No new FGFR3 inhibitor compounds

Abstract

This invention relates to novel FGFR3 inhibitor compounds or their pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, or prodrugs, and their use as medicine. These compounds can be used to treat cancers such as urothelial carcinoma, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, or Muenke syndrome.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to novel FGFR3 inhibitor compounds. This invention provides structurally novel FGFR3 inhibitor compounds or their pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, or prodrugs, and their uses as medicines. These compounds can be used to treat cancers such as urothelial carcinoma, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, or Muenke syndrome. Background Technology

[0002] Fibroblast growth factor (FGF) plays a crucial role in various physiological processes, including but not limited to cell proliferation, differentiation, migration, survival, and tissue repair. Members of the FGF family regulate cellular behavior through interactions with specific receptors, thereby influencing organismal development and maintaining tissue homeostasis. The Fibroblast Growth Factor Receptors (FGFRs) family consists of five members, four of which—FGFR1, FGFR2, FGFR3, and FGFR4—are structurally complex transmembrane glycoproteins with high structural homology. Each FGFR comprises three main parts: an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane region, and an intracellular tyrosine kinase domain.

[0003] The binding of FGF to FGFR triggers receptor dimerization and autophosphorylation, thereby activating the receptor's tyrosine kinase activity. This receptor activation process can recruit and activate specific downstream signaling molecules, thereby participating in the regulation of various important biological processes such as cell growth, metabolism, and survival. Activation of the FGF / FGFR signaling pathway is closely related to alterations in the biological behaviors of tumor cells, such as proliferation, migration, invasion, and angiogenesis.

[0004] Given the role of the FGF / FGFR signaling pathway in various biological processes, especially its crucial position in tumorigenesis, research and regulation of the FGF / FGFR signaling pathway have become a hot topic in biomedical research. Developing compounds or drugs that can specifically regulate the FGF / FGFR signaling pathway has significant clinical implications and promising applications for treating related diseases, particularly tumors. Summary of the Invention

[0005] This invention aims to provide a novel FGFR3 inhibitor that specifically inhibits FGFR3 activity, thereby regulating the FGF / FGFR signaling pathway and offering a new strategy and approach for the treatment of FGFR3-related diseases. The FGFR3 inhibitor of this invention exhibits high specificity, good bioavailability and pharmacokinetic properties, as well as low side effects, and shows significant promise for clinical application.

[0006] In a first aspect of the invention, a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof, is provided as an FGFR3 inhibitor.

[0007]

[0008] The variables R1, R2, m, X1, X2, Z1, Z2, Z3, Z4, R3, Cy1-Cy2, R4, p1, R5, p2, Y, R6, R7 and q are as defined in this application.

[0009] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof, is provided as an FGFR3 inhibitor.

[0010]

[0011] The variables R1, R2, m, X1, Z1, Z2, Z3, Z4, R3, Cy1-Cy2, R4, p1, R5, p2, Y, R6, R7 and q are as defined in this application.

[0012] In a second aspect of the invention, a pharmaceutical composition is provided comprising the compound of the invention, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0013] In a third aspect of the invention, the use of the compound of the invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof, is provided in the preparation of a medicament for the treatment or prevention of diseases such as systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer is provided.

[0014] In a fourth aspect of the invention, a method is provided for treating or preventing diseases such as cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or a combination thereof, said method comprising administering to a subject in need a compound of the invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof, the same as described herein.

[0015] In a fifth aspect of the invention, the compounds of the invention, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, or prodrugs thereof, are provided for the treatment or prevention of diseases such as cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or combinations thereof.

[0016] The present invention is described below with reference to specific implementation schemes and embodiments, but the scope of the present invention should not be limited thereto. Attached Figure Description

[0017] Figure 1 The left panel shows the tumor growth curve and body weight change trend of the RT112 mouse model in test case 4. Detailed Implementation Plan

[0018] definition

[0019] Unless specifically defined in this application, all technical and scientific terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0020] Unless the context clearly indicates otherwise, the singular forms of the terms “a / an” and “the” as used in this application (including the claims) include their respective plural references.

[0021] Unless otherwise expressly stated, the connection direction of groups or segments in this invention is read from left to right. For example, The left end of the segment is connected to R1, and its right end is connected to... Link; other groups or segments are interpreted in a similar manner.

[0022] Unless otherwise stated, bonds marked with wavy lines or dashed lines in the structure of this application represent positions where they are connected to other parts of the molecule.

[0023] The term "alkyl" includes those selected from those containing 1 to 18 carbon atoms. 1-18 Alkyl groups (e.g., 1 to 12 C) 1-12 Alkyl groups, further such as 1 to 10 C16 groups.1-10 Alkyl groups, and even more specifically, those with 1 to 8 carbon atoms. 1-8 Alkyl groups, or 1 to 6 C atoms 1-6 Alkyl groups, or 1 to 4 C16 groups 1-4 Alkyl groups are straight-chain and branched saturated hydrocarbon groups containing carbon atoms, either substituted or unsubstituted. Alkyl groups (i.e., C164-C65) are alkyl groups containing 1 to 6 carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0024] The term "alkenyl" includes those selected from those containing at least one C=C double bond and 2 to 18 C atoms. 2-18 Alkenyl groups (such as 2 to 8 C groups) 2-8 Alkenyl groups, further such as 2 to 6 C groups 2-6 Alkenyl groups, and even further, those with 2 to 4 carbon atoms. 2-4 Alkenyl (C2-alkenyl), a straight-chain or branched hydrocarbon group of an alkenyl carbon atom, is either substituted or unsubstituted. Examples of alkenyl groups include: vinyl (C2-alkenyl), 1-propenyl (C3-alkenyl), 2-propenyl (C3-alkenyl), 1-butenyl (C4-alkenyl), 2-butenyl (C4-alkenyl), butadienyl (C4-alkenyl), pentenyl (C5-alkenyl), pentadienyl (C5-alkenyl), hexenyl (C6-alkenyl), and so on.

[0025] The term "alkynyl" includes groups selected from those containing at least one C≡C triple bond and 2 to 18 C atoms. 2-18 Alkyne groups (e.g., 2 to 8 C groups) 2-8 Alkyne group, further such as 2 to 6 C 2-6 Alkyne groups, and even more so, 2 to 4 C groups. 2-4 Alkynyl group (a straight-chain or branched hydrocarbon group of an alkynyl group, substituted or unsubstituted). 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2 alkynyl), 1-propynyl (C3 alkynyl), 2-propynyl (C3 alkynyl), 1-butynyl (C4 alkynyl), 2-butynyl (C4 alkynyl), pentyynyl (C5 alkynyl), hexynyl (C6 alkynyl), etc.

[0026] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0027] The term “halogenated” or “halogenated” means substituted with F, Cl, Br or I, including but not limited to substituted with 1 to 10 substituents selected from F, Cl, Br or I, substituted with 1 to 6 substituents selected from F, Cl, Br or I, or substituted with 1 to 4 substituents selected from F, Cl, Br or I.

[0028] The term "halogenated alkyl" refers to the aforementioned alkyl group substituted with one or more halogen groups. In some embodiments, "halogenated alkyl" is C10. 1-2 Haloalkyl, C 1-4 Halogenated alkyl or C 1-6 Alkyl halogens. Exemplary alkyl halogens include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc.

[0029] The term "alkoxy" refers to a substituted or unsubstituted -O-alkyl group, where the alkyl group is as defined above. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. Similarly, the term "alkathio" refers to a substituted or unsubstituted -S-alkyl group, where the alkyl group is as defined above. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, cyclopropylthio, etc.

[0030] The term "amino" refers to -NH2.

[0031] The terms “alkylamino” and “dialkylamino” refer to amino groups that are substituted with one or two alkyl groups, namely -NH (alkyl) and -N (alkyl)2, respectively, with the alkyl group as defined above.

[0032] The terms "cycloalkyl" or "cycloalkane" are used interchangeably and refer to substituted or unsubstituted saturated carbocyclic hydrocarbon groups, typically with 3 to 12 carbon atoms (C12). 3-12 Cycloalkyl groups. Cycloalkyl groups include monocyclic C-rings. 3-8 For example, single-cycle C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.; cycloalkyl groups also include bicyclic cycloalkyl groups, such as bicyclic C 6-11Cycloalkyl groups, such as bicyclo[3.3.0]octyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.0]hexyl, or bicyclo[3.1.1]heptyl, etc. Cycloalkyl groups appearing in this application are defined as described above. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0033] The terms "heterocyclic group" or "heterocycle" are used interchangeably and include non-aromatic heterocyclic groups whose ring members include one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur, and the remaining ring members are carbon. These include monocyclic, fused, bridged, and spirocyclic groups, i.e., containing monocyclic, bridged, spirocyclic, and fused heterocyclic groups. Monocyclic heterocyclic groups include 3 to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur, such as azirropropyl, glycidyl, thioherropropyl, azirrobutyl, oxobutyran, thiobutyran, cyclobutanone, pyranyl, thiopyranyl, morpholinyl, or azirrophenone. Bridged heterocyclic groups include 7-14-membered bridged heterocyclic groups, which are ring systems containing 7-14 atoms, including at least one heteroatom selected from nitrogen, oxygen, or sulfur, formed by two non-adjacent rings sharing two or more atoms. Spiroheterocyclic groups include 5-14 membered spiroheterocyclic groups, which are carbon-containing cyclic structures formed by at least two rings sharing a single carbon atom. SpiroC 5-14Heterocyclic rings include, but are not limited to, azepam[2.2]pentyl, azepam[2.3]hexyl, azepam[2.4]heptyl, azepam[3.3]heptyl, azepam[2.5]octyl, azepam[3.4]octyl, azepam[2.6]nonyl, azepam[3.5]nonyl, azepam[4.4]nonyl, azepam[2.7]decyl, azepam[3.6]decyl, azepam[4.5]decyl, azepam[3.7]undecyl, azepam[ 4.6] Undecyl, azirspiro[5.5] Undecyl, azirspiro[4.7] Dodecyl, azirspiro[5.6] Dodecyl, diazaspiro[2.2] Pentyl, diazaspiro[2.3] Hexyl, diazaspiro[2.4] Heptyl, diazaspiro[3.3] Heptyl, diazaspiro[2.5] Octyl, diazaspiro[3.4] Octyl, diazaspiro[2.6] Nonyl, diazaspiro[3.5] Nonyl, diazaspiro[4.4] Nonyl, diazaspiro Spiro[2.7]decyl, diazaspiro[3.6]decyl, diazaspiro[4.5]decyl, diazaspiro[3.7]undecyl, diazaspiro[4.6]undecyl, diazaspiro[5.5]undecyl, diazaspiro[4.7]dodecyl, diazaspiro[5.6]dodecyl, azirospiro[2.2]pentyl, azirospiro[2.3]hexyl, azirospiro[2.4]heptyl, azirospiro[3.3]heptyl, azirospiro[2. 5] Octyl, azeospiro[3.4] Octyl, azeospiro[2.6] Nonyl, azeospiro[3.5] Nonyl, azeospiro[4.4] Nonyl, azeospiro[2.7] Decyl, azeospiro[3.6] Decyl, azeospiro[4.5] Decyl, azeospiro[3.7] Undecyl, azeospiro[4.6] Undecyl, azeospiro[5.5] Undecyl, azeospiro[4.7] Dodecyl or azeospiro[5.6] Dodecyl. Fused heterocyclic groups include bicyclic 6- to 14-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur, and formed by two or more rings sharing two adjacent atoms. 7-14-membered fused heterocyclic groups include, but are not limited to, octahydroquinoline, dihydroindole, or tetrahydropyrrolizine.

[0034] The term "aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group. The aryl group preferably has 6 to 10 carbon ring atoms, i.e., C6-C. 10 Aryl groups. Aryl groups include phenyl and naphthyl groups. In some embodiments, the aryl group is phenyl.

[0035] The term "heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, or S (=O)). n(where n is 0, 1, or 2). In some embodiments, a heteroaryl group refers to a 5-14 member containing a cyclic carbon atom and 1-4 cyclic heteroatoms, such as a 5-10 member monocyclic or bicyclic ring. Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, oxadiazinyl, and thioheptatrienyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazoleyl, benzotriazolyl, benzothiopheneyl, isobenzothiopheneyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent or tetravalent, the linking site is located on the heteroaryl ring.

[0036] Unless otherwise expressly defined, in the compounds of the general formulas (such as Formula A, Formula I, Formula IA, Formula IB, Formula II) of this application, each group (such as alkyl, alkylene, alkenyl, ynyl, cycloalkane or cycloalkyl, heterocyclic, aryl or heteroaryl) includes unsubstituted or substituted forms, where, when substituted, one or more (such as 1, 2 or 3) hydrogens in the group are replaced by substituents as defined herein. Unless otherwise defined, substituents in alkyl groups (including those commonly referred to as alkylene, alkenyl, ynyl and cycloalkyl) can be various groups selected from the group consisting of halogens, -OR a -NR a R b -SR a -SiR a R b R c OC(O)R a -C(O)R a -CO2R a -CONR a R b -OC(O)NRa R b -NR b C(O)R a -NR a -C(O)NR b Rc, -NR b C(O)2R a -NH-C(NH2)=NH, -NR a C(NH2)=NH、-NH-C(NH2)=NR a -S(O)R a -S(O)2R a -S(O)2NR a R b NR a S(O)2R b -CN and -NO2, in quantities ranging from zero to (2M+1), where M is the total number of carbon atoms in this group. R a R b and R c Each independently represents hydrogen, an unsubstituted C1-8 alkyl, an unsubstituted aryl, an aryl substituted with 1-3 halogens, a C1-8 alkoxy or C1-8 thioalkoxy, or an unsubstituted -C1-4 alkylene-aryl. When R a and R b When attached to the same nitrogen atom, they can combine with the nitrogen atom to form 3-, 4-, 5-, 6-, or 7-membered rings. For example, -NR a R b This refers to the inclusion of 1-pyrrolidinyl and 4-morpholinyl groups. Similarly, unless otherwise defined, the substituents of aryl and heteroaryl groups are diverse and are generally selected from: halogens, -OR... a -OC(O)R a -NR a R b -SR a -R a -CN, -NO2, -CO2R a CONR a R b C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R a -NR a -C(O)NR b Rc, NH C(NH2)=NH, -NR aC(NH2)=NH、-NH-C(NH2)=NR a -S(O)R a -S(O)2R a S(O)2NR a R b NR a S(O)2R b -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, in quantities ranging from zero to the total number of open valences on the aromatic ring system; where R a R b Rc is independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, unsubstituted aryl and heteroaryl, unsubstituted -C1-4 alkylene-aryl or heteroaryl and unsubstituted -C1-4 alkylene-aryloxy.

[0037] When listing a range of values, the given range includes each value and subranges within that range. For example, "C 1-6 "Alkyl" or "C1-C6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0038] For the compounds presented herein, a bond from a substituent (typically an R group) to the center of an aromatic ring (e.g., benzene, pyridine, etc.) will be understood as a bond that provides a connection at any available vertex of the aromatic ring. In some embodiments, this description also includes connections on the ring fused to the aromatic ring. For example, a bond drawn to the center of the indole benzene moiety would represent a bond connected to any available vertex of the six- or five-membered ring moiety of indole.

[0039] "Pharmaceutical-grade salts" refer to those salts that, within reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutical-grade salts can be prepared in situ during the final isolation and purification of the compounds disclosed in this application, or prepared separately by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0040] Furthermore, if the compound disclosed in this application is obtained as an acid addition salt, the free base can be obtained by alkalizing the solution of the acid salt. Conversely, if the product is a free base, the addition salt (such as a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize that various synthetic methodologies can be used to prepare non-toxic pharmaceutically acceptable addition salts without requiring excessive experimentation.

[0041] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably in this application.

[0042] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this application.

[0043] The term "treatment" means to suppress, slow down, stop, or reverse the progression or severity of existing symptoms, conditions, or disorders.

[0044] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0045] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0046] The compounds of this invention may also exist as tautomers. A compound is not limited to any particular tautomer, but is intended to cover all tautomer forms.

[0047] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (I) or (II), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of the present invention containing the aforementioned isotopes and / or other isotopes, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of the general formula of the present invention, such as compounds of formula (A) and their prodrugs, can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0048] The term "prodrug" refers to a compound that is metabolized into an active drug after administration. Examples of prodrugs include, but are not limited to, esters (e.g., phosphate esters, phosphonates, acetates, formates, and benzoates), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc.

[0049] The term "deuterium (D or 2"H)" is a stable isotope of hydrogen, which exists naturally at an abundance of 0.015 mol%. The term "deuteration" refers to the substitution of one or more hydrogen atoms (H) in a group or compound by the replacement of one or more hydrogen atoms (D).

[0050] The isotopic variants of this invention include deuterated compounds. "Deuterated compound" refers to a compound in which one or more carbon-bonded hydrogen atoms are replaced by one or more deuterium atoms. Similarly, "deuterated" refers to a chemical structure or organic group in which one or more carbon-bonded hydrogen atoms are replaced by one or more deuterium atoms, such as "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated aryl," etc. For example, "deuterated alkyl" refers to an alkyl group as defined in this application, wherein at least one carbon-bonded hydrogen atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to one deuterium atom; one carbon atom may be bonded to multiple deuterium atoms; multiple carbon atoms in an alkyl group may also be bonded to deuterium atoms. For example, deuterated methyl groups include methyl-D3, in which three hydrogen atoms are replaced by deuterium atoms; they also include monodeuterated methyl and dideuterated methyl groups. For example, a deuterated piperazine group refers to a piperazine group in which one or more hydrogen atoms are replaced by deuterium, including all eight hydrogen atoms being replaced by deuterium. In some embodiments, the compounds of the present invention include deuterated compounds.

[0051] The compounds of the present invention

[0052] As used herein, the term "compound of the invention" refers to the compound represented herein as of formula (A), (I), (IA), (IB), or (II). The term also includes various crystal forms, pharmaceutically acceptable salts, hydrates, or solvates of compounds of formula (A), (I), (IA), (IB), or (II).

[0053] The term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0054] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0055] Furthermore, the compounds of the present invention also include prodrugs of compounds represented by formulas (A), (I), (IA), (IB), or (II). The term "prodrug" includes compounds that are themselves biologically active or inactive, and which, when taken in a suitable manner, are metabolized or chemically reacted in the human body to form compounds represented by formulas (A), (I), (IA), (IB), or (II), or salts or solutions of a compound represented by formulas (A), (I), (IA), (IB), or (II). The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0056] In a first aspect of the invention, the invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof; wherein the compound is shown in formula (A);

[0057]

[0058] in

[0059] R1 is selected from the following group: none, H, cyano, -alkylene-cyano (e.g., -methylene-cyano), R 11 -SO2- and -alkylene-SO2-R 11 , where R 11 It can be hydrogen, alkyl, heterocyclic, aryl, or heteroaryl;

[0060] In It is a 4- to 10-membered heterocyclic ring or C 4-10 Cycloalkanes, of which

[0061] X1 is a carbon atom (CH) or a nitrogen atom (N).

[0062] X2 is selected from the following group: carbon (CH), nitrogen (N), oxygen (O), S, SO, and SO2.

[0063] m is 0, 1, 2, 3, or 4; and

[0064] R2 is independently selected from the group consisting of: hydrogen, hydroxyl, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, or two R2s substituted on the same carbon atom together with the carbon atom to which they are attached to form a 3-membered, 4-membered, 5-membered or 6-membered spirocycle (the 3-membered, 4-membered, 5-membered and 6-membered refers to the number of ring atoms in the ring formed by two R2s on the same carbon atom and the carbon atom to which they are attached), or two R2s substituted on adjacent carbon atoms together with the carbon atom to which they are attached to form a 3-membered, 4-membered, 5-membered or 6-membered fused ring (or fused ring) (the 3-membered, 4-membered, 5-membered and 6-membered refers to the number of ring atoms in the ring formed by two R2s on adjacent carbon atoms and the carbon atom to which they are attached);

[0065] Furthermore, when X2 is an oxygen atom (O), S, SO, or SO2, R1 is absent;

[0066] Z1, Z2, and Z3 are each independently carbon or nitrogen atoms;

[0067] Z4 either does not exist or is a carbon or nitrogen atom. The condition is that if Z4 does not exist, Z1 is directly bonded to the carbon atom connected to R3.

[0068] The prerequisite is In It is aromatic and It may also be optionally controlled by one or more (preferably, one) R 31 replace;

[0069] R3 is hydrogen, cycloalkyl, alkyl, deuterated alkyl, or deuterated cycloalkyl;

[0070] R 31 Selected from the group consisting of: cyano, halogen, cycloalkyl, alkyl, deuterated alkyl or deuterated cycloalkyl (preferably, R 31 (Cyano or halogen);

[0071] for The asterisk * indicates a parallelism. The sites connected, with asterisks ** indicating sites connected to Y, and

[0072] R4 and R5 are each independently selected from the following groups: hydrogen, halogens (such as F, Cl, Br), CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkenyl, alkynyl (such as ethynyl), cycloalkyl, aryl, heterocyclic, heteroaryl, -COOR 4a -COR 4a nitro, -N(R) 4b )R 4a -N(R) 4a COR4b -N(R) 4a SOR 4b -N(R) 4a SO2R 4b ,-alkylene-R 4b (e.g., methylene-R) 4b ), --alkenyl-R 4b (e.g. - vinylidene-R) 4b ) or -ethynyl-R 4b (e.g. - vinylidene-R) 4b ), where R 4a and R 4b Each is independently selected from the group consisting of: hydrogen, cyano, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclic or optionally substituted heteroaryl, wherein the optional substitution refers to the hydrogen on the group being replaced by one or more (e.g., 1, 2 or 3) R 4c Replaced; of which, R 4c Select the following group: halogen, cyano, alkyl, hydroxyl, -SH, -alkylthio, -C(O)H, -C(O)alkyl, -S(O) 1-2 H, -S(O) 1-2 Alkyl, amino, alkylamino, dialkylamino, -C(O)amino, -C(O)-(alkylamino), -C(O)-(dialkylamino), -S(O) 1-2 Amino group, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino); or alternatively, R4 and R5 are each independently selected from the group consisting of: hydrogen, halogens (e.g., F, Cl, Br), CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, -COOR 4a -COR 4a nitro (NO2), -N (R) 4b )R 4a -N(R) 4a COR 4b -N(R) 4a SOR 4b -N(R) 4a SO2R 4b ,-alkylene-R 4b (e.g., methylene-R) 4b ), --alkenyl-R 4b (e.g. - vinylidene-R) 4b ) or -ethynyl-R 4b (e.g., -ethynyl-R) 4b ), where R 4a and R 4bEach is independently selected from the group consisting of: hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclic or heteroaryl.

[0073] p1 and p2 can each be 0, 1, 2 or 3 independently, provided that the chemical valence bond theory is satisfied;

[0074] Y is -O-, -S-, or -NR8-, where R8 is hydrogen or alkyl;

[0075] R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein the alkyl group is unsubstituted or further substituted by hydroxyl, halogen, alkoxy, alkenyl, alkynyl, phosphonoalkoxy, aryl, heteroaryl, heterocyclic, or cycloalkyl, and the alkenyl and alkynyl groups are unsubstituted or further substituted by alkyl or cycloalkyl; and the aryl, heteroaryl, heterocyclic, and cycloalkyl groups are optionally substituted by one or more substituents selected from the group consisting of alkyl (e.g., methyl), oxo (=O), aryl, heteroaryl, heterocyclic, or cycloalkyl.

[0076] Does not exist or It is a six-membered heteroaryl, phenyl, cycloalkyl, or heterocyclic group, q is 0, 1, 2, 3, or 4, and R7 is a halogen, alkyl, hydroxyalkyl, or haloalkyl.

[0077] In some implementations, R1 is cyano or R 11 -SO2-, where R 11 It can be hydrogen, alkyl, heterocyclic, aryl, or heteroaryl.

[0078] In some implementations, R1 is a cyano group.

[0079] In some embodiments, X1 and X2 are separated by at least one ring atom; preferably, X1 and X2 are separated by one, two or three ring atoms.

[0080] In some implementation schemes, In this context, the heterocyclic or cycloalkanes can be monocyclic or spirocyclic.

[0081] In some implementation schemes, When the heterocycle is a 4- to 10-membered heterocycle, only X1 and X2 can be heteroatoms.

[0082] In some implementations, when X2 is a nitrogen atom, It is a nitrogen-containing 5- or 6-membered heterocyclic ring or a nitrogen-containing spirocyclic ring (such as a 7- to 9-membered spirocyclic ring). In some embodiments, when X2 is a carbon atom (CH), It is a 4, 5, or 6-membered heterocyclic ring or C 4-6 Cycloalkanes (such as cyclohexane) or spirocyclic compounds (such as C12-cyclohexane) 7-9(Spiral ring). In some embodiments, when X2 is an oxygen atom (O), S, SO, or SO2, It consists of 4, 5, or 6-membered heterocyclic rings or spiral rings (such as 7 to 9-membered spiral rings).

[0083] In some implementation schemes, Selected from the following group:

[0084]

[0085] Wherein, n1, n2, n3 and n4 are each independently 1, 2, 3 or 4, and R2 and m are as defined above; preferably, n1, n2, n3 and n4 are each independently 1 or 2.

[0086] In some embodiments, X2 is selected from the group consisting of carbon, nitrogen, and oxygen atoms. In some embodiments, R1 is a cyano or alkylene-cyano (e.g., methylene-cyano), and Selected from the following group:

[0087] In some embodiments, R6 is hydrogen or an alkyl group, wherein the alkyl group is unsubstituted or further substituted with hydroxyl, halogen, alkoxy, phosphonoalkoxy, aryl, heteroaryl or cycloalkyl.

[0088] In some implementations, the carbon atom containing R6 is a chiral carbon.

[0089] In some implementations, the carbon containing R6 is a chiral carbon with an S or R configuration; preferably, it is a chiral carbon with an S configuration.

[0090] In some implementation schemes, In this context, ring A is a six-membered heteroaryl, cycloalkyl, or heterocyclic group, where q is 0, 1, 2, 3, or 4, and R7 is a halogen, alkyl, hydroxyalkyl, or haloalkyl group.

[0091] In some implementation schemes,

[0092] Z1, Z2, Z3, Z4, R3, R4, p1, Y, R6, R7 and q are as defined above;

[0093] It is a 4- to 10-membered heterocyclic ring or C 4-10 Cycloalkanes, of which

[0094] X1 is a carbon atom (CH) or a nitrogen atom (N).

[0095] X2 is selected from the following group: carbon atom (CH), nitrogen atom (N).

[0096] m is 0, 1, 2, 3, or 4; and

[0097] R2 is selected from the group consisting of hydrogen, hydroxyl, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, or two R2s substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-membered, 4-membered, 5-membered or 6-membered spirocyclic ring, or two R2s substituted on adjacent carbon atoms together with the carbon atom to which they are attached form a 3-membered, 4-membered, 5-membered or 6-membered fused ring;

[0098] R1 is a cyano group;

[0099] for

[0100] (Preferably, ),in

[0101] The asterisk * indicates a pair. The sites connected, with asterisks ** indicating sites connected to Y, and

[0102] R4 is selected from the following group: hydrogen, halogen (e.g., F, Cl, Br), CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, -COOR 4a -COR 4a nitro (NO2), -N (R) 4b )R 4a -N(R) 4a COR 4b -N(R) 4a SOR 4b -N(R) 4a SO2R 4b ,-alkylene-R 4b (e.g., methylene-R) 4b ), --alkenyl-R 4b (e.g. - vinylidene-R) 4b ) or -ethynyl-R 4b (e.g., -ethynyl-R) 4b ), where R 4a and R 4b Each is independently selected from the following group: hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclic or heteroaryl; p1 is 0, 1 or 2, provided that the chemical valence bond theory is satisfied;

[0103] R5 is an alkynyl group (such as ethynyl) or -ynyl-R 4b (e.g., -ethynyl-R) 4b ), where R 4b Selected from the following group: hydrogen, cyano, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclic or heteroaryl, p2 is 1.

[0104] In some implementations, R4 is selected from the following group: -COOR 4a -COR 4a nitro (NO2), -N (R) 4b )R 4a -N(R) 4a COR 4b -N(R) 4a SOR 4b -N(R) 4a SO2R 4b ,-alkylene-R 4b (e.g., methylene-R) 4b ), --alkenyl-R 4b (e.g. - vinylidene-R) 4b ) or -ethynyl-R 4b (e.g., -ethynyl-R) 4b ), where R 4a and R 4b Each is independently selected from the following group: hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclic or heteroaryl; p1 is 0, 1 or 2, provided that the chemical valence bond theory is satisfied.

[0105] In some implementations, R5 is -ethynyl-R 4b ;Optionally, R 4b Selected from the group consisting of: cyano, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclic or optionally substituted heteroaryl, wherein the optional substitution refers to the hydrogen on the group being replaced by one or more R groups. 4c Replaced; wherein, optionally R 4c Select the following group: halogen, cyano, alkyl, hydroxyl, -SH, alkoxy, alkylthio -C(O)H, -C(O)alkyl, -S(O) 1-2 H, -S(O) 1-2 Alkyl, amino, alkylamino, dialkylamino, -C(O)amino, -C(O)-(alkylamino), -C(O)-(dialkylamino), -S(O) 1-2 Amino group, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino).

[0106] In some implementations, R5 is -ethynyl-R 4b ;Optionally, R 4b Selected from the group consisting of: cyano, optionally substituted alkyl, optionally substituted cycloalkyl, wherein the optional substitution refers to the hydrogen on the group being replaced by one or more R groups. 4c Replaced; wherein, optionally R 4cSelect the following group: halogen, cyano, alkyl, hydroxy, -SH, alkoxy, alkylthio.

[0107] In some implementations, R5 is -ethynyl-R 4b ;Optionally, R 4b Selected from the following groups: cyano, alkyl, cycloalkyl.

[0108] In some implementations, R5 is an acetylene group.

[0109] In some embodiments, R4 is selected from the group consisting of: hydrogen, halogen, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, -N(R) 4b )R 4a , where R 4a and R 4b Each is independently selected from the group consisting of: hydrogen, alkyl; and / or R5 is ethynyl or -ethynyl-R. 4b , where R 4b Selected from the group consisting of: cyano, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclic or optionally substituted heteroaryl, wherein the optional substitution refers to the hydrogen atom on the group being replaced by one or more (e.g., 1, 2 or 3) R... 4c Replaced; of which, R 4c Select the following group: halogen, cyano, alkyl, hydroxyl, -SH, -alkylthio, -C(O)H, -C(O)alkyl, -S(O) 1-2 H, -S(O) 1-2 Alkyl, amino, alkylamino, dialkylamino, -C(O)amino, -C(O)-(alkylamino), -C(O)-(dialkylamino), -S(O) 1-2 Amino group, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino).

[0110] In some implementation schemes, for The better location is

[0111] In some embodiments, R2 is selected from the group consisting of: hydrogen, hydroxyl, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl. In some embodiments, R2 is selected from the group consisting of: hydrogen, hydroxyl, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, or alkoxy. In some embodiments, R2 is hydrogen.

[0112] In some implementations, m is 0.

[0113] In some implementation schemes, middle It is a 4- to 6-membered heterocyclic ring or C 4-6 Cycloalkanes.

[0114] In some implementations, X1 is a carbon atom.

[0115] In some implementation schemes, Selected from the following group:

[0116] In some embodiments, X2 is a nitrogen atom. In some embodiments, for In some embodiments, the compound is as shown in formula (I);

[0117]

[0118] Among them, each variable (such as X1, Z1, Z2, Z3, Z4, R1, R2, R3, R4, R5, R6, R7, m, p1, p2, Cy1, Cy2, and ring A) is defined in equation (A).

[0119] In some implementations, Z1 is -CH-, -C=, or -N-; and / or, Z2 is -CH2-, -CH=, -N=, or -NH-; and / or, Z3 is -CH2-, -CH=, -N=, or -NH-; and / or, Z4 is absent or is -CH2-, -CH=, -N=, or -NH-.

[0120] In some implementations, at least one of Z1, Z2, Z3 and Z4 is a nitrogen atom.

[0121] In some embodiments, R4 and R5 are each independently hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, -COOR 4a -COR 4a or -NHR 4a COR 4b , where R 4a and R 4b Each can be independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclic or heteroaryl, and p1 and p2 can be independently 0, 1, 2 or 3, provided that the chemical valence bond theory is satisfied.

[0122] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof is provided.

[0123]

[0124] in

[0125] R1 is a cyano group or R 11 -SO2-, where R 11 It can be hydrogen, alkyl, heterocyclic, aryl, or heteroaryl;

[0126] It is a nitrogen-containing 5- or 6-membered heterocyclic ring or a nitrogen-containing spirocyclic ring, wherein X1 is a carbon atom or a nitrogen atom, and m is 0, 1, 2, 3 or 4; and R2 is hydrogen, hydroxyl, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, or two R2s substituted on the same carbon atom together with the carbon atoms to which they are attached form a 3-, 4-, 5- or 6-membered spirocyclic ring, or two R2s substituted on adjacent carbon atoms together with the carbon atoms to which they are attached form a 3-, 4-, 5- or 6-membered fused ring;

[0127] Z1 is -CH-, -C=, or -N-

[0128] Z2 is -CH2-, -CH=, -N=, or -NH-

[0129] Z3 is -CH2-, -CH=, -N=, or -NH-

[0130] Z4 either does not exist or is -CH2-, -CH=, -N=, or -NH-, provided that when Z4 does not exist, the carbon atom of Z1 is directly bonded to R3.

[0131] The prerequisite is In It is aromatic, and at least one of Z1, Z2, Z3 and Z4 is a nitrogen atom;

[0132] R3 is hydrogen, cycloalkyl, alkyl, deuterated alkyl, or deuterated cycloalkyl;

[0133] for

[0134] The asterisk * indicates a parallelism. The sites connected, with asterisks ** indicating sites connected to Y, and

[0135] R4 and R5 are each independently hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, -COOR 4a -COR 4a or -NHR 4a COR 4b , where R 4a and R 4bEach can be independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclic or heteroaryl, and p1 and p2 can be independently 0, 1, 2 or 3, provided that the chemical valence bond theory is satisfied.

[0136] Y is -O-, -S-, or -NR8-, where R8 is hydrogen or alkyl;

[0137] R6 is hydrogen or an alkyl group, wherein the alkyl group is unsubstituted or further converted to hydroxyl, halogen, alkoxy, phosphonoalkoxy, aryl, heteroaryl or cycloalkyl.

[0138] Ring A It is a six-membered heteroaryl, cycloalkyl, or heterocyclic group, wherein q is 0, 1, 2, 3, or 4, and R7 is a halogen, alkyl, hydroxyalkyl, or haloalkyl.

[0139] In some embodiments, X1 is a carbon atom. In some embodiments, X1 is a nitrogen atom.

[0140] In some implementation schemes, Selected from the following group:

[0141] Wherein, n1, n2, n3 and n4 are each independently 1, 2, 3 or 4, and R2 and m are as defined above; preferably, n1, n2, n3 and n4 are each independently 1 or 2.

[0142] In some implementation schemes, for Where m is 2; and R2 substitutes for the same carbon atom, the two R2 atoms together with the carbon atoms they are attached to form 3

[0143] 1, 4, 5 or 6 yuan helical rings; preferably, for

[0144] In some implementation schemes, for Where m is 2; and R2 substitutes for adjacent carbon atoms. The two R2 atoms, together with the carbon atoms they are attached to, form a 3-, 4-, 5-, or 6-membered fused ring; preferably, for

[0145] In some implementation schemes, for Where R2 and m are as defined above. In some implementations, for Wherein n1, n2, n3, and n4 are each independently 1, 2, 3, or 4, and R2 and m are as defined above; preferably, n1, n2, n3, and n4 are each independently 1 or 2. In some embodiments, for R2 and m are as defined above.

[0146] In some implementation schemes, Selected from the following group:

[0147]

[0148] In some implementation schemes, for

[0149] In some embodiments, the compound or compound of formula (I) is a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof:

[0150]

[0151] In some implementations, Z4 is a carbon atom or a nitrogen atom (i.e., Z4 is -CH=, -CR). 31 = or -N=).

[0152] In some implementations, R1 is connected to Z1.

[0153] In some implementation schemes, for

[0154] In some embodiments, the compound is a compound of formula (IA). In some embodiments, R1 is attached to Z1, where Z1 is a nitrogen atom or a carbon atom (Z1 is -N= or =C=), and Z2 is a carbon atom or a nitrogen atom (i.e., Z2 is -CH=, -CR=). 31 = or -N=), Z3 is a carbon atom or a nitrogen atom (i.e., Z3 is -CH=, -CR=). 31 = or -N=), and Z4 either does not exist or is a carbon atom or a nitrogen atom (i.e., Z4 either does not exist or is -CH=, -CR). 31 = or -N=). In some embodiments, R1 is connected to Z1, where Z1 is a nitrogen atom or a carbon atom, Z2 is a carbon atom or a nitrogen atom, Z3 is a carbon atom or a nitrogen atom, and Z4 is absent. In some embodiments, R1 is connected to Z1, where Z1 is a carbon atom, Z2 is a carbon atom or a nitrogen atom, Z3 is a carbon atom or a nitrogen atom, and Z4 is a nitrogen atom. In some embodiments, R1 is connected to Z1, where Z1 is a carbon atom, Z2 is a carbon atom or a nitrogen atom, Z3 is a carbon atom, and Z4 is a carbon atom or a nitrogen atom.

[0155] In some implementations, Z1, Z2, and Z3 are nitrogen atoms; Z4 is absent, and Z1 is directly bonded to the carbon atom connected to R3.

[0156] In some implementation schemes, Selected from the following group:

[0157] In some implementation schemes, for better for

[0158] In some implementation schemes, for

[0159] In some implementation schemes, for The better location is

[0160] In some implementation schemes, Selected from the following group: In some implementation schemes, R 31 It is hydrogen or cyano. In some embodiments, R3 is hydrogen or alkyl.

[0161] In some implementations, R3 is H.

[0162] In some implementations, R3 is C 3-8 Cycloalkyl. In some embodiments, R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R3 is an alkyl or deuterated alkyl group, preferably C10. 1-6 Alkyl or C 1-6 Deuterated alkyl, more preferably C 1-4 Alkyl or C 1-4 Deuterated alkyl groups, such as methyl or methyl-d3. In some embodiments, R3 is...

[0163] In some implementation schemes, for Where Z1, Z2, and Z3 are carbon atoms or nitrogen atoms, provided that at least one of Z1, Z2, and Z3 is a nitrogen atom. In some embodiments, for In the above implementation scheme, Z1, Z2 and Z3 are nitrogen atoms, or Z1 and Z2 are nitrogen atoms and Z3 is a carbon atom.

[0164] In some implementations, R2 is connected to Z4.

[0165] In some implementation schemes, for

[0166] In some implementations, R2 is connected to Z4, Z1 is a nitrogen atom (e.g., -N=) or a carbon atom (e.g., -CH=), Z2 is a carbon atom (e.g., -CH=) or a nitrogen atom (e.g., -N=), Z3 is a carbon atom (e.g., -CH=) or a nitrogen atom (e.g., -N=), and Z4 is a carbon atom (e.g., =CH=) or a nitrogen atom (e.g., -N=).

[0167] In some implementation schemes, Selected from the following group:

[0168] In some implementation schemes, for Z1, Z2, Z3, and R3 are defined as in equation (I). In some implementations, for In some implementations, R3 is C 1-6 alkyl.

[0169] In some implementation schemes, for

[0170] In some implementations, at least one of p1 and p2 is 1. In some implementations, one of p1 and p2 is 1, and the other is 0 or 1.

[0171] In some embodiments, R4 and R5 are each independently selected from the group consisting of: hydrogen, halogens (such as F, Cl, Br), CN, alkyl, haloalkyl, hydroxyl, alkynyl, cycloalkyl, -COOR. 4a -COR 4a nitro, -N(R) 4b )R 4a (e.g., -NH2), -NHSO2R 4b ,-alkylene-R 4b -Ideinyl-R 4b or -ethynyl-R 4b In some implementations, R 4a and R 4b Each is independently selected from the group consisting of: hydrogen, cyano, alkyl, or cycloalkyl (e.g., cyclopropyl).

[0172] In some embodiments, R4 and R5 are each independently selected from the group consisting of: hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, or -COOR. 4a In some implementations, R 4b It is hydrogen or alkyl.

[0173] In some implementations, R4 and R5 are each independently selected from the group consisting of: nitro, -N(R 4b )R 4a (e.g., -NH2), -N(R) 4a COR 4b -N(R) 4a SOR 4b and -NHSO2R 4b Preferably, R5 is selected from the group consisting of nitro, -NH2, and -NHSO2R. 4b In some implementations, R 4b It is an alkyl group.

[0174] In some implementations, R4 and R5 are each independently selected from the group consisting of: - vinylidene-R 4b or -ethynyl-R 4b In some implementations, R 4b Each is independently selected from the following group: hydrogen, cyano, alkyl (such as methyl), or cycloalkyl (such as cyclopropyl).

[0175] In some embodiments, R4 is selected from the group consisting of: hydrogen, halogen, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, -N(R) 4b )R 4a , where R 4a and R 4b Each is independently selected from the group consisting of hydrogen and alkyl groups. In some embodiments, R4 is hydrogen and / or p1 is 0. In some embodiments, p2 is 1.

[0176] In some embodiments, R5 is selected from the group consisting of: hydrogen, halogens (such as F, Cl, Br), CN, alkyl, haloalkyl, hydroxyl, alkynyl, cycloalkyl, -COOR. 4a -COR 4a nitro, -N(R) 4b )R 4a (e.g., -NH2), -NHSO2R 4b ,-alkylene-R 4b -Ideinyl-R 4b or -ethynyl-R 4b In some implementations, R 4a and R 4b Each is independently selected from the group consisting of hydrogen, alkyl, or cycloalkyl (e.g., cyclopropyl).

[0177] In some embodiments, R5 is selected from the group consisting of: hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, or -COOR. 4a In some implementations, R 4b It is hydrogen or alkyl.

[0178] In some implementations, R5 is selected from the group consisting of: nitro, -N(R) 4b )R 4a -N(R) 4a COR 4b -N(R) 4a SOR 4b and -NHSO2R 4b Preferably, R5 is selected from the group consisting of: nitro, -N(R 4b )R 4a and -NHSO2R 4b In some implementations, R 4a It is hydrogen or alkyl (such as C 1-4 Alkyl), R 4b Selected from the following group: hydrogen, alkyl (e.g., C10, C20, C30, C40, C50, C60, C7 ...70, C70, C70, C70, C70, C70, C7 1-4 Alkyl), cycloalkyl (such as C) 3-6 Cycloalkyl groups and heterocyclic groups (such as 3- to 6-membered heterocyclic groups). In some embodiments, R 4a It is hydrogen or alkyl (such as C 1-4 Alkyl), R 4b It is hydrogen or alkyl (such as C 1-4 Alkyl group). In some implementations,

[0179] R 4a For hydrogen, R 4b Selected from the following group: hydrogen, alkyl (e.g., C10, C20, C30, C40, C50, C60, C7 ...70, C70, C70, C70, C70, C70, C7 1-4 Alkyl), cycloalkyl (such as C) 3-6 Cycloalkyl groups and heterocyclic groups (such as 3- to 6-membered heterocyclic groups).

[0180] In some implementations, R5 is alkynyl or -ynyne-R 4b (Preferably ethynyl or -ethynyl-R) 4b ); optionally, where R 4b Selected from the group consisting of: hydrogen, optionally substituted alkyl (e.g., alkyl, haloalkyl, hydroxyalkyl), optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclic or optionally substituted heteroaryl (preferably, R 4b Selected from the group consisting of: optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, preferably, R 4b Selected from the following group: optionally substituted alkyl, optionally substituted cycloalkyl, preferably, R 4b Selected from the group consisting of alkyl and cycloalkyl groups; wherein the optional substitution refers to the substitution of hydrogen on the group by one or more (e.g., 1, 2, or 3) R groups. 4c Replaced; optionally, where R 4c Select the following group: halogen, cyano, alkyl, hydroxyl, -SH, alkoxy, alkylthio, -C(O)H, -C(O)alkyl, -S(O) 1-2H, -S(O) 1-2 Alkyl, amino, alkylamino, dialkylamino, -C(O)amino, -C(O)-(alkylamino), -C(O)-(dialkylamino), -S(O) 1-2 Amino group, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino)(preferably, R 4c Select the following group: halogen, cyano, alkyl, hydroxy, -SH, alkoxy, alkylthio.

[0181] In some implementations, R5 is selected from the group consisting of: - vinylidene-R 4b or -ethynyl-R 4b In some implementations, R 4b Each is independently selected from the group consisting of hydrogen, alkyl (such as methyl), or cycloalkyl (such as cyclopropyl).

[0182] In some implementation schemes, for

[0183] In some implementation schemes, for R5 can be hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, or -COOR. 4a , where R 4a and R 4b Each is independently hydrogen or alkyl.

[0184] In some implementation schemes, for R5 is hydrogen or alkyl.

[0185] In some implementation schemes, for R5 is selected from the following group: nitro, -N(R 4b )R 4a (e.g., -NH2), -N(R) 4a COR 4b -N(R) 4a SOR 4b and -NHSO2R 4b .

[0186] In some implementation schemes, for R5 is selected from the following group: nitro, -NH2, and -NHSO2R 4b .

[0187] In some implementations, R5 is hydrogen and / or p2 is 0. In some implementations, p1 is 1.

[0188] In some implementations, R4 is selected from the group consisting of: nitro, -N(R) 4b )R 4a (e.g., -NH2), -N(R) 4a COR 4b -N(R) 4a SOR 4b and -NHSO2R 4b Preferably, R5 is selected from the group consisting of nitro and -NH2.

[0189] In some implementation schemes, Selected from the following group: The better location is

[0190] In some implementations, p1 is 1 and p2 is 1.

[0191] In some implementations, R4 is selected from the group consisting of: nitro, -N(R) 4b )R 4a (e.g., -NH2), -N(R) 4a COR 4b -N(R) 4a SOR 4b and -NHSO2R 4b ; and / or, R5 is selected from the following group: R5 is selected from the following group: halogens (such as F, Cl, Br), CN, alkyl.

[0192] In some implementation schemes, Selected from the following group: The better location is

[0193] In some implementation schemes,

[0194] for (The better location is) Optionally, R5 is an alkynyl or -ynyne-R 4b (ethynyl or -ethynyl-R) 4b ); The asterisk ** indicates the site connected to Y.

[0195] Optionally, R4 is selected from the group consisting of: hydrogen, halogen, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, -N(R) 4b )R 4a , where R 4a and R 4b Each is independently selected from the following group: hydrogen, alkyl;

[0196] Optionally, R5 is ethynyl or -ethynyl-R 4b , where R 4bSelected from the group consisting of: optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclic or optionally substituted heteroaryl, wherein the optional substitution refers to the hydrogen atom on the group being replaced by one or more (e.g., 1, 2 or 3) R... 4c Replaced; of which, R 4c Select the following group: halogen, cyano, alkyl, hydroxyl, -SH, -alkylthio, -C(O)H, -C(O)alkyl, -S(O) 1-2 H, -S(O) 1-2 Alkyl, amino, alkylamino, dialkylamino, -C(O)amino, -C(O)-(alkylamino), -C(O)-(dialkylamino), -S(O) 1-2 Amino group, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino). In some embodiments, Selected from the following group:

[0197]

[0198] In some implementation schemes, Selected from the following group:

[0199]

[0200] wait.

[0201] In some implementation schemes, for (better location) ),and for R5 is hydrogen or an alkyl group (preferably hydrogen).

[0202] In some implementations, Y is O.

[0203] In some embodiments, in R6, the alkyl group is C6. 1-4 Alkyl, and / or the alkenyl group is C 2-4 The alkenyl group, and / or the ynyl group is C 2-4 Alkyne group. In some embodiments, in R6, the aryl group is phenyl, and / or the heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, in R6, the heterocyclic group is a 4- to 6-membered heterocyclic group, and / or the cycloalkyl group is C10. 3-6 Cycloalkyl.

[0204] In some implementations, R6 is C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or phosphonoyl C 1-4 Alkoxy-C 1-4 Alkyl (-C)1-4 Alkylene-OC 1-4 Alkylene-OP(=O)(OH)2). In some embodiments, R6 is methyl, hydroxymethyl (-CH2OH) or phosphonomethoxymethyl (-CH2OCH2O-P(=O)(OH)2).

[0205] In some implementations, R6 is an alkyl group (such as C6). 1-4 The alkyl group is alkyl, alkenyl, or alkynyl, wherein the alkyl group is further substituted with an alkenyl or alkynyl group and the alkenyl or alkynyl group is unsubstituted or further substituted with an alkyl or cycloalkyl group. In some embodiments, R6 is selected from the group consisting of: -methylene-C 2-4 alkenyl, -methylene-C 2-4 alkynyl, -ethynyl-C 1-4 Alkyl, -ethynyl-C 3-6 cycloalkyl, -vinylidene-C 1-4 Alkyl and -vinyl-C 3-6 Cycloalkyl. In some embodiments, R6 is selected from the group consisting of:

[0206]

[0207] In some implementations, R6 is an alkyl group (such as C6). 1-4 The alkyl group is further substituted with an aryl, heteroaryl, heterocyclic, or cycloalkyl group (preferably substituted with a heterocyclic group, more preferably substituted with a morpholine or piperazine group), and the aryl, heteroaryl, heterocyclic, and cycloalkyl groups are optionally substituted with one or more substituents selected from the group consisting of: alkyl (e.g., methyl), oxo (=O), aryl, heteroaryl, heterocyclic, or cycloalkyl. In some embodiments, R6 is methyl, wherein the methyl group is further substituted with a morpholine or piperazine group, and the morpholine and piperazine groups are optionally substituted with one or more substituents selected from the group consisting of: alkyl (e.g., methyl), oxo, and heterocyclic (e.g., oxetyl). In some embodiments, R6 is selected from the group consisting of:

[0208]

[0209] In some implementation schemes, ring A middle, It is a pyridine ring, a pyrimidine ring, or a monocyclic C 3-8 cycloalkyl, bicyclic C 6-11 Cycloalkyl or bicyclic heterocyclic groups, where R7 is independently halogenated or alkyl, and q is 0, 1, or 2. In some embodiments, cycloA... middle, It is a pyridine ring, a bicyclic [3.3.0]octyl, a bicyclic [3.2.0]heptyl, a bicyclic [2.2.1]heptyl, a bicyclic [2.2.0]hexyl, a bicyclic [3.1.1]heptyl, or a tetrahydro-1H-pyrrolazinyl (e.g., tetrahydro-1H-pyrrolazin-7-yl). R7 is a halogen, and q is 0, 1 or 2, wherein the group is unsubstituted or substituted by one or two halogens.

[0210] In some implementation schemes, ring A It is a pyridine ring, a bicyclic [3.3.0]octyl, a bicyclic [3.2.0]heptyl, a bicyclic [2.2.1]heptyl, a bicyclic [2.2.0]hexyl, a bicyclic [3.1.1]heptyl, or a tetrahydro-1H-pyrrolazinyl (e.g., tetrahydro-1H-pyrrolazin-7-yl). ), wherein the group is unsubstituted or substituted by one or two halogens.

[0211] In some implementation schemes, Selected from the following group:

[0212] In some implementation schemes, In the middle, ring A R7 is a phenyl group, R7 is a halogen or alkyl group, and q is 0, 1, or 2.

[0213] In some implementation schemes, Selected from the following group:

[0214]

[0215] In some implementation schemes, ring A for

[0216]

[0217] In some embodiments, the compound is as shown in formula (II), wherein the variables are as defined in formula (A) or (I);

[0218]

[0219] In a second aspect of the invention, a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof, is provided.

[0220]

[0221] in

[0222] R1 is a cyano group or R 11 -SO2-, where R 11 It can be hydrogen, alkyl, heterocyclic, aryl, or heteroaryl;

[0223] It is a nitrogen-containing 5- or 6-membered heterocyclic ring or a nitrogen-containing spirocyclic ring, wherein X1 is a carbon atom or a nitrogen atom, and m is 0, 1, 2, 3 or 4; and R2 is hydrogen, hydroxyl, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, or two R2s substituted on the same carbon atom together with the carbon atoms to which they are attached form a 3-, 4-, 5- or 6-membered spirocyclic ring, or two R2s substituted on adjacent carbon atoms together with the carbon atoms to which they are attached form a 3-, 4-, 5- or 6-membered fused ring;

[0224] Z1 is -CH-, -C=, or -N-

[0225] Z2 is -CH2-, -CH=, -N=, or -NH-

[0226] Z3 is -CH2-, -CH=, -N=, or -NH-

[0227] The prerequisite is In It is aromatic, and at least one of Z1, Z2 and Z3 is a nitrogen atom;

[0228] for The asterisk * indicates a parallelism. The connection sites are indicated by asterisks (**) to Y, and R4 and R5 are independently hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, and -COOR. 4a -COR 4a or -NHR 4a COR 4b , where R 4a and R 4b Each can be independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclic or heteroaryl, and p1 and p2 can be independently 0, 1, 2 or 3, provided that the chemical valence bond theory is satisfied.

[0229] Y is -O-, -S-, or -NR8-, where R8 is hydrogen or alkyl;

[0230] R6 is hydrogen or an alkyl group, wherein the alkyl group is unsubstituted or further converted to hydroxyl, halogen, alkoxy, phosphonoalkoxy, aryl, heteroaryl or cycloalkyl.

[0231] Ring A It is a six-membered heteroaryl, cycloalkyl, or heterocyclic group, wherein q is 0, 1, 2, 3, or 4, and R7 is a halogen, alkyl, hydroxyalkyl, or haloalkyl.

[0232] In some embodiments, X1 is a carbon atom. In some embodiments, X1 is a nitrogen atom. In some embodiments, for Wherein n1, n2, n3 and n4 are each independently 1, 2, 3 or 4, and R2 and m are as defined above; preferably, n1, n2, n3 and n4 are each independently 1 or 2.

[0233] In some implementation schemes, for Where m is 2; and R2 substituted on the same carbon atom, the two R2s together with the carbon atoms they are attached to form 3-membered, 4-membered, 5-membered or 6-membered spiro rings.

[0234] In some implementation schemes, for Where m is 2; and R2 substitutes for adjacent carbon atoms. The two R2 atoms together with the carbon atoms they are attached to form 3-membered, 4-membered, 5-membered or 6-membered fused rings.

[0235] In some implementation schemes, for Where R2 and m are as defined above. In some implementations, for Wherein n1, n2, n3, and n4 are each independently 1, 2, 3, or 4, and R2 and m are as defined above; preferably, n1, n2, n3, and n4 are each independently 1 or 2. In some embodiments, for R2 and m are as defined above.

[0236] In some implementation schemes, for

[0237] In some implementation schemes, for In the above implementation scheme, Z1, Z2 and Z3 are nitrogen atoms, or Z1 and Z2 are nitrogen atoms and Z3 is a carbon atom.

[0238] In some implementation schemes, for R5 can be hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, or -COOR. 4a, where R 4a and R 4b Each is independently hydrogen or alkyl;

[0239] In some implementation schemes, for

[0240]

[0241] In some implementations, Y is O.

[0242] In some implementations, R6 is C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or phosphonoyl C 1-4 Alkoxy-C 1-4 Alkyl group. In some embodiments, R6 is methyl, hydroxymethyl, or phosphonomethoxymethyl.

[0243] In some implementation schemes, In this context, ring A is a pyridine ring, a pyrimidine ring, a monocyclic C3-8 cycloalkyl ring, or a bicyclic C3-8 cycloalkyl ring. 6-11 Cycloalkyl or bicyclic heterocyclic groups, wherein R7 is a halogen or alkyl group, and q is 0, 1 or 2.

[0244] In some implementation schemes, In this context, ring A is a pyridine ring, a bicyclic [3.3.0]octyl, a bicyclic [3.2.0]heptyl, a bicyclic [2.2.1]heptyl, a bicyclic [2.2.0]hexyl, a bicyclic [3.1.1]heptyl, or a tetrahydro-1H-pyrrolazinyl ring (e.g., tetrahydro-1H-pyrrolazin-7-yl). ), wherein the group is unsubstituted or substituted with one or two halogens. In some embodiments, ring A for

[0245] In some implementations, X1, X2, Y, Z1, Z2, Z3, Z4, R1, R2, R3, R4, R5, R6, R7, subscript m, subscript p1, subscript p2, subscript q, Cy1, Cy2, and as well as Each of these groups is an independent group corresponding to a specific compound in this application (such as the specific compounds shown in Tables A and B).

[0246] In some embodiments, the compound is selected from compounds in Table B below, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof:

[0247] Table B

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255] Pharmaceutical Compositions and Administration

[0256] Because the compounds of the present invention have excellent in vitro inhibitory activity against FGFR3 and / or tumor cells, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate FGFR3-related or FGFR3-mediated diseases and tumors. According to the prior art, the compounds of the present invention can be used to treat the following diseases: cancers such as urothelial carcinoma, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, or Muenke syndrome, etc.; cancers such as urothelial carcinoma, bladder cancer (e.g., urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer), upper urinary tract cancer (e.g., urothelial upper urinary tract cancer), urethral cancer, breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, and small cell lung cancer), gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., oral cancer), thyroid cancer, kidney cancer (e.g., renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0257] In a third aspect of the invention, a pharmaceutical composition is provided comprising a compound as described in the first or second aspect, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0258] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-500 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0259] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0260] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0261] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0262] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0263] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0264] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0265] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0266] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0267] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0268] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0269] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0270] In a fourth aspect of the invention, the use of a compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, or prodrug thereof, as described in the first or second aspect, or a pharmaceutical composition as described in the third aspect, in the preparation of a medicament for treating or preventing a disease is provided.

[0271] In some implementations, the disease is an FGFR3-related disease.

[0272] In some implementations, the FGFR3-related association refers to an abnormal regulatory association with the expression, activity, or level of the FGFR3 gene, the FGFR3 kinase protein, or any of them.

[0273] In some implementations, the disease is selected from the group consisting of: cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or a combination thereof.

[0274] In some implementations, the disease is cancer.

[0275] In some implementations, the cancer is selected from the group consisting of: urothelial carcinoma, urothelial carcinoma, bladder cancer (e.g., urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer), upper urinary tract cancer (e.g., urothelial upper urinary tract cancer), urethral cancer, breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, and small cell lung cancer), gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., oral cancer), thyroid cancer, kidney cancer (e.g., renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0276] In some implementations, the cancer is selected from breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial urinary tract cancer, and glioblastoma.

[0277] In some implementations, the cancer is selected from bladder cancer, urinary tract epithelial bladder cancer, non-muscle-invasive bladder cancer, and muscle-invasive bladder cancer.

[0278] In some implementations, the cancer is urothelial carcinoma.

[0279] In some implementations, the disease is an FGFR3-related cancer.

[0280] In a fifth aspect of the invention, a method for treating or preventing a disease is provided, comprising the steps of administering to a subject in need a compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, or prodrug, as described in the first or second aspect of the invention, or a pharmaceutical composition as described in the third aspect.

[0281] In some implementations, the disease is as defined in the fourth aspect.

[0282] In some implementations, the disease is selected from the group consisting of: cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, Muenke syndrome, or a combination thereof.

[0283] In some embodiments, the present invention provides a method for treating or preventing diseases such as cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, Muenke syndrome, or others, the method comprising administering to a subject in need a compound of the present invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof.

[0284] In some embodiments, the cancers described in this invention are FGFR3-related cancers, which are associated with abnormal regulation related to the expression, activity, or level of the FGFR3 gene, FGFR3 kinase protein, or any of them. Examples of FGFR3-related cancers include, but are not limited to, urothelial carcinoma, urothelial carcinoma, bladder cancer (e.g., urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer), upper urinary tract cancer (e.g., urothelial upper urinary tract cancer), urethral cancer, breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, and small cell lung cancer), gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., oral cancer), thyroid cancer, kidney cancer (e.g., renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0285] The main advantages of this invention include

[0286] (a) The compounds of the present invention have excellent anti-tumor cell proliferation activity.

[0287] (b) The compounds of the present invention exhibit excellent selectivity, particularly for FGFR3, a member of the fibroblast growth factor receptor (FGFR) family. The preferred compounds of this application demonstrate superior inhibitory activity against FGFR3 compared to inhibitory activity against other members of the FGFR family, such as FGFR1.

[0288] (c) The preferred compounds of the present invention exhibit significant and excellent antitumor effects in animal models.

[0289] (d) The compounds of the present invention have low toxicity.

[0290] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0291] The reagents used in this invention are commercially available reagents that are purchased directly or synthesized using methods well-known in the art. Unless otherwise specified, the ee value of the chiral carbon contained in the (1S)-1-(5-fluoropyridin-2-yl) substituent in the examples ranges from 76% to 90%.

[0292] Preparation Examples

[0293] The reagents used in this invention are commercially available reagents that are purchased directly or synthesized using common methods known in the art.

[0294] Example 1: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrazol (Pyridine-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile

[0295]

[0296] Step 1: 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazolo[1,5-a] Pyridine

[0297] 6-Bromo-4-methoxypyrazolo[1,5-a]pyridine (20 g, 88.08 mmol), pinacol diborate (44.7 g, 176.1 mmol), and potassium acetate (25.9 g, 264.2 mmol) were dissolved in 1,4-dioxane (200 mL). Under nitrogen protection, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (3.22 g, 4.404 mmol) was added, and the mixture was heated to 85 °C and stirred for 4 hours. The reaction solution was cooled to room temperature and concentrated by filtration. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–20% ethyl acetate) to give the title compound (23 g, 75.51 mmol, yield: 85.73%). LC / MS (ESI) M / Z: 275.2 [M+H] + .

[0298] Step 2: 4-(5-cyclopropyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0299] 4-Azidoperidine-1-carboxylic acid tert-butyl ester (24 g, 106.1 mmol), ethyl 3-cyclopropyl-3-oxopropionic acid (19.88 g, 127.3 mmol), and potassium carbonate (43.97 g, 318.2 mmol) were dissolved in dimethyl sulfoxide (200 mL). The reaction mixture was heated to 85 °C and stirred for 5 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and water (500 mL) was added. Extraction was performed with ethyl acetate (3 x 200 mL). The organic phase was washed with water and saturated brine, dried under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 20%-40% ethyl acetate) to give the title compound (17.1 g, 46.92 mmol, yield: 44.24%). LC / MS (ESI) M / Z: 365.3 [M+H] + .

[0300] Step 3: 1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid

[0301] 4-(5-cyclopropyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (17.1 g, 46.92 mmol) was dissolved in water (150 mL) and methanol (30 mL), and potassium hydroxide (5.27 g, 93.84 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The pH of the reaction system was adjusted to 4 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with water and saturated brine and dried under reduced pressure to give the title compound (15.4 g, 45.78 mmol, yield: 97.57%). LC / MS (ESI) M / Z: 337.2 [M+H] + .

[0302] Step 4: 4-(4-bromo-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0303] 1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazol-4-carboxylic acid (15.4 g, 45.78 mmol) was dissolved in water (150 mL), and sodium acetate (4.51 g, 54.94 mmol) and N-bromosuccinimide (20.37 g, 114.5 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with water and saturated brine, dried under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-50% ethyl acetate) to give the title compound (13.0 g, 35.01 mmol, yield: 76.48%). LC / MS (ESI) M / Z: 371.2 / 373.3

[0304] [M+H] + .

[0305] Step 5: 4-(5-Cyclopropyl-4-(4-Methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1- tert-butyl piperidine-1-carboxylate

[0306] 4-(4-bromo-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (13.0 g, 35.01 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazolo[1,5-a]pyridine (11.52 g, 42.02 mmol) and potassium carbonate (14.52 g, 105.0 mmol) were dissolved in 1,4-dioxane (150 mL) and water (30 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (2.26 g, 3.50 mmol) was added, and the mixture was heated to 85 °C and stirred for 5 hours. The reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (200 mL) was added, and the mixture was extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with water and saturated brine, dried under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 50%-70% ethyl acetate) to give the title compound (16.2 g, 27.71 mmol, yield: 79.13%). LC / MS (ESI) M / Z: 439.3 [M+H] + .

[0307] Step 6: 4-(5-Cyclopropyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1- tert-butyl piperidine-1-carboxylic acid

[0308] Dodecane-1-thiol (2076.94 mg, 10.262 mmol) was added to a solution of N,N-dimethylacetamide (8 mL) containing 2-methyl-2-propyl-4-[5-cyclopropyl-4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester (450 mg, 1.026 mmol) and sodium hydroxide aqueous solution (136.82 mg, 1.710 mmol, 50% aqueous solution). The reaction was carried out under nitrogen protection and stirred at 100 °C for 2 hours. The reaction was then cooled to room temperature, and water (10 mL) and petroleum ether (3 mL) were added. The pH of the reaction system was adjusted to 4 with formic acid. Stirring was continued for 3 hours. The reaction solution was filtered under reduced pressure, and the solid was washed with water and then with petroleum ether. The product, 2-methyl-2-yl-4-[5-cyclopropyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester (365 mg, 0.860 mmol, yield: 83.79%), was obtained by vacuum drying. LC / MS (ESI) M / Z: 425.4 [M+H] + .

[0309] Step 7: 4-[5-Cyclopropyl-4-(4-{[1-(5-Fluoropyridin-2-yl)-4,4,5,5-Tetramethyl-3-oxa-4-silicon] [alkyl-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester

[0310] At room temperature, 2-methyl-2-yl-4-[5-cyclopropyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester (290 mg, 0.683 mmol), 1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl methanesulfonate (262.63 mg, 0.751 mmol), and cesium carbonate (667.76 mg, 2.049 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was heated to 110 °C and stirred for 30 minutes. The reaction mixture was then cooled to room temperature, and water (10 mL) was added. The mixture was extracted twice with ethyl acetate, and the organic phase was washed with water (3 x 30 mL) followed by washing with saturated sodium chloride. The resulting organic phase was dried over anhydrous sodium sulfate and filtered. The residue was subjected to column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%–50%) to give the product 4-[5-cyclopropyl-4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester (217 mg). Yield: 45%. LC / MS (ESI) M / Z: 678.3 [M+H] + .

[0311] Step 8: 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)- 3-Chloropyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester

[0312] At room temperature, N-chlorosuccinimide (34.81 mg, 0.261 mmol) was added to a solution of 2-methylpropyl-2-yl-4-[5-cyclopropyl-4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester (186 mg, 0.274 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was subjected to column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%–20%) to give the product 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (203 mg). Yield: 93%. LC / MS (ESI) M / Z: 712.4 [M+H] + .

[0313] Step 9: 2-((3-chloro-6-(5-cyclopropyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1, [5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0314] At room temperature, tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid (180 mg, 0.253 mmol) and a dioxane solution in hydrochloric acid (4 M in dioxane, 5 mL) were stirred for 1 hour. The reaction solution was then evaporated to dryness under pressure to give crude 2-((3-chloro-6-(5-cyclopropyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol (162 mg). LC / MS(ESI)M / Z:498.2[M+H] + .

[0315] Step 10: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrazol (Pyridine-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile

[0316] At room temperature, cyanogen bromide (57.20 mg, 0.540 mmol) was added to a solution of dichloromethane (6 mL) containing 2-((3-chloro-6-(5-cyclopropyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (162 mg, 0.270 mmol) and N,N-diisopropylethylamine (452.83 mg, 3.510 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with dichloromethane and water, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was subjected to column chromatography (eluent: methanol / dichloromethane, gradient: 0%–10%) to yield 80 mg of product, which was then purified by reverse-phase chromatography (ACN:H2O = 0% to 50%) to give 60 mg of 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile. Yield: 35%. LC / MS (ESI) M / Z: 523.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.60 (d, J=2.9Hz, 1H), 8.51 (s, 1H), 8.12 (s, 1H), 7.78 (td, J= 8.8,2.9Hz,1H),7.64(dd,J=8.8,4.5Hz,1H),6.99(s,1H),5.60(t,J=5.2Hz,1H),5.15( t,J=5.7Hz,1H),4.85-4.68(m,1H),3.94(t,J=5.4Hz,2H),3.60-3.57(m,2H),3.37-3. 32(m,2H),2.21-2.09(m,4H),2.09-1.95(m,1H),1.18-0.83(m,2H),0.54-0.34(m,2H).

[0317] Example 2: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrazol (Pyridine-6-yl)-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0318]

[0319]

[0320] Step 1: 4-(5-cyclobutyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0321] 3.6 g (15.9 mmol) of tert-butyl 4-azidopiperidine-1-carboxylate, ethyl 3-cyclobutyl-3-oxopropionic acid (3.0 g (17.5 mmol)), and potassium carbonate (6.6 g (47.7 mmol) were dissolved in dimethyl sulfoxide (36 mL). The reaction mixture was heated to 80 °C and stirred for 6 hours under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature, and 100 mL of water was added. The mixture was extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 20%-40% ethyl acetate) to give a pale yellow oily target compound (3.6 g, 9.5 mmol, yield: 60%). LC / MS (ESI) M / Z: 379.2 [M+H] + .

[0322] Step 2: 1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-cyclobutyl-1H-1,2,3-triazole-4-carboxylic acid

[0323] 3.6 g (9.5 mmol) of tert-butyl 4-(5-cyclobutyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate was dissolved in water (30 mL) and methanol (30 mL). Potassium hydroxide (1.1 g, 19.0 mmol) was added, and the reaction mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and the pH of the reaction system was adjusted to 4 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 50 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give a yellow oily target compound (2.3 g, 6.6 mmol, yield: 69%). LC / MS (ESI) M / Z: 295.2 [M+H-56] + .

[0324] Step 3: 4-(4-bromo-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0325] 1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-cyclobutyl-1H-1,2,3-triazol-4-carboxylic acid (500 mg, 1.4 mmol) was dissolved in water (5 mL), and potassium hydroxide (400 mg, 7.1 mmol) was added. The reaction mixture was placed at 0 °C, and bromine (1.1 g, 7.1 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and the bromine was quenched with saturated sodium sulfite aqueous solution. The mixture was extracted with ethyl acetate (3 x 50 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-50% ethyl acetate) to give a white solid target compound (430 mg, 1.1 mmol, yield: 78%). LC / MS (ESI) M / Z: 385.2 [M+H] + .

[0326] Step 4: 4-(5-Cyclobutyl-4-(4-Methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1- tert-butyl piperidine-1-carboxylate

[0327] 4-(4-bromo-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (430 mg, 1.1 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrazolo[1,5-a]pyridine (306 mg, 1.1 mmol) and potassium carbonate (456 mg, 3.3 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (71 mg, 0.1 mmol) was added, and the mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 50%-70% ethyl acetate) to give a yellow solid target compound (400 mg, 0.9 mmol, yield: 79%). LC / MS (ESI) M / Z: 453.4 [M+H] + .

[0328] Step 5: 4-(5-Cyclobutyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1- tert-butyl piperidine-1-carboxylate

[0329] Dodecane-1-thiol (716 mg, 3.5 mmol) was added to a solution of N,N-dimethylacetamide (10 mL) containing 4-(5-cyclobutyl-4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (400 mg, 0.9 mmol) and sodium hydroxide aqueous solution (211 mg, 5.3 mmol, 50% aqueous solution). The reaction was carried out under nitrogen protection and stirred at 100 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was subjected to column chromatography (eluent: dichloromethane / methanol, gradient: 3%-7%).

[0330] Purified with methanol, the target compound was given as a white solid (305 mg, 0.7 mmol, yield: 79%). LC / MS (ESI) M / Z: 439.2 [M+H] + .

[0331] Step 6: 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyridine Azo[1,5-a]pyridin-6-yl)-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0332] At room temperature, tert-butyl 4-(5-cyclobutyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylate (305 mg, 0.7 mmol), ethyl 2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)methanesulfonate (242 mg, 0.7 mmol) and cesium carbonate (226 mg, 2.1 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction mixture was heated to 110 °C and stirred for 10 minutes. The reaction solution was cooled to room temperature, and water (20 mL) was added. Extraction was performed with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-7% methanol) to give the target product as a white solid (240 mg, 0.35 mmol, yield: 50%). LC / MS (ESI) M / Z: 636.4

[0333] [M+H-56] + .

[0334] Step 7: 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3- chlorpyrizo[1,5-a]pyridin-6-yl)-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0335] At room temperature, N-chlorosuccinimide (46 mg, 0.3 mmol) was added to a solution of tert-butyl 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (240 mg, 0.35 mmol). The reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (3 x 30 mL). The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was subjected to column chromatography (eluent: dichloromethane / methanol, gradient: 3%-7% methanol) to give the target product as a yellow solid (190 mg, 0.26 mmol, yield: 75%). LC / MS (ESI) M / Z: 726.3 [M+H] + .

[0336] Step 8: 2-((3-chloro-6-(5-cyclobutyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1, [5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0337] At room temperature, a solution of 4M 1,4-dioxane hydrochloride (5 mL) was added to a solution of tert-butyl 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid (tert-butyl ester, 190 mg, 0.26 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was distilled under reduced pressure to obtain a yellow oily crude target product (130 mg, 0.25 mmol). LC / MS (ESI) M / Z: 512.4 [M+H] + .

[0338] Step 9: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridine- 6-yl)-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0339] At room temperature, cyanogen bromide (54 mg, 0.51 mmol) was added to a solution of 2-((3-chloro-6-(5-cyclobutyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (130 mg, 0.25 mmol) and N,N-diisopropylethylamine (394 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure. The residue was subjected to column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10%) to obtain 100 mg of crude product. This crude product was then purified by reverse-phase chromatography (ACN:H₂O = 0%-50%) to give a white solid target product (85 mg, 0.16 mmol, two-step yield: 48%). LC / MS (ESI) M / Z: 537.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=2.8Hz,1H),8.30(d,J=1.0Hz,1H),8.12(s,1H),7.78(td,J=8.8,2.8Hz,1H ),7.64(dd,J=8.8,4.4Hz,1H),6.63(d,J=1.0Hz,1H),5.60(t,J=5.2Hz,1H),5.13(t,J=5.6Hz,1H),4.47-4.3 7(m,1H),3.92(t,J=5.4Hz,2H),3.78(t,J=8.4Hz,1H),3.55(d,J=12.6Hz,2H),3.28(d,J=13.6Hz,2H),2.35- 2.28(m,1H),2.21-2.09(m,2H),2.05-1.97(m,2H),1.94-1.86(m,2H),1.85-1.73(m,2H),1.61-1.52(m,1H).

[0340] Example 3: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrazol (Pyr-6-yl)-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0341]

[0342] Step 1: 4-(5-cyclopentyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0343] 4-Azidepiperidine-1-carboxylic acid tert-butyl ester (3 g, 13.26 mmol), 3-cyclopentyl-3-oxopropionic acid ethyl ester (2.93 g, 15.91 mmol), and potassium carbonate (5.50 g, 39.77 mmol) were dissolved in dimethyl sulfoxide (50 mL). The reaction mixture was heated to 80 °C and stirred for 5 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and water (200 mL) was added. The mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-50% ethyl acetate) to give the title compound (2.1 g, 5.35 mmol, yield: 40.36%). LC / MS (ESI) M / Z: 393.4 [M+H] + .

[0344] Step 2: 1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-cyclopentyl-1H-1,2,3-triazole-4-carboxylic acid

[0345] 4-(5-cyclopentyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 5.350 mmol) was dissolved in water (20 mL) and methanol (4 mL), and potassium hydroxide (0.60 g, 10.70 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The pH of the reaction system was adjusted to 4 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.8 g, 4.939 mmol, yield: 92.31%). LC / MS (ESI) M / Z: 363.2 [MH] - .

[0346] Step 3: 4-(4-bromo-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0347] 1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-cyclopentyl-1H-1,2,3-triazol-4-carboxylic acid (360 mg, 0.988 mmol) was dissolved in water (10 mL), and sodium acetate (89 mg, 1.087 mmol) and N-bromosuccinimide (440 mg, 2.469 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-50% ethyl acetate) to give the title compound (240 mg, 0.601 mmol, yield: 60.84%). LC / MS (ESI) M / Z: 399.2 [M+H]+ .

[0348] Step 4: 4-(5-cyclopentyl-4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1- tert-butyl piperidine-1-carboxylate

[0349] 4-(4-bromo-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (240 mg, 0.601 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazolo[1,5-a]pyridine (165 mg, 0.601 mmol), and potassium carbonate (249 mg, 1.803 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (39 mg, 0.060 mmol) was added, and the mixture was heated to 85 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 70%–90% ethyl acetate) to give the title compound (230 mg, 0.493 mmol, yield: 82.02%). LC / MS (ESI) M / Z: 467.4 [M+H] + .

[0350] Step 5: 4-(5-cyclopentyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1- tert-butyl piperidine-1-carboxylate

[0351] 4-(5-cyclopentyl-4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (230 mg, 0.493 mmol) was dissolved in N,N-dimethylacetamide (4 mL), and dodecane-1-thiol (798 mg, 3.944 mmol) and sodium hydroxide aqueous solution (236 mg, 5.915 mmol, 50% aqueous solution) were added. The reaction solution was heated to 100 °C under nitrogen protection and stirred for 2 hours. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (3 mL) were added. The pH of the reaction system was adjusted to 4 with formic acid, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–10% methanol) to give the title compound (200 mg, 0.442 mmol, yield: 86.66%). LC / MS (ESI) M / Z: 453.4 [M+H] + .

[0352] Step 6: 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyr Azo[1,5-a]pyridin-6-yl)-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0353] At room temperature, tert-butyl 4-(5-cyclopentyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylate (200 mg, 0.442 mmol), ethyl 2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)methanesulfonate (170 mg, 0.486 mmol), and cesium carbonate (432 mg, 1.326 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was heated to 110 °C and stirred for 30 minutes. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10% methanol) to give the title compound (124 mg, 0.176 mmol, yield: 39.75%).

[0354] Step 7: 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3- chlorpyrizo[1,5-a]pyridin-6-yl)-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0355] At room temperature, tert-butyl 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (120 mg, 0.170 mmol) was dissolved in dichloromethane (3 mL), and N-chlorosuccinimide (21.56 mg, 0.161 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10% methanol) to give the title compound (100 mg, 0.135 mmol, yield: 79.46%).

[0356] Step 8: 2-((3-chloro-6-(5-cyclopentyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1, [5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0357] At room temperature, 100 mg (0.135 mmol) of tert-butyl 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid solution and 3 mL of 4 M 1,4-dioxane hydrochloride solution were stirred for 1 hour. The reaction solution was dried under reduced pressure by distillation to give crude (85 mg) of the title compound. LC / MS (ESI) M / Z: 526.2 [M+H] + .

[0358] Step 9: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridine- 6-yl)-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0359] At room temperature, 2-((3-chloro-6-(5-cyclopentyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (85 mg, 0.151 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (234 mg, 1.813 mmol) and cyanogen bromide (25 mg, 0.242 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10% methanol) to give 50 mg of crude product, which was then purified by reversed-phase chromatography (ACN:H2O = 0% to 50%) to give the title compound (white solid, 10 mg, 0.018 mmol, yield: 13.4%). LC / MS (ESI) M / Z: 551.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.58(d,J=2.9Hz,1H),8.28(d,J=1.0Hz,1H),8.13(s,1H),7.77(td,J=8.8,2.9 Hz,1H),7.61(dd,J=8.8,4.5Hz,1H),6.56(s,1H),5.58(t,J=5.2Hz,1H),5.13(t,J=5.6Hz,1H),4.62-4 .54(m,1H),3.91(t,J=5.3Hz,2H),3.59-3.51(m,2H),3.37-3.27(m,2H),3.24-3.17(m,1H),2.25-2.16 (m,2H),2.06-1.99(m,2H),1.93-1.86(m,1H),1.85-1.78(m,1H),1.56-1.50(m,4H),1.45-1.31(m,2H).

[0360] Example 4: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyridine (Pyridine-6-yl)-5-methyl-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxynitrile

[0361]

[0362] Step 1: 8-Methoxy-6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)imidazo[1, 2-a]pyridine

[0363] 6-Bromo-8-methoxyimidazo[1,2-a]pyridine (500 mg, 2.20 mmol), pinacol diborate (1678 mg, 6.61 mmol), and potassium acetate (649 g, 6.61 mmol) were dissolved in 1,4-dioxane (10 mL). Under nitrogen protection, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (162 mg, 0.220 mmol) was added, and the mixture was heated to 80 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-100% ethyl acetate) to give the title compound (360 mg, 1.32 mmol, yield: 59.64%). LC / MS (ESI) M / Z: 275.2 [M+H] + .

[0364] Step 2: 4-[4-(8-methoxyimidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentane] [1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0365] 8-Methoxy-6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)imidazo[1,2-a]pyridine (360 mg, 1.31 mmol), 4-(4-bromo-5-methyl-1,2,3-triazacyclopentan-1-yl)hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (499 mg, 1.45 mmol) and potassium carbonate (545 mg, 3.94 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2.5 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (85 mg, 0.13 mmol) was added, and the mixture was heated to 80 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to give the title compound (500 mg, 1.12 mmol, yield: 92.30%). LC / MS (ESI) M / Z: 413.4 [M+H] + .

[0366] Step 3: 4-[4-(8-hydroxyimidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentanyl- 1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0367] To a solution of 4-[4-(8-methoxyimidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (500 mg, 1.12 mmol) in N,N-dimethylacetamide (10 mL), sodium hydroxide (243 mg, 6.06 mmol) (dissolved in 0.5 mL of water) and dodecane-1-thiol (1472 mg, 7.27 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 110 °C for 2 hours. The reaction solution was cooled to room temperature, and water (100 mL) and ethyl acetate (10 mL) were added. The pH of the reaction system was adjusted to 4 with formic acid. Extracted with ethyl acetate (3 x 20 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%–10% anhydrous methanol) to give the title compound (270 mg, 0.678 mmol, yield: 55.90%). LC / MS (ESI) M / Z: 399.4 [M+H] + .

[0368] Step 4: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1- [1,2-a]pyridin-6-yl]-5-methyl-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-methyl 2-Methylpropyl-2-yl ester

[0369] At room temperature, 270 mg (0.678 mmol) of 4-[4-(8-hydroxyimidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester, 1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl methanesulfonate, and cesium carbonate (221 mg, 0.678 mmol) were dissolved in N,N-dimethylformamide (4 mL), and the reaction mixture was heated to 110 °C and stirred for 30 minutes. The reaction mixture was cooled to room temperature, and water (40 mL) was added. Extraction was performed with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%–5% anhydrous methanol) to give the title compound (180 mg, 0.276 mmol, yield: 40.75%). LC / MS (ESI) M / Z: 652.6 [M+H] + .

[0370] Step 5: 2-(5-Fluoropyridin-2-yl)-2-({6-[1-(hexahydropyridin-4-yl)-5-methyl-1,2,3-triazapyridine] Cyclopentanyl-4-yl]imidazo[1,2-a]pyridin-8-yl}oxy)ethyl-1-ol

[0371] At room temperature, 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxy}imidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (180 mg, 0.276 mmol) and a dioxane solution in hydrochloric acid (4 M in dioxane, 10 mL) were stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give crude 2-(5-fluoropyridin-2-yl)-2-({6-[1-(hexahydropyridin-4-yl)-5-methyl-1,2,3-triazacyclopentanyl-4-yl]imidazo[1,2-a]pyridin-8-yl}oxy)ethanol (120 mg, 0.274 mmol). LC / MS (ESI) M / Z: 438.4 [M+H] + .

[0372] Step 6: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyridine- 6-yl)-5-methyl-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxynitrile

[0373] At room temperature, cyanogen bromide (59 mg, 0.55 mmol) was added to a solution of 2-(5-fluoropyridin-2-yl)-2-({6-[1-(hexahydropyridin-4-yl)-5-methyl-1,2,3-triazacyclopentanyl-4-yl]imidazo[1,2-a]pyridin-8-yl}oxy) ethylene-1-ol (120 mg, 0.274 mmol) and N,N-diisopropylethylamine (710 mg, 5.49 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane and water, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was subjected to column chromatography (eluent: anhydrous methanol / dichloromethane, gradient: 0%-10% anhydrous methanol) to obtain a crude product, which was then purified by reversed-phase chromatography (ACN:H2O = 5% to 95%) to give 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxynitrile (30 mg, 0.065 mmol, yield: 23.65%). LC / MS (ESI) M / Z: 463.4

[0374] [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=2.8Hz,1H),8.46(d,J=1.3Hz,1H),8.01(d,J=1.2Hz,1H),7.7 2(td,J=8.8,2.9Hz,1H),7.62(dd,J=8.7,4.5Hz,1H),7.56(d,J=1.2Hz,1H),6.88(d,J=1.4Hz,1H ),5.74(t,J=5.2Hz,1H),5.25(t,J=5.8Hz,1H),4.59(tt,J=10.9,4.1Hz,1H),3.94(t,J=5.5Hz, 2H), 3.56 (dt, J=13.0, 3.7Hz, 2H), 3.26 (dd, J=12.6, 2.9Hz, 2H), 2.38 (s, 3H), 2.20-2.03 (m, 4H).

[0375] Example 5: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-(6-(6-(methanesulfonyl)- 2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1H-indazole

[0376]

[0377] Step 1: 5-Bromo-7-fluoro-1H-indazole-1-carboxylic acid tert-butyl ester

[0378] 5-Bromo-7-fluoro-1H-indazole (2.0 g, 9.30 mmol) was dissolved in DCM (30 mL), and di-tert-butyl dicarbonate (4.06 g, 18.6 mmol) was added. 4-Dimethylaminopyridine (227 mg, 1.86 mmol) was slowly added, and the mixture was stirred at room temperature for 18 hours. The mixture was extracted with water (30 mL), and the aqueous phase was extracted with dichloromethane (2 x 30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–40% ethyl acetate) to give the title compound (white solid, 1.7 g, 5.39 mmol, yield: 58.0%). LC / MS (ESI) M / Z: 314.9 [M+H] + .

[0379] Step 2: 7-Fluoro-5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole-1-carboxylic acid tert- Butyl acetate

[0380] 5-Bromo-7-fluoro-1H-indazole-1-carboxylic acid tert-butyl ester (1.7 g, 5.39 mmol), pinacol diborate (2.74 g, 10.8 mmol), and potassium acetate (2.12 g, 21.6 mmol) were dissolved in 1,4-dioxane (20 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (790 mg, 1.08 mmol) was added. The reaction mixture was reacted at 90 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to give the title compound (colorless oil, 1.95 g, 5.39 mmol, yield: 100%). LC / MS (ESI) M / Z: 363.2 [M+H] + .

[0381] Step 3: 7-Fluoro-5-hydroxy-1H-indazole-1-carboxylic acid tert-butyl ester

[0382] tert-butyl 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-indazole-1-carboxylate

[0383] (1.95 g, 5.39 mmol) dissolved in anhydrous methanol (30 mL), and 30% hydrogen peroxide aqueous solution (3.05 g, 26.9 mmol) was slowly added under ice bath conditions.

[0384] The solution was added in 1 mmol, and after the addition was complete, the ice bath was removed, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched by slow addition of sodium sulfite solution. Extraction was performed with ethyl acetate (3 x 30 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.3 g, 5.15 mmol, yield: 95.7%). LC / MS (ESI) M / Z: 253.1 [M+H]+ .

[0385] Step 4: 7-Fluoro-1H-indazole-5-ol hydrochloride

[0386] 1.3 g (5.15 mmol) of tert-butyl 7-fluoro-5-hydroxy-1H-indazole-1-carboxylic acid was dissolved in 25 mL of 4 M 1,4-dioxane hydrochloride solution at room temperature. The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution was added until no more bubbles were produced. The aqueous phase was extracted with dichloromethane (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (988 mg, crude product). LC / MS (ESI) M / Z: 152.9 [M+H] + .

[0387] Step 5: 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-1H-indazole

[0388] 7-Fluoro-1H-indazole-5-ol hydrochloride (988 mg, crude product) was dissolved in N,N-dimethylformamide (15 mL), and tert-butyldimethylchlorosilane (1.55 g, 10.3 mmol) and imidazole (1.4 g, 20.6 mmol) were added. The mixture was stirred at room temperature for 3 hours. Water (50 mL) was added, and the mixture was washed with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 5-

[0389] {[dimethyl(2-methylpropyl-2-yl)silyl]oxy}-1H-indazole (colorless oil, 1.1 g, 4.13 mmol, two-step yield .80.2%).

[0390] LC / MS (ESI) M / Z: 267.2 [M+H] + .

[0391] Step 6: 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1H-indazole

[0392] 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-1H-indazole (1.1 g, 4.13 mmol) was dissolved in dichloromethane (20 mL), and N-iodosuccinimide (929 g, 4.13 mmol) was added. The mixture was stirred overnight at room temperature. Water (30 mL) was added, and the mixture was extracted with dichloromethane (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to give the title compound (1.2 g, 3.06 mmol, yield: 74.1%). LC / MS (ESI) M / Z: 393.1 [M+H]+ .

[0393] Step 7: 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazole

[0394] 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1H-indazole

[0395] (1.2 g, 3.06 mmol) was dissolved in dichloromethane (15 mL), and p-toluenesulfonic acid (158 mg, 0.92 mmol) and 3,4-dihydro-2H-pyran (515 mg, 6.12 mmol) were added. The reaction was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium bicarbonate (20 mL) was added, and the mixture was extracted with dichloromethane (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–20% ethyl acetate) to give the title compound (980 mg, 2.06 mmol, yield: 67.3%). LC / MS (ESI) M / Z: 477.1 [M+H] + .

[0396] Step 8: 7-Fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-ol

[0397] At room temperature, 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-3-iod-1-(tetrahydro-2H-pyran-2-) 1H-indazole (980 mg, 2.06 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (10.3 mL, 1 M in THF) was added. The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution (20 mL) was added, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%–10% anhydrous methanol) to give the title compound (460 mg, 1.27 mmol, yield: 61.7%). LC / MS (ESI) M / Z: 363.2 [M+H] + .

[0398] Step 9: 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazole

[0399] At room temperature, (1S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonic acid (508 mg, 1.88 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-ol (680 mg, 1.88 mmol) and cesium carbonate (1.84 g, 5.64 mmol) were added. The mixture was stirred at 110 °C for 6 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (3 x 30 mL), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–40% ethyl acetate) to give the title compound (white solid, 560 mg, 1.04 mmol, yield: 55.3%). LC / MS (ESI) M / Z: 535.9 [M+H] + .

[0400] Step 10: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-iodo-1H-indazole

[0401] At room temperature, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (560 mg, 1.04 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature for 1 hour, concentrated under reduced pressure, and saturated sodium bicarbonate solution was added until no bubbles were produced. The aqueous phase was extracted with dichloromethane (2 x 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (400 mg, 0.88 mmol). LC / MS (ESI) M / Z: 452.1 [M+H] + .

[0402] Step 11: 3-(6-Fluoropyridin-3-yl)-5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-1H- Indazole

[0403] At room temperature, 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-iodo-1H-indazole (400 mg, 0.88 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3-dioxanepent-2-yl)pyridine (218 mg, 0.97 mmol), potassium carbonate (364 mg, 2.64 mmol), and [1,1"-bis(diphenylphosphine)ferrocene]palladium dichloride (66 mg, 0.09 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and water (30 mL) was added, followed by ethyl acetate (3x) Extraction was performed using 20 mL of the solution. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the title compound (200 mg, 0.47 mmol, yield: 53%). LC / MS (ESI) M / Z: 421.1 [M+H] + .

[0404] Step 12: ( R)-6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-1H-indazole-3-yl)pyridine tert-butyl 2-(pyridyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid

[0405] At room temperature, 3-(6-Fluoropyridin-3-yl)-5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}- 1H-Indazole (200 mg, 0.47 mmol) was dissolved in N-methylpyrrolidone (5 mL), and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester (186 mg, 0.94 mmol) and potassium carbonate (195 mg, 1.41 mmol) were added. The reaction mixture was stirred at 120 °C for 3 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to give the title compound (180 mg, 0.30 mmol, yield: 63.8%). LC / MS (ESI) M / Z: 599.1 [M+H] + .

[0406] Step 13: (R)-3-(6-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-5-(1-(3,5-dichloro) Pyridin-4-yl)ethoxy)-7-fluoro-1H-indazole

[0407] At room temperature, (R)-6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (180 mg, 0.30 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature for 1 hour, concentrated under reduced pressure, and the residue was added to saturated sodium bicarbonate solution until no bubbles were produced. The aqueous phase was extracted with dichloromethane (2 x 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound. Concentration under reduced pressure gave the target compound (130 mg, 0.26 mmol, yield 87%). LC / MS (ESI) M / Z: 499.1 [M+H] + .

[0408] Step 14: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-(6-(6-(methanesulfonyl)-2, 6-Diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1H-indazole

[0409] At room temperature, (R)-3-(6-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-1H-indazole (130 mg, 0.26 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (79 mg, 0.78 mmol) and methanesulfonyl chloride (45 mg, 0.39 mmol) were added. The mixture was stirred at room temperature for 1 hour. Add water (10 mL), extract with dichloromethane (3 x 10 mL), wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and extract the residue by column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10%) to obtain the crude product, which is then purified by reverse-phase chromatography (ACN:H2O = 5% to 95%) to give 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-{6-[2-(methyldioxane-λ6-thio)-2,6-diazaspiro[3.3]heptane-6-yl]pyridin-3-yl}-1H-indazole (40 mg, 0.069 mmol, yield: 26.5%). LC / MS (ESI) M / Z: 577.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ13.57(s,1H),8.60(s,2H),8.50(d,J=2.3Hz,1H),7.85(dd,J=8.6,2.4Hz,1H),7.01(dd,J=14.0 ,2.2Hz,2H),6.55(d,J=8.6Hz,1H),6.13(q,J=6.6Hz,1H),4.18(s,4H),4.12(s,4H),3.03(s,3H),1.76(d,J=6.6Hz,3H).

[0410] Example 6: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrazol (-6-yl)-5-(methyl-d3)-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0411]

[0412] Step 1: Ethyl 4,4,4-trideuteryl-3-oxonylbutyrate

[0413] Ethyl acetate (0.56 mL, 5.68 mmol) was dissolved in 1.5 mL of tetrahydrofuran and slowly added dropwise to a solution of lithium di(trimethylsilyl)amino(12.5 mL, 12.5 mmol) (1 M in THF) at -70 °C, with stirring for 1 hour. Then, 2,2,2-trideuterylacetyl chloride (463 mg, 5.68 mmol) was slowly added dropwise, and the reaction mixture was reacted at -70 °C for 2 hours. The reaction mixture was heated to room temperature, quenched with 6N hydrochloric acid solution, and extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with 3N hydrochloric acid and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude ethyl 4,4,4-trideuteryl-3-oxonylbutyrate (400 mg, 3.00 mmol).

[0414] Step 2: 4-[4-(ethoxycarbonyl)-5-(trideuterylmethyl)-1,2,3-triazacyclopentan-1-yl]hexahydropyr 2-Methylpropyl-2-yl pyridine-1-carboxylic acid ester

[0415] 4-Azidoperidine-1-carboxylic acid tert-butyl ester (570 mg, 2.52 mmol), ethyl 4,4,4-trideuteryl-3-oxomethylenebutyrate (400 mg, 3.00 mmol), and potassium carbonate (1044 mg, 7.56 mmol) were dissolved in dimethyl sulfoxide (10 mL). The reaction mixture was heated to 85 °C and stirred for 5 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and water (50 mL) was added. Extraction was performed with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to give the title compound (240 mg, 0.703 mmol, yield 27.90%). LC / MS (ESI) M / Z: 342.1 [M+H]+ .

[0416] Step 3: 1-(1-{[(2-methylpropyl-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-5-(trideuterylmethyl)- 1,2,3-Triazacyclopentan-4-carboxylic acid

[0417] 240 mg (0.70 mmol) of 4-[4-(ethoxycarbonyl)-5-(trideuterylmethyl)-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (2 mL) was dissolved in water (2 mL) and methanol (2 mL). Potassium hydroxide (78.9 mg, 1.40 mmol) was added, and the reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and 10 mL of water was added. The pH of the reaction system was adjusted to 4 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (200 mg, 0.64 mmol). LC / MS (ESI) M / Z: 314.2 [M+H] + .

[0418] Step 4: 4-[4-bromo-5-(trideuterylmethyl)-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxylic acid- 2-Methylpropyl-2-yl ester

[0419] 1-(1-{[(2-methylprop-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-5-(trideuterylmethyl)-1,2,3-triazacyclopentan-4-carboxylic acid (200 mg, 0.64 mmol) was dissolved in water (5 mL), and potassium hydroxide (86 mg, 1.53 mmol) and bromine (245 mg, 1.53 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated sodium sulfite solution, extracted with ethyl acetate (3 x 20 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to give the title compound (170 mg, 0.488 mmol, yield 76.48%). LC / MS (ESI) M / Z: 348.2 [M+H] + .

[0420] Step 5: 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuterylmethyl)-1,2,3-triazine Heterocyclopentan-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0421] 4-[4-bromo-5-(trideuterylmethyl)-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (170 mg, 0.488 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazolo[1,5-a]pyridine (161 mg, 0.586 mmol) and potassium carbonate (203 mg, 1.47 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (31.5 mg, 0.05 mmol) was added, and the mixture was heated to 85 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to give the title compound (200 mg, 0.481 mmol, yield 98.57%). LC / MS (ESI) M / Z: 416.4 [M+H] + .

[0422] Step 6: 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuterylmethyl)-1,2,3-triazapyridine] Cyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0423] To a solution of 200 mg (0.481 mmol) of 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuterylmethyl)-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (4 mL) in N,N-dimethylacetamide, sodium hydroxide (102 mg, 2.53 mmol) (dissolved in 0.2 mL of water) and dodecane-1-thiol (614 mg, 3.03 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 110 °C for 2 hours. The reaction solution was cooled to room temperature, and water (40 mL) and ethyl acetate (10 mL) were added. The pH of the reaction system was adjusted to 4 with formic acid. Extracted with ethyl acetate (3 x 20 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to give the title compound (170 mg, 0.423 mmol, yield 83.78%). LC / MS (ESI) M / Z: 402.4 [M+H] + .

[0424] Step 7: 4-[4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1- [1,5-a]pyridin-6-yl)-5-(trideuterylmethyl)-1,2,3-triazacyclopentan-1-yl]hexahydropyr 2-Methylpropyl-2-yl pyridine-1-carboxylic acid ester

[0425] At room temperature, 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuterylmethyl)-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (170 mg, 0.423 mmol), 1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl methanesulfonate (148 mg, 0.43 mmol) and cesium carbonate (207 mg, 0.64 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction mixture was heated to 110 °C and stirred for 30 minutes. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was extracted twice with ethyl acetate. The organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%-60%) to obtain the product 4-[4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuterylmethyl)-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (126 mg, 0.192 mmol, yield 64.37%).

[0426] 1 H NMR (400MHz, CDCl3) δ8.46(d,J=2.8Hz,1H),8.41(s,1H),7.95(d,J=2.3Hz,1H),7.49(dd,J= 8.7,4.4Hz,1H),7.37(td,J=8.4,2.8Hz,1H),6.80(dd,J=2.4,0.8Hz,1H),6.76(d,J=1.1Hz, 1H),5.63(dd,J=5.9,3.5Hz,1H),4.39-4.17(m,5H),2.92(s,1H),2.37-2.34(m,1H),2.29-2 .22(m,2H),2.05-2.00(m,2H),1.49(s,9H),0.84(s,9H),0.07(s,3H),0.01(d,J=4.2Hz,3H).

[0427] Step 8: 4-[4-(3-chloro-4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazane] [hexyl-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuterylmethyl)-1,2,3-triazacyclopentan-1-yl] Hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0428] At room temperature, N-chlorosuccinimide (24.2 mg, 0.181 mmol) was added to a solution of dichloromethane (3 mL) containing 4-[4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuterylmethyl)-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (126 mg, 0.192 mmol). The reaction solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined and washed with saturated sodium chloride. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%-60%) to give the product 4-[4-(3-chloro-4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuterylmethyl)-1,2,3-triazacyclopentanyl-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (100 mg, 0.145 mmol, yield 75.40%). 1 H NMR (400MHz, CDCl3) δ8.45 (d, J=2.7Hz, 1H), 8.27 (s, 1H), 7.84 (s, 1H), 7.71 (dd, J= 8.7,4.4Hz,1H),7.47(td,J=8.4,2.7Hz,1H),6.82(s,1H),5.76(dd,J=5.5,3.5Hz,1 H),4.37-4.18(m,5H),2.94(t,J=12.6Hz,2H),2.38(t,J=2.3Hz,1H),2.32-2.19(m ,2H),2.00(s,1H),1.49(s,9H),0.79(s,9H),-0.00(d,J=2.2Hz,3H),-0.06(s,3H).

[0429] Step 9: 2-((3-chloro-6-(5-(methyl-d3)-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazole [1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol

[0430] At room temperature, 100 mg (0.145 mmol) of 4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazole[1,5-a]pyridin-6-yl)-5-(methyl-d3)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 10 mL of 4 M dioxane hydrochloride solution and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate solution was added until no more bubbles were generated. The aqueous phase was extracted with dichloromethane (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-((3-chloro-6-(5-(methyl-d3)-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazol[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (50 mg, 0.105 mmol, yield 72.4%). LC / MS (ESI) M / Z: 476.1 [M+H] + .

[0431] Step 10: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrazol (-6-yl)-5-(methyl-d3)-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0432] At room temperature, cyanogen bromide (16.7 mg, 0.158 mmol) was added to a solution of dichloromethane (6 mL) containing 2-((3-chloro-6-(5-(methyl-d3)-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazol[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (50 mg, 0.105 mmol) and N,N-diisopropylethylamine (81.4 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with dichloromethane and water, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was subjected to column chromatography (eluent: methanol / dichloromethane, gradient: 0%–10%) to obtain a crude product, which was then purified by reverse-phase chromatography (ACN:H2O = 30% to 80%) to give 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (30 mg, 0.06 mmol). Yield: 57.1%. LC / MS (ESI) M / Z: 526.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.8Hz,1H),8.44(d,J=1.0Hz,1H),8.12(s,1H) ,7.77(td,J=8.8,3.0Hz,1H),7.64(dd,J=8.8,4.4Hz,1H),6.90(d,J=1.0Hz,1H), 5.63(t,J=5.2Hz,1H),5.15(t,J=5.6Hz,1H),4.66-4.56(m,1H),3.94(t,J=5.4Hz ,2H),3.56(d,J=12.6Hz,2H),3.31-3.24(m,2H),2.20-2.09(m,2H),2.03(s,2H).

[0433] Example 7: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyridine (Pyridine-6-yl)-5-methyl-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxynitrile

[0434]

[0435]

[0436] Step 1: 4-Bromo-2-methyl-6-(trifluoromethyl)aniline

[0437] NBS (4.18 g, 23.500 mmol) was added fractionally to a reaction mixture of 2-methyl-6-(trifluoromethyl)aniline (3.92 g, 22.381 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was washed with NaHCO3 (aqueous solution, saturated) and brine, and the organic layer was dried over Na2SO4 and filtered. The solvent was removed to give the crude product. Purification by column chromatography (petroleum ether:ethyl acetate = 25:1) yielded 6.5 g of 4-bromo-2-methyl-6-(trifluoromethyl)aniline, yield: 91.5%. LC / MS (ESI) M / Z: 254.2 [M+H] + .

[0438] Step 2: 5-Bromo-7-(trifluoromethyl)-1H-indazole

[0439] At 0 °C, acetic anhydride (602.42 mg, 5.904 mmol) was added dropwise to a mixture of 4-bromo-2-methyl-6-(trifluoromethyl)aniline (6 g, 23.617 mmol) and KOAc (2.78 g, 28.341 mmol) in CHCl3 (15 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was heated to 60 °C and stirred at 60 °C for 2 hours, followed by the dropwise addition of tert-butyl nitrite (4.14 g, 40.150 mmol) at 60 °C. The reaction mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (50 mL) and 6N HCl (50 mL). The mixture was stirred at room temperature for 4 hours, alkalized with 10N NaOH solution, and extracted twice with DCM. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to give 5-bromo-7-(trifluoromethyl)-1H-indazole (5.85 g, 86.3%). LC / MS (ESI) M / Z: 265.2 [M+H] + .

[0440] Step 3: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-7-(trifluoromethyl)-1H-indazole

[0441] Under nitrogen atmosphere, a reaction mixture of 5-bromo-7-(trifluoromethyl)-1H-indazole (5.35 g, 20.186 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (6.15 g, 24.224 mmol), Pd(dppf)Cl2 (1.48 g, 2.019 mmol), and KOAc (5.94 g, 60.559 mmol) in 1,4-dioxane (100 mL) was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the resulting liquid was evaporated to dryness to give the crude product. This crude product was used immediately for the next step without purification. LC / MS (ESI) M / Z: 313.2 [M+H] + .

[0442] Step 4: 7-(trifluoromethyl)-1H-indazole-5-ol

[0443] Hydrogen peroxide (3.42 g, 100.609 mmol) was added to a reaction mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-7-(trifluoromethyl)-1H-indazole (7.85 g, 20.122 mmol) in MeOH (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Sodium sulfite (saturated aqueous solution, 30 mL) was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. The mixture was extracted with ethyl acetate and water, the organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and the organic phase was removed under reduced pressure to give the crude product. The crude product was purified by column chromatography (dichloromethane:ethyl acetate = 1:2) to give 5.4 g of crude 7-(trifluoromethyl)-1H-indazole-5-ol. LC / MS (ESI) M / Z: 203.1 [M+H] + .

[0444] Step 5: 5-{[dimethyl(2-methylpropyl-2-yl)silyl]oxy}-7-(trifluoromethyl)-1H-indazole

[0445] At 0 °C, TBSCl (6.04 g, 40.071 mmol) was added dropwise to a reaction mixture of 7-(trifluoromethyl)-1H-indazole-5-ol (5.4 g, 26.714 mmol) and imidazole (2.73 g, 40.071 mmol) in DMF (100 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was extracted with ethyl acetate and water, the organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over Na2SO4, filtered, and the organic phase was removed under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give 3.5 g of pure 5-{[dimethyl(2-methylpropyl-2-yl)silyl]oxy}-7-(trifluoromethyl)-1H-indazole and 2.5 g of crude product. LC / MS (ESI) M / Z: 317.2 [M+H] + .

[0446] Step 6: 5-{[dimethyl(2-methylpropyl-2-yl)silyl]oxy}-3-iodo-7-(trifluoromethyl)-1H-indyl azole

[0447] NIS (N-iodosuccinimide) (1.96 g, 8.692 mmol) was added to a reaction mixture of 5-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-7-(trifluoromethyl)-1H-indazole (2.5 g, 7.901 mmol) in DCM (6 mL). The reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, and filtered. The solvent was removed to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 2.35 g of 5-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-3-iodo-7-(trifluoromethyl)-1H-indazole, yield: 67.24%. LC / MS (ESI) M / Z: 443.3 [M+H] + .

[0448] Step 7: 3-Iodo-7-(trifluoromethyl)-1H-indazole-5-ol

[0449] At room temperature, TBAF solution (6.783 mL, 6.783 mmol) was added to a reaction mixture of 5-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-3-iodo-7-(trifluoromethyl)-1H-indazole (2 g, 4.522 mmol) in THF (3 mL), and the resulting reaction was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate and water, the organic phase was washed with a saturated aqueous sodium chloride solution, dried over Na2SO4, filtered, and the organic phase was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 0% to 20%) to give 1.2 g of 3-iodo-7-(trifluoromethyl)-1H-indazole-5-ol, yield: 80.9%. LC / MS (ESI) M / Z: 329.1 [M+H] + .

[0450] Step 8: 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-iodo-7-(trifluoromethyl)-1H- Indazole

[0451] Dissolve 3-iodo-7-(trifluoromethyl)-1H-indazole-5-ol (500 mg, 1.52 mmol) in N,N-dimethylformamide (10 mL), add (1S)-1-(3,5-dichloropyridin-4-yl)methanesulfonate (412 mg, 1.52 mmol) and potassium carbonate (632 mg, 4.57 mmol), heat to 80 °C and stir for 30 minutes. After the reaction was complete, the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give the title compound 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-iodo-7-(trifluoromethyl)-1H-indazole (200 mg, 0.40 mmol, yield: 26.13%). LC / MS (ESI) M / Z: 501.9 [M+H] + .

[0452] Step 9: 3-(6-Fluoropyridin-3-yl)-5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-7- (trifluoromethyl)-1H-indazole

[0453] 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-iodo-7-(trifluoromethyl)-1H-indazole (150 mg, 0.3 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (87 mg, 0.39 mmol) and potassium carbonate (124 mg, 0.9 mmol) were dissolved in 1,4-dioxane (8 mL) and water (0.4 mL). Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol) was added, and the mixture was heated to 90 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give the title compound 3-(6-fluoropyridin-3-yl)-5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-7-(trifluoromethyl)-1H-indazole (100 mg, 0.21 mmol, yield: 71.03%). LC / MS (ESI) M / Z: 471.0 [M+H] + .

[0454] Step 10: 2-Methylpropyl-2-yl6-[5-(5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-7- (trifluoromethyl)-1H-indazol-3-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester

[0455] To a solution of 3-(6-fluoropyridin-3-yl)-5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-7-(trifluoromethyl)-1H-indazole (100 mg, 0.21 mmol) in N-methylpyrrolidone (5 mL), 2-methylpropyl-2-yl-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (85 mg, 0.42 mmol) and potassium carbonate (117 mg, 0.85 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 120 °C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to give the title compound 2-methylpropyl-2-yl-6-[5-(5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-7-(trifluoromethyl)-1H-indazol-3-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (80 mg, 0.123 mmol, yield: 58.04%). 1 H NMR (400MHz, DMSO-d6) δ13.57(s,1H),8.61(s,2H),8.52(d,J=2.3Hz,1H),7.90-7.85(m,1H),7.47(d,J=14.5Hz, 2H),6.55(d,J=8.6Hz,1H),6.22(d,J=6.7Hz,1H),4.16(s,4H),4.07(s,4H),1.78(d,J=6.5Hz,3H),1.40(s,9H).

[0456] Step 11: 3-[6-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl]-5-{[(1R)-1-(3,5-di] Chlorpyridin-4-yl)ethyl]oxy}-7-(trifluoromethyl)-1H-indazole

[0457] 2-Methylpropyl-2-yl 6-[5-(5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-7-(trifluoromethyl)-1H-indazole-3-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (80 mg, 0.123 mmol) was dissolved in dichloromethane (40 mL), and a dioxane solution of hydrochloric acid (5 mL) was added. After the reaction was completed, the solution was concentrated under reduced pressure to give the title compound 3-[6-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl]-5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-7-(trifluoromethyl)-1H-indazole (60 mg, 0.11 mmol, yield: 88.67%). LC / MS (ESI) M / Z: 549.2 [M+H] + .

[0458] Step 12: 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-{6-[2-(methyldioxy-l] <6-thioalkyl)-2,6-diazaspiro[3.3]heptane-6-yl]pyridin-3-yl}-7-(trifluoromethyl)-1H-indazole

[0459] At room temperature, triethylamine (22 mg, 0.22 mmol) and methanesulfonyl chloride (19 mg, 0.16 mmol) were added to a solution of 3-[6-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl]-5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-7-(trifluoromethyl)-1H-indazole (60 mg, 0.11 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane and water, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-70% ethyl acetate) to obtain a crude product, which was then purified by reverse-phase chromatography (ACN:H2O = 5% to 95%) to give the title compound 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-{6-[2-(methyldioxy-1<6-thioalkyl)-2,6-diazaspiro[3.3]heptane-6-yl]pyridin-3-yl}-7-(trifluoromethyl)-1H-indazole (10 mg, 0.02 mmol, yield: 14.59%). LC / MS (ESI) M / Z: 627.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ13.59(s,1H),8.61(s,2H),8.53(d,J=2.4Hz,1H),7.88(dd,J=8.6,2.4Hz,1H),7.47(d,J=13. 5Hz,2H),6.57(d,J=8.7Hz,1H),6.22(q,J=6.6Hz,1H),4.19(s,4H),4.12(s,4H),3.03(s,3H),1.78(d,J=6.6Hz,3H).

[0460] Example 8: 4-(4-(8-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)imidazo[1,5-a]pyridine-6- 5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0461]

[0462]

[0463] Step 1: (5-Bromo-3-fluoropyridin-2-yl)methyl)tert-butyl carbamate

[0464] 5-Bromo-3-fluoropyridinium nitrile (10 g, 49.8 mmol), di-tert-butyl dicarbonate (32.6 g, 149.2 mmol), and nickel chloride hexahydrate (1.2 g, 5.0 mmol) were dissolved in methanol (100 mL). The reaction mixture was cooled to 0 °C, and sodium borohydride (3.8 g, 99.5 mmol) was added in portions over 2 hours. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was cooled to 0 °C, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL * 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 5%-15% ethyl acetate) to give a colorless oily target compound (2.6 g, 8.5 mmol, yield: 17%). LC / MS (ESI) M / Z: 305.0 [M+H] + .

[0465] Step 2: (5-Bromo-3-fluoropyridin-2-yl)methylamine

[0466] (5-Bromo-3-fluoropyridin-2-yl)methyl)tert-butyl carbamate (2.6 g, 8.5 mmol) was dissolved in 1,4-dioxane (15 mL), and 4M hydrochloric acid solution of 1,4-dioxane (5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was distilled under reduced pressure to give a yellow oily crude target compound (1.8 g, 8.5 mmol). LC / MS (ESI) M / Z: 205.1 [M+H] + .

[0467] Step 3: N-((5-bromo-3-fluoropyridin-2-yl)methyl)formamide

[0468] Crude (5-bromo-3-fluoropyridin-2-yl)methylamine (1.8 g, 8.5 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (3 mL) and ethyl formate (20 mL) were added. The reaction mixture was heated to 65 °C and stirred overnight. After the reaction was complete, the reaction mixture was cooled to room temperature and dried under reduced pressure to give a reddish-brown crude target compound (1.8 g, 7.7 mmol). LC / MS (ESI) M / Z: 233.0 [M+H] + .

[0469] Step 4: 6-Bromo-8-fluoroimidazole[1,5-a]pyridine

[0470] Will N-((5-bromo-3-fluoropyridin-2-yl)methyl)formamide (2.1 g, 9.0 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic anhydride (3.8 g, 18.0 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was complete, saturated sodium bicarbonate was added at 0 °C to adjust the pH of the reaction mixture to alkaline. The mixture was extracted with dichloromethane (50 mL * 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to give the target compound (600 mg, 2.8 mmol, three-step yield: 33%). LC / MS (ESI) M / Z: 215.1 [M+H] + .

[0471] Step 5: 6-Bromo-8-(1-(5-Fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)imidazolium [1,5-a]pyridine

[0472] 1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethanol-1-ol (875 mg, 2.8 mmol) was dissolved in N,N-dimethylformamide (6 mL). The reaction mixture was kept at 0 °C, and sodium hydride (112 mg, 2.8 mmol) was added. The reaction mixture was stirred at 0 °C for 20 minutes. Then, 6-bromo-8-fluoroimidazolo[1,5-a]pyridine (600 mg, 2.8 mmol) dissolved in N,N-dimethylformamide (3 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with ice water, extracted with ethyl acetate (50 mL * 3), the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and distilled under reduced pressure. The residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to give the target compound (740 mg, 1.5 mmol, yield: 52%). LC / MS(ESI)M / Z:508.2

[0473] [M+H] + .

[0474] Step 6: 8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)-6-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,5-a]pyridine

[0475] 6-Bromo-8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)imidazo[1,5-a]pyridine (740 mg, 1.5 mmol) was dissolved in 1,4-dioxane (8 mL), and pinacol diboronate (740 mg, 2.9 mmol), potassium acetate (427 mg, 4.4 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (106 mg, 0.1 mmol) were added under a nitrogen atmosphere and the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to give a colorless oily target compound (300 mg, 0.5 mmol, yield: 37%). LC / MS (ESI) M / Z: 508.2 [M+H] + .

[0476] Step 7: 4-(4-(8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)imidazolium Azo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0477] 8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,5-a]pyridine (300 mg, 0.5 mmol), 4-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (155 mg, 0.5 mmol) and potassium carbonate (187 mg, 1.4 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (29 mg, 0.05 mmol) was added, and the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to give a pale yellow oily target compound (120 mg, 0.2 mmol, yield: 38%). LC / MS (ESI) M / Z: 694.3 [M+H] + .

[0478] Step 8: 2-(5-Fluoropyridin-2-yl)-2-(6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-) (Imidazolo[1,5-a]pyridin-8-yl)oxy)ethanol-1-ol)

[0479] At room temperature, a 4M solution of 1,4-dioxane hydrochloride (2 mL) was added to a 5 mL solution of dichloromethane containing 120 mg (0.2 mmol) of 4-(4-(8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)imidazo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (120 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to obtain a pale yellow oily crude product (60 mg, 0.1 mmol). LC / MS (ESI) M / Z: 438.2 [M+H] + .

[0480] Step 9: 4-(4-(8-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)imidazo[1,5-a]pyridine-6- 5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0481] At room temperature, cyanogen bromide (29 mg, 0.3 mmol) was added to a solution of 2-(5-fluoropyridin-2-yl)-2-(6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,5-a]pyridin-8-yl)oxy)ethanol-1-ol (60 mg, 0.1 mmol) and N,N-diisopropylethylamine (167 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was evaporated to dryness under reduced pressure and subjected to column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10%) to obtain 40 mg of crude product. The crude product was then purified by reverse-phase chromatography (ACN:H2O = 0% to 50%) to obtain the target product as a white solid (5 mg, 0.01 mmol, two-step yield: 6%). LC / MS (ESI) M / Z: 463.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ8.59(d,J=3.0Hz,1H),8.43(s,1H),8.27(s,1H),7. 75-7.69(m,1H),7.59-7.52(m,2H),6.34(s,1H),5.55(t,J=5.0Hz,1H),5.24 (t,J=6.0Hz,1H),4.66-4.53(m,1H),3.91(t,J=5.6Hz,2H),3.56(d,J=12.8H z,2H),3.29-3.22(m,2H),2.35(s,3H),2.19-2.10(m,2H),2.07-2.01(m,2H).

[0482] Example 9: 2-(5-Fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxane-λ6-thio)-2,6-diazolium] Miscellaneous snails [3.3] Geng alkyl [-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]eth-1-ol

[0483]

[0484] Step 1: 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester

[0485] 5-Bromo-2-fluoropyridine (487 mg, 2.77 mmol) was dissolved in dimethyl sulfoxide (8.0 mL), and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester (549 mg, 2.77 mmol) and N,N-diisopropylethylamine (1.79 g, 13.8 mmol) were added. The mixture was stirred at 90 °C for 4 hours. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the title compound (870 mg, 2.46 mmol, yield 88.75%). LC / MS (ESI) M / Z: 354.2 [M+H] + .

[0486] Step 2: 2-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane

[0487] 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester (700 mg, 1.98 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL, 65.3 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give the crude compound 2-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane (500 mg, 1.97 mmol). LC / MS (ESI) M / Z: 254.0 [M+H] + .

[0488] Step 3: 6-(5-bromopyridin-2-yl)-2-(methyldioxane-λ6-thio)-2,6-diazaspiro[3.3]heptane alkyl

[0489] 2-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane (500 mg, 1.97 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (0.55 mL, 3.94 mmol) and methanesulfonyl chloride (338 mg, 2.95 mmol) were added. The reaction was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate (20 mL) was added, and the mixture was extracted with dichloromethane (3 x 10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%–5% anhydrous methanol) to give the title compound (336 mg, 1.01 mmol, yield 51.40%). LC / MS (ESI) M / Z: 332.2 [M+H] + .

[0490] Step 4: 6-Bromopyrazolo[1,5-a]pyridine-4-phenol

[0491] To a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (500 mg, 2.20 mmol) in N,N-dimethylacetamide (8 mL), sodium hydroxide (441 mg, 11.0 mmol) (dissolved in 1 mL of water) and dodecane-1-thiol (2675 mg, 13.2 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 110 °C for 2 hours. The reaction solution was cooled to room temperature, and water (20 mL) and ethyl acetate (10 mL) were added. The pH of the reaction system was adjusted to 4 with formic acid. The mixture was extracted with ethyl acetate (3 x 20 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the title compound (300 mg, 1.41 mmol, 63.96%). LC / MS(ESI)M / Z:213.0[M+H] + .

[0492] Step 5: 6-Bromo-4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl] oxy}pyrazolo[1,5-a]pyridine

[0493] At room temperature, 6-bromopyrazolo[1,5-a]pyridine-4-phenol (300 mg, 1.41 mmol) was dissolved in N,N-dimethylformamide (4 mL), and cesium carbonate (345 mg, 1.06 mmol) and methanesulfonic acid-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl ester (271 mg, 0.78 mmol) were added. The reaction was carried out at 110 °C for 30 min. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%-20% ethyl acetate) to give the title compound (300 mg, 0.642 mmol, 64.93%). LC / MS (ESI) M / Z: 466.1 [M+H] + .

[0494] Step 6: 4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxo }-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine

[0495] 6-Bromo-4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxy}pyrazolo[1,5-a]pyridine (300 mg, 0.642 mmol), pinacol diborate (327 mg, 1.29 mmol), and potassium acetate (190 mg, 1.93 mmol) were dissolved in 1,4-dioxane (4.0 mL). Under nitrogen protection, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (48 mg, 0.064 mmol) was added, and the mixture was heated to 80 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–20% ethyl acetate) to give the title compound (270 mg, 0.526 mmol, yield: 81.57%). LC / MS(ESI)M / Z:514.3[M+H] + .

[0496] Step 7: 4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxo 2-[2-(methyldioxane-λ6-thio)-2,6-diazaspiro[3.3]heptane alkyl [-6-yl]pyridin-5-yl}pyrazole [1,5-a]pyridine

[0497] At room temperature, 4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (270 mg, 0.526 mmol), 6-(5-bromopyridin-2-yl)-2-(methyldioxane- λ6-thio)-2,6-diazaspiro[3.3]heptane (159 mg, 0.478 mmol) and potassium carbonate (199 mg, 1.44 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (31 mg, 0.046 mmol) was added, and the mixture was heated to 80 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to give the title compound (130 mg, 0.203 mmol, yield: 38.69%). LC / MS (ESI) M / Z: 639.3 [M+H] + .

[0498] Step 8: 2-(5-Fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxane-λ6-thio)-2,6-diaza] Snail [3.3] Gyn alkyl [-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]eth-1-ol

[0499] At room temperature, 4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxy}-6-{2-[2-(methyldioxane-λ6-thio)-2,6-diazaspiro[3.3]heptane-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridine (130 mg, 0.203 mmol) was dissolved in tetrahydrofuran (2.0 mL), and tetrabutylammonium fluoride (0.4 mL, 0.407 mmol) (1 M in tetrahydrofuran) was added. The reaction mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10% anhydrous methanol) to obtain a crude product, which was then purified by reverse-phase chromatography (ACN:H2O = 5% to 95%) to give 2-(5-fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxane-λ6-thio)-2,6-diazaspiro[3.3]heptane-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]eth-1-ol (30 mg, 0.06 mmol, 28.10%). LC / MS (ESI) M / Z: 525.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.9Hz,1H),8.55(d,J=1.0Hz,1H),8.33(d,J=2.4Hz, 1H),7.96(d,J=2.2Hz,1H),7.80(dd,J=8.6,2.5Hz,1H),7.72(td,J=8.7,2.9Hz,1H),7. 61(dd,J=8.8,4.5Hz,1H),6.78-6.74(m,2H),6.48(d,J=8.7Hz,1H),5.74(t,J=5.2Hz,1 H),5.22(t,J=5.9Hz,1H),4.13(s,4H),4.09(s,4H),3.95(t,J=5.5Hz,2H),3.01(s,3H).

[0500] Example 10: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyridine (Pyridine-6-yl)-5-methyl-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxynitrile

[0501]

[0502] Step 1: 5-Fluoro-2-vinylpyridine

[0503] To a 20 mL ethanolic solution (2.0 g, 11.4 mmol) of 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)imidazo[1,2-a]pyridine, potassium vinyltrifluoroborate (1.83 g, 13.6 mmol), triethylamine (1.72 g, 17 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (470 mg, 0.57 mmol) were added. The reaction solution was reacted at 85°C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, and water (40 mL) was added. The solution was then thawed with methyl tert-butyl ether (3x... Extracted with 20 mL of the extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 15°C to give crude 5-fluoro-2-vinylpyridine (8 g, 65 mmol), a yellow oil. LC / MS (ESI) M / Z: 124.2 [M+H] + .

[0504] Step 2: (1S)-1-(5-Fluoropyridin-2-yl)ethane-1,2-diol

[0505] To a solution of 5-fluoro-2-vinylpyridine (8 g, 65 mmol) in tert-butanol (4 mL) and water (4 mL), methanesulfonamide (6.18 g, 65 mmol) and AD-mix-a (91 g, 117 mmol) were added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, saturated sodium sulfite aqueous solution (100 mL) was added, and the mixture was extracted with ethyl acetate / isopropanol (1:1) (3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%–8% methanol) to give compound (1S)-1-(5-fluoropyridin-2-yl)ethane-1,2-diol (800 mg, 5.1 mmol, yield 7.84%), a colorless oil. LC / MS (ESI) M / Z: 158.2 [M+H] + .

[0506] Step 3: (1S)-1-(5-Fluoropyridin-2-yl)-2-{[tris(prop-2-yl)silyl]oxy}ethanol-1-ol

[0507] (1S)-1-(5-fluoropyridin-2-yl)ethane-1,2-diol (800 mg, 5.1 mmol) was dissolved in dichloromethane (10 mL), and imidazole (1.04 g, 15.3 mmol) and triisopropylchlorosilane (1.08 g, 5.6 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give the colorless oily target compound (1S)-1-(5-fluoropyridin-2-yl)-2-{[tris(prop-2-yl)methyl]oxy}ethanol-1-ol (1.5 g, 4.8 mmol, yield: 94%). LC / MS(ESI)M / Z:314.3[M+H] + .

[0508] Step 4: (5-bromo-3-fluoropyridin-2-yl)methyl)tert-butyl carbamate

[0509] 5-Bromo-3-fluoropyridinium nitrile (10 g, 49.8 mmol), di-tert-butyl dicarbonate (32.6 g, 149.2 mmol), and nickel chloride hexahydrate (1.2 g, 5.0 mmol) were dissolved in methanol (100 mL). The reaction mixture was cooled to 0 °C, and sodium borohydride (3.8 g, 99.5 mmol) was added in portions over 2 hours. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was cooled to 0 °C, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL * 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 5%-15% ethyl acetate) to give a colorless oily target compound (2.6 g, 8.5 mmol, yield: 17%). LC / MS (ESI) M / Z: 305.0 [M+H] + .

[0510] Step 5: (5-Bromo-3-fluoropyridin-2-yl)methylamine

[0511] (5-Bromo-3-fluoropyridin-2-yl)methyl)tert-butyl carbamate (2.6 g, 8.5 mmol) was dissolved in 1,4-dioxane (15 mL), and 4M hydrochloric acid solution of 1,4-dioxane (5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was distilled under reduced pressure to give a yellow oily crude target compound (1.8 g, 8.5 mmol). LC / MS (ESI) M / Z: 205.1 [M+H] + .

[0512] Step 6: N-((5-bromo-3-fluoropyridin-2-yl)methyl)formamide

[0513] Crude (5-bromo-3-fluoropyridin-2-yl)methylamine (1.8 g, 8.5 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (3 mL) and ethyl formate (20 mL) were added. The reaction mixture was heated to 65 °C and stirred overnight. After the reaction was complete, the reaction mixture was cooled to room temperature and dried under reduced pressure to give a reddish-brown crude target compound (1.8 g, 7.7 mmol). LC / MS (ESI) M / Z: 233.0 [M+H + ].

[0514] Step 7: 6-Bromo-8-fluoroimidazole[1,5-a]pyridine

[0515] N-((5-bromo-3-fluoropyridin-2-yl)methyl)formamide (2.1 g, 9.0 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic anhydride (3.8 g, 18.0 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was complete, saturated sodium bicarbonate was added at 0 °C to adjust the pH of the reaction mixture to alkaline. The mixture was extracted with dichloromethane (50 mL * 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to give the target compound (600 mg, 2.8 mmol, three-step yield: 33%). LC / MS (ESI) M / Z: 215.1 [M+H] + .

[0516] Step 8: 6-Bromo-8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propyl-2-yl)-3-oxa-} 4-Silylhex-1-yl]oxyimidazo[1,5-a]pyridine

[0517] (1S)-1-(5-fluoropyridin-2-yl)-2-{[tris(prop-2-yl)silyl]oxy}ethanol-1-ol (1093 mg, 3.5 mmol) was dissolved in N,N-dimethylformamide (10 mL). The reaction solution was placed at 0 °C, and sodium hydride (186 mg, 4.6 mmol) was added. The reaction mixture was stirred at 0 °C for 20 minutes. Then, 6-bromo-8-fluoroimidazolo[1,5-a]pyridine (500 mg, 2.3 mmol) was dissolved in N,N-dimethylformamide (3 mL) and added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with ice water, extracted with ethyl acetate (50 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to give the target compound 6-bromo-8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(prop-2-yl)-3-oxa-4-silylhex-1-yl]oxy}imidazo[1,5-a]pyridine (630 mg, 1.24 mmol, yield: 53.28%). LC / MS (ESI) M / Z: 508.2 [M+H] + .

[0518] Step 9: 8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silicon] Hex-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,5-a]pyridine

[0519] 6-Bromo-8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(prop-2-yl)-3-oxa-4-silylhex-1-yl]oxy}imidazo[1,5-a]pyridine (430 mg, 0.85 mmol) was dissolved in 1,4-dioxane (5 mL). Pinacol diborate (430 mg, 1.7 mmol), potassium acetate (249 mg, 2.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (62 mg, 0.08 mmol) were added under a nitrogen atmosphere and the mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to give the colorless oily target compound 8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(prop-2-yl)-3-oxa-4-silicon-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,5-a]pyridine (369 mg, 0.66 mmol, yield: 78.55%). LC / MS (ESI) M / Z: 556.4 [M+H] + .

[0520] Step 10: 2-Methylpropyl-2-yl-4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di] (propyl-2-yl)-3-oxa-4-silazhex-1-yl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazole- 1-yl]hexahydropyridine-1-carboxylate

[0521] 8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(prop-2-yl)-3-oxa-4-silhex-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,5-a]pyridine (369 mg, 0.66 mmol), 4-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (229 mg, 0.66 mmol) and potassium carbonate (276 mg, 2.0 mmol) were dissolved in a mixed solvent of 1,4-dioxane (8 mL) and water (2 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (44 mg, 0.07 mmol) was added, and the mixture was heated to 80 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to give the pale yellow oily target compound 2-methylpropyl-2-yl-4-(4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silazhex-1-yl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylate (336 mg, 0.48 mmol, yield: 72.9%). LC / MS(ESI)M / Z: 694.3 [M+H] + .

[0522] Step 11: (2S)-2-(5-Fluoropyridin-2-yl)-2-({6-[1-(hexahydropyridin-4-yl)-5-methyl-1,2,3- Triazol-4-yl]imidazo[1,5-a]pyridine-8-y}oxy)ethane-1-ol

[0523] At room temperature, 2 mL of 4 M 1,4-dioxane solution (4 mL) of 2-methylpropyl-2-yl 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silazhex-1-yl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylate (336 mg, 0.48 mmol) was added to a solution of 1,4-dioxane hydrochloride. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to obtain the crude, pale yellow oily product (2S)-2-(5-fluoropyridin-2-yl)-2-({6-[1-(hexahydropyridin-4-yl)-5-methyl-1,2,3-triazol-4-yl]imidazo[1,5-a]pyridin-8-y}oxy)ethane-1-ol (180 mg, 0.41 mmol). LC / MS (ESI) M / Z: 438.2 [M+H] + .

[0524] Step 12: 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,5-a]pyridine [Pyridine-6-yl]-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-onitrile

[0525] At room temperature, cyanogen bromide (87 mg, 0.8 mmol) was added to a solution of dichloromethane (4 mL) containing 2S)-2-(5-fluoropyridin-2-yl)-2-({6-[1-(hexahydropyridin-4-yl)-5-methyl-1,2,3-triazol-4-yl]imidazo[1,5-a]pyridin-8-y}oxy)ethane-1-ol (180 mg, 0.41 mmol) and N,N-diisopropylethylamine (691 mg, 5.35 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure and subjected to column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10%) to obtain the crude product. This crude product was then purified by reverse-phase chromatography (ACN:H2O = 0% to 95%) to obtain the white solid target product 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-onitrile (25 mg, 0.05 mmol, yield: 13.14%). LC / MS (ESI) M / Z: 463.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.9Hz,1H),8.43(d,J=1.0Hz,1H),8.27(s,1H) ,7.72(td,J=8.7,2.9Hz,1H),7.55(q,J=4.3Hz,2H),6.34(s,1H),5.55(t,J=5.1H z,1H),5.25(t,J=6.0Hz,1H),4.59(td,J=11.1,5.6Hz,1H),3.91(t,J=5.6Hz,2H) ,3.56(d,J=12.7Hz,2H),3.27(t,J=11.1Hz,2H),2.35(s,3H),2.16-2.02(m,4H).

[0526] Step 13: 4-[4-(1-chloro-8-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1, [5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridin-1-onitrile

[0527] Add N-chlorosuccinimide (5 mg, 0.04 mmol) to a solution of 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-onitrile (25 mg, 0.05 mmol) in dichloromethane (2 mL) and stir overnight at room temperature. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by reverse-phase chromatography (ACN:H2O = 0% to 95%) to obtain the crude product. This crude product was then purified by column chromatography (eluent: dichloromethane / ethyl acetate, gradient: 0%-90% ethyl acetate) to give the white solid target compound 4-[4-(1-chloro-8-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-onitrile (5 mg, 0.01 mmol, yield: 23.27%). LC / MS (ESI) M / Z: 497.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.9Hz,1H),8.37(s,1H),8.24(d,J=0.9Hz ,1H),7.76(td,J=8.8,2.9Hz,1H),7.63-7.58(m,1H),6.46(s,1H),5.57(t,J =5.2Hz,1H),5.13(t,J=5.6Hz,1H),4.63-4.55(m,1H),3.92(t,J=5.1Hz,2H) ,3.56(d,J=13.1Hz,2H),3.30-3.24(m,2H),2.38(s,3H),2.15-2.03(m,4H).

[0528] Example 11: 2-(5-Fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxane-λ6-thio)-2,6-di] Nitrogenous spirochete[3.3]heptane alkyl [-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]eth-1-ol

[0529]

[0530] Step 1: 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro [3.3]Heptane-2-carboxylic acid-2-methylpropyl-2-yl ester

[0531] At room temperature, 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester (170 mg, 0.480 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine (145 mg, 0.528 mmol), and potassium carbonate (199 mg, 1.44 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1.5 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (31 mg, 0.05 mmol) was added, and the mixture was heated to 80 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, and 1,4-dioxane was concentrated. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-100% ethyl acetate) to give the title compound (191 mg, 0.453 mmol, yield 94.4%). LC / MS (ESI) M / Z: 422.2 [M+H] + .

[0532] Step 2: 6-{2-[2-(methyldioxane-λ6-thio)-2,6-diazaspiro[3.3]heptane alkyl -6-yl]pyridine- 5-yl}pyrazolo[1,5-a]pyridine-4-phenol

[0533] To a solution of 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester (191 mg, 0.453 mmol) in N,N-dimethylacetamide (5 mL), sodium hydroxide (91 mg, 2.27 mmol) (dissolved in 0.2 mL of water) and dodecane-1-thiol (551 mg, 2.72 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 110 °C for 3 hours. The reaction solution was cooled to room temperature, and water (20 mL) and ethyl acetate (10 mL) were added. The pH of the reaction system was adjusted to 4 with formic acid. Extracted with ethyl acetate (3 x 20 mL), the organic phase was washed with water and saturated brine, dried under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-100% ethyl acetate) to give the title compound (150 mg, 0.368 mmol, yield 81.2%). LC / MS (ESI) M / Z: 408.2 [M+H] + .

[0534] Step 3: 6-[5-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1- [1,5-a]pyridin-6-yl]pyridin-2-yl]-2,6-diazaspiro[3,3]heptane-2-carboxylic acid-2-methyl propyl-2-yl ester

[0535] At room temperature, 6-{2-[2-(methyldioxane-λ6-thio)-2,6-diazaspiro[3.3]heptane-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridine-4-phenol (150 mg, 0.368 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (180 mg, 0.552 mmol) and methanesulfonic acid-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl ester (142 mg, 0.405 mmol) were added. The reaction was carried out at 80 °C for 30 min. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%–30% ethyl acetate) to give the title compound (170 mg, 0.257 mmol, yield 69.9%). LC / MS (ESI) M / Z: 661.3 [M+H] + .

[0536] Step 4: 2-(5-Fluoropyridin-2-yl)-2-({6-[2-(2,6-diazaspiro[3.3]heptane] alkyl -2-yl)pyridine-5- [1,5-a]pyrazolo[1,5-a]pyridin-4-yl]oxy)ethanol-1-ol

[0537] 6-[5-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL, 26.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give the crude compound 2-(5-fluoropyridin-2-yl)-2-({6-[2-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-5-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)ethanol-1-ol (110 mg, 0.246 mmol). LC / MS(ESI)M / Z:447.2[M+H] + .

[0538] Step 5: 6-[5-(4-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5-a]pyridine- [6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxynitrile

[0539] At room temperature, cyanogen bromide (52.2 mg, 0.493 mmol) was added to a solution of dichloromethane (3 mL) containing 2-(5-fluoropyridin-2-yl)-2-({6-[2-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-5-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)ethanol (110 mg, 0.246 mmol) and N,N-diisopropylethylamine (637 mg, 4.93 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (3 x 10 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10%) to obtain a crude product, which was then purified by reverse-phase chromatography (ACN:H2O = 5% to 95%) to give 6-[5-(4-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxynitrile (30 mg, 0.082 mmol, 24.74%). LC / MS (ESI) M / Z: 472.2 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ8.60(d,J=2.9Hz,1H),8.56(s,1H),8.37(s,1H),8.33(d,J=2 .5Hz,1H),7.97(d,J=2.2Hz,1H),7.80(dd,J=8.6,2.5Hz,1H),7.73(td,J=8.7,2.9Hz, 1H),7.62(dd,J=8.7,4.5Hz,1H),6.78(d,J=2.3Hz,1H),6.75(d,J=1.2Hz,1H),6.47(d ,J=8.7Hz,1H),5.75(t,J=5.1Hz,1H),4.38(s,4H),4.12(s,4H),3.96(d,J=5.1Hz,2H).

[0540] Example 12: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyridine (Pyridine-6-yl)-5-methyl-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxynitrile

[0541]

[0542] Step 1: (1R)-2-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-1-(5-fluoropyridin-2-yl) Ethane-1-ol

[0543] Triethylamine (3.73 g, 36.8 mmol) and methanesulfonyl chloride (3.17 g, 27.6 mmol) were added to a 20 mL solution of (1R)-2-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-1-(5-fluoropyridin-2-yl)ethane-1-ol (5.0 g, 18.4 mmol). The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give compound (1R)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhex-1-yl methanesulfonate (5.8 g, 16.6 mmol, yield 90.1%), a yellow oil. LC / MS (ESI) M / Z: 350.2 [M+H] + .

[0544] Step 2: 6-Bromopyrazolo[1,5-a]pyridine-4-phenol

[0545] To a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (4 g, 17.6 mmol) in N,N-dimethylacetamide (50 mL), an aqueous solution of sodium hydroxide (3.52 g, 88 mmol) dissolved in 3.5 mL of water and dodecyl mercaptan (21.3 g, 105 mmol) were added. The reaction mixture was stirred at 60 °C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (300 mL) was added. Formic acid was added to adjust the pH of the reaction mixture to 3-4. The mixture was extracted with ethyl acetate (3 x 100 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give 6-bromopyrazolo[1,5-a]pyridine-4-phenol (3 g, 14.1 mmol, yield 79.9%) as a white solid. LC / MS(ESI)M / Z:213.0[M+H] + .

[0546] Step 3: 6-Bromo-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silicon-1-} [1,5-a]pyridine

[0547] At room temperature, 6-bromopyrazolo[1,5-a]pyridine-4-phenol (3 g, 14.1 mmol) was dissolved in N,N-dimethylformamide (30 mL), and cesium carbonate (6.88 g, 21.1 mmol) and (1R)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhex-1-ylmethanesulfonate (5.41 g, 15.5 mmol) were added. The reaction was carried out at 110 °C for 30 minutes. After the reaction was complete, the reaction solution was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%-50% ethyl acetate) to give the title compound 6-bromo-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhexyl]oxy}pyrazol[1,5-a]pyridine (2.84 g, 6.09 mmol, yield 43.24%). LC / MS (ESI) M / Z: 466.1 [M+H] + .

[0548] Step 4: 4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhex-1-yl]oxy }-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazole[1,5-a]pyridine

[0549] 6-Bromo-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silhex-1-yl]oxy}pyrazol[1,5-a]pyridine (2.84 g, 6.09 mmol), pinacol diborate (3.1 g, 12.2 mmol), and potassium acetate (1.8 g, 18.3 mmol) were dissolved in 1,4-dioxane (4.0 mL). Under nitrogen protection, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (450 mg, 0.61 mmol) was added, and the mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-100% ethyl acetate) to give the title compound 4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silhexyl-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazol[1,5-a]pyridine (1.2 g, 2.34 mmol, yield: 38.38%). LC / MS (ESI) M / Z: 514.3 [M+H] + .

[0550] Step 5: Step 1: 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropane- 2-yl ester

[0551] 5-Bromo-2-fluoropyridine (200 mg, 1.14 mmol) was dissolved in dimethyl sulfoxide (3 mL), and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester (338 mg, 1.7 mmol) and N,N-diisopropylethylamine (735 mg, 5.68 mmol) were added. The mixture was stirred at 90 °C for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the title compound 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester (400 mg, 1.13 mmol, yield 99.36%). LC / MS (ESI) M / Z: 354.2 [M+H] + .

[0552] Step 6: 2-Methylpropyl-2-yl-6-[5-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3- [Oxa-4-silylhexyl]oxy}pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3,3]heptane- 2-Carboxylic Acid Ester

[0553] At room temperature, 200 mg (0.57 mmol) of 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester (200 mg, 0.57 mmol) and (4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-siloxane-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazole[1,5- [a] Pyridine (348 mg, 0.68 mmol) and potassium carbonate (234 mg, 1.69 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (37 mg, 0.06 mmol) was added, and the mixture was heated to 80 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, and water (10 mL) was added. The solution was then diluted with ethyl acetate (3x... Extracted by 10 mL, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to give the title compound 2-methylpropyl-2-yl-6-[5-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhex-1-yl]oxy}pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (294 mg, 0.45 mmol, yield: 78.8%). LC / MS (ESI) M / Z: 661.4 [M+H] + .

[0554] Step 7: 2-Methylpropyl-2-yl-6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl] [3-oxa-4-silylhex-1-yl]oxy}pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3] heptane-2-carboxylic acid ester

[0555] 2-Methylpropyl-2-yl 6-[5-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhex-1-yl]oxy}pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (294 mg, 0.45 mmol) was dissolved in dichloromethane (3 mL), and N-chlorosuccinimide (56 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with dichloromethane (3 x 10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the title compound 2-methylpropyl-2-yl-6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhex-1-yl]oxy}pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (150 mg, 0.22 mmol, yield: 48.5%). LC / MS (ESI) M / Z: 695.3 [M+H] + .

[0556] Step 8: (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-5-yl]pyrazol [1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0557] 150 mg (0.22 mmol) of 2-methylpropyl-2-yl 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silhex-1-yl]oxy}pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give the title compound (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-5-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (80 mg, 0.17 mmol, yield: 77.11%). LC / MS (ESI) M / Z: 481.3 [M+H] + .

[0558] Step 9: 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazole[1,5-a] [pyridin-6-yl]pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-nitrile

[0559] (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-5-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (80 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (65 mg, 0.5 mmol) and cyanogen bromide (35 mg, 0.33 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with dichloromethane (3 x 10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-100% ethyl acetate) to give the title compound. 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridine-2- [1,5-a]pyridin-6-yl]pyridin-2-yl]-2,6-diazaspiro[3,3]heptane-2-nitrile (35.7 mg, 0.07 mmol, yield: 42.42%). LC / MS (ESI) M / Z: 506.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.9Hz,1H),8.54(d,J=1.1Hz,1H),8.37(dd,J=2 .5,0.8Hz,1H),8.05(s,1H),7.83(dd,J=8.7,2.5Hz,1H),7.77(td,J=8.8,2.9Hz,1H ),7.69(dd,J=8.8,4.6Hz,1H),6.91(d,J=1.3Hz,1H),6.47(d,J=8.7Hz,1H),5.80(t ,J=5.0Hz,1H),5.11(t,J=5.7Hz,1H),4.37(s,4H),4.11(s,4H),4.00-3.91(m,2H).

[0560] Example 13: (S)-4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile

[0561]

[0562] Step 1: 5-Fluoro-2-vinylpyridine

[0563] 2-Bromo-5-fluoropyridine (50 g, 284.107 mmol), potassium vinyltrifluoroborate (45.67 g, 340.928 mmol), Pd(dppf)Cl2.DCM (9.28 g, 11.364 mmol), and triethylamine (59.235 mL, 426.161 mmol) were dissolved in ethanol (700 mL). The reaction was carried out under nitrogen protection at 80 °C with stirring for 3 hours. The reaction solution was cooled to room temperature, and methyl tert-butyl ether was added to the reaction solution, followed by filtration. The resulting solution was washed with water, saturated sodium bicarbonate solution, and saturated brine to remove ethanol. The resulting organic phase was dried over anhydrous sodium sulfate and filtered. Methyl tert-butyl ether was removed by vacuum distillation (the temperature was controlled below 15 °C during vacuum distillation) to obtain 43.5 g of crude 5-fluoro-2-vinylpyridine. The next step was immediately performed. No ion flow information was obtained for this product in LCMS.

[0564] Step 2: (R)-1-(5-Fluoropyridin-2-yl)ethane-1,2-diol

[0565] AD-mix-β (416.22 g, 534.313 mmol) was added in portions to a mixture of tert-butanol and water (100 mL, V / V = 1 / 1) containing 5-fluoro-2-vinylpyridine (43 g, 296.841 mmol) and methanesulfonamide (28.24 g, 296.841 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 16 hours. The mixture was then deactivated with an aqueous sodium sulfite solution and stirred at room temperature for 1 hour. The mixture was extracted with a 1:1 mixture of isopropanol and ethyl acetate (100 mL x 3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0%–8%) to give the title compound (R)-1-(5-fluoropyridin-2-yl)ethane-1,2-diol (35.8 g, crude). LC / MS (ESI) M / Z: 158.1 [M+H] + .

[0566] Step 3: (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethanol-1-ol

[0567] To a solution of compound (R)-1-(5-fluoropyridin-2-yl)ethane-1,2-diol (35.8 g, 227.822 mmol) dissolved in water (150 mL) and imidazole (46.53 g, 683.467 mmol) in N,N-dimethylformamide (350 mL), tert-butyldimethylchlorosilane (37.77 g, 250.605 mmol) was added at 0°C. The reaction was also heated to room temperature and stirred for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was washed with water (200 mL x 4), followed by washing with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%–20%) to give the title compound. ( R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethanol-1-ol (41 g, yield: 66.31%, ee.: 86.48%). LC / MS (ESI) M / Z: 272.2 [M+H] + .

[0568] Step 4: 4-(4-bromo-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0569] 1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazol-4-carboxylic acid (15.4 g, 45.78 mmol) was dissolved in water (150 mL), and sodium acetate (4.51 g, 54.94 mmol) and N-bromosuccinimide (20.37 g, 114.5 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (200 x 3 mL). The organic phase was washed with water and saturated brine, dried under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-50% ethyl acetate) to give the title compound (13.0 g, 35.01 mmol, yield: 76.48%). LC / MS (ESI) M / Z: 371.2 / 373.3

[0570] [M+H] + .

[0571] Step 5: 2-Methylpropyl-2-yl-4-[5-cyclopropyl-4-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5- Tetramethyl-3-oxa-4-silane-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyr 1-Pyridine-carboxylic acid esters

[0572] A solution of 2-methyl-2-yl-4-[5-cyclopropyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester (5.07 g, 11.943 mmol), 1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl methanesulfonate (4.59 g, 13.138 mmol), and cesium carbonate (11.67 g, 35.830 mmol) in N,N-dimethylformamide (50 mL) was stirred at 110 °C for 30 min. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic phase was washed with water (100 mL x 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%-50%) to give the title compound 2-methylpropyl-2-yl-4-[5-cyclopropyl-4-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester (5.7 g, 8.408 mmol, yield: 70.40%). LC / MS (ESI) M / Z: 678.4 [M+H] + .

[0573] Step 6: 2-Methyl-2-yl-4-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl] [3-oxa-4-silane-1-yl]oxy]pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1,2,3-triazol-1-yl] Hexahydropyridine-1-carboxylic acid ester

[0574] To a 90 mL solution of 2-methylpropyl-2-yl-4-[5-cyclopropyl-4-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester (5.7 g, 8.408 mmol), N-chlorosuccinimide (1.10 g, 8.240 mmol) was added, and the reaction was carried out at room temperature with stirring for 16 hours. 150 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%–20%) to give the title compound 2-methyl-2-yl-4-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester (4.4 g, 6.177 mmol, 73.46%). LC / MS (ESI) M / Z: 712.3 [M+H] + .

[0575] Step 7: (2S)-2-({3-chloro-6-[5-cyclopropyl-1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]pyridine Azo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0576] A solution of 2-methylpropyl-2-yl-4-[5-cyclopropyl-4-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid ester (4.4 g, 6.177 mmol) and a solution of dioxane (4 M, 4.6 mL) of hydrogen chloride in dioxane (60 mL) was stirred at room temperature for one hour. The reaction solution was distilled under reduced pressure using a rotary evaporator to give the title compound (2S)-2-({3-chloro-6-[5-cyclopropyl-1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol (3.8 g, yield: 98.84%). LC / MS (ESI) M / Z: 498.2 [M+H] + .

[0577] Step 8: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridine- 6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile

[0578] At room temperature, cyanogen bromide (1.31 g, 12.354 mmol) was added to a solution of dichloromethane (50 mL) containing (2S)-2-({3-chloro-6-[5-cyclopropyl-1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (3.84 g, 6.177 mmol) and N,N-diisopropylethylamine (3.98 g, 30.885 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with dichloromethane and water, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was subjected to column chromatography (eluent: methanol / dichloromethane, gradient: 0%–10%) to give 2.8 g of crude product. This crude product was further purified by reversed-phase chromatography (ACN:H₂O = 0% to 50%) to give 2.7 g of 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (yield: 83.58%). LC / MS (ESI) M / Z: 523.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.9Hz,1H),8.51(s,1H),8.12(s,1H),7.78(td,J=8.8,2 .9Hz,1H),7.64(dd,J=8.8,4.5Hz,1H),6.99(s,1H),5.60(t,J=5.2Hz,1H),5.15(s,1H),4. 85-4.68(m,1H),3.94(d,J=4.9Hz,2H),3.58(d,J=12.1Hz,2H),3.36(d,J=3.5Hz,1H),2.22 -2.09(m,4H),2.04-1.84(m,1H),1.15-1.01(m,1H),0.94-0.81(m,1H),0.57-0.29(m,2H).

[0579] Example 14: (S)-(2-((3-chloro-6-(1-(1-cyanopiperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-) 4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)methyl phosphate dihydrogen ester

[0580]

[0581]

[0582] Step 1: (S)-4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-((methylthio)methoxy)ethoxy)pyridine Azo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile

[0583] A sodium hydride suspension (172.09 mg, 4.302 mmol) in 10 mL of tetrahydrofuran was stirred at ambient temperature, and iodine (212.05 mg, 0.478 mmol) was added all at once. Then, 4-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1,2,3-triazol-1-yl]hexahydropyridin-1-carboxylonitrile (500 mg, 0.956 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The mixture was then cooled to <5°C, and (chloromethyl)(methyl)thione (184.66 mg, ...) was added.

[0584] 1.912 mmol), and the temperature was kept <5 degrees. The mixture was stirred at this temperature for 3 hours, and then slowly heated to room temperature and stirred for another 13 hours. At a temperature <5 degrees, ethyl acetate (20 mL) and saturated NH4Cl aqueous solution (20 mL) were added to the reaction mixture and stirred. After heating to ambient temperature, the layers were separated, the organic layer was washed with saturated sodium chloride aqueous solution (40 mL) and dried with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA / PE = 0% to 50%) to give the title compound (S)-4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-((methylthio)methoxy)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylonitrile (280 mg, yield: 50%). LC / MS (ESI) M / Z: 583.2 [M+H] + .

[0585] Step 2: (S)-(2-((3-chloro-6-(1-(1-cyanopiperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazol-4-) pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)methyl phosphate dihydrogen ester

[0586] A solution of 4-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-3-oxa-5-thio-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxynitrile (280 mg, 0.480 mmol), H3PO4 (387.52 mg, 3.361 mmol), and 4A molecular sieve (4 g) in THF (6 mL) was stirred at room temperature for 10 minutes. The mixture was cooled to 0 °C, and N-iodosuccinimide (162.06 mg, 0.720 mmol) was immediately added. After stirring the mixture for 35 minutes, ethyl acetate (20 mL) was added, followed by saturated aqueous Na2S2O3 (10 mL), and the pH was adjusted to 10 with a saturated aqueous NaHCO3 solution. The mixture was then filtered through diatomaceous earth. Separate the aqueous layer by back-extraction with ethyl acetate (10 mL). Concentrate the combined organic layers to obtain the crude product, which was purified by reversed-phase HPLC (ACN / H₂O: 5% to 45%) to give (S)-(2-((3-chloro-6-(1-(1-cyanopiperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)methyl dihydrogen phosphate (44.2 mg, yield: 14.54%). LC / MS (ESI) M / Z: 633.2

[0587] [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.64(d,J=2.8Hz,1H),8.53(s,1H),8.14(s,1H),7.83-7 .76(m,1H),7.68-7.65(m,1H),6.97(s,1H),5.83(t,J=5.1Hz,1H),5.17-5.09(m, 2H),4.86-4.71(m,1H),4.16(d,J=5.1Hz,2H),3.61-3.57(m,4H),3.37-3.28(m, 4H),2.25-2.10(m,4H),2.03-1.92(m,1H),1.16-0.76(m,2H),0.53-0.33(m,2H).

[0588] Example 17: 5-(4-(3-chloro-4-((S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)-2-azabicyclo[4.1.0]heptane-2-nitrile

[0589]

[0590] Reaction route:

[0591]

[0592] Operating steps:

[0593] Step 1: 4-Hydroxy-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0594] 4-O-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester (4.5 g, 19.4 mmol) was dissolved in methanol (50 mL), and cerium(III) chloride heptahydrate (10.9 g, 29.2 mmol) was added. Sodium borohydride (1.1 g, 29.2 mmol) was added at 0°C, and the mixture was stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and water (100 mL) was added. The mixture was extracted with ethyl acetate (3 x 10 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to give compound 4-hydroxy-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester (3.4 g, 14.6 mmol, yield: 74.9%). LC / MS (ESI) M / Z: 234.2 [M+H] + .

[0595] Step 2: 5-Hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester

[0596] Under nitrogen protection, 3.4 g (14.6 mmol) of 4-hydroxy-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester and 14.6 mL (1M, 146 mmol) were dissolved in dichloromethane (40 mL). Diiodomethane (39 g, 146 mmol) was added at 0°C, and the mixture was stirred for 3 hours. After the reaction was complete, 100 mL of water was added, and the mixture was extracted with dichloromethane (3 x 50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to give 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (2 g, 8.1 mmol, yield: 55.5%). LC / MS (ESI) M / Z: 248.2 [M+H] + .

[0597] Step 3: 5-Hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester

[0598] To a solution of 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (2 g, 8.1 mmol) in methanol (20 mL), palladium on carbon (200 mg) and di-tert-butyl dicarbonate (2.65 g, 12.2 mmol) were added. The reaction was carried out overnight under hydrogen protection with stirring. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to give 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester (1.1 g, 5.16 mmol, yield: 63.8%). LC / MS (ESI) M / Z: 214.4 [M+H] + .

[0599] Step 4: 5-((methanesulfonyl)oxy)-2-azabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester

[0600] At 0°C, triethylamine (1.56 g, 15.5 mmol) and p-toluenesulfonyl chloride (10.3 mmol) were added to a solution of 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester (1.1 g, 5.16 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound 5-((methanesulfonyl)oxy)-2-azabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester (1.15 g, 3.95 mmol). LC / MS (ESI) M / Z: 292.4 [M+H] + .

[0601] Step 5: 5-Azide-2-azabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester

[0602] 1.15 g (3.95 mmol) of 5-((methanesulfonyl)oxy)-2-azabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester was dissolved in N,N-dimethylformamide (10 mL), and sodium azide (513 mg, 7.9 mmol) was added. The mixture was heated to 80 °C and stirred for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give the title compound (780 mg, 3.28 mmol, yield 83%). LC / MS (ESI) M / Z: 239.4 [M+H] +.

[0603] Steps 6 to 14 were performed according to the synthetic method of Example 2 to obtain the target compound 5-(4-(3-chloro-4-((S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)-2-azabicyclo[4.1.0]heptane-2-nitrile. LC / MS (ESI) M / Z: 509.9 [M+H] + .

[0604] Example 24: (8-(4-(3-chloro-4-((S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1, [5-a]pyridin-6-yl)-5-(methyl- d 3)-1H-1,2,3-triazol-1-yl)-5-azaspiro[3.5]nonane-5-nitrile

[0605]

[0606] Using the synthetic route and steps of Example 115, ethyl 3-oxobutyrate was replaced with ethyl 3-oxobutyrate-4,4,4-d3 to synthesize compound Example 24.

[0607]

[0608] Operating steps:

[0609] Step 1: (8-(4-(3-chloro-4-((S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]) pyridin-6-yl)-5-(methyl-d3)-1H-1,2,3-triazol-1-yl)-5-azaspiro[3.5]nonane-5-nitrile

[0610] Under a nitrogen atmosphere at room temperature, (2S)-2-((3-chloro-6-(5-(methyl-d) 3)A solution of 1-(5-azaspiro[3.5]non-8-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (30 mg, 0.06 mmol) in dichloromethane DCM (2 mL) was prepared, and cyanogen bromide (12 mg, 0.12 mmol) and N,N-diisopropylamine (38 mg, 0.29 mmol) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, water (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was subjected to column chromatography (eluent: dichloromethane / methanol, gradient: 3%-5% methanol) to obtain the crude target compound. The crude product was then purified by reverse-phase chromatography (ACN:H2O = 10%-50%) to obtain the white solid target product (8-(4 -(3-chloro-4-((S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-(methyl-d3)-1H-1,2,3-triazol-1-yl)-5-azaspiro[3.5]nonane-5-onitrile (7.50 mg, 0.01 mmol, yield: 24%), LC / MS (ESI) M / Z: 540.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.60(d,J=2.8Hz,1H),8.44(s,1H),8.12(s,1H),7.77(td,J=8.8 ,2.8Hz,1H),7.64(dd,J=8.8,4.4Hz,1H),6.95-6.86(m,1H),5.63(dt,J=5.8,2.8Hz,1H), 5.15(t,J=5.6Hz,1H),4.65-4.52(m,1H),3.94(t,J=5.4Hz,2H),3.55-3.47(m,1H),3.30- 3.18(m,1H),2.42-2.37(m,2H),2.35-2.24(m,2H),2.10-2.00(m,4H),1.89-1.80(m,2H).

[0611] Example 36: (S)-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-4-(1- (5-Fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0612]

[0613]

[0614] Step 1: (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl tert-butyl pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid

[0615] Under a nitrogen atmosphere at room temperature, a mixture of 1,4-dioxane (5 mL) and water (0.5 mL) containing tert-butyl piperidine-1-carboxylate (300 mg, 0.9 mmol) was added to (S)-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazolo[1,5-a]pyridine (446 mg, 0.9 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (56 mg, 0.1 mmol), and potassium carbonate (357 mg, 2.6 mmol). The reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40%-60% ethyl acetate) to obtain a pale yellow oily (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.4 mmol, yield: 46%). LC / MS (ESI) M / Z: 652.3 [M+H] + .

[0616] Step 2: (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl 3-Iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0617] (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.4 mmol) was dissolved in dichloromethane (5 mL), and N-iodosuccinimide (68 mg, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (30 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40%-60% ethyl acetate) to obtain a pale yellow oily (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.3 mmol, yield: 81%). LC / MS (ESI) M / Z: 778.2 [M+H] + .

[0618] Step 3: (S)-6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)- 4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine- 3-Carboxylic Acid Methyl Ester

[0619] (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.3 mmol) was dissolved in dioxane (10 mL) and methanol (5 mL), and palladium acetate (2 mg, 0.01 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (10 mg, 0.02 mmol), 4-dimethylaminopyridine (11 mg, 0.1 mmol) and octacarbonyldicobalt (954 mg, 2.8 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40%-60% ethyl acetate) to give a pale yellow oily (S)-6-(1-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (44 mg, 0.06 mmol, yield: 19%). LC / MS (ESI) M / Z: 710.3 [M+H] + .

[0620] Step 4: (S)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(5-methyl-1-(piperidin-4-yl)- methyl 1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0621] Add 2 mL of 4 M dioxane hydrochloride solution to a solution containing (S)-6-(1-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (44 mg, 0.06 mmol). Stir the reaction mixture at room temperature for 2 hours. After the reaction was complete, the reaction solution was evaporated to dryness to obtain crude white solid (S)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (20 mg, 0.04 mmol, yield: 65%), which was used directly in the next step without further purification. LC / MS (ESI) M / Z: 496.2 [M+H] + .

[0622] Step 5: (S)-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-4-(1-(5- methyl 2-fluoropyridinium (2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0623] N,N-diisopropylamine (104 mg, 0.8 mmol) and brominated nitriles (13 mg, 0.1 mmol) were added to a solution of (S)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (20 mg, 0.04 mmol). The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, water (5 mL) was added, and the mixture was extracted with dichloromethane (15 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 60%-80% ethyl acetate) to give a white solid (S)-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (3.2 mg, 0.006 mmol, yield: 15%). LC / MS (ESI) M / Z: 521.2 [M+H] + .1H NMR(400MHz,DMSO-d6)δ8.67-8.57(m,2H),8.47(s,1H),7.75(td,J=8.6,2.8Hz,1H) ,7.67(dd,J=8.8,4.6Hz,1H),7.07(d,J=1.2Hz,1H),5.65(t,J=5.2Hz,1H),5.03(t, J=6.0Hz,1H),4.67-4.57(m,1H),3.94(t,J=5.6Hz,2H),3.86(s,3H),3.56(d,J=13. 0Hz, 2H), 3.26 (d, J = 10.8Hz, 2H), 2.39 (s, 3H), 2.19-2.10 (m, 2H), 2.05-1.96 (m, 2H).

[0624] Example 50: (S)-6-(5-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)-6-methylpyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-nitrile

[0625]

[0626] Step 1: 6-(5-bromo-6-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0627] To a solution of 5 mL of dimethyl sulfoxide containing 150 mg (0.8 mmol) of 3-bromo-6-fluoro-2-methylpyridine (300 mg, 0.8 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid was added (157 mg, 0.8 mmol) and N,N-diisopropylethylamine (306 mg, 2.4 mmol). The reaction mixture was stirred at 90 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, 15 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 20%-35% ethyl acetate) to obtain a pale yellow solid tert-butyl 6-(5-bromo-6-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid (200 mg, 0.5 mmol, yield: 69%). LC / MS (ESI) M / Z: 368.1 [M+H] + .

[0628] Step 2: (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl [Oxy)pyrazolo[1,5-a]pyridin-6-yl]-6-methylpyridin-2-yl]-2,6-diazaspiro[3,3]heptane-2-carboxylic acid tertiary Butyl acetate

[0629] Under a nitrogen atmosphere at room temperature, a mixture of dioxane (4 mL) and water (0.4 mL) containing 200 mg (200 mg, 0.5 mmol) of 6-(5-bromo-6-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 0.5 mmol) was added to (S)-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazolo[1,5-a]pyridine (279 mg, 0.5 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (35 mg, 0.05 mmol), and potassium carbonate (225 mg, 1.6 mmol). The reaction mixture was heated to 90 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-45% ethyl acetate) to obtain a pale yellow oily (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6-methylpyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (294 mg, 0.4 mmol, yield: 80%). LC / MS (ESI) M / Z: 675.3 [M+H] + .

[0630] Step 3: (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl (Oxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-6-methylpyridin-2-yl]-2,6-diazaspiro[3,3]heptane-2-carboxy tert-butyl ester

[0631] (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6-methylpyridin-2-yl]-2,6-diazaspiro[3,3]heptane-2-carboxylic acid tert-butyl ester (294 mg, 0.4 mmol) was dissolved in dichloromethane (5 mL), and N-chlorosuccinimide (57 mg, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with dichloromethane (30 mL * 3). The organic phase was treated with saturated brine. Washed, dried over anhydrous sodium sulfate, and distilled under reduced pressure, the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-45% ethyl acetate) to give a pale yellow oil (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-6-methylpyridin-2-yl]-2,6-diazaspiro[3,3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 0.3 mmol, yield: 65%). LC / MS (ESI) M / Z: 709.3 [M+H] + .

[0632] Step 4: (S)-2-((3-chloro-6-(2-methyl-6-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl) Pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0633] Trifluoroacetic acid (2 mL) was added to a solution of (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-6-methylpyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 0.3 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to alkaline with saturated sodium bicarbonate. Extracted with dichloromethane (30 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give a crude pale yellow solid (S)-2-((3-chloro-6-(2-methyl-6-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (80 mg, 0.2 mmol, yield: 57%). LC / MS (ESI) M / Z: 495.1 [M+H]+ .

[0634] Step 5: (S)-6-(5-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a] [pyridin-6-yl]-6-methylpyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-nitrile

[0635] N,N-diisopropylethylamine (104 mg, 0.8 mmol) and brominated nitriles (41 mg, 0.3 mmol) were added to dichloromethane (5 mL) containing (S)-2-((3-chloro-6-(2-methyl-6-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (80 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was added to water (10 mL), extracted with dichloromethane (30 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-45% ethyl acetate) to give a white solid (S)-6-(5-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6-methylpyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-onitrile (70 mg, 0.09 mmol, yield: 79%). LC / MS (ESI) M / Z: 520.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.8Hz,1H),8.18(s,1H),8.07(s,1H),7.77(td,J=8.8,2.8Hz,1H),7.64(dd,J=8.8,4.4Hz,1H),7.37(d,J=8.2Hz, 1H),6.50(s,1H),6.28(d,J=8.4Hz,1H),5.60(t,J=5.0Hz,1H),5.09(t,J= 5.6Hz,1H),4.36(s,4H),4.08(s,4H),3.93(t,J=5.4Hz,2H),2.08(s,3H).

[0636] Example 51: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyridine (Pyridine-6-yl)-5-methyl-1,2,3-trimethyl ... [Zycyclopentan-1-yl]hexahydropyridine-1-carboxynitrile

[0637]

[0638] Step 1: 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester

[0639] At room temperature, 2-methylpropyl-2-yl-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (243 mg, 1.23 mmol) and N,N-diisopropylethylamine (793 mg, 6.14 mmol) were added to a solution of 4,6-dichloro-5-methylpyrimidine (200 mg, 1.23 mmol) in 1,4-dioxane (5 mL), and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the title compound 2-methylpropyl-2-yl-6-(6-chloro-5-methylpyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (400 mg, 1.13 mmol, yield 97.9%). LC / MS (ESI) M / Z: 325.2 [M+H] + .

[0640] Step 2: 2-Methylpropyl-2-yl6-[6-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3- [Oxa-4-silhex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspirol [3.3] Heptane-2-carboxylic acid ester

[0641] At room temperature, 2-methylpropyl-2-yl-6-(6-chloro-5-methylpyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (200 mg, 0.62 mmol) was dissolved in 1,4-dioxane (4 mL) and water (1 mL), and potassium carbonate (255 mg, 1.85 mmol) and 4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silhex-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazolo[1,5-a]pyridine (317 mg, 0.62 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (40 mg, 0.06 mmol) were added. The reaction was carried out at 90°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (eluent: dichloromethane / ethyl acetate, gradient: 0%-80% ethyl acetate) to give compound 2-methylpropyl-2-yl-6-[6-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (240 mg, 0.36 mmol, yield: 57.7%). LC / MS (ESI) M / Z: 676.4 [M+H] + .

[0642] Step 3: 2-Methylpropyl-2-yl-6-[6-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl] [3-oxa-4-silylhex-1-yl]oxy[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazo Spiro[3.3]heptane-2-carboxylic acid ester

[0643] To a solution of 2-methylpropyl-2-yl 6-[6-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silhex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (240 mg, 0.36 mmol) in dichloromethane (3 mL), chlorosuccinimide (45 mg, 0.34 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL x 3), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to give 2-methylpropyl-2-yl-6-[6-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhexyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (180 mg, 0.25 mmol, yield: 71.4%), a yellow solid. LC / MS (ESI) M / Z: 710.4 [M+H] + .

[0644] Step 4: (2S)-2-({3-chloro-6-[4-(2,6-diazaspiro[3.3]heptane-2-yl)-5-methylpyrimidine-6- [1,5-a]pyrazolo[1,5-a]pyridin-4-yl]oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0645] 180 mg (0.25 mmol) of 2-methylpropyl-2-yl 6-[6-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silhex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure to give the title compound (2S)-2-({3-chloro-6-[4-(2,6-diazaspiro[3.3]heptan-2-yl)-5-methylpyrimidin-6-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (120 mg, 0.24 mmol). LC / MS (ESI) M / Z: 496.2 [M+H] + .

[0646] Step 5: 6-[6-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5-] [a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro[3.3]heptane-2-nitrile

[0647] (2S)-2-({3-chloro-6-[4-(2,6-diazaspiro[3.3]heptane-2-yl)-5-methylpyrimidin-6-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (120 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (94 mg, 0.73 mmol) and cyanogen bromide (51 mg, 0.48 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to give the title compound 6-[6-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro[3.3]heptane-2-onitrile (50.2 mg, 0.1 mmol, yield: 39.8%). LC / MS (ESI) M / Z: 521.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.60(d,J=2.9Hz,1H),8.44-8.38(m,2H),8.15(s,1H),7.77(td,J=8.8,3.0Hz,1H),7.65(dd,J=8.8,4.5Hz,1 H), 6.74 (d, J = 1.0Hz, 1H), 5.61 (t, J = 5.1Hz, 1H), 5.13 (t, J = 5.6Hz, 1H), 4.41-4.35 (m, 8H), 3.93 (td, J = 5.2, 2.4Hz, 2H), 1.98 (s, 3H).

[0648] Example 52: 6-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo] [1,5-a]pyridin-6-yl)-2-cyanophenyl]-2,6-diazaspiro[3.3]heptane-2-nitrile

[0649]

[0650] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 530.15 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.61(d,J=1.1Hz,1H),8.59(d,J=2.9Hz,1H),8.06(s,1H),7.91(d,J=2.2Hz,1H),7.77(td,J=9.0,2.6Hz,2H),7.70(dd,J =8.8,4.6Hz,1H),7.01(s,1H),6.63(d,J=8.9Hz,1H),5.90(t,J=5.1Hz, 1H),5.10(t,J=5.6Hz,1H),4.39(s,4H),4.32(s,4H),4.01-3.89(m,2H).

[0651] Example 53: 4-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo] [1,5-a]pyridin-6-yl)-2-cyanophenyl]piperazine-1-onitrile

[0652]

[0653] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 518.14 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=1.1Hz,1H),8.59(d,J=2.8Hz,1H),8.17(d,J=2.4Hz,1H),8.10( s,1H),7.97(dd,J=8.7,2.4Hz,1H),7.77(td,J=8.8,2.9Hz,1H),7.71(dd,J=8.8,4.6Hz,1H),7.28 (d,J=8.8Hz,1H),7.08(d,J=1.2Hz,1H),5.93(dd,J=6.0,3.9Hz,1H),5.10(t,J=5.6Hz,1H),4.02( ddd,J=11.7,5.5,3.9Hz,1H),3.93(dt,J=11.7,5.9Hz,1H),3.46-3.39(m,4H),3.29-3.22(m,4H).

[0654] Example 54: (S)-6-(5-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)-4-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-nitrile

[0655]

[0656] Following the synthetic route and steps of Example 50, but replacing 3-bromo-6-fluoro-2-methylpyridine with 5-bromo-2-fluoro-4-methylpyridine (as shown in the table below), compound Example 54 was synthesized. LC / MS (ESI) M / Z: 520.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.58(d,J=2.8Hz,1H),8.19(d,J=1.0Hz,1H),8.07(s,1H),7.87(s,1H),7.76(td,J=8.8,3.0Hz,1H),7.64(dd,J=8.8,4.4Hz, 1H),6.50(d,J=1.0Hz,1H),6.31(s,1H),5.60(t,J=5.2Hz,1H),5.09(t,J= 5.6Hz,1H),4.36(s,4H),4.08(s,4H),3.92(t,J=5.4Hz,2H),1.96(s,3H).

[0657] Example 55: (S)-4-(6-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- [a]pyridin-6-yl)-5-methylpyrimidin-4-yl)piperazine-1-onitrile

[0658]

[0659] Step 1: 4-(6-chloro-5-methylpyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0660] Under a nitrogen atmosphere at room temperature, piperazine-1-carboxylate tert-butyl ester (229 mg, 1.2 mmol) and N,N-diisopropylethylamine (476 mg, 3.7 mmol) were added to a solution of dimethyl sulfoxide (5 mL) containing 4,6-dichloro-5-methylpyrimidine (200 mg, 1.2 mmol). The reaction mixture was placed at 90 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 1%-3% methanol) to give a pale yellow solid 4-(6-chloro-5-methylpyrimidine-4-yl)piperazine-1-carboxylate tert-butyl ester (300 mg, 1.0 mmol, yield: 78%). LC / MS(ESI)M / Z:313.1[M+H] + .

[0661] Subsequent steps follow the synthetic route of Example 50. LC / MS (ESI) M / Z: 509.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.59(d,J=2.8Hz,1H),8.57(d,J=1.0Hz,1H),8.17(s,1H),7.78(td,J=8.8,2.8Hz,1H),7.67(dd,J=8.8,4. 4Hz,1H),6.93(d,J=1.0Hz,1H),5.67(dd,J=6.0,4.0Hz,1H),5.13(s,1H ),4.01-3.89(m,2H),3.52-3.45(m,4H),3.40-3.36(m,4H),2.13(s,3H)

[0662] Example 56: (S)-6-(5-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)-3-cyanopyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-nitrile

[0663]

[0664] Following the synthetic route and steps of Example 50, but replacing 3-bromo-6-fluoro-2-methylpyridine with 5-bromo-2-chloronicotinamide as shown in the table below, compound Example 56 was synthesized. LC / MS (ESI) M / Z: 531.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.72-8.68(m,2H),8.59(d,J=2.8Hz,1H),8.40(d,J=2.4Hz,1H),8.08(s,1H),7.81-7.75(m,1H),7.73-7.69(m,1H) ,7.06(d,J=1.2Hz,1H),5.91(dd,J=6.0,3.8Hz,1H),5.09(t,J=5.6Hz,1H),4.43(s,4H),4.39(s,4H),4.04-3.98(m,1H),3.98-3.89(m,1H).

[0665] Example 57: (S)-6-(5-(3-bromo-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- [a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-nitrile

[0666]

[0667] Following the synthetic route and steps of Example 50, but replacing 3-bromo-6-fluoro-2-methylpyridine with 5-bromo-2-fluoropyridine (as shown in the table below), and replacing NCS with NBS, compound Example 57 was synthesized. LC / MS (ESI) M / Z: 550.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.8Hz,1H),8.58(d,J=1.0Hz,1H),8.36(d,J=2.4Hz,1H),8.04(s,1H),7.83(dd,J=8.6,2.4Hz,1H),7.79-7.69 (m,2H),6.91(d,J=1.2Hz,1H),6.47(d,J=8.6Hz,1H),5.80(t,J=5.2Hz, 1H),5.09(t,J=5.6Hz,1H),4.37(s,4H),4.11(s,4H),4.01-3.92(m,2H).

[0668] Example 58: (S)-4-(6-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)pyrimidin-4-yl)piperazine-1-nitrile

[0669]

[0670] Using the synthetic route and steps of Example 50, 3-bromo-6-fluoro-2-methylpyridine was synthesized by replacing 3-bromo-6-fluoro-2-methylpyridine with 4,6-dichloropyrimidine as shown in the table below.

[0671] Example 58. LC / MS (ESI) M / Z: 507.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.09(d,J=1.0Hz,1H),8.61(d,J=2.8Hz,1H),8.51(d,J=1.0Hz,1H),8.18(s,1H),7.77(td,J=8.8,2.8Hz,1H),7.69- 7.64(m,1H),7.32(s,1H),6.98(d,J=1.2Hz,1H),5.76(t,J=5.0Hz,1H),5.14(t,J=5.6Hz,1H),4.39(s,4H),4.24(s,4H),4.00-3.90(m,2H).

[0672] Example 59: (S)-6-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-nitrile

[0673]

[0674] Step 1: 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0675] Under a nitrogen atmosphere at room temperature, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid was added to a solution of (4-bromophenyl)boric acid (200 mg, 1.0 mmol) in dichloromethane (5 mL), along with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid (99 mg, 0.5 mmol), triethylamine (252 mg, 2.5 mmol), and copper acetate (181 mg, 1.0 mmol). The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was purified by vacuum distillation. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 15%-20% ethyl acetate) to give a white solid of the target compound 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid (130 mg, 0.4 mmol, yield: 84%). LC / MS (ESI) M / Z: 353.0 [M+H] + .

[0676] Subsequent steps follow the synthetic route of Example 50. LC / MS (ESI) M / Z: 505.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.9Hz,1H),8.45(d,J=1.1Hz,1H),8.03(s,1H),7.80-7.73(m,1H),7.67(dd,J=8.8,4.5Hz,1H),7.47(d,J =8.5Hz,2H),6.87(s,1H),6.49(d,J=8.6Hz,2H),5.77(t,J=5.1Hz,1H),5.11(t,J=5.6Hz,1H),4.36(s,4H),3.98(s,4H),3.97-3.90(m,2H).

[0677] Example 60: (S)-6-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-nitrile

[0678]

[0679] Reaction route:

[0680]

[0681] Operating steps:

[0682] Step 1: 6-(4-bromo-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0683] Under a nitrogen atmosphere at room temperature, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (99 mg, 0.5 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (58 mg, 0.1 mmol), palladium acetate (11 mg, 0.05 mmol), and cesium carbonate (487 mg, 1.5 mmol) were added to a 5 mL solution of 1,4-dioxane (150 mg, 0.5 mmol), palladium acetate (11 mg, 0.05 mmol), and cesium carbonate (487 mg, 1.5 mmol) in 1,4-dioxane (5 mL) containing 4-bromo-2-fluoro-1-iodobenzene (0.5 mmol). The reaction mixture was then placed at 100 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 15%-20% ethyl acetate) to give a white solid target compound 6-(4-bromo-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (140 mg, 0.4 mmol, yield: 76%). LC / MS (ESI) M / Z: 371.0 [M+H] + .

[0684] Subsequent steps follow the synthetic route of Example 50. LC / MS (ESI) M / Z: 523.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.8Hz,1H),8.55(d,J=1.0Hz,1H),8.05(s,1H),7.7 7(td,J=8.6,2.8Hz,1H),7.69(dd,J=8.8,4.6Hz,1H),7.48(dd,J=14.0,2.0Hz,1H),7.3 5(dd,J=8.2,2.0Hz,1H),6.94(d,J=1.2Hz,1H),6.59(dd,J=9.6,8.4Hz,1H),5.88-5.8 1(m,1H),5.10(t,J=5.6Hz,1H),4.36(s,4H),4.08(d,J=2.0Hz,4H),4.02-3.90(m,2H).

[0685] Example 61: 4-(4-(3-chloro-4-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy (1,5-a)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0686]

[0687] Step 1: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methylmethanesulfonate

[0688] Under a nitrogen atmosphere at room temperature, triethylamine (385 mg, 3.8 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (200 mg, 1.3 mmol) in 5 mL of dichloromethane. The reaction mixture was stirred in an ice bath for 5 minutes, followed by the dropwise addition of methanesulfonyl chloride (216 mg, 1.9 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, a colorless oily crude product of the target compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanesulfonate (200 mg, 0.4 mmol, yield: 68%) was obtained. The intermediate structure was confirmed in the next step. The crude target product was used directly in the next step without further purification.

[0689] Step 2: 4-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)pyrazolo[1, [5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0690] Under a nitrogen atmosphere at room temperature, 4-(4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.4 mmol) and cesium carbonate (368 mg, 1.1 mmol) were added to a solution of N,N-dimethylformamide (5.00 mL) containing ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methylmethanesulfonate (134 mg, 0.6 mmol) at room temperature. The reaction mixture was placed at 90 °C and reacted for 15 minutes. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-6% methanol) to obtain the pale yellow oily target product 4-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.2 mmol, yield: 60%). LC / MS (ESI) M / Z: 540.3 [M+H] + .

[0691] Subsequent steps follow the synthetic route of Example 50. LC / MS (ESI) M / Z: 499.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.60(d,J=1.0Hz,1H),8.11(s,1H),7.19(d,J=1.2Hz,1H),4.96-4. 74(m,1H),4.70-4.60(m,1H),3.63-3.55(m,2H),3.31-3.29(m,2H),3.29-3.25(m,1H),3.0 7-2.98(m,2H),2.97-2.93(m,1H),2.84-2.77(m,2H),2.53(s,3H),2.48-2.45(m,1H),2.40 -2.29(m,2H),2.22-2.13(m,3H),2.10-2.04(m,2H),1.92-1.82(m,1H),1.52-1.43(m,1H).

[0692] Example 62: (S)-4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazol [1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0693]

[0694] Step 1: (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl oxy)-3-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1- tert-butyl piperidine-1-carboxylate

[0695] Under a nitrogen atmosphere at room temperature, trimethylsilylene (151 mg, 1.5 mmol), bis(triphenylphosphine)palladium dichloride Pd(PPh3)2Cl2 (36 mg, 0.05 mmol), triethylamine (260 mg, 2.5 mmol), and cuprous iodide (10 mg, 0.05 mmol) were added to a solution of tetrahydrofuran (10 mL) containing (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (400 mg, 0.5 mmol) After the reaction was complete, the reaction solution was added to water (15 mL), extracted with ethyl acetate (30 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by reverse-phase purification (ACN:H2O = 0%-50%) to obtain a pale yellow oily target compound (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (270 mg, 0.4 mmol, 70%). LC / MS (ESI) M / Z: 748.3 [M+H] + .

[0696] Step 2: (S)-4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1, [5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0697] Under a nitrogen atmosphere at room temperature, 0.3 mL of 1 mol / L tetrabutylammonium fluoride was added to a 2 mL solution of (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.1 mmol). The reaction mixture was allowed to react at room temperature for 6 hours. After the reaction was complete, the reaction solution was added to water (5 mL), extracted with dichloromethane (10 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-5% methanol) to obtain the yellow oily target compound (S)-4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol, 67%). LC / MS (ESI) M / Z: 562.2 [M+H] + .

[0698] Step 3: (S)-2-((3-ethynyl-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrene Azo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0699] At room temperature, zinc bromide (48 mg, 0.2 mmol) was added to a solution of (S)-4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol). The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to obtain the target product (S)-2-((3-ethynyl-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (20 mg, 0.04 mmol). LC / MS (ESI) M / Z: 462.2 [M+H] + .

[0700] Step 4: (S)-4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1, [5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0701] At room temperature, N,N-dimethylformamide (28 mg, 0.2 mmol) and cyanogen bromide (9 mg, 0.09 mmol) were added to a solution of N,N-dimethylformamide (2 mL) containing (S)-2-((3-ethynyl-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (20 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure. The residue was subjected to column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10%) to obtain 15 mg of crude product. This crude product was then purified by reverse-phase chromatography (ACN:H2O = 0%-50%) to obtain the white solid target product (S)-4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile (10 mg, 0.02 mmol, yield: 48%). LC / MS (ESI) M / Z: 487.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=3.0Hz,1H),8.50(s,1H),8.23(s,1H),7.82-7.71(m,2H),7.05(s,1H),5.72-5.62(m,1H),5.14-5.05(m, 1H),4.62(s,1H),4.22(s,1H),4.00-3.90(m,2H),3.62-3.52(m,2H), 3.30-3.24(m,2H),2.43(s,3H),2.19-2.10(m,2H),2.08-2.01(m,2H).

[0702] Example 63: ( S)-4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy (1,5-a)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile (ee: 77.14%)

[0703]

[0704] Operating steps:

[0705] Step 1: (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethanol

[0706] (1R)-2-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-1-(5-fluoropyridin-2-yl)ethanol (17.82 g, 65.756 mmol) was dissolved in dichloromethane (300 mL), and DIEA (25.447 mL, 197.268 mmol) was added. The reaction solution was cooled to 0 °C, and MsCl (5.57 mL, 72.331 mmol) was added dropwise. The reaction solution was then brought to room temperature and reacted for 1 hour. The reaction solution was diluted with 300 mL of water and extracted three times with 300 mL of dichloromethane. The organic phases were combined, washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. A yellow oily crude product (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethanol (25 g, crude product) was obtained. LC / MS(ESI)M / Z:272.1[M+H] + .

[0707] Step 2: (S)-6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy) Pyrazolo[1,5-a]pyridine

[0708] (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethanol (25 g) was dissolved in DMF (250 mL), and 6-bromopyrazolo[1,5-a]pyridin-4-ol (15.334 g, 72.331 mmol) and cesium carbonate (64.309 g, 197.268 mmol) were added. The reaction mixture was heated to 80°C and reacted for 1 hour. The reaction mixture was diluted with 300 mL of water and extracted three times with 300 mL of ethyl acetate. The organic phases were combined, washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was passed through a silica gel column (PE / EA = 10:1) to give a yellow oil (S)-6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine (19.55 g, 44.043 mmol, 63.9%). LC / MS (ESI) M / Z: 466.1 [M+H] + .

[0709] Step 3: (S)-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6- (4,4,5,5-Tetramethyl-1,3,2-dioxaborone-2-yl)pyrazolo[1,5-a]pyridine

[0710] (S)-6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine (17.72 g, 38.108 mmol) was dissolved in dioxane (400 mL), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)-1,3,2-dioxaboranene (11.71 g, 45.729 mmol), potassium acetate (11.22 g, 114.323 mmol), and Pd(dppf)Cl2 (2.79 g, 3.811 mmol) were added. The reaction was carried out under nitrogen protection, and the reaction solution was heated to 90 °C for 5 hours. No post-treatment was performed, and the reaction solution was directly used for the next step. LC / MS (ESI) M / Z: 514.2 [M+H] + .

[0711] Step 4: (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy tert-butyl pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid

[0712] To the previous reaction solution, add 10 mL of H₂O, 13.1 g (37.945 mmol) of 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester, 15.73 g (113.834 mmol), and 1.24 g (1.897 mmol) of Pd(dtbpf)Cl₂. The reaction solution was kept under nitrogen protection and the temperature was raised to 100 °C for 4 hours. The reaction solution was then diluted with 200 mL of water and extracted three times with 200 mL of ethyl acetate. The organic phases were combined, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was subjected to silica gel column chromatography (PE / (EA:EtOH = 3:1) = 3:1) to give a yellow oil (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (14.8 g, 22.734 mmol, 59.91%). LC / MS (ESI) M / Z: 652.3 [M+H] + .

[0713] Step 5: (S)-2-(5-Fluoropyridin-2-yl)-2-((6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-tris) (azol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethanol

[0714] (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (7.5 g, 11.521 mmol) was dissolved in dichloromethane (30 mL), and HCl (30 mL, 120.000 mmol) was added. The reaction solution was reacted at room temperature for 1 hour. Directly evaporated to dryness, yielding a yellow solid (S)-2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethanol (6 g, crude product). LC / MS (ESI) M / Z: 438.2 [M+H] + .

[0715] Step 6: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridine- 6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile

[0716] (S)-2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethanol (6 g, 13.715 mmol) was dissolved in DMF (50 mL), and DIEA (8.86 g, 68.575 mmol) and cyanogen bromide (2.18 g, 20.572 mmol) were added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with 100 mL of water and extracted three times with 100 mL of ethyl acetate. The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was subjected to silica gel column chromatography (DCM / MeOH = 10:1) to give a yellow oil (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (3.05 g, 6.595 mmol, 48.08%). LC / MS (ESI) M / Z: 463.2 [M+H] + .

[0717] Step 7: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-iodopyrazolo[1,5-a] Pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile

[0718] (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (3.05 g, 6.595 mmol) was dissolved in dichloromethane (50 mL), and N-iodosuccinimide (1.48 g, 6.595 mmol) was added. The reaction mixture was reacted at room temperature for 18 hours. The reaction mixture was then directly evaporated to dryness. The crude product was subjected to silica gel column chromatography (DCM / MeOH = 10:1) to give a yellow oil (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (3.98 g, 6.088 mmol, 92.31%). LC / MS (ESI) M / Z: 589.1 [M+H] + .

[0719] Step 8: (S)-4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyridine Azo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile

[0720] (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (3.88 g, 6.594 mmol) was dissolved in DMF (40 mL), and palladium dichloride bis(triphenylphosphine) (0.46 g, 0.659 mmol), cuprous iodide (0.13 g, 0.659 mmol) and DIEA (2.56 g, 19.783 mmol) were added. The reaction mixture was kept under nitrogen protection, and ethynylcyclopropane (1.31 g, 19.783 mmol) was added dropwise. The reaction mixture was heated to 50 °C and reacted for 3 hours. The reaction solution was diluted with 50 mL of water and extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was subjected to silica gel column chromatography (PE / (EA:EtOH=3:1)=1:1) to give the crude product (S)-4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (Example 63, 1.8 g, ee: 77.14%). LC / MS (ESI) M / Z: 527.2 [M+H] + .

[0721] 1H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.8Hz,1H),8.44(d,J=1.0Hz,1H),8.09(s,1H),7.79(td,J=8.8,2. 8Hz,1H),7.72(dd,J=8.6,4.6Hz,1H),6.97(d,J=1.2Hz,1H),5.65(dd,J=6.2,4.2Hz,1H),5.11(t,J=5. 6Hz,1H),4.66-4.55(m,1H),4.03-3.88(m,2H),3.60-3.52(m,2H),3.27(dd,J=12.4,2.6Hz,2H),2.41( s,3H),2.20-2.09(m,2H),2.07-2.01(m,2H),1.63-1.57(m,1H),0.92-0.85(m,2H),0.79-0.70(m,2H).

[0722] Example 64: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yne-1-) (1,5-a)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile (ee: 79%)

[0723]

[0724] Step 1: (S)-4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy (1,5-a)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1- tert-butyl formate

[0725] Under a nitrogen atmosphere at room temperature, potassium carbonate (133 mg, 1.0 mmol), tetratriphenylphosphine palladium (37 mg, 0.03 mmol), cuprous iodide (6 mg, 0.03 mmol), and triethylamine (162 mg, 1.6 mmol) were added to a methanol (3 mL) solution containing trimethyl(prop-1-yn-1-yl)silane (108 mg, 1.0 mmol). The mixture was stirred at room temperature for 30 minutes. Subsequently, a tetrahydrofuran (3 mL) solution of (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.3 mmol) was added to the mixture. The reaction mixture was placed at room temperature and reacted for 16 hours. After the reaction was complete, the reaction solution was added to water (15 mL), extracted with ethyl acetate (30 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by reverse-phase purification (ACN:H2O = 0%-50%) to give the pale yellow oily target compound (S)-4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.1 mmol, yield: 36%). LC / MS (ESI) M / Z: 690.3 [M+H] + .

[0726] Step 2: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyridine Azo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0727] Under a nitrogen atmosphere at room temperature, 0.7 mL of 1 mol / L tetrabutylammonium fluoride was added to a 2 mL solution of (S)-4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (80 mg, 0.1 mmol). The reaction mixture was allowed to react at room temperature for 6 hours. After the reaction was complete, the reaction solution was added to water (5 mL), extracted with dichloromethane (10 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-5% methanol) to give the yellow oily target compound (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol, yield: 60%). LC / MS (ESI) M / Z: 576.2 [M+H] + .

[0728] Step 3: (S)-2-(5-Fluoropyridin-2-yl)-2-(6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazole- 4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethanol-1-ol

[0729] Zinc bromide (59 mg, 0.3 mmol) was added to a 2 mL solution of dichloromethane containing (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol). The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to obtain the target product (S)-2-(5-fluoropyridin-2-yl)-2-(6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethanol-1-ol (25 mg, 0.05 mmol). LC / MS (ESI) M / Z: 476.2 [M+H] + .

[0730] Step 4: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyridine Azo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile

[0731] At room temperature, N,N-dimethylformamide (34 mg, 0.3 mmol) and cyanogen bromide (11 mg, 0.1 mmol) were added to a solution of (S)-2-(5-fluoropyridin-2-yl)-2-(6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethanol-1-ol (25 mg, 0.05 mmol) in 2 mL of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure. The residue was subjected to column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10%) to obtain 15 mg of crude product. This crude product was then purified by reverse-phase chromatography (acetonitrile:water = 0%-50%) to give the white solid target product (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-onitrile (8 mg, 0.02 mmol, yield: 30%). LC / MS (ESI) M / Z: 501.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.9Hz,1H),8.45(d,J=1.0Hz,1H),8.09( s,1H),7.81(td,J=8.6,2.8Hz,1H),7.74(dd,J=8.6,4.6Hz,1H),7.00(s,1H) ,5.66-5.61(m,1H),5.09(t,J=5.6Hz,1H),4.66-4.57(m,1H),4.02-3.90(m ,2H),3.60-3.53(m,2H),3.30-3.24(m,2H),2.42(s,3H),2.17-2.03(m,7H).

[0732] Example 65: ({1-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazol) [1,5-a]pyridin-6-yl)-2-cyanophenyl]-3-(hydroxymethyl)azacyclobutane-3-yl}methyl)azanitrile

[0733]

[0734] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 548.15 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.60(dd,J=4.0,2.0Hz,2H),8.05(s,1H),7.92(d,J=2.4 Hz,1H),7.77(ddd,J=11.4,8.8,2.5Hz,2H),7.71(dd,J=8.8,4.7Hz,1H),7.07-6. 94(m,2H),6.53(t,J=6.0Hz,1H),5.96-5.76(m,1H),5.33(t,J=5.1Hz,1H),5.09( t,J=5.6Hz,1H),4.06-3.87(m,6H),3.59(d,J=5.1Hz,2H),3.49(d,J=6.1Hz,2H).

[0735] Example 66: 4-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo [1,5-a]pyridin-6-yl)-3-cyanopyridin-2-yl]piperazine-1-onitrile

[0736]

[0737] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 519.14 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.82(d,J=2.5Hz,1H),8.78(d,J=1.1Hz,1H),8.59(d,J=2.8Hz ,1H),8.57(d,J=2.5Hz,1H),8.11(s,1H),7.78(td,J=8.7,2.9Hz,1H),7.72(dd,J=8.7, 4.7Hz,1H),7.13(d,J=1.2Hz,1H),5.94(dd,J=5.9,3.9Hz,1H),5.10(t,J=5.6Hz,1H), 4.07-3.99(m,2H),3.93(dt,J=11.7,5.9Hz,1H),3.76-3.71(m,4H),3.42-3.37(m,4H).

[0738] Example 67: 6-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo] [1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-nitrile

[0739]

[0740] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 506.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.78(d,J=1.1Hz,1H),8.62(d,J=2.9Hz,1H),8.14( s,1H),8.10(d,J=5.3Hz,1H),7.79(td,J=8.7,2.9Hz,1H),7.70(dd,J=8.7,4 .5Hz,1H),6.96(dd,J=5.4,1.5Hz,2H),6.61(d,J=1.5Hz,1H),5.83(t,J=5.1 Hz,1H),5.14(t,J=5.6Hz,1H),4.38(s,4H),4.13(s,4H),4.00-3.94(m,2H).

[0741] Example 68: 1-{6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazole [1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-yl} ethyl-1-one

[0742]

[0743] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 523.16 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.59(d,J=2.9Hz,1H),8.33(d,J=2.4Hz ,1H),8.09(s,1H),8.05(d,J=9.0Hz,1H),7.77(td,J=8.8,2.9Hz,1H),7.69( dd,J=8.8,4.6Hz,1H),6.95(s,1H),6.70(d,J=9.0Hz,1H),5.84(t,J=5.0Hz, 1H),4.32(s,2H),4.25(s,4H),4.04(s,2H),4.00-3.92(m,3H),1.76(s,3H).

[0744] Example 69: (2S)-2-({6-[2-(6-aza-2-oxaspiro[3.3]heptane-6-yl)pyridin-5-yl]-3-chloro Pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0745]

[0746] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 482.13 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.9Hz,1H),8.54(d,J=1.0Hz,1H),8.37(d,J= 2.5Hz,1H),8.05(s,1H),7.83(dd,J=8.7,2.5Hz,1H),7.77(td,J=8.7,2.9Hz,1H) ,7.69(dd,J=8.8,4.6Hz,1H),6.91(s,1H),6.47(d,J=8.7Hz,1H),5.80(dd,J=6.0 ,4.2Hz,1H),5.11(t,J=5.7Hz,1H),4.73(s,4H),4.14(s,4H),4.01-3.91(m,2H).

[0747] Example 70: 1-{6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazole [1,5-a]pyridin-6-yl)pyridin- 2-yl]-26-diazaspiro[3.3]heptane-2-yl}prop-2-en-1-one

[0748]

[0749] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 535.16 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.8Hz,1H),8.55(d,J=1.1Hz,1H),8.37(d,J=2.5Hz,1H),8.05(s,1H), 7.84(dd,J=8.7,2.5Hz,1H),7.77(td,J=8.7,2.9Hz,1H),7.69(dd,J=8.8,4.6Hz,1H),6.92(d,J=1.2Hz,1H ),6.48(d,J=8.7Hz,1H),6.30(dd,J=17.0,10.3Hz,1H),6.10(dd,J=17.0,2.3Hz,1H),5.80(dd,J=6.0,4.2 Hz,1H),5.68(dd,J=10.2,2.3Hz,1H),5.11(t,J=5.7Hz,1H),4.43(s,2H),4.14(s,6H),4.01-3.91(m,2H).

[0750] Example 71: 2-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo] [1,5-a]pyridin-6-yl)pyridin-2-yl]-2,7-diazaspiro[3,5]nonane-7-nitrile

[0751]

[0752] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 534.17 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.9Hz,1H),8.54(d,J=1.1Hz,1H),8.36(d,J=2. 5Hz,1H),8.05(s,1H),7.83(dd,J=8.7,2.5Hz,1H),7.77(td,J=8.8,2.9Hz,1H),7. 69(dd,J=8.8,4.6Hz,1H),6.91(s,1H),6.44(d,J=8.7Hz,1H),5.80(t,J=5.1Hz,1H ),5.11(t,J=5.6Hz,1H),4.01-3.91(m,2H),3.22-3.17(m,4H),1.84-1.77(m,4H).

[0753] Example 72: (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-5-yl]pyridine Azo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0754]

[0755] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 481.93 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.61-8.55(m,3H),8.37(d,J=2.4Hz,1H),8.07(s,1H),7.94(d,J=8.8Hz,1H),7.77(td,J=8.8,2.9Hz,1H),7. 69(dd,J=8.8,4.6Hz,1H),6.92(d,J=1.2Hz,1H),6.61(d,J=8.8Hz,1H),5.82(t,J=5.1Hz,1H),4.23-4.17(m,8H),3.99-3.93(m,2H).

[0756] Example 73: (S)-2-((3-chloro-6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridine (Pyridin-3-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0757]

[0758] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 559.13 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.9Hz,1H),8.55(d,J=1.1Hz,1H),8.38(d,J= 2.5Hz,1H),8.05(s,1H),7.85(dd,J=8.6,2.5Hz,1H),7.77(td,J=8.8,2.9Hz,1H ),7.69(dd,J=8.7,4.6Hz,1H),6.92(s,1H),6.49(d,J=8.7Hz,1H),5.81(t,J=5. 0Hz,1H),5.11(s,1H),4.14(s,4H),4.09(s,4H),4.00-3.91(m,2H),3.01(s,3H).

[0759] Example 74: (S)-5-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a] pyridin-6-yl)-2-(4-(methylsulfonyl) Acyl)piperazine-1-yl)nicotinamide

[0760]

[0761] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 572.12 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.82(d,J=2.5Hz,1H),8.79(d,J=1.1Hz,1H),8.59(d,J=2 .8Hz,1H),8.57(d,J=2.6Hz,1H),8.11(s,1H),7.81-7.70(m,2H),7.13(d,J=1.3Hz ,1H),5.94(dd,J=6.0,3.8Hz,1H),5.10(t,J=5.7Hz,1H),4.05-4.01(m,1H),3.93( dt,J=11.8,5.9Hz,1H),3.77(t,J=4.9Hz,4H),3.30(t,J=4.9Hz,4H),2.94(s,3H).

[0762] Example 75: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyridine (Pyridine-6-yl)-5-methyl-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxynitrile

[0763]

[0764] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 521.15 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.60(d,J=2.9Hz,1H),8.44-8.38(m,2H),8.15(s,1H),7.77(td,J=8.8,3.0Hz,1H),7.65(dd,J=8.8,4.5Hz,1 H), 6.74 (d, J = 1.0Hz, 1H), 5.61 (t, J = 5.1Hz, 1H), 5.13 (t, J = 5.6Hz, 1H), 4.41-4.35 (m, 8H), 3.93 (td, J = 5.2, 2.4Hz, 2H), 1.98 (s, 3H).

[0765] Example 76: 2-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo] [1,5-a]pyridin-6-yl)pyridin-2-yl]-2-azaspiro[3.3]heptane-6-nitrile

[0766]

[0767] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 505.15 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ_8.60(d,J=2.9Hz,1H),8.54(d,J=1.1Hz,1H),8.36(d ,J=2.5Hz,1H),8.05(s,1H),7.82(dd,J=8.7,2.5Hz,1H),7.77(td,J=8.8,2.9 Hz,1H),7.69(dd,J=8.8,4.6Hz,1H),6.91(s,1H),6.44(d,J=8.7Hz,1H),5.80 (t,J=5.1Hz,1H),5.10(t,J=5.6Hz,1H),4.02-3.90(m,6H),2.68-2.52(m,5H).

[0768] Example 77: (S)-2-((3-chloro-6-(6-(7-(methanesulfonyl)-2,7-diazaspiro[3.5]non-2-yl) Pyridin-3-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0769]

[0770] Refer to the experimental procedure in Example 51. LC / MS (ESI) M / Z: 587.16 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.9Hz,1H),8.54(d,J=1.1Hz,1H),8.37(d,J=2.5Hz,1H),8. 05(s,1H),7.83(dd,J=8.7,2.5Hz,1H),7.77(td,J=8.7,2.9Hz,1H),7.69(dd,J=8.7,4.6Hz,1H ),6.92(d,J=1.2Hz,1H),6.45(d,J=8.7Hz,1H),5.81(dd,J=6.0,4.2Hz,1H),5.11(t,J=5.7Hz, 1H),4.02-3.91(m,2H),3.74(s,4H),3.13(t,J=5.5Hz,4H),2.87(s,3H),1.85(t,J=5.6Hz,4H).

[0771] Example 81: (R)-4-(4-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile

[0772]

[0773] Operating steps:

[0774] Step 1: 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0775] 3-Iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-1H-indazole-5-ol (5 g, 14.528 mmol) was dissolved in dichloromethane (50 mL), and imidazole (2.97 g, 43.585 mmol) and TBSCl (2.63 g, 17.434 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 50 mL of water and extracted three times with 50 mL of dichloromethane. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a yellow solid 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.3 g, 12.369 mmol, 85.13%). LC / MS (ESI) M / Z: 459.1 [M+H] + .

[0776] Step 2: 5-[(tert-butyldimethylsilyl)oxy]-1-(tetrahydro-2H-pyran-2-yl)-3-(trimethyltin) 1H-indazole

[0777] 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2 g, 4.367 mmol) was dissolved in dioxane (3 mL), and hexamethyldistin (4.29 g, 13.100 mmol) and tetraphenylphosphine palladium (0.50 g, 0.437 mmol) were added. Under nitrogen protection, the reaction solution was heated to 115 °C and reacted for 8 hours. The reaction solution was quenched with 50 mL of 1 M KF aqueous solution and extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. A yellow solid crude 5-[(tert-butyldimethylsilyl)oxy]-1-(tetrahydro-2H-pyran-2-yl)-3-(trimethylstanyl)-1H-indazole (3 g, 6.048 mmol, 138.51%) was obtained. LC / MS(ESI)M / Z:497.1[M+H] + .

[0778] Step 3: 4-(4-(5-((tert-butyldimethylsilyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0779] 5-[(tert-butyldimethylsilyl)oxy]-1-(tetrahydro-2H-pyran-2-yl)-3-(trimethyltinyl)-1H-indazole (1436.68 mg, 1.738 mmol) was dissolved in toluene (20 mL), and 4-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (600 mg, 1.738 mmol) and Pd(dtbpf)Cl2 (113.14 mg, 0.174 mmol) were added. The reaction solution was heated to 125 °C and reacted for 8 hours. Directly evaporated to dryness, the crude product was passed through a silica gel column (PE / (EA:EtOH=3:1)=3:1) to give a yellow solid tert-butyl 4-(4-(5-((tert-butyldimethylsilyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylate (650 mg, 1.091 mmol, 62.75%). LC / MS (ESI) M / Z: 597.3 [M+H] + .

[0780] Step 4: 4-(4-(5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2, 3-Triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0781] 300 mg (0.503 mmol) of tert-butyl piperidine-1-carboxylate (4-(4-(5-((tert-butyldimethylsilyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate was dissolved in 10 mL of THF, and 1.007 mL (1.007 mmol) of 1 M TBAF in tetrahydrofuran was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with 30 mL of water and extracted three times with 30 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was obtained. The crude product was subjected to silica gel column chromatography (PE / EA = 1:1) to give a yellow oily substance 4-(4-(5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (230 mg, 0.477 mmol, 94.68%).

[0782] LC / MS(ESI)M / Z:482.3[M+H] + .

[0783] Step 5: (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate

[0784] (S)-1-(3,5-dichloropyridin-4-yl)ethanol (300 mg, 1.562 mmol) was dissolved in dichloromethane (10 mL), and DIEA (201.91 mg, 1.562 mmol) was added. The reaction solution was cooled to 0 °C, and MsCl (178.93 mg, 1.562 mmol) was added dropwise. The reaction solution was reacted at 0 °C for 1 hour. The reaction solution was diluted with 30 mL of water and extracted three times with 30 mL of dichloromethane. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. A yellow oily crude product (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (500 mg, 1.859 mmol, 118.98%) was obtained.

[0785] LC / MS (ESI) M / Z: 270.1 [M+H] + .

[0786] Step 6: 4-(4-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-) 1H-indazole-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0787] 4-(4-(5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.372 mmol) was dissolved in DMF (3 mL), and (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (358.80 mg, 0.743 mmol) and cesium carbonate (363.37 mg, 1.115 mmol) were added. The reaction mixture was heated to 100 °C and reacted for 5 hours. The reaction mixture was diluted with 20 mL of water and extracted three times with 20 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. A crude yellow oil was obtained. The crude product was subjected to silica gel column chromatography (PE / EA = 1:1) to give a yellow oil, tert-butyl 4-(4-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid (130 mg, 0.198 mmol, 53.26%). LC / MS (ESI) M / Z: 656.2 [M+H] + .

[0788] Step 7: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-methyl-1-(piperidin-4-yl)-1H- 1,2,3-Triazol-4-yl)-1H-Indazole

[0789] 4-(4-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (130 mg, 0.198 mmol) was dissolved in DCM (2 mL), and a 4M HCl solution of dioxane (1 mL, 4.000 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was directly evaporated to dryness to give (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (150 mg, 0.318 mmol, 109.74%). LC / MS (ESI) M / Z: 472.1 [M+H] + .

[0790] Step 8: (R)-4-(4-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-5-methyl- 1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile

[0791] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (150 mg, 0.318 mmol) was dissolved in DMF (2 mL), and DIEA (205.21 mg, 1.588 mmol) and cyanogen bromide (33.63 mg, 0.318 mmol) were added. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction solution was directly filtered and passed through a C18 reversed-phase column (0.1% aqueous FA / ACN) to give a white solid (R)-4-(4-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (24.32 mg, 0.049 mmol, 15.40%). LC / MS (ESI) M / Z: 497.1 [M+H] + .

[0792] 1 H NMR (400MHz, DMSO-d6) δ13.06(s,1H),8.57(s,2H),7.67(d,J=2.3Hz,1H),7.47(d,J=9.0Hz,1H),7.11(dd,J=9.0,2.4Hz,1H),6.06 (q,J=6.6Hz,1H),4.68-4.54(m,1H),3.61-3.58(m,2H),3.31-3.24(m,2H),2.62(s,3H),2.29-2.05(m,4H),1.76(d,J=6.6Hz,3H).

[0793] Example 82: (S)-4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile

[0794]

[0795] Operating steps:

[0796] Step 1: (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl methanesulfonate

[0797] (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethanol (200 mg, 0.737 mmol) was dissolved in dichloromethane (5 mL), and DIEA (285.73 mg, 2.211 mmol) was added. The reaction solution was cooled to 0 °C, and MsCl (0.063 mL, 0.811 mmol) was added dropwise. The reaction solution was then brought to room temperature and reacted for 1 hour. The reaction solution was diluted with 10 mL of water and extracted three times with 10 mL of dichloromethane. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. A yellow oily crude product (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl methanesulfonate (235 mg, 0.673 mmol, 91.38%) was obtained. LC / MS (ESI) M / Z: 350.1 [M+H] + .

[0798] Step 2: 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester

[0799] (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl methanesulfonate (235 mg, 0.673 mmol) was dissolved in DMF (2 mL), and 4-(4-(5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.207 mmol) and cesium carbonate (202.55 mg, 0.622 mmol) were added. The reaction mixture was heated to 100 °C and reacted for 2 hours. The reaction mixture was diluted with 20 mL of water and extracted three times with 20 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. A crude yellow oil was obtained. The crude product was subjected to silica gel column chromatography (PE / EA = 1:1) to obtain a yellow oily substance, 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (90 mg, 0.122 mmol, 59.06%), LC / MS (ESI) M / Z: 736.4 [M+H]. + .

[0800] Step 3: 5-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0801] 70 mg (0.095 mmol) of 4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (5 mL), and zinc bromide (107.09 mg (0.476 mmol) was added. The reaction mixture was allowed to react at room temperature for 24 hours. The reaction solution was directly evaporated to dryness to give a yellow solid 5-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (130 mg, 0.204 mmol, 214.96%). LC / MS (ESI) M / Z: 636.3 [M+H] + .

[0802] Step 4: 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile

[0803] 5-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (130 mg, 0.204 mmol) was dissolved in DMF (4 mL), and DIEA (79.38 mg, 0.614 mmol) and cyanogen bromide (32.53 mg, 0.307 mmol) were added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted three times with 20 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. A yellow oily crude product, 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (94 mg, 0.142 mmol), was obtained. LC / MS (ESI) M / Z: 661.3 [M+H] + .

[0804] Step 5: (S)-4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile

[0805] 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile (94 mg, 0.142 mmol) was dissolved in dichloromethane (2 mL) and methanol (0.3 mL), and a 4M HCl solution of dioxane (2 mL, 8.000 mmol) was added. The reaction was carried out at room temperature for 18 hours. The reaction solution was evaporated to dryness and then passed through a reverse-phase column (C18) in a (1 / 1000 ammonium bicarbonate aqueous solution: acetonitrile) system to give a white solid (S)-4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (9.09 mg, 0.020 mmol, 13.80%). LC / MS (ESI) M / Z: 463.2 [M+H] + .

[0806] 1H NMR (400MHz, DMSO-d6) δ13.04 (s, 1H), 8.57 (d, J = 2.8Hz, 1H), 7.72-7.64 (m, 2H), 7.52(dd,J=8.8,4.5Hz,1H),7.46(d,J=9.0Hz,1H),7.16(dd,J=9.0,2.3Hz,1H), 5.40-5.29(m,1H),5.14(t,J=6.0Hz,1H),4.68-4.55(m,1H),3.83-3.82(m,2H), 3.59(d,J=12.9Hz,2H),3.29(d,J=10.1Hz,2H),2.63(s,3H),2.25-2.03(m,4H).

[0807] Example 84: 4-(4-(3-chloro-4-((1-(4-fluorophenyl)but-2-yn-1-yl)oxy)pyrazolo[1,5-a]pyrazol (Pyridine-6-yl)-5-

[0808] Methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile

[0809]

[0810] Step 1: 1-(4-fluorophenyl)but-2-yn-1-ol

[0811] 4-Fluorobenzaldehyde (2 g, 16.129 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction temperature was lowered to 0 °C, and a tetrahydrofuran solution of magnesium 1-propyne bromide (35 mL, 17.742 mmol, 0.5 M) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL * 3), and the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was obtained. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give 1-(4-fluorophenyl)but-2-yn-1-ol (2.4 g, 14.634 mmol, yield: 90.90%). LC / MS (ESI) M / Z: 165.1 [M+H] + .

[0812] Step 2: 1-(4-fluorophenyl)but-2-yn-1-ylmethanesulfonate

[0813] 1-(4-fluorophenyl)but-2-yn-1-ol (400 mg, 2.436 mmol) was dissolved in DCM (8 mL), and DIEA (314.90 mg, 2.436 mmol) was added. The reaction solution was cooled to 0 °C, and MsCl (279.06 mg, 2.436 mmol) was added dropwise. The reaction solution was reacted at 0 °C for 1 hour. The reaction solution was diluted with 50 mL of water, and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. A yellow oily crude product, 1-(4-fluorophenyl)but-2-yn-1-yl methanesulfonate (496 mg, 2.050 mmol, 84.12%), was obtained. It was not purified and proceeded directly to the next step. LC / MS (ESI) M / Z: 243.0 [M+H] +

[0814] Step 3: 1-tert-butyl-4-(4-(4-((1-(4-fluorophenyl)but-2-yn-1-yl)oxy)pyrazolo[1,5-a] Pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid ester

[0815] 2-Methyl-2-propanolyl 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylate (500 mg, 1.255 mmol) was dissolved in DMF (10 mL), ...

Claims

1. A compound or its pharmaceutically acceptable salt or stereoisomer, characterized in that, The compound is selected from the group consisting of: , , , , and .

2. The compound of claim 1, or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein The compound is selected from the group consisting of: , , , and .

3. The compound of claim 1, or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein The compound is selected from the group consisting of: , and .

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein For Or .

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

6. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, or a stereoisomer thereof, or a pharmaceutical composition according to claim 5, for the manufacture of a FGFR3 inhibitor.

7. Use of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition of claim 5, in the manufacture of a medicament for the treatment or prevention of a cancer associated with FGFR3; wherein, The cancer is selected from the group consisting of: bladder cancer, and renal pelvis cancer.

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