Heteroaromatic compound, pharmaceutical composition thereof, and use thereof

Abstract

The present application provides a heteroaromatic compound represented by formula I, a pharmaceutical composition thereof, and use thereof. The heteroaromatic compound has high inhibitory activity against CDK2, CDK4, and / or CDK6.

Description

Heterocyclic aromatic compounds, their pharmaceutical compositions and their uses

[0001] Cross-references to related applications

[0002] This application claims Chinese patent application number CN202510115103.0, filed January 24, 2025, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof," filed February 26, 2025, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof," and Chinese patent application number CN202510215490.5, filed March 27, 2025, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof." Chinese patent applications CN202510371237.9, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof," filed on April 27, 2025; CN202510537833.X, also entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof," filed on May 28, 2025; and CN202510698966.5, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof," respectively. The priority of the following Chinese patent applications filed on June 24, 2025, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof", including application number CN202510850767.1 filed on June 24, 2025, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof", application number CN202511113367.9 filed on August 8, 2025, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof", application number CN202511423512.3 filed on September 30, 2025, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof", and application number CN202511772316.7 filed on November 28, 2025, entitled "Heteroaromatic Compounds, Pharmaceutical Compositions Thereof, and Uses Thereof", is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to heterocyclic aromatic compounds, pharmaceutical compositions thereof, methods of preparation thereof, 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. Proteins in the CDK family include 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 safe CDK2, CDK4, and / or CDK6 inhibitors that can overcome resistance. Summary of the Invention

[0009] On one hand, the present invention 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] X1 Selected from N and CH;

[0012] X 2 Selected from N and CR 2 ;

[0013] X 3 Selected from N and CR 3 ;

[0014] X 4 Selected from N and C;

[0015] X 5 Selected from O, S, CR 4 ;

[0016] When X 1 When selected from N, X 2 Selected from N;

[0017] It can be a single bond or a double bond;

[0018] R 1 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C 1-6 Alkylene-OR a 3-12 membered heterocyclic group, 3-12 membered heterocyclic group = C(C 1-6 alkyl)-, C 3-12 cycloalkyl = C(C) 1-6 Alkyl)-, -C(=O)-C 1-6 Alkyl, -C(=O)-N(R) 6 )R 7 , -N(R 6 )R 7 and -OR a The alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace;

[0019] R 2 Selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0020] R 3 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0021] R 4 Selected from H, deuterium, halogen, cyano, 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, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups;

[0022] Or, R 1 R 4 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0023] R 5 Each is independently selected from H, deuterium, halogen, cyano, hydroxyl, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-OR a C 2-6 Alkylene, C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, alkylene, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0024] Or, two Rs 5 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0025] R 6 and R 7 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0026] Or, R 6 and R 7 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0027] 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. 8 replace;

[0028] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0029] Or, R 8 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; or two substituents that substituted on the same ring atom of the 3-8 membered heterocycle together form C. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups;

[0030] 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) a )-、-C 1-6 Alkylene-O-, -N(R) a )-、-O-、-N(R a )-C 1-6 Alkylene-N(R) a )-、-N(R a )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) a )-、-C(=O)-C 1-6 Alkylene -O-, -C(=O)-C 1-6 Alkylene-N(R) a - and -S(=O)2-; or, L forms C fused with Y. 6-10Aryl, 5-10 heteroaryl, C 5-10 Cycloalkyl or 5-10 membered heterocyclic group; the aryl, heteroaryl, cycloalkyl, and heterocyclic group are optionally composed of one or more elements selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Substituents of haloalkyl groups;

[0031] Z is selected from H, -NR e R f C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups, said heterocyclic group optionally being surrounded by one or more R groups. 9 replace;

[0032] R 9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(R) c )R d -C 1-6 Alkylene-N(R) c )R d -C 1-6 Alkylene-OR c -C(=O)-N(R) c )R d -C(=O)-R c -S(=O)2-R c -S(=O)2-N(R) c )R d C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl and -C 1-6 Alkylene-3-12-membered heterocyclic group, wherein the alkyl, alkylene, cycloalkyl, and heterocyclic group 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) c )R d replace;

[0033] R a Selected from H and C 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups.1-6 Alkyl substituents;

[0034] R c and R d Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0035] R e and R f Each is independently selected from H and C. 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents.

[0036] A second aspect of the present invention 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.

[0037] A third aspect of the present invention provides a medicine box product comprising:

[0038] a) at least one compound of the present invention 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;

[0039] 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

[0040] c) Optional packaging and / or instructions.

[0041] A fourth aspect of the invention provides the use of 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 thereof, in the preparation of medicaments for treating and / or preventing diseases or symptoms associated with CDK2, CDK4 and / or CDK6 activity.

[0042] The fifth aspect of the invention 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 symptoms associated with CDK2, CDK4 and / or CDK6 activity.

[0043] A sixth aspect of the invention provides a method for treating and / or preventing diseases or symptoms associated with CDK2, CDK4, and / or CDK6 activity, the method comprising administering to an individual in need an effective amount of the compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, or pharmaceutical composition, or kit product thereof.

[0044] A seventh aspect of the present invention provides a method for preparing the compounds of the present invention.

[0045] definition

[0046] 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 explain the invention.

[0047] 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.”

[0048] 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.

[0049] 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 1-5And 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.

[0050] As used herein, an asterisk (*) in a compound structural formula indicates that the labeled carbon atom is a chiral carbon atom, and the invention includes a pair of enantiomers formed from that chiral carbon atom. If a compound contains two different chiral carbon atoms, the invention includes four optical isomers formed from that chiral carbon atom.

[0051] As used in this article, This indicates the location where a structural segment connects to other parts of the molecule.

[0052] 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.

[0053] The term "alkylene" refers to a divalent group formed by losing two hydrogen atoms from the same or different carbon atoms of a straight-chain or branched alkane. For example, the term "C" in this invention... 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.

[0054] 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 invention... 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.

[0055] 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 invention... 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.

[0056] 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.

[0057] 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.

[0058] 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 ...70, C60, C70, C70, C70, C70, C70, C70, C70, C 5-8 Spirocycloalkyl, C5-8 Bridged cycloalkyl, C 5-8 fused cycloalkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl groups.

[0059] The term "heterocyclic (group)" or "heterocyclic alkyl" 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 through 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" 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.

[0060] The term "saturated heterocycle" refers to a fully saturated heterocycle, such as the tetrahydrofuran ring, piperidine ring, tetrahydropyran ring, piperazine ring, etc. 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, dihydrofuran, etc.

[0061] 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.

[0062] The term "oxygen-containing heterocycle (group)" refers to a heterocycle as described above with one or more (e.g., 1, 2, or 3) ring atoms being 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.

[0063] The "nitrogen-containing heterocycle (group)" as described in this invention refers to the heterocycle described above with one or more (e.g., 1, 2 or 3) ring atoms being nitrogen atoms.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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" 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.

[0071] 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 C1-2 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. The alkoxy groups in this invention are optionally substituted by one or more substituents described in this invention.

[0072] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, or 4) alkoxy groups, wherein the definitions of alkoxy and alkyl groups are as described above. For example, the term "C" as used in this invention... 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.

[0073] The term "halogenated" or "halogenated" is defined as including F, Cl, Br, or I.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0079] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, 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 the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0080] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is substantially non-toxic to organisms. Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0081] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to organisms and hydrolyzes in vivo to form the compound of the present invention or its salt. Additionally, the compound of the present invention may itself be an ester.

[0082] 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.

[0083] 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. Since the compounds of this invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, this invention also includes these stereoisomers and mixtures thereof. Because the compounds of this invention (or pharmaceutically acceptable salts thereof) comprise 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. Unless otherwise stated, all stereoisomers of the compounds of this invention are within the scope of this invention.

[0084] Solid lines may be used in this article. solid wedge Or virtual wedge The carbon-carbon bonds of the compounds of the present invention 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 the present invention 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-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0085] The term "polymorph" (or "polymorphic form") refers to the solid crystalline form of a compound or complex. This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of multiple polymorphs in any proportion.

[0086] The term "solvent" refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. The compounds of the present invention may exist as solvates, containing a polar solvent as an element of the crystal structure. The amount of polar solvent may be stoichiometric or non-stoichiometric.

[0087] The term "isotope-labeled compound" refers to a derivative compound formed by replacing specific atoms in the compounds of this invention with their isotopic atoms. Unless otherwise indicated, the compounds of this invention 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, 32 P, 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 be2 H(D, deuterium) or 3 H(T, tritium) substitution; 16 O can be 18 O substitution, etc.

[0088] 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.

[0089] The term "metabolite" refers to a derivative compound formed after the compounds of the present invention are metabolized, for example, by reactions such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, or enzymatic hydrolysis. The present invention covers all possible metabolite forms of the compounds of the present invention, i.e., substances formed in the body of an individual administering the compounds of the present invention. Metabolites of the compounds can be identified using techniques known in the art, and their activity can be characterized experimentally.

[0090] The term "prodrug" refers to a derived compound that, upon administration to an individual, can directly or indirectly provide the compounds of the present invention. Particularly preferred derived compounds or prodrugs are those that, upon administration to an individual, can improve the bioavailability of the compounds of the present invention (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 the present invention are within the scope of the present invention, and various prodrug forms are known in the art. Furthermore, the present invention also covers compounds of the present invention containing protecting groups. During any process of preparing the compounds of the present invention, 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 the present invention. These protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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 invention, “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.).

[0096] compound

[0097] In some embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof:

[0098] in,

[0099] X 1 Selected from N and CH;

[0100] X 2 Selected from N and CR 2 ;

[0101] X 3 Selected from N and CR 3 ;

[0102] X 4 Selected from N and C;

[0103] X 5 Selected from O, S, CR 4 ;

[0104] When X 1 When selected from N, X 2 Selected from N;

[0105] It can be a single bond or a double bond;

[0106] R 1 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C 1-6 Alkylene-OR a 3-12 membered heterocyclic group, 3-12 membered heterocyclic group = C(C 1-6 alkyl)-, C 3-12 cycloalkyl = C(C) 1-6 Alkyl)-, -C(=O)-C 1-6 Alkyl, -C(=O)-N(R) 6 )R 7 , -N(R 6 )R 7 and -OR a The alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace;

[0107] R 2 Selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0108] R 3 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0109] R 4 Selected from H, deuterium, halogen, cyano, 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, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups;

[0110] Or, R 1 R 4 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C.1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0111] R 5 Each is independently selected from H, deuterium, halogen, cyano, hydroxyl, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-OR a C 2-6 Alkylene, C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, alkylene, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0112] Or, two Rs 5 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0113] R 6 and R 7 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0114] Or, R 6 and R 7 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0115] 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. 8 replace;

[0116] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0117] Or, R 8 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 Haloalkyl, C 3-10 cycloalkyl and -OC 1-6 Alkyl group substitution; or two substituents that substituted on the same ring atom of the 3-8 membered heterocycle together form C. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups;

[0118] 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) a )-、-C 1-6 Alkylene-O-, -N(R) a )-、-O-、-N(R a )-C 1-6 Alkylene-N(R) a )-、-N(R a )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) a )-、-C(=O)-C 1-6 Alkylene -O-, -C(=O)-C 1-6 Alkylene-N(R) a - and -S(=O)2-; or, L forms C fused with Y. 6-10 Aryl, 5-10 heteroaryl, C 5-10 Cycloalkyl or 5-10 membered heterocyclic group; the aryl, heteroaryl, cycloalkyl, and heterocyclic group are optionally composed of one or more elements selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Substituents of haloalkyl groups;

[0119] Z is selected from H, -NR e R f C 1-6 Alkyl, C 3-12 Cycloalkyl groups and 3-12 membered heterocyclic groups, said heterocyclic group optionally being surrounded by one or more R groups. 9 replace;

[0120] R 9Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(R) c )R d -C 1-6 Alkylene-N(R) c )R d -C 1-6 Alkylene-OR c -C(=O)-N(R) c )R d -C(=O)-R c -S(=O)2-R c -S(=O)2-N(R) c )R d C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl and -C 1-6 Alkylene-3-12-membered heterocyclic group, wherein the alkyl, alkylene, cycloalkyl, and heterocyclic group 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) c )R d replace;

[0121] R a Selected from H and C 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents;

[0122] R c and R d Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl; the alkyl group is optionally radicalized by one or more elements selected from deuterium, halogen, hydroxyl, cyano, and -OC. 1-6 Alkyl substituents;

[0123] R e and R f Each is independently selected from H and C. 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents.

[0124] In some implementation schemes:

[0125] X 1 Selected from N and CH;

[0126] X 2 Selected from N and CR 2 ;

[0127] X 3 Selected from N and CR 3 ;

[0128] X 4 Selected from N and C;

[0129] X 5 Selected from O, S, CR 4 ;

[0130] When X 1 When selected from N, X 2 Selected from N;

[0131] It can be a single bond or a double bond;

[0132] R 1 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C 1-6 Alkylene-OR a 3-12 membered heterocyclic group, 3-12 membered heterocyclic group = C(C 1-6 alkyl)-, C 3-12 cycloalkyl = C(C) 1-6 Alkyl)-, -C(=O)-C 1-6 Alkyl, -C(=O)-N(R) 6 )R 7 , -N(R 6 )R 7 and -OR a The alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace;

[0133] R 2 Selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0134] R 3 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC1-6 Halogenated alkyl groups;

[0135] R 4 Selected from H, deuterium, halogen, cyano, 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, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups;

[0136] Or, R 1 R 4 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0137] R 5 Each is independently selected from H, deuterium, halogen, cyano, hydroxyl, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-OR a C 2-6 Alkylene, C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, alkylene, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0138] Or, two Rs 5 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0139] R 6 and R 7 Each is independently selected from H and C.1-6 Alkyl and C 3-8 cycloalkyl;

[0140] Or, R 6 and R 7 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0141] 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. 8 replace;

[0142] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0143] Or, R 8 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; or two substituents that substituted on the same ring atom of the 3-8 membered heterocycle together form C. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups;

[0144] 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) a )-、-C 1-6 Alkylene-O-, -N(R) a )-、-O-、-N(R a )-C 1-6 Alkylene-N(R) a )-、-N(R a )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) a )-、-C(=O)-C 1-6 Alkylene -O-, -C(=O)-C 1-6 Alkylene-N(R) a- and -S(=O)2-; or, L forms C fused with Y. 6-10 Aryl, 5-10 heteroaryl, C 5-10 Cycloalkyl or 5-10 membered heterocyclic group; the aryl, heteroaryl, cycloalkyl, and heterocyclic group are optionally composed of one or more elements selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Substituents of haloalkyl groups;

[0145] Z is selected from H, -NR e R f C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups, said heterocyclic group optionally being surrounded by one or more R groups. 9 replace;

[0146] R 9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(R) c )R d -C 1-6 Alkylene-N(R) c )R d -C 1-6 Alkylene-OR c -C(=O)-N(R) c )R d -C(=O)-R c -S(=O)2-R c -S(=O)2-N(R) c )R d C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl and -C 1-6 Alkylene-3-12-membered heterocyclic group, wherein the alkyl, alkylene, cycloalkyl, and heterocyclic group 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) c )R d replace;

[0147] R a Selected from H and C 1-6Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents;

[0148] R c and R d Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0149] R e and R f Each is independently selected from H and C. 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents.

[0150] In some implementation schemes: X 1 Selected from N and CH;

[0151] X 2 Selected from N and CR 2 ;

[0152] X 3 Selected from N and CR 3 ;

[0153] X 4 Selected from N and C;

[0154] X 5 Selected from O, S, CR 4 ;

[0155] When X 1 When selected from N, X 2 Selected from N;

[0156] It can be a single bond or a double bond;

[0157] R 1 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C 1-6 Alkylene-OR a 3-12 membered heterocyclic group, 3-12 membered heterocyclic group = C(C 1-6 alkyl)-, C 3-12 cycloalkyl = C(C) 1-6 Alkyl)-, -C(=O)-C 1-6 Alkyl, -C(=O)-N(R) 6 )R 7 , -N(R6 )R 7 and -OR a The alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace;

[0158] R 2 Selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0159] R 3 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0160] R 4 Selected from H, deuterium, halogen, cyano, 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, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups;

[0161] Or, R 1 R 4 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0162] R 5 Each is independently selected from H, deuterium, halogen, cyano, hydroxyl, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-OR a C 2-6 Alkylene, C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, alkylene, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, C1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0163] Or, two Rs 5 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0164] R 6 and R 7 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0165] Or, R 6 and R 7 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0166] 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. 8 replace;

[0167] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0168] Or, R 8 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; or two substituents that substituted on the same ring atom of the 3-8 membered heterocycle together form C. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups;

[0169] L is selected from covalent bonds, C 1-6 Alkylene, C 2-6 imidene group, C 2-6Ethyne group, -C 1-6 Alkylene-N(R) a )-、-C 1-6 Alkylene-O-, -N(R) a )-、-O-、-N(R a )-C 1-6 Alkylene-N(R) a )-、-N(R a )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) a )-、-C(=O)-C 1-6 Alkylene -O-, -C(=O)-C 1-6 Alkylene-N(R) a - and -S(=O)2-;

[0170] Z is selected from H, -NR e R f C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups, said heterocyclic group optionally being surrounded by one or more R groups. 9 replace;

[0171] R 9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(R) c )R d -C 1-6 Alkylene-N(R) c )R d -C 1-6 Alkylene-OR c -C(=O)-N(R) c )R d -C(=O)-R c -S(=O)2-R c -S(=O)2-N(R) c )R d C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl and -C 1-6 Alkylene-3-12-membered heterocyclic group, wherein the alkyl, alkylene, cycloalkyl, and heterocyclic group are optionally replaced by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC1-6 Alkyl and -N(R) c )R d replace;

[0172] R a Selected from H and C 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents;

[0173] R c and R d Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0174] R e and R f Each is independently selected from H and C. 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents.

[0175] In some implementation schemes: X 1 Selected from N and CH;

[0176] X 2 Selected from N and CR 2 ;

[0177] X 3 Selected from N and CR 3 ;

[0178] X 4 Selected from N and C;

[0179] X 5 Selected from O, S, CR 4 ;

[0180] When X 1 When selected from N, X 2 Selected from N;

[0181] It can be a single bond or a double bond;

[0182] R 1 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C 1-6 Alkylene-OR a 3-12 membered heterocyclic group, 3-12 membered heterocyclic group = C(C 1-6 alkyl)-, C 3-12cycloalkyl = C(C) 1-6 Alkyl)-, -C(=O)-C 1-6 Alkyl, -C(=O)-N(R) 6 )R 7 , -N(R 6 )R 7 and -OR a The alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace;

[0183] R 2 Selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0184] R 3 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0185] R 4 Selected from H, deuterium, halogen, cyano, 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, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups;

[0186] Or, R 1 R 4 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0187] R 5 Each is independently selected from H, deuterium, halogen, cyano, hydroxyl, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6Alkylene-OR a C 2-6 Alkylene, C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, alkylene, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, C 1-6 Alkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution;

[0188] Or, two Rs 5 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0189] R 6 and R 7 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0190] Or, R 6 and R 7 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution;

[0191] 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. 8 replace;

[0192] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups;

[0193] Or, R 8 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;

[0194] L is selected from covalent bonds, C1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -C 1-6 Alkylene-N(R) a )-、-C 1-6 Alkylene-O-, -N(R) a )-、-O-、-N(R a )-C 1-6 Alkylene-N(R) a )-、-N(R a )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) a )-、-C(=O)-C 1-6 Alkylene -O-, -C(=O)-C 1-6 Alkylene-N(R) a - and -S(=O)2-;

[0195] Z is selected from H, -NR e R f C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups, said heterocyclic group optionally being surrounded by one or more R groups. 9 replace;

[0196] R 9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(R) c )R d -C 1-6 Alkylene-N(R) c )R d -C 1-6 Alkylene-OR c -C(=O)-N(R) c )R d -C(=O)-R c -S(=O)2-R c -S(=O)2-N(R) c )R d C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the 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) c )Rd replace;

[0197] R a Selected from H and C 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents;

[0198] R c and R d Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0199] R e and R f Each is independently selected from H and C. 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents.

[0200] In some implementation schemes, X 2 Selected from N and CR 2 ;R 2 Selected from H, halogen, cyano, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups. In some embodiments, X 2 Selected from N and CR 2 ;R 2 Selected from H, halogens, and cyano groups.

[0201] In some implementation schemes, X 2 Selected from N and CR 2 ;R 2 Selected from H, F, Cl, or cyano groups.

[0202] In some implementation schemes, X 2 Selected from N and CR 2 ;R 2 Selected from halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0203] In some implementation schemes, X 2 Selected from N and CR 2 ;R 2 Selected from halogen, cyano, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0204] In some implementation schemes, X 2 Selected from N and CR 2 ;R 2 Selected from halogens and cyano groups.

[0205] In some implementation schemes, X 2 Selected from N and CR 2 ;R 2 Selected from F, Cl, or cyano groups.

[0206] In some implementation schemes, X 3 Selected from N and CR 3 ;R 3 Selected from H, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups.

[0207] In some implementation schemes, X 3 Selected from N and CR 3 ;R 3 Selected from H, deuterium, halogens and cyano groups.

[0208] In some implementation schemes, X 3 Selected from N and CH.

[0209] In some implementation schemes, X 5 Selected from O, S, and CR 4 ;R 4 Selected from H, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 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, -OC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3- 10 Substitution with cycloalkyl and 3-8 membered heterocyclic groups.

[0210] In some implementation schemes, X 5 Selected from O, S, and CR 4 ;R 4 Selected from H, deuterium, halogen, cyano and C 1-4 Alkyl; or, R 1 R 4 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC1-6 Alkyl groups are substituted.

[0211] In some implementation schemes, R 4 Selected from H; or, R 1 R 4 And the attached atoms form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl groups are substituted.

[0212] In some implementation schemes, R 4 Selected from H; or, R 1 R 4 The bonded atoms form a 3-6 member nitrogen-containing heterocyclic group or a 3-6 member oxygen-containing heterocyclic group, wherein the heterocyclic group is optionally bonded by one or more atoms selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl groups are substituted.

[0213] In some implementation schemes, R 4 Selected from H; or, R 1 R 4 The atoms bonded to it form tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolylyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyrazinyl, or piperidinyl; wherein the tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolylyl, dihydropyrrolyl, pyrazolyl, imidazoylyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyrazinyl, or piperidinyl is optionally selected from one or more atoms selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl groups are substituted.

[0214] In some implementation schemes, R 4 Selected from H; or, R 1 R 4The bonded atom forms a tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolylyl, dihydropyrrolyl, pyrazolylyl, imidazoylyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyrazinyl, or piperidinyl; wherein the tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolylyl, dihydropyrrolyl, pyrazolylyl, imidazoylyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyridazinyl, or piperidinyl is optionally bonded by one or more C atoms. 1-6 Alkyl substitution.

[0215] In some implementation schemes, R 4 Selected from H; or, R 1 R 4 The bonded atoms form a tetrahydropyranyl or piperidinyl group; said tetrahydropyranyl or piperidinyl group is optionally bonded by one or more atoms selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl groups are substituted.

[0216] In some implementation schemes, R 4 Selected from H; or, R 1 R 4 The bonded atoms form a tetrahydropyranyl or piperidinyl group; the tetrahydropyranyl or piperidinyl group is optionally bonded by one or more C atoms. 1-6 Alkyl substitution.

[0217] In some implementation schemes, R 6 and R 7 Each is independently selected from H and C. 1-6 alkyl.

[0218] In some implementation schemes, R 1 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 10 cycloalkyl, -C 1-6 Alkylene-OR a 3-12 membered heterocyclic group, 3-12 membered heterocyclic group = C(C 1-6 alkyl)-, C 3-12 cycloalkyl = C(C) 1-6 Alkyl)-, -C(=O)-C 1-6 Alkyl, -C(=O)-N(R) 6 )R 7 , The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are optionally represented by one or more R groups.5 replace;

[0219] Or, R 1 R 4 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl groups are substituted.

[0220] In some implementation schemes, R 1 Selected from H, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3- 8-cycloalkyl, -C 1-4 Alkylene-OR a 3-8 membered heterocyclic group, 3-8 membered heterocyclic group = C(C 1-4 alkyl)-, C 3-8 cycloalkyl = C(C) 1- 4alkyl)-、-C(=O)-C 1-4 Alkyl, -C(=O)-N(R) 6 )R 7 , -N(R 6 )R 7 and -OR a The alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace;

[0221] Or, R 1 R 4 And the attached atoms form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl groups are substituted.

[0222] In some implementation schemes, R 1 Selected from H, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3- 8-cycloalkyl, -C 1-4 Alkylene-OR a 3-8 membered heterocyclic group, 3-8 membered heterocyclic group = C(C1-4 alkyl)-, C 3-8 cycloalkyl = C(C) 1- 4alkyl)-、-C(=O)-C 1-4 Alkyl, -C(=O)-N(R) 6 )R 7 , The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are optionally represented by one or more R groups. 5 replace;

[0223] Or, R 1 R 4 And the attached atoms form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl groups are substituted.

[0224] In some implementation schemes, R 1 Selected from H, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, -C 1-4 Alkylene-OR a 3-8 membered heterocyclic group, 3-8 membered heterocyclic group = C(C 1-4 alkyl)-, C 3-8 cycloalkyl = C(C) 1-4 Alkyl)-, -C(=O)-C 1-4 Alkyl, -C(=O)-N(R) 6 )R 7 , -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2 and -OC 1-6 Alkyl, wherein the alkyl, alkenyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R 5 replace;

[0225] Or, R 1 R 4 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 and -OC 1-6 Alkyl groups are substituted.

[0226] In some implementation schemes, R 1Selected from H, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, -C 1-4 Alkylene-OR a 3-8 membered heterocyclic group, 3-8 membered heterocyclic group = C(C 1-4 alkyl)-, C 3-8 cycloalkyl = C(C) 1-4 Alkyl)-, -C(=O)-C 1-4 Alkyl, -C(=O)-N(R) 6 )R 7 , The alkyl, alkenyl, cycloalkyl, and heterocyclic groups are optionally separated by one or more R groups. 5 replace;

[0227] Or, R 1 R 4 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 and -OC 1-6 Alkyl groups are substituted.

[0228] In some implementation schemes, R 1 Selected from methyl, ethyl, propyl, butyl, pentyl, vinyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 1-4 Alkylene-OC 1-4 Alkyl, 3-6 membered oxygen-containing heterocyclic group, 3-6 membered nitrogen-containing heterocyclic group, 3-6 membered heterocyclic group =C(C 1-4 alkyl)-, C 3-6 cycloalkyl = C(C) 1-4 Alkyl)-, -C(=O)-C 1-4 Alkyl, -C(=O)-N(R) 6 )R 7 , The methyl, ethyl, propyl, butyl, pentyl, vinyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and heterocyclic groups are optionally separated by one or more R groups. 5 replace;

[0229] Or, R 1 R 4 The bonded atoms form a 3-6 member nitrogen-containing heterocyclic group or a 3-6 member oxygen-containing heterocyclic group, wherein the heterocyclic group is optionally bonded by one or more atoms selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8cycloalkyl and -OC 1-6 Alkyl groups are substituted.

[0230] In some implementation schemes, R 1 for:

[0231] Or, R 1 R 4 Formed with adjacent atoms:

[0232] In some implementation schemes, R 1 for:

[0233] Or, R 1 R 4 Formed with adjacent atoms:

[0234] In some implementation schemes, R 5 Each is independently selected from H, deuterium, halogen, cyano, hydroxyl, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-OR a The alkyl group is optionally replaced by one or more radicals selected from deuterium, halogen, cyano, C. 1-6 Alkyl and -OC 1-6 Alkyl group substitution;

[0235] Or, two Rs 5 And the attached atoms form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 Alkyl groups are substituted.

[0236] In some implementation schemes, R 5 Each is independently selected from H, deuterium, halogen, cyano, -OC 1-6 Alkyl, or C 1-6 alkyl.

[0237] In some embodiments, Y is selected from phenyl or 5-6 nitrogen-containing heteroaryl groups, wherein the phenyl or nitrogen-containing heteroaryl group is optionally surrounded by one or more R groups. 8 Substitution: The nitrogen-containing heteroaryl group may contain 1, 2, 3, 4 or 5 heteroatoms, and may further contain 1 or 2 heteroatoms;

[0238] R 8Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0239] Or, R 8 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 group substitution; or two substituents that substituted on the same ring atom of the 3-6 membered heterocycle together form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0240] In some embodiments, Y is selected from phenyl or 5-6 nitrogen-containing heteroaryl groups, wherein the phenyl or nitrogen-containing heteroaryl group is optionally surrounded by one or more R groups. 8 Substitution: The nitrogen-containing heteroaryl group may contain 1, 2, 3, 4 or 5 heteroatoms, and may further contain 1 or 2 heteroatoms;

[0241] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0242] Or, R 8 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.

[0243] In some embodiments, Y is selected from phenyl or a 6-membered nitrogen-containing heteroaryl group, wherein the phenyl or nitrogen-containing heteroaryl group is optionally surrounded by one or more R groups. 8 Substitution: The nitrogen-containing heteroaryl group can contain 1, 2, 3, 4, or 5 heteroatoms;

[0244] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0245] Or, R 8Formation 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 group substitution; or two substituents that substituted on the same ring atom of the 3-6 membered heterocycle together form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0246] In some embodiments, Y is selected from phenyl or a 6-membered nitrogen-containing heteroaryl group, wherein the phenyl or nitrogen-containing heteroaryl group is optionally surrounded by one or more R groups. 8 Substitution: The nitrogen-containing heteroaryl group can contain 1, 2, 3, 4, or 5 heteroatoms;

[0247] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0248] Or, R 8 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.

[0249] In some embodiments, Y is selected from 5-6-membered heteroaryl groups, said heteroaryl group optionally being surrounded by one or more R groups. 8 replace;

[0250] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0251] Or, R 8 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 group substitution; or two substituents that substituted on the same ring atom of the 3-6 membered heterocycle together form C. 3-6 Cycloalkyl.

[0252] In some embodiments, Y is selected from 5-6-membered heteroaryl groups, said heteroaryl group optionally being surrounded by one or more R groups. 8 replace;

[0253] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0254] Or, R 8 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.

[0255] In some embodiments, Y is selected from 5-6 nitrogen-containing heteroaryl groups, said nitrogen-containing heteroaryl group optionally being surrounded by one or more R groups. 8 replace;

[0256] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0257] Or, R 8 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 group substitution; or two substituents that substituted on the same ring atom of the 3-6 membered heterocycle together form C. 3-6 Cycloalkyl.

[0258] In some embodiments, Y is selected from 5-6 nitrogen-containing heteroaryl groups, said nitrogen-containing heteroaryl group optionally being surrounded by one or more R groups. 8 replace;

[0259] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0260] Or, R 8Formation 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.

[0261] In some embodiments, Y is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, preferably phenyl, pyridyl, and pyrimidinyl, wherein the pyridyl, pyrimidinyl, pyridazinyl, or triazinyl group is optionally surrounded by one or more R groups. 8 replace;

[0262] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0263] Or, R 8 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 group substitution; or two substituents that substituted on the same ring atom of the 3-6 membered heterocycle together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0264] In some embodiments, Y is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, preferably phenyl, pyridyl, and pyrimidinyl, wherein the pyridyl, pyrimidinyl, pyridazinyl, or triazinyl group is optionally surrounded by one or more R groups. 8 replace;

[0265] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0266] Or, R 8 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.

[0267] In some embodiments, Y is selected from phenyl, pyridyl, or pyrimidinyl, said phenyl, pyridyl, or pyrimidinyl group optionally influenced by one or more R groups. 8 replace;

[0268] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0269] Or, R 8 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 group substitution; or two substituents that substituted on the same ring atom of the 3-6 membered heterocycle together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0270] In some embodiments, Y is selected from phenyl, pyridyl, or pyrimidinyl, said phenyl, pyridyl, or pyrimidinyl group optionally influenced by one or more R groups. 8 replace;

[0271] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0272] Or, R 8 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.

[0273] In some embodiments, Y is selected from pyridinyl, said pyridinyl group optionally being reacted with one or more R groups. 8 replace;

[0274] R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups;

[0275] Or, R 8Formation 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.

[0276] 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) a )-、-C 1-4 Alkylene-O-, -N(R) a )-、-O-、-N(R a )-C 1-4 Alkylene-N(R) a )-、-N(R a )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) a )-、-C(=O)-C 1-4 Alkylene -O-, -C(=O)-C 1-4 Alkylene-N(R) a - and -S(=O)2-; or, L forms C fused with Y. 5-6 Cycloalkyl or 5-6 membered heterocyclic group; said cycloalkyl and heterocyclic group optionally being formed by one or more elements selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Substituents of haloalkyl groups;

[0277] 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) a )-、-C 1-4 Alkylene-O-, -N(R) a )-、-O-、-N(R a )-C 1-4 Alkylene-N(R) a )-、-N(R a )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) a )-、-C(=O)-C 1-4 Alkylene -O-, -C(=O)-C 1-4Alkylene-N(R) a - and -S(=O)2-; or, L forms a 5-6 member nitrogen-containing heterocyclic group fused with Y; said nitrogen-containing heterocyclic group is optionally surrounded by one or more elements selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 The alkyl halogroup is substituted by a substituent.

[0278] 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) a )-、-C 1-4 Alkylene-O-, -N(R) a )-、-O-、-N(R a )-C 1-4 Alkylene-N(R) a )-、-N(R a )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) a )-、-C(=O)-C 1-4 Alkylene -O-, -C(=O)-C 1-4 Alkylene-N(R) a )- and -S(=O)2-.

[0279] In some implementations, L is selected from covalent bonds, C 1-4 Alkylene, -C 1-4 Alkylene-N(R) a )-、-C 1-4 Alkylenes -O-, -O-, -N(R) a )-、-N(R a )-C 1-4 Alkylene-N(R) a -, -C(=O)-, -N(R) a )-C 1-6 Alkylene-O- and -S(=O)2-.

[0280] In some implementations, L is selected from covalent bonds, C 1-4 Alkylene, -C 1-4 Alkylene-N(R) a )-、-C 1-4 Alkylene-O-, -N(R) a )-、-N(R a )-C 1-4 Alkylene-N(R)a -, -C(=O)-, -N(R) a )-C 1-6 Alkylene-O- and -S(=O)2-.

[0281] In some implementations, L is selected from covalent bonds, C 1-4 Alkylene, -C 1-4 Alkylene-N(R) a )-、-C 1-4 Alkylene-O-, -N(R) a )-、-N(R a )-C 1-4 Alkylene-N(R) a )-, and -N(R a )-C 1-6 Alkylene-O-.

[0282] In some implementations, Z is selected from H, -N(C) 1-4 Alkyl)2、-NHC 1-4 Alkyl, C 1-4 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 9 replace.

[0283] In some implementations, Z is selected from H, -N(C) 1-4 Alkyl)2、-NHC 1-4 Alkyl, C 1-4 Alkyl, C 4-6 Monocyclic cycloalkyl, 3-6 membered monocyclic heterocyclic groups, C 7-10 cycloalkyl, 7-10 fused heterocyclic groups, C 6-11 Spirocyclic cycloalkyl, 6-11 membered spirocyclic heterocyclic, C 7-9 Bridged cycloalkyl, 7-9 membered bridged heterocyclic group, wherein the alkyl, cycloalkyl and heterocyclic group are optionally connected by one or more R 9 replace.

[0284] In some implementations, Z is selected from H, -N(C) 1-4 Alkyl)2、-NHC 1-4 Alkyl, C 1-4 Alkyl, C 4-6 Monocyclic cycloalkyl, 3-6 membered monocyclic nitrogen-containing heterocyclic group, 3-6 membered monocyclic oxygen-containing heterocyclic group, C 7-10 cycloalkyl groups, 7-10 fused cycloalkyl nitrogen-containing heterocyclic groups, C 6-11 Spirocyclic cycloalkyl, 6-11 membered spirocyclic nitrogen-containing heterocyclic groups, C 7-9 Bridged ring cycloalkyl, 7-9 membered bridged ring nitrogen-containing heterocyclic group, wherein the alkyl, cycloalkyl and heterocyclic group are optionally separated by one or more R9 replace.

[0285] In some implementations, Z is selected from H, -N(C) 1-4 Alkyl)2、-NHC 1-4 Alkyl, C 1-4 Alkyl, C 4-6 Monocyclic cycloalkyl groups, 3-6 membered monocyclic nitrogen-containing heterocyclic groups, C 7-10 cycloalkyl groups, 7-10 fused cycloalkyl nitrogen-containing heterocyclic groups, C 6-11 Spirocyclic cycloalkyl, 6-11 membered spirocyclic nitrogen-containing heterocyclic groups, C 7-9 Bridged ring cycloalkyl, 7-9 membered bridged ring nitrogen-containing heterocyclic group, wherein the alkyl, cycloalkyl and heterocyclic group are optionally separated by one or more R 9 replace.

[0286] In some implementation schemes, Z is selected from H and C. 1-4 Alkyl, -NR e R f C 3-8 Cycloalkyl and 3-11 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 9 Replace; the R e and R f Each is independently selected from H and C. 1- 6 alkyl groups, wherein the alkyl group is optionally radicaled by one or more radicals selected from deuterium, halogen, hydroxyl, cyano, and -OC. 1-6 Alkyl substituents.

[0287] In some implementations, Z is selected from H, -NR e R f C 1-4 Alkyl groups and 3-11 membered heterocyclic groups, wherein the alkyl groups and heterocyclic groups are optionally surrounded by one or more R groups. 9 Replace; the R e and R f Each is independently selected from H and C. 1-6 alkyl.

[0288] In some implementation schemes, Z is selected from H and C. 1-4 Alkyl, 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. 9 replace.

[0289] In some implementations, Z is selected from H, -N(C) 1-4 Alkyl)2、-NHC 1-4 Alkyl, C 1-4 Alkyl groups and 3-8 membered heterocyclic groups, wherein the alkyl groups and heterocyclic groups are optionally surrounded by one or more R groups. 9 replace.

[0290] In some implementation schemes, Z is selected from H and C. 1-4 Alkyl groups and 3-8 membered heterocyclic groups, wherein the alkyl groups and heterocyclic groups are optionally surrounded by one or more R groups. 9 replace.

[0291] In some implementations, Z is selected from H, -N(C) 1-4 Alkyl)2、-NHC 1-4 Alkyl, C 1-4 Alkyl groups and 3-6 membered heterocyclic groups, wherein the alkyl groups and heterocyclic groups are optionally surrounded by one or more R groups. 9 replace.

[0292] In some implementation schemes, Z is selected from H and C. 1-4 Alkyl groups and 3-6 membered heterocyclic groups, wherein the alkyl groups and heterocyclic groups are optionally surrounded by one or more R groups. 9 replace.

[0293] In some implementations, Z is selected from H, -N(C) 1-4 Alkyl)2、-NHC 1-4 Alkyl, C 1-4 Alkyl groups and 3-6 membered nitrogen-containing heterocyclic groups, wherein the alkyl groups and heterocyclic groups are optionally surrounded by one or more R groups. 9 replace.

[0294] In some implementation schemes, Z is selected from H and C. 1-4 Alkyl groups and 3-6 membered nitrogen-containing heterocyclic groups, wherein the alkyl groups and heterocyclic groups are optionally surrounded by one or more R groups. 9 replace.

[0295] In some embodiments, Z is selected from H, -NH2, -N(CH3)2, -NHCH3, methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyrazinyl, tetrahydropyranyl, morpholinyl, piperidinyl, The methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyrazinyl, tetrahydropyranyl, morpholinyl, and piperidinyl groups are mentioned. Optionally by one or more R 9 replace.

[0296] In some embodiments, Z is selected from H, -NH2, -N(CH3)2, -NHCH3, methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyrazinyl, morpholinyl, piperidinyl, The methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyridinyl, morpholinyl, and piperidinyl groups are mentioned. Optionally by one or more R 9 replace.

[0297] In some embodiments, Z is selected from H, -NH2, -N(CH3)2, -NHCH3, methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyrazinyl, morpholinyl, piperidinyl, The methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyridinyl, morpholinyl, and piperidinyl groups are mentioned. Optionally by one or more R 9 replace.

[0298] In some embodiments, Z is selected from H, -NH2, -N(CH3)2, -NHCH3, methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyrazinyl, morpholinyl, piperidinyl, The methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyridinyl, morpholinyl, and piperidinyl groups are mentioned. Optionally by one or more R 9 replace.

[0299] In some embodiments, Z is selected from H, -NH2, -N(CH3)2, -NHCH3, methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazolyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyrazinyl, morpholinyl, or piperidinyl, wherein the methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazolyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyridazinyl, morpholinyl, or piperidinyl group is optionally replaced by one or more R groups. 9 replace.

[0300] In some embodiments, Z is selected from H, -NH2, -N(CH3)2, -NHCH3, methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyrazinyl, or piperidinyl, wherein the methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyridazinyl, or piperidinyl group is optionally replaced by one or more R groups. 9 replace.

[0301] In some embodiments, Z is selected from H, methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyridazinyl, or piperidinyl, wherein the methyl, ethyl, propyl, butyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazoyl, hexahydropyridazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, piperazinyl, tetrahydropyridazinyl, or piperidinyl group is optionally replaced by one or more R groups. 9 replace.

[0302] In some embodiments, Z is selected from -N(CH3)2, -NHCH3, methyl, morpholino, piperazine, or piperidinyl, wherein the methyl, piperazine, or piperidinyl group is optionally surrounded by one or more R groups. 9 replace.

[0303] In some embodiments, Z is selected from -N(CH3)2, -NHCH3, methyl, piperazine, or piperidinyl, wherein the methyl, piperazine, or piperidinyl group is optionally replaced by one or more R groups. 9 replace.

[0304] In some embodiments, Z is selected from methyl, piperazine, or piperidinyl, wherein the methyl, piperazine, or piperidinyl group is optionally surrounded by one or more R groups. 9 replace.

[0305] In some implementation schemes, R9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo (=O), C 1- 4-alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -N(R) c )R d -C 1-4 Alkylene-N(R) c )R d -C 1-4 Alkylene-OR c -C(=O)-N(R) c )R d 、 -S(=O)2-R c -S(=O)2-N(R) c )R d 3-8 membered heterocyclic groups, -C 1-6 Alkylene-C 3-8 cycloalkyl and -C 1-6 Alkylene-3-8-membered heterocyclic group, wherein the alkyl, alkylene, cycloalkyl, or heterocyclic group is 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) c )R d replace.

[0306] In some implementation schemes, R 9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo (=O), C 1- 4-alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -N(R) c )R d -C 1-4 Alkylene-N(R) c )R d -C 1-4 Alkylene-OR c -C(=O)-N(R) c )R d 、 -S(=O)2-R c -S(=O)2-N(R) c )R d 3-8 membered heterocyclic groups, -C 1-6 Alkylene-C 3-8 cycloalkyl and -C 1-6Alkylene-3-8-membered heterocyclic group, wherein the alkyl, alkylene, or heterocyclic group is optionally surrounded by one or more elements selected from deuterium, halogen, hydroxyl, cyano, C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -N(R) c )R d replace.

[0307] In some implementation schemes, R 9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo (=O), C 1- 4-alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -N(R) c )R d -C 1-4 Alkylene-N(R) c )R d -C 1-4 Alkylene-OR c -C(=O)-N(R) c )R d 、 -S(=O)2-R c -S(=O)2-N(R) c )R d and 3-8 membered heterocyclic groups, said heterocyclic groups optionally being surrounded 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) c )R d replace.

[0308] In some implementation schemes, R 9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo (=O), C 1- 4-alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -N(R) c )R d -C 1-4 Alkylene-N(R) c )R d -C 1-4 Alkylene-OR c -C(=O)-N(R) c )R d 3-8 membered heterocyclic groups, -C 1-6 Alkylene-C3-6 cycloalkyl and -C 1-6 Alkylene-3-6-membered heterocyclic group, wherein the alkyl, alkylene, or heterocyclic group is optionally surrounded by one or more elements selected from deuterium, halogen, hydroxyl, cyano, C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -N(R) c )R d replace.

[0309] In some implementation schemes, R 9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo (=O), C 1- 4-alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -N(R) c )R d -C 1-4 Alkylene-N(R) c )R d -C 1-4 Alkylene-OR c -C(=O)-N(R) c )R d and 3-8 membered heterocyclic groups, said heterocyclic groups optionally being surrounded 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) c )R d replace.

[0310] In some implementation schemes, R 9 Each is independently selected from 3-6 membered heterocyclic groups, wherein the heterocyclic group is optionally selected from one or more halogens and -OC. 1-4 Alkyl substituents.

[0311] In some implementation schemes, R 9 Each is independently selected from aziridine, aziridine, morpholinyl, and 3-azirbis[3.1.0]hexyl.

[0312] In some implementation schemes, R 9 Each independently selected

[0313] In some implementation schemes, R a Selected from H and C 1-4 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-4 Alkyl substituents.

[0314] In some implementation schemes, R c and R d Each is independently selected from H and C. 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents.

[0315] In some implementation schemes, R c and R d Each is independently selected from H and C. 1-6 Alkyl groups, wherein the alkyl group is optionally composed of one or more elements selected from halogens and -OC. 1-4 Alkyl substituents.

[0316] In some implementation schemes, R c and R d Each is independently selected from H and C. 1-4 Alkyl groups, wherein the alkyl group is optionally composed of one or more elements selected from halogens and -OC. 1-4 Alkyl substituents.

[0317] In some implementation schemes, R c and R d Each is independently selected from H and C. 1-6 alkyl.

[0318] In some implementation schemes, R e and R f Each is independently selected from H and C. 1-3 Alkyl; preferably, R e and R f Each is independently selected from H and methyl.

[0319] In some embodiments, the compounds of the present invention are selected from:

[0320] Preparation method

[0321] On the other hand, the present invention provides a method for preparing the compound of formula (I):

[0322] 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 X 2 X 3 X 4 X 5 R 1 Y, L, and Z are as defined above.

[0323] In some implementation schemes, B 1 Selected from Cl, Br, I, -B(OH)2, Trimethyltinyl and tributyltinyl; preferably, B 1 Selected from Cl, -B(OH)2, And tributyltin.

[0324] In some implementation schemes, B 2 It can be Cl, Br or I, preferably Cl.

[0325] In some implementation schemes, A 1 Selected from -B(OH)2, Cl, Br, and I; preferably -B(OH)2 Cl or Br.

[0326] In some implementation schemes, the method is performed according to the following steps:

[0327] Step A: Compound I-1 and compound I-2 undergo a coupling reaction to obtain compound I-3.

[0328] Preferably, the coupling reaction is carried out in the presence of a metal catalyst and a base.

[0329] The metal catalyst may 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 may 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., a nitrogen atmosphere). The coupling reaction is preferably carried out at 70-110°C. The coupling reaction is preferably carried out for 1-24 hours.

[0330] Step B: Compound I-3 and compound I-4 undergo a coupling reaction to give compound I.

[0331] Preferably, the coupling reaction is carried out in the presence of a metal catalyst, a ligand, and a base.

[0332] The metal catalyst may be a palladium metal catalyst, such as tetra(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylacetone)palladium, or 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. The base may be an inorganic base, such as potassium phosphate, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, or 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.

[0333] On the other hand, the present invention provides a method for preparing the compound of formula (I):

[0334] Among them, B 3 Selected from halogen, borate group, borate ester group, and -Sn(C 1-6 Alkyl)3; B 4 It is a halogen; A 2Selected from borate groups, borate ester groups, and halogens; PG 1 and PG 2 For protection base; X 1 X 2 X 3 X 4 X 5 R 1 Y, L, and Z are as defined above.

[0335] In some implementation schemes, B 3 Selected from Cl, Br, I, -B(OH)2, Trimethyltinyl and tributyltinyl; preferably, B 3 Selected from Cl and tributyltin.

[0336] In some implementation schemes, B 4 It can be Cl, Br or I, preferably Cl.

[0337] In some implementation schemes, A 2 Selected from -B(OH)2, Cl, Br, and I; preferably -B(OH)2 Cl or Br.

[0338] In some implementations, the PG 1 and PG 2 Each of the following groups is independently selected from benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), triphenylmethyl (Trt), toluenesulfonyl (Tos), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), and trimethylsilyl (TMS), with tert-butyloxycarbonyl (Boc) being the most preferred.

[0339] In some implementation schemes, the method is performed according to the following steps:

[0340] Step C: Compound I-5 and compound I-6 undergo a coupling reaction to give compound I-7.

[0341] Preferably, the coupling reaction is carried out in the presence of a metal catalyst.

[0342] The metal catalyst may be a palladium metal catalyst, such as tetratetraphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(triphenylphosphine)palladium dichloride, preferably tetratetraphenylphosphine palladium. 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.

[0343] Step D: Compound I-7 undergoes a deprotection reaction to give compound I-8.

[0344] Preferably, the deprotection reaction is carried out in the presence of an acid.

[0345] The acid can be selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, zinc bromide, preferably hydrochloric acid or trifluoroacetic acid. The deprotection reaction is carried out in a suitable organic solvent, such as 1,4-dioxane, dichloromethane, tetrahydrofuran, ethyl acetate, for example, dichloromethane. The deprotection reaction is preferably carried out at room temperature. The deprotection reaction is preferably carried out for 1-12 hours.

[0346] Step E: Compound I-8 and compound I-9 undergo a coupling reaction to give compound I.

[0347] Preferably, the coupling reaction is carried out in the presence of a metal catalyst, a ligand, and a base.

[0348] The metal catalyst may be a palladium metal catalyst, such as tetra(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylacetone)palladium, or 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. The base may be an inorganic base, such as potassium phosphate, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, or 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.

[0349] On the other hand, the present invention provides a method for preparing the compound of formula (I):

[0350] Among them, B 1 B 2 A 1 X 1 X 2 X 3 X 4 X 5 R 1 Y, L, and Z are as defined above; R 1A R as mentioned above 1 The group formed after dehydrogenation; the PG 3 For example, a protecting group (e.g., trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS), tert-butyldiphenylsilyl ether (TBDPS), tetrahydropyran (THP), methoxymethyl (MOM), benzyl (Bn), or p-methoxybenzyl (PMB)); preferably, the PG 3 It is tert-butyl dimethyl silyl ether (TBS).

[0351] In some implementations, step F is carried out under the reaction conditions described in step A above.

[0352] In some implementations, step G is carried out under the reaction conditions described in step B above.

[0353] In some embodiments, in step H: compound 1-5A undergoes a deprotection reaction to generate compound I.

[0354] In some embodiments, step H is carried out in the presence of one or more reagents selected from tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid, ammonium fluoride, triethylamine trihydrofluoride, hydrochloric acid, and trifluoroacetic acid.

[0355] In some embodiments, step H is carried out in a suitable organic solvent, which may be selected from one or more of tetrahydrofuran, dichloromethane, methanol, N,N-dimethylformamide, 1,4-dioxane, and acetonitrile.

[0356] On the other hand, the present invention provides a method for preparing the compound of formula (I):

[0357] Among them, B 1 B 2 A 1 X 1 X 2 X 3 X 4 X5 R 1 Y, L, and Z are as defined above;

[0358] In some implementations, step I is carried out under the reaction conditions described in step B above.

[0359] In some embodiments, step J is carried out in the presence of a metal catalyst, a reducing agent, and a base.

[0360] In some embodiments, the metal catalyst may be a nickel metal catalyst, such as nickel chloride, nickel bromide and nickel iodide, with nickel chloride being preferred.

[0361] In some embodiments, the reducing agent is preferably zinc powder.

[0362] In some embodiments, the alkali may be an inorganic alkali, such as lithium chloride, lithium bromide and potassium fluoride, with lithium chloride being preferred.

[0363] In some embodiments, step J is a coupling reaction, which is carried out in a suitable organic solvent; preferably, the organic solvent may be N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone or a mixture of the above organic solvents, for example N,N-dimethylformamide.

[0364] In some embodiments, step J is a coupling reaction, which is preferably carried out under a suitable protective atmosphere (e.g., a nitrogen atmosphere).

[0365] In some embodiments, step J is a coupling reaction, which is preferably carried out at 60-100°C. The coupling reaction is preferably carried out for 1-24 hours.

[0366] Synthetic intermediates

[0367] In some embodiments, the present invention provides the following synthetic intermediates:

[0368] Wherein: LG is a leaving group, PG, PG 1 PG 2 B is an amino protecting group. 1 B 2 X 1 X 2 X 3 X 4 X 5 Y, L, Z, R 1 R 1A R 9 PG 3 As stated in any of the above.

[0369] In some embodiments, the LG is a halogen, more preferably Cl or Br.

[0370] In some implementations, the PG, PG 1 and PG 2 The derivatives are benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), triphenylmethyl (Trt), toluenesulfonyl (Tos), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), trimethylsilyl (Tms), and more preferably tert-butyloxycarbonyl (Boc).

[0371] In some embodiments, the present invention provides the following synthetic intermediates: (For example: ),

[0372] Pharmaceutical compositions, formulations and packaging

[0373] In some embodiments, the present invention provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0374] A further object of the present invention is to provide a method for preparing a pharmaceutical composition of the present invention, the method comprising combining a compound of the present invention or a pharmaceutically acceptable form thereof or a mixture thereof with one or more pharmaceutically acceptable carriers, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs.

[0375] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Pharmaceutically acceptable carriers include pharmaceutical excipients.

[0376] Pharmaceutical compositions can be administered in any form, provided they achieve the purpose of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms depending on the route of administration.

[0377] When taken orally, the pharmaceutical composition may be formulated into any orally acceptable dosage form.

[0378] When applied transdermally or topically, the pharmaceutical composition may be formulated as a suitable ointment, lotion, or liniment, wherein the active ingredient may be suspended or dissolved in one or more carriers.

[0379] The pharmaceutical composition can also be administered in injectable form, including injectable solutions, sterile powders for injection, and concentrated solutions for injection.

[0380] Another aspect of the present invention relates to a pharmaceutical formulation comprising the compound described in the present invention or a pharmaceutically acceptable form thereof or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs.

[0381] In some embodiments, the formulation is in the form of a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0382] A further object of the present invention is to provide 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, the article of the present invention 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 the present invention 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-labeled substances, metabolites, or prodrugs; and (c) optionally, a packaging instruction.

[0383] The package insert, such as a trademark, label, or marking, lists 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 package insert specifically lists the approved indications for which the pharmaceutical composition is used. The package insert can be made of any material from which information contained therein or on the material can be read. Preferably, the package insert is 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).

[0384] Treatment methods and uses

[0385] The object of this invention is to provide the use of the compounds described herein or pharmaceutically acceptable forms 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, CDK4, and / or CDK6 activity; wherein the pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0386] Another object of the present invention is to provide the compounds described herein or pharmaceutically acceptable forms thereof, or pharmaceutical compositions, or kit products, for the treatment and / or prevention of diseases or symptoms associated with CDK2, CDK4, and / or CDK6 activity; wherein the pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0387] Another object of the present invention is to provide a method for treating and / or preventing diseases or symptoms associated with CDK2, CDK4 and / or CDK6 activity, the method comprising administering to an individual in need an effective amount of the compound of the present invention or a pharmaceutically acceptable form thereof, or a pharmaceutical composition, or a kit product; said pharmaceutically acceptable form being selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs.

[0388] Another object of the present invention is to provide 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 of the present invention or a pharmaceutically acceptable form thereof, or a pharmaceutical composition, or a kit product; the pharmaceutically acceptable form being selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0389] In some implementations, the diseases or conditions associated with CDK2, CDK4, and / or CDK6 activity include (but are not limited to) tumor-related or cancer-related diseases or conditions.

[0390] In some embodiments, the diseases or conditions associated with CDK2, CDK4, and / or CDK6 activity 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). 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

[0391] This invention provides a novel class of CDK2, CDK4, and / or CDK6 inhibitors, capable of achieving at least one of the following technical effects:

[0392] (1) It has high inhibitory activity against CDK2, CDK4 and / or CDK6.

[0393] (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability).

[0394] (3) Excellent pharmacokinetic properties (e.g., good bioavailability, appropriate half-life and duration of action).

[0395] (4) Excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc. Detailed Implementation

[0396] The present invention will be further illustrated by the following embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of the present invention. Those skilled in the art can make some non-essential improvements and adjustments, which still fall within the protection scope of the present invention.

[0397] 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.

[0398] 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).

[0399] The instrument used for MS measurements was an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0400] Preparation method of high performance liquid chromatograph:

[0401] 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.

[0402] 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.

[0403] 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.

[0404] Preparation method of reverse column chromatography:

[0405] Preparation method A:

[0406] Instrument model: Biotage rapid medium-pressure preparative chromatography; Column: Agela C18 reverse-flow 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;

[0407] Preparation method B:

[0408] Instrument model: Biotage rapid medium-pressure preparative chromatography; Column: Agela C18 reverse-flow column (Spherical; 20-35 μm; 100A); Column temperature: 25℃; Flow rate: 28.0 mL / min; Detection wavelength: 220 nm; Mobile phase A: acetonitrile; Mobile phase B: 0.05% NH4HCO3 aqueous solution;

[0409] The microwave reaction was performed using a Biotage Initiator+ (400W, RT~300℃) microwave reactor.

[0410] 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.

[0411] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~35℃).

[0412] The reagents used in this invention were purchased from Acros Organics, Aldrich Chemical Company, and TEB Chemicals, among others.

[0413] In the conventional synthesis methods and examples, as well as intermediate synthesis examples, the meanings of the abbreviations are as follows.

[0414] Preparation Example 1: Preparation of 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine (Int1)

[0415] Step 1: Preparation of 1-amino-4-(benzyloxy)pyridine-1-onium.

[0416] 4-Benzyloxypyridine (4 g, 21.60 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (5.16 g, 25.92 mmol) were added to dichloromethane (60 mL) at room temperature and reacted at 25 °C for 14 hours. The reaction solution was concentrated to give the title compound of this step (4.3 g, yield: 100%).

[0417] MS m / z(ESI): 201.2 [M+H] + .

[0418] Step 2: Preparation of 1-(5-(benzyloxy)pyrazolo[1,5-a]pyridin-3-yl)ethyl-1-one

[0419] 1-Amino-4-(benzyloxy)pyridine-1-onium (4 g, 19.88 mmol), 3-alkynyl-2-butanone (1.89 g, 27.83 mmol), and potassium carbonate (5.49 g, 39.75 mmol) were added to N,N-dimethylformamide (20 mL) and reacted at 25 °C for 2 hours. The reaction solution was quenched with water, extracted with dichloromethane, and the organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 (v / v)) to give the title compound of this step (2.3 g, yield: 43.5%).

[0420] MS m / z(ESI): 267.2 [M+H] + .

[0421] Step 3: Preparation of 5-(benzyloxy)-3-(prop-1-en-2-yl)pyrazolo[1,5-a]pyridine

[0422] Methyltriphenylphosphine bromide (10.76 g, 30.04 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to -20 °C, and n-butyllithium (2.5 M, 12.02 mL) was slowly added. The reaction was carried out at -20 °C for 1 hour, followed by the addition of a tetrahydrofuran solution (30 mL) of 1-(5-(benzyloxy)pyrazolo[1,5-a]pyridin-3-yl)ethyl-1-one (1.6 g, 6.01 mmol). The reaction was carried out at -20 °C for 2 hours and then overnight at room temperature. The reaction solution was quenched with methanol, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 (v / v)) to give the title compound of this step (1.0 g, yield: 64.3%).

[0423] MS m / z(ESI): 265.1 [M+H] + .

[0424] Step 4: Preparation of 3-isopropylpyrazolo[1,5-a]pyridine-5-ol

[0425] 5-(benzyloxy)-3-(prop-1-en-2-yl)pyrazolo[1,5-a]pyridine (855 mg, 3.23 mmol) was added to methanol (30 mL) and tetrahydrofuran (2 mL), followed by the addition of 10% palladium on carbon (170 mg). The mixture was purged with hydrogen and reacted overnight at room temperature. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the title compound of this step (537 mg, yield: 94.3%).

[0426] MS m / z (ESI): 177.2 [M+H] + .

[0427] Step 5: Preparation of 3-isopropylpyrazolo[1,5-a]pyridine-5-yltrifluoromethanesulfonate

[0428] 3-Isopropylpyrazolo[1,5-a]pyridine-5-ol (311 mg, 1.77 mmol) and N,N-diisopropylethylamine (342.69 mg, 2.65 mmol) were added to dichloromethane (10 mL), followed by the addition of trifluoromethanesulfonic anhydride (0.75 g, 2.65 mmol). The mixture was purged with nitrogen and reacted at 0 °C for 2 hours. The reaction solution was diluted with dichloromethane and washed with water and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound of this step (420 mg, yield: 77.1%).

[0429] MS m / z(ESI): 309.1 [M+H] + .

[0430] Step 6: Preparation of 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine

[0431] 3-Isopropylpyrazolo[1,5-a]pyridin-5-yltrifluoromethanesulfonate (363 mg, 1.18 mmol), pinacol diboronate (0.90 g, 3.54 mmol), potassium acetate (0.35 g, 3.54 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (96.3 mg, 117.86 μmol) were added to 1,4-dioxane (6 mL), purged with nitrogen, and reacted at 110 °C for 2 hours. The reaction mixture was filtered through diatomaceous earth, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 (v / v)) to give the title compound of this step (317 mg, yield: 93.9%).

[0432] MS m / z(ESI): 287.2 [M+H] + .

[0433] Preparation Example 2: Preparation of 4-(dimethylamino)piperidin-2-one (Int2)

[0434] Step 1: Preparation of 4-(dimethylamino)-5,6-dihydropyridine-2(1H)-one

[0435] To a solution of piperidine-2,4-dione (30.0 g, 265 mmol) in dichloromethane (150 mL), tetraisopropyl titanate (75.4 g, 265 mmol, 78.3 mL) was added. 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 slowly added dropwise. The mixture was allowed to rise naturally to room temperature for two hours. The reaction mixture was quenched with 200 mL of water, filtered, and extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (500 mL) and concentrated to give the title compound of this step (6.26 g, yield: 18.2%).

[0436] MS m / z (ESI): 141.1 [M+H] + .

[0437] Step 2: Preparation of 4-(dimethylamino)piperidin-2-one

[0438] Solution 1 (S1): 4-(dimethylamino)-5,6-dihydropyridine-2(1H)-one (7.50 g, 53.5 mmol) was dissolved in methanol (180 mL).

[0439] The fixed bed (named FLR1, with a volume of 5 mL) was completely filled with 5% palladium on carbon (1.1 g, WXC1030) granular catalyst.

[0440] The hydrogen back pressure regulator was adjusted to 1.5 MPa, and the hydrogen flow rate was 30 mL / min.

[0441] Solution 1 (S1) was pumped into the fixed bed {FLR1, PFA, fixed bed, 6.350 (1 / 4) mm, 1 mL, 60 °C by pump No. 1.

[0442] Solution S1 was passed through {FLR1, 3.3 min}, exiting the reactor zone, and the reaction mixture was 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%).

[0443] MS m / z (ESI): 143.1 [M+H] + .

[0444] 1H 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).

[0445] Preparation Example 3: Preparation of 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (Int3)

[0446] Dissolve 4-(dimethylamino)piperidin-2-one (800 mg, 5.63 mmol) in 1,4-dioxane (20 mL), then add 5-iodopyridin-2-amine (1.61 g, 7.31 mmol) and (1S,2S)-N 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%).

[0447] MS m / z(ESI): 235.1 [M+H] + .

[0448] 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).

[0449] Preparation Example 4: Preparation of 5-(2-chloro-5-fluoropyridin-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidine (Int4)

[0450] Step 1: Preparation of (2-chloro-5-fluoropyridin-4-yl)boronic acid

[0451] 2-Chloro-5-fluoro-4-iodopyridine (1 g, 3.89 mmol) and pinacol diborate (2.97 g, 11.68 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of potassium acetate (1.15 g, 11.68 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (318.47 mg, 0.39 mmol). The mixture was purged with nitrogen and reacted at 100 °C for 4 hours. The reaction solution was purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 10%-90%) to give the title compound of this step (650 mg, yield: 95.4%).

[0452] MS m / z(ESI): 176.0 [M+H] + .

[0453] Step 2: Preparation of 5-(2-chloro-5-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidine

[0454] (2-chloro-5-fluoropyridin-4-yl)boronic acid (284.3 mg, 1.63 mmol) and 5-bromopyrazolo[1,5-a]pyrimidine (200.0 mg, 1.02 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1 mL). Potassium carbonate (422.9 mg, 3.06 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (83.3 mg, 0.102 mmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 6 hours. The reaction solution was poured into water (10 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (30 mL), 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 (volume ratio)) to give the title compound of this step (148 mg, yield: 58.8%).

[0455] MS m / z(ESI): 249.0 [M+H] + .

[0456] Step 3: Preparation of 5-(2-chloro-5-fluoropyridin-4-yl)-3-iodipyrazolo[1,5-a]pyrimidine

[0457] 5-(2-chloro-5-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidine (74 mg, 298.35 μmol) was dissolved in N,N-dimethylformamide (3 mL), and N-iodosuccinimide (134.25 mg, 596.70 μmol) was added. The reaction mixture was reacted at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was filtered. The filter cake was dried to give the title compound of this step (90 mg, yield: 77.9%).

[0458] MS m / z (ESI): 374.9 [M+H] + .

[0459] Step 4: Preparation of 5-(2-chloro-5-fluoropyridin-4-yl)-3-(prop-1-en-2-yl)pyrazolo[1,5-a]pyrimidine

[0460] 5-(2-chloro-5-fluoropyridin-4-yl)-3-iodopyrazolo[1,5-a]pyrimidine (85.0 mg, 227.32 μmol) and pinacol isopropenylborate (49.7 mg, 295.52 μmol) were dissolved in 1,4-dioxane (5 mL) and water (0.8 mL). Cesium carbonate (148.13 mg, 454.64 μmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (18.56 mg, 22.73 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 14 hours. The reaction solution was poured into water (10 mL), extracted three times with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (20 mL), 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 (volume ratio)) to give the title compound of this step (14 mg, yield: 21.4%).

[0461] MS m / z(ESI): 289.1 [M+H] + .

[0462] Step 5: Preparation of 5-(2-chloro-5-fluoropyridin-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidine

[0463] 5-(2-chloro-5-fluoropyridin-4-yl)-3-(prop-1-en-2-yl)pyrazolo[1,5-a]pyrimidine (12.0 mg, 41.66 μmol) was dissolved in tetrahydrofuran (2 mL), and platinum dioxide (9.46 mg, 41.66 μmol) was added. The mixture was purged with hydrogen and reacted at room temperature for 14 hours. The reaction solution was filtered through iodine-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 (4 mg, yield: 33.1%).

[0464] MS m / z(ESI): 291.1 [M+H] + .

[0465] Preparation Example 5: Preparation of 3-(2-methoxypropane-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzo[c]isothiazole (Int5)

[0466] Step 1: Preparation of 5-bromo-3-(2-methoxypropyl-2-yl)benzo[c]isothiazol

[0467] 2-(5-bromobenzo[c]isothiazo-3-yl)-2-propanol (500 mg, 1.84 mmol) was dissolved in N,N-dimethylformamide (5 mL), cooled to 0 °C, and sodium hydride (88.2 mg, 2.20 mmol) was added in portions. The reaction was carried out at 0 °C for 30 minutes, followed by the dropwise addition of iodomethane (391 mg, 2.76 mmol) and the reaction was carried out at room temperature for 3 hours. The reaction was quenched with saturated ammonium chloride solution (5 mL), extracted three times with ethyl acetate (5 mL), the organic layers were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (525 mg, yield: 99.5%).

[0468] MS m / z(ESI): 288.0 [M+H] + .

[0469] Step 2: Preparation of 3-(2-methoxypropane-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzo[c]isothiazol

[0470] 5-Bromo-3-(2-methoxypropyl-2-yl)benzo[c]isothiazol (525 mg, 1.83 mmol) was dissolved in 1,4-dioxane (10 mL), and pinacol diboronate (559 mg, 2.20 mmol), potassium acetate (360 mg, 3.67 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (134 mg, 183 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 1.5 h. The reaction mixture was filtered, and the filtrate was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered again, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 97 / 3 (v / v)) to give the title compound of this step (586 mg, yield: 91.1%).

[0471] MS m / z(ESI): 334.1 [M+H] + .

[0472] Preparation Example 6: Preparation of 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzo[c]isothiazole (Int6)

[0473] Step 1: Preparation of 5-bromobenzo[c]isothiazol

[0474] Methanesulfonamide (14.4 g, 151 mmol) was dissolved in toluene (20 mL), and thionyl chloride (26.2 g, 220 mmol) was added. The mixture was reacted at 120 °C for 18 hours, and the reaction solution was concentrated to obtain the residue. 4-Bromo-2-methylaniline (4.00 g, 21.5 mmol) was dissolved in toluene (80 mL), cooled to 0 °C in an ice-water bath, and thionyl chloride (2.81 g, 23.7 mmol) was added dropwise. After the addition was complete, the mixture was reacted at 120 °C for 18 hours. The residue obtained above and pyridine (2 mL) were added to the reaction solution, and the mixture was reacted at 120 °C for 18 hours. The reaction solution was cooled to room temperature, concentrated, diluted with ethyl acetate (100 mL), washed successively with water (100 mL) and saturated brine (50 mL), 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 = 96 / 4 (v / v)) to give the title compound of this step (4.5 g, yield: 97.8%).

[0475] MS m / z(ESI): 213.9 [M+H] + .

[0476] Step 2: Preparation of 2-(5-bromobenzo[c]isothiazo-3-yl)-2-propanol

[0477] 5-Bromobenzo[c]isothiazol (4.50 g, 21.0 mmol) was dissolved in tetrahydrofuran (45 mL), and diisopropylaminolithium (2 M, 52.6 mL) was added dropwise at -75 °C. The reaction was maintained at -75 °C for 30 minutes, followed by the addition of anhydrous acetone (12.2 g, 210 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate (50 mL), extracted three times with ethyl acetate (50 mL), and the organic layers were combined and washed with saturated brine (50 mL). The mixture was 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 = 85 / 15 (v / v)) to give the title compound of this step (2.5 g, yield: 43.8%).

[0478] MS m / z(ESI): 271.9 [M+H] + .

[0479] Step 3: Preparation of 5-bromo-3-isopropylbenzo[c]isothiazol

[0480] 2-(5-bromobenzo[c]isothiazo-3-yl)-2-propanol (1.00 g, 3.67 mmol) and triethylsilane (5 mL) were added to trifluoroacetic acid (5 mL) and reacted at 75 °C for 2 hours. The reaction solution was diluted with dichloromethane (10 mL), washed with saturated brine (10 mL), 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 = 95 / 5 (v / v)) to give the title compound of this step (913 mg, yield: 97.0%).

[0481] MS m / z(ESI): 258.0 [M+H] + .

[0482] Step 4: Preparation of 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzo[c]isothiazol

[0483] 5-Bromo-3-isopropylbenzo[c]isothiazol (816 mg, 3.19 mmol) was dissolved in 1,4-dioxane (16 mL), and pinacol diboronate (971 mg, 3.82 mmol), potassium acetate (625 mg, 6.37 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (233 mg, 319 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 1.5 h. The reaction mixture was filtered, and the filtrate was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 97 / 3 (v / v)) to give the title compound of this step (913 mg, yield: 86.5%).

[0484] MS m / z (ESI): 304.1 [M+H] + .

[0485] Preparation Example 7: Preparation of 3-(3-methoxyoxecyclobutane-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (Int7)

[0486] Step 1: Preparation of 3-(5-bromopyrazolo[1,5-a]pyridin-3-yl)oxecyclobutane-3-ol

[0487] 5-Bromo-3-iodopyrazolo[1,5-a]pyridine (300 mg, 0.929 mmol) was dissolved in tetrahydrofuran (2 mL), purged with nitrogen, and cooled to -40 to -50 °C. A tetrahydrofuran solution of isopropyl magnesium chloride (0.929 mL, 2.00 M, 1.86 mmol) was added dropwise. After reacting for 30 minutes, a tetrahydrofuran solution of 3-oxetane (87.0 mg, 1.21 mmol) in tetrahydrofuran (1.00 mL) was added dropwise. The reaction was carried out at -40 to -50 °C for 1.5 hours, and then at 0 °C for 1 hour. The reaction was quenched with saturated ammonium chloride (5 mL), and the mixture was extracted three times with ethyl acetate (5 mL). The combined organic layers were washed with saturated brine (10 mL), 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 = 4 / 1 (volume ratio)) to give the title compound of this step (148 mg, yield: 59.2%).

[0488] MS m / z(ESI): 269.0 [M+H] + .

[0489] Step 2: Preparation of 5-bromo-3-(3-methoxyoxetane-3-yl)pyrazolo[1,5-a]pyridine

[0490] 3-(5-bromopyrazolo[1,5-a]pyridin-3-yl)oxecyclobutane-3-ol (795 mg, 2.95 mmol) was dissolved in tetrahydrofuran (8 mL), purged with nitrogen, cooled to 0 °C, and sodium hydride (355 mg, 8.86 mmol) was added in portions. The reaction was carried out at 0 °C for 12 minutes, followed by the dropwise addition of iodomethane (1.26 g, 8.86 mmol) and the reaction was carried out at room temperature for 2 hours. The reaction solution was quenched in saturated ammonium chloride (15 mL), extracted three times with ethyl acetate (15 mL), and the combined organic phases were washed with saturated brine (15 mL), 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 = 85 / 15 (v / v)) to give the title compound of this step (607 mg, yield: 72.5%).

[0491] MS m / z(ESI): 282.8 [M+H] + .

[0492] Step 3: Preparation of 3-(3-methoxyoxetane-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrazolo[1,5-a]pyridine

[0493] 5-Bromo-3-(3-methoxyoxetane-3-yl)pyrazolo[1,5-a]pyridine (607 mg, 2.14 mmol) was dissolved in 1,4-dioxane (10 mL), and pinacol diboronate (817 mg, 3.22 mmol), potassium acetate (526 mg, 5.36 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (157 mg, 0.214 mmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 16 hours. The reaction mixture was filtered, and the filtrate was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. 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 (649 mg, yield: 92.1%).

[0494] MS m / z(ESI): 331.2 [M+H] + .

[0495] Preparation Example 8: Preparation of 3-(1-methoxycyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine (Int8)

[0496] Step 1: Preparation of 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-ol

[0497] Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (3.00 g, 11.15 mmol) and tetraisopropyl titanate (4.75 g, 16.71 mmol) were dissolved in dichloromethane (30 mL), cooled to -78 °C, and ethyl magnesium bromide (3 M, 11.1 mL, 33.30 mmol) was added dropwise. The reaction mixture was reacted at 0 °C for 1 hour. The reaction solution was quenched in saturated ammonium chloride (100 mL), extracted three times with dichloromethane (100 mL), and the combined organic phases were 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 = 4 / 1 (v / v)) to give the title compound of this step (1.36 g, yield: 48.2%).

[0498] MS m / z(ESI): 252.8 [M+H] + .

[0499] Step 2: Preparation of 5-bromo-3-(1-methoxycyclopropyl)pyrazolo[1,5-a]pyridine

[0500] 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-ol (1.00 g, 3.95 mmol) was added to thionyl chloride (10 mL) and reacted at 40 °C for 1 hour. The reaction solution was then added dropwise to methanol (30 mL) and concentrated to give the title compound of this step (700 mg, yield: 66.3%).

[0501] MS m / z (ESI): 266.8 [M+H] + .

[0502] Step 3: Preparation of 3-(1-methoxycyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine

[0503] 5-Bromo-3-(1-methoxycyclopropyl)pyrazolo[1,5-a]pyridine (600 mg, 2.25 mmol) was dissolved in 1,4-dioxane (10 mL), and pinacol diboronate (684 mg, 2.69 mmol), potassium acetate (440 mg, 4.48 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (164 mg, 0.22 mmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 2 hours. The reaction mixture was filtered, and the filtrate was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. 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 (670 mg, yield: 94.7%).

[0504] MS m / z (ESI): 315.2 [M+H] + .

[0505] Preparation Example 9: Preparation of tert-butyl 4-(6-aminopyridin-3-yl)-3-oxoperpiperazine-1-carboxylate (Int9)

[0506] 5-Iodopyridin-2-amine (500 mg, 2.27 mmol), tert-butyl 3-oxopiperazine-1-carboxylate (546.07 mg, 2.73 mmol), and (1S,2S)-N 1 N 2Dimethylcyclohexane-1,2-diamine (64.65 mg, 454.52 μmol), potassium phosphate (1.45 g, 6.82 mmol), and cuprous iodide (129.85 mg, 681.79 μmol) were added to 1,4-dioxane (25 mL), and the reaction was carried out overnight at 110 °C. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 92 / 8 (v / v)) to give the title compound (510 mg, yield: 76.8%).

[0507] MS m / z(ESI): 293.2 [M+H] + .

[0508] Preparation Example 10: Preparation of (R)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (Int3A) and (S)-1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (Int3B)

[0509] 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; flow rate: 130mL / min; 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%).

[0510] MS m / z(ESI): 235.1 [M+H] + .

[0511] Preparation Example 11: Preparation of 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzo[c]isoxazole (Int10)

[0512] Step 1: Preparation of 1-(2-amino-5-bromophenyl)-2-methylprop-1-one

[0513] 2-Amino-5-bromobenzonitrile (5 g, 25.38 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 °C in an ice-water bath, and isopropyl magnesium bromide (2 M, 38.1 mL) was slowly added dropwise. The reaction was maintained at 0 °C for 30 minutes, and then slowly returned to room temperature for 1.5 hours. 6 M hydrochloric acid was added to the reaction solution to adjust the pH to 6–7. The solution was diluted with water (50 mL), extracted twice with ethyl acetate (100 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound of this step (6.30 g, crude product).

[0514] MS m / z(ESI): 242.0 [M+H] + .

[0515] Step 2: Preparation of 5-bromo-3-isopropylbenzo[c]isoxazole

[0516] 1-(2-amino-5-bromophenyl)-2-methylprop-1-one (5.19 g, 21.4 mmol) was dissolved in methanol (210 mL), and potassium hydroxide (3.61 g, 64.3 mmol) and iodobenzene acetate (7.60 g, 23.6 mmol) were added in portions. The reaction was allowed to proceed at room temperature for 12 hours. The reaction was quenched with saturated sodium sulfite (100 mL), diluted with water (100 mL), and extracted three times with ethyl acetate (100 mL). 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 = 97 / 3 (v / v)) to give the title compound of this step (3.62 g, yield: 70.6%).

[0517] MS m / z(ESI): 240.0 [M+H] + .

[0518] Step 3: Preparation of 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzo[c]isoxazole

[0519] 5-Bromo-3-isopropylbenzo[c]isoxazole (2.00 g, 8.33 mmol) was dissolved in 1,4-dioxane (40.0 mL), and pinacol diboronate (2.54 g, 10.0 mmol), potassium acetate (1.64 g, 16.7 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (609 mg, 833 μmol) were added. The mixture was purged with nitrogen and reacted at 85 °C for 2 hours. The reaction solution was filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 97 / 3 (v / v)) to give the title compound of this step (1.20 g, yield: 47.7%).

[0520] MS m / z(ESI): 288.1 [M+H] + .

[0521] Preparation Example 12: Preparation of 3-(1-methoxy-2-methylpropyl-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (Int11)

[0522] Step 1: Preparation of dimethyl 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)malonate

[0523] 5-Bromo-3-iodopyrazolo[1,5-a]pyridine (10.0 g, 30.9 mmol), dimethyl malonate (4.91 g, 37.1 mmol), cuprous iodide (1.18 g, 6.19 mmol), pyridinecarboxylic acid (953 mg, 7.74 mmol), and cesium carbonate (30.2 g, 92.9 mmol) were added to 1,4-dioxane (120 mL), purged with nitrogen, and reacted at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted three times with ammonia (20 mL) and water (100 mL), followed by ethyl acetate (100 mL). 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 (3.10 g, yield: 30.7%).

[0524] MS m / z(ESI): 327.0 [M+H] + .

[0525] Step 2: Preparation of methyl 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)acetate

[0526] Dimethyl 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)malonate (2.60 g, 7.95 mmol) was dissolved in DMSO (15 mL) and water (0.75 mL), and lithium chloride (1.69 g, 39.8 mmol) was added. The reaction mixture was reacted at 105 °C for 16 hours. The reaction solution was diluted with water (100 mL), extracted three times with ethyl acetate (300 mL), 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 = 85 / 15 (v / v)) to give the title compound of this step (1.80 g, yield: 84.2%).

[0527] MS m / z(ESI): 269.0 [M+H] + .

[0528] Step 3: Preparation of 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)acetamide

[0529] 1.50 g (5.57 mmol) of methyl 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)acetate was added to ammonia-methanol (45 mL) and reacted at 40 °C for 16 hours. The reaction solution was concentrated to obtain the title compound of this step (1.50 g, crude product).

[0530] MS m / z (ESI): 253.8 [M+H] + .

[0531] Step 4: Preparation of 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)acetonitrile

[0532] 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)acetamide (1.42 g, 5.57 mmol) was dissolved in tetrahydrofuran (20 mL), and pyridine (1.32 g, 16.7 mmol) and trifluoroacetic anhydride (2.34 g, 11.1 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with water (100 mL), extracted three times with ethyl acetate (300 mL), 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 = 4 / 1 (v / v)) to give the title compound of this step (1.10 g, yield: 83.7%).

[0533] MS m / z(ESI): 236.0 [M+H] + .

[0534] Step 5: Preparation of 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-2-methylpropionitrile

[0535] 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)acetonitrile (1.10 g, 4.66 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and sodium hydride (559 mg, 13.9 mmol) was added. The mixture was stirred for 30 minutes, and iodomethane (1.98 g, 13.9 mmol) was added. The mixture was reacted at room temperature for 8 hours. The reaction solution was added to saturated ammonium chloride (50 mL), and extracted three times with ethyl acetate (50 mL). 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 = 4 / 1 (v / v)) to give the title compound of this step (880 mg, yield: 71.5%).

[0536] MS m / z(ESI): 264.0 [M+H] + .

[0537] Step 6: Preparation of 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-2-methylpropionic acid

[0538] 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-2-methylpropionitrile (880 mg, 3.33 mmol) was added to concentrated hydrochloric acid (10 mL) and reacted at 70 °C for 2 hours. The reaction solution was concentrated to obtain the title compound of this step (970 mg, crude product).

[0539] MS m / z(ESI): 282.9 [M+H] + .

[0540] Step 7: Preparation of 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-2-methylpropanol

[0541] 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-2-methylpropionic acid (850 mg, 3.00 mmol) was dissolved in tetrahydrofuran (16 mL), and triethylamine (759 mg, 7.51 mmol) and isopropyl chloroformate (412 mg, 3.36 mmol) were added. The mixture was reacted at 0 °C for 1 hour, filtered, and kept at 0 °C. A mixture of tetrahydrofuran (4 mL) and water (12 mL) containing sodium borohydride (360 mg, 9.52 mmol) was added dropwise to the filtrate, and the mixture was reacted at 0 °C for 1 hour. The reaction solution was diluted with water (100 mL), extracted three times with ethyl acetate (100 mL), 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 = 65 / 35 (volume ratio)) to give the title compound of this step (330 mg, yield: 41.0%).

[0542] MS m / z(ESI): 269.0 [M+H] + .

[0543] Step 8: Preparation of 5-bromo-3-(1-methoxy-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyridine

[0544] 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-2-methylpropanol (300 mg, 1.11 mmol) was dissolved in tetrahydrofuran (6 mL), cooled to 0 °C, and sodium hydride (111 mg, 2.79 mmol) was added. The mixture was stirred for 30 minutes, and iodomethane (316 mg, 2.23 mmol) was added. The mixture was reacted at room temperature for 16 hours. The reaction solution was added to saturated ammonium chloride (10 mL), and extracted three times with ethyl acetate (10 mL). 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 = 4 / 1 (v / v)) to give the title compound of this step (256 mg, yield: 81.1%).

[0545] MS m / z(ESI): 283.0 [M+H] + .

[0546] Step 9: Preparation of 3-(1-methoxy-2-methylpropyl-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine

[0547] 5-Bromo-3-(1-methoxy-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyridine (200 mg, 706.21 μmol) was dissolved in 1,4-dioxane (4 mL), and pinacol diboronate (215 mg, 847 μmol), potassium acetate (138 mg, 1.41 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (51.7 mg, 70.6 μmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 2 hours. The reaction solution was 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 (210 mg, yield: 90.1%).

[0548] MS m / z (ESI): 249.3 [M-82+H] + .

[0549] Preparation Example 13: Preparation of 2-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazolo[1,5-a]pyridin-3-yl)propionitrile (Int12)

[0550] 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-2-methylpropionitrile (420 mg, 1.59 mmol) was dissolved in 1,4-dioxane (8 mL), and pinacol diboronate (484 mg, 1.91 mmol), potassium acetate (312 mg, 3.18 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (116 mg, 159 μmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 2 hours. The reaction solution was 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 (441 mg, yield: 89.3%).

[0551] MS m / z (ESI): 230.1 [M-82+H] + .

[0552] Preparation Example 14: Dimethyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridin-3-yl)imino)-λ 6 - Preparation of thiophenes (Int13)

[0553] Step 1: ((5-bromopyrazolo[1,5-a]pyridin-3-yl)imino)dimethyl-λ 6 Preparation of thiophenes

[0554] 5-Bromo-3-iodopyrazolo[1,5-a]pyridine (5.00 g, 15.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), and dimethyl sulfinimide (5.05 g, 21.1 mmol) and (1S,2S)-N 1 N 2 Dimethylcyclohexane-1,2-diamine (400 mg, 2.81 mmol), potassium phosphate (8.96 g, 42.2 mmol), and cuprous iodide (590 mg, 3.10 mmol) were added under nitrogen purging at 100 °C for 3 hours. The reaction solution was 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 (860 mg, yield: 18.1%).

[0555] MS m / z(ESI): 287.9 ​​[M+H] + .

[0556] Step 2: Dimethyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridin-3-yl)imino)-λ 6 Preparation of thiophenes

[0557] ((5-bromopyrazolo[1,5-a]pyridin-3-yl)imino)dimethyl-λ 6 Thione (760 mg, 2.64 mmol) was dissolved in 1,4-dioxane (30 mL), and pinacol diboronate (1.00 g, 3.96 mmol), potassium acetate (776 mg, 7.91 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (193 mg, 264 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 2 hours. The reaction solution was 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 (567 mg, yield: 68.7%).

[0558] MS m / z (ESI): 336.1 [M+H] + .

[0559] Preparation Example 15: Preparation of 3-(1-(methoxymethyl)cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (Int14)

[0560] Step 1: Preparation of methyl 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)acrylate

[0561] 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)methyl acetate (1 g, 3.72 mmol) was dissolved in N,N-dimethylformamide (20 mL), and benzyltriethylammonium chloride (84.6 mg, 372 μmol), potassium carbonate (1.03 g, 7.43 mmol), and paraformaldehyde (669 mg, 22.30 mmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 2 hours. The reaction solution was 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 (460 mg, yield: 39.6%).

[0562] MS m / z(ESI): 281.0 [M+H] + .

[0563] Step 2: Preparation of methyl 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-carboxylate

[0564] Trimethyl thionyl chloride (316 mg, 2.45 mmol) was dissolved in tetrahydrofuran (10 mL), and potassium tert-butoxide (275 mg, 2.45 mmol) was added. The reaction was carried out at 0 °C for 1 hour. Then, a solution of methyl 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)acrylate (460 mg, 1.64 mmol) in tetrahydrofuran (10 mL) was added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was 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 (162 mg, yield: 30.2%).

[0565] MS m / z(ESI): 294.9 [M+H] + .

[0566] Step 3: Preparation of 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-carboxylic acid

[0567] 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-carboxylic acid methyl ester (340 mg, 1.15 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), and lithium hydroxide monohydrate (242 mg, 5.76 mmol) was added. The reaction mixture was reacted at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 5-6 by adding 1 M dilute hydrochloric acid, diluted with water (50 mL), and extracted three times with ethyl acetate (50 mL). 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 (300 mg, yield: 92.6%).

[0568] MS m / z(ESI): 280.8 [M+H] + .

[0569] Step 4: Preparation of (1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropyl)methanol

[0570] 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-carboxylic acid (300 mg, 1.07 mmol) was dissolved in tetrahydrofuran (10 mL), and triethylamine (121 mg, 1.20 mmol) and isopropyl chloroformate (146 mg, 1.20 mmol) were added. The mixture was reacted at 0 °C for 1 hour, filtered, and kept at 0 °C. A mixture of tetrahydrofuran (8 mL) and water (2 mL) containing sodium borohydride (80 mg, 2.11 mmol) was added dropwise to the filtrate, and the mixture was reacted at 0 °C for 1 hour. The reaction solution was diluted with water (50 mL), extracted three times with ethyl acetate (50 mL), 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 = 7 / 3 (v / v)) to give the title compound of this step (108 mg, yield: 34.9%).

[0571] MS m / z(ESI): 267.0 [M+H] + .

[0572] Step 5: Preparation of 5-bromo-3-(1-(methoxymethyl)cyclopropyl)pyrazolo[1,5-a]pyridine

[0573] (1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropyl)methanol (108 mg, 404 μmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 °C, and sodium hydride (30.3 mg, 1.01 mmol) was added. The mixture was stirred for 30 minutes, and iodomethane (143 mg, 1.01 mmol) was added. The mixture was reacted at room temperature for 16 hours. The reaction solution was added to saturated ammonium chloride (10 mL), and extracted three times with ethyl acetate (10 mL). 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 = 7 / 3 (v / v)) to give the title compound of this step (113 mg, yield: 86.3%).

[0574] MS m / z(ESI): 281.0 [M+H] + .

[0575] Step 6: Preparation of 3-(1-(methoxymethyl)cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine

[0576] 5-Bromo-3-(1-(methoxymethyl)cyclopropyl)pyrazolo[1,5-a]pyridine (113 mg, 402 μmol) was dissolved in 1,4-dioxane (10 mL), and pinacol diboronate (153 mg, 603 μmol), potassium acetate (118 mg, 1.21 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (29.4 mg, 40.2 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 2 hours. The reaction solution was 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 (94 mg, yield: 48.4%).

[0577] MS m / z(ESI): 329.2 [M+H] + .

[0578] Preparation Example 16: Preparation of (tert-butyloxycarbonyl)(6-(tributyltinalkyl)pyrimidin-4-yl)carbamate tert-butyl ester (Int15)

[0579] Step 1: Preparation of (tert-butyloxycarbonyl)(6-chloropyrimidin-4-yl)carbamate tert-butyl ester

[0580] 6-Chloropremine-4-amine (2 g, 15.44 mmol) and di-tert-butyl dicarbonate (10.11 g, 46.32 mmol) were dissolved in tetrahydrofuran (20 mL), and 4-dimethylaminopyridine (377.22 mg, 3.09 mmol) was added. The reaction mixture was reacted at room temperature for 16 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine. The residue obtained by concentrating the organic phase was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to give the title compound of this step (3.5 g, yield: 55.0%).

[0581] MS m / z (ESI): 330.1 [M+H] + .

[0582] Step 2: Preparation of (tert-butyloxycarbonyl)(6-(tributyltinalkyl)pyrimidin-4-yl)carbamate tert-butyl ester

[0583] 280 mg (849.05 μmol) of tert-butyl (tert-butyloxycarbonyl)(6-chloropyrimidin-4-yl)carbamate was dissolved in 7 mL of 1,4-dioxane. Tetraphenylphosphine palladium (49.06 mg, 42.45 μmol) and hexabutylditin (1.48 g, 2.55 mmol) were added, and the mixture was purged with nitrogen and reacted at 110 °C for 16 hours. A saturated potassium fluoride solution was added to the reaction mixture, and the mixture was stirred for half an hour. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (450 mg, crude product).

[0584] MS m / z (ESI): 586.3 [M+H] + .

[0585] Preparation Example 17: Preparation of 6-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidine-4-amine (Int16)

[0586] 3-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine (350 mg, 1.22 mmol) and 6-bromopyrimidine-4-amine (230.29 mg, 1.32 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL). Potassium carbonate (512.26 mg, 3.67 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (99.87 mg, 122.30 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 16 hours. The residue obtained after concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 85 / 15 (v / v)) to give the title compound (270 mg, yield: 87.2%).

[0587] MS m / z (ESI): 254.1 [M+H] + .

[0588] Preparation Example 18: Preparation of 5-(2-chloropyrimidin-4-yl)-3-isopropylpyrazolo[1,5-a]pyridine (Int17)

[0589] 3-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine (2.16 g, 7.55 mmol) was dissolved in dioxane (60 mL) and water (4 mL). 2,4-Dichloropyrimidine (1.35 g, 9.06 mmol) and sodium carbonate (2.41 g, 22.7 mmol) were added, the mixture was purged with nitrogen, and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (552 mg, 755 μmol) was added. The reaction mixture was reacted at 110 °C for 4 hours. The reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, and the crude product obtained by organic phase concentration was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1 (v / v)) to give the title compound (620 mg, yield: 30.1%).

[0590] MS m / z(ESI): 273.1 [M+H] + .

[0591] 1 H NMR (400MHz, CDCl3) δ8.69(d,J=8.0Hz,1H),8.51(d,J=8.0Hz,1H),8.37(s,1H),7.90(s,1 H), 7.68 (d, J = 8.0Hz, 1H), 7.38 (d, J = 8.0Hz, 1H), 3.23-3.40 (m, 1H), 1.40 (d, J = 8.0Hz, 6H).

[0592] Preparation Example 19: Preparation of (6-aminopyridin-3-yl)(4-(dimethylamino)piperidin-1-yl)methyl ketone (Int18)

[0593] 6-Aminonicotinic acid (100 mg, 687.79 μmol) and carbonyl diimidazole (150.01 mg, 1.03 mmol) were added to N,N-dimethylformamide (2 mL) and reacted at 70 °C for 10 min. Then, 4-dimethylaminopiperidine (185.65 mg, 1.38 mmol) was added and the mixture was reacted overnight at room temperature. The residue obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 5 / 1 (v / v)) to give the title compound (80 mg, yield: 44.5%).

[0594] MS m / z(ESI): 249.2 [M+H] + .

[0595] Preparation Example 20: Preparation of 1-(6-chloropyridin-3-yl)-4-(dimethylamino)piperidin-2-one (Int19)

[0596] 4-(dimethylamino)piperidin-2-one (200 mg, 1.41 mmol) and 2-chloro-5-iodopyridine (673.54 mg, 2.81 mmol) were dissolved in 1,4-dioxane (6 mL), and cuprous iodide (80.36 mg, 421.95 μmol), potassium phosphate (895.79 mg, 4.22 mmol), and (1S,2S)-N 1 N 2 -Dimethylcyclohexane-1,2-diamine (200.06 mg, 1.41 mmol), nitrogen purged, reacted at 100 °C for 12 h, the reaction solution was directly purified by reversed-phase column chromatography (preparation method A, elution gradient: mobile phase A% = 5%-90%), to give the title compound (70 mg, yield: 19.6%).

[0597] MS m / z (ESI): 254.1 [M+H] + .

[0598] Preparation Example 21: Preparation of 3-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (Int20)

[0599] Step 1: Preparation of 3-(benzyloxy)-5-bromopyrazolo[1,5-a]pyridine

[0600] 5-Bromo-3-iodopyrazolo[1,5-a]pyridine (500 mg, 1.55 mmol), benzyl alcohol (334.87 mg, 3.10 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (36.59 mg, 154.83 μmol), cesium carbonate (1.01 g, 3.10 mmol), and cuprous iodide (20.64 mg, 108.38 μmol) were added to toluene (20 mL), purged with nitrogen, and reacted at 120 °C for 48 hours. The reaction solution was concentrated and diluted with an appropriate amount of water, extracted three times 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 = 4 / 1 (v / v)) to give the title compound of this step (142.5 mg, yield: 30.3%).

[0601] MS m / z(ESI): 303.0 [M+H] + .

[0602] Step 2: Preparation of 5-bromopyrazolo[1,5-a]pyridine-3-ol

[0603] 3-(benzyloxy)-5-bromopyrazolo[1,5-a]pyridine (132 mg, 348.34 μmol) was added to trifluoromethanesulfonic acid (0.4 mL) and dichloromethane (4 mL), and the reaction was carried out at room temperature for 2 hours. The pH of the reaction solution was adjusted to neutral by adding saturated sodium bicarbonate, and the mixture was extracted three times 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 reverse-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 40%-80%) to give the title compound of this step (73.3 mg, yield: 98.7%).

[0604] MS m / z (ESI): 212.9 [M+H] + .

[0605] Step 3: Preparation of 5-bromo-3-isopropoxypyrazolo[1,5-a]pyridine

[0606] Under ice-water bath cooling, 5-bromopyrazolo[1,5-a]pyridine-3-ol (70 mg, 328.64 μmol) and sodium hydride (39.44 mg, 985.92 μmol) were added to tetrahydrofuran (4 mL). After reacting for half an hour, 2-bromopropane (121.27 mg, 985.92 μmol) was added, and the reaction was carried out at room temperature for 16 hours. The reaction was quenched with water, extracted three times 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 (80.0 mg, yield: 95.5%).

[0607] MS m / z(ESI): 255.0 [M+H] + .

[0608] Step 4: Preparation of 3-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine

[0609] 5-Bromo-3-isopropoxypyrazolo[1,5-a]pyridine (80 mg, 313.73 μmol) was dissolved in 1,4-dioxane (2 mL), and pinacol diboronate (398.34 mg, 1.57 mmol), potassium acetate (92.37 mg, 941.19 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (25.62 mg, 31.37 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 2 hours. The reaction solution was filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 9 / 1 (v / v)) to give the title compound of this step (90.0 mg, yield: 94.7%).

[0610] MS m / z(ESI): 303.2 [M+H] + .

[0611] Preparation Example 22: Preparation of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)pyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-onitrile (Int21)

[0612] Step 1: Preparation of 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-carboxamide

[0613] 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-carboxylic acid (104 mg, 369.97 μmol) was dissolved in dichloromethane (3 mL), and oxalyl chloride (140.88 mg, 1.11 mmol) and N,N-dimethylformamide (2.70 mg, 37.00 mol) were added. The reaction was carried out at room temperature for 1 hour. The residue obtained by concentrating the reaction solution was dissolved in dichloromethane (3 mL), and ammonia water (428.98 mg, 3.67 mmol) was slowly added dropwise. The reaction was carried out at room temperature for 3 hours. The reaction solution was diluted with water (10 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3 (v / v)) to give the title compound of this step (80 mg, yield: 66.4%).

[0614] MS m / z(ESI): 279.8 [M+H] + .

[0615] Step 2: Preparation of 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-onitrile

[0616] 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-carboxamide (80.0 mg, 286 μmol) was dissolved in tetrahydrofuran (2 mL), and pyridine (67.8 mg, 857 μmol) and trifluoroacetic anhydride (89.9 mg, 428 μmol) were added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL), extracted three times with ethyl acetate (20 mL), 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 = 7 / 3 (v / v)) to give the title compound of this step (42 mg, yield: 50.9%).

[0617] MS m / z (ESI): 263.8 [M+H] + .

[0618] Step 3: Preparation of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-onitrile

[0619] 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropane-1-onitrile (42 mg, 160 μmol) was dissolved in 1,4-dioxane (2 mL), and pinacol diboronate (61.04 mg, 240 μmol), potassium acetate (47.2 mg, 480 μmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11.7 mg, 16.0 μmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 16 hours. The reaction solution was 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 (17.1 mg, yield: 30.9%).

[0620] MS m / z (ESI): 227.9 [M+H-82] + .

[0621] Preparation Example 23: Preparation of 3-(1-(ethoxymethyl)cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (Int22)

[0622] Step 1: Preparation of 5-bromo-3-(1-(ethoxymethyl)cyclopropyl)pyrazolo[1,5-a]pyridine

[0623] (1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropyl)methanol (80.0 mg, 299 μmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of iodoethane (30.3 mg, 1.01 mmol) and 18-crown ether-6 (15.8 mg, 59.9 μmol). The mixture was purged with nitrogen and reacted at 0 °C for 0.5 h. Sodium hydride (43.1 mg, 1.08 mmol) was then added, and the reaction was continued at room temperature for 1.5 h. The reaction mixture was quenched dropwise in ammonium chloride solution, extracted three times 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 = 7 / 3 (v / v)) to give the title compound of this step (113 mg, yield: 95.1%).

[0624] MS m / z(ESI): 294.9 [M+H] + .

[0625] Step 2: Preparation of 3-(1-(ethoxymethyl)cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine

[0626] 5-Bromo-3-(1-(ethoxymethyl)cyclopropyl)pyrazolo[1,5-a]pyridine (110 mg, 372 μmol) was dissolved in 1,4-dioxane (4 mL), and pinacol diboronate (142 mg, 559 μmol), potassium acetate (110 mg, 1.12 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (27.3 mg, 37.3 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 4 hours. The reaction solution was 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 (124 mg, yield: 92.8%).

[0627] MS m / z(ESI): 261.1 [M+H-82] + .

[0628] Preparation Example 24: Preparation of 3-(1-((methoxy-d3)methyl)cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (Int23)

[0629] Following the synthetic route of compound Int22, iodoethane was replaced with deuterated iodomethane to obtain the title compound (105 mg).

[0630] MS m / z(ESI): 250.0 [M+H-82] + .

[0631] Preparation Example 25: Preparation of 5-(6-chloropyrimidin-4-yl)-3-(1-methoxycyclopropyl)pyrazolo[1,5-a]pyridine (Int24)

[0632] 3-(1-methoxycyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine (150 mg, 477 μmol), 4,6-dichloropyrimidine (284 mg, 1.91 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (39.0 mg, 47.7 μmol), and potassium carbonate (333 mg, 2.39 mmol) were added to a mixed solution of 1,4-dioxane (6 mL) and water (1 mL), and the mixture was purged with nitrogen and reacted at 90 °C for 6 hours. The reaction solution was 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 (120 mg, yield: 83.6%).

[0633] MS m / z (ESI): 301.1 [M+H] + .

[0634] Preparation Example 26: Preparation of 4-amino-N-methylbenzenesulfonamide (Int25)

[0635] Step 1: Preparation of N-methyl-4-nitrobenzenesulfonamide

[0636] 4-Nitrobenzenesulfonyl chloride (1 g, 4.51 mmol) was dissolved in dichloromethane (10 mL), and methylamine hydrochloride (615.49 mg, 9.02 mmol) and N,N-diisopropylethylamine (1.77 g, 13.54 mmol) were added. The mixture was reacted at room temperature for 16 hours. The reaction solution was poured into water (30 mL), and the mixture was extracted three times with dichloromethane (10 mL). 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: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound of this step (400 mg, yield: 40.9%).

[0637] MS m / z(ESI): 217.0 [M+H] + .

[0638] Step 2: Preparation of 4-amino-N-methylbenzenesulfonamide

[0639] N-methyl-4-nitrobenzenesulfonamide (150 mg, 693.76 μmol) was dissolved in methanol (6 mL), and 10% palladium on carbon (100 mg) was added. The mixture was then purged with hydrogen and reacted at room temperature for 5 hours. The reaction solution was filtered through a diatomaceous earth filter, and the filtrate was concentrated to give the title compound of this step (125.0 mg, yield: 96.8%).

[0640] MS m / z (ESI): 187.1 [M+H] + .

[0641] Preparation Example 27: Preparation of 2-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazolo[1,5-a]pyridin-3-yl)cyclopropyl)acetonitrile (Int26)

[0642] Step 1: Preparation of (1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropyl)methylmethanesulfonate

[0643] (1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropyl)methanol (100 mg, 374 μmol) was dissolved in dichloromethane (5 mL), and triethylamine (114 mg, 1.12 mmol) was added. The mixture was cooled to 0 °C, and methanesulfonic anhydride (97.8 mg, 562 μmol) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with water, extracted three times with dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (140 mg, yield: 39.6%).

[0644] MS m / z(ESI): 347.0 [M+H] + .

[0645] Step 2: Preparation of 2-(1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropyl)acetonitrile

[0646] Sodium cyanide (26.0 mg, 531 μmol) was added to dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature for 1 hour. Then, a solution of (1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropyl)methylmethanesulfonate (90.0 mg, 261 μmol) in dimethyl sulfoxide (2 mL) was added, and the mixture was reacted at 50 °C for 1 hour. The reaction mixture was then added to a 20% sodium bicarbonate aqueous solution, extracted three times 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 = 7 / 3 (v / v)) to give the title compound of this step (41.0 mg, yield: 39.9%).

[0647] MS m / z(ESI): 276.0 [M+H] + .

[0648] Step 3: Preparation of 2-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazolo[1,5-a]pyridin-3-yl)cyclopropyl)acetonitrile

[0649] 2-(1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cyclopropyl)acetonitrile (41.0 mg, 148 μmol) was dissolved in 1,4-dioxane (5 mL), and pinacol diboronate (56.6 mg, 223 μmol), potassium acetate (43.7 mg, 445 μmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (10.8 mg, 14.8 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 2 hours. The reaction solution was 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 (46 mg, yield: 75.3%).

[0650] MS m / z(ESI): 324.1 [M+H] + .

[0651] Preparation Example 28: Preparation of 5-bromo-3-(1-ethoxy-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyrimidine (Int27)

[0652] Step 1: Preparation of 5-(benzyloxy)-3-iodopyrazolo[1,5-a]pyrimidine

[0653] 5-Bromo-3-iodopyrazolo[1,5-a]pyrimidine (28.0 g, 86.44 mmol) was dissolved in acetonitrile (280 mL), and sodium tert-butoxide (12.5 g, 130 mmol) and benzyl alcohol (10.3 g, 95.1 mmol) were added in portions. The mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with water, extracted three times 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 = 10 / 1 (v / v)) to give the title compound of this step (25.0 g, yield: 82.4%).

[0654] MS m / z(ESI): 352.0 [M+H] + .

[0655] Step 2: Preparation of dimethyl 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)malonate

[0656] 5-(benzyloxy)-3-iodopyrazolo[1,5-a]pyrimidine (14 g, 39.87 mmol) was dissolved in 1,4-dioxane (200 mL), and dimethyl malonate (6.32 g, 47.8 mmol), pyridinecarboxylic acid (982 mg, 7.97 mmol), cesium carbonate (39.0 g, 120 mmol), and cuprous iodide (759 mg, 3.99 mmol) were added. The mixture was purged with nitrogen and reacted at 100 °C for 12 hours. Ammonia was added to the reaction solution, and the mixture was extracted three times 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: petroleum ether / ethyl acetate = 76 / 24 (v / v)) to give the title compound of this step (8.50 g, yield: 59.9%).

[0657] MS m / z(ESI): 356.0 [M+H] + .

[0658] Step 3: Preparation of methyl 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)acetate

[0659] Dimethyl 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)malonate (8.50 g, 23.9 mmol) was dissolved in DMSO (170 mL), and lithium chloride (5.07 g, 120 mmol) was added. The reaction mixture was reacted at 110 °C for 2 hours. The pH of the reaction solution was adjusted to 3–4 with 1 N hydrochloric acid, and the mixture was extracted three times 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: petroleum ether / ethyl acetate = 88 / 12 (v / v)) to give the title compound of this step (4.60 g, yield: 64.9%).

[0660] MS m / z(ESI): 298.0 [M+H] + .

[0661] Step 4: Preparation of methyl 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylpropionate

[0662] 4.60 g (15.5 mmol) of methyl 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)acetate was dissolved in 100 mL of N,N-dimethylformamide. 18-crown ether-6 (409 mg, 1.55 mmol) and methyl iodide (6.59 g, 46.4 mmol) were added, and the mixture was cooled to 0–5 °C in an ice-water bath. Sodium hydride (1.86 g, 46.4 mmol) was added in portions, and the reaction was carried out at 0 °C for 1 hour. The reaction solution was quenched with saturated ammonium chloride at 0–5 °C, extracted three times 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 = 88 / 12 (v / v)) to give the title compound of this step (2.80 g, yield: 55.5%).

[0663] MS m / z(ESI): 326.1 [M+H] + .

[0664] Step 5: Preparation of 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylprop-1-ol

[0665] Methyl 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylpropionate (2.60 g, 7.99 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0–5 °C in an ice-water bath, and diisobutylaluminum hydride (1 M, 20 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with saturated sodium potassium tartrate at 0–5 °C, extracted three times 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 = 88 / 12 (v / v)) to give the title compound of this step (2.38 g, yield: 100%).

[0666] MS m / z(ESI): 298.2 [M+H] + .

[0667] Step 6: Preparation of 5-(benzyloxy)-3-(1-ethoxy-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyrimidine

[0668] 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylprop-1-ol (400 mg, 1.35 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 18-crown ether-6 (71.1 mg, 269 μmol) and iodoethane (1.26 g, 8.07 mmol) were added. The mixture was cooled to 0–5 °C in an ice-water bath, and sodium hydride (194 mg, 4.84 mmol) was added in portions. The reaction mixture was reacted at 0 °C for 2 hours. The reaction solution was quenched with saturated ammonium chloride at 0–5 °C, extracted three times with ethyl acetate, and 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 (410 mg, yield: 93.3%).

[0669] MS m / z(ESI): 326.2 [M+H] + .

[0670] Step 7: Preparation of 5-bromo-3-(1-ethoxy-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyrimidine

[0671] 5-(benzyloxy)-3-(1-ethoxy-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyrimidine (363 mg, 1.12 mmol) was dissolved in acetonitrile (7 mL), and phosphorus tribromooxy (959 mg, 3.35 mmol) was added. The mixture was reacted at 80 °C for 2 hours. The reaction solution was diluted with water, extracted three times 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 high performance liquid chromatography to give the title compound of this step (114 mg, yield: 34.3%).

[0672] MS m / z(ESI): 297.9 [M+H] + .

[0673] Preparation Example 29: Preparation of 5-bromo-3-(1-(methoxy-d3)-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyrimidine (Int28)

[0674] Step 1: Preparation of 5-(benzyloxy)-3-(1-(methoxy-d3)-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyrimidine

[0675] 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylprop-1-ol (500 mg, 1.68 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 18-crown ether-6 (789 mg, 336 μmol) and deuterated iodomethane (1.46 g, 10.1 mmol) were added. The mixture was cooled to 0–5 °C in an ice-water bath, and sodium hydride (242 mg, 6.05 mmol) was added in portions. The reaction mixture was reacted at 0 °C for 2 hours. The reaction solution was quenched with saturated ammonium chloride at 0–5 °C, extracted three times with ethyl acetate, and 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 (364 mg, yield: 69.0%).

[0676] MS m / z (ESI): 315.2 [M+H] + .

[0677] Step 2: Preparation of 5-bromo-3-(1-(methoxy-d3)-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyrimidine

[0678] 5-(benzyloxy)-3-(1-(methoxy-d3)-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyrimidine (314 mg, 999 μmol) was dissolved in acetonitrile (7 mL), and phosphorus tribromooxy (859 mg, 3.00 mmol) was added. The reaction mixture was reacted at 80 °C for 2 hours. The reaction solution was diluted with water, extracted three times 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 high performance liquid chromatography to give the title compound of this step (98.9 mg, yield: 33.8%).

[0679] MS m / z (ESI): 286.8 [M+H] + .

[0680] Preparation Example 30: Preparation of 2-(5-bromopyrazolo[1,5-a]pyrimidin-3-yl)-2-methylpropionitrile (Int29)

[0681] Step 1: Preparation of 2-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)acetamide

[0682] 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)acetic acid methyl ester (800 mg, 2.69 mmol) was dissolved in a methanol solution of ammonia (7 M, 5 mL), and reacted at 45 °C for 2 hours. The reaction solution was then concentrated to give the title compound of this step (750 mg, yield: 98.9%).

[0683] MS m / z(ESI): 283.1 [M+H] + .

[0684] Step 2: Preparation of 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)acetonitrile

[0685] 2-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)acetamide (750 mg, 2.66 mmol) was dissolved in tetrahydrofuran (10 mL), and pyridine (420 mg, 5.31 mmol) and trifluoroacetic anhydride (1.12 g, 5.31 mmol) were added dropwise. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with water, extracted three times 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 = 88 / 12 (v / v)) to give the title compound of this step (372 mg, yield: 53.0%).

[0686] MS m / z(ESI): 265.1 [M+H] + .

[0687] Step 3: Preparation of 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylpropionitrile

[0688] 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)acetonitrile (372 mg, 1.41 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 18-crown ether-6 (37.2 mg, 141 μmol) and iodomethane (599 mg, 4.22 mmol) were added. The mixture was cooled to 0–5 °C in an ice-water bath, and sodium hydride (169 mg, 4.22 mmol) was added in portions. The reaction mixture was allowed to react at room temperature for 12 hours. The reaction solution was quenched with saturated ammonium chloride at 0–5 °C, extracted three times 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 = 88 / 12 (v / v)) to give the title compound of this step (166 mg, yield: 40.3%).

[0689] MS m / z(ESI): 293.0 [M+H] + .

[0690] Step 4: Preparation of 2-(5-bromopyrazolo[1,5-a]pyrimidin-3-yl)-2-methylpropionitrile

[0691] 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylpropionitrile (110 mg, 376 μmol) was dissolved in acetonitrile (2 mL), and phosphorus tribromooxy (108 mg, 376 μmol) was added. The mixture was reacted at 80 °C for 2 hours. The reaction solution was diluted with water, extracted three times 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 high performance liquid chromatography to give the title compound of this step (57.8 mg, yield: 56.8%).

[0692] MS m / z(ESI): 264.9 [M+H] + .

[0693] Preparation Example 31: Preparation of N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazolo[1,5-a]pyridine-3-amine (Int30)

[0694] Step 1: Preparation of 5-bromo-3-nitropyrazolo[1,5-a]pyridine

[0695] The mixture was cooled in an ice-water bath. 5-Bromopyrazolo[1,5-a]pyridine (3.00 g, 15.2 mmol) was dissolved in concentrated sulfuric acid (22.5 mL), and concentrated nitric acid (10.5 g, 166 mmol) was added dropwise. The mixture was reacted at 0 °C for 0.5 h. The reaction solution was then added dropwise to saturated sodium bicarbonate and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (2 g, yield: 54.3%).

[0696] MS m / z(ESI): 242.0 [M+H] + .

[0697] Step 2: Preparation of 5-bromopyrazolo[1,5-a]pyridine-3-amine

[0698] 5-Bromo-3-nitropyrazolo[1,5-a]pyridine (2.00 g, 8.23 ​​mmol) was dissolved in anhydrous ethanol (32 mL) and water (8 mL), and iron powder (2.31 g, 41.3 mmol) and ammonium chloride (2.21 g, 41.3 mmol) were added. The mixture was reacted at 80 °C for 4 hours. The reaction solution was filtered, and the residue obtained by concentration was diluted with water and extracted three times 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 = 98 / 2 (v / v)) to give the title compound of this step (350 mg, yield: 20.0%).

[0699] MS m / z(ESI): 212.0 [M+H]+ .

[0700] Step 3: Preparation of 5-bromo-N,N-dimethylpyrazolo[1,5-a]pyridine-3-amine

[0701] 5-Bromopyrazolo[1,5-a]pyridine-3-amine (350 mg, 1.65 mmol) was dissolved in dichloromethane (8 mL), and paraformaldehyde (297 mg, 9.90 mmol) was added. The reaction mixture was reacted at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, and sodium triacetoxyborohydride (1.05 g, 4.95 mmol) was added. The reaction mixture was reacted at room temperature for 10 hours. The reaction mixture was diluted with water, extracted three times 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 (90 mg, yield: 22.4%).

[0702] MS m / z(ESI): 240.0 [M+H] + .

[0703] Step 4: Preparation of N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine-3-amine

[0704] 5-Bromo-N,N-dimethylpyrazolo[1,5-a]pyridine-3-amine (70.0 mg, 291 μmol) was dissolved in 1,4-dioxane (2 mL), and pinacol diboronate (88.8 mg, 349 μmol), potassium acetate (57.2 mg, 583 μmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (23.8 mg, 29.1 μmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 2 hours. 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 (60 mg, yield: 72.4%).

[0705] MS m / z(ESI): 206.1 [M+H-82] + .

[0706] Preparation Example 32: Preparation of 3-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (Int31)

[0707] Step 1: Preparation of 5-bromo-3-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyrazolo[1,5-a]pyridine

[0708] 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)cycloprop-1-ol (85 mg, 335.84 μmol) was dissolved in dichloromethane (5 mL), and imidazole (114.32 mg, 1.681 mmol) and tert-butyldimethylchlorosilane (101.24 mg, 671.68 μmol) were added. The reaction mixture was reacted at room temperature for 4 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2 (v / v)) to give the title compound of this step (120 mg, yield: 97.3%).

[0709] MS m / z (ESI): 367.1 [M+H] + .

[0710] Step 2: Preparation of 3-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine

[0711] 5-Bromo-3-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyrazolo[1,5-a]pyridine (120 mg, 326.66 μmol), pinacol diborate (165.9 mg, 653.32 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 added to 1,4-dioxane (6 mL), the mixture was purged with nitrogen, and the reaction was carried out at 95 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound of this step (130 mg, yield: 96.0%).

[0712] MS m / z (ESI): 415.3 [M+H] + .

[0713] Preparation Example 33: Preparation of 5-bromo-3-(1-((methoxy-d3)methyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine (Int32)

[0714] Step 1: Preparation of methyl 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)acrylate

[0715] 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)methyl acetate (12.0 g, 40.4 mmol) was dissolved in N,N-dimethylformamide (240 mL), and potassium carbonate (16.7 g, 121 mmol) and paraformaldehyde (3.63 g, 121 mmol) were added in portions. The mixture was reacted at 60 °C for 1 hour. The reaction solution was diluted with water, extracted three times 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: petroleum ether / ethyl acetate = 88 / 12 (v / v)) to give the title compound of this step (4.8 g, yield: 38.4%).

[0716] MS m / z(ESI): 310.1 [M+H] + .

[0717] Step 2: Preparation of methyl 1-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-carboxylate

[0718] Trimethyl thionyl chloride (312 mg, 2.42 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 °C in an ice-water bath, and sodium tert-butoxide (272 mg, 2.42 mmol) was added in portions. The reaction was carried out at 0 °C for 1 hour. While maintaining 0 °C, a solution of methyl 2-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)acrylate (500 mg, 1.62 mmol) in tetrahydrofuran (10 mL) was added dropwise, and the reaction was carried out at 0 °C for half an hour. The reaction solution was diluted with water, extracted three times 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 = 9 / 1 (v / v)) to give the title compound of this step (375 mg, yield: 71.6%).

[0719] MS m / z(ESI): 324.1 [M+H] + .

[0720] Step 3: Preparation of (1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropyl)methanol

[0721] 1-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-carboxylic acid methyl ester (1.00 g, 3.09 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C in an ice-water bath, and diisobutylaluminum hydride (1 M, 7.73 mL) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. The mixture was then cooled to 0 °C in an ice-water bath, and the reaction was quenched by slow addition of saturated sodium potassium tartrate. The mixture was extracted three times with ethyl acetate, and 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 (840 mg, yield: 91.9%).

[0722] MS m / z(ESI): 296.1 [M+H] + .

[0723] Step 4: 5-(benzyloxy)-3-(1-((methoxy-d3)methyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine

[0724] (1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropyl)methanol (300 mg, 1.02 mmol) was dissolved in N,N-dimethylformamide (6 mL), and 18-crown ether-6 (53.7 mg, 203 μmol) and deuterated iodomethane (883 mg, 6.09 mmol) were added. The mixture was cooled to 0–5 °C in an ice-water bath, and sodium hydride (146 mg, 3.66 mmol) was added in portions. The reaction mixture was reacted at 0 °C for 2 hours. The reaction solution was quenched with saturated ammonium chloride at 0–5 °C, extracted three times with ethyl acetate, and 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 (140 mg, yield: 43.9%).

[0725] MS m / z (ESI): 313.2 [M+H] + .

[0726] Step 5: Preparation of 5-bromo-3-(1-((methoxy-d3)methyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine

[0727] 5-(benzyloxy)-3-(1-((methoxy-d3)methyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine (140 mg, 448 μmol) was dissolved in acetonitrile (3 mL), and phosphorus tribromooxy (385 mg, 1.34 mmol) was added. The mixture was reacted at 80 °C for 1 hour. The reaction solution was diluted with water, extracted three times 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 high performance liquid chromatography to give the title compound of this step (18.1 mg, yield: 13.9%).

[0728] MS m / z(ESI): 286.9 [M+H] + .

[0729] Preparation Example 34: Preparation of (R)-1-(6-chloropyridin-3-yl)-4-(dimethylamino)piperidin-2-one (Int19A) and (S)-1-(6-chloropyridin-3-yl)-4-(dimethylamino)piperidin-2-one (Int19B)

[0730] 1-(6-chloropyridin-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% = 40%, isobaric elution mode; flow rate: 130mL / min; detection wavelength: 220nm), yielding (R)-1-(6-chloropyridin-3-yl)-4-(dimethylamino)piperidin-2-one (11.2g, ee value: 99.4%) and (S)-1-(6-chloropyridin-3-yl)-4-(dimethylamino)piperidin-2-one (12.0g, ee value: 99.9%).

[0731] MS m / z (ESI): 254.1 [M+H] + .

[0732] Preparation Example 35: Preparation of 5-bromo-3-(1-(ethoxymethyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine (Int33)

[0733] Following the synthetic route of compound Int32, deuterated iodomethane was replaced with iodoethane to obtain the title compound (31.2 mg).

[0734] MS m / z(ESI): 297.8 [M+H] + .

[0735] Preparation Example 36: Preparation of 1-(5-bromopyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-onitrile (Int34)

[0736] Step 1: Preparation of 1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-carboxylic acid

[0737] Methyl 1-(5-benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-carboxylate (700 mg, 2.16 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), and lithium hydroxide monohydrate (453 mg, 10.8 mmol) was added. The reaction mixture was reacted at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 5-6 by adding 1 M dilute hydrochloric acid, diluted with water, extracted three times 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 (609 mg, yield: 91.2%).

[0738] MS m / z(ESI): 310.1 [M+H] + .

[0739] Step 2: Preparation of 1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-carboxamide

[0740] 1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-carboxylic acid (450 mg, 1.45 mmol) was dissolved in dichloromethane (9 mL), five drops of N,N-dimethylformamide were added dropwise, and oxaloyl chloride (369 mg, 2.91 mmol) was slowly added dropwise. The reaction was carried out at room temperature for half an hour. The residue obtained by concentrating the reaction solution was dissolved in tetrahydrofuran (10 mL), and the resulting solution was slowly added dropwise to ammonia water (20.0 mL, 193 mmol). The reaction solution was filtered, the filter cake was washed with water, and dried to give the title compound of this step (220 mg, yield: 49.2%).

[0741] MS m / z(ESI): 309.0 [M+H] + .

[0742] Step 3: Preparation of 1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-onitrile

[0743] 1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-carboxamide (220 mg, 714 μmol) was dissolved in tetrahydrofuran (4 mL), and pyridine (113 mg, 1.43 mmol) and trifluoroacetic anhydride (300 mg, 1.43 mmol) were added dropwise. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with water, extracted three times 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 (200 mg, yield: 96.5%).

[0744] MS m / z(ESI): 291.1 [M+H] + .

[0745] Step 4: Preparation of 1-(5-bromopyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-onitrile

[0746] 1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropane-1-onitrile (50.0 mg, 172 μmol) was dissolved in acetonitrile (1 mL), and phosphorus tribromooxy (148 mg, 517 μmol) was added. The reaction mixture was reacted at 80 °C for 1 hour. The reaction solution was diluted with water, extracted three times 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 high performance liquid chromatography to give the title compound of this step (15.3 mg, yield: 32.1%).

[0747] MS m / z (ESI): 264.8 [M+H] + .

[0748] Preparation Example 37: Preparation of (2-bromopyridin-4-yl)(4-methylpiperazin-1-yl)methyl ketone (Int35)

[0749] 2-Bromoisocyanic acid (300 mg, 1.49 mmol) and 1-methylpiperazine (148.75 mg, 1.49 mmol) were dissolved in N,N-dimethylformamide (4 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (855.58 mg, 2.23 mmol) and N,N-diisopropylethylamine (581.62 mg, 4.46 mmol) were added. The reaction mixture was reacted at room temperature for 12 hours. The reaction solution was purified by high-performance liquid chromatography to give the title compound (300 mg, yield: 67.5%).

[0750] MS m / z(ESI): 284.0 [M+H] + .

[0751] Preparation Example 38: Preparation of 1-(6-chloropyridin-3-yl)-4-methylpiperazine (Int36)

[0752] 5-Bromo-2-chloropyridine (249.77 mg, 1.30 mmol), 1-methylpiperazine (100.00 mg, 998.39 μmol), tris(dibenzylacetone)palladium (18.28 mg, 19.97 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (34.66 mg, 59.90 μmol), and potassium tert-butoxide (168.05 mg, 1.50 mmol) were added to toluene (5 mL), purged with nitrogen, and reacted at 100 °C for 3 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 10%-20%) to give the title compound (90.0 mg, yield: 42.6%).

[0753] MS m / z(ESI): 212.1 [M+H] + .

[0754] Preparation Example 39: Preparation of 1-(6-chloropyridin-3-yl)-4-methylpiperazin-2-one (Int37)

[0755] Step 1: Preparation of tert-butyl 4-(6-chloropyridin-3-yl)-3-oxoperpiperazine-1-carboxylate

[0756] 5-Bromo-2-chloropyridine (2 g, 10.39 mmol), tert-butyl 3-oxoperazine-1-carboxylate (2.50 g, 12.47 mmol), tris(dibenzylacetone)dipalladium (951.69 mg, 1.04 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.20 g, 2.08 mmol), and cesium carbonate (6.77 g, 20.79 mmol) were added to 1,4-dioxane (50 mL), purged with nitrogen, and reacted at 90 °C for 1 hour. The reaction solution was filtered, and the crude product obtained by concentration was purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 35%-50%) to give the title compound of this step (1.5 g, yield: 46.3%).

[0757] MS m / z(ESI): 312.1 [M+H] + .

[0758] Step 2: Preparation of 1-(6-chloropyridin-3-yl)piperazin-2-one

[0759] 4-(6-chloropyridin-3-yl)-3-oxoperpiperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.60 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4 M, 6 mL) and reacted at room temperature for 4 hours. The reaction solution was filtered, and the filter cake was dried to give the title compound of this step (300 mg, yield: 88.4%).

[0760] MS m / z(ESI): 212.1 [M+H] + .

[0761] Step 3: Preparation of 1-(6-chloropyridin-3-yl)-4-methylpiperazin-2-one

[0762] 1-(6-chloropyridin-3-yl)piperazin-2-one hydrochloride (26 mg, 122.85 μmol) and aqueous formaldehyde solution (11.1 mg, 368.54 μmol) were dissolved in methanol (2 mL) and acetic acid (0.5 mL), and reacted at room temperature for 20 min. Sodium triacetoxyborohydride (79.44 mg, 374.82 μmol) was added, and the reaction was continued at room temperature for 16 h. The reaction solution was directly purified by reversed-phase column chromatography (Preparation Method A, elution gradient: mobile phase A% = 10%-20%) to give the title compound of this step (14.0 mg, yield: 50.5%).

[0763] MS m / z(ESI): 226.1 [M+H] + .

[0764] Preparation Example 40: Preparation of 1-(6-chloropyridin-3-yl)-4-(2,2,2-trifluoroethyl)piperazin-2-one (Int38)

[0765] 1-(6-chloropyridin-3-yl)piperazin-2-one (50 mg, 236.24 μmol) and potassium carbonate (65.30 mg, 472.48 μmol) were added to acetonitrile (5 mL), followed by 2,2,2-trifluoroethyltrifluoromethanesulfonate (109.66 mg, 472.48 μmol). The reaction mixture was reacted at 70 °C for 2 h. The reaction solution was then purified directly by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 20%-30%) to give the title compound (27.1 mg, yield: 38.9%).

[0766] MS m / z(ESI): 294.1 [M+H] + .

[0767] Preparation Example 41: Preparation of 1-(6-chloropyridin-3-yl)-4-(cyclopropylmethyl)piperazin-2-one (Int39)

[0768] 1-(6-chloropyridin-3-yl)piperazin-2-one (30 mg, 141.74 μmol) and potassium carbonate (39.18 mg, 283.49 μmol) were dissolved in N,N-dimethylformamide (3 mL), and bromomethylcyclopropane (47.84 mg, 354.36 μmol) was added. The reaction mixture was reacted at room temperature for 4 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method A, elution gradient: mobile phase A% = 20%-30%) to give the title compound (16.1 mg, yield: 42.5%).

[0769] MS m / z(ESI): 266.1 [M+H] + .

[0770] Preparation Example 42: Preparation of 1-(6-chloropyridin-3-yl)-4-cyclopropylpiperazin-2-one (Int40)

[0771] 1-(6-chloropyridin-3-yl)piperazin-2-one (30 mg, 141.74 μmol), potassium cyclopropyltrifluoroborate (62.92 mg, 425.23 μmol), copper acetate (51.49 mg, 283.49 μmol), and 1,10-phenanthroline (51.09 mg, 283.50 μmol) were added to toluene (3 mL) and water (1 mL), and reacted at 80 °C for 16 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%-40%) to give the title compound (30.1 mg, yield: 84.1%).

[0772] MS m / z(ESI): 252.1 [M+H] + .

[0773] Preparation Example 43: Preparation of 5-bromo-N,N-dimethylpyrazolo[1,5-a]pyrimidine-3-amine (Int41)

[0774] Step 1: Preparation of 5-bromo-3-nitropyrazolo[1,5-a]pyrimidine

[0775] 5-Bromopyrazolo[1,5-a]pyrimidine (500 mg, 2.52 mmol) was dissolved in concentrated sulfuric acid (3.75 mL), cooled to 0 °C in an ice-water bath, and fuming nitric acid (1.75 g, 27.8 mmol, 1.25 mL) was slowly added dropwise. The reaction mixture was then slowly added dropwise to ice water (10 mL), filtered, the filter cake was washed with water, and dried to give the title compound of this step (522 mg, yield: 85.3%).

[0776] MS m / z(ESI): 243.0 [M+H]+ .

[0777] Step 2: Preparation of 5-bromopyrazolo[1,5-a]pyrimidine-3-amine

[0778] 5-Bromo-3-nitropyrazolo[1,5-a]pyrimidine (235 mg, 967 μmol) was dissolved in ethanol (3.2 mL) and water (0.8 mL). Iron powder (270 mg, 4.84 mmol) and ammonium chloride (259 mg, 4.84 mmol) were added in portions, and the mixture was reacted at 60 °C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated, the residue was diluted with water, extracted three times 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 (105 mg, yield: 51.0%).

[0779] MS m / z(ESI): 212.8 [M+H] + .

[0780] Step 3: Preparation of 5-bromo-N,N-dimethylpyrazolo[1,5-a]pyrimidine-3-amine

[0781] 5-Bromopyrazolo[1,5-a]pyrimidine-3-amine (105 mg, 493 μmol) was dissolved in methanol (20 mL), and formaldehyde aqueous solution (367 μL, 4.93 mmol) was added. The reaction was carried out at room temperature for half an hour, and the pH was adjusted to 3 with glacial acetic acid. Sodium triacetoxyborohydride (46.5 mg, 739 μmol) was added in portions, and the reaction was carried out at room temperature for 12 hours. The residue obtained by concentration of the reaction solution was diluted with water, extracted three times 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 = 9 / 1 (v / v)) to give the title compound of this step (67.5 mg, yield: 56.2%).

[0782] MS m / z(ESI): 242.8 [M+H] + .

[0783] Preparation Example 44: Preparation of 2-chloro-5-(1-methylpiperidin-4-yl)pyridine (Int42)

[0784] 2-Chloro-5-(piperidin-4-yl)pyridine (1.2 g, 5.15 mmol), aqueous formaldehyde solution (1.25 g, 15.44 mmol), and sodium triacetoxyborohydride (3.27 g, 15.44 mmol) were added to ethanol (25 mL) and reacted at room temperature for 3 hours. The residue obtained by concentration of 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 of the filtrate was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 85 / 15 (v / v)) to give the title compound (750 mg, yield: 65.7%).

[0785] MS m / z(ESI): 211.2 [M+H] + .

[0786] Preparation Example 45: Preparation of 2-(1-(5-bromopyrazolo[1,5-a]pyrimidin-3-yl)cyclopropyl)acetonitrile (Int43)

[0787] Step 1: Preparation of 2-(1-(cyanomethyl)cyclopropyl)-3-(dimethylamino)acrylonitrile

[0788] 2,2'-(cyclopropane-1,1-diyl)acetonitrile (1.10 g, 9.16 mmol) was dissolved in N,N-dimethylformamide (11 mL), and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (3.19 g, 18.3 mmol) was added. The reaction mixture was reacted at 50 °C for 12 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 filtrate was concentrated to obtain the crude title compound of this step.

[0789] 1 H NMR (400MHz, CDCl3): δ6.58 (s, 1H), 3.08 (s, 6H), 2.47 (s, 2H), 0.82 (d, J = 4.0Hz, 2H), 0.78 (s, 2H).

[0790] Step 2: Preparation of 2-(1-(5-amino-1H-pyrazole-4-yl)cyclopropyl)acetonitrile

[0791] 2-(1-(cyanomethyl)cyclopropyl)-3-(dimethylamino)acrylonitrile (1.10 g, 6.28 mmol) was dissolved in ethanol (11 mL), and hydrazine acetate (1.16 g, 12.6 mmol) was added. The reaction mixture was reacted at 80 °C for 12 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 95 / 5 (v / v)) to give the title compound of this step (826 mg, yield: 61.7%).

[0792] MS m / z (ESI): 163.4 [M+H] + .

[0793] Step 3: Preparation of 2-(1-(5-hydroxypyrazolo[1,5-a]pyrimidin-3-yl)cyclopropyl)acetonitrile

[0794] 2-(1-(5-amino-1H-pyrazol-4-yl)cyclopropyl)acetonitrile (826 mg, 5.09 mmol) was dissolved in N,N-dimethylformamide (8 mL), and cesium carbonate (2.49 g, 7.64 mmol) and ethyl 3-ethoxyacrylate (881 mg, 6.11 mmol) were added. The reaction mixture was reacted at 110 °C for 1 hour. The reaction solution was diluted with water, extracted with ethyl acetate, and the aqueous phase was adjusted to pH 1-2 with 1N hydrochloric acid, extracted with ethyl acetate, and 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 (560 mg, yield: 44.1%).

[0795] MS m / z (ESI): 215.1 [M+H] + .

[0796] Step 4: Preparation of 2-(1-(5-bromopyrazolo[1,5-a]pyrimidin-3-yl)cyclopropyl)acetonitrile

[0797] 2-(1-(5-hydroxypyrazolo[1,5-a]pyrimidin-3-yl)cyclopropyl)acetonitrile (550 mg, 2.57 mmol) was dissolved in acetonitrile (10 mL), and phosphorus tribromooxy (2.21 g, 7.70 mmol) was added. The mixture was purged with nitrogen and reacted at 80 °C for 2 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 filtrate was concentrated to give the title compound (430 mg, yield: 59.2%).

[0798] MS m / z(ESI): 277.2 [M+H] + .

[0799] Preparation Example 46: Preparation of 1-(5-bromopyrazolo[1,5-a]pyrimidin-3-yl)cyclobutane-1-onitrile (Int44)

[0800] Step 1: Preparation of (1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropyl)methylmethanesulfonate

[0801] (1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropyl)methanol (470 mg, 1.59 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (483 mg, 4.77 mmol) was added. The mixture was cooled to 0 °C, and methanesulfonic anhydride (416 mg, 2.39 mmol) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude title compound of this step.

[0802] MS m / z(ESI): 374.0 [M+H] + .

[0803] Step 2: Preparation of 1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclobutane-1-onitrile

[0804] Sodium cyanide (195 mg, 3.98 mmol) was dissolved in dimethyl sulfoxide (10 mL), and (1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclopropyl)methylmethanesulfonate (594 mg, 1.59 mmol) was added. The mixture was reacted at 50 °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: petroleum ether / ethyl acetate = 4 / 1 (v / v)) to give the title compound of this step (118 mg, yield: 24.5%).

[0805] MS m / z (ESI): 305.1 [M+H] + .

[0806] Step 3: Preparation of 1-(5-bromopyrazolo[1,5-a]pyrimidin-3-yl)cyclobutane-1-onitrile

[0807] 1-(5-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)cyclobutane-1-onitrile (118 mg, 388 μmol) was dissolved in acetonitrile (3 mL), and phosphorus tribromooxy (335 mg, 1.17 mmol) was added. The mixture was reacted at 80 °C for 1 hour. The reaction solution was diluted with water, extracted three times 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 high performance liquid chromatography to give the title compound (51 mg, yield: 47.4%).

[0808] MS m / z(ESI): 277.1 [M+H] + .

[0809] Preparation Example 47: Preparation of 5-chloro-3-isopropylisoxazolo[4,3-b]pyridine (Int45)

[0810] Step 1: Preparation of 1-(3-amino-6-chloropyridin-2-yl)-2-methylprop-1-one

[0811] 3-Amino-6-chloropyridinium carboxynitrile (1.00 g, 6.51 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and isopropyl magnesium chloride (3 M, 13.0 mmol, 4.34 mL) was added dropwise. The mixture was purged with nitrogen and reacted at room temperature for 2 hours. The reaction was quenched with 2N hydrochloric acid, the pH was adjusted to 8 with 2N sodium hydroxide, and the mixture was 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 (1.40 g, yield: 97.4%).

[0812] MS m / z(ESI): 198.9 [M+H] + .

[0813] Step 2: Preparation of 5-chloro-3-isopropylisoxazolo[4,3-b]pyridine

[0814] 1-(3-amino-6-chloropyridin-2-yl)-2-methylprop-1-one (1.20 g, 6.04 mmol) was dissolved in methanol (20 mL), and potassium hydroxide (2.37 g, 42.3 mmol) and iodobenzene acetate (5.84 g, 18.1 mmol) were added. The reaction was carried out at room temperature for 1 hour. The reaction was quenched with sodium sulfite solution, 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 high performance liquid chromatography to give the title compound (230 mg, yield: 19.0%).

[0815] MS m / z (ESI): 197.1 [M+H] + .

[0816] Preparation Example 48: Preparation of 2-chloro-5-(1-ethylpiperidin-4-yl)pyridine (Int46)

[0817] Following the synthetic route of compound Int42, formaldehyde was replaced with acetaldehyde to obtain the title compound (800 mg, yield: 65.7%).

[0818] MS m / z (ESI): 225.2 [M+H] + .

[0819] Preparation Example 49: Preparation of 2-chloro-5-(1-isopropylpiperidin-4-yl)pyridine (Int47)

[0820] 2-Chloro-5-(piperidin-4-yl)pyridine (1.2 g, 5.15 mmol), acetone (896.83 mg, 15.44 mmol), and sodium cyanoborohydride (970.35 mg, 15.44 mmol) were added to ethanol (20 mL) and reacted at room temperature for 3 hours. The residue obtained by concentrating 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 filtrate was concentrated to give the title compound (920 mg, yield: 74.9%).

[0821] MS m / z(ESI): 239.2 [M+H] + .

[0822] Preparation Example 50: Preparation of 2-chloro-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridine (Int48)

[0823] 2-Chloro-5-(piperidin-4-yl)pyridine (1.17 g, 5.03 mmol) and potassium carbonate (1.39 g, 10.06 mmol) were added to acetonitrile (30 mL), cooled to 0 °C, and 2,2,2-trifluoroethyltrifluoromethanesulfonate (1.7 g, 7.32 mmol) was added dropwise. The reaction mixture was reacted at 70 °C for 2 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 = 7 / 3 (v / v)) to give the title compound (1.2 g, yield: 77.0%).

[0824] MS m / z(ESI): 279.0 [M+H] + .

[0825] Preparation Example 51: Preparation of 3-(5-bromopyrazolo[1,5-a]pyrimidin-3-yl)-3-methylbutyronitrile (Int49)

[0826] Following the synthetic route of compound Int43, 2,2'-(cyclopropane-1,1-diyl)acetonitrile was replaced with 3,3-dimethylglutaronitrile to obtain the title compound (491 mg).

[0827] MS m / z(ESI): 279.2 [M+H] + .

[0828] Preparation Example 52: Preparation of 2-chloro-5-(1-(2-methoxyethyl)piperidin-4-yl)pyridine (Int50)

[0829] 2-Chloro-5-(piperidin-4-yl)pyridine (100 mg, 428.93 μmol), 1-bromo-2-methoxyethane (89.43 mg, 643.40 μmol), and potassium carbonate (177.84 mg, 1.29 mmol) were added to acetonitrile (5 mL), and the reaction was carried out at 80 °C for 3 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% = 10%-35%) to give the title compound (40 mg, yield: 34.8%).

[0830] MS m / z (ESI): 255.1 [M+H] + .

[0831] Preparation Example 53: Preparation of (1R,5S)-3-(6-chloropyridin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane (Int51)

[0832] 5-Bromo-2-chloropyridine (200 mg, 1.04 mmol), (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane (186.59 mg, 1.25 mmol), tris(dibenzylacetone)palladium (95.09 mg, 103.93 μmol), cesium carbonate (846.54 mg, 2.60 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (60.13 mg, 103.93 μmol) were added to 1,4-dioxane (5 mL), the mixture was purged with nitrogen, 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound (45 mg, yield: 18.3%).

[0833] MS m / z (ESI): 225.1 [M+H] + .

[0834] Preparation Example 54: Preparation of 2-chloro-5-(tetrahydro-2H-pyran-4-yl)pyridine (Int52)

[0835] Step 1: Preparation of 2-chloro-5-(3,6-dihydro-2H-pyran-4-yl)pyridine

[0836] 5-Bromo-2-chloro-pyridine (500 mg, 2.60 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (655 mg, 3.12 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (106 mg, 130 μmol), and anhydrous potassium carbonate (1.08 g, 7.80 mmol) were added to a mixed solution of 1,4-dioxane (10 mL) and water (1 mL), purged with nitrogen, and reacted at 80 °C for 4 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 to 2 / 1 (v / v)) to give the title compound of this step (414 mg, yield: 77.4%).

[0837] MS m / z(ESI): 196.1 [M+H] + .

[0838] Step 2: Preparation of 2-chloro-5-(tetrahydro-2H-pyran-4-yl)pyridine

[0839] 2-Chloro-5-(3,6-dihydro-2H-pyran-4-yl)pyridine (414 mg, 2.12 mmol) was dissolved in anhydrous ethanol (8 mL), and platinum dioxide (192.2 mg, 846.4 μmol) was added. The mixture was then purged with hydrogen and reacted at room temperature for 3 hours. The reaction solution was filtered through a diatomaceous earth sieve, and the filtrate was concentrated to give the title compound (350 mg, yield: 79.5%).

[0840] MS m / z (ESI): 198.1 [M+H] + .

[0841] Preparation Example 55: Preparation of 1-(6-chloropyridin-3-yl)-4-(2-methoxyethyl)piperazine (Int53)

[0842] 1-(6-chloro-3-pyridyl)piperazine hydrochloride (50.0 mg, 253 μmol), 1-bromo-2-methoxyethane (70.3 mg, 506 μmol), and anhydrous potassium carbonate (105 mg, 759 μmol) were added to acetonitrile (5 mL), and the reaction was carried out at 50 °C for 3 hours. The reaction solution was filtered, and the crude product obtained by concentration was purified by reverse-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-50%) to give the title compound (40.0 mg, yield: 58.7%).

[0843] MS m / z (ESI): 256.3 [M+H] + .

[0844] Preparation Example 56: Preparation of (1R,4R)-5-(6-chloropyridin-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (Int54)

[0845] 5-Bromo-2-chloropyridine (200 mg, 1.04 mmol), (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (155 mg, 1.14 mmol), tris(dibenzylacetone)dipalladium (95.1 mg, 104 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (60.1 mg, 104 μmol), and anhydrous cesium carbonate (847 mg, 2.60 mmol) were added to anhydrous 1,4-dioxane (5 mL), purged with nitrogen, and reacted at 110 °C for 3 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 to 1 / 1 (v / v)) to give the title compound (140 mg, yield: 60.8%).

[0846] MS m / z(ESI): 211.0 [M+H] + .

[0847] Preparation Example 57: Preparation of (1S,4S)-5-(6-chloropyridin-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (Int55)

[0848] Following the synthetic route of compound Int54, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was replaced with (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride to obtain the title compound (90 mg, yield: 39.1%).

[0849] MS m / z(ESI): 211.0 [M+H] + .

[0850] Preparation Example 58: Preparation of 1-(6-chloropyridin-3-yl)-4-(2,2,2-trifluoroethyl)piperazine (Int56)

[0851] 1-(6-chloro-3-pyridyl)piperazine hydrochloride (513 mg, 2.19 mmol) and anhydrous potassium carbonate (605.65 mg, 4.38 mmol) were added to acetonitrile (10 mL), and 2,2,2-trifluoroethyltrifluoromethanesulfonate (762.85 mg, 3.29 mmol) was added dropwise. The reaction mixture was reacted at 70 °C for 3 hours. The reaction mixture was 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 (600 mg, yield: 88.1%).

[0852] MS m / z (ESI): 280.1 [M+H] + .

[0853] Preparation Example 59: Preparation of 2-chloro-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-1,6-naphthidine (Int57)

[0854] 2-Chloro-5,6,7,8-tetrahydro-1,6-naphthylidine hydrochloride (400 mg, 1.95 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (679 mg, 2.93 mmol), and anhydrous potassium carbonate (674 mg, 4.88 mmol) were added to acetonitrile (10 mL) and reacted at 70 °C for 4 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 to 2 / 1 (v / v)) to give the title compound (470 mg, yield: 91.3%).

[0855] MS m / z(ESI): 251.0 [M+H] + .

[0856] Preparation Example 60: Preparation of 5-bromo-3-isopropoxypyrazolo[1,5-a]pyrimidine (Int58)

[0857] Step 1: Preparation of 2-Isopropoxyacetamide

[0858] 2-Isopropoxyacetic acid (2.10 g, 17.8 mmol) was dissolved in dichloromethane (15 mL), and N,N-dimethylformamide (129 mg, 0.178 mmol) and oxaloyl chloride (3.38 g, 26.7 mmol) were added. The reaction mixture was reacted at room temperature for 1 hour. The crude product obtained by concentrating the reaction solution was dissolved in dichloromethane (20 mL). At 0 °C, the dichloromethane solution of 2-isopropoxyacetic acid (20 mL) was added dropwise to ammonia water (10.4 g, 88.9 mmol), and the reaction mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of the title compound of this step, which was used directly in the next step (1.11 g).

[0859] 1 H NMR (400MHz, CDCl3): δ7.22(s,1H),7.02(s,1H),3.76(s,2H),3.75-3.56(m,1H),1.13(dd,J=7.2,6.0Hz,6H).

[0860] Step 2: Preparation of 2-isopropoxyacetonitrile

[0861] 2-Isopropoxyacetamide (1.10 g, 9.39 mmol) was dissolved in tetrahydrofuran (12 mL), and trifluoroacetic anhydride (4.93 g, 23.5 mmol) and pyridine (2.23 g, 28.2 mmol) were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with water, extracted with methyl tert-butyl ether, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude title compound of this step, which was used directly in the next step (850 mg).

[0862] 1 H NMR (400MHz, CDCl3): δ4.26 (s, 2H), 3.88-3.81 (m, 1H), 1.24 (d, J = 10.0Hz, 6H).

[0863] Step 3: Preparation of 3-(dimethylamino)-2-isopropoxyacrylonitrile

[0864] 2-Isopropoxyacetonitrile (550 mg, 5.55 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (1.93 g, 11.1 mmol) was added. The reaction mixture was reacted at 80 °C for 16 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 filtrate was concentrated to obtain the crude title compound of this step, which was used directly in the next step (450 mg, yield: 37.9%).

[0865] MS m / z (ESI): 154.9 [M+H] + .

[0866] Step 4: Preparation of 4-isopropoxy-1H-pyrazole-5-amine

[0867] 3-(dimethylamino)-2-isopropoxyacrylonitrile (445 mg, 2.89 mmol) was dissolved in ethanol (15 mL), and hydrazine acetate (318.9 mg, 12.6 mmol) was added. The reaction mixture was reacted at 80 °C for 12 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: dichloromethane / methanol ester = 95 / 5 (v / v)) to give the title compound of this step (309 mg, yield: 65.2%).

[0868] MS m / z(ESI): 142.0 [M+H] + .

[0869] Step 5: Preparation of 3-isopropoxypyrazolo[1,5-a]pyrimidine-5-ol

[0870] 4-Isopropoxy-1H-pyrazole-5-amine (309 mg, 2.19 mmol) was dissolved in N,N-dimethylformamide (8 mL), and cesium carbonate (2.49 g, 7.64 mmol) and ethyl 3-ethoxyacrylate (347 mg, 2.41 mmol) were added. The reaction mixture was reacted at 110 °C for 1 hour. The reaction solution was diluted with water, extracted with ethyl acetate, and the pH of the aqueous phase was adjusted to 1-2 with 1N hydrochloric acid. The aqueous phase was 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 (200 mg, yield: 42.0%).

[0871] MS m / z (ESI): 193.9 [M+H] + .

[0872] Step 6: Preparation of 5-bromo-3-isopropoxypyrazolo[1,5-a]pyrimidine

[0873] 3-Isopropoxypyrazolo[1,5-a]pyrimidine-5-ol (180 mg, 0.94 mmol) was dissolved in acetonitrile (10 mL), and phosphorus oxybromide (801 mg, 2.80 mmol) was added. The mixture was purged with nitrogen and reacted at 80 °C for 2 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 filtrate was concentrated to give the title compound (125 mg, yield: 51.9%).

[0874] MS m / z(ESI): 258.1 [M+H] + .

[0875] Preparation Example 61: Preparation of 2-bromo-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridine (Int59)

[0876] 2-Bromo-5-(piperidin-4-yloxy)pyridine (380 mg, 1.48 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (514 mg, 2.22 mmol), and anhydrous potassium carbonate (510 mg, 3.69 mmol) were added to acetonitrile (10 mL) and reacted at 70 °C for 4 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 to 2 / 1 (v / v)) to give the title compound (400 mg, yield: 75.8%).

[0877] MS m / z(ESI): 339.0 [M+H] + .

[0878] Preparation Example 62: Preparation of 2-chloro-5-(1-(2-fluoroethyl)piperidin-4-yl)pyridine (Int60)

[0879] 2-Chloro-5-(piperidin-4-yl)pyridine hydrochloride (80.0 mg, 343 μmol), 1-fluoro-2-iodoethane (89.5 mg, 515 μmol), and N,N-diisopropylethylamine (133 mg, 1.03 mmol) were added to N,N-dimethylformamide (2 mL), and the reaction was carried out at 50 °C for 3 hours. The reaction solution was purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-40%) to give the title compound (40.0 mg, yield: 45.6%).

[0880] MS m / z(ESI): 243.1 [M+H] + .

[0881] Preparation Example 63: Preparation of 2-(4-(6-chloropyridin-3-yl)piperidin-1-yl)acetonitrile (Int61)

[0882] 2-Chloro-5-(piperidin-4-yl)pyridine hydrochloride (80.0 mg, 343 μmol), bromoacetonitrile (53.5 mg, 447 μmol), and N,N-diisopropylethylamine (133 mg, 1.03 mmol) were added to N,N-dimethylformamide (2 mL), and the reaction was carried out at 50 °C for 3 hours. The reaction solution was purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-45%) to give the title compound (50.0 mg, yield: 58.7%).

[0883] MS m / z(ESI): 236.1 [M+H] + .

[0884] Preparation Example 64: Preparation of 2-(6-chloropyridin-3-yl)-6-methyl-2,6-diazaspiro[3.4]octane (Int62)

[0885] Step 1: Preparation of tert-butyl 2-(6-chloropyridin-3-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate

[0886] 5-Bromo-2-chloro-pyridine (150 mg, 779.46 μmol), tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (150.43 mg, 708.60 μmol), tris(dibenzylideneacetone)dipalladium (12.98 mg, 14.17 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (24.60 mg, 42.52 μmol), and potassium tert-butoxide (119.27 mg, 1.06 mmol) were added to toluene (7 mL), and the mixture was purged with nitrogen and reacted at 100 °C for 3 hours. The reaction mixture was 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 (170 mg, yield: 74.1%).

[0887] MS m / z(ESI): 324.1 [M+H] + .

[0888] Step 2: Preparation of 2-(6-chloropyridin-3-yl)-2,6-diazaspiro[3.4]octane

[0889] 170 mg (524.99 μmol) of tert-butyl 2-(6-chloropyridin-3-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate was added to a mixed solution of trifluoroacetic acid (1.5 mL) and dichloromethane (6 mL), and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated to give the title compound of this step (117 mg, yield: 99.6%).

[0890] MS m / z(ESI): 224.1 [M+H] + .

[0891] Step 3: Preparation of 2-(6-chloropyridin-3-yl)-6-methyl-2,6-diazaspiro[3.4]octane

[0892] 2-(6-chloropyridin-3-yl)-2,6-diazaspiro[3,4]octane (120 mg, 536.43 μmol) and 37% formaldehyde aqueous solution (130.60 mg, 1.61 mmol) were dissolved in a mixed solution of tetrahydrofuran (6 mL) and glacial acetic acid (0.2 mL). After reacting at room temperature for 20 min, sodium triacetoxyborohydride (346.88 mg, 1.64 mmol) was added, and the reaction was continued at room temperature for 1 h. The reaction was quenched with water, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 6 / 1 (v / v)) to give the title compound of this step (125 mg, yield: 98.0%).

[0893] MS m / z(ESI): 238.1 [M+H] + .

[0894] Preparation Example 65: Preparation of 2-(6-chloropyridin-3-yl)-7-methyl-2,7-diazaspiro[3.5]nonane (Int63)

[0895] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate to obtain the title compound (130 mg).

[0896] MS m / z(ESI): 252.1 [M+H] + .

[0897] Preparation Example 66: Preparation of 2-(6-chloropyridin-3-yl)-6-methyl-2,6-diazaspiro[3.3]heptane (Int64)

[0898] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate to obtain the title compound (95 mg).

[0899] MS m / z(ESI): 224.1 [M+H] + .

[0900] Preparation Example 67: Preparation of 2-(6-chloropyridin-3-yl)-8-methyl-2,8-diazaspiro[4.5]decane (Int65)

[0901] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate to obtain the title compound (150 mg).

[0902] MS m / z(ESI): 266.1 [M+H] + .

[0903] Preparation Example 68: Preparation of 6-(6-chloropyridin-3-yl)-2-methyl-2,6-diazaspiro[3.4]octane (Int66)

[0904] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate to obtain the title compound (150 mg).

[0905] MS m / z(ESI): 238.1 [M+H] + .

[0906] Preparation Example 69: Preparation of 2-bromo-5-((1-(2-methoxyethyl)piperidin-4-yl)oxy)pyridine (Int67)

[0907] 2-Bromo-5-(piperidin-4-yloxy)pyridine hydrochloride (300 mg, 1.02 mmol), 1-bromo-2-methoxyethane (190 mg, 1.37 mmol), and anhydrous potassium carbonate (282.45 mg, 2.04 mmol) were added to acetonitrile (10 mL) and reacted at 60 °C for 16 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 85 / 15 (v / v)) to give the title compound (200 mg, yield: 55.9%).

[0908] MS m / z(ESI): 315.0 [M+H] + .

[0909] Preparation Example 70: Preparation of 2-bromo-5-((1-(2-fluoroethyl)piperidin-4-yl)oxy)pyridine (Int68)

[0910] Following the synthetic route of compound Int67, 1-bromo-2-methoxyethane was replaced with 1-fluoro-2-iodoethane to obtain the title compound (100 mg).

[0911] MS m / z(ESI): 303.0 [M+H] + .

[0912] Preparation Example 71: Preparation of 2-chloro-5-(1-(2-methoxyethyl)piperidin-4-yl)pyridine (Int69)

[0913] 2-Chloro-5-(piperidin-4-yl)pyridine hydrochloride (300 mg, 1.29 mmol), 1-bromo-2-methoxyethane (286 mg, 2.06 mmol), and N,N-diisopropylethylamine (499 mg, 3.86 mmol) were added to acetonitrile (6 mL) and reacted at 50 °C for 3 hours. The reaction solution was purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-35%) to give the title compound (200 mg, yield: 58.0%).

[0914] MS m / z(ESI): 255.0 [M+H] + .

[0915] Preparation Example 72: Preparation of 8-(6-chloropyridin-3-yl)-2-methyl-2,8-diazaspiro[4.5]decane (Int70)

[0916] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate to obtain the title compound (100 mg).

[0917] MS m / z(ESI): 266.1 [M+H] + .

[0918] Preparation Example 73: Preparation of 3-(6-chloropyridin-3-yl)-9-methyl-3,9-diazaspiro[5.5]undecane (Int71)

[0919] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate to obtain the title compound (80 mg).

[0920] MS m / z (ESI): 280.2 [M+H] + .

[0921] Preparation Example 74: Preparation of 7-(6-chloropyridin-3-yl)-2-methyl-2,7-diazaspiro[3.5]nonane (Int72)

[0922] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate to obtain the title compound (100 mg).

[0923] MS m / z(ESI): 252.1 [M+H] + .

[0924] Preparation Example 75: Preparation of 2-chloro-5-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)pyridine (Int73)

[0925] Step 1: Preparation of 3,3-difluorocyclobutyltrifluoromethanesulfonate

[0926] 3,3-Difluorocyclobut-1-ol (200 mg, 1.85 mmol) and 4-dimethylaminopyridine (271 mg, 2.22 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C, and trifluoromethanesulfonic anhydride (626 mg, 2.22 mmol) was slowly added. The reaction mixture was allowed to react at room temperature for 1 hour. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic phases were combined and concentrated to give the title compound of this step (400 mg, yield: 85.5%).

[0927] MS m / z(ESI): 241.0 [M+H] + .

[0928] Step 2: Preparation of 2-chloro-5-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)pyridine

[0929] 2-Chloro-5-(piperidin-4-yl)pyridine hydrochloride (200 mg, 858 μmol), 3,3-difluorocyclobutyltrifluoromethanesulfonate (309 mg, 1.29 mmol), and anhydrous potassium carbonate (356 mg, 2.57 mmol) were added to acetonitrile (6 mL), and the reaction was carried out at 50 °C for 3 hours. The reaction solution was purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-60%) to give the title compound (200 mg, yield: 77.2%).

[0930] MS m / z(ESI): 287.2 [M+H] + .

[0931] Preparation Example 76: Preparation of 7-((6-bromopyridin-3-yl)oxy)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane (Int74)

[0932] Step 1: Preparation of tert-butyl 7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate

[0933] 318 mg (1.32 mmol) of 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester was dissolved in methanol (10 mL), and sodium borohydride (149.57 mg, 3.95 mmol) was added in portions at 0 °C. The reaction was carried out at room temperature for 1 hour. The reaction was quenched with water, concentrated, and the residue was extracted three times with dichloromethane. 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 (300 mg, yield: 93.6%).

[0934] MS m / z(ESI): 244.1 [M+H] + .

[0935] Step 2: Preparation of tert-butyl 7-((6-bromopyridin-3-yl)oxy)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate

[0936] 2-Bromo-5-fluoropyridine (198.92 mg, 1.13 mmol), 7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (250 mg, 1.03 mmol), and potassium tert-butoxide (230.60 mg, 2.06 mmol) were added to anhydrous tetrahydrofuran (8 mL), and the reaction was carried out at room temperature for 5 hours. 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 / 1 (v / v)) to give the title compound of this step (300 mg, yield: 73.1%).

[0937] MS m / z(ESI): 399.1 [M+H] + .

[0938] Step 3: Preparation of 7-((6-bromopyridin-3-yl)oxy)-3-oxa-9-azabicyclo[3.3.1]nonane

[0939] 300 mg (751.35 μmol) of tert-butyl 7-((6-bromopyridin-3-yl)oxy)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate was dissolved in a mixed solution of trifluoroacetic acid (1.5 mL) and dichloromethane (6 mL), and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated to give the title compound of this step (200 mg, yield: 89.0%).

[0940] MS m / z(ESI): 299.1 [M+H] + .

[0941] Step 4: Preparation of 7-((6-bromopyridin-3-yl)oxy)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane

[0942] 7-((6-bromopyridin-3-yl)oxy)-3-oxa-9-azabicyclo[3.3.1]nonane (180 mg, 601.68 μmol) and 37% formaldehyde aqueous solution (130.60 mg, 1.61 mmol) were dissolved in a mixture of tetrahydrofuran (6 mL) and acetic acid (0.2 mL). After reacting at room temperature for 20 minutes, sodium triacetoxyborohydride (346.88 mg, 1.64 mmol) was added, and the reaction was continued at room temperature for 1 hour. The reaction was quenched with water, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 6 / 1 (v / v)) to give the title compound (100 mg, yield: 53.1%).

[0943] MS m / z(ESI): 313.1 [M+H] + .

[0944] Preparation Example 77: Preparation of 2-(6-chloropyridin-3-yl)-6-methyl-6-azaspiro[3.4]octane (Int75)

[0945] Step 1: Preparation of tert-butyl 2-(((trifluoromethyl)sulfonyl)oxy)-6-azaspiro[3.4]oct-1-ene-6-carboxylate

[0946] 600 mg (2.66 mmol) of tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate was dissolved in 10 mL of dry tetrahydrofuran. The solution was cooled to -78 °C, and a tetrahydrofuran solution of lithium diisopropylamino in 2 M (2.66 mL) was slowly added. The reaction was carried out at -78 °C for 1 hour. Then, N-phenylbis(trifluoromethanesulfonyl)imide (1.24 g, 3.46 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 10 / 1 (v / v)) to give the title compound of this step (560 mg, yield: 55.9%).

[0947] MS m / z(ESI): 302.1 [M+H-56] + .

[0948] Step 2: Preparation of tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-6-azaspiro[3,4]oct-1-en-6-carboxylate

[0949] 2-(((trifluoromethyl)sulfonyl)oxy)-6-azaspiro[3.4]oct-1-en-6-carboxylic acid tert-butyl ester (560 mg, 1.57 mmol), pinacol diboronate (677 mg, 2.66 mmol), potassium acetate (461 mg, 4.70 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (128 mg, 157 μmol) were added to 1,4-dioxane (10 mL), the mixture was purged with nitrogen, and the reaction was carried out at 95 °C for 3 hours. The reaction solution was used directly in the next step.

[0950] MS m / z(ESI): 280.1 [M+H-56] + .

[0951] Step 3: Preparation of tert-butyl 2-(6-chloropyridin-3-yl)-6-azaspiro[3.4]oct-1-en-6-carboxylate

[0952] 2-Chloro-5-bromopyridine (448 mg, 2.33 mmol), anhydrous potassium carbonate (643 mg, 4.65 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (126 mg, 155 μmol), and water (1 mL) were added to the reaction solution from the previous step. The mixture was purged with nitrogen and reacted at 80 °C for 3 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 to 4 / 1 (v / v)) to give the title compound of this step (350 mg, yield: 66.8%).

[0953] MS m / z(ESI): 321.2 [M+H] + .

[0954] Step 4: Preparation of tert-butyl 2-(6-chloropyridin-3-yl)-6-azaspiro[3.4]octane-6-carboxylate

[0955] 340 mg (1.06 mmol) of tert-butyl 2-(6-chloropyridin-3-yl)-6-azaspiro[3.4]oct-1-en-6-carboxylic acid was dissolved in anhydrous ethanol (10 mL), and platinum dioxide (48.1 mg, 212 μmol) was added. The mixture was then purged with hydrogen and reacted at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to give the title compound of this step (340 mg, yield: 94.4%).

[0956] MS m / z(ESI): 323.2 [M+H] + .

[0957] Step 5: Preparation of 2-(6-chloropyridin-3-yl)-6-azaspiro[3.4]octane

[0958] 340 mg, 1.05 mmol of tert-butyl 2-(6-chloropyridin-3-yl)-6-azaspiro[3.4]octane-6-carboxylate was added to a mixed solution of dichloromethane (8 mL) and trifluoroacetic acid (2 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated to give the title compound of this step (228 mg, yield: 97.2%).

[0959] MS m / z(ESI): 223.2 [M+H] + .

[0960] Step 6: Preparation of 2-(6-chloropyridin-3-yl)-6-methyl-6-azaspiro[3.4]octane

[0961] 2-(6-chloropyridin-3-yl)-6-azaspiro[3.4]octane (240 mg, 1.08 mmol), aqueous formaldehyde solution (262 mg, 3.23 mmol), and sodium triacetoxyborohydride (697 mg, 3.29 mmol) were added to tetrahydrofuran (8 mL) and acetic acid (0.2 mL), and reacted at room temperature for 2 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1 to 4 / 1 (v / v)) to give the title compound (190 mg, yield: 70.8%).

[0962] MS m / z(ESI): 237.2 [M+H] + .

[0963] Preparation Example 78: Preparation of 2-(6-chloropyridin-3-yl)-7-methyl-7-azaspiro[3.5]nonane (Int76)

[0964] Following the synthetic route of compound Int75, 2-oxo-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester was replaced with 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester to obtain the title compound (260 mg).

[0965] MS m / z(ESI): 251.1 [M+H] + .

[0966] Preparation Example 79: Preparation of 6-(6-chloropyridin-3-yl)-2-methyl-2-azaspiro[3.3]heptane (Int77)

[0967] Following the synthetic route of compound Int75, 2-oxo-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester was replaced with 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester to obtain the title compound (60 mg).

[0968] MS m / z(ESI): 223.1 [M+H] + .

[0969] Preparation Example 80: Preparation of 7-(6-chloropyridin-3-yl)-9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane (Int78)

[0970] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate to obtain the title compound (55 mg).

[0971] MS m / z (ESI): 254.1 [M+H] + .

[0972] Preparation Example 81: Preparation of 2-bromo-5-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)oxy)pyridine (Int79)

[0973] 2-Bromo-5-(piperidin-4-yloxy)pyridine hydrochloride (65 mg, 253 μmol), 3,3-difluorocyclobutyltrifluoromethanesulfonate (91.1 mg, 379 μmol), and anhydrous potassium carbonate (105 mg, 758 μmol) were added to acetonitrile (5 mL), and the mixture was reacted at 40 °C for 6 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8 / 1 to 1 / 1 (v / v)) to give the title compound (70.0 mg, yield: 75.8%).

[0974] MS m / z (ESI): 347.2 [M+H] + .

[0975] Preparation Example 82: Preparation of 1-(6-chloropyridin-3-yl)-4-(3,3-difluorocyclobutyl)piperazine (Int80)

[0976] Following the synthetic route of compound Int79, 2-bromo-5-(piperidin-4-yloxy)pyridine hydrochloride was replaced with 1-(6-chloropyridin-3-yl)piperazine hydrochloride to obtain the title compound (61 mg).

[0977] MS m / z(ESI): 288.1 [M+H] + .

[0978] Preparation Example 83: Preparation of 2-bromo-5-((1-(2,2-difluoroethyl)piperidin-4-yl)oxy)pyridine (Int81)

[0979] 2-Bromo-5-(piperidin-4-yloxy)pyridine hydrochloride (100 mg, 340.61 μmol), 2,2-difluoroethyl trifluoromethanesulfonate (145.86 mg, 681.23 μmol), and anhydrous potassium carbonate (141.22 mg, 1.02 mmol) were added to N,N-dimethylformamide (3 mL), and the mixture was reacted at 40 °C for 3 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound (80.0 mg, yield: 65.8%).

[0980] MS m / z(ESI): 321.0 [M+H] + .

[0981] Preparation Example 84: Preparation of 1-(6-chloropyridin-3-yl)-4-(2-fluoroethyl)piperazine (Int82)

[0982] 1-(6-chloro-3-pyridyl)piperazine hydrochloride (50.0 mg, 253 μmol), 1-fluoro-2-iodoethane (66.00 mg, 379.43 μmol), and anhydrous potassium carbonate (69.92 mg, 505.91 μmol) were added to acetonitrile (5 mL), and the reaction was carried out at 60 °C for 16 hours. The reaction solution was filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 85 / 15 (v / v)) to give the title compound (57 mg, yield: 87.8%).

[0983] MS m / z(ESI): 244.1 [M+H] + .

[0984] Preparation Example 85: Preparation of 1-(6-chloropyridin-3-yl)-4-(2,2-difluoroethyl)piperazine (Int83)

[0985] 1-(6-chloro-3-pyridyl)piperazine hydrochloride (40 mg, 202.36 μmol), 2,2-difluoroethyl trifluoromethanesulfonate (86.66 mg, 404.73 μmol), and anhydrous potassium carbonate (83.90 mg, 607.09 μmol) were added to N,N-dimethylformamide (3 mL), and the mixture was reacted at 40 °C for 3 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound (50 mg, yield: 89.7%).

[0986] MS m / z(ESI): 262.1 [M+H] + .

[0987] Preparation Example 86: Preparation of 9-(6-chloropyridin-3-yl)-3-methyl-3-azaspiro[5.5]undecane (Int84)

[0988] Following the synthetic route of compound Int75, tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate to obtain the title compound (100 mg).

[0989] MS m / z(ESI): 279.2 [M+H] + .

[0990] Preparation Example 87: Preparation of 1-(6-chloropyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)piperazine (Int85)

[0991] Following the synthetic route of compound Int54, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was replaced with 1-(tetrahydro-2H-pyran-4-yl)piperazine to obtain the title compound (150 mg).

[0992] MS m / z(ESI): 282.1 [M+H] + .

[0993] Preparation Example 88: Preparation of 2-bromo-5-((1-(oxecyclobutan-3-yl)piperidin-4-yl)oxy)pyridine (Int86)

[0994] 2-Bromo-5-(piperidin-4-yloxy)pyridine hydrochloride (50.0 mg, 252.79 μmol), 3-oxetane (36.8 mg, 511 μmol), and sodium triacetoxyborohydride (144 mg, 681 μmol) were added to anhydrous ethanol (4 mL) and reacted at 40 °C for 6 hours. The reaction solution was quenched with saturated ammonium chloride solution, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1 to 4 / 1 (v / v)) to give the title compound (50.0 mg, yield: 89.1%).

[0995] MS m / z(ESI): 313.0 [M+H] + .

[0996] Preparation Example 89: Preparation of 1-(6-chloropyridin-3-yl)-4-(oxecyclobutane-3-yl)piperazine (Int87)

[0997] Following the synthetic route of compound Int86, 2-bromo-5-(piperidin-4-yloxy)pyridine hydrochloride was replaced with 1-(6-chloropyridin-3-yl)piperazine hydrochloride to obtain the title compound (50 mg).

[0998] MS m / z (ESI): 254.1 [M+H] + .

[0999] Preparation Example 90: Preparation of 2-(6-chloropyridin-3-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole (Int88)

[1000] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3,4]octane-6-carboxylate was replaced with hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate to obtain the title compound (100 mg).

[1001] MS m / z(ESI): 238.1 [M+H] + .

[1002] Preparation Example 91: Preparation of 3-(6-chloropyridin-3-yl)-6-methyl-3,6-diazabicyclo[3.1.1]heptane (Int89)

[1003] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate to obtain the title compound (100 mg).

[1004] MS m / z(ESI): 224.1 [M+H] + .

[1005] Preparation Example 92: Preparation of (R)-8-(6-chloropyridin-3-yl)octahydropyrazino[2,1-c][1,4]oxazine (Int90)

[1006] Following the synthetic route of compound Int54, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was replaced with (R)-octahydropyrazine[2,1-c][1,4]oxazine to obtain the title compound (150 mg, yield: 76.3%).

[1007] MS m / z (ESI): 254.1 [M+H] + .

[1008] Preparation Example 93: Preparation of 1-(5-chloropyrazin-2-yl)-4-methylpiperazin-2-one (Int91)

[1009] Following the synthetic route of compound Int54, 5-bromo-2-chloropyridine was replaced with 2-bromo-5-chloropyrazine, and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was replaced with 4-methylpiperazin-2-one, yielding the title compound (95 mg, yield: 38.5%).

[1010] MS m / z(ESI): 227.1 [M+H] + .

[1011] Preparation Example 94: Preparation of 1-(6-chloro-4-fluoropyridin-3-yl)-4-methylpiperazin-2-one (Int92)

[1012] 2-Chloro-4-fluoro-5-iodopyridine (200 mg, 776.91 μmol), 4-methylpiperazin-2-one (106.42 mg, 932.29 μmol), cuprous iodide (147.96 mg, 776.91 μmol), 1,10-phenanthroline (70.00 mg, 388.45 μmol), and cesium carbonate (506.26 mg, 1.55 mmol) were added to 1,4-dioxane (10 mL), purged with nitrogen, and reacted at 110 °C for 6 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%-35%) to give the title compound (130 mg, yield: 65.2%).

[1013] MS m / z(ESI): 244.0 [M+H]+ .

[1014] Preparation Example 95: Preparation of 1-(6-chloro-5-fluoropyridin-3-yl)-4-methylpiperazin-2-one (Int93)

[1015] Following the synthetic route of compound Int54, 5-bromo-2-chloropyridine was replaced with 5-bromo-2-chloro-3-fluoropyridine, and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was replaced with 4-methylpiperazin-2-one to obtain the title compound (100 mg, yield: 41.0%).

[1016] MS m / z(ESI): 244.1 [M+H] + .

[1017] Preparation Example 96: Preparation of 1-(6-chloropyridin-3-yl)-4-methyl-2-(trifluoromethyl)piperazine (Int94)

[1018] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3,4]octane-6-carboxylate was replaced with tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate to obtain the title compound (18 mg).

[1019] MS m / z (ESI): 280.1 [M+H] + .

[1020] Preparation Example 97: Preparation of (S)-8-(6-chloropyridin-3-yl)octahydropyrazino[2,1-c][1,4]oxazine (Int95)

[1021] Following the synthetic route of compound Int54, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was replaced with (S)-octahydropyrazine[2,1-c][1,4]oxazine to obtain the title compound (150 mg, yield: 75.6%).

[1022] MS m / z (ESI): 254.1 [M+H] + .

[1023] Preparation Example 98: Preparation of (1R,5S)-3-(6-chloropyridin-3-yl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (Int96)

[1024] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate to obtain the title compound (25 mg).

[1025] MS m / z(ESI): 238.1 [M+H] + .

[1026] Preparation Example 99: Preparation of 3-(6-chloropyridin-3-yl)-9-methyl-3,9-diazabicyclo[3.3.1]nonane (Int97)

[1027] Following the synthetic route of compound Int62, tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was replaced with tert-butyl 3,9-diazabicyclo[3.3.1]nonane-9-carboxylate to obtain the title compound (25 mg).

[1028] MS m / z(ESI): 252.1 [M+H] + .

[1029] Preparation Example 100: Preparation of (1R,5S)-3-(6-chloropyridin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane (Int98)

[1030] Following the synthetic route of compound Int75, 2-oxo-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester was replaced with (1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester to obtain the title compound (70 mg).

[1031] MS m / z(ESI): 237.1 [M+H] + .

[1032] Preparation Example 101: Preparation of tert-butyl (1-(6-chloropyridin-3-yl)-2-oxopiperidin-4-yl)(methyl)carbamate (Int99)

[1033] Step 1: Preparation of 4-(methylamino)-5,6-dihydropyridine-2(1H)-one

[1034] Piperidine-2,4-dione (5 g, 44.2 mmol) was dissolved in methylaminetetrahydrofuran solution (2 M, 66 mL), and two drops of acetic acid were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give the title compound of this step (5.2 g, yield 83.9%).

[1035] MS m / z (ESI): 127.2 [M+H] + .

[1036] Step 2: Preparation of tert-butyl methyl(2-oxopiperidin-4-yl)carbamate

[1037] 4-(methylamino)-5,6-dihydropyridine-2(1H)-one (5.00 g, 39.6 mmol) and di-tert-butyl dicarbonate (17.3 g, 79.2 mmol) were dissolved in methanol (100 mL), and the resulting solution was delivered by a plunger pump at a flow rate of 0.30 mL / min. A fixed bed (outer diameter: 6.35 mm (1 / 4 inch); internal volume: 5.00 mL) was completely packed with 5% palladium on carbon (3.32 g, WXC1030) granular catalyst. Hydrogen flow rate was 20.0 sccm, and the system was maintained at 2.00 MPa. The liquid and gas were mixed using a T-mixer, and the mixed solution was introduced into a stainless steel fixed-bed reactor, maintained at 100 °C. After the reaction solution was completely injected, the solvent feed was switched to methanol at a rate of 6.00 mL / min, and the reactor was flushed for 30 minutes. The collected reaction solution was concentrated to obtain the title compound of this step (7.02 g, yield 69.8%).

[1038] MS m / z(ESI): 229.2 [M+H] + .

[1039] Step 3: Preparation of tert-butyl (1-(6-chloropyridin-3-yl)-2-oxopiperidin-4-yl)(methyl)carbamate

[1040] 4 g (17.52 mmol) of methyl (2-oxopiridine-4-yl)carbamate tert-butyl ester, 2-chloro-5-iodopyridine (5.03 g, 21.03 mmol), cuprous iodide (667.40 mg, 3.50 mmol), potassium phosphate (7.44 g, 35.04 mmol), and tetramethylethylenediamine (814.45 mg, 7.01 mmol) were dissolved in 1,4-dioxane (50 mL), and the mixture was purged with nitrogen and reacted at 110 °C for 16 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 (980 mg, yield: 15.6%).

[1041] MS m / z(ESI): 339.9 [M+H] + .

[1042] Preparation Example 102: Preparation of 6-(3-(1-((methoxy-d3)methyl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidin-4-amine (Int100)

[1043] Following steps one and two of the synthetic route for compound C-102, 5-bromo-3-(1-ethoxy-2-methylpropyl-2-yl)pyrazolo[1,5-a]pyrimidine was replaced with 5-bromo-3-(1-((methoxy-d3)methyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine to obtain the title compound (19 g).

[1044] MS m / z(ESI): 300.2 [M+H] + .

[1045] Preparation Example 103: Preparation of 1-(6-chloropyridin-3-yl)-4-(3-fluorozacricyclobutan-1-yl)piperidin-2-one (Int103)

[1046] Step 1: Preparation of 4-(3-fluorozacricyclobutan-1-yl)-5,6-dihydropyridine-2(1H)-one

[1047] Piperidine-2,4-dione (3.00 g, 26.5 mmol) and 3-fluorozacyclobutane hydrochloride (2.96 g, 26.5 mmol) were dissolved in tetrahydrofuran (20.0 mL), and N,N-diisopropylethylamine (4.11 g, 31.8 mmol) was added dropwise. After stirring for 5 minutes, acetic acid (2.39 g, 39.78 mmol) was added, and the reaction was carried out at room temperature for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to give the title compound of this step (5.81 g, yield: 72.1%).

[1048] MS m / z (ESI): 171.1 [M+H] + .

[1049] Step 2: Preparation of 4-(3-fluorozacriane-1-yl)piperidin-2-one

[1050] 4-(3-fluorozacricyclobutan-1-yl)-5,6-dihydropyridine-2(1H)-one (3.00 g, 17.63 mmol) was dissolved in methanol (60 mL), and the resulting solution was delivered by a plunger pump at a flow rate of 0.30 mL / min. A fixed bed (outer diameter: 6.35 mm (1 / 4 inch); internal volume: 5.00 mL) was completely packed with 5% palladium on carbon (3.5 g, WXC1030) granular catalyst. The hydrogen flow rate was 20.0 sccm, and the system was maintained at 2.00 MPa. The liquid and gas were mixed using a T-mixer, and the mixed solution was introduced into a stainless steel fixed-bed reactor, maintained at 100 °C. After the reaction solution was completely injected, the solvent feed was switched to methanol at a rate of 6.00 mL / min, and the reactor was flushed for 30 minutes. The collected reaction solution was concentrated to obtain the title compound of this step (2.5 g, yield: 57.7%).

[1051] MS m / z (ESI): 173.1 [M+H] + .

[1052] Step 3: Preparation of 1-(6-chloropyridin-3-yl)-4-(3-fluorozacriane-1-yl)piperidin-2-one

[1053] 4-(3-fluorozacricyclobutan-1-yl)piperidin-2-one (1.90 g, 11.03 mmol), 2-chloro-5-iodopyridine (3.17 g, 13.24 mmol), cuprous iodide (420 mg, 2.21 mmol), potassium phosphate (4.68 g, 22.07 mmol), and tetramethylethylenediamine (513 mg, 4.41 mmol) were dissolved in 1,4-dioxane (20 mL), and the mixture was purged with nitrogen and reacted at 110 °C for 12 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 96 / 4 (v / v)) to give the title compound of this step (200 mg, yield: 3.29%).

[1054] MS m / z(ESI): 284.1 [M+H] + .

[1055] Preparation Example 104: Preparation of 1-(6-chloropyridin-3-yl)-4-morpholinylpiperidin-2-one (Int104)

[1056] Following the synthetic route of compound Int103, 3-fluorozahexacyclic butane was replaced with morpholine to obtain the title compound (1.43 g).

[1057] MS m / z(ESI): 296.1 [M+H] + .

[1058] Preparation Example 105: Preparation of 4-(azacyclobutane-1-yl)-1-(6-chloropyridin-3-yl)piperidin-2-one (Int105)

[1059] Following the synthetic route of compound Int103, 3-fluoroazacyclobutane was replaced with azacyclobutane to obtain the title compound (200 mg).

[1060] MS m / z(ESI): 266.1 [M+H] + .

[1061] Preparation Example 106: Preparation of 1-(6-chloropyridin-3-yl)-4-(3-methoxyazacyclobutane-1-yl)piperidin-2-one (Int106)

[1062] Following the synthetic route of compound Int103, 3-fluoroazacyclobutane was replaced with 3-methoxyazacyclobutane to obtain the title compound (653 mg).

[1063] MS m / z(ESI): 296.1 [M+H] + .

[1064] Preparation Example 107: Preparation of 1-(6-chloropyridin-3-yl)-4-(pyrrolidone-1-yl)piperidin-2-one (Int107)

[1065] Following the synthetic route of compound Int103, 3-fluorozahexacyclic butane was replaced with pyrrolidine to obtain the title compound (952 mg).

[1066] MS m / z (ESI): 280.1 [M+H] + .

[1067] Preparation Example 108: Preparation of 1-(6-chloropyridin-3-yl)-4-(3,3-difluoroazacyclobutan-1-yl)piperidin-2-one (Int108)

[1068] Following the synthetic route of compound Int103, 3-fluoroazacyclobutane was replaced with 3,3-difluoroazacyclobutane to obtain the title compound (250 mg).

[1069] MS m / z (ESI): 302.1 [M+H] + .

[1070] Preparation Example 109: Preparation of 4-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-1-(6-chloropyridin-3-yl)piperidin-2-one (Int109)

[1071] Following the synthetic route of compound Int103, 3-fluoroazacyclobutane was replaced with (1R,5S)-3-azabicyclo[3.1.0]hexane to obtain the title compound (520 mg).

[1072] MS m / z(ESI): 292.1 [M+H] + .

[1073] Preparation Example 110: Preparation of 4-(bis(2-methoxyethyl)amino)-1-(6-chloropyridin-3-yl)piperidin-2-one (Int110)

[1074] Following the synthetic route of compound Int103, 3-fluorozacriane was replaced with bis(2-methoxyethyl)amine to obtain the title compound (520 mg).

[1075] MS m / z(ESI): 342.0 [M+H] + .

[1076] Example 1: Preparation of 4-(dimethylamino)-1-(6-((5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)amino)pyridin-3-yl)piperidin-2-one (C-1)

[1077] Step 1: Preparation of 5-(2-chloro-5-fluoropyridin-4-yl)-3-isopropylpyrazolo[1,5-a]pyridine

[1078] 3-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine (150 mg, 0.524 mmol) and 2-chloro-5-fluoro-4-iodopyridine (134.64 mg, 0.524 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1.5 mL). Potassium carbonate (144.84 mg, 1.048 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (85.58 mg, 0.105 mmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 6 hours. The reaction system was cooled to room temperature, and the reaction solution was poured into water (100 mL). It was extracted three times with ethyl acetate (20 mL), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL), dried with 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 (volume ratio)) to obtain the title compound of this step (130 mg, yield: 85.8%).

[1079] MS m / z(ESI): 290.1 ​​[M+H] + .

[1080] Step 2: Preparation of 4-(dimethylamino)-1-(6-((5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)amino)pyridin-3-yl)piperidin-2-one

[1081] 5-(2-chloro-5-fluoropyridin-4-yl)-3-isopropylpyrazolo[1,5-a]pyridine (30 mg, 103.778 μmol) and 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (24.30 mg, 103.778 μmol) were dissolved in 1,4-dioxane (3 mL), and tris(dibenzylideneacetone)dipalladium (9.50 mg, 10.378 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (4.84 mg, 10.378 μmol) and cesium carbonate (101.44 mg, 311.334 μmol) were added. The mixture was purged with nitrogen and reacted at 110 °C for 3 hours. The crude product obtained by concentrating the reaction solution was dissolved in N,N-dimethylformamide and purified by reversed-phase column chromatography (preparation method A, elution gradient: mobile phase A% = 10%-90%) to obtain the title compound of this step (25.0 mg, yield: 49.4%).

[1082] MS m / z (ESI): 488.3 [M+H] + .

[1083] 1H NMR(400MHz, DMSO-d6)δ9.92(s,1H),8.75-8.77(dd,J=7.2,0.8Hz,1H),8.34-8.35(d,J=2.4 Hz,1H),8.13-8.15(m,1H),7.99-8.03(m,2H),7.95-7.96(m,1H),7.71-7.73(m,1H),7.59-7. 62(m,1H),7.03-7.05(m,1H),3.59-3.68(m,2H),3.22-3.29(m,2H),2.63-2.69(m,1H),2.54- 2.56(m,1H),2.42(s,6H),2.16-2.20(m,1H),1.84-1.94(m,1H),1.32-1.34(d,J=6.8Hz,6H).

[1084] Example 2: Preparation of 4-(dimethylamino)-1-(6-((6-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-2)

[1085] Following the synthetic route of compound C-1, 2-chloro-5-fluoro-4-iodopyridine was replaced with 4,6-dichloropyrimidine to obtain the title compound (44 mg).

[1086] MS m / z (ESI): 471.3 [M+H] + .

[1087] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.84-8.85(d,J=1.2Hz,1H),8.74-8.76(dd,J=7.2,0.8Hz,1H),8.40-8. 41(dd,J=2.0,0.8Hz,1H),8.31(d,J=2.8Hz,1H),8.22(s,1H),7.98(s,1H),7.92-7.94(d,J=8.8Hz,1H),7.72- 7.75(dd,J=8.8,2.8Hz,1H),7.37-7.39(dd,J=7.2,2.0Hz,1H),3.63-3.73(m,2H),3.26-3.33(m,2H),2.69-2. 75(m,1H),2.56-2.63(m,1H),2.47(s,6H),2.21-2.26(m,1H),1.89-1.99(m,1H),1.32-1.36(d,J=6.8Hz,6H).

[1088] Example 3: Preparation of 6-((5-(4-(dimethylamino)-2-oxopiperidin-1-yl)pyridin-2-yl)amino)-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)nicotinonitrile (C-34)

[1089] Following the synthetic route of compound C-1, 2-chloro-5-fluoro-4-iodopyridine was replaced with 6-chloro-4-iodonicotinonitrile to obtain the title compound (20 mg).

[1090] MS m / z (ESI): 495.3 [M+H] + .

[1091] 1 H NMR (400MHz, DMSO-d6) δ10.56 (s, 1H), 8.85-8.75 (m, 2H), 8.23 ​​(d, J = 4.0Hz, 1H), 8.02-8.0 1(m,2H),7.93(s,1H),7.86(d,J=8.0Hz,1H),7.71(dd,J=8.0,4.0Hz,1H),7.04(dd,J=8.0, 4.0Hz,1H),3.67-3.59(m,2H),3.33-3.21(m,1H),2.75-2.65(m,1H),2.58-2.57(m,1H),2. 44-2.37(m,1H),2.21(s,6H),2.10-2.07(m,1H),1.86-1.73(m,1H),1.34(d,J=4.0Hz,6H).

[1092] Example 4: Preparation of 4-(dimethylamino)-1-(6-((5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-yl)amino)pyridin-3-yl)piperidin-2-one (C-36)

[1093] 5-(2-chloro-5-fluoropyridin-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidine (4 mg, 13.76 μmol) and 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (3.22 mg, 13.76 μmol) were dissolved in 1,4-dioxane (3 mL), and tris(dibenzylacetone)dipalladium (1.26 mg, 1.38 μmol) and 2-dicyclohexylphosphine-2 were added. ',6'-diisopropoxy-1,1'-biphenyl (642.04 μg, 1.38 μmol) and cesium carbonate (13.45 mg, 41.28 μmol) were reacted at 110 °C for 3 hours under nitrogen purging. The crude product obtained by concentration of the reaction solution was dissolved in N,N-dimethylformamide and purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-90%) to give the title compound (2.3 mg, yield: 34.2%).

[1094] MS m / z (ESI): 489.2 [M+H] + .

[1095] 1 H NMR (400MHz, DMSO-d6) δ10.07(d,J=4.0Hz,1H),9.19(d,J=8.0Hz,1H),8.53-8.37(m,2H),8.22(d,J=2.0Hz,1H),8.12(m,1H),7.69(m,1H),7.61(dd, J=8.0,2.0Hz,1H),7.38(m,1H),3.69-3.55(m,2H),2.80(m,2H),2.47-2.4 1(m,1H),2.27(s,6H),2.18-2.04(m,1H),1.80(m,2H),1.48-0.94(m,6H).

[1096] Example 5: Preparation of 4-(dimethylamino)-1-(6-((6-(3-(2-methoxypropane-2-yl)benzo[c]isothiazo-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-52)

[1097] Step 1: Preparation of 5-(6-chloropyrimidin-4-yl)-3-(2-methoxypropane-2-yl)benzo[c]isothiazol

[1098] 4,6-Dichloropyrimidine (50 mg, 302.06 μmol), 3-(2-methoxypropane-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzo[c]isothiazol (111.85 mg, 302.06 μmol), tetrakis(triphenylphosphine)palladium (35.24 mg, 30.21 μmol), and potassium carbonate (105.26 mg, 755.15 μmol) were added to ethylene glycol dimethyl ether (3 mL) and water (0.3 mL), purged with nitrogen, and reacted at 85 °C for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound of this step (98 mg, crude product).

[1099] MS m / z (ESI): 320.2 [M+H] + .

[1100] Step 2: Preparation of 4-(dimethylamino)-1-(6-((6-(3-(2-methoxypropane-2-yl)benzo[c]isothiazo-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one

[1101] 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (40 mg, 153.65 μmol), 5-(6-chloropyrimidin-4-yl)-3-(2-methoxypropane-2-yl)benzo[c]isothiazol (54.60 mg, 153.65 μmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (14.46 mg, 30.73 μmol), tris(dibenzylideneacetone)dipalladium (14.20 mg, 15.37 μmol) and potassium carbonate (53.55 mg, 384.13 μmol) were added to 1,4-dioxane (3 mL), the mixture was purged with nitrogen, and the reaction was carried out 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% = 5%-20%) to obtain the title compound of this step (27 mg, yield: 29.6%).

[1102] MS m / z (ESI): 518.4 [M+H] + .

[1103] 1H NMR (400MHz, DMSO-d6): δ10.41(s,1H),8.86(s,1H),8.77(s,1H),8.28(d,J=4.0Hz,1H),8.23(br,1H),8.12-8.09(m,1H),7.97-7.90(m,2H),7.74- 7.71(m,1H),3.67-3.63(m,2H),3.21(s,3H),2.76-2.69(m,1H),2.60-2.5 3(m,1H),2.46-2.39(m,1H),2.23(s,6H),2.12-2.07(m,1H),1.81(s,7H).

[1104] Example 6: Preparation of 4-(dimethylamino)-1-(6-((5-fluoro-4-(3-(2-methoxypropane-2-yl)benzo[c]isothiazo-5-yl)pyridin-2-yl)amino)pyridin-3-yl)piperidin-2-one (C-53)

[1105] Step 1: Preparation of 5-(2-chloro-5-fluoropyridin-4-yl)-3-(2-methoxypropane-2-yl)benzo[c]isothiazole

[1106] 2-Chloro-5-fluoro-4-iodopyridine (85 mg, 297.17 μmol), 3-(2-methoxypropane-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzo[c]isothiazolium (110.03 mg, 297.17 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (21.94 mg, 29.72 μmol), and sodium carbonate (79.54 mg, 742.92 μmol) were added to 1,4-dioxane (3 mL) and water (0.3 mL), purged with nitrogen, and reacted at 85 °C for 5 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 obtain the title compound of this step (110 mg, crude product).

[1107] MS m / z(ESI): 337.2 [M+H] + .

[1108] Step 2: Preparation of 4-(dimethylamino)-1-(6-((5-fluoro-4-(3-(2-methoxypropane-2-yl)benzo[c]isothiazolyl-5-yl)pyridin-2-yl)amino)pyridin-3-yl)piperidin-2-one

[1109] 5-(2-chloro-5-fluoropyridin-4-yl)-3-(2-methoxypropane-2-yl)benzo[c]isothiazol (52.38 mg, 153.65 μmol), 1-(6-aminopyridin-3-yl)-4-(dimethylamino)piperidin-2-one (40 mg, 153.65 μmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (14.46 mg, 30.73 μmol), tris(dibenzylideneacetone)dipalladium (14.20 mg, 15.37 μmol) and potassium carbonate (53.55 mg, 384.13 μmol) were added to 1,4-dioxane (3 mL), the mixture was purged with nitrogen, and the reaction was carried out 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% = 5%-20%) to obtain the title compound of this step (20 mg, yield: 21.3%).

[1110] MS m / z (ESI): 535.5 [M+H] + .

[1111] 1 H NMR (400MHz, DMSO-d6): δ9.95(s,1H),8.35(s,1H),8.28(s,1H),8.12(s,1 H),8.02(d,J=4.0Hz,1H),7.92(d,J=12.0Hz,1H),7.75-7.70(m,2H),7.62 -7.59(m,1H),3.62-3.58(m,2H),3.22(s,3H),2.73-2.66(m,1H),2.57-2. 52(m,1H),2.43-2.36(m,1H),2.22(s,6H),2.09-2.05(m,1H),1.79(s,7H).

[1112] Example 7: Preparation of 4-(dimethylamino)-1-(6-((6-(3-isopropylbenzo[c]isothiazo-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-6)

[1113] Following the synthetic route of compound C-52, 3-(2-methoxypropane-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopent-2-yl)benzo[c]isothiazole was replaced with 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopent-2-yl)benzo[c]isothiazole to obtain the title compound (35 mg).

[1114] MS m / z (ESI): 488.4 [M+H] + .

[1115] 1 H NMR (400MHz, DMSO-d6): δ10.39(s,1H),8.85(s,1H),8.62(s,1H),8.30-8.29(d,J=4 .0Hz,1H),8.25(s,1H),8.10-8.08(m,1H),7.93-7.87(m,2H),7.74-7.71(m,1H),4.0 3-3.97(m,1H),3.67-3.63(m,2H),2.73-2.70(m,1H),2.60-2.53(m,1H),2.46-2.40( m,1H),2.24(s,6H),2.12-2.08(m,1H),1.87-1.77(m,1H),1.55(s,3H),1.53(s,3H).

[1116] Example 8: Preparation of 4-(dimethylamino)-1-(6-((5-fluoro-4-(3-isopropylbenzo[c]isothiazo-5-yl)pyridin-2-yl)amino)pyridin-3-yl)piperidin-2-one (C-5)

[1117] Following the synthetic route of compound C-53, 3-(2-methoxypropane-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopent-2-yl)benzo[c]isothiazole was replaced with 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopent-2-yl)benzo[c]isothiazole to obtain the title compound (15 mg).

[1118] MS m / z (ESI): 505.1 [M+H] + .

[1119] 1 H NMR (400MHz, DMSO-d6): δ9.91 (s, 1H), 8.34 (s, 1H), 8.15-8.13 (d, J = 8.0Hz, 2H), 8 .00-7.99(d,J=4.0Hz,1H),7.89-7.86(d,J=12.0Hz,1H),7.73-7.68(m,2H),7.61 -7.59(m,1H),3.98-3.95(m,1H),3.61(s,3H),2.70-2.68(m,1H),2.22(s,6H),2. 08-2.06(m,1H),1.79-1.78(m,1H),1.53(s,3H),1.51(s,3H),1.23-1.22(m,1H).

[1120] Example 9: Preparation of 4-(dimethylamino)-1-(6-((6-(3-(3-methoxyoxetane-3-yl)pyrazolo[1,5-a]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-14)

[1121] Following the synthetic route of compound C-52, 3-(2-methoxypropane-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzo[c]isothiazolium was replaced with 3-(3-methoxyoxacyclobutane-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine to obtain the title compound (25 mg).

[1122] MS m / z (ESI): 515.3 [M+H] + .

[1123] 1 H NMR (400MHz, DMSO-d6): δ10.45(s,1H),8.89-8.85(m,2H),8.34-8.21(m,5H),7.93(s,1H),7.73(s,1H),7.51(s,1 H),4.90(s,4H),3.64(s,2H),3.05(s,3H),2.74-2.72(m,1H),2.24(s,6H),2.09-2.07(m,1H),1.82-1.76(m,2H).

[1124] Example 10: Preparation of 4-(dimethylamino)-1-(6-((5-fluoro-4-(3-(3-methoxyoxetane-3-yl)pyrazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)amino)pyridin-3-yl)piperidin-2-one (C-13)

[1125] Following the synthetic route of compound C-53, 3-(2-methoxypropane-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)benzo[c]isothiazolium was replaced with 3-(3-methoxyoxacyclobutane-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrazolo[1,5-a]pyridine to obtain the title compound (12 mg).

[1126] MS m / z (ESI): 532.2 [M+H] + .

[1127] 1 H NMR (400MHz, DMSO-d6): δ9.95 (s, 1H), 8.90 (d, J = 4.0Hz, 1H), 8.35 (d, J = 8.0Hz, 2H),8.28(s,1H),8.13(s,1H),8.01(d,J=4.0Hz,1H),7.83(s,1H),7.73-7.71(m ,1H),7.62-7.60(m,1H),7.20-7.19(m,1H),4.88(s,4H),3.62-3.59(m,2H),3.0 6(s,3H),2.70-2.68(m,2H),2.22(s,6H),2.08-2.06(m,1H),1.81-1.79(m,1H).

[1128] Example 11: Preparation of 4-(dimethylamino)-1-(6-((6-(3-(1-methoxycyclopropyl)pyrazolo[1,5-a]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-58)

[1129] Following the synthetic route of compound C-52, 3-(2-methoxypropane-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzo[c]isothiazolium was replaced with 3-(1-methoxycyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine to obtain the title compound (20 mg).

[1130] MS m / z (ESI): 499.2 [M+H] + .

[1131] 1 H NMR (400MHz, DMSO-d6): δ10.44(s,1H),8.86(s,1H),8.83(d,J=4.0Hz,1H),8.54(d,J=4.0Hz ,1H),8.30(d,J=4.0Hz,1H),8.05(s,1H),7.96-7.93(m,1H),7.76-7.72(m,1H),7.48-7.46(m ,1H),3.70-3.60(m,2H),3.11(s,3H),2.76-2.70(m,1H),2.60-2.55(m,1H),2.46-2.39(m,2 H),2.23(s,6H),2.12-2.06(m,1H),1.86-1.77(m,1H),1.20-1.17(m,2H),0.97-0.94(m,2H).

[1132] Example 12: Preparation of 4-(dimethylamino)-1-(6-((5-fluoro-4-(3-(1-methoxycyclopropyl)pyrazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)amino)pyridin-3-yl)piperidin-2-one (C-59)

[1133] Following the synthetic route of compound C-53, 3-(2-methoxypropane-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopent-2-yl)benzo[c]isothiazolium was replaced with 3-(1-methoxycyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopent-2-yl)pyrazolo[1,5-a]pyridine to obtain the title compound (10 mg).

[1134] MS m / z (ESI): 516.2 [M+H] + .

[1135] 1 H NMR (400MHz, DMSO-d6): δ9.96 (s, 1H), 8.84 (d, J = 8.0Hz, 1H), 8.36 (s, 1H), 8.14 ( s,1H),8.05-8.02(m,3H),7.74-7.72(m,1H),7.62-7.60(m,1H),7.16-7.14(m,1H ),3.63-3.59(m,2H),3.13(s,3H),2.89-2.87(m,1H),2.59-2.57(m,2H),2.33(s, 6H),2.12-2.10(m,1H),1.84-1.75(m,1H),1.17-1.14(m,2H),0.86-0.84(m,2H).

[1136] Example 13: Preparation of 1-(6-((5-chloro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)amino)pyridin-3-yl)-4-(dimethylamino)piperidin-2-one (C-35)

[1137] Following the synthetic route of compound C-1, 2-chloro-5-fluoro-4-iodopyridine was replaced with 2,5-dichloro-4-iodopyridine to obtain the title compound (9 mg).

[1138] MS m / z (ESI): 504.1 [M+H] + .

[1139] 1H NMR (400MHz, DMSO-d6) δ10.07(s,1H),8.73(d,J=8.0Hz,1H),8.39(s,1H),8.13(d,J=2.0Hz,1H) ,7.98(s,1H),7.88(s,1H),7.83(s,1H),7.74(d,J=8.0Hz,1H),7.62(dd,J=8.0,2.0Hz,1H),6.94 (dd,J=8.0,2.0Hz,1H),3.66-3.54(m,2H),3.30-3.19(m,1H),2.73-2.62(m,1H),2.60-2.53(m,1 H),2.43-2.34(m,1H),2.21(s,6H),2.10-2.01(m,1H),1.85-1.72(m,1H),1.31(d,J=8.0Hz,6H).

[1140] Example 14: Preparation of 4-(6-((6-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-N,N-dimethyl-3-oxoperazine-1-sulfonamide (C-60)

[1141] Step 1: Preparation of tert-butyl 4-(6-((6-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-oxoperazine-1-carboxylate

[1142] 5-(6-chloropyrimidin-4-yl)-3-isopropylpyrazolo[1,5-a]pyridine (24.0 mg, 88.0 μmol), 4-(6-aminopyridin-3-yl)-3-oxoperazin-1-carboxylic acid tert-butyl ester (33.4 mg, 114 μmol), tris(dibenzylacetone)dipalladium (8.10 mg, 8.8 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (10.2 mg, 17.6 μmol), and anhydrous cesium carbonate (57.0 mg, 176 μmol) were added to 1,4-dioxane (4 mL), the mixture was purged with nitrogen, and the reaction was carried out at 90 °C for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude title compound of this step (36.0 mg, yield: 77.4%).

[1143] MS m / z (ESI): 529.3 [M+H] + .

[1144] Step 2: Preparation of 1-(6-((6-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazin-2-one

[1145] 30.0 mg (56.8 μmol) of 4-(6-(6-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-oxoperpiperazine-1-carboxylic acid tert-butyl ester was added to a 1,4-dioxane hydrochloride solution (4 M, 3 mL) and reacted 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 A, elution gradient: mobile phase A% = 10%-40%) to give the title compound of this step (22.0 mg, yield: 86.0%).

[1146] MS m / z(ESI): 429.3 [M+H] + .

[1147] Step 3: Preparation of 4-(6-((6-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)-N,N-dimethyl-3-oxopiperazine-1-sulfonamide

[1148] 1-(6-((6-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazin-2-one (20.0 mg, 46.7 μmol), dimethylaminosulfonyl chloride (16.8 mg, 117 μmol), and N,N-diisopropylethylamine (30.2 mg, 233 μmol) were added to anhydrous tetrahydrofuran (2 mL), and the reaction was carried out at 60 °C for 2 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%-90%) to give the title compound of this step (9.60 mg, yield: 36.5%).

[1149] MS m / z (ESI): 536.4 [M+H] + .

[1150] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.85(s,1H),8.75(d,J=8.0Hz,1H),8.41( s,1H),8.38(d,J=4.0Hz,1H),8.22(s,1H),7.99(s,1H),7.95(d,J=8.0Hz,1H),7. 80(dd,J=8.0,4.0Hz,1H),7.38(dd,J=8.0,4.0Hz,1H),3.96(s,2H),3.81-3.78( m,2H),3.65-3.62(m,2H),3.32-3.27(m,1H),2.86(s,6H),1.35(d,J=8.0Hz,6H).

[1151] Example 15: Preparation of 4-(dimethylamino)-1-(6-((4-(3-(2-methoxypropane-2-yl)benzo[c]isothiazo-5-yl)pyridin-2-yl)amino)pyridin-3-yl)piperidin-2-one (C-67)

[1152] Following the synthetic route of compound C-52, 4,6-dichloropyrimidine was replaced with 2-chloro-4-iodopyridine to obtain the title compound (17 mg).

[1153] MS m / z (ESI): 517.2 [M+H] + .

[1154] 1 H NMR (400MHz, DMSO-d6): δ9.90(s,1H),8.34(d,J=4.0Hz,1H),8.30(s,1H),8.15(s,1H),8.03(s,1H),7.94-7.89(m,2H),7.84-7.81(m,1H),7.63-7 .60(m,1H),7.30-7.29(m,1H),3.67-3.58(m,2H),3.23(s,3H),2.74-2.7 0(m,1H),2.44-2.38(m,2H),2.23(s,6H),2.11-2.07(m,1H),1.81(s,7H).

[1155] Example 16: Preparation of (S)-4-(dimethylamino)-1-(6-((6-(3-isopropylbenzo[c]isoxazol-5-yl)pyrimidin-4-yl)amino)pyridin-3-yl)piperidin-2-one (C-4B)...

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 CH; X 2 Selected from N and CR 2 ; X 3 Selected from N and CR 3 ; X 4 Selected from N and C; X 5 Selected from O, S, CR 4 ; When X 1 When selected from N, X 2 Selected from N; It can be a single bond or a double bond; R 1 Selected from H, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C 1-6 Alkylene-OR a 3-12 membered heterocyclic group, 3-12 membered heterocyclic group = C(C 1-6 alkyl)-, C 3-12 cycloalkyl = C(C) 1- 6-alkyl)-、-C(=O)-C 1-6 Alkyl, -C(=O)-N(R) 6 )R 7 , -N(R 6 )R 7 and -OR a The alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace; R 2 Selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 3 Selected from H, deuterium, 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, deuterium, halogen, cyano, 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, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of cycloalkyl and 3-12 membered heterocyclic groups; Or, R 1 R 4 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution; R 5 Each is independently selected from H, deuterium, halogen, cyano, hydroxyl, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-OR a C 2-6 Alkylene, C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the alkyl, alkylene, cycloalkyl and heterocyclic groups are optionally selected from one or more of deuterium, halogen, cyano, C 1-6 Alkyl, C 3- 8-cycloalkyl and -OC 1-6 Alkyl group substitution; Or, two Rs 5 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution; R 6 and R 7 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl; Or, R 6 and R 7 And the attached atoms form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Alkyl group substitution; 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. 8 replace; R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Halogenated alkyl groups; Or, R 8 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 Haloalkyl, C 3-10 cycloalkyl and -OC 1-6 Alkyl group substitution; or two substituents that substituted on the same ring atom of the 3-8 membered heterocycle together form C. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups; 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) a )-、-C 1- 6-alkylene-O-,-N(R) a )-、-O-、-N(R a )-C 1-6 Alkylene-N(R) a )-、-N(R a )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) a )-、-C(=O)-C 1-6 Alkylene -O-, -C(=O)-C 1-6 Alkylene-N(R) a - and -S(=O)2-; or, L forms C fused with Y. 6-10 Aryl, 5-10 heteroaryl, C 5-10 Cycloalkyl or 5-10 membered heterocyclic group; the aryl, heteroaryl, cycloalkyl, and heterocyclic group are optionally composed of one or more elements selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Substituents of haloalkyl groups; Z is selected from H, -NR e R f C 1-6 Alkyl, C 3-12 Cycloalkyl groups and 3-12 membered heterocyclic groups, said heterocyclic group optionally being surrounded by one or more R groups. 9 replace; R 9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -N(R) c )R d -C 1-6 Alkylene-N(R) c )R d -C 1-6 Alkylene-OR c -C(=O)-N(R) c )R d -C(=O)-R c -S(=O)2-R c -S(=O)2-N(R) c )R d C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl and -C 1-6 Alkylene-3-12-membered heterocyclic group, wherein the alkyl, alkylene, cycloalkyl, and heterocyclic group 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) c )R d replace; R a Selected from H and C 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents; R c and R d Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl; the alkyl group is optionally radicalized by one or more elements selected from deuterium, halogen, hydroxyl, cyano, and -OC. 1-6 Alkyl substituents; R e and R f Each is independently selected from H and C. 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein the compound meets one or more of the following conditions: (1)X 2 Selected from N and CR 2 ;R 2 Selected from H, halogen, cyano, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; (2)X 3 Selected from N and CR 3 ;R 3 Selected from H, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups; (3)X 5 Selected from O, S, and CR 4 ;R 4 Selected from H, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 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, -OC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution with cycloalkyl and 3-8 membered heterocyclic groups. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein: R 1 Selected from H, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 cycloalkyl, -C 1- 4-alkylene-OR a 3-8 membered heterocyclic group, 3-8 membered heterocyclic group = C(C 1-4 alkyl)-, C 3-8 cycloalkyl = C(C) 1-4 Alkyl)-, -C(=O)-C 1-4 Alkyl, -C(=O)-N(R) 6 )R 7 , -N(R 6 )R 7 and -OR a The alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace; Or, R 1 R 4 And the attached atoms form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -OC 1-6 Alkyl group substitution; Preferably, R 1 Selected from H, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, -C 1- 4-alkylene-OR a 3-8 membered heterocyclic group, 3-8 membered heterocyclic group = C(C 1-4 alkyl)-, C 3-8 cycloalkyl = C(C) 1-4 Alkyl)-, -C(=O)-C 1-4 Alkyl, -C(=O)-N(R) 6 )R 7 , -N(R 6 )R 7 and -OR a The alkyl, alkenyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace; Or, R 1 R 4 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 Halogenated alkyl groups and -OC 1-6 Alkyl groups are substituted. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein: Y is selected from phenyl or 5-6 nitrogen-containing heteroaryl groups, wherein the phenyl and nitrogen-containing heteroaryl groups are optionally separated by one or more R groups. 8 replace; R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups; Or, R 8 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 Haloalkyl, C 3-10 cycloalkyl and -OC 1-4 Alkyl group substitution; or two substituents that substituted on the same ring atom of the 3-6 membered heterocycle together form C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups; Preferably, Y is selected from phenyl or a 6-membered nitrogen-containing heteroaryl group, wherein the phenyl and nitrogen-containing heteroaryl group are optionally separated by one or more R groups. 8 replace; R 8 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups; Or, R 8 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 group substitution; or two substituents that substituted on the same ring atom of the 3-6 membered heterocycle together form C. 3-6 Cycloalkyl. The compound of any one of claims 1 to 4, 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, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -C 1-4 Alkylene-N(R) a )-、-C 1- 4-alkylene-O-,-N(R) a )-、-O-、-N(R a )-C 1-4 Alkylene-N(R) a )-、-N(R a )-C 1-6 Alkylene-O-, -C(=O)-, -C(=O)-N(R) a )-、-C(=O)-C 1-4 Alkylene -O-, -C(=O)-C 1-4 Alkylene-N(R) a - and -S(=O)2-; or, L forms C fused with Y. 5-6 Cycloalkyl or 5-6 membered heterocyclic group; said cycloalkyl and heterocyclic group optionally being formed by one or more elements selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 Substituents of haloalkyl groups; Preferably, L is selected from covalent bonds, C 1-4 Alkylene, -C 1-4 Alkylene-N(R) a )-、-C 1-4 Alkylene-O-, -N(R) a )-、-N(R a )-C 1-4 Alkylene-N(R) a -, -C(=O)-, -N(R) a )-C 1-6 Alkyl-O- and -S(=O)2-; or, L forms a 5-6 membered nitrogen-containing heterocyclic group fused with Y; said nitrogen-containing heterocyclic group is optionally surrounded by one or more elements selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl and -OC 1-6 The alkyl halogroup is substituted by a substituent. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein: Z is selected from H and C. 1-4 Alkyl, -NR e R f C 3-8 Cycloalkyl and 3-11 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally surrounded by one or more R groups. 9 Replace; the R e and R f Each is independently selected from H and C. 1-6 Alkyl groups, optionally formed by one or more radicals selected from deuterium, halogens, hydroxyl groups, cyano groups, and -OC groups. 1-6 Alkyl substituents; Preferably, Z is selected from H and -NR. e R f C 1-4 Alkyl groups and 3-11 membered heterocyclic groups, wherein the alkyl groups and heterocyclic groups are optionally surrounded by one or more R groups. 9 Replace; the R e and R f Each is independently selected from H and C. 1-6 alkyl; Preferably, Z is selected from H, -N(C) 1-4 Alkyl)2、-NHC 1-4 Alkyl, C 1-4 Alkyl groups, 3-6 membered monocyclic nitrogen-containing heterocyclic groups, 7-10 membered fused-ring nitrogen-containing heterocyclic groups, 6-11 membered spirocyclic nitrogen-containing heterocyclic groups, and 7-9 membered bridged-ring nitrogen-containing heterocyclic groups, wherein the alkyl and heterocyclic groups are optionally separated by one or more R groups. 9 replace. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein: R 9 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, oxo (=O), C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -N(R) c )R d -C 1-4 Alkylene-N(R) c )R d -C 1-4 Alkylene-OR c -C(=O)-N(R) c )R d -S(=O)2-R c -S(=O)2-N(R) c )R d 3-8 membered heterocyclic groups, -C 1-6 Alkylene-C 3-8 cycloalkyl and -C 1-6 Alkylene-3-8-membered heterocyclic group, wherein the alkyl, alkylene, cycloalkyl, and heterocyclic group 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) c )R d replace. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof, wherein the compound has the following structure: A pharmaceutical composition comprising 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, and one or more pharmaceutically acceptable carriers. Use of any compound of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for treating and / or preventing diseases or symptoms associated with CDK2, CDK4 and / or CDK6 activity. The compound of any one of claims 1-8 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or the pharmaceutical composition of claim 9, is used to treat and / or prevent diseases or symptoms associated with CDK2, CDK4 and / or CDK6 activity. A method for treating and / or preventing diseases or symptoms associated with CDK2, CDK4, and / or CDK6 activity, the method comprising administering to an individual in need an effective amount of any one of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, or the pharmaceutical composition of claim 9. A method for preparing the compound according to any one of claims 1-8, wherein, The steps of the preparation method are as follows: 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 X 2 X 3 X 4 X 5 R 1 Y, L, and Z are as defined in any one of claims 1-8; or The steps of the preparation method are as follows: Among them, B 3 Selected from halogen, borate group, borate ester group, and -Sn(C 1-6 Alkyl)3; B 4 It is a halogen; A 2 Selected from borate groups, borate ester groups, and halogens; PG 1 and PG 2 For protection base; X 1 X 2 X 3 X 4 X 5 R 1 Y, L, and Z are as defined in any one of claims 1-8; or The steps of the preparation method are as follows: Among them, B 1 B 2 A 1 X 1 X 2 X 3 X 4 X 5 R 1 Y, L, and Z are as defined above; R 1A R as mentioned above 1 The group formed after dehydrogenation; the PG 3 For example, a protecting group (e.g., trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS), tert-butyldiphenylsilyl ether (TBDPS), tetrahydropyran (THP), methoxymethyl (MOM), benzyl (Bn), or p-methoxybenzyl (PMB)); preferably, the PG 3 It is tert-butyl dimethyl silyl ether (TBS); or The steps of the preparation method are as follows: Among them, B 1 B 2 A 1 X 1 X 2 X 3 X 4 X 5 R 1 Y, L, and Z are as defined above. An intermediate compound or a pharmaceutically acceptable salt thereof, wherein the structure of said compound is shown below: in: LG is a leaving group, PG, PG 1 PG 2 B is an amino protecting group. 1 B 2 X 1 X 2 X 3 X 4 X 5 Y, L, Z, R 1 R 1A R 9 PG 3 As stated in any of the above; Preferably, the intermediate compound is as follows: (For example: )、

Images