-2-yl)boronic acid (Int7)

[0481] Following the synthetic method of compound Int6, 5,5-dimethylpyrrolidone-2-one was replaced with 6,6-dimethylpiperidin-2-one to obtain the title compound (40 mg).

[0482] MS m / z(ESI): 246.1 [M+H] + .

[0483] Preparation Example 9: Preparation of 1,3,3-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazo (Int8)

[0484] Step 1: Preparation of 2-((5-bromo-2-nitrophenyl)amino)-2-methylprop-1-ol

[0485] 4-Bromo-2-fluoro-1-nitrobenzene (10.0 g, 45.5 mmol) and 2-amino-2-methylpropane-1-ol (8.10 g, 90.9 mmol) were added to tetrahydrofuran (100 mL) and reacted at 80 °C for 48 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 55 / 45 (v / v)) to give the title compound of this step (12.0 g, yield: 91.2%).

[0486] MS m / z(ESI): 289.2 [M+H] + .

[0487] Step 2: Preparation of 2-((2-amino-5-bromophenyl)amino)-2-methylprop-1-ol

[0488] 2-((5-bromo-2-nitrophenyl)amino)-2-methylprop-1-ol (13.5 g, 46.7 mmol) was dissolved in ethanol (216 mL) and water (54 mL), and iron powder (13.0 g, 233 mmol) and ammonium chloride (12.5 g, 233 mmol) were added. The mixture was reacted at 80 °C for 4 hours. The reaction solution was filtered, the filtrate was concentrated and diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (10.5 g, yield: 76.2%).

[0489] MS m / z (ESI): 258.8 [M+H] + .

[0490] Step 3: Preparation of 2-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-2-methylpropanol

[0491] 2-((2-amino-5-bromophenyl)amino)-2-methylprop-1-ol (5.00 g, 19.3 mmol) was dissolved in methanol (50 mL), and a dichloromethane solution of cyanogen bromide (3 M, 30.3 mmol) was added. The reaction was carried out at room temperature for 16 hours. The reaction was quenched dropwise with saturated sodium carbonate solution (50 mL), and the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 89 / 11 (v / v)) to give the title compound of this step (4.95 g, yield: 90.2%).

[0492] MS m / z(ESI): 284.0 [M+H] + .

[0493] Step 4: Preparation of 6-bromo-3,3-dimethyl-1-(methanesulfonyl)-2,3-dihydro-1H-benzo[d]imidazo[1,2-a ...

[0494] 2-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-2-methylpropanol (4.95 g, 43.6 mmol) was dissolved in pyridine (50 mL), and methanesulfonic anhydride (7.59 g, 43.6 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to give the title compound of this step (18.0 g, crude product).

[0495] MS m / z (ESI): 345.8 [M+H]+ .

[0496] Step 5: Preparation of 6-bromo-3,3-dimethyl-2,3-dihydro-1H-benzo[d]imidazo[1,2-a ...

[0497] 6-Bromo-3,3-dimethyl-1-(methanesulfonyl)-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazolium (18.0 g, 52.3 mmol) was dissolved in methanol (180 mL), and potassium hydroxide (5.87 g, 104 mmol) was added. The reaction mixture was reacted at 60 °C for 16 hours. The reaction mixture was filtered, and the residue obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 94 / 6 (v / v)) to give the title compound of this step (2.87 g, yield: 20.7%).

[0498] MS m / z(ESI): 266.2 [M+H] + .

[0499] Step 6: Preparation of 6-bromo-1,3,3-trimethyl-2,3-dihydro-1H-benzo[d]imidazo[1,2-a ...

[0500] 6-Bromo-3,3-dimethyl-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazolium (2.50 g, 9.39 mmol) was dissolved in tetrahydrofuran (25 mL), cooled to 0 °C, and sodium hydride (601 mg, 15.0 mmol) was added. After stirring at this temperature for half an hour, iodomethane (1.73 g, 12.2 mmol) was added, and the reaction was carried out at room temperature for 11.5 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 96 / 4 (v / v)) to give the title compound of this step (1.10 g, yield: 41.9%).

[0501] MS m / z (ESI): 280.1 [M+H] + .

[0502] Step 7: Preparation of 1,3,3-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazolium

[0503] 6-Bromo-1,3,3-trimethyl-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazol (1 g, 3.57 mmol), pinacol diboronate (1.09 g, 4.28 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (261 mg, 0.36 mmol), and potassium acetate (700 mg, 7.14 mmol) were added to 1,4-dioxane (30.0 mL), purged with nitrogen, and reacted at 90 °C for 2 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 4 (v / v)) to give the title compound of this step (980 mg, yield: 83.8%).

[0504] MS m / z(ESI): 328.2 [M+H] + .

[0505] Preparation Example 10: Preparation of (1-(5-bromo-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropyl)methanol (Int9)

[0506] Step 1: Preparation of (1-((6-bromo-3-nitropyridin-2-yl)amino)cyclopropyl)methanol

[0507] 2,6-Dibromo-3-nitropyridine (1 g, 3.51 mmol), N,N-diisopropylethylamine (1.28 g, 9.83 mmol), and (1-aminocyclopropyl)methanol (502.55 mg, 3.86 mmol) were added to N-methylpyrrolidone (8 mL), and the reaction was carried out at room temperature for 3 hours. The reaction solution was then purified directly by reversed-phase column chromatography (Preparation Method A, elution gradient: mobile phase A% = 40%-50%) to give the title compound of this step (985 mg, yield: 92.5%).

[0508] MS m / z(ESI): 288.1 [M+H] + .

[0509] 1 H NMR (400MHz, DMSO-d6): δ 8.52 (br, 1H), 8.30 (d, J = 8.0Hz, 1H), 7.00 (d, J = 8.0Hz, 1H), 4.79 (t, J = 4.0Hz, 1H), 3.56 (d, J = 4.0Hz, 2H), 0.89-0.80 (m, 4H).

[0510] Step 2: Preparation of (1-((3-amino-6-bromopyridin-2-yl)amino)cyclopropyl)methanol

[0511] (1-((6-bromo-3-nitropyridin-2-yl)amino)cyclopropyl)methanol (985 mg, 3.25 mmol), reduced iron powder (366.47 mg, 6.50 mmol), and acetic acid (98.43 mg, 1.62 mmol) were added to tetrahydrofuran (15 mL), and the reaction was carried out at 40 °C for 2 hours. The reaction solution was filtered, and the residue obtained by concentration was purified by reverse-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 30%-38%) to give the title compound of this step (750 mg, yield: 85.0%).

[0512] MS m / z(ESI): 258.0 [M+H] + .

[0513] Step 3: Preparation of (1-(5-bromo-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropyl)methanol

[0514] (1-((3-amino-6-bromopyridin-2-yl)amino)cyclopropyl)methanol (500 mg, 1.84 mmol) and 1,1,1-triethoxyethane (6.29 g, 36.81 mmol) were added to acetic acid (557.66 mg, 9.20 mmol) and reacted at 100 °C for 1 hour. The residue obtained by concentration of the reaction solution was purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 25%-30%) to give the title compound of this step (410 mg, yield: 75.0%).

[0515] MS m / z(ESI): 282.0 [M+H] + .

[0516] 1 H NMR (400MHz, CDCl3): δ7.68 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.85 (s, 2H), 2.76 (s, 3H), 1.38-1.28 (m, 4H).

[0517] Preparation Example 11: Preparation of (3-(2-cyanopropane-2-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int10)

[0518] Step 1: Preparation of 2-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)acetonitrile

[0519] 5-Chloro-2-methyl-3H-imidazo[4,5-b]pyridine (1 g, 5.67 mmol), chloroacetonitrile (495.52 mg, 6.24 mmol), tetrabutylammonium iodide (10 mg, 0.05 mmol), triethylamine (578.29 mg, 5.67 mmol), and potassium carbonate (217.58 mg, 5.67 mmol) were added to acetonitrile (20 mL), and the reaction was carried out at 80 °C for 4 hours. The residue obtained by concentration of the reaction solution was purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 30%-35%) to give the title compound of this step (810 mg, yield: 33.9%).

[0520] MS m / z(ESI): 207.1 [M+H] + .

[0521] 1 H NMR (400MHz, DMSO-d6): δ 8.08 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 5.54 (s, 2H), 2.66 (s, 3H).

[0522] Step 2: Preparation of 2-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile

[0523] Under ice-water bath cooling, 2-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)acetonitrile (800 mg, 3.68 mmol), sodium hydride (178.33 mg, 7.36 mmol), and methyl iodide (824.30 mg, 5.52 mmol) were added to dimethyl sulfoxide (8 mL), and the reaction was carried out at room temperature for 1 hour. The reaction was quenched with ice water, and the residue obtained by concentration was purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 40%-45%) to give the title compound of this step (78 mg, yield: 8.6%).

[0524] MS m / z(ESI): 235.1 [M+H] + .

[0525] Step 3: Preparation of (3-(2-cyanopropane-2-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0526] 2-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile (70 mg, 283.36 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (20.92 mg, 28.34 μmol), pinacol diboronate (109.05 mg, 425.04 μmol), and potassium acetate (56.10 mg, 566.72 μmol) were added to toluene (3 mL), the mixture was purged with nitrogen, and the reaction was carried out at 110 °C for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product of the title compound of this step.

[0527] MS m / z (ESI): 245.2 [M+H] + .

[0528] Preparation Example 12: Preparation of (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid (Int11)

[0529] Step 1: Preparation of 2-((6-chloro-3-nitropyridin-2-yl)amino)-2-methyl-1-propanol

[0530] 2,6-Dichloro-3-nitropyridine (2.00 g, 10.3 mmol) and 2-amino-2-methyl-1-propanol (1.85 g, 20.7 mmol) were added to tetrahydrofuran (10 mL) and reacted at 80 °C for 24 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 55 / 45 (v / v)) to give the title compound of this step (2.30 g, yield: 85.8%).

[0531] 1 H NMR (400MHz, DMSO-d6): δ8.66(s,1H),8.43(d,J=8.0Hz,1H),6.78(d,J=8.0Hz,1H),5.32-5.18(m,1H),3.50(d,J=8.0Hz,2H),1.42(s,6H).

[0532] Step 2: Preparation of 2-((3-amino-6-chloropyridin-2-yl)amino)-2-methyl-1-propanol

[0533] 2-((6-chloro-3-nitropyridin-2-yl)amino)-2-methyl-1-propanol (2.3 g, 9.36 mmol) was dissolved in ethanol (32 mL) and water (2 mL), and iron powder (2.27 g, 40.7 mmol) and ammonium chloride (2.18 g, 40.7 mmol) were added. The mixture was reacted at 80 °C for 4 hours. The reaction solution was filtered, the filtrate was concentrated, the residue was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (1.8 g, yield: 89.2%).

[0534] MS m / z(ESI): 216.1 [M+H] + .

[0535] Step 3: Preparation of 2-(2-amino-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2-methyl-1-propanol

[0536] 2-((3-amino-6-chloropyridin-2-yl)amino)-2-methyl-1-propanol (1.5 g, 6.95 mmol) was dissolved in methanol (15 mL), and a solution of cyanogen bromide in dichloromethane (3 M, 2.93 mL) was added. The reaction was carried out at room temperature for 12 hours. The reaction was quenched dropwise with saturated sodium carbonate solution, and the methanol was removed by concentration. The residue was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentration of the filtrate was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 94 / 6 (v / v)) to give the title compound of this step (1.05 g, yield: 63.0%).

[0537] MS m / z (ESI): 240.9 [M+H] + .

[0538] Step 4: Preparation of 6-chloro-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine

[0539] 2-(2-amino-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2-methyl-1-propanol (1.00 g, 4.15 mmol) was dissolved in pyridine (10 mL), and methanesulfonic anhydride (1.81 g, 10.4 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was filtered, and the residue obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 94 / 6 (v / v)) to give the title compound of this step (200 mg, yield: 19.5%).

[0540] MS m / z(ESI): 223.1 [M+H] + .

[0541] Step 5: Preparation of 6-chloro-1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine

[0542] 6-Chloro-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine (200 mg, 898 μmol) was dissolved in anhydrous tetrahydrofuran (4 mL), cooled to 0 °C, and sodium hydride (53.9 mg, 1.35 mmol) was added. The reaction was allowed to proceed for 0.5 h, followed by the addition of iodomethane (254 mg, 1.80 mmol) and the reaction proceeding to room temperature for 6 h. The reaction mixture was filtered, and the residue obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 94 / 6 (v / v)) to give the title compound of this step (198 mg, yield: 93.4%).

[0543] MS m / z(ESI): 237.1 [M+H] + .

[0544] Step 6: Preparation of (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid

[0545] 6-Chloro-1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine (70 mg, 295.73 μmol) and pinacol diboronate (150.20 mg, 591.47 μmol) were dissolved in 1,4-dioxane (3 mL). Tricyclohexylphosphine (49.76 mg, 177.44 μmol), potassium acetate (58.05 mg, 591.47 μmol), and tris(dibenzylacetone)dipalladium (81.24 mg, 88.72 μmol) were added. The mixture was purged with nitrogen and microwaved at 130 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude title compound of this step.

[0546] MS m / z(ESI): 247.1 [M+H] + .

[0547] Preparation Example 13: Preparation of 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine (Int12)

[0548] Step 1: Preparation of 3-((5-bromo-2-nitrophenyl)amino)-3-methyl-1-butanol

[0549] 3-Amino-3-methyl-1-butanol (562.71 mg, 5.45 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 4-bromo-2-fluoro-1-nitrobenzene (1 g, 4.55 mmol) and potassium carbonate (1.88 g, 13.64 mmol) were added. The mixture was reacted at 110 °C for 4 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 (v / v)) to give the title compound of this step (1.3 g, yield: 94.3%).

[0550] MS m / z (ESI): 303.1 [M+H] + .

[0551] Step 2: Preparation of 3-((2-amino-5-bromophenyl)amino)-3-methyl-1-butanol

[0552] 3-((5-bromo-2-nitrophenyl)amino)-3-methyl-1-butanol (1.3 g, 4.29 mmol) and tetrahydroxydiboron (1.15 g, 12.86 mmol) were dissolved in N,N-dimethylformamide (8 mL), cooled to 0 °C, and 4,4'-bipyridine (33.49 mg, 214.41 μmol) was added. The reaction mixture was reacted at room temperature for 5 min. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 20%-25%) to give the title compound of this step (1 g, yield: 85.4%).

[0553] MS m / z(ESI): 273.1 [M+H] + .

[0554] Step 3: Preparation of 3-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-methyl-1-butanol

[0555] 3-((2-amino-5-bromophenyl)amino)-3-methyl-1-butanol (700 mg, 2.56 mmol) was dissolved in methanol (10 mL), and cyanogen bromide (542.85 mg, 5.13 mmol) was added. The reaction mixture was reacted at 60 °C for 16 hours. The reaction solution was cooled to room temperature and purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 20%-25%) to give the title compound of this step (400 mg, yield: 52.4%).

[0556] MS m / z(ESI): 298.1 [M+H] + .

[0557] Step 4: Preparation of 7-bromo-4,4-dimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine

[0558] 3-(2-amino-6-bromo-1H-benzo[d]imidazol-1-yl)-3-methyl-1-butanol (380 mg, 1.27 mmol) was dissolved in pyridine (6 mL), and methanesulfonic anhydride (332.98 mg, 1.91 mmol) was added. The mixture was purged with nitrogen and reacted at room temperature for 12 hours. The reaction solution was then purified directly by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 25%-30%) to give the title compound of this step (300 mg, yield: 84.0%).

[0559] MS m / z (ESI): 280.1 [M+H] + .

[0560] Step 5: Preparation of 7-bromo-1,4,4-trimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine

[0561] The mixture was cooled in an ice-water bath. 7-Bromo-4,4-dimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine (100 mg, 356.93 μmol) and sodium hydride (42.83 mg, 1.07 mmol) were added to anhydrous tetrahydrofuran (6 mL). The reaction was allowed to proceed for 0.5 h, followed by the dropwise addition of iodomethane (75.99 mg, 535.40 μmol), and the reaction was allowed to continue at room temperature for 4 h. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound of this step (80 mg, yield: 76.2%).

[0562] MS m / z(ESI): 294.2 [M+H] + .

[0563] Step 6: Preparation of 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine

[0564] 7-Bromo-1,4,4-trimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine (80 mg, 271.93 μmol), pinacol diboronate (151.92 mg, 598.25 μmol), potassium acetate (79.95 mg, 815.80 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (22.21 mg, 27.19 μmol) were added to anhydrous 1,4-dioxane (6 mL), purged with nitrogen, and reacted at 110 °C for 6 hours. The reaction solution was filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound of this step (90 mg, yield: 97.0%).

[0565] MS m / z(ESI): 342.2 [M+H] + .

[0566] Preparation Example 14: Preparation of (6,9,9-trimethyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrimidin-2-yl)boronic acid (Int13)

[0567] Step 1: Preparation of 3-((6-chloro-3-nitropyridin-2-yl)amino)-3-methyl-1-butanol

[0568] 3-Amino-3-methyl-1-butanol (960 mg, 9.33 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 2,6-dichloro-3-nitropyridine (1.5 g, 7.77 mmol) and potassium carbonate (3.22 g, 23.32 mmol) were added. The mixture was reacted at 110 °C for 4 hours. The reaction solution was diluted with water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 (v / v)) to give the title compound of this step (1.9 g, yield: 94.1%).

[0569] MS m / z(ESI): 260.1 [M+H] + .

[0570] Step 2: Preparation of 3-((3-amino-6-chloropyridin-2-yl)amino)-3-methyl-1-butanol

[0571] 3-((6-chloro-3-nitropyridin-2-yl)amino)-3-methyl-1-butanol (1.6 g, 6.16 mmol) and tetrahydroxydiboron (1.66 g, 18.48 mmol) were dissolved in N,N-dimethylformamide (8 mL), cooled to 0 °C, and 4,4'-bipyridine (48.11 mg, 308.06 μmol) was added. The reaction mixture was reacted at room temperature for 5 min. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 20%-25%) to give the title compound of this step (0.75 g, yield: 53.0%).

[0572] MS m / z(ESI): 230.0 [M+H] + .

[0573] Step 3: Preparation of 3-(2-amino-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-3-methyl-1-butanol

[0574] 3-((3-amino-6-chloropyridin-2-yl)amino)-3-methyl-1-butanol (650 mg, 2.83 mmol) was dissolved in methanol (10 mL), and cyanogen bromide (599.45 mg, 5.66 mmol) was added. The reaction mixture was reacted at 60 °C for 4 hours. The reaction solution was cooled to room temperature and purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 15%-20%) to give the title compound of this step (700 mg, yield: 97.1%).

[0575] MS m / z (ESI): 255.1 [M+H] + .

[0576] Step 4: Preparation of 2-chloro-9,9-dimethyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrimidine

[0577] 3-(2-amino-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-3-methyl-1-butanol (700 mg, 2.75 mmol) was dissolved in pyridine (6 mL), and methanesulfonic anhydride (574.44 mg, 3.3 mmol) was added. The mixture was purged with nitrogen and reacted at room temperature for 12 hours. The reaction solution was then purified directly by reversed-phase column chromatography (Preparation Method A, elution gradient: mobile phase A% = 25%-30%) to give the title compound of this step (280 mg, yield: 43.0%).

[0578] MS m / z (ESI): 237.3 [M+H] + .

[0579] Step 5: Preparation of 2-chloro-6,9,9-trimethyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrimidine

[0580] The mixture was cooled in an ice-water bath. 2-Chloro-9,9-dimethyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrimidine (100 mg, 422.48 μmol) and sodium hydride (50.7 mg, 1.27 mmol) were added to anhydrous tetrahydrofuran (6 mL). The reaction was allowed to proceed for 0.5 h, followed by the dropwise addition of iodomethane (89.95 mg, 633.71 μmol), and the reaction was allowed to continue at room temperature for 4 h. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound of this step (55 mg, yield: 51.9%).

[0581] MS m / z(ESI): 251.1 [M+H] + .

[0582] Step 6: Preparation of (6,9,9-trimethyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrimidin-2-yl)boronic acid

[0583] 2-Chloro-6,9,9-trimethyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrimidine (44 mg, 175.49 μmol) and pinacol diboronate (89.13 mg, 350.98 μmol) were dissolved in 1,4-dioxane (4 mL). Tricyclohexylphosphine (29.53 mg, 105.29 μmol), potassium acetate (34.35 mg, 350.98 μmol), and tris(dibenzylideneacetone)palladium (32.14 mg, 35.10 μmol) were added. The mixture was purged with nitrogen and microwaved at 140 °C for 3.5 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude title compound of this step.

[0584] MS m / z(ESI): 261.1 [M+H] + .

[0585] Preparation Example 15: Preparation of (6-(cyclopropylmethyl)-9,9-dimethyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrimidin-2-yl)boronic acid (Int14)

[0586] Following the synthetic route of compound Int13, iodomethane was replaced with (bromomethyl)cyclopropane to obtain the crude product of the title compound.

[0587] MS m / z (ESI): 301.1 [M+H] + .

[0588] Preparation Example 16: (2-(2-cyanopropane-2-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int15)

[0589] Step 1: Preparation of 6-bromo-N-isopropyl-3-nitropyridine-2-amine

[0590] 2,6-Dibromo-3-nitropyridine (3.5 g, 12.42 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and isopropylamine (807.3 mg, 13.66 mmol) and N,N-diisopropylethylamine (4.81 g, 37.25 mmol) were added. The mixture was reacted at room temperature for 24 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 (v / v)) to give the title compound of this step (3 g, yield: 92.9%).

[0591] MS m / z(ESI): 260.1 [M+H] + .

[0592] Step 2: 6-Bromo-N 2 Preparation of -isopropylpyridine-2,3-diamine

[0593] 6-Bromo-N-isopropyl-3-nitropyridine-2-amine (3 g, 11.53 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and acetic acid (5 mL), and zinc powder (3.02 g, 46.14 mmol) was added. The reaction mixture was reacted at 60 °C for 1 hour. The reaction solution was filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 2 (v / v)) to give the title compound of this step (2.2 g, yield: 82.9%).

[0594] MS m / z(ESI): 230.0 [M+H] + .

[0595] Step 3: Preparation of N-(6-bromo-2-(isopropylamino)pyridin-3-yl)-2-cyano-2-methylpropionamide

[0596] 6-bromo-N 2- Isopropylpyridine-2,3-diamine (500 mg, 2.17 mmol), 2-cyano-2-methylpropionic acid (270.37 mg, 2.39 mmol), and N,N-diisopropylethylamine (842.49 mg, 6.52 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.07 g, 2.82 mmol) was added. The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 15%-20%) to give the title compound of this step (680 mg, yield: 96.2%).

[0597] MS m / z (ESI): 325.1 [M+H] + .

[0598] Step 4: Preparation of 2-(5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropionitrile

[0599] N-(6-bromo-2-(isopropylamino)pyridin-3-yl)-2-cyano-2-methylpropionamide (250 mg, 768.75 μmol) was dissolved in acetic acid (6 mL), and the mixture was microwaved at 140 °C for 4 hours. After cooling to room temperature, the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3 (v / v)) to give the title compound of this step (150 mg, yield: 63.5%).

[0600] MS m / z(ESI): 307.0 [M+H] + .

[0601] Step 5: Preparation of (2-(2-cyanopropane-2-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0602] 2-(5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropionitrile (120 mg, 390.64 μmol), pinacol diborate (148.80 mg, 585.96 μmol), potassium acetate (114.85 mg, 1.17 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (28.35 mg, 39.06 μmol) were dissolved in 1,4-dioxane (6 mL) and reacted at 95 °C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give the crude title compound of this step (100 mg, yield: 94.1%).

[0603] MS m / z(ESI): 273.2 [M+H]+ .

[0604] Preparation Example 17: Preparation of (6,6-dimethyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)boronic acid (Int16)

[0605] Step 1: Preparation of N-(6-bromo-2-fluoropyridin-3-yl)-3,3-dimethylpiperidine-2-imine

[0606] 6-Bromo-2-fluoropyridin-3-amine (650 mg, 3.40 mmol) was dissolved in toluene (12 mL), and 3,3-dimethylpiperidin-2-one (866 mg, 6.81 mmol), triethylamine (517 mg, 5.10 mmol), and phosphorus oxychloride (783 mg, 5.10 mmol) were added. The mixture was reacted at 120 °C for 3 hours. After cooling to room temperature, the crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 9 / 1 (v / v)) to give the title compound of this step (1 g, yield: 97.9%).

[0607] MS m / z(ESI): 300.1 [M+H] + .

[0608] Step 2: Preparation of 2-bromo-6,6-dimethyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridine

[0609] N-(6-bromo-2-fluoropyridin-3-yl)-3,3-dimethylpiperidin-2-imine (300 mg, 999 μmol) and potassium tert-butoxide (280 mg, 2.50 mmol) were added to N-methylpyrrolidone (9 mL), and the mixture was microwaved at 200 °C for 2 hours. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 97 / 3 (v / v)) to give the title compound of this step (130 mg, yield: 44.1%).

[0610] MS m / z(ESI): 281.9 [M+H] + .

[0611] Step 3: Preparation of (6,6-dimethyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)boronic acid

[0612] 2-Bromo-6,6-dimethyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridine (50 mg, 178.47 μmol), pinacol diborate (135.96 mg, 535.40 μmol), potassium acetate (52.55 mg, 535.40 μmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (43.69 mg, 53.54 μmol) were dissolved in 1,4-dioxane (3 mL), and the mixture was microwaved at 100 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to give the crude title compound of this step (41 mg, yield: 93.4%).

[0613] MS m / z(ESI): 246.1 [M+H] + .

[0614] Preparation Example 18: Preparation of (2-(2-hydroxypropyl-2-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int17)

[0615] Step 1: Preparation of 6-bromo-N-isopropyl-3-nitropyridine-2-amine

[0616] 2,6-Dibromo-3-nitropyridine (3.5 g, 12.42 mmol), isopropylamine (807.31 mg, 13.66 mmol), and N,N-diisopropylethylamine (4.81 g, 37.25 mmol) were added to tetrahydrofuran (20 mL) and reacted at room temperature for 20 hours. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration of the filtrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound of this step (3 g, yield: 92.9%).

[0617] MS m / z(ESI): 260.1 [M+H] + .

[0618] Step 2: 6-Bromo-N 2 Preparation of -isopropylpyridine-2,3-diamine

[0619] 6-Bromo-N-isopropyl-3-nitropyridine-2-amine (3 g, 11.53 mmol) was dissolved in tetrahydrofuran (20 mL) and acetic acid (5 mL), cooled in an ice-water bath, and zinc powder (3.02 g, 46.14 mmol) was added. The reaction mixture was reacted at 60 °C for 1 hour. The reaction solution was filtered, the filtrate was concentrated, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration of the filtrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 2 (v / v)) to give the title compound of this step (2.2 g, yield: 82.9%).

[0620] MS m / z(ESI): 230.1 [M+H] + .

[0621] Step 3: Preparation of 5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridine

[0622] 6-bromo-N 2 Isopropylpyridine-2,3-diamine (600 mg, 2.61 mmol), p-toluenesulfonic acid (224.51 mg, 1.30 mmol), and triethyl orthoformate (5.80 g, 39.11 mmol) were added to tetrahydrofuran (6 mL) and reacted at 100 °C for 2 h. The crude product obtained by concentration was purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 55%-60%) to give the title compound of this step (620 mg, yield: 99.0%).

[0623] MS m / z(ESI): 240.1 [M+H] + .

[0624] Step 4: Preparation of 2-(5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)prop-2-ol

[0625] 5-Bromo-3-isopropyl-3H-imidazo[4,5-b]pyridine (180 mg, 749.69 μmol) was dissolved in anhydrous tetrahydrofuran (6 mL), purged with nitrogen, cooled to -70 °C, and diisopropylaminolithium (2 M, 562.27 μL) was added dropwise. The reaction was carried out at -70 °C for 30 min, followed by the addition of acetone (65.31 mg, 1.12 mmol) and the reaction was carried out at 0 °C for 2 h. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound of this step (112 mg, yield: 50.1%).

[0626] MS m / z(ESI): 298.1 [M+H]+ .

[0627] Step 5: Preparation of (2-(2-hydroxypropyl-2-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0628] 2-(5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)prop-2-ol (85 mg, 285.06 μmol), pinacol diborate (108.6 mg, 427.60 μmol), potassium acetate (96.04 mg, 0.981 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (28.35 mg, 39.06 μmol) were dissolved in 1,4-dioxane (6 mL) and reacted at 95 °C for 4 hours. The reaction solution was filtered, and the filtrate was concentrated to give the crude title compound of this step (70 mg, yield: 93.3%).

[0629] MS m / z(ESI): 264.2 [M+H] + .

[0630] Preparation Example 19: Preparation of (3-isopropyl-2-(2-methoxypropyl-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int18)

[0631] Step 1: Preparation of 5-bromo-3-isopropyl-2-(2-methoxypropyl-2-yl)-3H-imidazo[4,5-b]pyridine

[0632] 2-(5-bromo-3-isopropyl-imidazolium[4,5-b]pyridin-2-yl)prop-2-ol (150 mg, 503 μmol) was dissolved in N,N-dimethylformamide (4 mL), cooled to 0 °C, and sodium hydride (24.2 mg, 603 μmol) was added. After stirring for 30 minutes, iodomethane (71.4 mg, 503 μmol) was slowly added, and the reaction was carried out at room temperature for 2 hours. The crude product obtained by concentration of the reaction solution was purified by reverse-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-80%) to give the title compound of this step (85 mg, yield: 51.4%).

[0633] MS m / z(ESI): 312.0 [M+H] + .

[0634] Step 2: Preparation of (3-isopropyl-2-(2-methoxypropyl-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0635] 5-Bromo-3-isopropyl-2-(2-methoxypropyl-2-yl)-3H-imidazo[4,5-b]pyridine (85.0 mg, 272 μmol), pinacol diborate (117.5 mg, 463 μmol), potassium acetate (80.0 mg, 817 μmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (22.2 mg, 27.2 μmol) were added to anhydrous 1,4-dioxane (5 mL), and the mixture was purged with nitrogen and reacted at 100 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude title compound of this step (71 mg, yield: 94.3%).

[0636] MS m / z(ESI): 278.2 [M+H] + .

[0637] Preparation Example 20: Preparation of (2-(2-ethoxypropyl-2-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int19)

[0638] Following the synthetic method for compound Int18, iodomethane was replaced with iodoethane to obtain the crude product of the title compound (71 mg).

[0639] MS m / z(ESI): 292.2 [M+H] + .

[0640] Preparation Example 21: Preparation of (3-isopropyl-2-(2-(methoxy-d3)propyl-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int20)

[0641] Following the synthetic method of compound Int18, iodomethane was replaced with deuterated iodomethane to obtain the crude product of the title compound (130 mg).

[0642] MS m / z(ESI): 281.2 [M+H] + .

[0643] Preparation Example 22: Preparation of (3-isopropyl-2-morpholino-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int21)

[0644] Step 1: Preparation of 2,5-dibromo-3-isopropyl-3H-imidazo[4,5-b]pyridine

[0645] 5-Bromo-3-isopropyl-imidazo[4,5-b]pyridine (600 mg, 2.5 mmol), N-bromosuccinimide (667 mg, 3.75 mmol), and azobisisobutyronitrile (123 mg, 0.75 mmol) were dissolved in 1,2-dichloroethane (4 mL) and reacted at 60 °C for 8 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 (v / v)) to give the title compound of this step (700 mg, yield: 83.4%).

[0646] MS m / z (ESI): 319.9 [M+H] + .

[0647] Step 2: Preparation of 4-(5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)morpholine

[0648] 2,5-Dibromo-3-isopropyl-3H-imidazo[4,5-b]pyridine (150 mg, 470 μmol) was added to morpholine (5 mL), and the reaction was carried out at 100 °C for 3 hours. The crude product obtained by concentration of the reaction solution was purified by reverse-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 10%-50%) to give the title compound of this step (80.0 mg, yield: 52.3%).

[0649] MS m / z (ESI): 327.1 [M+H] + .

[0650] Step 3: Preparation of (3-isopropyl-2-morpholino-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0651] 4-(5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)morpholine (70 mg, 215 μmol), pinacol diborate (93.0 mg, 366 μmol), potassium acetate (63.3 mg, 645 μmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (17.6 mg, 21.5 μmol) were added to anhydrous 1,4-dioxane (5 mL), and the mixture was purged with nitrogen and reacted at 100 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the crude title compound of this step (60.0 mg, yield: 91.3%).

[0652] MS m / z(ESI): 291.2 [M+H] + .

[0653] Preparation Example 23: Preparation of (3-isopropyl-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int22)

[0654] Following the synthetic method of compound Int21, morpholine was replaced with tetrahydropyrrole to obtain the crude product of the title compound (60 mg).

[0655] MS m / z(ESI): 275.2 [M+H] + .

[0656] Preparation Example 24: Preparation of 1-((methoxy-d3)methyl)cyclopropyl-1-amine (Int23)

[0657] Step 1: Preparation of tert-butyl (1-((methoxy-d3)methyl)cyclopropyl)carbamate

[0658] 1 g (5.34 mmol) of tert-butyl (1-hydroxymethylcyclopropyl)carbamate was dissolved in 10 mL of N,N-dimethylformamide. The solution was cooled to 0 °C, and sodium hydride (256 mg, 6.41 mmol) was added. After stirring for 30 minutes, deuterated iodomethane (851 mg, 5.87 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was poured into a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound of this step (1 g, yield: 87.1%).

[0659] MS m / z(ESI): 205.1 [M+H] + .

[0660] Step 2: Preparation of 1-((methoxy-d3)methyl)cyclopropyl-1-amine

[0661] 1 g (4.90 mmol) of tert-butyl (1-((methoxy-d3)methyl)cyclopropyl)carbamate was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 8 mL) and reacted at room temperature for 2 hours. The reaction solution was then concentrated to give the title compound of this step (500 mg, yield: 93.2%).

[0662] MS m / z (ESI): 105.1 [M+H] + .

[0663] Preparation Example 25: Preparation of (2-(2-hydroxypropyl-2-yl)-3-(1-((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int24)

[0664] Step 1: Preparation of 6-bromo-N-(1-((methoxy-d3)methyl)cyclopropyl)-3-nitropyridine-2-amine

[0665] 2,6-Dibromo-3-nitropyridine (1.35 g, 4.80 mmol), 1-((methoxy-d3)methyl)cyclopropyl-1-amine (500 mg, 4.80 mmol), and N,N-diisopropylethylamine (3.10 g, 24.0 mmol) were added to anhydrous tetrahydrofuran (10 mL), and the mixture was reacted at room temperature for 24 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to give the title compound of this step (700 mg, yield: 47.8%).

[0666] MS m / z (ESI): 305.1 [M+H] + .

[0667] Step 2: 6-Bromo-N 2 Preparation of 1-((methoxy-d3)methyl)cyclopropyl)pyridine-2,3-diamine

[0668] 6-Bromo-N-(1-((methoxy-d3)methyl)cyclopropyl)-3-nitropyridine-2-amine (700 mg, 2.29 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and acetic acid (1 mL), and zinc powder (600 mg, 9.18 mmol) was slowly added. The reaction mixture was reacted at 60 °C for 2 hours. The reaction solution was filtered through diatomaceous earth, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound of this step (450 mg, yield: 67.7%).

[0669] MS m / z(ESI): 275.0 [M+H] + .

[0670] Step 3: Preparation of 5-bromo-3-(1-((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridine

[0671] 6-bromo-N 2 -(1-((methoxy-d3)methyl)cyclopropyl)pyridine-2,3-diamine (450 mg, 1.64 mmol), triethyl orthoformate (3.64 g, 24.53 mmol), and p-toluenesulfonic acid (141 mg, 818 μmol) were added to anhydrous tetrahydrofuran (8 mL), and the reaction was carried out at 100 °C for 2 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 4 (v / v)) to give the title compound of this step (380 mg, yield: 77.4%).

[0672] MS m / z (ESI): 285.3 [M+H] + .

[0673] Step 4: Preparation of 2-(5-bromo-3-(1-(((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-2-yl)prop-2-ol

[0674] 5-Bromo-3-(1-((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridine (380 mg, 1.33 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to -78 °C, and diisopropylaminolithium (2 M, 1.33 mL) was slowly added. After stirring for 30 minutes, acetone (124 mg, 2.13 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution, and the crude product obtained by concentration was purified by reverse-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 10%-60%) to give the title compound of this step (270 mg, yield: 56.0%).

[0675] MS m / z(ESI): 343.3 [M+H] + .

[0676] Step 5: Preparation of (2-(2-hydroxypropyl-2-yl)-3-(1-((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0677] 2-(5-bromo-3-(1-((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-2-yl)prop-2-ol (100 mg, 291 μmol), pinacol diboronate (126 mg, 495 μmol), potassium acetate (85.7 mg, 874 μmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (23.8 mg, 29.1 μmol) were dissolved in 1,4-dioxane (3 mL), the mixture was purged with nitrogen, and the reaction was carried out at 100 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product of the title compound of this step (90 mg, yield: 95.2%).

[0678] MS m / z(ESI): 309.3 [M+H] + .

[0679] Preparation Example 26: Preparation of (3-isopropyl-2-((1-methoxycyclopentyl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int25)

[0680] Step 1: Preparation of 5-bromo-3-isopropyl-2-methyl-imidazo[4,5-b]pyridine

[0681] 6-bromo-N 2- Isopropylpyridine-2,3-diamine (1 g, 4.35 mmol) was added to acetic acid (5 mL) and reacted at 130 °C for 24 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 4 (v / v)) to give the title compound of this step (800 mg, yield: 68.8%).

[0682] MS m / z (ESI): 254.3 [M+H] + .

[0683] Step 2: Preparation of 1-((5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl)cyclopentan-1-ol

[0684] 5-Bromo-3-isopropyl-2-methylimidazo[4,5-b]pyridine (685 mg, 2.70 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to -40 °C, and diisopropylaminolithium (2 M, 2.70 mL) was added dropwise. After stirring for 30 minutes, cyclopentanone (340 mg, 4.04 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was poured into a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3 (v / v)) to give the title compound of this step (900 mg, yield: 93.8%).

[0685] MS m / z (ESI): 338.1 [M+H] + .

[0686] Step 3: Preparation of 5-bromo-3-isopropyl-2-((1-methoxycyclopentyl)methyl)-3H-imidazo[4,5-b]pyridine

[0687] 1-((5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl)cyclopentan-1-ol (100 mg, 296 μmol) was dissolved in N,N-dimethylformamide (4 mL), and 18-crown ether-6 (15.6 mg, 59.1 μmol) and iodomethane (210 mg, 1.48 mmol) were added. The mixture was cooled to 0–5 °C in an ice-water bath, and sodium hydride (59.1 mg, 1.48 mmol) was added in portions. The reaction mixture was reacted at 0 °C for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 2 (v / v)) to give the title compound of this step (65.0 mg, yield: 59.3%).

[0688] MS m / z (ESI): 352.1 [M+H] + .

[0689] Step 4: Preparation of (3-isopropyl-2-((1-methoxycyclopentyl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0690] 5-Bromo-3-isopropyl-2-((1-methoxycyclopentyl)methyl)-3H-imidazo[4,5-b]pyridine (55 mg, 156 μmol), pinacol diboronate (67.4 mg, 265 μmol), potassium acetate (45.9 mg, 468 μmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (12.8 mg, 15.6 μmol) were dissolved in 1,4-dioxane (2 mL), the mixture was purged with nitrogen, and the reaction was carried out at 100 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product of the title compound of this step (48 mg, yield: 92.1%).

[0691] MS m / z (ESI): 318.2 [M+H] + .

[0692] Preparation Example 27: Preparation of (1-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid (Int26)

[0693] Step 1: Preparation of 6-chloro-1-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine

[0694] 6-Chloro-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine (100 mg, 449 μmol), copper acetate (24.4 mg, 134 μmol), and cyclopropylboronic acid (115 mg, 1.35 mmol) were added to pyridine (4 mL), and the mixture was purged with oxygen at 80 °C for 12 hours. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound of this step (100 mg, yield: 84.9%).

[0695] MS m / z(ESI): 263.1 [M+H] + .

[0696] Step 2: Preparation of (1-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid

[0697] 6-Chloro-1-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine (60 mg, 228.36 μmol) and pinacol diboronate (115.98 mg, 456.73 μmol) were dissolved in 1,4-dioxane (4 mL). Tris(dibenzylideneacetone)dipalladium (41.82 mg, 45.67 μmol), tricyclohexylphosphine (38.42 mg, 137.02 μmol), and potassium acetate (44.82 mg, 456.73 μmol) were added. The mixture was purged with nitrogen and microwaved at 130 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product of the title compound (50 mg, yield: 80.5%).

[0698] MS m / z(ESI): 273.1 [M+H] + .

[0699] Preparation Example 28: Preparation of (3,3-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid (Int27)

[0700] Step 1: Preparation of 6-chloro-3,3-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine

[0701] 6-Chloro-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine (750 mg, 3.37 mmol) was dissolved in N,N-dimethylformamide (15 mL), and cesium carbonate (3.29 g, 10.10 mmol) and 4-iodotetrahydro-2H-pyran (1.43 g, 6.74 mmol) were added. The reaction mixture was reacted at 120 °C for 2 hours. The reaction solution was concentrated, and the crude product was purified by high performance liquid chromatography to give the title compound of this step (80.2 mg, yield: 7.7%).

[0702] MS m / z (ESI): 306.9 [M+H] + .

[0703] Step 2: Preparation of (3,3-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid

[0704] 6-Chloro-3,3-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine (50 mg, 162.98 μmol) and pinacol diboronate (124.16 mg, 488.93 μmol) were dissolved in 1,4-dioxane (4 mL). Tris(dibenzylideneacetone)dipalladium (29.85 mg, 32.60 μmol), tricyclohexylphosphine (27.42 mg, 97.79 μmol), and potassium acetate (31.99 mg, 325.96 μmol) were added. The mixture was purged with nitrogen and microwaved at 130 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product of the title compound (50 mg, yield: 92.2%).

[0705] MS m / z (ESI): 317.2 [M+H] + .

[0706] Preparation Example 29: Preparation of (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid (Int28)

[0707] Step 1: Preparation of 2-(5-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropyl 1H-imidazo-1-carboxylate

[0708] 2-((3-amino-6-chloropyridin-2-yl)amino)-2-methylprop-1-ol (600 mg, 2.78 mmol) and N,N'-carbonyldiimidazole (1.60 g, 11.13 mmol) were dissolved in anhydrous tetrahydrofuran (6 mL) and reacted at 60 °C for 24 hours. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3 (v / v)) to give the title compound of this step (0.93 g, yield: 99.6%).

[0709] MS m / z (ESI): 336.1 [M+H] + .

[0710] Step 2: Preparation of 5-chloro-3-(1-hydroxy-2-methylpropyl-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0711] 2-(5-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropyl 1H-imidazo-1-carboxylate (900 mg, 2.68 mmol) was dissolved in concentrated hydrochloric acid (4 mL) and tetrahydrofuran (10 mL) and reacted at 60 °C for 2 hours. The reaction solution was concentrated, diluted with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound of this step (630 mg, yield: 97.3%).

[0712] MS m / z(ESI): 242.1 [M+H] + .

[0713] Step 3: Preparation of 2-(5-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropanal

[0714] Oxaloyl chloride (689.06 mg, 5.43 mmol) was dissolved in anhydrous dichloromethane (15 mL), cooled to -78 °C, and dimethyl sulfoxide (848.31 mg, 10.86 mmol) was slowly added dropwise. The reaction was allowed to proceed for 0.5 h. Then, 5-chloro-3-(1-hydroxy-2-methylpropyl-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (656 mg, 2.71 mmol) was added, and the reaction was allowed to proceed for 2 h at -78 °C. Finally, triethylamine (2.20 g, 21.72 mmol) was added, and the reaction was allowed to proceed for 0.5 h at -78 °C. The reaction was then allowed to proceed for 0.5 h at room temperature. The reaction solution was diluted with water, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 3 (volume ratio)) to give the title compound of this step (350 mg, yield: 53.8%).

[0715] MS m / z(ESI): 240.0 [M+H] + .

[0716] Step 4: Preparation of 1-((2-(5-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropyl)amino)cyclopropane-1-nitrile)

[0717] 2-(5-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionaldehyde (150 mg, 625.89 μmol) and 1-aminocyclopropionitrile (185.52 mg, 1.56 mmol) were dissolved in dichloromethane (4 mL) and methanol (1 mL), and acetic acid (55.13 mg, 917.98 μmol) was added. The reaction was carried out at room temperature for 0.5 h, and sodium cyanoborohydride (57.69 mg, 917.98 μmol) was added. The reaction was carried out at room temperature for 4 h. The reaction solution was quenched with saturated ammonium chloride solution, and the crude product obtained by concentration was dissolved in methanol and purified by reverse-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 35%-40%) to obtain the title compound of this step (70 mg, yield: 36.6%).

[0718] MS m / z(ESI): 306.0 [M+H] + .

[0719] Step 5: Preparation of 1-(6-chloro-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-1-yl)cyclopropionitrile

[0720] 1-((2-(5-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropyl)amino)cyclopropion-1-onitrile (70 mg, 228.94 μmol) was added to phosphorus oxychloride (4 mL) and concentrated hydrochloric acid (0.04 mL), and reacted at 100 °C for 4 hours. The reaction solution was concentrated, cooled in an ice-water bath, and the pH was adjusted to neutral by adding sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2 (v / v)) to give the title compound of this step (50 mg, yield: 75.9%).

[0721] MS m / z(ESI): 288.1 [M+H] + .

[0722] Step 6: Preparation of (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid

[0723] 1-(6-chloro-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-1-yl)cyclopropion-1-onitrile (50 mg, 173.76 μmol) and pinacol diboronate (88.25 mg, 347.53 μmol) were dissolved in 1,4-dioxane (5 mL). Tricyclohexylphosphine (29.24 mg, 104.26 μmol), potassium acetate (34.11 mg, 347.53 μmol), and tris(dibenzylacetone)palladium (31.82 mg, 34.75 μmol) were added. The mixture was purged with nitrogen and microwaved at 130 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude title compound (50 mg, yield: 96.9%).

[0724] MS m / z(ESI): 298.1 [M+H] + .

[0725] Preparation Example 30: Preparation of (3-(1-((methoxy-d3)methyl)cyclopropyl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int29)

[0726] Step 1: Preparation of 2,5-dibromo-3-(1-((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridine

[0727] 5-Bromo-3-(1-((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridine (190 mg, 666.31 μmol), azobisisobutyronitrile (10.20 mg, 66.63 μmol), and N-bromosuccinimide (177.88 mg, 999.46 μmol) were dissolved in 1,2-dichloroethane (5 mL) and reacted at 70 °C for 18 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 (v / v)) to give the title compound of this step (130 mg, yield: 53.6%).

[0728] MS m / z(ESI): 363.1 [M+H] + .

[0729] Step 2: Preparation of 5-bromo-3-(1-((methoxy-d3)methyl)cyclopropyl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridine

[0730] 2,5-Dibromo-3-(1-((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridine (100 mg, 312.89 μmol) was added to tetrahydropyrrole (3 mL), and the reaction was carried out at 70 °C for 3 hours. The reaction solution was concentrated, and the crude product was purified by reverse-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 45%-50%) to give the title compound of this step (100 mg, yield: 90.2%).

[0731] MS m / z (ESI): 354.1 [M+H] + .

[0732] Step 3: Preparation of (3-(1-((methoxy-d3)methyl)cyclopropyl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0733] 5-Bromo-3-(1-((methoxy-d3)methyl)cyclopropyl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridine (90 mg, 254.05 μmol) and pinacol diboronate (129.03 mg, 508.10 μmol) were dissolved in 1,4-dioxane (4 mL), and potassium acetate (62.33 mg, 635.13 μmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (18.44 mg, 25.41 μmol) were added. The mixture was purged with nitrogen and reacted at 95 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the crude title compound of this step (70 mg, yield: 86.3%).

[0734] MS m / z (ESI): 320.1 [M+H] + .

[0735] Preparation Example 31: Preparation of (3-(1-((methoxy-d3)methyl)cyclopropyl)-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int30)

[0736] Following the synthetic method of compound Int29, tetrahydropyrrole was replaced with 2-oxa-6-azaspiro[3.3]heptane to obtain the crude product of the title compound (35 mg).

[0737] MS m / z (ESI): 348.2 [M+H] + .

[0738] Preparation Example 32: Preparation of (3-(1-cyanocyclopropyl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int31)

[0739] Step 1: Preparation of 1-((6-bromo-3-nitropyridin-2-yl)amino)cyclopropion-1-onitrile

[0740] 2,6-Dibromo-3-nitropyridine (1 g, 3.55 mmol) and 1-aminocyclopropionitrile hydrochloride (630.91 mg, 5.32 mmol) were dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (1.83 g, 14.19 mmol) was added. The reaction mixture was reacted at 44 °C for 16 hours. After cooling to room temperature, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 (v / v)) to give the title compound of this step (600 mg, yield: 60.0%).

[0741] MS m / z(ESI): 283.0 [M+H] + .

[0742] Step 2: Preparation of 1-((3-amino-6-bromopyridin-2-yl)amino)cyclopropion-1-onitrile

[0743] 1-((6-bromo-3-nitropyridin-2-yl)amino)cyclopropion-1-onitrile (600 mg, 2.12 mmol) and zinc powder (554.39 mg, 8.48 mmol) were added to tetrahydrofuran (6 mL) and acetic acid (3 mL), and reacted at 60 °C for 1 hour. The reaction solution was concentrated, and sodium bicarbonate aqueous solution was added. The mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration of the filtrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 (v / v)) to give the title compound of this step (375 mg, yield: 69.9%).

[0744] MS m / z(ESI): 253.0 [M+H] + .

[0745] Step 3: Preparation of 1-(5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropion-1-onitrile

[0746] 1-((3-amino-6-bromopyridin-2-yl)amino)cyclopropion-1-onitrile (375 mg, 1.48 mmol), triethyl orthoformate (3.29 g, 22.22 mmol), and p-toluenesulfonic acid (123.98 mg, 0.72 mmol) were added to tetrahydrofuran (10 mL) and reacted at 100 °C for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound of this step (198 mg, yield: 50.9%).

[0747] MS m / z(ESI): 263.1 [M+H] + .

[0748] Step 4: Preparation of 1-(5-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropion-1-onitrile

[0749] 1-(5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropion-1-onitrile (150 mg, 570.14 μmol) was dissolved in tetrahydrofuran (3 mL), cooled to -70 °C, purged with nitrogen, and diisopropylaminolithium (2 M, 1.14 mL) was added. The reaction was allowed to proceed for 0.5 h, and then a tetrahydrofuran solution of hexachloroethane (809.85 mg, 3.42 mmol) (3 mL) was added dropwise. The reaction was allowed to proceed for 1 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound of this step (110 mg, yield: 64.9%).

[0750] MS m / z(ESI): 297.0 [M+H] + .

[0751] Step 5: Preparation of 1-(5-bromo-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropion-1-onitrile

[0752] 1-(5-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropion-1-onitrile (105 mg, 352.90 μmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (136.82 mg, 1.06 mmol) and tetrahydropyrrole (125.49 mg, 1.76 mmol) were added. The mixture was reacted at 60 °C for 3 hours. The reaction solution was purified by high performance liquid chromatography to obtain the title compound of this step (53 mg, yield: 45.2%).

[0753] MS m / z(ESI): 332.1 [M+H] + .

[0754] Step 6: Preparation of (3-(1-cyanocyclopropyl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0755] 1-(5-bromo-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropion-1-onitrile (50 mg, 150.51 μmol) and pinacol diboronate (76.44 mg, 301.03 μmol) were dissolved in 1,4-dioxane (5 mL), potassium acetate (36.93 mg, 376.28 μmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12.29 mg, 15.05 μmol) were added, nitrogen was purged, and the reaction was carried out at 95 °C for 2 hours. The reaction solution was used directly for the next step of the reaction.

[0756] MS m / z(ESI): 298.1 [M+H] + .

[0757] Preparation Example 33: Preparation of (3-(1-cyanocyclopropyl)-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int32)

[0758] Following the synthetic method of compound Int31, tetrahydropyrrole was replaced with 2-oxa-6-azaspiro[3.3]heptane to obtain the title compound.

[0759] MS m / z(ESI): 326.1 [M+H] + .

[0760] Preparation Example 34: Preparation of 1-(methoxy-d3)-2-methylpropyl-2-amine (Int33)

[0761] Following the synthetic method of compound Int23, tert-butyl (1-hydroxymethylcyclopropyl)carbamate was replaced with tert-butyl (1-hydroxy-2-methylpropyl-2-yl)carbamate to obtain the title compound (500 mg).

[0762] MS m / z (ESI): 107.1 [M+H] + .

[0763] Preparation Example 35: Preparation of (3-(1-(methoxy-d3)-2-methylpropyl-2-yl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int34)

[0764] Following the synthetic method of compound Int31, 1-aminocyclopropionitrile hydrochloride was replaced with 1-(methoxy-d3)-2-methylprop-2-amine to obtain the title compound.

[0765] MS m / z(ESI): 322.2 [M+H] + .

[0766] Preparation Example 36: Preparation of (3-(2-cyanopropan-2-yl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int35)

[0767] Step 1: Preparation of 2-((6-bromo-3-nitropyridin-2-yl)amino)acetonitrile

[0768] 2,6-Dibromo-3-nitropyridine (2 g, 7.09 mmol), 2-aminoacetonitrile hydrochloride (853 mg, 9.22 mmol), and N,N-diisopropylethylamine (2.75 g, 21.3 mmol) were added to N,N-dimethylformamide (10 mL), and the mixture was reacted at room temperature for 16 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 (v / v)) to give the title compound of this step (1.23 g, yield: 63.8%).

[0769] MS m / z(ESI): 257.0 [M+H] + .

[0770] Step 2: Preparation of 2-((3-amino-6-bromopyridin-2-yl)amino)acetonitrile

[0771] 2-((6-bromo-3-nitropyridin-2-yl)amino)acetonitrile (900 mg, 3.50 mmol) was dissolved in tetrahydrofuran (10 mL) and acetic acid (2 mL), and zinc powder (916 mg, 14.0 mmol) was slowly added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound of this step (650 mg, yield: 77.7%).

[0772] MS m / z(ESI): 229.0 [M+H] +.

[0773] Step 3: Preparation of 2-(5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)acetonitrile

[0774] 2-((3-amino-6-bromopyridin-2-yl)amino)acetonitrile (650 mg, 2.86 mmol), triethyl orthoformate (4.24 g, 28.6 mmol), and p-toluenesulfonic acid (246 mg, 1.43 mmol) were added to tetrahydrofuran (8 mL) and reacted at 100 °C for 2 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 4 (v / v)) to give the title compound of this step (560 mg, yield: 77.0%).

[0775] MS m / z(ESI): 237.0 [M+H] + .

[0776] Step 4: Preparation of 2-(5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile

[0777] 2-(5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)acetonitrile (560 mg, 2.36 mmol), 18-crown ether-6 (624 mg, 2.36 mmol), and iodomethane (1.68 g, 11.8 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL), cooled to 0 °C, and sodium hydride (472 mg, 11.8 mmol) was added in portions. The reaction was carried out at 0 °C for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 5 (v / v)) to give the title compound of this step (550 mg, yield: 83.4%).

[0778] MS m / z(ESI): 265.0 [M+H] + .

[0779] Step 5: Preparation of 2-(5-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile

[0780] 2-(5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile (100 mg, 377 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), cooled to -78 °C, and diisopropylaminolithium (2 M, 565 μL) was added dropwise. The reaction was allowed to proceed for 30 minutes, followed by the addition of hexachloroethane (125 mg, 528 μmol), and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 (v / v)) to give the title compound of this step (80 mg, yield: 67.2%).

[0781] MS m / z(ESI): 299.0 [M+H] + .

[0782] Step 6: Preparation of 2-(5-bromo-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile

[0783] 2-(5-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile (80.0 mg, 267 μmol) was dissolved in tetrahydrofuran (4 mL), and N,N-diisopropylethylamine (103 mg, 801 μmol) and 2-oxa-6-azaspiro[3.3]heptane (53.0 mg, 534 μmol) were added. The reaction mixture was reacted at 60 °C for 2 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 10 (v / v)) to give the title compound of this step (80.0 mg, yield: 78.6%).

[0784] MS m / z(ESI): 362.1 [M+H] + .

[0785] Step 7: Preparation of (3-(2-cyanopropane-2-yl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0786] 2-(5-bromo-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile (80.0 mg, 221 μmol) and pinacol diboronate (95.3 mg, 376 μmol) were dissolved in 1,4-dioxane (5 mL), potassium acetate (65.0 mg, 662 μmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (18.0 mg, 22.1 μmol) were added, nitrogen was purged, and the reaction was carried out at 100 °C for 4 hours. The reaction solution was used directly for the next step of the reaction.

[0787] MS m / z(ESI): 328.1 [M+H] + .

[0788] Preparation Example 37: Preparation of (3-(2-cyanopropan-2-yl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int36)

[0789] Following the synthetic method of compound Int35, 2-oxa-6-azaspiro[3.3]heptane was replaced with tetrahydropyrrole to obtain the title compound.

[0790] MS m / z(ESI): 300.1 [M+H] + .

[0791] Preparation Example 38: Preparation of (3-isopropyl-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int37)

[0792] Following the synthetic method of compound Int21, morpholine was replaced with 2-oxa-6-azaspiro[3.3]heptane to obtain the title compound.

[0793] MS m / z (ESI): 303.1 [M+H] + .

[0794] Preparation Example 39: Preparation of (3-cyclopropyl-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int38)

[0795] Following the synthetic method of compound Int31, 1-aminocyclopropionitrile hydrochloride was replaced with cyclopropylamine, and tetrahydropyrrole was replaced with 2-oxa-6-azaspiro[3.3]heptane to obtain the title compound.

[0796] MS m / z (ESI): 301.1 [M+H] + .

[0797] Preparation Example 40: Preparation of (2-cyclopropyl-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Int39)

[0798] Step 1: Preparation of 5-bromo-2-iodo-3-isopropyl-3H-imidazo[4,5-b]pyridine

[0799] 5-Bromo-3-isopropyl-3H-imidazo[4,5-b]pyridine (313 mg, 1.30 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -78 °C, purged with nitrogen, and diisopropylaminolithium (2 M, 1.96 mL) was slowly added. The reaction was allowed to proceed for 30 minutes, followed by the addition of iodine (330.87 mg, 1.30 mmol) in tetrahydrofuran solution, and the reaction was allowed to proceed for 1 hour. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 (v / v)) to give the title compound of this step (360 mg, yield: 74.4%).

[0800] MS m / z (ESI): 365.9 [M+H] + .

[0801] Step 2: Preparation of 5-bromo-2-cyclopropyl-3-isopropyl-3H-imidazo[4,5-b]pyridine

[0802] 5-Bromo-2-iodo-3-isopropyl-3H-imidazo[4,5-b]pyridine (208 mg, 568.31 μmol), cyclopropylboronic acid (244.08 mg, 2.84 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (69.61 mg, 85.25 μmol), and potassium carbonate (392.14 mg, 2.84 mmol) were dissolved in dioxane (4 mL) and water (0.4 mL), purged with nitrogen, and reacted at 90 °C for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3 (v / v)) to give the title compound of this step (120 mg, yield: 75.3%).

[0803] MS m / z (ESI): 280.1 [M+H] + .

[0804] Step 3: Preparation of (2-cyclopropyl-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0805] 5-Bromo-2-cyclopropyl-3-isopropyl-3H-imidazo[4,5-b]pyridine (103 mg, 367.64 μmol) and pinacol diboronate (280.08 mg, 1.10 mmol) were dissolved in 1,4-dioxane (4 mL), potassium acetate (90.20 mg, 919.11 μmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (26.68 mg, 36.76 μmol) were added, nitrogen was purged, and the reaction was carried out at 100 °C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product of the title compound.

[0806] MS m / z(ESI): 246.1 [M+H] + .

[0807] Preparation Example 41: Preparation of 1-(6-aminopyridin-3-yl)-4-(2,2,2-trifluoroethyl)piperazin-2-one (Int40)

[0808] Step 1: Preparation of 1-(6-nitropyridin-3-yl)-4-(2,2,2-trifluoroethyl)piperazin-2-one

[0809] 1-(6-nitropyridin-3-yl)piperazin-2-one (500 mg, 1.93 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (897.32 mg, 3.87 mmol), and potassium carbonate (801.47 mg, 5.80 mmol) were added to acetonitrile (20 mL) and reacted at 70 °C for 2 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 9 / 1 (v / v)) to give the title compound of this step (500 mg, yield: 80.8%).

[0810] MS m / z (ESI): 305.1 [M+H] + .

[0811] Step 2: Preparation of 1-(6-aminopyridin-3-yl)-4-(2,2,2-trifluoroethyl)piperazin-2-one

[0812] 1-(6-nitropyridin-3-yl)-4-(2,2,2-trifluoroethyl)piperazin-2-one (500 mg, 1.64 mmol) was dissolved in methanol (20 mL), 10% palladium on carbon (170 mg) was added, hydrogen was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to give the title compound (400 mg, yield: 84.3%).

[0813] MS m / z(ESI): 275.1 [M+H] + .

[0814] Preparation Example 42: Preparation of 1-(6-aminopyridin-3-yl)-4-cyclopropylpiperazin-2-one (Int41)

[0815] Step 1: Preparation of 4-cyclopropyl-1-(6-nitropyridin-3-yl)piperazin-2-one

[0816] 1-(6-nitropyridin-3-yl)piperazin-2-one (1.2 g, 5.40 mmol), cyclopropylboronic acid (1.39 g, 16.20 mmol), copper acetate (980.92 mg, 5.40 mmol), 2,2-bipyridine (843.46 mg, 5.40 mmol), and sodium carbonate (1.43 g, 13.50 mmol) were added to 30 mL of 1,2-dichloroethane and reacted at 70 °C for 6 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 9 / 1 (v / v)) to give the title compound of this step (700 mg, yield: 46.9%).

[0817] MS m / z(ESI): 263.2 [M+H] + .

[0818] Step 2: Preparation of 1-(6-aminopyridin-3-yl)-4-cyclopropylpiperazin-2-one

[0819] 4-Cyclopropyl-1-(6-nitropyridin-3-yl)piperazin-2-one (700 mg, 2.67 mmol) was dissolved in methanol (20 mL), 10% palladium on carbon (280 mg) was added, hydrogen was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to give the title compound (500 mg, yield: 76.6%).

[0820] MS m / z(ESI): 233.1 [M+H] + .

[0821] Preparation Example 43: Preparation of 1-(5-aminopyrazin-2-yl)-4-methylpiperazin-2-one (Int42)

[0822] 5-Bromopyrazin-2-amine (100 mg, 574.72 μmol) and 4-methylpiperazin-2-one (131 mg, 1.15 mmol) were dissolved in 1,4-dioxane (8 mL), and cesium carbonate (562 mg, 1.72 mmol), cuprous iodide (109 mg, 574.72 μmol), and N were added.1 N 2 -Dimethylethane-1,2-diamine (101.32 mg, 1.15 mmol) was reacted by microwave heating at 115 °C for 2 hours. The reaction solution was filtered, and the crude product obtained by concentration of the filtrate was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 5 / 1 (v / v)) to give the title compound (105 mg, yield: 88.2%).

[0823] MS m / z(ESI): 208.2 [M+H] + .

[0824] Preparation Example 44: Preparation of 1-(6-amino-5-fluoropyridin-3-yl)-4-methylpiperazin-2-one (Int43)

[0825] Step 1: Preparation of 3-fluoro-5-iodopyridine-2-amine

[0826] 3-Fluoropyridine-2-amine (250 mg, 2.23 mmol) and N-iodosuccinimide (752.58 mg, 3.35 mmol) were dissolved in N,N-dimethylformamide (5 mL) and reacted at room temperature for 3 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 2 (v / v)) to give the title compound of this step (458 mg, yield: 86.3%).

[0827] MS m / z(ESI): 238.9 [M+H] + .

[0828] Step 2: Preparation of 1-(6-amino-5-fluoropyridin-3-yl)-4-methylpiperazin-2-one

[0829] 3-Fluoro-5-iodopyridin-2-amine (200 mg, 840.33 μmol) and 4-methylpiperazin-2-one (191.84 mg, 1.68 mmol) were dissolved in 1,4-dioxane (10 mL), and cesium carbonate (821.39 mg, 2.25 mmol), cuprous iodide (160.04 mg, 840.33 μmol), and N were added. 1 N 2 -Dimethylethane-1,2-diamine (148.15 mg, 1.68 mmol) was reacted by microwave heating at 105 °C for 6 hours. The reaction solution was filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 5 / 1 (v / v)) to give the title compound (160 mg, yield: 84.9%).

[0830] MS m / z (ESI): 225.1 [M+H] + .

[0831] Preparation Example 45: Preparation of 1-(6-amino-4-fluoropyridin-3-yl)-4-methylpiperazin-2-one (Int44)

[0832] Step 1: Preparation of 4-fluoro-5-iodopyridine-2-amine

[0833] 4-Fluoropyridine-2-amine (250 mg, 2.23 mmol) and N-iodosuccinimide (752.58 mg, 3.35 mmol) were dissolved in N,N-dimethylformamide (5 mL) and reacted at room temperature for 3 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 2 (v / v)) to give the title compound of this step (220 mg, yield: 41.5%).

[0834] MS m / z(ESI): 238.9 [M+H] + .

[0835] Step 2: Preparation of 1-(6-amino-4-fluoropyridin-3-yl)-4-methylpiperazin-2-one

[0836] 4-Fluoro-5-iodopyridin-2-amine (200 mg, 840.33 μmol) and 4-methylpiperazin-2-one (191.84 mg, 1.68 mmol) were dissolved in 1,4-dioxane (10 mL), and cesium carbonate (821.39 mg, 2.25 mmol), cuprous iodide (160.04 mg, 840.33 μmol), and N were added. 1 N 2 -Dimethylethane-1,2-diamine (148.15 mg, 1.68 mmol) was reacted by microwave heating at 105 °C for 6 hours. The reaction solution was filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 5 / 1 (v / v)) to give the title compound (100 mg, yield: 58.8%).

[0837] MS m / z (ESI): 225.1 [M+H] + .

[0838] Example 1: Preparation of 4-(dimethylamino)-1-(6-((6-(3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (compound C-1)

[0839] Step 1: Preparation of 5-(6-chloropyrimidin-4-yl)-3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridine

[0840] (3-Isopropyl-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (52 mg, 237.39 μmol) and 4,6-dichloropyrimidine (106.10 mg, 712.17 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (19.37 mg, 23.74 μmol) and sodium carbonate (75.48 mg, 712.17 μmol) were added. The mixture was purged with nitrogen and reacted at 110 °C for 3 hours. The crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 (v / v)) to give the title compound of this step (50 mg, yield: 65.9%).

[0841] MS m / z(ESI): 288.0 [M+H] + .

[0842] Step 2: Preparation of 4-(dimethylamino)-1-(6-((6-(3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one

[0843] 5-(6-chloropyrimidin-4-yl)-3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridine (45 mg, 156.39 μmol) and 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (43.97 mg, 187.66 μmol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (14 mL) was added. 32 mg (15.64 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (7.30 mg (15.64 μmol)) and cesium carbonate (101.91 mg (312.77 μmol) were added, and the mixture was purged with nitrogen at 110 °C for 2 hours. The reaction solution was then purified directly by high performance liquid chromatography to obtain the title compound of this step (28 mg, yield: 35.0%).

[0844] MS m / z (ESI): 486.2 [M+H] + .

[0845] 1H NMR (400MHz, DMSO-d6): δ10.51(s,1H),8.81(s,1H),8.75(s,1H),8.27(d,J=8.0Hz,1H),8.2 3(d,J=4.0Hz,1H),8.03(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.71(dd,J=8.0,4.0Hz,1H) ,4.87-4.80(m,1H),3.69-3.61(m,2H),2.74-2.68(m,1H),2.66(s,3H),2.60-2.54(m,1H),2 .46-2.39(m,1H),2.23(s,6H),2.11-2.08(m,1H),1.86-1.80(m,1H),1.78(d,J=8.0Hz,6H).

[0846] Example 2: Preparation of 1-(6-((6-(1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (compound C-4)

[0847] Step 1: Preparation of 7-(6-chloropyrimidin-4-yl)-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

[0848] 1,1-Dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (40 mg, 128.12 μmol), 4,6-dichloropyrimidine (114.52 mg, 768.71 μmol), potassium carbonate (89.43 mg, 640.59 μmol) and [1, 1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (10.46 mg, 12.81 μmol) was added to 1,4-dioxane (3 mL) and water (0.5 mL), purged with nitrogen, and reacted at 105 °C for 24 hours. The residue obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound of this step (27 mg, yield: 70.5%).

[0849] MS m / z(ESI): 299.2 [M+H] + .

[0850] Step 2: Preparation of 1-(6-((6-(1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one

[0851] The following ingredients were added: 7-(6-chloropyrimidin-4-yl)-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (27 mg, 90.37 μmol), 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (31.76 mg, 108.44 μmol), tris(dibenzylideneacetone)dipalladium (8.28 mg, 9.04 μmol), and 4,5-bisdiphenylphosphine. -9,9-Dimethyloxanthracene (5.23 mg, 9.04 μmol) and cesium carbonate (88.33 mg, 271.11 μmol) were added to 1,4-dioxane (3 mL), purged with nitrogen, and reacted at 110 °C for 5 hours. The residue obtained by concentration of the reaction solution was purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 5%-45%) to give the title compound of this step (9.2 mg, yield: 19.6%).

[0852] MS m / z (ESI): 497.2 [M+H] + .

[0853] 1 H NMR (400MHz, DMSO-d6): δ10.27(s,1H),8.80(s,1H),8.28(d,J=4.0Hz,2H),8.16 (s,1H),7.94(d,J=8.0Hz,1H),7.83(dd,J=8.0,4.0Hz,1H),7.74-7.66(m,2H),3. 67-3.59(m,2H),3.06(t,J=8.0Hz,2H),2.72-2.65(m,1H),2.61-2.52(m,3H),2. 45-2.37(m,1H),2.22(s,6H),2.14-2.06(m,1H),1.85-1.76(m,1H),1.66(s,6H).

[0854] Example 3: Preparation of 1-(6-((6-(1,1-dimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (compound C-6)

[0855] Following the synthetic method for compound C-4, 1,1-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium was replaced with 1,1-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine to obtain the title compound (4.2 mg).

[0856] MS m / z (ESI): 511.2 [M+H] + .

[0857] 1 H NMR (400MHz, DMSO-d6): δ10.27(s,1H),8.81(s,1H),8.41(d,J=4.0Hz,1H),8.27(d,J=4.0Hz,1 H),8.16(s,1H),7.96(d,J=8.0Hz,1H),7.84(dd,J=8.0,4.0Hz,1H),7.71(dd,J=8.0,4.0Hz,1H) ,7.65(d,J=8.0Hz,1H),3.68-3.61(m,2H),2.97(t,J=8.0Hz,2H),2.73-2.67(m,1H),2.63-2.54 (m,1H),2.42(d,J=8.0Hz,1H),2.23(s,6H),2.15-2.02(m,4H),1.95-1.89(m,2H),1.72(s,6H).

[0858] Example 4: Preparation of (S)-1-(6-((6-(8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (Compound C-5B)

[0859] Step 1: Preparation of 2-(6-chloropyrimidin-4-yl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine

[0860] (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid (41.0 mg, 178 μmol), 4,6-dichloropyrimidine (159 mg, 1.07 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (14.6 mg, 17.8 μmol), and potassium carbonate (124 mg, 891 μmol) were added to a mixed solution of 1,4-dioxane (4 mL) and water (0.5 mL), purged with nitrogen, and reacted at 110 °C for 24 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 (v / v)) to give the title compound of this step (40.0 mg, yield: 74.9%).

[0861] MS m / z(ESI): 300.2 [M+H] + .

[0862] Step 2: Preparation of (S)-1-(6-((6-(8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one

[0863] 2-(6-chloropyrimidin-4-yl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine (40.0 mg, 133 μmol), (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (37.5 mg, 160 μmol), tris(dibenzylideneacetone)dipalladium (12.2 mg, 13.3 μmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (7.7 mg, 13.3 μmol) and cesium carbonate (130 mg, 400 μmol) were added to anhydrous 1,4-dioxane (3 mL), purged with nitrogen, and reacted at 110 °C for 5 hours. The reaction solution was concentrated, and the crude product was purified by reversed-phase column chromatography (preparation method A, elution gradient: A% = 10%-25%) to obtain the title compound of this step (15.9 mg, yield: 22.8%).

[0864] MS m / z (ESI): 498.2 [M+H] + .

[0865] 1H NMR (400MHz, DMSO-d6): δ10.48(s,1H),8.81(d,J=4.0Hz,1H),8.64(s,1H),8.28(d ,J=8.0Hz,1H),8.24(d,J=4.0Hz,1H),8.05(d,J=8.0Hz,2H),7.72(dd,J=8.0,4.0Hz ,1H),3.70-3.60(m,2H),3.17-3.09(m,2H),2.75-2.67(m,1H),2.61-2.52(m,3H), 2.46-2.39(m,1H),2.23(s,6H),2.12-2.06(m,1H),1.86-1.80(m,1H),1.78(s,6H).

[0866] Example 5: Preparation of (S)-1-(6-((6-(9,9-dimethyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']bipyridin-2-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (compound C-7B)

[0867] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (9,9-dimethyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']bipyridin-2-yl)boronic acid to obtain the title compound (14.7 mg).

[0868] MS m / z (ESI): 512.3 [M+H] + .

[0869] 1 H NMR (400MHz, DMSO-d6): δ10.53(s,1H),8.81(d,J=4.0Hz,2H),8.28(d,J=8.0Hz,1H),8.24( d,J=4.0Hz,1H),8.03(d,J=8.0Hz,1H),7.92(d,J=8.0Hz,1H),7.71(dd,J=8.0,4.0Hz,1H), 3.70-3.59(m,2H),3.00(t,J=4.0Hz,2H),2.75-2.67(m,1H),2.60-2.55(m,1H),2.46-2.39 (m,1H),2.23(s,6H),2.13-2.02(m,3H),1.98-1.95(m,2H),1.89(s,6H),1.83-1.78(m,1H).

[0870] Example 6: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazo-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (Compound C-8B)

[0871] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with 1,3,3-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazolium to obtain the title compound (19.4 mg).

[0872] MS m / z (ESI): 512.3 [M+H] + .

[0873] 1 H NMR (400MHz, DMSO-d6): δ10.20(s,1H),8.75(d,J=4.0Hz,1H),8.27(d,J=4.0Hz,1H),8.0 8(s,1H),7.97-7.87(m,2H),7.69(dd,J=8.0,4.0Hz,2H),7.32(dd,J=8.0,4.0Hz,1H),3. 72(s,2H),3.67-3.61(m,2H),2.96(d,J=4.0Hz,3H),2.71(d,J=4.0Hz,1H),2.60-2.56(m ,1H),2.45-2.38(m,1H),2.22(s,6H),2.09-2.04(m,1H),1.84-1.75(m,1H),1.64(s,6H).

[0874] Example 7: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(3-(1-(methoxymethyl)cyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (Compound C-2B)

[0875] Step 1: Preparation of 5-bromo-3-(1-(methoxymethyl)cyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridine

[0876] Under ice-water bath cooling, (1-(5-bromo-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropyl)methanol (80 mg, 269.37 μmol), sodium hydride (21.55 mg, 538.75 μmol), and methyl iodide (60.37 mg, 404.06 μmol) were added to tetrahydrofuran (2 mL), and the reaction was carried out at room temperature for 2 hours. The reaction was quenched with ice water, and the residue obtained by concentration was purified by reverse-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 50%-55%) to give the title compound of this step (65 mg, yield: 77.4%).

[0877] MS m / z(ESI): 296.1 [M+H] + .

[0878] Step 2: Preparation of (3-(1-(methoxymethyl)cyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0879] 5-Bromo-3-(1-(methoxymethyl)cyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridine (60 mg, 192.46 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (14.21 mg, 19.25 μmol), pinacol diboronate (74.07 mg, 288.69 μmol), and potassium acetate (38.10 mg, 384.92 μmol) were added to 1,4-dioxane (2 mL), the mixture was purged with nitrogen, and the reaction was carried out at 110 °C for 5 hours. The reaction solution was used directly in the next step.

[0880] MS m / z(ESI): 262.1 [M+H] + .

[0881] Step 3: Preparation of 5-(6-chloropyrimidin-4-yl)-3-(1-(methoxymethyl)cyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridine

[0882] 4,6-Dichloropyrimidine (51.36 mg, 327.48 μmol), (3-(1-(methoxymethyl)cyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (45 mg, 163.74 μmol), potassium carbonate (45.65 mg, 327.48 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (12.09 mg, 16.37 μmol) were added to 1,4-dioxane (3 mL), purged with nitrogen, and reacted at 110 °C for 5 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 50%-55%) to give the title compound of this step (25 mg, yield: 44.0%).

[0883] MS m / z(ESI): 330.1 [M+H] + .

[0884] Step 4: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(3-(1-(methoxymethyl)cyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one

[0885] (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (25.24 mg, 102.34 μmol), 5-(6-chloropyrimidin-4-yl)-3-(1-(methoxymethyl)cyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridine (25 mg, 68.23 μmol), cesium carbonate (5.57 mg, 170.57 μmol), tris(dibenzylideneacetone)palladium (6.31 mg, 6.82 μmol), and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (4.82 mg, 10.23 μmol) were added to 1,4-dioxane (2 mL), the mixture was purged with nitrogen, and the reaction was carried out at 110 °C for 4 hours. The reaction solution was directly purified by reversed-phase column chromatography (preparation method A, elution gradient: mobile phase A% = 25%-35%) to obtain the title compound of this step (14 mg, yield: 33.9%).

[0886] MS m / z(ESI): 528.3 [M+H] + .

[0887] 1H NMR (400MHz, DMSO-d6): δ10.05(br,1H),8.81(s,1H),8.76(s,1H),8.29(d,J=12. 0Hz,1H),8.27(d,J=4.0Hz,1H),8.03(d,J=8.0Hz,1H),7.91-7.89(m,1H),7.72-7. 69(m,1H),3.70-3.61(m,4H),3.28(s,3H),2.73(s,3H),2.60-2.54(m,1H),2.46-2 .39(m,2H),2.23(s,6H),2.12-2.09(m,1H),1.86-1.79(m,1H),1.46-1.35(m,4H).

[0888] Example 8: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(3-(1-(ethoxymethyl)cyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (Compound C-23B)

[0889] Following the synthetic route of compound C-2B, iodomethane was replaced with iodoethane to obtain the title compound (6 mg).

[0890] MS m / z (ESI): 542.3 [M+H] + .

[0891] 1 H NMR (400MHz, DMSO-d6): δ10.51(s,1H),8.81-8.78(m,2H),8.31-8.26(m,3H),8.03(d,J=8.0Hz,1H),7.89(d,J=8.0Hz,1H),7.71(d,J=8 .0Hz,1H),3.68-3.50(m,6H),2.72(m,4H),2.23(s,6H),2.10-2.08(m,2H),1.79-1.77(m,1H),1.44-1.34(m,4H),0.92(t,J=8.0Hz,3H).

[0892] Example 9: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(3-(1-((methoxy-d3)methyl)cyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (Compound C-31B)

[0893] Following the synthetic route of compound C-2B, iodomethane was replaced with deuterated iodomethane to obtain the title compound (5 mg).

[0894] MS m / z (ESI): 531.3 [M+H] + .

[0895] 1 H NMR (400MHz, DMSO-d6): δ10.51(br,1H),8.81(s,1H),8.75(s,1H),8.31-8.26(m,3H),8.03(d,J=8.0Hz,1H),7.89-7.88(m,1 H),7.72-7.70(m,1H),3.64(s,4H),2.71-2.69(m,5H),2.23(s,6H),2.12-2.09(m,1H),1.90-1.89(m,1H),1.46-1.35(m,4H).

[0896] Example 10: Preparation of (S)-2-(5-(6-((5-(4-(dimethylamino)-2-oxopiperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile (C-19B)

[0897] Step 1: Preparation of 2-(5-(6-chloropyrimidin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile

[0898] 4,6-Dichloropyrimidine (27.75 mg, 184.38 μmol), (3-(2-cyanopropan-2-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (50 mg, 184.38 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (13.61 mg, 18.44 μmol), and potassium carbonate (64.25 mg, 460.96 μmol) were added to 1,4-dioxane (2 mL), purged with nitrogen, and reacted at 110 °C for 4 hours. The reaction solution was cooled to room temperature and purified directly by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 25%-35%) to give the title compound of this step (15 mg, yield: 20.9%).

[0899] MS m / z(ESI): 313.1 [M+H] + .

[0900] Step 2: Preparation of (S)-2-(5-(6-((5-(4-(dimethylamino)-2-oxopiperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile

[0901] (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (11.24 mg, 43.16 μmol), 2-(5-(6-chloropyrimidin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropionitrile (15 mg, 43.16 μmol), cesium carbonate (35.53 mg, 107.91 μmol), tris(dibenzylideneacetone)dipalladium (3.99 mg, 4.32 μmol), and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (2.03 mg, 4.32 μmol) were added to 1,4-dioxane (2 mL), the mixture was purged with nitrogen, and the reaction was carried out at 110 °C for 4 hours. The reaction solution was cooled to room temperature and purified directly by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 5%-20%) to obtain the title compound of this step (6 mg, yield: 23.7%).

[0902] MS m / z (ESI): 511.2 [M+H] + .

[0903] 1 H NMR (400MHz, DMSO-d6): δ10.54(br,1H),8.85-8.82(m,2H),8.36(d,J=8.0Hz,1H),8.26-8.25(m,2H),8.13(d,J=8.0Hz,1H),7.82 -7.69(m,2H),3.68-3.60(m,3H),2.89(s,3H),2.75-2.65(m,1H),2.41(s,6H),2.21(s,6H),2.16-2.10(m,1H),1.82-1.80(m,1H).

[0904] Example 11: Preparation of 1-(6-((6-(3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one (C-16)

[0905] Following the synthetic method of compound C-1, 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 1-(6-aminopyridin-3-yl)-4-methylpiperazin-2-one to obtain the title compound (28 mg).

[0906] MS m / z (ESI): 458.2 [M+H] + .

[0907] 1 H NMR (400MHz, DMSO-d6): δ10.53(br,1H),8.81(s,1H),8.76(s,1H),8.30-8.26(m,2H),8.03(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,1H),7.79-7 .75(m,1H),4.87-4.80(m,1H),3.70(t,J=4.0Hz,2H),3.14(s,2H),2.76(t,J=4.0Hz,2H),2.66(s,3H),2.30(s,3H),1.78(d,J=8.0Hz,6H).

[0908] Example 12: Preparation of 4-ethyl-1-(6-((6-(3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazin-2-one (C-17)

[0909] Following the synthetic method of compound C-1, 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one to obtain the title compound (25 mg).

[0910] MS m / z(ESI): 472.2 [M+H] + .

[0911] 1 H NMR (400MHz, DMSO-d6): δ10.53(s,1H),8.81(s,1H),8.76(s,1H),8.31-8.26(m,2H) ,8.03(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,1H),7.80-7.77(m,1H),4.87-4.77(m,1H) ,3.69(t,J=4.0Hz,2H),3.55-3.51(m,1H),3.19-3.16(m,2H),2.81-2.78(t,J=4.0H z, 2H), 2.64 (s, 3H), 2.46-2.41 (m, 1H), 1.78 (d, J = 8.0Hz, 6H), 1.07 (t, J = 8.0Hz, 3H).

[0912] Example 13: Preparation of 4-isopropyl-1-(6-((6-(3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazin-2-one (C-18)

[0913] Following the synthetic method of compound C-1, 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 1-(6-aminopyridin-3-yl)-4-isopropylpiperazin-2-one to obtain the title compound (23 mg).

[0914] MS m / z (ESI): 486.2 [M+H] + .

[0915] 1 H NMR (400MHz, DMSO-d6): δ10.53(s,1H),8.81(s,1H),8.76(s,1H),8.31-8.26(m,2H),8.03(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.80-7.77 (m,1H),4.87-4.80(m,1H),3.67(t,J=4.0Hz,2H),3.26(s,2H),2.84-2.81(m,3H),2.66(s,3H),1.78(d,J=8.0Hz,6H),1.03(d,J=4.0Hz,6H).

[0916] Example 14: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-9B)

[0917] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid to obtain the title compound (15 mg).

[0918] MS m / z (ESI): 513.2 [M+H] + .

[0919] 1H NMR (400MHz, DMSO-d6): δ10.37(s,1H),8.74(s,1H),8.49(s,1H),8.23(d,J=4.0Hz,1 H),8.08(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.70(dd,J=8.0,4.0Hz,1H),7.55(d, J=8.0Hz,1H),3.81(s,2H),3.71-3.56(m,3H),3.00(s,3H),2.76-2.66(m,1H),2.46-2 .37(m,1H),2.22(s,6H),2.14-2.05(m,1H),1.87-1.78(m,1H),1.76(d,J=8.0Hz,6H).

[0920] Example 15: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(1,4,4-trimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidin-7-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-10B)

[0921] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine to obtain the title compound (15 mg).

[0922] MS m / z (ESI): 526.3 [M+H] + .

[0923] 1 H NMR (400MHz, DMSO-d6): δ10.20(s,1H),8.75(s,1H),8.26(d,J=4.0Hz,1H),8 .10(d,J=12.0Hz,2H),7.95(d,J=8.0Hz,1H),7.69(dd,J=8.0,4.0Hz,2H),7.3 0(d,J=8.0Hz,1H),3.63(s,2H),3.11(s,3H),2.69(s,1H),2.51(s,3H),2.46- 2.35(m,1H),2.22(s,6H),2.15-2.00(m,3H),1.95-1.75(m,1H),1.69(s,6H).

[0924] Example 16: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(6,9,9-trimethyl-6,7,8,9-tetrahydropyridano[3',2':4,5]imidazo[1,2-a]pyrimidin-2-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-11B)

[0925] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (6,9,9-trimethyl-6,7,8,9-tetrahydropyridino[3',2':4,5]imidazo[1,2-a]pyrimidin-2-yl)boronic acid to obtain the title compound (25 mg).

[0926] MS m / z (ESI): 527.2 [M+H] + .

[0927] 1 H NMR (400MHz, DMSO-d6): δ10.42(s,1H),8.73(s,1H),8.67(s,1H),8.21(d,J=4.0 Hz,1H),8.09(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),7.69(dd,J=8.0,4.0Hz,1H ),7.53(d,J=8.0Hz,1H),3.68-3.59(m,4H),3.14(s,3H),2.76-2.66(m,1H),2.6 0-2.54(m,1H),2.46-2.39(m,1H),2.23(s,6H),2.19-2.01(m,4H),1.86(s,6H).

[0928] Example 17: Preparation of (S)-1-(6-((6-(6-(cyclopropylmethyl)-9,9-dimethyl-6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyrimidin-2-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (C-15B)

[0929] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (6-(cyclopropylmethyl)-9,9-dimethyl-6,7,8,9-tetrahydropyridolo[3',2':4,5]imidazo[1,2-a]pyrimidin-2-yl)boronic acid to obtain the title compound (35 mg).

[0930] MS m / z (ESI): 567.3 [M+H] + .

[0931] 1 H NMR (400MHz, DMSO-d6): δ10.43(s,1H),8.74(s,1H),8.68(s,1H),8.23(d,J=4.0Hz,1H),8.10(d ,J=8.0Hz,1H),7.92(d,J=8.0Hz,1H),7.69(dd,J=8.0,4.0Hz,1H),7.52(d,J=8.0Hz,1H),3.80- 3.42(m,6H),2.79-2.65(m,1H),2.60-2.55(m,1H),2.46-2.39(m,1H),2.22(s,6H),2.18-2.01( m,3H),1.87(s,6H),1.84-1.71(m,1H),1.23-1.04(m,1H),0.60-0.44(m,2H),0.39-0.25(m,2H).

[0932] Example 18: Preparation of (S)-2-(5-(6-((5-(4-(dimethylamino)-2-oxopiperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropionitrile (C-34B)

[0933] Following the synthetic method of compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (2-(2-cyanopropane-2-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (101 mg).

[0934] MS m / z (ESI): 539.2 [M+H] + .

[0935] 1H NMR (400MHz, DMSO-d6): δ10.57(s,1H),8.84(s,2H),8.35(d,J=12.0Hz,1H),8.29-8.18(m,2H),7.93(s,1H),7.72(dd,J=8.0,4.0Hz,1H),5.36 -4.81(m,1H),3.65-3.75(m,2H),2.83-2.70(m,1H),2.61-2.56(m,1H), 2.48-2.41(m,1H),2.25(s,6H),2.21-2.09(m,1H),2.00-1.70(m,13H).

[0936] Example 19: Preparation of 1-(6-((6-(1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-ethylpiperazin-2-one (C-39)

[0937] Following the synthetic method of compound C-4, 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one to obtain the title compound (13.82 mg).

[0938] MS m / z (ESI): 483.2 [M+H] + .

[0939] 1 H NMR (400MHz, DMSO-d6): δ10.29(s,1H),8.81(d,J=4.0Hz,1H),8.34(d,J=4.0Hz,1H) ,8.27(d,J=4.0Hz,1H),8.16(s,1H),7.95(d,J=8.0Hz,1H),7.81-7.77(m,2H),7.68 (d,J=8.0Hz,1H),3.70-3.68(m,2H),3.18(s,2H),3.06(t,J=4.0Hz,2H),2.79(t,J= 4.0Hz, 2H), 2.54 (s, 2H), 2.47 (d, J = 8.0Hz, 2H), 1.66 (s, 6H), 1.06 (t, J = 7.2Hz, 3H).

[0940] Example 20: Preparation of 1-(6-((6-(1,1-dimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-ethylpiperazin-2-one (C-40)

[0941] Following the synthetic method for compound C-4, 1,1-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium was replaced with 1,1-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine, and 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one, yielding the title compound (8.82 mg).

[0942] MS m / z (ESI): 497.2 [M+H] + .

[0943] 1 H NMR (400MHz, DMSO-d6): δ10.29(s,1H),8.81(d,J=4.0Hz,1H),8.41(d,J=4.0Hz,1H),8.34(d,J=4.0 Hz,1H),8.18(s,1H),7.98(d,J=8.0Hz,1H),7.84(dd,J=8.0,4.0Hz,1H),7.78(dd,J=8.0,4.0Hz,1H ),7.65(d,J=8.0Hz,1H),3.73-3.68(m,2H),3.18(s,2H),2.97(t,J=4.0Hz,2H),2.79(t,J=4.0Hz,2 H), 2.46 (t, J = 8.0 Hz, 2H), 2.08-2.01 (m, 2H), 1.96-1.88 (m, 2H), 1.72 (s, 6H), 1.06 (t, J = 8.0 Hz, 3H).

[0944] Example 21: Preparation of (R)-4-(dimethylamino)-1-(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-9A)

[0945] Following the synthetic method of compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with (R)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one, yielding the title compound (18 mg).

[0946] MS m / z (ESI): 513.3 [M+H] + .

[0947] 1 H NMR (400MHz, DMSO-d6): δ10.36(s,1H),8.74(s,1H),8.49(s,1H),8.23(d,J =4.0Hz,1H),8.08(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.70(dd,J=12.0 ,4.0Hz,1H),7.55(d,J=8.0Hz,1H),3.81(s,2H),3.69-3.58(m,3H),3.00(s ,3H),2.77-2.65(m,2H),2.23(s,6H),2.11-2.08(m,1H),1.87-1.70(m,7H).

[0948] Example 22: Preparation of (S)-1-(6-((6,6-dimethyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (C-41B)

[0949] Following the synthetic method of compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (6,6-dimethyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)boronic acid to obtain the title compound (3 mg).

[0950] MS m / z (ESI): 512.3 [M+H] + .

[0951] 1H NMR (400MHz, DMSO-d6): δ10.43(s,1H),8.81(s,1H),8.65(s,1H),8.34(d,J=8.4H z,1H),8.28(d,J=2.4Hz,1H),8.09(d,J=8.4Hz,1H),7.91(d,J=8.4Hz,1H),7.70( dd,J=8.4,2.4Hz,1H),4.30-4.22(m,2H),3.70-3.62(m,3H),2.78-2.65(m,2H),2 .21(s,6H),2.19-2.12(m,3H),1.93-1.86(m,2H),1.85-1.75(m,1H),1.44(s,6H).

[0952] Example 23: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(2-(2-hydroxypropyl-2-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-20B)

[0953] Following the synthetic method of compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (2-(2-hydroxypropane-2-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (33 mg).

[0954] MS m / z (ESI): 530.3 [M+H] + .

[0955] 1 H NMR (400MHz, DMSO-d6): δ10.55(s,1H),8.83-8.75(m,2H),8.32-8.19(m,2H),8 .12(d,J=8.4Hz,1H),7.93(s,1H),7.72(dd,J=8.8,2.8Hz,1H),5.86(s,1H),5.7 2-5.66(m,1H),3.72-3.53(m,3H)2.76-2.67(m,1H),2.60-2.55(m,1H),2.46-2 .40(m,1H),2.23(s,6H),2.15-2.05(m,1H),1.83(d,J=6.8Hz,6H),1.67(s,6H).

[0956] Example 24: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(3-isopropyl-2-(2-methoxypropyl-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-21B)

[0957] Following the synthetic method of compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (3-isopropyl-2-(2-methoxypropyl-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (37 mg).

[0958] MS m / z (ESI): 544.4 [M+H] + .

[0959] 1 H NMR (400MHz, DMSO-d6): δ10.55(s,1H),8.83(d,J=4.0Hz,2H),8.30(d,J=8.0Hz,1H),8.25(d ,J=4.0Hz,1H),8.17(d,J=4.0Hz,1H),7.92(s,1H),7.72(dd,J=8.0,4.0Hz,1H),5.52-5.45(m ,1H),3.69-3.60(m,2H),3.14(s,3H),2.75-2.70(m,1H),2.60-2.54(m,1H),2.43(d,J=8.0Hz ,1H),2.24(s,6H),2.13-2.07(m,1H),1.85(d,J=8.0Hz,6H),1.80-1.75(m,1H),1.69(s,6H).

[0960] Example 25: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(2-(2-ethoxypropyl-2-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-29B)

[0961] Following the synthetic method of compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (2-(2-ethoxypropyl-2-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (30 mg).

[0962] MS m / z (ESI): 558.3 ​​[M+H] + .

[0963] 1 H NMR (400MHz, DMSO-d6): δ10.55(s,1H),8.82(d,J=1.0Hz,2H),8.30(d,J=8.0Hz,1H),8.25(d,J=4. 0Hz,1H),8.16(d,J=4.0Hz,1H),7.91(s,1H),7.72(dd,J=8.0,4.0Hz,1H),5.55-5.51(m,1H),3.70- 3.61(m,2H),3.29(s,2H),2.77-2.71(m,1H),2.61-2.57(m,1H),2.43(d,J=8.0Hz,1H),2.24(s,6H ), 2.14-2.07(m,1H),1.85(d,J=8.0Hz,6H),1.83-1.76(m,1H),1.70(s,6H),1.17(t,J=6.9Hz,3H).

[0964] Example 26: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(3-isopropyl-2-(2-(methoxy-d3)propyl-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-33B)

[0965] Following the synthetic method of compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (3-isopropyl-2-(2-(methoxy-d3)propyl-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (70 mg).

[0966] MS m / z (ESI): 547.1 [M+H] + .

[0967] 1H NMR (400MHz, DMSO-d6): δ10.56(s,1H),8.84(s,2H),8.32(d,J=8.4Hz,1H),8.26(d,J=2. 4Hz,1H),8.17(d,J=8.4Hz,1H),7.94(d,J=8.4Hz,1H),7.73(dd,J=8.8,2.8Hz,1H),5.54 -5.47(m,1H),3.71-3.60(m,2H),2.76-2.71(m,1H),2.64-2.55(m,1H),2.48-2.41(m,1H ), 2.24 (s, 6H), 2.16-2.03 (m, 1H), 1.86 (d, J = 6.8Hz, 6H), 1.84-1.76 (m, 1H), 1.70 (s, 6H).

[0968] Example 27: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(3-isopropyl-2-morpholino-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-49B)

[0969] Following the synthetic method of compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (3-isopropyl-2-morpholino-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (25 mg).

[0970] MS m / z (ESI): 557.2 [M+H] + .

[0971] 1H NMR (400MHz, DMSO-d6): δ10.49(s,1H),8.79(d,J=4.0Hz,1H),8.74(s,1H),8.26-8.18(m,2H),7.9 4(d,J=8.0Hz,1H),7.89(d,J=8.0Hz,1H),7.71(dd,J=8.0,4.0Hz,1H),4.65-4.61(m,1H),3.82(t,J =4.0Hz,4H),3.69-3.60(m,2H),3.28(t,J=4.0Hz,4H),2.75-2.70(m,1H),2.61-2.55(m,1H),2.43 (dd,J=16.0,8.0Hz,1H),2.23(s,6H),2.15-2.08(m,1H),1.84-1.81(m,1H),1.76(d,J=8.0Hz,6H).

[0972] Example 28: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(3-isopropyl-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-50B)

[0973] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (3-isopropyl-2-(pyrrolidine-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (37 mg).

[0974] MS m / z (ESI): 541.3 [M+H] + .

[0975] 1H NMR (400MHz, DMSO-d6): δ10.45(s,1H),8.75(s,2H),8.23(d,J=4.0Hz,1H),8.13(d,J=8. 0Hz,1H),7.90(s,1H),7.70(dd,J=8.0,4.0Hz,1H),7.64(d,J=8.0Hz,1H),4.83-4.79(m,1 H),3.80-3.62(m,6H),2.77-2.65(m,1H),2.63-2.57(m,1H),2.46-2.38(m,1H),2.23(s, 6H), 2.10 (d, J = 12.0Hz, 1H), 1.95-1.92 (m, 4H), 1.84-1.80 (m, 1H), 1.78 (d, J = 8.0Hz, 6H).

[0976] Example 29: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(2-(2-hydroxypropyl-2-yl)-3-(1-((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-53B)

[0977] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (2-(2-hydroxypropyl-2-yl)-3-(1-((methoxy-d3)methyl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (30 mg).

[0978] MS m / z (ESI): 575.3 [M+H] + .

[0979] 1H NMR (400MHz, DMSO-d6): δ10.54(s,1H),8.82(d,J=4.0Hz,2H),8.33(d,J=8.0Hz,1H),8.26(d,J=4.0Hz,1H),8.09 (d,J=8.0Hz,1H),7.88(s,1H),7.71(dd,J=8.0,4.0Hz,1H),5.52(s,1H),4.06(d,J=12.0Hz,1H),3.69-3.60(m,2H ),3.56(d,J=12.0Hz,1H),2.75-2.68(m,1H),2.60-2.54(m,1H),2.43(d,J=8.0Hz,1H),2.23(s,6H),2.10(d,J=12 .0Hz,1H),1.86-1.79(m,1H),1.75(s,3H),1.74-1.70(m,1H),1.66(s,3H),1.59-1.51(m,2H),1.21-1.15(m,1H).

[0980] Example 30: Preparation of 1-(6-((6-(3-isopropyl-2-((1-methoxycyclopentyl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one (C-72)

[0981] Step 1: Preparation of 5-(6-bromopyrimidin-4-yl)-3-isopropyl-2-((1-methoxycyclopentyl)methyl)-3H-imidazo[4,5-b]pyridine

[0982] (3-Isopropyl-2-((1-methoxycyclopentyl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (50 mg, 158 μmol), 4,6-dibromopyrimidine (113 mg, 473 μmol), potassium carbonate (65 mg, 473 μmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (12.9 mg, 15.8 μmol) were added to 1,4-dioxane (3 mL) and water (0.3 mL), purged with nitrogen, and reacted at 80 °C for 4 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 (v / v)) to give the title compound of this step (60 mg, yield: 84.0%).

[0983] MS m / z (ESI): 430.1 [M+H] + .

[0984] Step 2: Preparation of 1-(6-((6-(3-isopropyl-2-((1-methoxycyclopentyl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one

[0985] 5-(6-bromopyrimidin-4-yl)-3-isopropyl-2-((1-methoxycyclopentyl)methyl)-3H-imidazo[4,5-b]pyridine (45 mg, 105 μmol), 1-(6-aminopyridin-3-yl)-4-methylpiperazin-2-one (23.8 mg, 115 μmol), tris(dibenzylideneacetone)dipalladium (9.6 mg, 10.5 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (6.10 mg, 10.5 μmol), and cesium carbonate (85.0 mg, 262 μmol) were added to anhydrous 1,4-dioxane (3 mL), the mixture was purged with nitrogen, and the reaction was carried out at 100 °C for 4 hours. The reaction solution was concentrated, and the crude product was purified by reversed-phase column chromatography (preparation method A, elution gradient: mobile phase A% = 10%-30%) to obtain the title compound of this step (21.2 mg, yield: 34.6%).

[0986] MS m / z (ESI): 556.2 [M+H] + .

[0987] 1 H NMR (400MHz, DMSO-d6): δ10.56 (s, 1H), 8.82 (d, J = 4.0Hz, 2H), 8.34-8.25 (m, 2 H),8.08(d,J=8.0Hz,1H),7.94(d,J=8.0Hz,1H),7.78(dd,J=8.0,4.0Hz,1H), 4.97-4.89(m,1H),3.71-3.68(m,2H),3.26(s,2H),3.20(s,3H),3.14(s,2H), 2.75(t,J=4.0Hz,2H),2.30(s,3H),1.80(d,J=8.0Hz,6H),1.77-1.48(m,8H).

[0988] Example 31: Preparation of (S)-1-(6-((6-(1-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (C-42B)

[0989] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid to obtain the title compound (15 mg).

[0990] MS m / z (ESI): 539.2 [M+H] + .

[0991] 1 H NMR (400MHz, DMSO-d6): δ10.37(s,1H),8.74(d,J=1.2Hz,1H),8.50(s,1H),8.22(d,J=2.8Hz,1H) ,8.09(d,J=8.4Hz,1H),8.04(d,J=8.8Hz,1H),7.70(dd,J=8.8,2.8Hz,1H),7.59(d,J=8.4Hz,1H) ,3.84(s,2H),3.67-3.58(m,2H),2.74-2.68(m,2H),2.63-2.54(m,1H),2.45-2.39(m,1H),2.23( s,6H),2.11-2.08(m,1H),1.87-1.76(m,1H),1.72(s,6H),0.89-0.83(m,2H),0.80-0.73(m,2H).

[0992] Example 32: Preparation of 4-methyl-1-(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazin-2-one (C-59)

[0993] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 1-(6-aminopyridin-3-yl)-4-methylpiperazin-2-one, yielding the title compound (30 mg).

[0994] MS m / z (ESI): 485.1 [M+H]+ .

[0995] 1 H NMR (400MHz, DMSO-d6): δ10.40(s,1H),8.75(d,J=1.2Hz,1H),8.51(s,1H),8.29(dd,J=2.8,0.8Hz,1H),8.10-8.05(m,2H),7.77(dd,J=8.8 ,2.8Hz,1H),7.55(d,J=8.4Hz,1H),3.81(s,2H),3.70-3.63(m,2H),3.14(s,2H),3.01(s,3H),2.76-2.73(m,2H),2.30(s,3H),1.75(s,6H).

[0996] Example 33: Preparation of N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidine-4-amine (C-58)

[0997] Following the synthetic method of compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 5-(4-methylpiperazin-1-yl)pyridin-2-amine to obtain the title compound (55 mg).

[0998] MS m / z(ESI): 471.1 [M+H] + .

[0999] 1 H NMR (400MHz, DMSO-d6): δ10.05(s,1H),8.67(d,J=1.2Hz,1H),8.38(s,1H),8.07(d,J=8.4Hz,1H),8.00(d,J=3.2Hz,1H),7.91(d,J=9.2Hz,1H),7. 55(d,J=8.4Hz,1H),7.47(dd,J=9.2,3.2Hz,1H),3.82(s,2H),3.14(t,J= 5.2Hz, 4H), 3.01 (s, 3H), 2.49 (t, J = 5.2Hz, 4H), 2.24 (s, 3H), 1.75 (s, 6H).

[1000] Example 34: Preparation of morpholino(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl) methyl ketone (C-64)

[1001] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with (6-aminopyridin-3-yl)(morpholino)methyl ketone, yielding the title compound (11 mg).

[1002] MS m / z (ESI): 486.2 [M+H] + .

[1003] 1 H NMR (400MHz, DMSO-d6): δ10.56(s,1H),8.77(d,J=1.2Hz,1H),8.66(s,1H),8.38(dd,J=2.4,0.8Hz,1H),8.09(d,J=8.0Hz,1H),8. 01(d,J=8.8Hz,1H),7.86(dd,J=8.8,2.4Hz,1H),7.55(d,J=8.0Hz,1H),3.82(s,2H),3.74-3.55(m,8H),3.01(s,3H),1.75(s,6H).

[1004] Example 35: Preparation of (4-methylpiperazin-1-yl)(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl) methyl ketone (C-68)

[1005] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with (6-aminopyridin-3-yl)(4-methylpiperazin-1-yl)methyl ketone, yielding the title compound (13 mg).

[1006] MS m / z (ESI): 499.3 [M+H] + .

[1007] 1 H NMR (400MHz, DMSO-d6): δ10.56(s,1H),8.78(d,J=1.2Hz,1H),8.67(s,1H),8.36(d,J=2.4Hz,1H),8.10(d,J=8.0Hz,1H),8.01(d,J=8.8H z,1H),7.84(dd,J=8.8,2.4Hz,1H),7.56(d,J=8.0Hz,1H),3.82(s,2H),3.55(s,4H),3.01(s,3H),2.37(s,4H),2.22(s,3H),1.76(s,6H).

[1008] Example 36: Preparation of N-(5-morpholinopyridin-2-yl)-6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidine-4-amine (C-63)

[1009] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 5-morpholinopyridin-2-amine to obtain the title compound (5 mg).

[1010] MS m / z (ESI): 458.2 [M+H] + .

[1011] 1H NMR (400MHz, DMSO-d6): δ10.05(s,1H),8.66(d,J=1.2Hz,1H),8.38(s,1H),8.13-7.86(m,3H),7.54(d,J= 8.0Hz, 1H), 7.47 (dd, J = 9.2, 3.2Hz, 1H), 3.84-3.73 (m, 6H), 3.14-3.06 (m, 4H), 3.00 (s, 3H), 1.74 (s, 6H).

[1012] Example 37: Preparation of N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)-6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidine-4-amine (C-65)

[1013] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 5-(1-methylpiperidin-4-yl)pyridin-2-amine to obtain the title compound (4 mg).

[1014] MS m / z (ESI): 470.3 [M+H] + .

[1015] 1 H NMR (400MHz, DMSO-d6): δ10.20(s,1H),8.71(d,J=1.2Hz,1H),8.56(s,1H),8.18 (d,J=2.4Hz,1H),8.07(d,J=8.0Hz,1H),7.89(d,J=8.8Hz,1H),7.67(dd,J=8.8, 2.4Hz,1H),7.55(d,J=8.0Hz,1H),3.81(s,2H),3.01(s,3H),2.86(dd,J=8.8,6. 0Hz,2H),2.48-2.43(m,3H),2.19(s,3H),2.01-1.93(m,2H),1.80-1.68(m,8H).

[1016] Example 38: Preparation of N-(4-(4-methylpiperazin-1-yl)pyridin-2-yl)-6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidine-4-amine (C-66)

[1017] Following the synthetic method of compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 4-(4-methylpiperazin-1-yl)pyridin-2-amine to obtain the title compound (4 mg).

[1018] MS m / z (ESI): 471.3 [M+H] + .

[1019] 1 H NMR (400MHz, DMSO-d6): δ9.89(s,1H),8.75-8.63(m,2H),8.06(d,J=8.4Hz,1H),7.94(d,J=6.0Hz,1H),7.54(d,J=8.4Hz,1H),7.3 2(s,1H),6.58(dd,J=6.4,2.4Hz,1H),3.80(s,2H),3.32-3.25(m,4H),3.00(s,3H),2.47-2.39(m,4H),2.23(s,3H),1.73(s,6H).

[1020] Example 39: Preparation of N-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidine-4-amine (C-69)

[1021] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 5-((1-methylpiperidin-4-yl)oxy)pyridin-2-amine, yielding the title compound (4 mg).

[1022] MS m / z (ESI): 486.3 [M+H] + .

[1023] 1 H NMR (400MHz, DMSO-d6): δ10.12(s,1H),8.67(d,J=1.0Hz,1H),8.42(s,1H),8.06(d ,J=8.4Hz,1H),8.01(d,J=2.8Hz,1H),7.92(d,J=9.2Hz,1H),7.54(d,J=8.4Hz,1H) ,7.49(dd,J=9.2,2.8Hz,1H),4.43-4.29(m,1H),3.81(s,2H),3.00(s,3H),2.70-2 .58(m,3H),2.24-2.11(m,4H),2.01-1.86(m,2H),1.75(s,6H),1.69-1.59(m,2H).

[1024] Example 40: Preparation of 6-methyl-N-(6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-amine (C-70)

[1025] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with 6-methyl-5,6,7,8-tetrahydro-1,6-naphthidine-2-amine to obtain the title compound (3 mg).

[1026] MS m / z (ESI): 442.3 [M+H] + .

[1027] 1 H NMR (400MHz, DMSO-d6): δ10.16(s,1H),8.85(s,1H),8.70(d,J=0.8Hz,1H),8.11(d,J=8.4Hz,1H),7.54(d,J=8.4Hz,1H),7.5 2-7.40(m,2H),3.81(s,2H),3.48-3.43(m,2H),3.00(s,3H),2.95-2.86(m,2H),2.74-2.69(m,2H),2.37(s,3H),1.76(s,6H).

[1028] Example 41: Preparation of (4-methylpiperazin-1-yl)(2-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-4-yl)methyl ketone (C-67)

[1029] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid, and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one was replaced with (2-aminopyridin-4-yl)(4-methylpiperazin-1-yl)methyl ketone, yielding the title compound (8 mg).

[1030] MS m / z (ESI): 499.3 [M+H] + .

[1031] 1H NMR (400MHz, DMSO-d6): δ10.47 (s, 1H), 8.76 (d, J = 0.8Hz, 1H), 8.61 (s, 1H), 8. 37(d,J=5.2Hz,1H),8.09(d,J=8.4Hz,1H),7.95(s,1H),7.55(d,J=8.4Hz,1H), 6.99(dd,J=5.2,1.2Hz,1H),3.82(s,2H),3.68-3.61(m,3H),3.01(s,3H),2.69 -2.64(m,1H),2.44-2.36(m,2H),2.34-2.27(m,2H),2.21(s,3H),1.75(s,6H).

[1032] Example 42: Preparation of (S)-1-(6-((6-(3,3-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (C-47B)

[1033] Following the synthetic method for compound C-5B, (8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)boronic acid was replaced with (3,3-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid to obtain the title compound (8 mg).

[1034] MS m / z (ESI): 583.3 [M+H] + .

[1035] 1H NMR (400MHz, DMSO-d6): δ10.38(s,1H),8.75(d,J=0.8Hz,1H),8.51(s,1H),8.24(d,J=2.4Hz, 1H),8.10(d,J=8.4Hz,1H),8.05(d,J=8.8Hz,1H),7.71(dd,J=8.8,2.4Hz,1H),7.56(d,J=8.4 Hz,1H),4.03-3.92(m,2H),3.93-3.81(m,3H),3.74-3.59(m,3H),2.79-2.66(m,1H),2.64-2. 54(m,2H),2.48-2.38(m,1H),2.24(s,6H),2.15-2.07(m,1H),1.97-1.81(m,5H),1.75(s,6H).

[1036] Example 43: Preparation of 1-(3,3-dimethyl-6-(6-((5-(4-methyl-2-oxoperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-1-yl)cyclopropionitrile (C-71)

[1037] Step 1: Preparation of 1-(6-(6-bromopyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-1-yl)cyclopropionitrile

[1038] (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid (45 mg, 151.45 μmol) and 4,6-dibromopyrimidine (144.11 mg, 605.82 μmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Potassium carbonate (52.33 mg, 378.64 μmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12.37 mg, 15.15 μmol) were added, and the mixture was purged with nitrogen and reacted at 90 °C for 6 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound of this step (28 mg, yield: 45.1%).

[1039] MS m / z(ESI): 410.0 [M+H] + .

[1040] Step 2: Preparation of 1-(3,3-dimethyl-6-(6-((5-(4-methyl-2-oxopirarin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-1-yl)cyclopropionitrile

[1041] 1-(6-(6-bromopyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-1-yl)cyclopropion-1-onitrile (20 mg, 48.5 μmol) and 1-(6-aminopyridin-3-yl)-4-methylpiperazin-2-one (20 mg, 96.97 μmol) were added to 1,4-dioxane (5 mL), followed by tris(dibenzylideneacetone)dipalladium (8.88 mg, 9.70 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (4.53 mg, 9.70 μmol), and cesium carbonate (39.5 mg, 121.21 μmol). The mixture was purged with nitrogen and reacted at 105 °C for 4 hours. The reaction solution was concentrated, and the crude product was purified by reversed-phase column chromatography (preparation method A, elution gradient: mobile phase A% = 35%-40%) to obtain the title compound of this step (3 mg, yield: 10.9%).

[1042] MS m / z (ESI): 536.1 [M+H] + .

[1043] 1 H NMR (400MHz, DMSO-d6): δ10.43(s,1H),8.77(d,J=1.2Hz,1H),8.55(s,1H),8.29(d,J=2.8Hz,1H),8.18(d,J=8.4Hz,1H),8.06(d,J=8.8Hz ,1H),7.84-7.67(m,2H),3.95(s,2H),3.73-3.65(m,2H),3.14(s,2H),2.75(t,J=5.6Hz,2H),2.30(s,3H),1.77(s,6H),1.70-1.61(m,4H).

[1044] Example 44: Preparation of 1-(6-((6-(3-(1-((methoxy-d3)methyl)cyclopropyl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one (C-74)

[1045] Following the synthetic method for compound C-71, (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid was replaced with (3-(1-((methoxy-d3)methyl)cyclopropyl)-2-(pyrrolidine-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (20 mg).

[1046] MS m / z (ESI): 558.3 ​​[M+H] + .

[1047] 1 H NMR (400MHz, DMSO-d6): δ10.45(s,1H),8.75(d,J=1.2Hz,1H),8.73(s,1H),8.31( d,J=2.4Hz,1H),8.14(d,J=8.0Hz,1H),7.90(d,J=8.8Hz,1H),7.76(dd,J=8.8,2. 8Hz,1H),7.57(d,J=8.0Hz,1H),4.04(d,J=10.4Hz,1H),3.92-3.61(m,7H),3.14( s,2H),2.75(t,J=5.2Hz,2H),2.30(s,3H),2.11-1.79(m,4H),1.50-1.25(m,4H).

[1048] Example 45: Preparation of 1-(6-((6-(3-(1-((methoxy-d3)methyl)cyclopropyl)-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one (C-75)

[1049] Following the synthetic method for compound C-71, (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid was replaced with (3-(1-((methoxy-d3)methyl)cyclopropyl)-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (5 mg).

[1050] MS m / z (ESI): 586.3 [M+H] + .

[1051] 1H NMR (400MHz, DMSO-d6): δ10.44(s,1H),8.75(d,J=1.2Hz,1H),8.71(s,1H),8 .30(d,J=2.4Hz,1H),8.16(d,J=8.4Hz,1H),7.88(d,J=8.8Hz,1H),7.76(dd,J =8.8,2.8Hz,1H),7.63(d,J=8.0Hz,1H),4.77(s,4H),4.53(s,4H),3.81-3.6 0(m,4H),3.14(s,2H),2.75(t,J=5.2Hz,2H),2.30(s,3H),1.52-1.20(m,4H).

[1052] Example 46: Preparation of 1-(5-(6-((5-(4-methyl-2-oxoperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropion-1-onitrile (C-82)

[1053] Following the synthetic method for compound C-71, (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid was replaced with (3-(1-cyanocyclopropyl)-2-(pyrrolidine-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (9.23 mg).

[1054] MS m / z (ESI): 536.3 [M+H] + .

[1055] 1 H NMR (400MHz, DMSO-d6): δ10.61(s,1H),8.80(d,J=1.2Hz,1H),8.66(s,1H),8.35(d,J=2.8Hz,1H),8.22(d,J=8.0Hz,1H),8.05(d,J=9.2Hz,1H),7.7 9(dd,J=8.8,2.8Hz,1H),7.69(d,J=8.0Hz,1H),4.00(s,4H),3.82(d,J=6. 0Hz,4H),3.63(s,2H),2.90(s,3H),2.24-2.13(m,2H),2.11-1.91(m,6H).

[1056] Example 47: Preparation of 1-(5-(6-((5-(4-methyl-2-oxoperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropion-1-onitrile (C-91)

[1057] Following the synthetic method for compound C-71, (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid was replaced with (3-(1-cyanocyclopropyl)-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (6.22 mg).

[1058] MS m / z (ESI): 564.3 [M+H] + .

[1059] 1 H NMR (400MHz, DMSO-d6): δ10.48(s,1H),8.77(d,J=4.0Hz,1H),8.70(s,1H),8.3 4(d,J=4.0Hz,1H),8.22(d,J=8.0Hz,1H),7.93(s,1H),7.77(dd,J=8.0,4.0Hz,1 H),7.72(d,J=8.0Hz,1H),4.80(s,4H),4.61(s,4H),3.72-3.66(m,2H),3.14(s ,2H),2.75(t,J=4.0Hz,2H),2.30(s,3H),2.17-2.11(m,2H),1.99-1.93(m,2H).

[1060] Example 48: Preparation of 1-(6-((6-(3-(1-(methoxy-d3)-2-methylpropyl-2-yl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one (C-81)

[1061] Following the synthetic method for compound C-71, (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid was replaced with (3-(1-(methoxy-d3)-2-methylpropyl-2-yl)-2-(pyrrolidine-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (23.6 mg).

[1062] MS m / z (ESI): 560.2 [M+H] + .

[1063] 1 H NMR (400MHz, DMSO-d6): δ10.51(s,1H),8.79(d,J=4.0Hz,2H),8.30(d,J=4.0Hz,1H),8.23(d,J=8.0Hz,1H),7.90-7.82(m,2H),7.77(dd,J=8.0 ,4.0Hz,1H),4.20(s,2H),3.70(dd,J=8.0,4.0Hz,2H),3.43-3.37(m,4H ), 3.14 (s, 2H), 2.75 (t, J = 4.0Hz, 2H), 2.30 (s, 3H), 1.93-1.85 (m, 10H).

[1064] Example 49: Preparation of 2-methyl-2-(5-(6-((5-(4-methyl-2-oxoperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-3-yl)propionitrile (C-87)

[1065] Following the synthetic method for compound C-71, (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid was replaced with (3-(2-cyanopropane-2-yl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (27.0 mg).

[1066] MS m / z (ESI): 566.1 [M+H] + .

[1067] 1H NMR (400MHz, DMSO-d6): δ10.49(s,1H),8.78(d,J=4.0Hz,1H),8.73(s,1H),8.30(d,J=4.0Hz,1H),8.26(d,J=8.0Hz,1H),7.91-7.81(m,2H ),7.76(dd,J=8.0,4.0Hz,1H),4.75(s,4H),4.51(s,4H),3.72-3.67(m,2H),3.14(s,2H),2.76(t,J=4.0Hz,2H),2.38(s,6H),2.30(s,3H).

[1068] Example 50: Preparation of 2-methyl-2-(5-(6-((5-(4-methyl-2-oxoperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-(pyrrolidone-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)propionitrile (C-79)

[1069] Following the synthetic method for compound C-71, (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid was replaced with (3-(2-cyanopropane-2-yl)-2-(pyrrolidine-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (29.5 mg).

[1070] MS m / z (ESI): 538.1 [M+H] + .

[1071] 1 H NMR (400MHz, DMSO-d6): δ10.51(s,1H),8.79(d,J=4.0Hz,1H),8.76(s,1H), 8.32(d,J=4.0Hz,1H),8.27(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),7.87(s, 1H),7.77(dd,J=8.0,4.0Hz,1H),3.73-3.63(m,2H),3.58-3.50(m,4H),3.14 (s,2H),2.76(t,J=4.0Hz,2H),2.40(s,6H),2.30(s,3H),1.99-1.91(m,4H).

[1072] Example 51: Preparation of 1-(6-((6-(3-isopropyl-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one (C-90)

[1073] Following the synthetic method of compound C-71, (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid was replaced with (3-isopropyl-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (12 mg).

[1074] MS m / z (ESI): 541.3 [M+H] + .

[1075] 1 H NMR (400MHz, DMSO-d6): δ10.47(s,1H),8.76(d,J=1.2Hz,1H),8.70(s,1H),8. 29(d,J=2.4Hz,1H),8.15(d,J=8.0Hz,1H),7.93(d,J=8.8Hz,1H),7.76(dd,J=8 .8,2.8Hz,1H),7.69(d,J=8.0Hz,1H),4.76(s,4H),4.53-4.43(m,5H),3.75-3. 65(m,2H),3.14(s,2H),2.79-2.70(m,2H),2.32(s,3H),1.75(d,J=6.8Hz,6H).

[1076] Example 52: Preparation of 1-(6-((6-(3-cyclopropyl-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one (C-92)

[1077] Following the synthetic method for compound C-71, (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid was replaced with (3-cyclopropyl-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (16.5 mg).

[1078] MS m / z (ESI): 539.2 [M+H] + .

[1079] 1 H NMR (400MHz, DMSO-d6): δ10.44(s,1H),8.79-8.67(m,2H),8.33(d,J=4.0Hz,1 H),8.16(d,J=8.0Hz,1H),7.87(d,J=8.0Hz,1H),7.76(dd,J=8.0,4.0Hz,1H), 7.63(d,J=8.0Hz,1H),4.77(s,4H),4.56(s,4H),3.71-3.66(m,2H),3.30-3.2 7(m,1H),3.14(s,2H),2.75(t,J=4.0Hz,2H),2.30(s,3H),1.26-1.19(m,4H).

[1080] Example 53: Preparation of 1-(6-((6-(2-cyclopropyl-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one (C-95)

[1081] Following the synthetic method for compound C-71, (1-(1-cyanocyclopropyl)-3,3-dimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid was replaced with (2-cyclopropyl-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid to obtain the title compound (11.4 mg).

[1082] MS m / z (ESI): 484.2 [M+H] + .

[1083] 1H NMR (400MHz, DMSO-d6): δ10.52(s,1H),8.81(d,J=0.8Hz,1H),8.75(s,1H),8.3 1(d,J=2.4Hz,1H),8.26(d,J=8.4Hz,1H),7.99(d,J=8.4Hz,2H),7.78(dd,J=8. 8,2.8Hz,1H),5.39-4.98(m,1H),3.79-3.60(m,2H),3.14(s,2H),2.79-2.71(m ,2H),2.45-2.36(m,1H),2.29(s,3H),1.81(d,J=8.8Hz,6H),1.18-1.11(m,4H).

[1084] Example 54: Preparation of 4-ethyl-1-(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazin-2-one (C-93)

[1085] Step 1: Preparation of 6-(6-bromopyrimidin-4-yl)-1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine

[1086] (1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)boronic acid (590 mg, 2.16 mmol) and 4,6-dibromopyrimidine (1.71 g, 6.47 mmol) were dissolved in 1,4-dioxane (25 mL) and water (1 mL). Potassium carbonate (1.05 g, 7.55 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (159.34 mg, 215.79 μmol) were added, and the mixture was purged with nitrogen and reacted at 90 °C for 6 hours. The reaction mixture was cooled to room temperature and purified directly by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 50%-55%) to give the title compound of this step (580 mg, yield: 67.3%).

[1087] MS m / z (ESI): 359.1 [M+H] + .

[1088] Step 2: Preparation of 4-ethyl-1-(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazin-2-one

[1089] 6-(6-bromopyrimidin-4-yl)-1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridine (15 mg, 41.76 μmol) and 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one (18.40 mg, 83.51 μmol) were added to 1,4-dioxane (3 mL), followed by tris(dibenzylideneacetone)palladium (3.82 mg, 4.18 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (4.83 mg, 8.35 μmol), and cesium carbonate (34.01 mg, 104.39 μmol). The mixture was purged with nitrogen and reacted at 110 °C for 2 hours. The crude product obtained by concentrating the reaction solution was purified by reversed-phase column chromatography (preparation method B, elution gradient: mobile phase A% = 5%-35%) to give the title compound (7.84 mg, yield: 35.8%).

[1090] MS m / z (ESI): 499.3 [M+H] + .

[1091] 1 H NMR (400MHz, DMSO-d6): δ10.38(s,1H),8.74(s,1H),8.50(s,1H),8.29(d, J=4.0Hz,1H),8.10-8.02(m,2H),7.77(dd,J=8.0,4.0Hz,1H),7.55(d,J=8. 0Hz,1H),3.81(s,2H),3.68(t,J=4.0Hz,2H),3.18(s,2H),3.00(s,3H),2. 79(t,J=4.0Hz,2H),2.47-2.42(m,2H),1.75(s,6H),1.06(t,J=8.0Hz,3H).

[1092] Example 55: Preparation of 4-isopropyl-1-(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazin-2-one (C-94)

[1093] Following the synthetic method of compound C-93, 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one was replaced with 1-(6-aminopyridin-3-yl)-4-isopropylpiperazin-2-one to obtain the title compound (8.8 mg).

[1094] MS m / z (ESI): 513.2 [M+H] + .

[1095] 1 H NMR (400MHz, DMSO-d6): δ10.38 (s, 1H), 8.74 (d, J = 4.0Hz, 1H), 8.51 (s, 1H), 8.31-8.27(m,1H),8.08-8.01(m,2H),7.77(dd,J=8.0,4.0Hz,1H),7.55(d,J =8.0Hz,1H),3.81(s,2H),3.65(t,J=4.0Hz,2H),3.26(s,2H),3.00(s,3H),2 .82(t,J=4.0Hz,2H),2.79-2.73(m,1H),1.75(s,6H),1.04(d,J=8.0Hz,6H).

[1096] Example 56: Preparation of 4-(2,2,2-trifluoroethyl)-1-(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazin-2-one (C-62)

[1097] Following the synthetic method of compound C-93, 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one was replaced with 1-(6-aminopyridin-3-yl)-4-(2,2,2-trifluoroethyl)piperazin-2-one to obtain the title compound (4.8 mg).

[1098] MS m / z (ESI): 553.2 [M+H] + .

[1099] 1 H NMR (400MHz, DMSO-d6): δ10.40(s,1H),8.74(d,J=4.0Hz,1H),8.49(s,1H),8.31(d,J=4.0Hz,1H),8.09-8.01(m,2H),7.79(dd,J=8.0,4.0Hz,1H) ,7.55(d,J=8.0Hz,1H),3.81(s,2H),3.71(t,J=4.0Hz,2H),3.47(s,2H), 3.42(d,J=12.0Hz,2H), 3.07(t,J=4.0Hz,2H), 3.00(s,3H), 1.75(s,6H).

[1100] Example 57: Preparation of 4-cyclopropyl-1-(6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazin-2-one (C-60)

[1101] Following the synthetic method of compound C-93, 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one was replaced with 1-(6-aminopyridin-3-yl)-4-cyclopropylpiperazin-2-one to obtain the title compound (8.9 mg).

[1102] MS m / z (ESI): 511.2 [M+H] + .

[1103] 1 H NMR (400MHz, DMSO-d6): δ10.38(s,1H),8.74(d,J=4.0Hz,1H),8.50(s,1H),8.27(d,J=4.0Hz,1H),8.09-8.02(m,2H),7.75(dd,J=8.0,4.0Hz,1H) ,7.55(d,J=8.0Hz,1H),3.81(s,2H),3.69-3.62(m,2H),3.04-2.95(m,5H ),2.63-2.54(m,2H),1.85-1.81(m,1H),1.74(s,6H),0.53-0.38(m,4H).

[1104] Example 58: Preparation of 4-methyl-1-(5-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyrazin-2-yl)piperazin-2-one (C-96)

[1105] Following the synthetic method of compound C-93, 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one was replaced with 1-(5-aminopyridin-2-yl)-4-methylpiperazin-2-one to obtain the title compound (8 mg).

[1106] MS m / z (ESI): 486.3 [M+H] + .

[1107] 1H NMR (400MHz, DMSO-d6): δ10.63(s,1H),9.21(s,1H),8.83(d,J=1.6Hz,1H),8.78(d,J=1.2Hz,1H),8.44(s,1H),8.09(d,J=8.4Hz,1H),7. 55(d,J=8.4Hz,1H),3.85(dd,J=6.4,4.4Hz,2H),3.82(s,2H),3.22(s,2H),3.01(s,3H),2.77(t,J=5.6Hz,2H),2.30(s,3H),1.75(s,6H).

[1108] Example 59: Preparation of 1-(5-fluoro-6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one (C-97)

[1109] Following the synthetic method of compound C-93, 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one was replaced with 1-(6-amino-5-fluoropyridin-3-yl)-4-methylpiperazin-2-one to obtain the title compound (6 mg).

[1110] MS m / z (ESI): 503.3 [M+H] + .

[1111] 1 H NMR (400MHz, DMSO-d6): δ9.98(s,1H),8.68(d,J=1.2Hz,1H),8.48(d,J=1.2Hz,1H),8.26(d,J=2.4Hz,1H),8.09(d,J=8.0Hz,1H),7.91(dd,J=11.6 ,2.4Hz,1H),7.55(d,J=8.0Hz,1H),3.81(s,2H),3.74(t,J=5.2Hz,2H),3 .17(s,2H),3.00(s,3H),2.76(t,J=5.2Hz,2H),2.30(s,3H),1.72(s,6H).

[1112] Example 60: Preparation of 1-(4-fluoro-6-((6-(1,3,3-trimethyl-2,3-dihydro-1H-imidazo[2',1':2,3]imidazo[4,5-b]pyridin-6-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-4-methylpiperazin-2-one (C-98)

[1113] Following the synthetic method of compound C-93, 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one was replaced with 1-(6-amino-4-fluoropyridin-3-yl)-4-methylpiperazin-2-one to obtain the title compound (15 mg).

[1114] MS m / z (ESI): 503.3 [M+H] + .

[1115] 1 H NMR (400MHz, DMSO-d6): δ10.66(s,1H),8.80(s,1H),8.42-8.29(m,2H),8.17(d,J=12.8Hz,1H),8.09(d,J=8.4Hz,1H),7.55(d ,J=8.0Hz,1H),3.81(s,2H),3.63(t,J=5.2Hz,2H),3.16(s,2H),3.01(s,3H),2.76(t,J=5.6Hz,2H),2.31(s,3H),1.75(s,6H).

[1116] Other compounds disclosed herein were prepared by the methods described in Examples 1-45 and 1-60.

[1117] Biological tests

[1118] Experimental Example 1: Detection of the inhibitory effect of compounds on CDK2 / 4 / 6 enzyme activity

[1119] Experimental materials: CDK2 / Cyclin E1, CDK4 / Cyclin D1, CDK6 / Cyclin D3, Histone H1 Protein, ATP, DMSO, Kinase Buffer.

[1120] Reagent Kit Name / Manufacturer: ADP-Glo ​​Kinase Assay / Promega

[1121] The test compound was serially diluted with DMSO.

[1122] CDK2 / Cyclin E1 enzyme reaction system: CDK2 / Cyclin E1 (final concentration 2.5 nM) was mixed with the diluted analyte (final concentration 0.02 nM–5000 nM) and incubated at room temperature for 10 min. Substrate (final concentration 0.1 mg / mL) and ATP (final concentration 20 μM) were added and mixed, and incubated at room temperature for 1 h. ADP-Glo ​​reagent was added and incubated at room temperature for 2 h. Kinase detection reagent was then added and incubated at room temperature for 1 h. Fluorescence signal was detected using the ADP-Glo ​​method.

[1123] CDK4 / Cyclin D1 enzyme reaction system: Mix CDK4 / Cyclin D1 (final concentration of 16 nM) with the diluted analyte and incubate at room temperature for 10 min. Add substrate (final concentration 0.2 mg / mL) and ATP (final concentration 200 μM) and incubate at room temperature for 1 h. Add ADP-Glo ​​reagent and incubate at room temperature for 2 h. Add kinase detection reagent and incubate at room temperature for 1 h. Detect fluorescence signal using the ADP-Glo ​​method.

[1124] CDK6 / Cyclin D3 enzyme reaction system: Mix CDK6 / Cyclin D3 (final concentration of 31 nM) with the diluted analyte and incubate at room temperature for 10 min. Add substrate (final concentration 0.2 mg / mL) and ATP (final concentration 200 μM) and incubate at room temperature for 1 h. Add ADP-Glo ​​reagent and incubate at room temperature for 1 h. Add kinase detection reagent and incubate at room temperature for 1 h. Detect fluorescence signal using the ADP-Glo ​​method.

[1125] Using the solvent group (DMSO) as a negative control and the buffer group (containing no CDK2 / Cyclin E1, CDK4 / Cyclin D1 and CDK6 / Cyclin D3 proteins) as a blank control, the percentage inhibition rate of different concentrations of compounds was calculated according to the following formula.

[1126] Percentage suppression rate = 100 - (signal value) 化合物 -Signal value 空白 ) / (signal value) 阴性 –Signal value 空白 *100, fit the detection signal value based on the Top maximum inhibition rate and the Bottom baseline inhibition rate, and calculate IC. 50 Values. The inhibitory effect of the compound on CDKs was determined according to the above method.

[1127] Table 1-1 Inhibitory activity of compounds against CDK2 kinase

[1128] Table 1-2 Inhibitory activities of compounds against CDK4 kinase

[1129] Table 1-3 Inhibitory activities of compounds against CDK6 kinase

[1130] The results show that the disclosed compounds have strong inhibitory effects on CDK2 kinase, CDK4 kinase, and CDK6 kinase.

[1131] Experimental Example 2: Inhibition of Proliferation of Compounds in MCF-7 Breast Cancer Cells

[1132] Cell name / source: MCF-7 / Nanjing Kebai.

[1133] Reagent Kit Name / Manufacturer: CellCounting-Lite 2.0 Luminescent Cell Viability Assay (Nanjing Novizan Biotechnology Co., Ltd.)

[1134] Cell count: MCF-7: 500 cells / well. Culture medium: RPMI-1640, EMEM + 10% FBS, DMSO content: ≤0.1%. Compound incubation conditions: 37℃, 5% CO2. Incubation time: 144 hours. Detection temperature: room temperature. Testing instrument: Pherastar-FS microplate reader (BMG LABTECH).

[1135] After MCF-7 cells were cultured in vitro as a monolayer, they were seeded into 96-well plates at a rate of 400-500 cells / well. After overnight culture, pre-diluted test compound was added (initial concentration 20 μM, final concentration 0.05 nM, dilution factor 5). DMSO was added to the negative control group, and culture medium was added to the blank control group. After incubation for 144 hours, the test reagent Cell was added to each well. Read the chemiluminescence unit value (RLU) using the ELISA reader in chemiluminescence detection mode, and calculate the proliferation inhibition rate (%) using the following formula:

[1136] The proliferation inhibition rate (%) = (1 - (test well reading - average value of culture medium wells) / (average value of negative control - average value of culture medium wells)) × 100%. Using the concentration of the analyte as the X-axis and the proliferation inhibition rate as the Y-axis, the IC50 value was obtained by fitting a four-parameter equation. 50 value.

[1137] Table 2 Results of the inhibitory activity of the compounds on the proliferation of MCF-7 cells

[1138] The disclosed compound exhibits good inhibitory effects on the proliferative activity of tumor cells.

[1139] The methods and products disclosed herein have been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and products described herein without departing from the content, spirit, and scope of this disclosure to achieve the technology disclosed herein. In particular, it should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the spirit, scope, and content of this disclosure.

Claims

A compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein the compound has a structure as shown in Formula I: in, X 1 Selected from N and CR 1 ; (1) When X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups; R 3 Selected from H, C 1-6 Alkyl, -C 1-6 Alkylene-OR c C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 6 replace; Or, R 2 R 3 The atoms bonded to it form 3-8 membered heterocyclic groups, said heterocyclic groups optionally bonded by one or more elements selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-OR a3 The alkyl, cycloalkyl, and heterocyclic groups are substituted with groups selected from cyano, -C, and cycloalkyl groups, respectively. 1-6 alkylene-cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-OR a3 Substitution of groups; (2) When X 1 For CR 1 At that time, R 2 R 3 The atoms bonded to it form 3-8 membered heterocyclic groups, said heterocyclic groups optionally bonded by one or more elements selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-OR a4 -OC 1-6 The alkyl and 3-8 membered heterocyclic groups are substituted, and the alkyl, cycloalkyl and heterocyclic groups are further replaced by one or more groups selected from cyano, -C 1-6 alkylene-cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-OR a4 Substitution of groups; R 1 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups; R 4 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups; R 5 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups; R 6 Each is independently selected from H, deuterium, halogen, cyano, and -OR. d1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-OR d2 C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution; Y is selected from phenyl and 5-10 heteroaryl groups, wherein the phenyl and heteroaryl groups are optionally separated by one or more R groups. 7 replace; R 7 Each is independently selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups; Or, R 7 Formation of 3-10 membered heterocycles fused with Y, wherein the heterocycles are optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution; L is selected from covalent bonds, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -C 1-6 Alkylene-N(R) e1 )-、-C 1-6 Alkylene-O-, -N(R) e2 )-、-O-、-N(R e3 )-C 1-6 Alkylene-N(R) e4 )-、-N(R e5 )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) e6 )-、-C(=O)-C 1-6 Alkylene -O-, -C(=O)-C 1-6 Alkylene-N(R) e7 - and -S(=O)2-; Z is selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 8 replace; R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo (=O), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(R) g1 )R h1 -C 1-6 Alkylene-N(R) g2 )R h2 -C 1-6 Alkylene-OR g3 -C(=O)-N(R) g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4 C 3-10 cycloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -N(R) g8 )R h5 Substitution of groups; R a1 R a2 R a3 and R a4 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen; R b Selected from H and C 1-6 alkyl; R c Selected from H, C 1-6 Alkyl and C 3-8 cycloalkyl; R d1 and R d2 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with one or more groups selected from deuterium, cyano, and halogen; R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H and C. 1-6 alkyl; R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 R h1 R h2 R h3 R h4 and R h5 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, When X 1 When R is N, 2 Selected from H, deuterium, halogen, cyano, -N(R) a1 )R b C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, -OR a2 C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Substitution of cycloalkyl and 3-6 membered heterocyclic groups; Preferably, when X 1 When R is N, 2 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and 3-7 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally selected from one or more cyano and -OR groups. a2 Substitution of groups; More preferably, when X 1 When R is N, 2 Selected from methyl, isopropyl, cyclopropyl, morpholino, tetrahydropyrrolyl, -CH2-cyclopropyl, -CH2-cyclopentyl, The methyl, isopropyl, cyclopropyl, morpholino, tetrahydropyrrolyl, and cyclopentyl groups mentioned above... Optionally selected by one or more groups selected from cyano and -OR a2 Substitution of groups; More preferably, when X 1 When R is N, 2 Selected from methyl, isopropyl, cyclopropyl, morpholino, tetrahydropyrrolyl, -CH2-cyclopropyl, -CH2-cyclopentyl, The methyl, isopropyl, cyclopropyl, morpholino, tetrahydropyrrolyl, and cyclopentyl groups mentioned above... Optionally selected by one or more groups selected from cyano and -OR a2 Group substitution; R a2 Selected from H, methyl, ethyl, cyclopropyl, -CF3 and deuterated methyl, further, R a2 Selected from H, methyl, ethyl, cyclopropyl and -CD3; More preferably, when X 1 When R is N, 2 Selected from methyl, The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, When X 1 When R is N, 3 Selected from H, C 1-6 Alkyl, -C 1-4 Alkylene-OR c C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 6 replace; Preferably, when X 1 When R is N, 3 Selected from C 1-4 Alkyl and C 3-6 cycloalkyl, wherein the alkyl and cycloalkyl groups are optionally separated by one or more R 6 replace; Preferably, when X 1 When R is N, 3 Selected from isopropyl, tert-butyl, and cyclopropyl, wherein the isopropyl, tert-butyl, and cyclopropyl groups are optionally oxidized by one or more R groups. 6 replace; More preferably, R 3 Selected from isopropyl, cyclopropyl, The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, R 2 R 3 The atoms bonded to it form 3-6 membered heterocyclic groups, each of which is optionally bonded by one or more atoms selected from deuterium, halogens, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, -OC 1-4 Alkyl and -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-OR a3 The alkyl, cycloalkyl, and heterocyclic groups are substituted with groups selected from cyano, -C, and cycloalkyl groups, respectively. 1-4 alkylene-cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -C 1-4 Alkylene-OR a3 Substitution of groups; Preferably, R 2 R 3 and connected atoms form The Each is optionally selected by one or more of C 1-4 Alkyl, C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 cycloalkyl, 3-6 membered heterocyclic groups Substitution of the group, further, the Each is optionally bounded by one or more compounds selected from methyl, cyclopropyl, -CH2-cyclopropyl, tetrahydropyranyl, Substitution of groups; Furthermore, R 2 R 3 and connected atoms form The compound of any one of claims 1 or 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, When X 1 For CR 1 At that time, R 1 Selected from H. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, The compound satisfies one or more of the following characteristics: (1)R 4 Selected from H; (2)R 5 Selected from H. The compound of any one of claims 1-3 or 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, R 6 Each is independently selected from cyano, -OR d1 C 1-4 Alkyl and -C 1-4 Alkylene-OR d2 The alkyl group is optionally substituted with one or more groups selected from cyano; R d1 and R d2 Each is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3, -CD3, -CH2CD3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Preferably, R 6 Each is independently selected from cyano, -OR d1 -CH2CN and -C 1-4 Alkylene-OR d2 ;R d1 and R d2 Each is independently selected from methyl, ethyl, -CF3 and -CD3; More preferably, R 6 Each is independently selected from cyano, -CH2CN, -CH2OCH3, -CH2OCH2CH3, -OCH3, -OCH2CH3, -OCF3, -CH2OCF3, -OCD3 and -CH2OCD3. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, Y is selected from phenyl and 5-6-membered heteroaryl groups, wherein the phenyl and heteroaryl groups are optionally separated by one or more R groups. 7 replace; Further, Y is selected from pyridinyl and pyrazinyl, said pyridinyl and pyrazinyl groups optionally being converted by one or more R groups. 7 replace; Furthermore, Y is selected from The Optionally by one or more R 7 Replace; R 7 Each is independently selected from H, F, Cl, hydroxyl, cyano, methyl, ethyl, -CF3, -CH2CF3, methoxy, ethoxy, -O-CF3, and -O-CH2CF3; further, Y is selected from... The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, Y is selected from 5-6-membered heteroaryl groups, wherein the heteroaryl group is optionally surrounded by one or more R groups. 7 Replace, and R 7 Formation of 3-8 membered heterocycles fused with Y, wherein the heterocycles are optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution; Further, Y is selected from pyridinyl, said pyridinyl group being reacted with one or more R groups. 7 Replace, and R 7 Formation of a 5-8 membered heterocycle fused with Y, wherein the heterocycle is optionally bonded by one or more elements selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution; Furthermore, Y is selected from The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, L is selected from covalent bonds, methylene, vinylene, ethynylene, -methylene-N(R) e1 )-、-methylene-O-、-N(R e2 )-、-O-、-N(R e3 )-Methylene-N(R e4 )-、-N(R e5 -methylene-O-, -C(=O)-, -C(=O)-N(R) e6 -, -C(=O)-methylene-O-, -C(=O)-methylene-N(R) e7 - and -S(=O)2-; R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H and methyl; Preferably, L is selected from covalent bonds, methylene, vinylene, ethynylene, -methylene-NH-, -methylene-O-, -NH-, -O-, -NH-methylene-NH-, -NH-methylene-O-, -C(=O)-, -C(=O)-NH-, -C(=O)-methylene-O-, -C(=O)-methylene-NH- and -S(=O)2-; More preferably, L is selected from covalent bonds, methylene, -NH-, -O-, -C(=O)- and -S(=O)2-; More preferably, L is selected from covalent bonds, -O- and -C(=O)-. The compound of any one of claims 1-8 or 10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein, Z is selected from 3-6 membered heterocyclic groups, which are optionally surrounded by one or more R groups. 8 Replace, further, R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF3, -CH2-CF3, -OCH3, -OCF3, -N(R) g1 )R h1 ,-methylene-N(R) g2 )R h2 ,-methylene-OR g3 -C(=O)-N(R) g4 )R h3 -C(=O)-R g5 -S(=O)2-R g6 -S(=O)2-N(R) g7 )R h4 Cyclopropyl, aziridine, -CH2-cyclopropyl, ethylene oxide, and oxetane; R g1 R g2 R g3 R g4 R g5 R g6 R g7 R h1 R h2 R h3 and R h4 Each is independently selected from H, methyl, ethyl, and cyclopropyl; Preferably, Z is selected from 3-6 membered heterocyclic groups, which are optionally surrounded by one or more R groups. 8 replace, More preferably, Z is selected from piperidinyl, piperazinyl, and morpholinyl, wherein the piperidinyl, piperazinyl, and morpholinyl are optionally surrounded by one or two R. 8 replace; R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl, -CF3, -CH2-CF3, cyclopropyl, -CH2-cyclopropyl, -N(R) g1 )R h1 and R g1 and R h1 Each is independently selected from methyl groups; More preferably, Z is selected from The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein the compound satisfies one or more of the following characteristics: (1)R 7 Each is independently selected from H; (2)R 8 Each is independently selected from oxo, methyl, ethyl, isopropyl, -CF3, -CH2-CF3, cyclopropyl, -CH2-cyclopropyl and -N(R) g1 )R h1 ; (3)R a1 Selected from H, methyl, ethyl, and cyclopropyl; (4)R a2 Selected from H, methyl, ethyl, cyclopropyl, -CF3 and deuterated methyl, further, R a2 Selected from H, methyl, ethyl, cyclopropyl and -CD3; (5)R a3 and R a4 Each is independently selected from H, methyl, ethyl, cyclopropyl, -CF3 and deuterated methyl; (6)R b Selected from H, methyl, and cyclopropyl; (7)R c Selected from H, methyl, and cyclopropyl; (8)R d1 and R d2 Each is independently selected from methyl, ethyl, -CF3 and -CD3; (9)R e1 R e2 R e3 R e4 R e5 R e6 and R e7 Each is independently selected from H; (10)R g1 R g2 R g3 R g4 R g5 R g6 R g7 R g8 R h1 R h2 R h3 R h4 and R h5 Each is independently selected from methyl groups. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein the compound is selected from: A pharmaceutical composition comprising the compound of any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers. A pharmaceutical formulation comprising, as an active ingredient, any one of the compounds of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or a mixture thereof, or a mixture thereof, or the pharmaceutical composition of claim 14. A medicine box comprising: (a) a first container; (b) a pharmaceutical composition as claimed in claim 14 located in the first container, wherein the composition comprises: a first therapeutic agent comprising: The compound of any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or a mixture thereof; and (c) the optional packaging instructions. Use of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or mixture thereof, the pharmaceutical composition of claim 14, the pharmaceutical formulation of claim 15, or the cassette of claim 16 in the preparation of a medicament for the treatment and / or prevention of diseases or symptoms associated with CDK2 / 4 / 6 activity. The compound of any one of claims 1-13 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or mixture thereof, the pharmaceutical composition of claim 14, the pharmaceutical formulation of claim 15, or the cassette of claim 16, are for the treatment and / or prevention of diseases or symptoms associated with CDK2 / 4 / 6 activity. A method for treating and / or preventing diseases or symptoms associated with CDK2 / 4 / 6 activity, the method comprising administering to an individual in need an effective amount of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or mixture thereof, the pharmaceutical composition of claim 14 or the pharmaceutical formulation of claim 15. Methods for preparing the compound according to any one of claims 1-13 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug: in, B 1 Selected from halogen, borate group, borate ester group and -Sn(C 1-6 Alkyl)3; B 2 It is a halogen; A 1 Selected from borate groups, borate ester groups, and halogens; X 1 R 2 R 3 R 4 R 5 Y, L and Z are as defined in any one of claims 1-13. Compounds having the following structure: Among them, X 1 R 2 R 3 R 4 R 5 Y, L, and Z are as defined in any one of claims 1-13; B 2 It is a halogen; A 1 Selected from borate groups, borate ester groups, and halogens; Furthermore, the compound is selected from:

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