Novel FGFR3 inhibitor compounds

Abstract

The present invention relates to FGFR3 inhibitor compounds of novel structure or pharmaceutically acceptable salts, isotope variants, tautomers, stereoisomers or prodrugs thereof, and their use as medicine. The compounds are useful in the treatment of cancers such as urothelial carcinoma, systemic sclerosis, fibrosis, pulmonary fibrosis, cartilage insufficiency, lethal insufficiency, severe cartilage insufficiency accompanied by developmental retardation and atrachis ossicular, or muenke syndrome. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and specifically relates to novel FGFR3 inhibitor compounds. The present invention provides novel structural FGFR3 inhibitor compounds or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, or prodrugs thereof, as well as their use as pharmaceuticals. These compounds can be used to treat cancers such as urothelial carcinoma, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatogenic dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, or Muenke syndrome. Background Art

[0002] Fibroblast Growth Factor (FGF) plays a key role in a variety of physiological processes, including but not limited to cell proliferation, differentiation, migration, survival, and tissue repair. FGF family members regulate cell behavior by interacting with specific receptors, thereby affecting the development of organisms and maintaining tissue homeostasis. The Fibroblast Growth Factor Receptors (FGFRs) family consists of five members, four of which, namely FGFR1, FGFR2, FGFR3, and FGFR4, are complex transmembrane glycoproteins with high structural homology. Each FGFR is composed of 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 recruits and activates specific downstream signaling molecules, thereby regulating various important biological processes such as cell growth, metabolism, and survival. Activation of the FGF / FGFR signaling pathway is closely linked to changes in tumor cell biological behaviors such as proliferation, migration, invasion, and angiogenesis.

[0004] Given the role of the FGF / FGFR signaling pathway in various biological processes, especially its crucial role in tumorigenesis, the study and regulation of the FGF / FGFR signaling pathway has become a hot area in biomedical research. The development of compounds or drugs that can specifically regulate the FGF / FGFR signaling pathway has important clinical significance and application prospects for the treatment of related diseases, especially tumors. Summary of the Invention

[0005] The present invention aims to provide a novel FGFR3 inhibitor that specifically inhibits FGFR3 activity and modulates the FGF / FGFR signaling pathway, offering a novel strategy and approach for the treatment of FGFR3-related diseases. The FGFR3 inhibitor of this invention exhibits high specificity, good bioavailability and pharmacokinetic properties, and minimal side effects, and holds great promise for clinical application.

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

[0007]

[0008] wherein 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 herein.

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

[0010]

[0011] wherein 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 present invention, a pharmaceutical composition is provided, comprising a compound of the present invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof, and a pharmaceutically acceptable excipient.

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

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

[0015] In a fifth aspect of the present invention, a compound of the present invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof is provided for use in treating or preventing a disease (such as cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or a combination thereof).

[0016] The present invention is described below with reference to specific embodiments and examples, but the scope of the present invention should not be limited thereto. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The tumor growth curve (left panel) and body weight change trend (right panel) of the mouse RT112 model in Example D are shown. Specific implementation plan

[0018] definition

[0019] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0020] As used in this application (including the claims), the singular forms of the terms "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0021] Unless otherwise indicated, the direction of attachment of groups or fragments in the present invention is read from left to right. For example,

[0022] The left end of the fragment is connected to R1, and the right end is connected to other groups or fragments are interpreted in a similar manner.

[0023] Unless otherwise indicated, bonds marked with wavy lines or dashed lines in the structures herein represent the point of attachment to the rest of the molecule.

[0024] The term "alkyl" includes a group selected from the group consisting of 1 to 18 carbon atoms. 1-18 Alkyl (such as 1 to 12 C1-12 Alkyl, further such as 1 to 10 C 1-10 Alkyl, further such as 1 to 8 C 1-8 Alkyl, or 1 to 6 C 1-6 Alkyl, or 1 to 4 C 1-4 Alkyl) carbon atoms in the straight chain and branched saturated hydrocarbon group of substituted or unsubstituted hydrocarbon groups. Alkyl containing 1 to 6 carbon atoms (i.e. C 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.

[0025] The term "alkenyl" includes groups selected from the group consisting of at least one C=C double bond and 2 to 18 C=C 2-18 Alkenyl (e.g. 2 to 8 C 2-8 Alkenyl, further such as 2 to 6 C 2-6 Alkenyl, further such as 2 to 4 C 2-4 The term "alkenyl" refers to a substituted or unsubstituted straight-chain or branched hydrocarbon group containing 1 to 2 carbon atoms (e.g., 1 to 4 carbon atoms). 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 the like.

[0026] The term "alkynyl" includes radicals selected from the group consisting of radicals containing at least one C≡C triple bond and 2 to 18 C 2-18 Alkynyl (e.g. 2 to 8 C 2-8 Alkynyl, further such as 2 to 6 C 2-6 Alkynyl, further such as 2 to 4 C 2-4 Alkynyl) carbon atoms of straight chain and branched hydrocarbon groups substituted or unsubstituted hydrocarbon groups. 2-6Examples 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), pentynyl (C5 alkynyl), hexynyl (C6 alkynyl), and the like.

[0027] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0028] The term "halogen-substituted" or "halo" refers to substitution by F, Cl, Br or I, including but not limited to substitution by 1 to 10 substituents selected from F, Cl, Br or I, substitution by 1 to 6 substituents selected from F, Cl, Br or I, and substitution by 1 to 4 substituents selected from F, Cl, Br or I.

[0029] The term "haloalkyl" refers to an alkyl group as described above that is substituted with one or more halogen groups. In some embodiments, "haloalkyl" is C 1-2 Halogenated alkyl, C 1-4 Haloalkyl or C 1-6 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.

[0030] The term "alkoxy" refers to substituted or unsubstituted-O-alkyl, and alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy. Similarly, the term "alkylthio" refers to substituted or unsubstituted-S-alkyl, and alkyl is as defined above. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, cyclopropylthio etc.

[0031] The term "amino" refers to -NH2.

[0032] The terms "alkylamino" and "dialkylamino" refer to amino groups substituted with one or two alkyl groups, ie, -NH(alkyl) and -N(alkyl)2, respectively, wherein alkyl is as defined above.

[0033] The term "cycloalkyl" or "cycloalkane" is used interchangeably to refer to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, i.e., C 3-12 Cycloalkyl. Cycloalkyl includes monocyclic C 3-8 , such as monocyclic C 3-6Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.; cycloalkyl also includes bicyclic cycloalkyl, such as bicyclic C 6-11 Cycloalkyl, for example, 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 as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.

[0034] The terms "heterocyclyl" 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, including monocyclic, fused, bridged and spirocyclic groups, i.e., containing monocyclic heterocyclic groups, bridged heterocyclic groups, spiro heterocyclic groups and fused heterocyclic groups. Monocyclic heterocyclic groups include 3 to 8 membered heterocyclic groups, which contain 1, 2 or 3 heteroatoms selected from oxygen, nitrogen or sulfur, such as aziridine, oxetane, thiirane, azetidinyl, oxetane, thietanyl, cyclobutanone, pyranyl, thiopyranyl, morpholinyl or azepine. Bridged heterocyclic groups include 7-14 membered bridged heterocyclic groups, which are ring systems containing 7-14 atoms in total, including at least one heteroatom selected from nitrogen, oxygen or sulfur, formed by two non-adjacent rings sharing two or more atoms. Spiro heterocyclic groups include 5-14 membered spiro heterocyclic groups, which are carbon atom-containing cyclic structures formed by at least two rings sharing one carbon atom. 5-14Heterocyclyl rings include, but are not limited to, azaspiro[2.2]pentyl, azaspiro[2.3]hexyl, azaspiro[2.4]heptyl, azaspiro[3.3]heptyl, azaspiro[2.5]octyl, azaspiro[3.4]octyl, azaspiro[2.6]nonyl, azaspiro[3.5]nonyl, azaspiro[4.4]nonyl, azaspiro[2.7]decyl, azaspiro[3.6]decyl, azaspiro[4.5]decyl, azaspiro[3.7]undecyl, azaspiro[ 4.6]undecyl, azaspiro[5.5]undecyl, azaspiro[4.7]dodecyl, azaspiro[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[3.5] 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, azaoxaspiro[2.2]pentyl, azaoxaspiro[2.3]hexyl, azaoxaspiro[2.4]heptyl, azaoxaspiro[3.3]heptyl, azaoxaspiro[2. [5.5] octyl, azaoxaspiro [3.4] octyl, azaoxaspiro [2.6] nonyl, azaoxaspiro [3.5] nonyl, azaoxaspiro [4.4] nonyl, azaoxaspiro [2.7] decyl, azaoxaspiro [3.6] decyl, azaoxaspiro [4.5] decyl, azaoxaspiro [3.7] undecyl, azaoxaspiro [4.6] undecyl, azaoxaspiro [5.5] undecyl, azaoxaspiro [4.7] dodecyl or azaoxaspiro [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.

[0035] 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. Aryl includes phenyl and naphthyl. In some embodiments, aryl is phenyl.

[0036] 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, n is 0, 1, or 2). In some embodiments, heteroaryl refers to a 5-14-membered, for example, 5-10-membered, monocyclic or bicyclic ring containing ring carbon atoms and 1-4 ring heteroatoms. Examples of 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Examples of 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Examples of 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl. Examples of 6-membered heteroaryls 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 tetrazinyl. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepatrienyl, and thieptatrienyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the point of attachment is on the heteroaryl ring.

[0037] Unless otherwise specifically defined, in the compounds of the general formulae of the present application (such as Formula A, Formula I, Formula IA, Formula IB, Formula II), each group (such as alkyl, alkylene, alkenyl, alkynyl, cycloalkane or cycloalkyl, heterocycle, aryl or heteroaryl) includes unsubstituted or substituted forms. When substituted, one or more (such as 1, 2 or 3) hydrogen atoms in the group are replaced by substituents as defined herein. Unless otherwise defined, the substituents of alkyl (including those groups commonly referred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be various groups selected from the group consisting of halogen, -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 numbers ranging from zero to (2M+1), where M is the total number of carbon atoms in the group. a 、R b and R c Each independently represents hydrogen, unsubstituted C1-8 alkyl, unsubstituted aryl, aryl substituted by 1-3 halogens, C1-8 alkoxy or C1-8 thioalkoxy or unsubstituted -C1-4 alkylene-aryl. a and R b When attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR a R b is meant to include 1-pyrrolidinyl and 4-morpholinyl. Similarly, unless otherwise defined, substituents for aryl and heteroaryl groups are various and are typically selected from: halogen, -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, the number of which ranges from zero to the total number of open valences on the aromatic ring system; wherein R a 、R b and Rc are 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.

[0038] When a numerical range is listed, the intended range includes each value and sub-range within the stated 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.

[0039] For the compounds provided 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 to mean a bond providing attachment at any available vertex of the aromatic ring. In some embodiments, this description also includes attachment to a ring fused to an aromatic ring. For example, a bond drawn to the center of an indole benzene moiety will represent a bond attached to any available vertex of a six-membered or five-membered ring moiety of indole.

[0040] "Pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0041] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. In contrast, if the product is a free base, an addition salt (e.g., a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize that various synthetic methodologies can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0042] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females 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, e.g., 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 herein.

[0043] "Disease," "disorder," and "condition" are used interchangeably in this application.

[0044] The terms "treat," ...

[0045] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0046] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present 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 enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0047] The compounds of the present invention may also exist as tautomers. A compound that exists in different tautomeric forms is not limited to any specific tautomer, but is intended to encompass all tautomeric forms.

[0048] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I) or (II) but for which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually 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, 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. Compounds of the present invention, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of the present invention, such as compounds of formula (A), and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when performing the processes disclosed in the following schemes and / or the Examples and Preparations.

[0049] The term "prodrug" refers to a compound that is converted to an active drug by metabolism after administration. Examples of prodrugs include, but are not limited to, esters (e.g., phosphates, phosphonates, acetates, formates, and benzoates), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), and the like.

[0050] The term "deuterium (D or 2H)" is a stable isotope of hydrogen that occurs at a natural abundance of 0.015 mol %. The term "deuterated" refers to a group or compound in which one or more hydrogen atoms H are replaced by D.

[0051] Isotopic variants of the present 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, for example, "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated aryl," etc. For example, "deuterated alkyl" refers to an alkyl group as defined herein in which 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; a single carbon atom may be bonded to multiple deuterium atoms; and multiple carbon atoms in an alkyl group may be bonded to deuterium atoms. For example, deuterated methyl includes methyl-D3, in which three hydrogen atoms are replaced by deuterium; monodeuterated methyl and dideuterated methyl are also included. For example, deuterated piperazinyl means that one or more hydrogen atoms on the piperazinyl group are replaced by deuterium, including all 8 hydrogen atoms replaced by deuterium. In some embodiments, the compounds of the present invention include deuterated compounds.

[0052] Compounds of the present invention

[0053] As used herein, the term "compound of the present invention" refers to a compound of Formula (A), (I), (IA), (IB), or (II) as described herein. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of a compound of Formula (A), (I), (IA), (IB), or (II).

[0054] The term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention with an acid. Suitable acids 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 salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0055] The term "solvate" refers to a complex formed by the coordination of a compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0056] In addition, the compounds of the present invention also include prodrugs of compounds represented by formula (A), (I), (IA), (IB), or (II). The term "prodrug" includes a class of compounds that may be biologically active or inactive, and when administered by appropriate methods, undergo metabolism or chemical reactions in the human body to convert into a compound represented by formula (A), (I), (IA), (IB), or (II), or a salt or solution composed of a compound represented by formula (A), (I), (IA), (IB), or (II). The prodrugs include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino, carbamate, azo, phosphoramide, glucoside, ether, acetal, and the like forms of the compounds.

[0057] In the first aspect of the present invention, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof; wherein the compound is represented by formula (A);

[0058]

[0059] in

[0060] R1 is selected from the group consisting of none, H, cyano, -alkylene-cyano (such as -methylene-cyano), R 11 -SO2- and -alkylene-SO2-R 11 , where R 11 is hydrogen, alkyl, heterocyclyl, aryl or heteroaryl;

[0061] in is a 4- to 10-membered heterocyclic ring or C 4-10 Cycloalkanes, among which

[0062] X1 is a carbon atom (CH) or a nitrogen atom (N),

[0063] X2 is selected from the group consisting of carbon atom (CH), nitrogen atom (N), oxygen atom (O), S, SO and SO2,

[0064] m is 0, 1, 2, 3, or 4; and

[0065] R2 is each independently selected from the group consisting of hydrogen, hydroxy, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or two R2 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 (the 3-membered, 4-membered, 5-membered and 6-membered rings refer to the number of ring atoms in the ring formed by two R2 on the same carbon atom and the carbon atom to which they are attached), or two R2 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 (or fused ring) (the 3-membered, 4-membered, 5-membered and 6-membered rings refer to the number of ring atoms in the ring formed by two R2 on adjacent carbon atoms and the carbon atom to which they are attached);

[0066] and when X2 is an oxygen atom (O), S, SO or SO2, R1 is absent;

[0067] Z1, Z2 and Z3 are each independently a carbon atom or a nitrogen atom;

[0068] Z4 is absent or is a carbon atom or a nitrogen atom, provided that when Z4 is absent, Z1 is directly connected to the carbon atom to which R3 is attached,

[0069] The prerequisite is in It is aromatic and Also optionally one or more (preferably one) R 31 replace;

[0070] R3 is hydrogen, cycloalkyl, alkyl, deuterated alkyl or deuterated cycloalkyl;

[0071] R 31 Selected from the group consisting of cyano, halogen, cycloalkyl, alkyl, deuterated alkyl or deuterated cycloalkyl (preferably, R 31 is cyano or halogen);

[0072] for The asterisk * indicates The asterisk ** indicates the site of attachment to Y, and

[0073] R4 and R5 are each independently selected from the group consisting of hydrogen, halogen (e.g., F, Cl, Br), CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkenyl, alkynyl (e.g., ethynyl), cycloalkyl, aryl, heterocyclyl, 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 (such as -methylene-R 4b ), -alkenylene-R 4b (such as vinylidene-R 4b ) or -alkynylene-R 4b (such as vinylidene-R 4b ), where R 4a and R 4b Each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the optional substitution refers to the replacement of hydrogen on the group by one or more (e.g., 1, 2 or 3) R 4c replaced by; among them, R 4c Select the following group: halogen, cyano, alkyl, hydroxy, -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, -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, halogen (e.g., F, Cl, Br), CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, 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 (such as -methylene-R 4b ), -alkenylene-R 4b (such as vinylidene-R 4b ) or -alkynylene-R 4b (such as -ethynylene-R 4b ), where R 4a and R 4bare each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl,

[0074] p1 and p2 are each independently 0, 1, 2 or 3, provided that the chemical valence bond theory is satisfied;

[0075] Y is -O-, -S- or -NR8-, wherein R8 is hydrogen or alkyl;

[0076] R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein the alkyl is unsubstituted or further substituted with hydroxy, halogen, alkoxy, alkenyl, alkynyl, phosphinoylalkoxy, aryl, heteroaryl, heterocyclyl, or cycloalkyl, and the alkenyl and alkynyl are unsubstituted or further substituted with alkyl or cycloalkyl; and the aryl, heteroaryl, heterocyclyl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of alkyl (e.g., methyl), oxo (=O), aryl, heteroaryl, heterocyclyl, or cycloalkyl;

[0077] does not exist or is a six-membered heteroaryl, phenyl, cycloalkyl or heterocyclyl, q is 0, 1, 2, 3 or 4, and R7 is halogen, alkyl, hydroxyalkyl or haloalkyl.

[0078] In some embodiments, R1 is cyano or R 11 -SO2-, where R 11 is hydrogen, alkyl, heterocyclyl, aryl or heteroaryl.

[0079] In some embodiments, R1 is cyano.

[0080] In some embodiments, X1 and X2 are separated by at least one ring atom; preferably, X1 and X2 are separated by 1, 2 or 3 ring atoms.

[0081] In some embodiments, In the above, the heterocycle or cycloalkane may be a monocyclic or spirocyclic ring.

[0082] In some embodiments, When it is a 4- to 10-membered heterocyclic ring, only X1 and X2 of the heterocyclic ring may be heteroatoms.

[0083] In some embodiments, when X2 is a nitrogen atom, is a nitrogen-containing 5-membered 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), is a 4-, 5- or 6-membered heterocyclic ring or C 4-6 Cycloalkanes (such as cyclohexane) or spirocycles (such as C 7-9In some embodiments, X2 is an oxygen atom (O), S, SO or SO2, is a 4-, 5- or 6-membered heterocyclic ring or a spirocyclic ring (e.g., a 7- to 9-membered spirocyclic ring).

[0084] In some embodiments, Select from the following groups:

[0085]

[0086] 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.

[0087] In some embodiments, X2 is selected from the group consisting of a carbon atom, a nitrogen atom, and an oxygen atom. In some embodiments, R1 is a cyano group or an -alkylene-cyano group (such as a -methylene-cyano group), and Select from the following groups:

[0088] In some embodiments, R6 is hydrogen or alkyl, wherein the alkyl is unsubstituted or further substituted with hydroxy, halogen, alkoxy, phosphonooxyalkoxy, aryl, heteroaryl, or cycloalkyl.

[0089] In some embodiments, the carbon at which R6 is located is a chiral carbon.

[0090] In some embodiments, the carbon where R6 is located is a chiral carbon with S configuration or R configuration; preferably, it is a chiral carbon with S configuration.

[0091] In some embodiments, In the embodiment, ring A is a six-membered heteroaryl, cycloalkyl or heterocyclyl group, wherein q is 0, 1, 2, 3 or 4, and R7 is halogen, alkyl, hydroxyalkyl or haloalkyl.

[0092] In some embodiments,

[0093] Z1, Z2, Z3, Z4, R3, R4, p1, Y, R6, R7 and q are as defined above;

[0094] is a 4- to 10-membered heterocyclic ring or C 4-10 Cycloalkanes, among which

[0095] X1 is a carbon atom (CH) or a nitrogen atom (N),

[0096] X2 is selected from the group consisting of a carbon atom (CH), a nitrogen atom (N),

[0097] m is 0, 1, 2, 3, or 4; and

[0098] R2 is selected from the group consisting of hydrogen, hydroxy, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or two R2 substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered spirocyclic ring, or two R2 substituted on adjacent carbon atoms together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered fused ring;

[0099] R1 is cyano;

[0100] for

[0101] (Preferably, ),in

[0102] Asterisk * indicates The asterisk ** indicates the site of attachment to Y, and

[0103] R4 is selected from the group consisting of hydrogen, halogen (e.g., F, Cl, Br), CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, 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 (such as -methylene-R 4b ), -alkenylene-R 4b (such as vinylidene-R 4b ) or -alkynylene-R 4b (such as -ethynylene-R 4b ), where R 4a and R 4b Each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl; p1 is 0, 1 or 2, provided that the chemical valence theory is satisfied;

[0104] R5 is an alkynyl group (such as ethynyl) or an alkynylene group-R 4b (such as -ethynylene-R 4b ), where R 4b is selected from the group consisting of hydrogen, cyano, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl, and p2 is 1.

[0105] In some embodiments, R4 is selected from the group consisting of: -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 (such as -methylene-R 4b ), -alkenylene-R 4b (such as vinylidene-R 4b ) or -alkynylene-R 4b (such as -ethynylene-R 4b ), where R 4a and R 4b Each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl; p1 is 0, 1 or 2, provided that the chemical valence theory is satisfied.

[0106] In some embodiments, R5 is -ethynylene-R 4b ; Optionally, R 4b is selected from the group consisting of cyano, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the optional substitution refers to the replacement of hydrogen on the group by one or more R 4c substituted; wherein, optionally R 4c Select the following group: halogen, cyano, alkyl, hydroxy, -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, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino).

[0107] In some embodiments, R5 is -ethynylene-R 4b ; Optionally, R 4b Selected from the following group: cyano, optionally substituted alkyl, optionally substituted cycloalkyl, wherein the optional substitution means that the hydrogen on the group is replaced by one or more R 4c substituted; wherein, optionally R 4cSelect from the following group: halogen, cyano, alkyl, hydroxy, -SH, alkoxy, alkylthio.

[0108] In some embodiments, R5 is -ethynylene-R 4b ; Optionally, R 4b Selected from the group consisting of cyano, alkyl, and cycloalkyl.

[0109] In some embodiments, R5 is ethynyl.

[0110] In some embodiments, R4 is selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, -N(R 4b )R 4a , where R 4a and R 4b Each independently selected from the group consisting of hydrogen, alkyl; and / or R5 is ethynyl or -ethynylene-R 4b , where R 4b is selected from the group consisting of cyano, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the optional substitution refers to the replacement of hydrogen on the group by one or more (e.g., 1, 2 or 3) R 4c replaced by; among them, R 4c Select the following group: halogen, cyano, alkyl, hydroxy, -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, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino).

[0111] In some embodiments, for Preferably,

[0112] In some embodiments, R2 is selected from the group consisting of hydrogen, hydroxy, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R2 is selected from the group consisting of hydrogen, hydroxy, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy. In some embodiments, R2 is hydrogen.

[0113] In some embodiments, m is 0.

[0114] In some embodiments, middle is a 4- to 6-membered heterocyclic ring or C 4-6 Cycloalkanes.

[0115] In some embodiments, X1 is a carbon atom.

[0116] In some embodiments, Select from the following groups:

[0117] In some embodiments, X2 is a nitrogen atom. In some embodiments, for In some embodiments, the compound is as shown in formula (I);

[0118]

[0119] Wherein, 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 as defined in Formula (A).

[0120] In some embodiments, 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-.

[0121] In some embodiments, at least one of Z1, Z2, Z3 and Z4 is a nitrogen atom.

[0122] In some embodiments, R4 and R5 are each independently hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, -COOR 4a 、-COR 4a or -NHR 4a COR 4b , where R 4a and R 4b Each is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl, and p1 and p2 are each independently 0, 1, 2 or 3, provided that the chemical valence theory is satisfied.

[0123] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof is provided.

[0124]

[0125] in

[0126] R1 is cyano or R 11 -SO2-, where R 11 is hydrogen, alkyl, heterocyclyl, aryl or heteroaryl;

[0127] 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, m is 0, 1, 2, 3 or 4; and R2 is hydrogen, hydroxy, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or two R2 substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered spirocyclic ring, or two R2 substituted on adjacent carbon atoms together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered fused ring;

[0128] Z1 is -CH-, -C= or -N-

[0129] Z2 is -CH2-, -CH=, -N= or -NH-

[0130] Z3 is -CH2-, -CH=, -N= or -NH-

[0131] Z4 is absent or is -CH2-, -CH=, -N= or -NH-, provided that when Z4 is absent, Z1 is directly connected to the carbon atom to which R3 is attached,

[0132] The prerequisite is in It is aromatic, and at least one of Z1, Z2, Z3 and Z4 is a nitrogen atom;

[0133] R3 is hydrogen, cycloalkyl, alkyl, deuterated alkyl or deuterated cycloalkyl;

[0134] for

[0135] The asterisk * indicates The asterisk ** indicates the site of attachment to Y, and

[0136] R4 and R5 are each independently hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, -COOR 4a 、-COR 4a or -NHR 4a COR 4b , where R 4a and R 4bare each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl, and p1 and p2 are each independently 0, 1, 2 or 3, provided that the chemical valence theory is satisfied;

[0137] Y is -O-, -S- or -NR8-, wherein R8 is hydrogen or alkyl;

[0138] R6 is hydrogen or alkyl, wherein the alkyl is unsubstituted or further substituted by hydroxy, halogen, alkoxy, phosphinoylalkoxy, aryl, heteroaryl or cycloalkyl;

[0139] Ring A is a six-membered heteroaryl, cycloalkyl or heterocyclic group, wherein q is 0, 1, 2, 3 or 4, and R7 is halogen, alkyl, hydroxyalkyl or haloalkyl.

[0140] In some embodiments, X1 is a carbon atom. In some embodiments, X1 is a nitrogen atom.

[0141] In some embodiments, Select from the following groups:

[0142] 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.

[0143] In some embodiments, for Where m is 2; and R2 is substituted on the same carbon atom, and the two R2 together with the carbon atom to which they are attached form 3

[0144] 1-, 4-, 5- or 6-membered spiro ring; preferably, for

[0145] In some embodiments, for wherein m is 2; and R2 is substituted on adjacent carbon atoms. The two R2 together with the carbon atoms to which they are attached form a 3-membered, 4-membered, 5-membered or 6-membered fused ring; preferably, for

[0146] In some embodiments, for wherein R2 and m are as defined above. 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. In some embodiments, for wherein R2 and m are as defined above.

[0147] In some embodiments, Select from the following groups:

[0148]

[0149] In some embodiments, for

[0150] 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:

[0151]

[0152] In some embodiments, Z4 is a carbon atom or a nitrogen atom (ie, Z4 is -CH=, -CR 31 = or -N =).

[0153] In some embodiments, R1 is linked to Z1.

[0154] In some embodiments, for

[0155] In some embodiments, the compound is a compound of formula (IA). In some embodiments, R1 is connected to Z1, Z1 is a nitrogen atom or a carbon atom (Z1 is -N= or =C=), 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 does not exist or is a carbon atom or a nitrogen atom (ie, Z4 does not exist or is -CH=, -CR 31 = or -N=). In some embodiments, R1 is attached to Z1, 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 attached to Z1, 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 attached to Z1, 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.

[0156] In some embodiments, Z1, Z2, and Z3 are nitrogen atoms; Z4 is absent, and Z1 is directly attached to the carbon atom to which R3 is attached.

[0157] In some embodiments, Select from the following groups:

[0158] In some embodiments, for preferably for

[0159] In some embodiments, for

[0160] In some embodiments, for Preferably

[0161] In some embodiments, Select from the following groups: In some embodiments, R 31 In some embodiments, R3 is hydrogen or alkyl.

[0162] In some embodiments, R3 is H.

[0163] In some embodiments, R3 is C 3-8 In some embodiments, R3 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R3 is alkyl or deuterated alkyl, preferably C 1-6 Alkyl or C 1-6 Deuterated alkyl, more preferably C 1-4 Alkyl or C 1-4 Deuterated alkyl, such as methyl or methyl-d3. In some embodiments, R3 is

[0164] In some embodiments, for wherein 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 embodiment, Z1, Z2 and Z3 are nitrogen atoms, or Z1 and Z2 are nitrogen atoms, and Z3 is a carbon atom.

[0165] In some embodiments, R2 is linked to Z4.

[0166] In some embodiments, for

[0167] In some embodiments, R2 is connected to Z4, Z1 is a nitrogen atom (such as -N=) or a carbon atom (such as -CH=), Z2 is a carbon atom (such as -CH=) or a nitrogen atom (such as -N=), Z3 is a carbon atom (such as -CH=) or a nitrogen atom (such as -N=), and Z4 is a carbon atom (such as =CH=) or a nitrogen atom (such as -N=).

[0168] In some embodiments, Select from the following groups:

[0169] In some embodiments, for wherein Z1, Z2, Z3 and R3 are as defined in formula (I). In some embodiments, for In some embodiments, R3 is C 1-6 alkyl.

[0170] In some embodiments, for

[0171] In some embodiments, at least one of p1 and p2 is 1. In some embodiments, one of p1 and p2 is 1 and the other is 0 or 1.

[0172] In some embodiments, R4 and R5 are each independently selected from the group consisting of hydrogen, halogen (eg, F, Cl, Br), CN, alkyl, haloalkyl, hydroxy, alkynyl, cycloalkyl, -COOR 4a 、-COR 4a , nitro, -N(R 4b )R 4a (such as -NH2), -NHSO2R 4b , -alkylene-R 4b , -alkenylene-R 4b or -alkynylene-R 4b In some embodiments, R 4a and R 4b Each is independently selected from the group consisting of hydrogen, cyano, alkyl, or cycloalkyl (eg, cyclopropyl).

[0173] 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 embodiments, R 4b is hydrogen or alkyl.

[0174] In some embodiments, R4 and R5 are each independently selected from the group consisting of nitro, -N(R 4b )R 4a (such as -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 embodiments, R 4b For alkyl.

[0175] In some embodiments, R4 and R5 are each independently selected from the group consisting of: -vinylene-R 4b or -ethynylene-R 4b In some embodiments, R 4b Each is independently selected from the group consisting of hydrogen, cyano, alkyl (such as methyl), or cycloalkyl (such as cyclopropyl).

[0176] In some embodiments, R4 is selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, -N(R 4b )R 4a , where R 4a and R 4b Each is independently selected from the group consisting of hydrogen, alkyl, In some embodiments, R4 is hydrogen and / or p1 is 0. In some embodiments, p2 is 1.

[0177] In some embodiments, R5 is selected from the group consisting of hydrogen, halogen (eg, F, Cl, Br), CN, alkyl, haloalkyl, hydroxy, alkynyl, cycloalkyl, -COOR 4a 、-COR 4a , nitro, -N(R 4b )R 4a (such as -NH2), -NHSO2R 4b , -alkylene-R 4b , -alkenylene-R 4b or -alkynylene-R 4b In some embodiments, R 4a and R 4b Each is independently selected from the group consisting of hydrogen, alkyl, or cycloalkyl (eg, cyclopropyl).

[0178] In some embodiments, R5 is selected from the group consisting of hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, or -COOR 4a In some embodiments, R 4b is hydrogen or alkyl.

[0179] In some embodiments, 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 embodiments, R 4a is hydrogen or alkyl (such as C 1-4 alkyl), R 4b Selected from the group consisting of hydrogen, alkyl (such as C 1-4 Alkyl), cycloalkyl (such as C 3-6 In some embodiments, R 4a is hydrogen or alkyl (such as C 1-4 alkyl), R 4b is hydrogen or alkyl (such as C 1-4 In some embodiments,

[0180] R 4a is hydrogen, R 4b Selected from the group consisting of hydrogen, alkyl (such as C 1-4 Alkyl), cycloalkyl (such as C 3-6 cycloalkyl) and heterocyclic groups (e.g., 3- to 6-membered heterocyclic groups).

[0181] In some embodiments, R5 is alkynyl or -alkynylene-R 4b (Preferably ethynyl or -ethynylene-R 4b ); optionally wherein R 4b is selected from the group consisting of hydrogen, optionally substituted alkyl (e.g., alkyl, haloalkyl, hydroxyalkyl), optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl (preferably, R 4b is selected from the group consisting of an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted cycloalkyl group or an optionally substituted heteroaryl group, more preferably, R 4b Selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and most preferably, R 4b is selected from the following groups: alkyl, cycloalkyl); wherein, the optional substitution means that the hydrogen on the group is replaced by one or more (such as 1, 2 or 3) R 4c substituted; optionally wherein, R 4c Select the following group: halogen, cyano, alkyl, hydroxy, -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, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino) (preferably, R 4c Select from the following group: halogen, cyano, alkyl, hydroxy, -SH, alkoxy, alkylthio).

[0182] In some embodiments, R5 is selected from the group consisting of: -vinylene-R 4b or -ethynylene-R 4b In some embodiments, R 4b Each is independently selected from the group consisting of hydrogen, alkyl (such as methyl), or cycloalkyl (such as cyclopropyl).

[0183] In some embodiments, for

[0184] In some embodiments, for Wherein R5 is hydrogen, F, Cl, Br, CN, alkyl, haloalkyl or -COOR 4a , where R 4a and R 4b Each is independently hydrogen or alkyl.

[0185] In some embodiments, for Wherein, R5 is hydrogen or alkyl.

[0186] In some embodiments, for Wherein, R5 is selected from the following group: nitro, -N(R 4b )R 4a (such as -NH2), -N(R 4a )COR 4b 、-N(R 4a )SOR 4b and -NHSO2R 4b .

[0187] In some embodiments, for wherein R5 is selected from the group consisting of nitro, -NH2, and -NHSO2R 4b .

[0188] In some embodiments, R5 is hydrogen and / or p2 is 0. In some embodiments, p1 is 1.

[0189] In some embodiments, R4 is selected from the group consisting of nitro, -N(R 4b )R 4a (such as -NH2), -N(R 4a )COR 4b 、-N(R 4a )SOR 4b and -NHSO2R 4b ; Preferably, R5 is selected from the following group: nitro, -NH2.

[0190] In some embodiments, Select from the following groups: Preferably

[0191] In some embodiments, p1 is 1 and p2 is 1.

[0192] In some embodiments, R4 is selected from the group consisting of nitro, -N(R 4b )R 4a (such as -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: halogen (such as F, Cl, Br), CN, alkyl.

[0193] In some embodiments, Select from the following groups: Preferably

[0194] In some embodiments,

[0195] for (Preferably ); optionally R5 is R5 is alkynyl or -alkynylene-R 4b (ethynyl or -ethynylene-R 4b ); the asterisk ** indicates the site of attachment to Y

[0196] Alternatively, R4 is selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, -N(R 4b )R 4a , where R 4a and R 4b are each independently selected from the group consisting of hydrogen, alkyl;

[0197] Alternatively, R5 is ethynyl or -ethynylene-R 4b , where R 4bis selected from the group consisting of an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl, wherein the optionally substituted group is selected from the group consisting of an optionally substituted alkyl, an optionally substituted aryl ... 4c replaced by; among them, R 4c Select the following group: halogen, cyano, alkyl, hydroxy, -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, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino). In some embodiments, Select from the following groups:

[0198]

[0199] In some embodiments, Select from the following groups:

[0200]

[0201] wait.

[0202] In some embodiments, for (Preferably ),and for Wherein R5 is hydrogen or alkyl (preferably hydrogen).

[0203] In some embodiments, Y is O.

[0204] In some embodiments, in R6, the alkyl group is C 1-4 Alkyl, and / or the alkenyl is C 2-4 Alkenyl, and / or the alkynyl is C 2-4 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 heterocyclyl group is a 4- to 6-membered heterocyclyl group, and / or the cycloalkyl group is C 3-6 Cycloalkyl.

[0205] In some embodiments, R6 is C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or phosphonooxy C 1-4 Alkoxy-C 1-4 Alkyl (-C1-4 Alkylene-OC 1-4 In some embodiments, R6 is methyl, hydroxymethyl (-CH2OH), or phosphonooxymethoxymethyl (-CH2OCH2O-P(=O)(OH)2).

[0206] In some embodiments, R6 is alkyl (eg, C 1-4 In some embodiments, R6 is selected from the group consisting of: -methylene-C 2-4 Alkenyl, -methylene-C 2-4 Alkynyl, -ethynylene-C 1-4 Alkyl, -ethynylene-C 3-6 Cycloalkyl, -vinylene-C 1-4 Alkyl and -vinylene-C 3-6 In some embodiments, R6 is selected from the group consisting of:

[0207]

[0208] In some embodiments, R6 is alkyl (eg, C 1-4 alkyl), wherein the alkyl is further substituted by aryl, heteroaryl, heterocyclyl or cycloalkyl (preferably, further substituted by heterocyclyl, more preferably, further substituted by morpholine or piperazine), and the aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted by one or more substituents selected from the group consisting of alkyl (such as methyl), oxo (=O), aryl, heteroaryl, heterocyclyl or cycloalkyl. In some embodiments, R6 is methyl, wherein the methyl is further substituted by morpholine or piperazine, and the morpholine and piperazine are optionally substituted by one or more substituents selected from the group consisting of alkyl (such as methyl), oxo and heterocyclyl (such as oxetane). In some embodiments, R6 is selected from the group consisting of:

[0209]

[0210] In some embodiments, Ring A middle, For pyridine ring, pyrimidine ring, monocyclic C 3-8 Cycloalkyl, bicyclic C 6-11 cycloalkyl or bicyclic heterocyclyl, R7 are each independently halogen or alkyl, q is 0, 1 or 2. In some embodiments, ring A middle, is a pyridine ring, bicyclo[3.3.0]octyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.1.1]heptyl or tetrahydro-1H-pyrrolazinyl (e.g., tetrahydro-1H-pyrrolazin-7-yl) ), R7 are each independently halogen, q is 0, 1 or 2 wherein said group is unsubstituted or substituted with one or two halogens.

[0211] In some embodiments, Ring A is a pyridine ring, bicyclo[3.3.0]octyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.1.1]heptyl or tetrahydro-1H-pyrrolazinyl (e.g., tetrahydro-1H-pyrrolazin-7-yl) ), wherein the group is unsubstituted or substituted by one or two halogens.

[0212] In some embodiments, Select from the following groups:

[0213] In some embodiments, Middle, Ring A is phenyl, R7 is halogen or alkyl, and q is 0, 1 or 2.

[0214] In some embodiments, Select from the following groups:

[0215]

[0216] In some embodiments, Ring A for

[0217]

[0218] In some embodiments, the compound is represented by formula (II), wherein each variable is defined as in formula (A) or (I);

[0219]

[0220] In a second aspect of the present invention, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof

[0221]

[0222] in

[0223] R1 is cyano or R 11 -SO2-, where R 11 is hydrogen, alkyl, heterocyclyl, aryl or heteroaryl;

[0224] 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, m is 0, 1, 2, 3 or 4; and R2 is hydrogen, hydroxy, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or two R2 substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered spirocyclic ring, or two R2 substituted on adjacent carbon atoms together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered fused ring;

[0225] Z1 is -CH-, -C= or -N-

[0226] Z2 is -CH2-, -CH=, -N= or -NH-

[0227] Z3 is -CH2-, -CH=, -N= or -NH-

[0228] The prerequisite is in It is aromatic, and at least one of Z1, Z2 and Z3 is a nitrogen atom;

[0229] for The asterisk * indicates The asterisk ** indicates the site of attachment to Y, and R4 and R5 are each independently hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, -COOR 4a 、-COR 4a or -NHR 4a COR 4b , where R 4a and R 4b are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl, and p1 and p2 are each independently 0, 1, 2 or 3, provided that the chemical valence theory is satisfied;

[0230] Y is -O-, -S- or -NR8-, wherein R8 is hydrogen or alkyl;

[0231] R6 is hydrogen or alkyl, wherein the alkyl is unsubstituted or further substituted by hydroxy, halogen, alkoxy, phosphinoylalkoxy, aryl, heteroaryl or cycloalkyl;

[0232] Ring A is a six-membered heteroaryl, cycloalkyl or heterocyclic group, wherein q is 0, 1, 2, 3 or 4, and R7 is halogen, alkyl, hydroxyalkyl or haloalkyl.

[0233] 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.

[0234] In some embodiments, for wherein m is 2; and R2 is substituted on the same carbon atom, and the two R2 together with the carbon atom to which they are connected form a 3-membered, 4-membered, 5-membered or 6-membered spiro ring.

[0235] In some embodiments, for wherein m is 2; and R2 is substituted on adjacent carbon atoms. The two R2 together with the carbon atoms to which they are attached form a 3-membered, 4-membered, 5-membered or 6-membered fused ring.

[0236] In some embodiments, for wherein R2 and m are as defined above. 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. In some embodiments, for wherein R2 and m are as defined above.

[0237] In some embodiments, for

[0238] In some embodiments, for In the above embodiment, Z1, Z2 and Z3 are nitrogen atoms, or Z1 and Z2 are nitrogen atoms, and Z3 is a carbon atom.

[0239] In some embodiments, for Wherein R5 is hydrogen, F, Cl, Br, CN, alkyl, haloalkyl or -COOR 4a, where R 4a and R 4b are each independently hydrogen or alkyl;

[0240] In some embodiments, for

[0241]

[0242] In some embodiments, Y is O.

[0243] In some embodiments, R6 is C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or phosphonooxy C 1-4 Alkoxy-C 1-4 In some embodiments, R6 is methyl, hydroxymethyl, or phosphonooxymethoxymethyl.

[0244] In some embodiments, In the embodiment, ring A is a pyridine ring, a pyrimidine ring, a monocyclic C3-8 cycloalkyl ring, a bicyclic C 6-11 Cycloalkyl or bicyclic heterocyclyl, wherein R7 is halogen or alkyl, and q is 0, 1 or 2.

[0245] In some embodiments, wherein Ring A is a pyridine ring, bicyclo[3.3.0]octyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.1.1]heptyl, or tetrahydro-1H-pyrrolazinyl (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

[0246] In some embodiments, X1, X2, Y, Z1, Z2, Z3, Z4, R1, R2, R3, R4, R5, R6, R7, subscript m, subscript p1, subscript p2, Table q below, Cy1, Cy2, and as well as Each independently represents a corresponding group in a specific compound of the present application (such as the specific compounds shown in Table A and Table B).

[0247] In some embodiments, the compound is a compound selected from Table B below, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof:

[0248] Table B

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256] Pharmaceutical compositions and methods of administration

[0257] Since 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 crystalline 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, thanatogenic 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.

[0258] In the third aspect of the present invention, a pharmaceutical composition is provided, which contains the compound as described in the first or second aspect, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof and a pharmaceutically acceptable excipient.

[0259] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means 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 per dose. Preferably, "one dose" is one capsule or tablet.

[0260] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which 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 the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0261] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0262] 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 the following ingredients: (a) fillers or solubilizers, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0263] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0264] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0265] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0266] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0267] 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.

[0268] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0269] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0270] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0271] In the fourth aspect of the present invention, there is provided the use of the compound as described in the first or second aspect, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof, or the pharmaceutical composition as described in the third aspect in the preparation of a medicament for treating or preventing a disease.

[0272] In some embodiments, the disease is a FGFR3-related disease.

[0273] In some embodiments, the FGFR3-associated refers to dysregulation associated with the expression, activity, or level of the FGFR3 gene, FGFR3 kinase protein, or any of them.

[0274] In some embodiments, the disease is selected from the group consisting of cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome, or a combination thereof.

[0275] In some embodiments, the disease is cancer.

[0276] In some embodiments, 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.

[0277] In some embodiments, 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, upper urinary tract cancer of the urothelial line, and glioblastoma.

[0278] In some embodiments, the cancer is selected from bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, and muscle invasive bladder cancer.

[0279] In some embodiments, the cancer is urothelial carcinoma.

[0280] In some embodiments, the disease is FGFR3-associated cancer.

[0281] In the fifth aspect of the present invention, a method for treating or preventing a disease is provided, comprising the steps of administering to a subject in need thereof a compound as described in the first or second aspect of the present invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof, or a pharmaceutical composition as described in the third aspect.

[0282] In some embodiments, the disease is as defined in the fourth aspect.

[0283] In some embodiments, the disease is selected from the group consisting of cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatosplasia, severe achondroplasia with developmental delay and acanthosis nigricans, Muenke syndrome, or a combination thereof.

[0284] In some embodiments, the present invention provides a method for treating or preventing a disease (such as cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatosplasia, severe achondroplasia with developmental delay and acanthosis nigricans, Muenke syndrome or), which comprises administering to a subject in need thereof a compound of the present invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof.

[0285] In some embodiments, the cancer described herein is an FGFR3-related cancer, which is associated with an abnormal regulation of the expression or 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., skin 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.

[0286] The main advantages of the present invention include

[0287] (a) The compounds of the present invention have excellent anti-tumor cell proliferation activity.

[0288] (b) The compounds of the present invention have excellent selectivity, in particular, selectivity for FGFR3 in the fibroblast growth factor receptor (FGFRs) family. Compared to the inhibitory activity against other members of the FGFRs family such as FGFR1, the preferred compounds of the present application show more excellent inhibitory activity against FGFR3.

[0289] (c) The preferred compounds of the present invention exhibit remarkable anti-tumor effects in animal models.

[0290] (d) The compounds of the present invention have low toxicity.

[0291] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0292] The reagents used in the present invention were either purchased commercially or synthesized using commonly known methods in the art. Unless otherwise specified, the chiral carbons of the (1S)-1-(5-fluoropyridin-2-yl) substituents described in the examples exhibit ee values ​​ranging from 76% to 90%.

[0293] Preparation Example

[0294] The reagents used in the present invention are commercial reagents purchased directly or synthesized using common methods well known in the art.

[0295] Embodiment 1: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrrolidone (6-pyridin-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0296]

[0297] Step 1: 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a] Pyridine

[0298] Dissolve 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (20 g, 88.08 mmol), pinacol diboronate (44.7 g, 176.1 mmol), and potassium acetate (25.9 g, 264.2 mmol) in 1,4-dioxane (200 mL). Add 1,1'-bis(diphenylphosphinoferrocenepalladium) dichloride (3.22 g, 4.404 mmol) under nitrogen. Heat to 85°C and stir for 4 hours. The reaction mixture is cooled to room temperature, filtered, and concentrated. The residue is purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to obtain the title compound (23 g, 75.51 mmol, yield: 85.73%). LC / MS (ESI) M / Z: 275.2 [M+H] + .

[0299] Step 2: tert-Butyl 4-(5-cyclopropyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0300] Dissolve tert-butyl 4-azidopiperidine-1-carboxylate (24 g, 106.1 mmol), ethyl 3-cyclopropyl-3-oxopropanoate (19.88 g, 127.3 mmol), and potassium carbonate (43.97 g, 318.2 mmol) in dimethyl sulfoxide (200 mL). Heat the reaction mixture to 85°C under nitrogen and stir for 5 hours. Cool the reaction mixture to room temperature, add water (500 mL), and extract with ethyl acetate (3 x 200 mL). The organic phase is washed with water and saturated brine, dried under reduced pressure, and the residue is purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 20%-40% ethyl acetate) to obtain the title compound (17.1 g, 46.92 mmol, yield: 44.24%). LC / MS (ESI) M / Z: 365.3 [M+H] + .

[0301] Step 3: 1-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4-carboxylic acid

[0302] Dissolve tert-butyl 4-(5-cyclopropyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (17.1 g, 46.92 mmol) in water (150 mL) and methanol (30 mL). Add potassium hydroxide (5.27 g, 93.84 mmol). Heat the reaction mixture to 50°C and stir for 2 hours. Cool the reaction mixture to room temperature, add water (50 mL), adjust the pH of the reaction system to 4 with 1N hydrochloric acid, and extract with ethyl acetate (3 x 200 mL). The organic phase is washed with water and saturated brine, and dried under reduced pressure to obtain the title compound (15.4 g, 45.78 mmol, yield: 97.57%). LC / MS (ESI) M / Z: 337.2 [M+H] + .

[0303] Step 4: tert-Butyl 4-(4-bromo-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0304] 1-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-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 obtain the title compound (13.0 g, 35.01 mmol, yield: 76.48%). LC / MS (ESI) M / Z: 371.2 / 373.3

[0305] [M+H] + .

[0306] Step 5: 4-(5-cyclopropyl-4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazole-1- tert-Butyl)piperidine-1-carboxylate

[0307] tert-Butyl 4-(4-bromo-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (13.0 g, 35.01 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (2.26 g, 3.50 mmol) was added under nitrogen protection, and the mixture was heated to 85 °C and stirred for 5 hours. The reaction mixture was cooled to room temperature, 1,4-dioxane was concentrated, water (200 mL) was added, and the mixture was extracted with ethyl acetate (3*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 obtain the title compound (16.2 g, 27.71 mmol, yield: 79.13%). LC / MS (ESI) M / Z: 439.3 [M+H] + .

[0308] Step 6: 4-(5-cyclopropyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazole-1- tert-Butyl)piperidine-1-carboxylate

[0309] Dodecan-1-thiol (2076.94 mg, 10.262 mmol) was added to a solution of 2-methyl-2-propyl-4-[5-cyclopropyl-4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]piperidine-1-carboxylate (450 mg, 1.026 mmol) and aqueous sodium hydroxide (136.82 mg, 1.710 mmol, 50% aqueous solution) in N,N-dimethylacetamide (8 mL). The reaction was stirred at 100°C for 2 hours under nitrogen. The reaction mixture was 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 was dried under reduced pressure to obtain 2-methyl-2-yl-4-[5-cyclopropyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]piperidine-1-carboxylate (365 mg, 0.860 mmol, yield: 83.79%). LC / MS (ESI) M / Z: 425.4 [M+H] + .

[0310] Step 7: 4-[5-cyclopropyl-4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanol [alkyl-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylate

[0311] 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]piperidine-1-carboxylate (290 mg, 0.683 mmol), 1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-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 cooled to room temperature, and water (10 mL) was added. The mixture was extracted twice with ethyl acetate. The organic phase was washed with water (3 x 30 mL) and then with saturated sodium chloride. The resulting organic phase was dried over anhydrous sodium sulfate and filtered. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0% to 50%) to afford 4-[5-cyclopropyl-4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylate (217 mg). Yield: 45%. LC / MS (ESI) M / Z: 678.3 [M+H] + .

[0312] Step 8: 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)- tert-Butyl 3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0313] To a solution of 2-methylpropan-2-yl 4-[5-cyclopropyl-4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]piperidine-1-carboxylate (186 mg, 0.274 mmol) in dichloromethane (1 mL) was added N-chlorosuccinimide (34.81 mg, 0.261 mmol) at room temperature. 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 and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0% to 20%) to give 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)piperidine-1-carboxylate (203 mg). Yield: 93%. LC / MS (ESI) M / Z: 712.4 [M+H] + .

[0314] 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)ethan-1-ol

[0315] A solution of 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)piperidine-1-carboxylate (180 mg, 0.253 mmol) and hydrochloric acid in dioxane (4M in dioxane, 5 mL) was stirred at room temperature for 1 hour. The reaction solution was 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)ethan-1-ol (162 mg). LC / MS(ESI)M / Z:498.2[M+H] + .

[0316] Step 10: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrrolidone (6-pyridin-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0317] To a solution of 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)ethan-1-ol (162 mg, 0.270 mmol) and N,N-diisopropylethylamine (452.83 mg, 3.510 mmol) in dichloromethane (6 mL) was added cyanogen bromide (57.20 mg, 0.540 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane and water, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0% to 10%) to afford 80 mg of the product, which was then purified by reverse phase purification (ACN:H2O = 0% to 50%) to afford 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)piperidine-1-carbonitrile (60 mg). 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).

[0318] Example 2: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrrolidone (6-pyridinyl)-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0319]

[0320]

[0321] Step 1: tert-Butyl 4-(5-cyclobutyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0322] Dissolve tert-butyl 4-azidopiperidine-1-carboxylate (3.6 g, 15.9 mmol), ethyl 3-cyclobutyl-3-oxopropanoate (3.0 g, 17.5 mmol), and potassium carbonate (6.6 g, 47.7 mmol) in dimethyl sulfoxide (36 mL). The reaction mixture was heated to 80°C under nitrogen and stirred for 6 hours. After completion, the reaction mixture was cooled to room temperature, water (100 mL) was added, and 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 20%-40% ethyl acetate) to obtain the title compound (3.6 g, 9.5 mmol, yield: 60%) as a light yellow oil. LC / MS (ESI) M / Z: 379.2 [M+H] + .

[0323] Step 2: 1-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-5-cyclobutyl-1H-1,2,3-triazole-4-carboxylic acid

[0324] Dissolve tert-butyl 4-(5-cyclobutyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (3.6 g, 9.5 mmol) in water (30 mL) and methanol (30 mL). Add potassium hydroxide (1.1 g, 19.0 mmol). Heat the reaction mixture to 50°C and stir for 2 hours. After completion, cool the reaction mixture to room temperature, adjust the pH to 4 with 1 M hydrochloric acid, and extract with ethyl acetate (3 x 50 mL). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford the title compound as a yellow oil (2.3 g, 6.6 mmol, yield: 69%). LC / MS (ESI) M / Z: 295.2 [M+H-56]. + .

[0325] Step 3: tert-Butyl 4-(4-bromo-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0326] 1-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-5-cyclobutyl-1H-1,2,3-triazole-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 completion of the reaction, the reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium sulfite, and extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-50% ethyl acetate) to obtain the title compound as a white solid (430 mg, 1.1 mmol, yield: 78%). LC / MS (ESI) M / Z: 385.2 [M+H] + .

[0327] Step 4: 4-(5-cyclobutyl-4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazole-1- tert-Butyl)piperidine-1-carboxylate

[0328] Tert-butyl 4-(4-bromo-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (430 mg, 1.1 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (71 mg, 0.1 mmol) was added under nitrogen protection, and the mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the reaction mixture 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 50%-70% ethyl acetate) to obtain the title compound as a yellow solid (400 mg, 0.9 mmol, yield: 79%). LC / MS (ESI) M / Z: 453.4 [M+H] + .

[0329] Step 5: 4-(5-cyclobutyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazole-1- tert-Butyl)piperidine-1-carboxylate

[0330] Dodecan-1-thiol (716 mg, 3.5 mmol) was added to a solution of tert-butyl 4-(5-cyclobutyl-4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (400 mg, 0.9 mmol) and sodium hydroxide aqueous solution (211 mg, 5.3 mmol, 50% aqueous solution) in N,N-dimethylacetamide (10 mL). The reaction was stirred at 100°C for 3 hours under nitrogen protection. 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*100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-7%).

[0331] The target compound (305 mg, 0.7 mmol, yield: 79%) was obtained as a white solid by purification with methanol. LC / MS (ESI) M / Z: 439.2 [M+H] + .

[0332] Step 6: 4-(4-(2-(tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyridin- tert-Butyl (oxazolo[1,5-a]pyridin-6-yl)-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0333] At room temperature, tert-butyl 4-(5-cyclobutyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)piperidine-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 solution was heated to 110°C and stirred for 10 minutes. The reaction mixture was cooled to room temperature, 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-7% methanol) to obtain the desired product as a white solid (240 mg, 0.35 mmol, yield: 50%). LC / MS (ESI) M / Z: 636.4

[0334] [M+H-56] + .

[0335] Step 7: 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3- tert-Butyl chloropyrazolo[1,5-a]pyridin-6-yl)-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0336] 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-carboxylate (240 mg, 0.35 mmol) in dichloromethane (5 mL) was added N-chlorosuccinimide (46 mg, 0.3 mmol) at room temperature, and the reaction 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-7% methanol) to obtain the desired product as a yellow solid (190 mg, 0.26 mmol, yield: 75%). LC / MS (ESI) M / Z: 726.3 [M+H] + .

[0337] 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

[0338] 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)piperidine-1-carboxylate (190 mg, 0.26 mmol) in dichloromethane (3 mL) was added 4 M hydrochloric acid in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was distilled under reduced pressure to obtain the crude target product (130 mg, 0.25 mmol) as a yellow oil. LC / MS (ESI) M / Z: 512.4 [M+H] + .

[0339] 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)piperidine-1-carbonitrile

[0340] 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) in dichloromethane (5 mL) was added cyanogen bromide (54 mg, 0.51 mmol) at room temperature. The reaction solution 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 purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10%) to obtain 100 mg of a crude product. This crude product was then subjected to reverse phase purification (ACN:H2O = 0%-50%) to obtain the desired product as a white solid (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).

[0341] Example 3: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrrolidone (6-pyridin-5-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0342]

[0343] Step 1: tert-Butyl 4-(5-cyclopentyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0344] Dissolve tert-butyl 4-azidopiperidine-1-carboxylate (3 g, 13.26 mmol), ethyl 3-cyclopentyl-3-oxopropanoate (2.93 g, 15.91 mmol), and potassium carbonate (5.50 g, 39.77 mmol) in dimethyl sulfoxide (50 mL). The reaction mixture was heated to 80°C under nitrogen and stirred for 5 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added, and 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 obtain the title compound (2.1 g, 5.35 mmol, yield: 40.36%). LC / MS (ESI) M / Z: 393.4 [M+H] + .

[0345] Step 2: 1-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-5-cyclopentyl-1H-1,2,3-triazole-4-carboxylic acid

[0346] Dissolve tert-butyl 4-(5-cyclopentyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (2.1 g, 5.350 mmol) in water (20 mL) and methanol (4 mL). Add potassium hydroxide (0.60 g, 10.70 mmol). Heat the reaction mixture to 50°C and stir for 3 hours. Cool the reaction mixture to room temperature, add water (20 mL), adjust the pH of the reaction system to 4 with 1N hydrochloric acid, and extract with ethyl acetate (3 x 50 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.8 g, 4.939 mmol, yield: 92.31%). LC / MS (ESI) M / Z: 363.2 [MH] - .

[0347] Step 3: tert-Butyl 4-(4-bromo-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0348] 1-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-5-cyclopentyl-1H-1,2,3-triazole-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 obtain the title compound (240 mg, 0.601 mmol, yield: 60.84%). LC / MS (ESI) M / Z: 399.2 [M+H]+ .

[0349] Step 4: 4-(5-cyclopentyl-4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazole-1- tert-Butyl)piperidine-1-carboxylate

[0350] Dissolve tert-butyl 4-(4-bromo-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (240 mg, 0.601 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (165 mg, 0.601 mmol), and potassium carbonate (249 mg, 1.803 mmol) in 1,4-dioxane (5 mL) and water (1 mL). Add 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (39 mg, 0.060 mmol) under nitrogen, and heat to 85°C with stirring for 2 hours. The reaction mixture is cooled to room temperature, and water (5 mL) is added. The mixture is extracted with ethyl acetate (3 x 20 mL). The combined organic phases are 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] + .

[0351] Step 5: 4-(5-cyclopentyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazole-1- tert-Butyl)piperidine-1-carboxylate

[0352] Dissolve tert-butyl 4-(5-cyclopentyl-4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (230 mg, 0.493 mmol) in N,N-dimethylacetamide (4 mL). Add dodecane-1-thiol (798 mg, 3.944 mmol) and aqueous sodium hydroxide (236 mg, 5.915 mmol, 50% aqueous solution). Heat the reaction mixture to 100°C under nitrogen and stir for 2 hours. Cool the reaction mixture to room temperature, add water (10 mL) and ethyl acetate (3 mL), adjust the pH of the reaction system to 4 with formic acid, and extract with ethyl acetate (3 x 20 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate 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] + .

[0353] Step 6: 4-(4-(2-(tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyridin- tert-Butyl (oxazolo[1,5-a]pyridin-6-yl)-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0354] At room temperature, tert-butyl 4-(5-cyclopentyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)piperidine-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%).

[0355] Step 7: 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3- tert-Butyl chloropyrazolo[1,5-a]pyridin-6-yl)-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0356] 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). N-chlorosuccinimide (21.56 mg, 0.161 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, 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%).

[0357] 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

[0358] 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)piperidine-1-carboxylate (100 mg, 0.135 mmol) and a 4M hydrochloric acid-1,4-dioxane solution (3 mL) were stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure to obtain the crude title compound (85 mg). LC / MS (ESI) M / Z: 526.2 [M+H] + .

[0359] 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)piperidine-1-carbonitrile

[0360] 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) at room temperature. N,N-diisopropylethylamine (234 mg, 1.813 mmol) and cyanogen bromide (25 mg, 0.242 mmol) were added, and 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 reverse phase purification (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).

[0361] Example 4: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyrrolidone [(6-pyridin-5-yl)-1,2,3-triazacyclopentan-1-yl)hexahydropyridine-1-carbonitrile]

[0362]

[0363] Step 1: 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1, 2-a]pyridine

[0364] 6-Bromo-8-methoxyimidazo[1,2-a]pyridine (500 mg, 2.20 mmol), pinacol diboronate (1678 mg, 6.61 mmol), and potassium acetate (649 g, 6.61 mmol) were dissolved in 1,4-dioxane (10 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride (162 mg, 0.220 mmol) was added under nitrogen. The mixture was heated to 80°C and stirred for 2 hours. 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%-100% ethyl acetate) to obtain the title compound (360 mg, 1.32 mmol, yield: 59.64%). LC / MS (ESI) M / Z: 275.2 [M+H] + .

[0365] Step 2: 4-[4-(8-methoxyimidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentane [piperidine-1-carboxylic acid 2-methylpropane-2-yl] ester

[0366] 8-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (360 mg, 1.31 mmol), 2-methylprop-2-yl-4-(4-bromo-5-methyl-1,2,3-triazacyclopentan-1-yl)piperidine-1-carboxylate (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). 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (85 mg, 0.13 mmol) was added under nitrogen protection, and the mixture was heated to 80 ° C and stirred for 3 hours. The reaction mixture 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to obtain the title compound (500 mg, 1.12 mmol, yield: 92.30%). LC / MS (ESI) M / Z: 413.4 [M+H] + .

[0367] Step 3: 4-[4-(8-hydroxyimidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentane- 1-aminobenzoic acid 2-methylpropane-2-yl ester

[0368] To a solution of 2-methylpropane-2-yl-4-[4-(8-methoxyimidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentan-1-yl]piperidine-1-carboxylate (500 mg, 1.12 mmol) in N,N-dimethylacetamide (10 mL) was added sodium hydroxide (243 mg, 6.06 mmol) dissolved in 0.5 mL of water and dodecan-1-thiol (1472 mg, 7.27 mmol). The reaction was stirred at 110°C for 2 hours under nitrogen. The reaction mixture 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. The mixture was extracted with ethyl acetate (3 x 20 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to obtain the title compound (270 mg, 0.678 mmol, yield: 55.90%). LC / MS (ESI) M / Z: 399.4 [M+H] + .

[0369] Step 4: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhexane-1- [1,2-a]pyridin-6-yl]-5-methyl-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-yl] 2-Methylpropanediol

[0370] At room temperature, 4-[4-(8-hydroxyimidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentan-1-yl]piperidine-1-carboxylic acid-2-methylpropane-2-yl ester (270 mg, 0.678 mmol), 1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl methanesulfonate (174 mg, 0.50 mmol) and cesium carbonate (221 mg, 0.678 mmol) were dissolved in N,N-dimethylformamide (4 mL), and the reaction solution was heated to 110 ° C. and stirred for 30 minutes. The reaction mixture was cooled to room temperature, water (40 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-5% anhydrous methanol) to obtain the title compound (180 mg, 0.276 mmol, yield: 40.75%). LC / MS (ESI) M / Z: 652.6 [M+H] + .

[0371] Step 5: 2-(5-fluoropyridin-2-yl)-2-({6-[1-(hexahydropyridin-4-yl)-5-methyl-1,2,3-triaza]- [4-(cyclopentyl)imidazo[1,2-a]pyridin-8-yl]oxy]ethan-1-ol

[0372] A solution of 2-methylpropan-2-yl 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}imidazo[1,2-a]pyridin-6-yl)-5-methyl-1,2,3-triazacyclopentan-1-yl]piperidine-1-carboxylate (180 mg, 0.276 mmol) and hydrochloric acid in dioxane (4M in dioxane, 10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude 2-(5-fluoropyridin-2-yl)-2-({6-[1-(hexahydropyridin-4-yl)-5-methyl-1,2,3-triazacyclopentan-4-yl]imidazo[1,2-a]pyridin-8-yl}oxy)ethan-1-ol (120 mg, 0.274 mmol). LC / MS (ESI) M / Z: 438.4 [M+H] + .

[0373] 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-carbonitrile

[0374] To a solution of 2-(5-fluoropyridin-2-yl)-2-({6-[1-(hexahydropyridin-4-yl)-5-methyl-1,2,3-triazacyclopentan-4-yl]imidazo[1,2-a]pyridin-8-yl}oxy)ethan-1-ol (120 mg, 0.274 mmol) and N,N-diisopropylethylamine (710 mg, 5.49 mmol) in dichloromethane (10 mL) was added cyanogen bromide (59 mg, 0.55 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane and water, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was purified by column chromatography (eluent: anhydrous methanol / dichloromethane, gradient: 0%-10% anhydrous methanol) to give a crude product, which was then purified by reverse phase purification (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-triazacyclopentan-1-yl]hexahydropyridine-1-carbonitrile (30 mg, 0.065 mmol, yield: 23.65%). LC / MS (ESI) M / Z: 463.4

[0375] [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).

[0376] Example 5: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-(6-(6-(methylsulfonyl)- 2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1H-indazole

[0377]

[0378] Step 1: tert-Butyl 5-bromo-7-fluoro-1H-indazole-1-carboxylate

[0379] Dissolve 5-bromo-7-fluoro-1H-indazole (2.0 g, 9.30 mmol) in DCM (30 mL), add di-tert-butyl dicarbonate (4.06 g, 18.6 mmol), and slowly add 4-dimethylaminopyridine (227 mg, 1.86 mmol). Stir at room temperature for 18 hours. Add water (30 mL) and extract the mixture. The aqueous phase is extracted with dichloromethane (2 x 30 mL). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to obtain the title compound as a white solid, 1.7 g, 5.39 mmol, yield: 58.0%. LC / MS (ESI) M / Z: 314.9 [M+H] + .

[0380] Step 2: tert-7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylic acid Butyl ester

[0381] Dissolve tert-butyl 5-bromo-7-fluoro-1H-indazole-1-carboxylate (1.7 g, 5.39 mmol), bis(pinacol borate) (2.74 g, 10.8 mmol), and potassium acetate (2.12 g, 21.6 mmol) in 1,4-dioxane (20 mL). Add 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (790 mg, 1.08 mmol) and allow to react at 90°C for 3 hours. The reaction mixture was concentrated under reduced pressure, added to silica gel, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to obtain the title compound as a colorless oil (1.95 g, 5.39 mmol, yield: 100%). LC / MS (ESI) M / Z: 363.2 [M+H] + .

[0382] Step 3: tert-Butyl 7-fluoro-5-hydroxy-1H-indazole-1-carboxylate

[0383] tert-Butyl 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate

[0384] (1.95 g, 5.39 mmol) was dissolved in anhydrous methanol (30 mL), and 30% aqueous hydrogen peroxide solution (3.05 g, 26.9

[0385] mmol), and after the addition, the ice bath was removed and the reaction was allowed to react at room temperature overnight. Sodium sulfite solution was slowly added to quench the reaction. The mixture was extracted with ethyl acetate (3 x 30 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (1.3 g, 5.15 mmol, yield: 95.7%). LC / MS (ESI) M / Z: 253.1 [M+H]+ .

[0386] Step 4: 7-Fluoro-1H-indazol-5-ol hydrochloride

[0387] Dissolve tert-butyl 7-fluoro-5-hydroxy-1H-indazole-1-carboxylate (1.3 g, 5.15 mmol) in 4 M hydrochloric acid in 1,4-dioxane (25 mL) at room temperature and stir for 4 hours. The reaction mixture is concentrated under reduced pressure and saturated sodium bicarbonate solution is added until bubbles disappear. The aqueous phase is extracted with dichloromethane (3 x 30 mL). The organic phases are 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] + .

[0388] Step 5: 5-((tert-Butyldimethylsilyl)oxy)-7-fluoro-1H-indazole

[0389] 7-Fluoro-1H-indazol-5-ol hydrochloride (988 mg, crude product) was dissolved in N,N-dimethylformamide (15 mL), tert-butyldimethylsilyl chloride (1.55 g, 10.3 mmol) and imidazole (1.4 g, 20.6 mmol) were added, and 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 crude 5-

[0390] {[Dimethyl(2-methylpropan-2-yl)silyl]oxy}-1H-indazole (colorless oil, 1.1 g, 4.13 mmol, two-step yield: 80.2%).

[0391] LC / MS(ESI)M / Z:267.2[M+H] + .

[0392] Step 6: 5-((tert-Butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1H-indazole

[0393] Dissolve 5-((tert-Butyldimethylsilyl)oxy)-7-fluoro-1H-indazole (1.1 g, 4.13 mmol) in dichloromethane (20 mL), add N-iodosuccinimide (929 g, 4.13 mmol), and stir overnight at room temperature. Add water (30 mL) and extract with dichloromethane (3 x 30 mL). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to obtain the title compound (1.2 g, 3.06 mmol, yield: 74.1%). LC / MS (ESI) M / Z: 393.1 [M+H]+ .

[0394] Step 7: 5-((tert-Butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazole

[0395] 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1H-indazole

[0396] (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. Saturated aqueous sodium bicarbonate solution (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, 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 (980 mg, 2.06 mmol, yield: 67.3%). LC / MS (ESI) M / Z: 477.1 [M+H] + .

[0397] Step 8: 7-Fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol

[0398] At room temperature, 5-((tert-Butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2- yl)-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. A saturated aqueous sodium bicarbonate 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, and concentrated under reduced pressure. 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] + .

[0399] Step 9: 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran- 2-aminobenzoic acid)-1H-indazole

[0400] At room temperature, (1S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (508 mg, 1.88 mmol) was dissolved in N,N-dimethylformamide (8 mL). 7-Fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol (680 mg, 1.88 mmol) and cesium carbonate (1.84 g, 5.64 mmol) were added, and the mixture was stirred at 110°C for 6 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0% to 40% ethyl acetate) to afford the title compound as a white solid, 560 mg, 1.04 mmol, yield: 55.3%. LC / MS(ESI)M / Z:535.9[M+H] + .

[0401] Step 10: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-iodo-1H-indazole

[0402] 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) at room temperature, and trifluoroacetic acid (5 mL) was added. The reaction was allowed to proceed at room temperature for 1 hour, then concentrated under reduced pressure. Saturated sodium bicarbonate solution was added until no bubbles were generated. The aqueous phase was extracted with dichloromethane (2 x 20 mL), and 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] + .

[0403] Step 11: 3-(6-fluoropyridin-3-yl)-5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-1H- Indazole

[0404] 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-dioxolane-2-yl)pyridine (218 mg, 0.97 mmol), potassium carbonate (364 mg, 2.64 mmol) and [1,1"-bis(diphenylphosphino)ferrocene]palladium dichloride (66 mg, 0.09 mmol) were added. The reaction solution was stirred at 90 ° C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, water (30 mL) was added, and ethyl acetate (3x The mixture was extracted with 20 mL of 4% paraformaldehyde (20 mL), and the organic phase was washed with saturated sodium chloride, 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%-50% ethyl acetate) to obtain the title compound (200 mg, 0.47 mmol, yield: 53%). LC / MS (ESI) M / Z: 421.1 [M+H] + .

[0405] Step 12: R)-6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-1H-indazol-3-yl)pyrrolidone tert-Butyl pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0406] 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-methylprop-2-yl 2,6-diazaspiro[3.3]heptane-2-carboxylate (186 mg, 0.94 mmol) and potassium carbonate (195 mg, 1.41 mmol) were added. The reaction solution was stirred at 120°C for 3 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated sodium chloride, 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 the title compound (180 mg, 0.30 mmol, yield: 63.8%). LC / MS (ESI) M / Z: 599.1 [M+H] + .

[0407] Step 13: (R)-3-(6-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-5-(1-(3,5-dichloro (4-pyridinyl)ethoxy)-7-fluoro-1H-indazole

[0408] At room temperature, (R)-tert-butyl 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-carboxylate (180 mg, 0.30 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added. The reaction was allowed to proceed for 1 hour at room temperature and concentrated under reduced pressure. The residue was added with saturated sodium bicarbonate solution until bubbles disappeared. The aqueous phase was extracted with dichloromethane (2 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (130 mg, 0.26 mmol, 87% yield). LC / MS (ESI) M / Z: 499.1 [M+H] + .

[0409] Step 14: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-(6-(6-methylsulfonyl)-2, 6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1H-indazole

[0410] 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, and the 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 purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10%) to give the crude product, which was then purified by reverse phase purification (ACN:H2O = 5% to 95%) to give 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-{6-[2-(methyldioxyylidene-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).

[0411] Example 6: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrrolidone pyridin-6-yl)-5-(methyl-d3)-1H-1,2,3-triazol-1-yl)piperidin-1-carbonitrile

[0412]

[0413] Step 1: Ethyl 4,4,4-trideuterium-3-oxydeoxybutyrate

[0414] 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 bis(trimethylsilyl)amide (12.5 mL, 12.5 mmol) (1 M in THF) at -70°C. The mixture was stirred for 1 hour. 2,2,2-Trideuteroacetyl chloride (463 mg, 5.68 mmol) was then slowly added dropwise, and the reaction mixture was allowed to react at -70°C for 2 hours. The reaction mixture was warmed to room temperature, quenched with 6N hydrochloric acid, 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 yield crude ethyl 4,4,4-trideutero-3-oxyidenebutanoate (400 mg, 3.00 mmol).

[0415] Step 2: 4-[4-(Ethoxycarbonyl)-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl]hexahydropyridine 2-Methylpropane-1-carboxylate

[0416] Tert-butyl 4-azidopiperidine-1-carboxylate (570 mg, 2.52 mmol), ethyl 4,4,4-trideuteride-3-oxobutyrate (400 mg, 3.00 mmol), and potassium carbonate (1044 mg, 7.56 mmol) were dissolved in dimethyl sulfoxide (10 mL). The reaction solution was heated to 85°C and stirred under nitrogen for 5 hours. The reaction solution was cooled to room temperature, water (50 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, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to obtain the title compound (240 mg, 0.703 mmol, 27.90% yield). LC / MS (ESI) M / Z: 342.1 [M+H]+ .

[0417] Step 3: 1-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-5-(trideuteriomethyl)- 1,2,3-Triazacyclopentane-4-carboxylic acid

[0418] Dissolve 2-methylpropane-2-yl 4-[4-(ethoxycarbonyl)-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl]piperidin-1-carboxylate (240 mg, 0.70 mmol) in water (2 mL) and methanol (2 mL). Add potassium hydroxide (78.9 mg, 1.40 mmol). The reaction mixture is heated to 50°C and stirred for 2 hours. The reaction mixture is cooled to room temperature, and water (10 mL) is added. The pH of the reaction system is adjusted to 4 with 1N hydrochloric acid. The mixture is extracted with ethyl acetate (3 x 20 mL). The organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (200 mg, 0.64 mmol). LC / MS (ESI) M / Z: 314.2 [M+H] + .

[0419] Step 4: 4-[4-Bromo-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl]piperidine-1-carboxylic acid 2-Methylprop-2-yl ester

[0420] 1-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-5-(trideuteriomethyl)-1,2,3-triazacyclopentane-4-carboxylic acid (200 mg, 0.64 mmol) was dissolved in water (5 mL). Potassium hydroxide (86 mg, 1.53 mmol) and bromine (245 mg, 1.53 mmol) were added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to obtain the title compound (170 mg, 0.488 mmol, 76.48% yield). LC / MS(ESI)M / Z:348.2[M+H] + .

[0421] Step 5: 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteriomethyl)-1,2,3-triazine Heterocyclopentan-1-yl]hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester

[0422] 2-Methylpropane-2-yl-4-[4-bromo-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxylate (170 mg, 0.488 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (31.5 mg, 0.05 mmol) was added under nitrogen protection, and the mixture was heated to 85 ° C and stirred for 3 hours. The reaction mixture 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to obtain the title compound (200 mg, 0.481 mmol, 98.57% yield). LC / MS (ESI) M / Z: 416.4 [M+H] + .

[0423] Step 6: 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteriomethyl)-1,2,3-triaza 2-Methylpropane-2-yl]cyclopentan-1-ylpiperidine-1-carboxylate

[0424] To a solution of 2-methylpropan-2-yl 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl]piperidine-1-carboxylate (200 mg, 0.481 mmol) in N,N-dimethylacetamide (4 mL) was added sodium hydroxide (102 mg, 2.53 mmol) dissolved in 0.2 mL of water and dodecan-1-thiol (614 mg, 3.03 mmol). The reaction was stirred at 110°C for 2 hours under nitrogen. The reaction mixture 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. The mixture was extracted with ethyl acetate (3 x 20 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to obtain the title compound (170 mg, 0.423 mmol, 83.78% yield). LC / MS (ESI) M / Z: 402.4 [M+H] + .

[0425] Step 7: 4-[4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhexyl-1- [1,5-a]pyridin-6-yl]-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl]hexahydropyridine 2-Methylpropane-1-carboxylate

[0426] At room temperature, 2-methylpropane-2-yl-4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxylate (170 mg, 0.423 mmol), 1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-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 solution was heated to 110 ° C. and stirred for 30 minutes. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%-60%) to give the product 4-[4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhexyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropane-2-yl ester (126 mg, 0.192 mmol, yield 64.37%).

[0427] 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).

[0428] Step 8: 4-[4-(3-chloro-4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanol] [hexyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl] 2-Methylpropanepiperidin-1-carboxylate

[0429] To a solution of 2-methylpropan-2-yl 4-[4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxylate (126 mg, 0.192 mmol) in dichloromethane (3 mL) was added N-chlorosuccinimide (24.2 mg, 0.181 mmol) at room temperature, and 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× 20 mL). The organic phases were combined and washed with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by 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-silanhexyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteriomethyl)-1,2,3-triazacyclopentan-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropane-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).

[0430] 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)ethan-1-ol

[0431] At room temperature, tert-butyl 4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-(methyl-d3)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (100 mg, 0.145 mmol) was dissolved in 4 M hydrochloric acid solution in dioxane (10 mL) and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated sodium bicarbonate solution was added until no bubbles formed. The aqueous phase was extracted with dichloromethane (3*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)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol (50 mg, 0.105 mmol, 72.4% yield). LC / MS (ESI) M / Z: 476.1 [M+H] + .

[0432] Step 10: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyrrolidone pyridin-6-yl)-5-(methyl-d3)-1H-1,2,3-triazol-1-yl)piperidin-1-carbonitrile

[0433] To a solution of 2-((3-chloro-6-(5-(methyl-d3)-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[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) in dichloromethane (6 mL) was added cyanogen bromide (16.7 mg, 0.158 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane and water, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0% to 10%) to give a crude product, which was then purified by reverse phase purification (ACN:H2O = 30% to 80%) to afford 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)piperidine-1-carbonitrile (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).

[0434] Example 7: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyrrolidone [(6-pyridin-5-yl)-1,2,3-triazacyclopentan-1-yl)hexahydropyridine-1-carbonitrile]

[0435]

[0436]

[0437] Step 1: 4-Bromo-2-methyl-6-(trifluoromethyl)aniline

[0438] To the reaction mixture of 2-methyl-6-(trifluoromethyl)aniline (3.92 g, 22.381 mmol) in DCM (10 mL) was added NBS (4.18 g, 23.500 mmol) in batches. The reaction mixture was stirred at room temperature for 2 hours. The mixture was washed with NaHCO (aqueous solution, saturated solution) and brine, the organic layer was dried over NaSO and filtered. The solvent was removed to give a crude product. Purification by column chromatography (petroleum ether: ethyl acetate = 25: 1) gave 6.5 g of 4-bromo-2-methyl-6-(trifluoromethyl)aniline in a yield of 91.5%. LC / MS (ESI) M / Z: 254.2 [M+H] + .

[0439] Step 2: 5-Bromo-7-(trifluoromethyl)-1H-indazole

[0440] 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) was added acetic anhydride (602.42 mg, 5.904 mmol) dropwise at 0°C and stirred at room temperature for 1 hour. The reaction mixture was heated to 60°C and stirred at 60°C for 2 hours. Then, tert-butyl nitrite (4.14 g, 40.150 mmol) was added dropwise 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, basified with 10N aqueous 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] + .

[0441] Step 3: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)-1H-indazole

[0442] Under nitrogen, 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-dioxaborolane) (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 spin-dried to give a crude product. This crude product was immediately carried to the next step without purification. LC / MS (ESI) M / Z: 313.2 [M+H] + .

[0443] Step 4: 7-(Trifluoromethyl)-1H-indazol-5-ol

[0444] To the reaction mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)-1H-indazole (7.85 g, 20.122 mmol) in MeOH (10 mL) was added hydrogen peroxide (3.42 g, 100.609 mmol) 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 obtain a crude product. The crude product was purified by column chromatography (dichloromethane: ethyl acetate = 1: 2) to give 5.4 g of 7-(trifluoromethyl)-1H-indazole-5-ol crude product. LC / MS(ESI)M / Z:203.1[M+H] + .

[0445] Step 5: 5-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-7-(trifluoromethyl)-1H-indazole

[0446] To the 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) was added TBSCl (6.04 g, 40.071 mmol) dropwise at 0 ° C., 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 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 (petroleum ether: ethyl acetate = 5: 1) to give 3.5 g of pure product and 2.5 g of crude product of 5-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-7-(trifluoromethyl)-1H-indazole. LC / MS (ESI) M / Z: 317.2 [M+H] + .

[0447] Step 6: 5-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-3-iodo-7-(trifluoromethyl)-1H-indole Azoles

[0448] To the 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) was added NIS (N-iodosuccinimide) (1.96 g, 8.692 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, and filtered. The solvent was removed to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give 5-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-3-iodo-7-(trifluoromethyl)-1H-indazole 2.35 g, yield: 67.24%. LC / MS(ESI)M / Z:443.3[M+H] + .

[0449] Step 7: 3-Iodo-7-(trifluoromethyl)-1H-indazol-5-ol

[0450] At room temperature, TBAF solution (6.783mL, 6.783mmol) was added to the reaction mixture of 5-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-3-iodo-7-(trifluoromethyl)-1H-indazole (2g, 4.522mmol) in THF (3mL), 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 3-iodo-7-(trifluoromethyl)-1H-indazole-5-ol 1.2g, yield: 80.9%. LC / MS(ESI)M / Z:329.1[M+H] + .

[0451] Step 8: 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-iodo-7-(trifluoromethyl)-1H- Indazole

[0452] Dissolve 3-iodo-7-(trifluoromethyl)-1H-indazol-5-ol (500 mg, 1.52 mmol) in N,N-dimethylformamide (10 mL), add ethyl (1S)-1-(3,5-dichloropyridin-4-yl)methanesulfonate (412 mg, 1.52 mmol) and potassium carbonate (632 mg, 4.57 mmol), and heat to 80°C with stirring for 30 minutes. After the reaction, 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to obtain 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] + .

[0453] Step 9: 3-(6-fluoropyridin-3-yl)-5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-7- (Trifluoromethyl)-1H-indazole

[0454] 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-dioxaborolan-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(diphenylphosphino)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, 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to obtain 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] + .

[0455] Step 10: 2-Methylprop-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-carboxylate

[0456] 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) was added 2-methylpropan-2-yl 2,6-diazaspiro[3.3]heptane-2-carboxylate (85 mg, 0.42 mmol) and potassium carbonate (117 mg, 0.85 mmol). The reaction was stirred at 120°C under nitrogen for 6 hours. After the reaction, 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to give the title compound, 2-methylpropan-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-carboxylate (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).

[0457] Step 11: 3-[6-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl]-5-{[(1R)-1-(3,5-di [4-Chloropyridin-1-yl]ethyl]oxy]-7-(trifluoromethyl)-1H-indazole

[0458] 2-Methylpropan-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-carboxylate (80 mg, 0.123 mmol) was dissolved in dichloromethane (40 mL), and a solution of hydrochloric acid in dioxane (5 mL) was added. After completion of the reaction, the mixture was concentrated under reduced pressure to afford 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, 88.67% yield). LC / MS(ESI)M / Z:549.2[M+H] + .

[0459] Step 12: 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-{6-[2-(methyldioxy-1 <6-sulfanyl)-2,6-diazaspiro[3.3]heptane-6-yl]pyridin-3-yl}-7-(trifluoromethyl)-1H-indazole

[0460] 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) was added triethylamine (22 mg, 0.22 mmol) and methanesulfonyl chloride (19 mg, 0.16 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane and water, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-70% ethyl acetate) to give a crude product, which was then purified by reverse phase purification (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-sulfanyl)-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).

[0461] Example 8: 4-(4-(8-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)imidazo[1,5-a]pyridine-6- 1-Methyl-5-(1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0462]

[0463]

[0464] Step 1: tert-Butyl (5-bromo-3-fluoropyridin-2-yl)methyl)carbamate

[0465] 5-Bromo-3-fluoropyridinecarbonitrile (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 solution was cooled to 0°C, and sodium borohydride (3.8 g, 99.5 mmol) was added portionwise over 2 hours. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was cooled to 0°C, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 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 obtain the title compound as a colorless oil (2.6 g, 8.5 mmol, yield: 17%). LC / MS (ESI) M / Z: 305.0 [M+H] + .

[0466] Step 2: (5-Bromo-3-fluoropyridin-2-yl)methanamine

[0467] Tert-butyl (5-bromo-3-fluoropyridin-2-yl)methyl)carbamate (2.6 g, 8.5 mmol) was dissolved in 1,4-dioxane (15 mL). 4 M hydrochloric acid in 1,4-dioxane (5 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was distilled under reduced pressure to obtain the crude title compound (1.8 g, 8.5 mmol) as a yellow oil. LC / MS (ESI) M / Z: 205.1 [M+H] + .

[0468] Step 3: N-((5-Bromo-3-fluoropyridin-2-yl)methyl)formamide

[0469] Dissolve crude (5-bromo-3-fluoropyridin-2-yl)methanamine (1.8 g, 8.5 mmol) in tetrahydrofuran (5 mL), add triethylamine (3 mL) and ethyl formate (20 mL), and heat the reaction mixture to 65°C and stir overnight. After the reaction is complete, cool the reaction mixture to room temperature and dry under reduced pressure to obtain a reddish-brown crude title compound (1.8 g, 7.7 mmol). LC / MS (ESI) M / Z: 233.0 [M+H] + .

[0470] Step 4: 6-Bromo-8-fluoroimidazo[1,5-a]pyridine

[0471] 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 under nitrogen for 3 hours. After completion of the reaction, 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 x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to obtain the title compound (600 mg, 2.8 mmol, three-step yield: 33%). LC / MS (ESI) M / Z: 215.1 [M+H] + .

[0472] Step 5: 6-Bromo-8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)imidazole 1,5-a]pyridine

[0473] 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 cooled to 0°C and sodium hydride (112 mg, 2.8 mmol) was added. The reaction mixture was stirred at 0°C for 20 minutes. 6-Bromo-8-fluoroimidazo[1,5-a]pyridine (600 mg, 2.8 mmol) was dissolved in N,N-dimethylformamide (3 mL) and added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction was quenched with ice water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to obtain the title compound (740 mg, 1.5 mmol, yield: 52%). LC / MS (ESI) M / Z: 508.2

[0474] [M+H] + .

[0475] Step 6: 8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)-6-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine

[0476] 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). Under a nitrogen atmosphere, pinacol diboron (740 mg, 2.9 mmol), potassium acetate (427 mg, 4.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (106 mg, 0.1 mmol) were added. The mixture was heated to 100°C and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and extraction was performed with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to obtain the title compound as a colorless oil (300 mg, 0.5 mmol, yield: 37%). LC / MS (ESI) M / Z: 508.2 [M+H] + .

[0477] Step 7: 4-(4-(8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)amidine tert-Butyl (oxazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0478] 8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (300 mg, 0.5 mmol), tert-butyl 4-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (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)ferrocenepalladium 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to obtain the title compound as a light yellow oil (120 mg, 0.2 mmol, yield: 38%). LC / MS (ESI) M / Z: 694.3 [M+H] + .

[0479] Step 8: 2-(5-fluoropyridin-2-yl)-2-(6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazole-4-yl)- 1-[4-(2-Yl)imidazo[1,5-a]pyridin-8-yl)oxy)ethanol-1-ol

[0480] To a solution of tert-butyl 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)piperidine-1-carboxylate (120 mg, 0.2 mmol) in dichloromethane (5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure to obtain the crude target product (60 mg, 0.1 mmol) as a pale yellow oil. LC / MS (ESI) M / Z: 438.2 [M+H] + .

[0481] Step 9: 4-(4-(8-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)imidazo[1,5-a]pyridine-6- 1-Methyl-5-(1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0482] 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) in dichloromethane (3 mL) was added cyanogen bromide (29 mg, 0.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated to dryness under reduced pressure and purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10%) to afford 40 mg of a crude product. This crude product was then purified by reverse phase purification (ACN:H₂O = 0% to 50%) to afford the desired 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).

[0483] Example 9: 2-(5-fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxyylidene-λ6-thio)-2,6-dihydro Spiro[3.3]gen alkyl -6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]ethan-1-ol

[0484]

[0485] Step 1: 2-Methylpropane-2-yl 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0486] 5-Bromo-2-fluoropyridine (487 mg, 2.77 mmol) was dissolved in dimethyl sulfoxide (8.0 mL), and 2-methylprop-2-yl 2,6-diazaspiro[3.3]heptane-2-carboxylate (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, and concentrated under reduced pressure. 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, 88.75% yield). LC / MS (ESI) M / Z: 354.2 [M+H] + .

[0487] Step 2: 2-(5-Bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane

[0488] Dissolve 2-methylpropane-2-yl-6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (700 mg, 1.98 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (5 mL, 65.3 mmol), and stir at room temperature for 1 hour. Concentrate under reduced pressure to obtain 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] + .

[0489] Step 3: 6-(5-bromopyridin-2-yl)-2-(methyldioxyylidene-λ6-thio)-2,6-diazaspiro[3.3]heptane alkyl

[0490] 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. Saturated aqueous 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0% to 5% anhydrous methanol) to give the title compound (336 mg, 1.01 mmol, 51.40% yield). LC / MS (ESI) M / Z: 332.2 [M+H] + .

[0491] Step 4: 6-Bromopyrazolo[1,5-a]pyridin-4-ol

[0492] To a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (500 mg, 2.20 mmol) in N,N-dimethylacetamide (8 mL) was added sodium hydroxide (441 mg, 11.0 mmol) dissolved in 1 mL of water and dodecan-1-thiol (2675 mg, 13.2 mmol). The reaction was stirred at 110°C for 2 hours under nitrogen. The reaction mixture 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to yield the title compound (300 mg, 1.41 mmol, 63.96%). LC / MS(ESI)M / Z:213.0[M+H] + .

[0493] Step 5: 6-Bromo-4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhex-1-yl] oxy}pyrazolo[1,5-a]pyridine

[0494] 6-Bromopyrazolo[1,5-a]pyridin-4-ol (300 mg, 1.41 mmol) was dissolved in N,N-dimethylformamide (4 mL) at room temperature, and cesium carbonate (345 mg, 1.06 mmol) and 1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahex-1-yl methanesulfonate (271 mg, 0.78 mmol) were added. The reaction was allowed to proceed at 110°C 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 organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%-20% ethyl acetate) to afford the title compound (300 mg, 0.642 mmol, 64.93%). LC / MS(ESI)M / Z:466.1[M+H] + .

[0495] Step 6: 4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhex-1-yl]oxy 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

[0496] 6-Bromo-4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhexan-1-yl]oxy}pyrazolo[1,5-a]pyridine (300 mg, 0.642 mmol), pinacol diboronate (327 mg, 1.29 mmol), and potassium acetate (190 mg, 1.93 mmol) were dissolved in 1,4-dioxane (4.0 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride (48 mg, 0.064 mmol) was added under nitrogen. 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 obtain the title compound (270 mg, 0.526 mmol, yield: 81.57%). LC / MS(ESI)M / Z:514.3[M+H] + .

[0497] Step 7: 4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhex-1-yl]oxy methyl}-6-{2-[2-(methyldioxyylidene-λ6-sulfanyl)-2,6-diazaspiro[3.3]heptyl alkyl -6-yl]pyridin-5-yl}pyrazole 1,5-a]pyridine

[0498] At room temperature, 4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhexan-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (270 mg, 0.526 mmol), 6-(5-bromopyridin-2-yl)-2-(methyldioxy- λ6-sulfanyl)-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). 1,1'-Bis(di-tert-butylphosphino)ferrocenepalladium dichloride (31 mg, 0.046 mmol) was added under nitrogen, and the mixture was heated to 80°C and stirred for 1 hour. The reaction mixture was cooled to room temperature, concentrated to 1,4-dioxane, and water (10 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to afford the title compound (130 mg, 0.203 mmol, yield: 38.69%). LC / MS(ESI)M / Z:639.3[M+H] + .

[0499] Step 8: 2-(5-fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxyylidene-λ6-thio)-2,6-diazepine Spiro[3.3]gen alkyl -6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]ethan-1-ol

[0500] At room temperature, 4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhexan-1-yl]oxy}-6-{2-[2-(methyldioxyylidene-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 aqueous sodium bicarbonate (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 purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10% anhydrous methanol) to give the crude product, which was then purified by reverse phase purification (ACN:H2O = 5% to 95%) to give 2-(5-fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxyylidene-λ6-thio)-2,6-diazaspiro[3.3]heptane-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]ethan-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).

[0501] Example 10: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyrrolidone [(6-pyridin-5-yl)-1,2,3-triazacyclopentan-1-yl)hexahydropyridine-1-carbonitrile]

[0502]

[0503] Step 1: 5-Fluoro-2-vinylpyridine

[0504] To an ethanol solution (20 mL) of 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (2.0 g, 11.4 mmol) was added potassium vinyl trifluoroborate (1.83 g, 13.6 mmol), triethylamine (1.72 g, 17 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (470 mg, 0.57 mmol). The reaction mixture was reacted at 85 degrees under nitrogen protection for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water (40 mL) was added, and methyl tert-butyl ether (3x The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 15°C to give the crude compound 5-fluoro-2-vinylpyridine (8 g, 65 mmol) as a yellow oil. LC / MS (ESI) M / Z: 124.2 [M+H] + .

[0505] Step 2: (1S)-1-(5-Fluoropyridin-2-yl)ethane-1,2-diol

[0506] To a solution of 5-fluoro-2-vinylpyridine (8 g, 65 mmol) in tert-butanol (4 mL) and water (4 mL) was added methanesulfonamide (6.18 g, 65 mmol) and AD-mix-a (91 g, 117 mmol), and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, a saturated aqueous sodium sulfite 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% to 8% methanol) to obtain compound (1S)-1-(5-fluoropyridin-2-yl)ethane-1,2-diol (800 mg, 5.1 mmol, 7.84% yield) as a colorless oil. LC / MS (ESI) M / Z: 158.2 [M+H] + .

[0507] Step 3: (1S)-1-(5-Fluoropyridin-2-yl)-2-{[tri(propyl-2-yl)silyl]oxy}ethanol-1-ol

[0508] (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 triisopropylsilyl chloride (1.08 g, 5.6 mmol) were added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to obtain the target compound (1S)-1-(5-fluoropyridin-2-yl)-2-{[tri(propyl-2-yl)silyl]oxy}ethanol-1-ol (1.5 g, 4.8 mmol, yield: 94%) as a colorless oil. LC / MS(ESI)M / Z:314.3[M+H] + .

[0509] Step 4: tert-Butyl (5-bromo-3-fluoropyridin-2-yl)methyl)carbamate

[0510] 5-Bromo-3-fluoropyridinecarbonitrile (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 solution was cooled to 0°C, and sodium borohydride (3.8 g, 99.5 mmol) was added portionwise over 2 hours. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was cooled to 0°C, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 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 obtain the title compound as a colorless oil (2.6 g, 8.5 mmol, yield: 17%). LC / MS (ESI) M / Z: 305.0 [M+H] + .

[0511] Step 5: (5-Bromo-3-fluoropyridin-2-yl)methanamine

[0512] Tert-butyl (5-bromo-3-fluoropyridin-2-yl)methyl)carbamate (2.6 g, 8.5 mmol) was dissolved in 1,4-dioxane (15 mL). 4 M hydrochloric acid in 1,4-dioxane (5 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was distilled under reduced pressure to obtain the crude title compound (1.8 g, 8.5 mmol) as a yellow oil. LC / MS (ESI) M / Z: 205.1 [M+H] + .

[0513] Step 6: N-((5-Bromo-3-fluoropyridin-2-yl)methyl)formamide

[0514] The crude product (1.8 g, 8.5 mmol) of (5-bromo-3-fluoropyridin-2-yl)methanamine was dissolved in tetrahydrofuran (5 mL), and triethylamine (3 mL) and ethyl formate (20 mL) were added. The reaction solution was heated to 65°C and stirred overnight. After the reaction was completed, the reaction solution was cooled to room temperature and dried under reduced pressure to obtain a reddish-brown crude target compound (1.8 g, 7.7 mmol). LC / MS (ESI) M / Z: 233.0 [M+H + ].

[0515] Step 7: 6-Bromo-8-fluoroimidazo[1,5-a]pyridine

[0516] N-((5-bromo-3-fluoropyridin-2-yl)methyl)formamide (2.1 g, 9.0 mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic anhydride (3.8 g, 18.0 mmol) was added at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 3 hours. After completion, 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 x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to obtain the title compound (600 mg, 2.8 mmol, three-step yield: 33%). LC / MS (ESI) M / Z: 215.1 [M+H] + .

[0517] Step 8: 6-Bromo-8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propan-2-yl)-3-oxa- 4-silanhex-1-yl]oxy}imidazo[1,5-a]pyridine

[0518] (1S)-1-(5-Fluoropyridin-2-yl)-2-{[tri(propyl-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-fluoroimidazo[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 completion of the reaction, the reaction was quenched with ice water and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to obtain the target compound 6-bromo-8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propan-2-yl)-3-oxa-4-silan-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] + .

[0519] Step 9: 8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propan-2-yl)-3-oxa-4-silanol Hexyl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine

[0520] 6-Bromo-8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silan-1-yl]oxy}imidazo[1,5-a]pyridine (430 mg, 0.85 mmol) was dissolved in 1,4-dioxane (5 mL). Under a nitrogen atmosphere, pinacol diboron (430 mg, 1.7 mmol), potassium acetate (249 mg, 2.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (62 mg, 0.08 mmol) were added, and the mixture was heated to 80°C and stirred for 2 hours. After completion of the reaction, the reaction mixture 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 x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to obtain the target compound 8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propan-2-yl)-3-oxa-4-silan-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine as a colorless oil (369 mg, 0.66 mmol, yield: 78.55%). LC / MS (ESI) M / Z: 556.4 [M+H] + .

[0521] Step 10: 2-Methylprop-2-yl 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-diol (Propan-2-yl)-3-oxa-4-silanhexyl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazole- 1-aminobenzoic acid ester

[0522] 8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silan-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (369 mg, 0.66 mmol), tert-butyl 4-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (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). 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (44 mg, 0.07 mmol) was added under nitrogen protection, 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to obtain the target compound 2-methylpropan-2-yl 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propan-2-yl)-3-oxa-4-silanahex-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%) as a light yellow oil. LC / MS(ESI)M / Z:694.3[M+H] + .

[0523] 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]pyridin-8-y}oxy)ethan-1-ol

[0524] To a solution of 2-methylpropan-2-yl 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silan-1-yl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylate (336 mg, 0.48 mmol) in dichloromethane (4 mL) was added 4 M hydrochloric acid solution in 1,4-dioxane (2 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure to obtain the target 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)ethan-1-ol (180 mg, 0.41 mmol) as a pale yellow oily crude product. LC / MS (ESI) M / Z: 438.2 [M+H] + .

[0525] Step 12: 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,5-a]pyrrolidone [(6-pyridin-5-yl)-1,2,3-triazol-1-yl)hexahydropyridine-1-carbonitrile]

[0526] To a solution of 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)ethan-1-ol (180 mg, 0.41 mmol) and N,N-diisopropylethylamine (691 mg, 5.35 mmol) in dichloromethane (4 mL) was added cyanogen bromide (87 mg, 0.8 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure and purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10%) to obtain a crude product. The crude product was then subjected to reverse phase purification (ACN:H2O = 0% to 95%) to obtain the desired 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-carbonitrile (25 mg, 0.05 mmol, yield: 13.14%), as a white solid. 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).

[0527] 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]hexahydropyridine-1-carbonitrile

[0528] 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-carbonitrile (25 mg, 0.05 mmol) in dichloromethane (2 mL) was added N-chlorosuccinimide (5 mg, 0.04 mmol), and the mixture was stirred at room temperature overnight. After the reaction, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by reverse phase chromatography (ACN:H2O = 0% to 95%) to obtain a crude product. This crude product was further purified by column chromatography (eluent: dichloromethane / ethyl acetate, gradient: 0% to 90% ethyl acetate) to obtain the 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-carbonitrile as a white solid (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).

[0529] Example 11: 2-(5-fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxyylidene-λ6-thio)-2,6-di Azaspiro[3.3]heptane alkyl -6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]ethan-1-ol

[0530]

[0531] Step 1: 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro [3.3] 2-Methylpropane-2-carboxylate

[0532] At room temperature, 2-methylpropane-2-yl-6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (170 mg, 0.480 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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)ferrocenepalladium dichloride (31 mg, 0.05 mmol) was added, and the mixture was heated to 80°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, 1,4-dioxane was concentrated, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-100% ethyl acetate) to obtain the title compound (191 mg, 0.453 mmol, 94.4% yield). LC / MS (ESI) M / Z: 422.2 [M+H] + .

[0533] Step 2: 6-{2-[2-(methyldioxy-1-[1-(6-thio)-2,6-diazaspiro[3.3]heptyl]- alkyl -6-yl]pyridine- 5-yl}pyrazolo[1,5-a]pyridin-4-ol

[0534] To a solution of 2-methylpropan-2-yl 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (191 mg, 0.453 mmol) in N,N-dimethylacetamide (5 mL) was added sodium hydroxide (91 mg, 2.27 mmol) (dissolved in 0.2 mL of water) and dodecan-1-thiol (551 mg, 2.72 mmol). The reaction was stirred at 110°C for 3 hours under nitrogen. The reaction mixture 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 water and saturated brine, and dried under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-100% ethyl acetate) to obtain the title compound (150 mg, 0.368 mmol, 81.2% yield). LC / MS (ESI) M / Z: 408.2 [M+H] + .

[0535] Step 3: 6-[5-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhexane-1- 2-Methyl-2-[[(1,5-a]pyridin-6-yl]pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid]-1,2-dimethyl ... Propan-2-yl ester

[0536] At room temperature, 6-{2-[2-(methyldioxyylidene-λ6-thio)-2,6-diazaspiro[3.3]heptan-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-ol (150 mg, 0.368 mmol) was dissolved in N,N-dimethylformamide (3 mL). Cesium carbonate (180 mg, 0.552 mmol) and methanesulfonic acid-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahexan-1-yl ester (142 mg, 0.405 mmol) were added. The reaction was allowed to proceed at 80°C for 30 minutes. The reaction mixture 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 purified by 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] + .

[0537] Step 4: 2-(5-fluoropyridin-2-yl)-2-({6-[2-(2,6-diazaspiro[3.3]heptyl alkyl -2-yl)pyridine-5- 1-Pyrazolo[1,5-a]pyridin-4-yl}oxy)ethan-1-ol

[0538] Dissolve 2-methylpropan-2-yl 6-[5-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silanhexan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate in dichloromethane (4 mL). Add trifluoroacetic acid (2 mL, 26.1 mmol) and stir at room temperature for 1 hour. Concentrate under reduced pressure to obtain 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)ethan-1-ol (110 mg, 0.246 mmol). LC / MS(ESI)M / Z:447.2[M+H] + .

[0539] 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-carbonitrile

[0540] To a solution of 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)ethan-1-ol (110 mg, 0.246 mmol) and N,N-diisopropylethylamine (637 mg, 4.93 mmol) in dichloromethane (3 mL) was added cyanogen bromide (52.2 mg, 0.493 mmol) at room temperature. 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 purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10%) to give the crude product, which was then purified by reverse phase purification (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-carbonitrile (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).

[0541] Example 12: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyrrolidone [(6-pyridin-5-yl)-1,2,3-triazacyclopentan-1-yl)hexahydropyridine-1-carbonitrile]

[0542]

[0543] Step 1: (1R)-2-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-1-(5-fluoropyridin-2-yl) Ethan-1-ol

[0544] To a 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) in dichloromethane (20 mL) was added triethylamine (3.73 g, 36.8 mmol) and methylsulfonyl chloride (3.17 g, 27.6 mmol). The reaction mixture was stirred at 0°C for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution (20 mL) 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 afford compound (1R)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl methanesulfonate (5.8 g, 16.6 mmol, 90.1% yield) as a yellow oil. LC / MS (ESI) M / Z: 350.2 [M+H] + .

[0545] Step 2: 6-Bromopyrazolo[1,5-a]pyridin-4-ol

[0546] To a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (4 g, 17.6 mmol) in N,N-dimethylacetamide (50 mL) was added aqueous sodium hydroxide (3.52 g, 88 mmol) dissolved in 3.5 mL of water and dodecanethiol (21.3 g, 105 mmol). The reaction mixture was stirred at 60°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water (300 mL) was added, and formic acid was added to adjust the pH to 3-4. The mixture was extracted with ethyl acetate (3 x 100 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%-50% ethyl acetate) to afford 6-bromopyrazolo[1,5-a]pyridine-4-ol (3 g, 14.1 mmol, 79.9% yield) as a white solid. LC / MS(ESI)M / Z:213.0[M+H] + .

[0547] Step 3: 6-Bromo-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1- 1,5-a]pyridine

[0548] 6-Bromopyrazolo[1,5-a]pyridin-4-ol (3 g, 14.1 mmol) was dissolved in N,N-dimethylformamide (30 mL) at room temperature, and cesium carbonate (6.88 g, 21.1 mmol) and (1R)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl methanesulfonate (5.41 g, 15.5 mmol) were added. The reaction was carried out at 110°C for 30 minutes. After the reaction, 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%-50% ethyl acetate) to obtain the title compound 6-bromo-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridine (2.84 g, 6.09 mmol, yield 43.24%). LC / MS (ESI) M / Z: 466.1 [M+H] + .

[0549] Step 4: 4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

[0550] Dissolve 6-bromo-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridine (2.84 g, 6.09 mmol), pinacol diboron (3.1 g, 12.2 mmol), and potassium acetate (1.8 g, 18.3 mmol) in 1,4-dioxane (4.0 mL). Add 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (450 mg, 0.61 mmol) under nitrogen protection, and heat to 80°C with stirring for 2 hours. After the reaction is complete, cool the reaction solution to room temperature, filter, and concentrate 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-silan-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (1.2 g, 2.34 mmol, yield: 38.38%). LC / MS (ESI) M / Z: 514.3 [M+H] + .

[0551] Step 5: Step 1: 6-(5-Bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropane- 2-amino ester

[0552] 5-Bromo-2-fluoropyridine (200 mg, 1.14 mmol) was dissolved in dimethyl sulfoxide (3 mL), and 2-methylprop-2-yl 2,6-diazaspiro[3.3]heptane-2-carboxylate (338 mg, 1.7 mmol) and N,N-diisopropylethylamine (735 mg, 5.68 mmol) were added, and the mixture was stirred at 90°C for 4 hours. After the reaction, the reaction mixture 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to obtain the title compound, 2-methylprop-2-yl 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (400 mg, 1.13 mmol, yield 99.36%). LC / MS (ESI) M / Z: 354.2 [M+H] + .

[0553] Step 6: 2-Methylprop-2-yl 6-[5-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3- [1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane- 2-Carboxylate

[0554] At room temperature, 2-methylpropane-2-yl-6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 0.57 mmol), (4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol[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). 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (37 mg, 0.06 mmol) was added under nitrogen protection and 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 ethyl acetate (3x The organic phase was extracted with 10 mL of 4% paraformaldehyde (10 mL), washed with saturated brine, 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 obtain the title compound, 2-methylpropan-2-yl 6-[5-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (294 mg, 0.45 mmol, yield: 78.8%). LC / MS (ESI) M / Z: 661.4 [M+H] + .

[0555] Step 7: 2-Methylprop-2-yl 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl [3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3] Heptane-2-carboxylate

[0556] 2-Methylpropan-2-yl 6-[5-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (294 mg, 0.45 mmol) was dissolved in dichloromethane (3 mL), N-chlorosuccinimide (56 mg, 0.42 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to obtain the title compound, 2-methylpropan-2-yl 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (150 mg, 0.22 mmol, yield: 48.5%). LC / MS (ESI) M / Z: 695.3 [M+H] + .

[0557] Step 8: (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-5-yl]pyrazolo[3.3]heptan-2-yl] ... [1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0558] 2-Methylpropan-2-yl 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (150 mg, 0.22 mmol) 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, the mixture was concentrated under reduced pressure to give the title compound (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptane-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] + .

[0559] Step 9: 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazol[1,5-a] [pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carbonitrile

[0560] (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptane-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 completed, 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-100% ethyl acetate) to obtain 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-carbonitrile (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).

[0561] 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)piperidine-1-carbonitrile

[0562]

[0563] Step 1: 5-Fluoro-2-vinylpyridine

[0564] 2-Bromo-5-fluoropyridine (50 g, 284.107 mmol), potassium vinyl trifluoroborate (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 stirred at 80°C under nitrogen for 3 hours. The reaction solution was cooled to room temperature, methyl tert-butyl ether was added, and the solution was filtered. The resulting solution was washed with water, saturated sodium bicarbonate solution, and saturated brine to remove ethanol from the reaction solution. The resulting organic phase was dried over anhydrous sodium sulfate and filtered. The methyl tert-butyl ether was removed by vacuum distillation (the temperature was kept below 15°C during the vacuum distillation process) to obtain 43.5 g of the crude product, 5-fluoro-2-vinylpyridine. Proceed immediately to the next step. The product showed no ion current information in LCMS.

[0565] Step 2: (R)-1-(5-Fluoropyridin-2-yl)ethane-1,2-diol

[0566] 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) was added AD-mix-β (416.22 g, 534.313 mmol) in portions under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Aqueous sodium sulfite solution was added to the reaction mixture to quench the reaction mixture, which was then stirred at room temperature for 1 hour. The mixture was extracted with a mixture of isopropanol and ethyl acetate (1:1) (100 mL x 3). The organic phases were combined, washed with 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 product). LC / MS (ESI) M / Z: 158.1 [M+H] + .

[0567] Step 3: (R)-2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol

[0568] 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) was added tert-butyldimethylsilyl chloride (37.77 g, 250.605 mmol) at 0°C. The reaction mixture was also warmed to room temperature and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with water (200 mL x 4) and then 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 obtain the title compound. ( R)-2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol (41 g, yield: 66.31%, ee.: 86.48%). LC / MS (ESI) M / Z: 272.2 [M+H] + .

[0569] Step 4: tert-Butyl 4-(4-bromo-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0570] 1-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-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 mL 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 obtain the title compound (13.0 g, 35.01 mmol, yield: 76.48%). LC / MS (ESI) M / Z: 371.2 / 373.3

[0571] [M+H] + .

[0572] Step 5: 2-Methylprop-2-yl 4-[5-cyclopropyl-4-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5- [tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine Pyridine-1-carboxylate

[0573] 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]piperidine-1-carboxylate (5.07 g, 11.943 mmol), 1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-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 minutes. 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) and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%-50%) to give the title compound, 2-methylpropan-2-yl 4-[5-cyclopropyl-4-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]piperidine-1-carboxylate (5.7 g, 8.408 mmol, yield: 70.40%). LC / MS (ESI) M / Z: 678.4 [M+H] + .

[0574] 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-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1,2,3-triazol-1-yl] Hexahydropyridine-1-carboxylate

[0575] To a solution of 2-methylpropan-2-yl 4-[5-cyclopropyl-4-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]piperidine-1-carboxylate (5.7 g, 8.408 mmol) in dichloromethane (90 mL) was added N-chlorosuccinimide (1.10 g, 8.240 mmol). The reaction was stirred at room temperature 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 saturated sodium chloride aqueous 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-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1,2,3-triazol-1-yl]piperidine-1-carboxylate (4.4 g, 6.177 mmol, 73.46%). LC / MS (ESI) M / Z: 712.3 [M+H] + .

[0576] Step 7: (2S)-2-({3-chloro-6-[5-cyclopropyl-1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]pyrrolidone oxazolo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol

[0577] A solution of 2-methylpropan-2-yl 4-[5-cyclopropyl-4-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]piperidine-1-carboxylate (4.4 g, 6.177 mmol) and a solution of hydrogen chloride in dioxane (4 M, 4.6 mL) in dioxane (60 mL) was stirred at room temperature for one hour. The reaction solution was distilled under reduced pressure on 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)ethan-1-ol (3.8 g, yield: 98.84%). LC / MS (ESI) M / Z: 498.2 [M+H] + .

[0578] 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-carbonitrile

[0579] To a solution of (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)ethan-1-ol (3.84 g, 6.177 mmol) and N,N-diisopropylethylamine (3.98 g, 30.885 mmol) in dichloromethane (50 mL) was added cyanogen bromide (1.31 g, 12.354 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with dichloromethane and water, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0% to 10%) to give 2.8 g of a crude product, which was then purified by reverse phase purification (ACN:H2O = 0% to 50%) 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)piperidine-1-carbonitrile (2.7 g, 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).

[0580] 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 dihydrogen phosphate

[0581]

[0582]

[0583] Step 1: (S)-4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-((methylthio)methoxy)ethoxy)pyridin-2-yl)-2-((methylthio)methoxy)ethoxy)pyridin-2-yl) (1,5-a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0584] A solution of sodium hydride suspension (172.09 mg, 4.302 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature, and iodine (212.05 mg, 0.478 mmol) was added in one portion. 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]hexahydropyridine-1-carbonitrile (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 degrees, and (chloromethyl)(methyl)sulfane (184.66 mg,

[0585] The mixture was stirred at this temperature for 3 hours, then slowly warmed to room temperature and stirred for 13 hours. Ethyl acetate (20 mL) and saturated aqueous NH4Cl solution (20 mL) were added to the reaction mixture at a temperature below 5 degrees Celsius and stirred. After warming to ambient temperature, the layers were separated, and the organic layer was washed with saturated aqueous sodium chloride solution (40 mL) and dried over 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 obtain 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)piperidine-1-carbonitrile (280 mg, yield: 50%). LC / MS(ESI)M / Z:583.2[M+H] + .

[0586] Step 2: (S)-(2-((3-chloro-6-(1-(1-cyanopiperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazole-4- (5-fluoropyridin-2-yl)ethoxy)methyl dihydrogen phosphate

[0587] A solution of 4-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-3-oxa-5-thioxo-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carbonitrile (280 mg, 0.480 mmol), H3PO4 (387.52 mg, 3.361 mmol), and 4A molecular sieves (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 saturated aqueous NaHCO3. The mixture was then filtered through celite. The mixture was separated and the aqueous layer was back-extracted with ethyl acetate (10 mL). The combined organic layers were concentrated to give a crude product, which was purified by reverse phase HPLC (ACN / H 2O: 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

[0588] [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).

[0589] 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-carbonitrile

[0590]

[0591] Reaction route:

[0592]

[0593] Steps:

[0594] Step 1: Benzyl 4-hydroxy-3,4-dihydropyridine-1(2H)-carboxylate

[0595] Benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (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 stirred for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water (100 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 purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to obtain benzyl 4-hydroxy-3,4-dihydropyridine-1(2H)-carboxylate (3.4 g, 14.6 mmol, yield: 74.9%). LC / MS (ESI) M / Z: 234.2 [M+H] + .

[0596] Step 2: Benzyl 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate

[0597] Under nitrogen, benzyl 4-hydroxy-3,4-dihydropyridine-1(2H)-carboxylate (3.4 g, 14.6 mmol) and diethylzinc (14.6 ml, 1 M, 146 mmol) were dissolved in dichloromethane (40 mL). Diiodomethane (39 g, 146 mmol) was added at 0°C and stirred for 3 hours. After the reaction, water (100 mL) 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to afford benzyl 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate (2 g, 8.1 mmol, yield: 55.5%). LC / MS (ESI) M / Z: 248.2 [M+H] + .

[0598] Step 3: tert-Butyl 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate

[0599] To a solution of benzyl 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate (2 g, 8.1 mmol) in methanol (20 mL) were added palladium on carbon (200 mg) and di-tert-butyl dicarbonate (2.65 g, 12.2 mmol). The reaction was stirred overnight under a hydrogen atmosphere. After completion of the reaction, 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to afford tert-butyl 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.1 g, 5.16 mmol, yield: 63.8%). LC / MS (ESI) M / Z: 214.4 [M+H] + .

[0600] Step 4: tert-Butyl 5-((methylsulfonyl)oxy)-2-azabicyclo[4.1.0]heptane-2-carboxylate

[0601] To a solution of tert-butyl 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.1 g, 5.16 mmol) in dichloromethane (15 mL) was added triethylamine (1.56 g, 15.5 mmol) and p-toluenesulfonyl chloride (10.3 mmol) at 0°C, and the mixture was stirred at room temperature for 1 hour. After the reaction, water (30 mL) was added, and the mixture was extracted with dichloromethane (3*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 tert-butyl 5-((methylsulfonyl)oxy)-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.15 g, 3.95 mmol). LC / MS (ESI) M / Z: 292.4 [M+H] + .

[0602] Step 5: tert-Butyl 5-azido-2-azabicyclo[4.1.0]heptane-2-carboxylate

[0603] Dissolve tert-butyl 5-((methylsulfonyl)oxy)-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.15 g, 3.95 mmol) in N,N-dimethylformamide (10 mL), add sodium azide (513 mg, 7.9 mmol), and heat to 80°C under nitrogen with stirring for 3 hours. After the reaction, cool the reaction solution to room temperature, add water (50 mL), and extract with ethyl acetate (3 x 20 mL). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to obtain the title compound (780 mg, 3.28 mmol, 83% yield). LC / MS (ESI) M / Z: 239.4 [M+H] +.

[0604] Steps 6 to 14 were performed according to the synthesis 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-carbonitrile. LC / MS (ESI) M / Z: 509.9 [M+H] + .

[0605] 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-carbonitrile

[0606]

[0607] Using the synthetic route and steps of Example 115, replacing ethyl 3-oxobutyrate with ethyl 3-oxobutyrate-4,4,4-d3, Compound Example 24 was synthesized.

[0608]

[0609] Steps:

[0610] 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-carbonitrile

[0611] Under nitrogen atmosphere at room temperature, a solution of (2S)-2-((3-chloro-6-(5-(methyl-d 3)To a solution of 1-(5-azaspiro[3.5]nonan-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) were added cyanogen bromide (12 mg, 0.12 mmol) and N,N-diisopropylamine (38 mg, 0.29 mmol). The reaction mixture was left to react at room temperature for 1 hour. After the reaction was completed, 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 purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-5% methanol) to obtain a crude target compound. The crude product was then subjected to reverse phase purification (ACN:H2O=10%-50%) to obtain a 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-carbonitrile (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).

[0612] Example 36: (S)-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-4-(1- Methyl (5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

[0613]

[0614]

[0615] Step 1: (S)-4-(4-(4-(2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl tert-Butyl (1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0616] To a mixed solution of tert-butyl 4-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (300 mg, 0.9 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added (S)-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (446 mg, 0.9 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (56 mg, 0.1 mmol), and potassium carbonate (357 mg, 2.6 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 90°C for 2 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 (100 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40%-60% ethyl acetate) to obtain (S)-tert-butyl 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-carboxylate (260 mg, 0.4 mmol, yield: 46%) as a light yellow oil. LC / MS (ESI) M / Z: 652.3 [M+H] + .

[0617] Step 2: (S)-4-(4-(4-(2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl tert-Butyl (3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0618] (S)-tert-Butyl 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-carboxylate (260 mg, 0.4 mmol) was dissolved in dichloromethane (5 mL), N-iodosuccinimide (68 mg, 0.4 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40%-60% ethyl acetate) to obtain (S)-tert-butyl 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-carboxylate (250 mg, 0.3 mmol, yield: 81%) as a light yellow oil. LC / MS (ESI) M / Z: 778.2 [M+H] + .

[0619] Step 3: (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

[0620] (S)-tert-Butyl 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-carboxylate (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(diphenylphosphino-9,9-dimethylxanthene) (10 mg, 0.02 mmol), 4-dimethylaminopyridine (11 mg, 0.1 mmol) and dicobalt octacarbonyl (954 mg, 2.8 mmol) were added. The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 2 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 (100 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40%-60% ethyl acetate) to obtain (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%) as a pale yellow oil. LC / MS (ESI) M / Z: 710.3 [M+H] + .

[0621] Step 4: (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

[0622] To a solution of (S)-methyl 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-carboxylate (44 mg, 0.06 mmol) in dichloromethane (2 mL) was added 4 M hydrochloric acid solution in dioxane (2 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was dried to give a crude white solid (S)-methyl 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-carboxylate (20 mg, 0.04 mmol, 65% yield), which was used directly in the next step without further purification. LC / MS (ESI) M / Z: 496.2 [M+H] + .

[0623] Step 5: (S)-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-4-(1-(5- (2-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0624] To a solution of (S)-methyl 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-carboxylate (20 mg, 0.04 mmol) in dichloromethane (3 mL) were added N,N-diisopropylamine (104 mg, 0.8 mmol) and nitrile bromide (13 mg, 0.1 mmol), and 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 60%-80% ethyl acetate) to obtain (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%) as a white solid. 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).

[0625] 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-carbonitrile

[0626]

[0627] Step 1: tert-Butyl 6-(5-bromo-6-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0628] To a solution of 3-bromo-6-fluoro-2-methylpyridine (150 mg, 0.8 mmol) in dimethyl sulfoxide (5 mL) was added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (157 mg, 0.8 mmol) and N,N-diisopropylethylamine (306 mg, 2.4 mmol), and the reaction mixture was stirred at 90°C for 3 hours. After completion of the reaction, the reaction mixture 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 20%-35% ethyl acetate) to obtain tert-butyl 6-(5-bromo-6-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 0.5 mmol, yield: 69%) as a light yellow solid. LC / MS(ESI)M / Z:368.1[M+H] + .

[0629] Step 2: (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl tert-(2-(2-(2-(2-(2-pyridin-2-yl)pyrazolo[1,5-a]pyridin-6-yl)-6-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid) Butyl ester

[0630] To a mixed solution of tert-butyl 6-(5-bromo-6-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 0.5 mmol) in dioxane (4 mL) and water (0.4 mL) was added (S)-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) at room temperature under a nitrogen atmosphere. The reaction solution was heated to 90°C and stirred for 2 hours. After the reaction was completed, 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-45% ethyl acetate) to give (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%) as a light yellow oil. LC / MS (ESI) M / Z: 675.3 [M+H] + .

[0631] Step 3: (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl [1,5-a]pyridin-6-yl)-3-chloropyrazolo[1,5-a]pyridin-6-yl]-6-methylpyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic Tert-butyl ester

[0632] (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), N-chlorosuccinimide (57 mg, 0.4 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with dichloromethane (30 mL*3). The organic phase was washed with saturated brine. The product was washed, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-45% ethyl acetate) to give (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%) as a pale yellow oil. LC / MS (ESI) M / Z: 709.3 [M+H] + .

[0633] 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

[0634] 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) was added trifluoroacetic acid (2 mL), and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the pH of the reaction solution was adjusted to alkaline with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (30 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain 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]+ .

[0635] 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-carbonitrile

[0636] To a solution of (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) in dichloromethane (5 mL) were added N,N-diisopropylethylamine (104 mg, 0.8 mmol) and nitrile bromide (41 mg, 0.3 mmol), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was added to water (10 mL) and extracted with dichloromethane (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-45% ethyl acetate) to give (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-carbonitrile (70 mg, 0.09 mmol, yield: 79%) as a white solid. 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).

[0637] Example 51: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyrrolidone (6-pyridinyl)-5-methyl-1,2,3-triazol- [Azacyclopentyl]hexahydropyridine-1-carbonitrile

[0638]

[0639] Step 1: 2-Methylpropane-2-yl 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0640] To a solution of 4,6-dichloro-5-methylpyrimidine (200 mg, 1.23 mmol) in 1,4-dioxane (5 mL) were added 2-methylpropan-2-yl 2,6-diazaspiro[3.3]heptane-2-carboxylate (243 mg, 1.23 mmol) and N,N-diisopropylethylamine (793 mg, 6.14 mmol) at room temperature and stirred at 50 degrees for 2 hours. After the reaction, 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to obtain the title compound, 2-methylpropan-2-yl-6-(6-chloro-5-methylpyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (400 mg, 1.13 mmol, yield 97.9%). LC / MS (ESI) M / Z: 325.2 [M+H] + .

[0641] Step 2: 2-Methylprop-2-yl 6-[6-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3- [oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro [3.3] Heptane-2-carboxylate

[0642] 2-Methylpropan-2-yl-6-(6-chloro-5-methylpyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 0.62 mmol) was dissolved in 1,4-dioxane (4 mL) and water (1 mL) at room temperature, and potassium carbonate (255 mg, 1.85 mmol) and 4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (317 mg, 0.62 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (40 mg, 0.06 mmol) were added. The reaction was carried out at 90 degrees Celsius for 2 hours under nitrogen protection. After the reaction, 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, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / ethyl acetate, gradient: 0%-80% ethyl acetate) to obtain the compound 2-methylpropan-2-yl 6-[6-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (240 mg, 0.36 mmol, yield: 57.7%). LC / MS(ESI)M / Z:676.4[M+H] + .

[0643] Step 3: 2-Methylprop-2-yl 6-[6-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl [3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazo Heterospiro[3.3]heptane-2-carboxylate

[0644] To a solution of 2-methylpropan-2-yl 6-[6-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (240 mg, 0.36 mmol) in dichloromethane (3 mL) was added chlorosuccinimide (45 mg, 0.34 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL*3), and 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 the product, 2-methylpropan-2-yl 6-[6-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (180 mg, 0.25 mmol, yield: 71.4%), as a yellow solid. LC / MS (ESI) M / Z: 710.4 [M+H] + .

[0645] Step 4: (2S)-2-({3-chloro-6-[4-(2,6-diazaspiro[3.3]heptane-2-yl)-5-methylpyrimidine-6- 1-[(5-fluoropyridin-2-yl)-1-ol]pyrazolo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol

[0646] 2-Methylpropan-2-yl 6-[6-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (180 mg, 0.25 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature overnight. 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]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). LC / MS (ESI) M / Z: 496.2 [M+H] + .

[0647] 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-carbonitrile

[0648] (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, and the mixture was stirred at room temperature for 1 hour. After the reaction, 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, and concentrated under reduced pressure. 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-carbonitrile (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).

[0649] Example 52: 6-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[3-(4-(5-fluoropyridin-2-yl)-2-hydroxyethyl)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy]pyrazolo[3-(4-(5-fluoropyridin-2-yl)-2-hydroxyethyl)-1-(5-fluoropy [1,5-a]pyridin-6-yl)-2-cyanophenyl]-2,6-diazaspiro[3.3]heptane-2-carbonitrile

[0650]

[0651] Refer to the experimental procedure of 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).

[0652] Example 53: 4-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[3-( ... [1,5-a]pyridin-6-yl)-2-cyanophenyl]piperazine-1-carbonitrile

[0653]

[0654] Refer to the experimental procedure of 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).

[0655] 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-carbonitrile

[0656]

[0657] Using the synthetic route and steps of Example 50, replacing 3-bromo-6-fluoro-2-methylpyridine with 5-bromo-2-fluoro-4-methylpyridine 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).

[0658] 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-carbonitrile

[0659]

[0660] Step 1: tert-Butyl 4-(6-chloro-5-methylpyrimidin-4-yl)piperazine-1-carboxylate

[0661] To a solution of 4,6-dichloro-5-methyl-pyrimidine (200 mg, 1.2 mmol) in dimethyl sulfoxide (5 mL) at room temperature under a nitrogen atmosphere were added tert-butyl piperazine-1-carboxylate (229 mg, 1.2 mmol) and N,N-diisopropylethylamine (476 mg, 3.7 mmol). The reaction mixture was allowed to react at 90°C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 1% to 3% methanol) to afford tert-butyl 4-(6-chloro-5-methylpyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 1.0 mmol, yield: 78%) as a light yellow solid. LC / MS(ESI)M / Z:313.1[M+H] + .

[0662] The subsequent steps refer to 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)

[0663] 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-carbonitrile

[0664]

[0665] Using the synthetic route and steps of Example 50, replacing 3-bromo-6-fluoro-2-methylpyridine with 5-bromo-2-chloronicotinamide 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).

[0666] 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-carbonitrile

[0667]

[0668] Using the synthetic route and steps of Example 50, replacing 3-bromo-6-fluoro-2-methylpyridine with 5-bromo-2-fluoropyridine 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).

[0669] 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-carbonitrile

[0670]

[0671] Using the synthetic route and steps of Example 50, 3-bromo-6-fluoro-2-methylpyridine was replaced with 4,6-dichloropyrimidine in the table below to synthesize compound

[0672] 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).

[0673] 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-carbonitrile

[0674]

[0675] Step 1: tert-Butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0676] Under a nitrogen atmosphere at room temperature, to a solution of (4-bromophenyl)boronic acid (200 mg, 1.0 mmol) in dichloromethane (5 mL) were added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (99 mg, 0.5 mmol), triethylamine (252 mg, 2.5 mmol), and copper acetate (181 mg, 1.0 mmol). The reaction mixture was left to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered through celite, the filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 15%-20% ethyl acetate) to obtain the target compound tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (130 mg, 0.4 mmol, yield: 84%) as a white solid. LC / MS (ESI) M / Z: 353.0 [M+H] + .

[0677] The subsequent steps refer to 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).

[0678] 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-carbonitrile

[0679]

[0680] Reaction route:

[0681]

[0682] Steps:

[0683] Step 1: tert-Butyl 6-(4-bromo-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0684] Under nitrogen atmosphere at room temperature, to a solution of 4-bromo-2-fluoro-1-iodobenzene (150 mg, 0.5 mmol) in 1,4-dioxane (5 mL) were added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (99 mg, 0.5 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.1 mmol), palladium acetate (11 mg, 0.05 mmol), and cesium carbonate (487 mg, 1.5 mmol). The reaction mixture was incubated at 100°C for 2 hours. After completion of the reaction, 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 obtain the target compound, tert-butyl 6-(4-bromo-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (140 mg, 0.4 mmol, yield: 76%), as a white solid. LC / MS (ESI) M / Z: 371.0 [M+H] + .

[0685] The subsequent steps refer to 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).

[0686] Example 61: 4-(4-(3-chloro-4-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy 1-Methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0687]

[0688] Step 1: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl methanesulfonate

[0689] 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 dichloromethane (5 mL). The reaction mixture was stirred in an ice bath for 5 minutes. Methanesulfonyl chloride (216 mg, 1.9 mmol) was then added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the target compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl methanesulfonate (200 mg, 0.4 mmol, 68% yield) was obtained as a colorless oil. The structure of the intermediate was confirmed in the next step. The crude target product was used directly in the next step without further purification.

[0690] Step 2: 4-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrazolo[1, tert-Butyl 5-(5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0691] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl methanesulfonate (134 mg, 0.6 mmol) in N,N-dimethylformamide (5.00 mL) at room temperature under a nitrogen atmosphere were added tert-butyl 4-(4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (150 mg, 0.4 mmol) and cesium carbonate (368 mg, 1.1 mmol). The reaction mixture was incubated at 90°C for 15 minutes. After completion of the reaction, 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 evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-6% methanol) to obtain the target product, tert-butyl 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-carboxylate (120 mg, 0.2 mmol, yield: 60%) as a pale yellow oil. LC / MS (ESI) M / Z: 540.3 [M+H] + .

[0692] The subsequent steps refer to 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).

[0693] Example 62: (S)-4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[3-(4-(3-ethynyl) ... [1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0694]

[0695] 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-triazole-1- tert-Butyl)piperidine-1-carboxylate

[0696] To a solution of tert-butyl (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-carboxylate (400 mg, 0.5 mmol) in tetrahydrofuran (10 mL) at room temperature under a nitrogen atmosphere were added trimethylsilylene (151 mg, 1.5 mmol), bistriphenylphosphine palladium dichloride (Pd(PPh3)2Cl2) (36 mg, 0.05 mmol), triethylamine (260 mg, 2.5 mmol), and cuprous iodide (10 mg, 0.05 mmol). The reaction mixture was incubated at 60°C for 4 hours. After completion of the reaction, the reaction solution was added to water (15 mL) and extracted with ethyl acetate (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by reverse phase purification (ACN:H2O = 0%-50%) to obtain the target compound (S)-tert-butyl 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-carboxylate (270 mg, 0.4 mmol, 70%) as a pale yellow oil. LC / MS (ESI) M / Z: 748.3 [M+H] + .

[0697] Step 2: (S)-4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1, tert-Butyl 5-(5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0698] Under a nitrogen atmosphere at room temperature, 1 mol / L tetrabutylammonium fluoride (0.3 mL) was added to a solution of tert-butyl (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-carboxylate (80 mg, 0.1 mmol) in dichloromethane (2 mL). The reaction mixture was left to react at room temperature for 6 hours. After completion of the reaction, the reaction mixture was added to water (5 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-5% methanol) to obtain the target compound (S)-tert-butyl 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-carboxylate (40 mg, 0.07 mmol, 67%) as a yellow oil. LC / MS (ESI) M / Z: 562.2 [M+H] + .

[0699] Step 3: (S)-2-((3-ethynyl-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolidone) Oxazo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0700] To a solution of tert-butyl (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-carboxylate (40 mg, 0.07 mmol) in dichloromethane (2 mL) was added zinc bromide (48 mg, 0.2 mmol) at room temperature, and the reaction mixture was stirred at 40°C for 24 hours. After the reaction was completed, 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) as a light brown solid crude product. LC / MS (ESI) M / Z: 462.2 [M+H] + .

[0701] 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)piperidine-1-carbonitrile

[0702] To a solution of (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) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylamine (28 mg, 0.2 mmol) and cyanogen bromide (9 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10%) to obtain 15 mg of a crude product. The crude product was then purified by reverse phase purification (ACN:H2O = 0%-50%) to obtain the 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)piperidine-1-carbonitrile (10 mg, 0.02 mmol, yield: 48%) as a white solid. 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).

[0703] Example 63: ( S)-4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy) 1-[(1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile (ee: 77.14%)

[0704]

[0705] Steps:

[0706] Step 1: (R)-2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethanol

[0707] (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). 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 warmed 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 spin-dried to dryness. This afforded the crude product (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethanol (25 g, crude) as a yellow oil. LC / MS(ESI)M / Z:272.1[M+H] + .

[0708] Step 2: (S)-6-Bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy) Pyrazolo[1,5-a]pyridine

[0709] Dissolve (R)-2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethanol (25 g) in DMF (250 mL), add 6-bromopyrazolo[1,5-a]pyridin-4-ol (15.334 g, 72.331 mmol) and cesium carbonate (64.309 g, 197.268 mmol), and heat the reaction mixture to 80 degrees Celsius for 1 hour. Dilute the reaction mixture with 300 mL of water and extract the reaction mixture three times with 300 mL of ethyl acetate. Combine the organic phases, wash with 300 mL of saturated brine, dry over anhydrous sodium sulfate, and spin dry. The crude product was purified by silica gel column chromatography (PE / EA = 10:1) to give (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%) as a yellow oil. LC / MS (ESI) M / Z: 466.1 [M+H] + .

[0710] Step 3: (S)-4-(2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

[0711] Dissolve (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) in dioxane (400 mL). Add 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)-1,3,2-dioxaborolane (11.71 g, 45.729 mmol), potassium acetate (11.22 g, 114.323 mmol), and Pd(dppf)Cl2 (2.79 g, 3.811 mmol). The reaction mixture was heated to 90°C for 5 hours under nitrogen protection. The reaction mixture was directly carried out to the next step without post-treatment. LC / MS(ESI)M / Z:514.2[M+H] + .

[0712] Step 4: (S)-4-(4-(4-(2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy) tert-Butyl (1,5-a)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0713] To the reaction mixture from the previous step, add H2O (10 mL), tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylate (13.1 g, 37.945 mmol), K2CO3 (15.73 g, 113.834 mmol), and Pd(dtbpf)Cl2 (1.24 g, 1.897 mmol). The reaction mixture was protected by nitrogen and heated to 100°C for 4 hours. The reaction mixture was 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 spin-dried. The crude product was purified by silica gel column chromatography (PE / (EA:EtOH=3:1)=3:1) to afford (S)-tert-butyl 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-carboxylate (14.8 g, 22.734 mmol, 59.91%) as a yellow oil. LC / MS (ESI) M / Z: 652.3 [M+H] + .

[0714] Step 5: (S)-2-(5-fluoropyridin-2-yl)-2-(6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-trifluoromethyl)-1H-1,2,3-trifluoromethyl)-2-(6-(5-methyl-1-piperidin-4-yl)-1H-1,2,3-trifluoromethyl ...2-(6-(5 oxazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethanol

[0715] (S)-tert-Butyl 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-carboxylate (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. The product was directly dried to give (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) as a yellow solid. LC / MS(ESI)M / Z:438.2[M+H] + .

[0716] 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-carbonitrile

[0717] (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). 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 spin-dried. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10:1) to afford (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)piperidine-1-carbonitrile (3.05 g, 6.595 mmol, 48.08%) as a yellow oil. LC / MS (ESI) M / Z: 463.2 [M+H] + .

[0718] Step 7: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-iodopyrazolo[1,5-a] (6-pyridinyl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0719] Dissolve (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)piperidine-1-carbonitrile (3.05 g, 6.595 mmol) in dichloromethane (50 mL). Add N-iodosuccinimide (1.48 g, 6.595 mmol). Allow the reaction mixture to react at room temperature for 18 hours. Dried mixture was then spun down to dryness. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10:1) to afford (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)piperidine-1-carbonitrile (3.98 g, 6.088 mmol, 92.31%) as a yellow oil. LC / MS (ESI) M / Z: 589.1 [M+H] + .

[0720] Step 8: (S)-4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrrolidone (1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0721] (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)piperidine-1-carbonitrile (3.88 g, 6.594 mmol) was dissolved in DMF (40 mL), and bistriphenylphosphine palladium dichloride (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 solution was protected by nitrogen, and ethynylcyclopropane (1.31 g, 19.783 mmol) was added dropwise. The reaction solution 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 then spin-dried. The crude product was purified by silica gel column chromatography (PE / (EA:EtOH=3:1)=1:1) to obtain 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)piperidine-1-carbonitrile (Example 63, 1.8 g, ee: 77.14%). LC / MS (ESI) M / Z: 527.2 [M+H] + .

[0722] 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).

[0723] Example 64: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1- 1-[(1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile (ee: 79%)

[0724]

[0725] Step 1: (S)-4-(4-(2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy 1-(3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl tert-Butyl formate

[0726] To a solution of trimethyl(prop-1-yn-1-yl)silane (108 mg, 1.0 mmol) in methanol (3 mL) at room temperature under a nitrogen atmosphere were added potassium carbonate (133 mg, 1.0 mmol), tetrakistriphenylphosphine palladium (37 mg, 0.03 mmol), cuprous iodide (6 mg, 0.03 mmol) and triethylamine (162 mg, 1.6 mmol), and the mixture was stirred at room temperature for 30 minutes. Subsequently, a solution of tert-butyl (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-carboxylate (250 mg, 0.3 mmol) in tetrahydrofuran (3 mL) was added the mixture. The reaction mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was added to water (15 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by reverse phase purification (ACN:H₂O = 0%-50%) to obtain the target compound (S)-tert-butyl 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-carboxylate (80 mg, 0.1 mmol, yield: 36%) as a pale yellow oil. LC / MS (ESI) M / Z: 690.3 [M+H] + .

[0727] Step 2: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyrrolidone tert-Butyl (oxazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0728] Under a nitrogen atmosphere at room temperature, 1 mol / L tetrabutylammonium fluoride (0.7 mL) was added to a solution of tert-butyl (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-carboxylate (80 mg, 0.1 mmol) in dichloromethane (2 mL). The reaction mixture was left to react at room temperature for 6 hours. After completion of the reaction, the reaction mixture was added to water (5 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3%-5% methanol) to obtain the target compound (S)-tert-butyl 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-carboxylate (50 mg, 0.09 mmol, yield: 60%) as a yellow oil. LC / MS (ESI) M / Z: 576.2 [M+H] + .

[0729] 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

[0730] To a solution of tert-butyl (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-carboxylate (50 mg, 0.09 mmol) in dichloromethane (2 mL) was added zinc bromide (59 mg, 0.3 mmol) at room temperature, and the reaction mixture was stirred at 40°C for 24 hours. After the reaction was completed, 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) as a light brown solid crude product. LC / MS (ESI) M / Z: 476.2 [M+H] + .

[0731] Step 4: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyrrolidone (1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0732] 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 N,N-dimethylformamide (2 mL) was added N,N-diisopropylamine (34 mg, 0.3 mmol) and cyanogen bromide (11 mg, 0.1 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10%) to obtain 15 mg of a crude product. The crude product was then purified by reverse phase purification (acetonitrile: water = 0%-50%) to obtain the 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)piperidine-1-carbonitrile (8 mg, 0.02 mmol, yield: 30%) as a white solid. 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).

[0733] Example 65: ({1-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[omicron]- [1,5-a]pyridin-6-yl)-2-cyanophenyl]-3-(hydroxymethyl)azetidin-3-yl}methyl)azetidin-3-yl azetidin-3-yl

[0734]

[0735] Refer to the experimental procedure of 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).

[0736] Example 66: 4-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[3-(4-[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy] ... [1,5-a]pyridin-6-yl)-3-cyanopyridin-2-yl]piperazine-1-carbonitrile

[0737]

[0738] Refer to the experimental procedures of 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).

[0739] Example 67: 6-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[3-(4-(5-fluoropyridin-2-yl)-2-hydroxyethyl)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy]pyrazolo[3-(4-(5-fluoropyridin-2-yl)-2-hydroxyethyl)-1-(5-fluoropy [1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carbonitrile

[0740]

[0741] Refer to the experimental procedures of 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).

[0742] 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]heptan-2-yl}ethan-1-one

[0743]

[0744] Refer to the experimental procedure of 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).

[0745] 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

[0746]

[0747] Refer to the experimental procedure of 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).

[0748] Example 70: 1-{6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazole 6-pyridin-2-yl)pyridine- 2-yl]-2,6-diazaspiro[3.3]heptan-2-yl}prop-2-en-1-one

[0749]

[0750] Refer to the experimental procedures of 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).

[0751] Example 71: 2-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[3-(4-[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy] ... [1,5-a]pyridin-6-yl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane-7-carbonitrile

[0752]

[0753] Refer to the experimental procedure of 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).

[0754] Example 72: (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-5-yl]pyridin-2-yl] Oxazo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0755]

[0756] Refer to the experimental procedures of 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).

[0757] Example 73: (S)-2-((3-chloro-6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyrrolidone pyridin-3-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0758]

[0759] Refer to the experimental procedure of 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).

[0760] 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)piperazin-1-yl)nicotinamide

[0761]

[0762] Refer to the experimental procedures of 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).

[0763] Example 75: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyrrolidone [(6-pyridin-5-yl)-1,2,3-triazacyclopentan-1-yl)hexahydropyridine-1-carbonitrile]

[0764]

[0765] Refer to the experimental procedure of 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).

[0766] Example 76: 2-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[3-(4-[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy] ... [1,5-a]pyridin-6-yl)pyridin-2-yl]-2-azaspiro[3.3]heptane-6-carbonitrile

[0767]

[0768] Refer to the experimental procedure of 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).

[0769] Example 77: (S)-2-((3-chloro-6-(6-(7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl) pyridin-3-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0770]

[0771] Refer to the experimental procedure of 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).

[0772] 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-carbonitrile

[0773]

[0774] Steps:

[0775] Step 1: 5-((tert-Butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0776] 3-Iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol (5 g, 14.528 mmol) was dissolved in dichloromethane (50 mL). Imidazole (2.97 g, 43.585 mmol) and TBSCl (2.63 g, 17.434 mmol) were added, and 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 spin-dried to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.3 g, 12.369 mmol, 85.13%) as a yellow solid. LC / MS(ESI)M / Z:459.1[M+H] + .

[0777] Step 2: 5-[(tert-butyldimethylsilyl)oxy]-1-(tetrahydro-2H-pyran-2-yl)-3-(trimethyltin yl)-1H-indazole

[0778] 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). Hexamethyltin (4.29 g, 13.100 mmol) and tetrakistriphenylphosphine palladium (0.50 g, 0.437 mmol) were added. Under nitrogen, the reaction mixture was heated to 115°C for 8 hours. The reaction mixture was quenched with 50 mL of 1M 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 spin-dried to dryness. This afforded crude 5-[(tert-Butyldimethylsilyl)oxy]-1-(tetrahydro-2H-pyran-2-yl)-3-(trimethyltinyl)-1H-indazole (3 g, 6.048 mmol, 138.51%) as a yellow solid. LC / MS(ESI)M / Z:497.1[M+H] + .

[0779] Step 3: 4-(4-(5-((tert-Butyldimethylsilyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- tert-Butyl 3-methyl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0780] 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 tert-butyl 4-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (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. The crude product was directly spin-dried and passed through a silica gel column (PE / (EA:EtOH=3:1)=3:1) to obtain 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)piperidine-1-carboxylate (650 mg, 1.091 mmol, 62.75%) as a yellow solid. LC / MS (ESI) M / Z: 597.3 [M+H] + .

[0781] Step 4: 4-(4-(5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2, tert-Butyl 3-triazol-1-yl)piperidine-1-carboxylate

[0782] Dissolve 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)piperidine-1-carboxylate (300 mg, 0.503 mmol) in THF (10 mL). Add 1M TBAF in tetrahydrofuran (1.007 mL, 1.007 mmol). The reaction mixture is allowed to react at room temperature for 1 hour. Dilute the reaction mixture with 30 mL of water and extract it three times with 30 mL of ethyl acetate. Combine the organic phases, wash with 50 mL of saturated brine, dry over anhydrous sodium sulfate, and spin dry. The crude product was purified by silica gel column chromatography (PE / EA=1:1) to give a yellow oily substance, tert-butyl 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-carboxylate (230 mg, 0.477 mmol, 94.68%).

[0783] LC / MS(ESI)M / Z:482.3[M+H] + .

[0784] Step 5: (S)-1-(3,5-Dichloropyridin-4-yl)ethyl methanesulfonate

[0785] (S)-1-(3,5-dichloropyridin-4-yl)ethanol (300 mg, 1.562 mmol) was dissolved in dichloromethane (10 mL). 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 allowed to react 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 spin-dried to dryness. This afforded crude (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (500 mg, 1.859 mmol, 118.98%) as a yellow oil.

[0786] LC / MS(ESI)M / Z:270.1[M+H] + .

[0787] Step 6: 4-(4-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl) tert-Butyl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0788] Tert-butyl 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-carboxylate (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 solution was heated to 100°C and reacted for 5 hours. The reaction solution 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 spin-dried. A crude yellow oil was obtained. The crude product was purified by silica gel column chromatography (PE / EA = 1:1) to afford 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-carboxylate (130 mg, 0.198 mmol, 53.26%) as a yellow oil. LC / MS (ESI) M / Z: 656.2 [M+H] + .

[0789] 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

[0790] 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-carboxylate (130 mg, 0.198 mmol) was dissolved in DCM (2 mL), and a 4M solution of HCl in dioxane (1 mL, 4.000 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was directly spin-dried 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] + .

[0791] 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-carbonitrile

[0792] (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 solution was reacted at room temperature for 1 hour. The reaction mixture was directly filtered and passed through a C18 reverse phase column (0.1% FA in water / ACN) to afford (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-carbonitrile (24.32 mg, 0.049 mmol, 15.40%) as a white solid. LC / MS (ESI) M / Z: 497.1 [M+H] + .

[0793] 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).

[0794] 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-carbonitrile

[0795]

[0796] Steps:

[0797] Step 1: (R)-2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl methanesulfonate

[0798] (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 warmed 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 spin-dried to dryness. This afforded crude (R)-2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl methanesulfonate (235 mg, 0.673 mmol, 91.38%) as a yellow oil. LC / MS(ESI)M / Z:350.1[M+H] + .

[0799] Step 2: tert-Butyl 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-carboxylate

[0800] (R)-2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethyl methanesulfonate (235 mg, 0.673 mmol) was dissolved in DMF (2 mL). 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 (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 spin-dried to obtain a crude yellow oil. The crude product was purified by silica gel column chromatography (PE / EA=1:1) to give tert-butyl 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-carboxylate (90 mg, 0.122 mmol, 59.06%) as a yellow oil. LC / MS (ESI) M / Z: 736.4 [M+H] + .

[0801] 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

[0802] Tert-butyl 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-carboxylate (70 mg, 0.095 mmol) was dissolved in dichloromethane (5 mL), zinc bromide (107.09 mg, 0.476 mmol) was added, and the reaction solution was reacted at room temperature for 24 hours. The reaction mixture was directly dried 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] + .

[0803] 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)piperidine-1-carbonitrile

[0804] 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). DIEA (79.38 mg, 0.614 mmol) and cyanogen bromide (32.53 mg, 0.307 mmol) were added, and 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 spin-dried. The 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)piperidine-1-carbonitrile (94 mg, 0.142 mmol) was obtained as a yellow oil. LC / MS (ESI) M / Z: 661.3 [M+H] + .

[0805] 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)piperidine-1-carbonitrile

[0806] 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-carbonitrile (94 mg, 0.142 mmol) was dissolved in dichloromethane (2 mL) and methanol (0.3 mL), and a 4M HCl solution in dioxane (2 mL, 8.000 mmol) was added. The reaction solution was reacted at room temperature for 18 hours. The reaction mixture was dried by rotary evaporation and passed through a reverse phase column (C18) using a (1 / 1000 ammonium bicarbonate aqueous solution:acetonitrile) system to afford (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-carbonitrile (9.09 mg, 0.020 mmol, 13.80%) as a white solid. LC / MS (ESI) M / Z: 463.2 [M+H] + .

[0807] 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).

[0808] Example 84: 4-(4-(3-chloro-4-((1-(4-fluorophenyl)but-2-yn-1-yl)oxy)pyrazolo[1,5-a]pyrrolidone pyridin-6-yl)-5-

[0809] Methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0810]

[0811] Step 1: 1-(4-Fluorophenyl)but-2-yn-1-ol

[0812] 4-Fluorobenzaldehyde (2 g, 16.129 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction temperature was lowered to 0°C, and a solution of 1-propynylmagnesium bromide in tetrahydrofuran (35 mL, 17.742 mmol, 0.5 M) was added dropwise. After complete addition, the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and dried to dryness. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford 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] + .

[0813] Step 2: 1-(4-Fluorophenyl)but-2-yn-1-yl methanesulfonate

[0814] 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 allowed to react at 0°C for 1 hour. The reaction solution was diluted with 50 mL of water and extracted with dichloromethane (30 mL*3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and spin-dried to dryness. The crude product 1-(4-fluorophenyl)but-2-yn-1-yl methanesulfonate (496 mg, 2.050 mmol, 84.12%) was obtained as a yellow oil. The product was directly processed into the next step without purification. LC / MS (ESI) M / Z: 243.0 [M+H] +

[0815] 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-carboxylate

[0816] Dissolve 2-methyl-2-propanol 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylate (500 mg, 1.255 mmol) in DMF (10 mL). Add cesium carbonate (1226.53 mg, 3.764 mmol) and tert-butyl 4-(4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (304 mg, 1.255 mmol). Heat the reaction mixture to 40°C for 3 hours. Dilute the reaction mixture with 30 mL of water and extract with ethyl acetate (30 mL x 3). Combine the organic phases, wash with 50 mL of saturated brine, dry over anhydrous sodium sulfate, and spin dry. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20:1) to afford the crude product. The crude product was then purified by reverse phase column chromatography (0.05% FA in H2O / ACN) to afford 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-carboxylate (87 mg, 0.160 mmol, 12.73%). LC / MS (ESI) M / Z: 545.3 [M+H] +

[0817] Step 4: tert-Butyl 4-(4-(3-chloro-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-carboxylate

[0818] 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-carboxylate (87 mg, 0.160 mmol) was dissolved in DCM (5 mL), and NCS (20.26 mg, 0.152 mmol) was added. The reaction mixture was reacted at room temperature for 8 hours. The reaction mixture was dried to give a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3:1) to give tert-butyl 4-(4-(3-chloro-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-carboxylate (70 mg, 0.109 mmol, 68.11%) as a yellow solid. LC / MS (ESI) M / Z: 579.2 [M+H] + .

[0819] Step 5: 3-chloro-4-((1-(4-fluorophenyl)but-2-yn-1-yl)oxy)-6-(5-methyl-1-(piperidin-4-yl) -1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine

[0820] Tert-butyl 4-(4-(3-chloro-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-carboxylate (62 mg, 0.107 mmol) was dissolved in DCM (10 mL) and ZnBr2 (120.55 mg, 0.535 mmol) was added. The reaction solution was heated to 35°C for 24 hours. The crude product 3-chloro-4-((1-(4-fluorophenyl)but-2-yn-1-yl)oxy)-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine (100 mg, 0.209 mmol, 195.01%) was obtained by direct spin drying. The product was directly used for the next step without purification. LC / MS (ESI) M / Z: 479.2 [M+H] + .

[0821] Step 6: 4-(4-(3-chloro-4-((1-(4-fluorophenyl)but-2-yn-1-yl)oxy)pyrazolo[1,5-a] (6-pyridinyl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0822] 3-Chloro-4-((1-(4-fluorophenyl)but-2-yn-1-yl)oxy)-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine (100 mg, crude product) was dissolved in DMF (3 mL), cyanogen bromide (27.86 mg, 0.263 mmol) was added, and the reaction solution was reacted at room temperature for 1 hour. The reaction mixture was directly passed through a reverse phase column (C18, 0.1% H2O:ACN) to obtain 4-(4-(3-chloro-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-carbonitrile (3.33 mg, 0.007 mmol, 5.02%) as a white solid. LC / MS (ESI) M / Z: 504.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),8.11(s,1H),7.62-7.58(m,2H),7.25(t,J=8.8Hz,2H),6.06(d,J=4.2Hz,1H),5.87-5. 86(d,J=4.6Hz,1H),4.63-4.58(m,1H),3.60-3.57(m,2H),3.29-3.26(m,2H),2.26(s,3H),2.21-2.02(m,4H),1.33(s,3H).

[0823] Example 90: (S)-2-(4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazole (1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)acetonitrile

[0824]

[0825] Steps:

[0826] Step 1: (S)-2-(4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[3-(4-(3-ethynyl) ... [1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)acetonitrile

[0827] Under a nitrogen atmosphere at room temperature, to a solution of (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 (see Example 62, 30 mg, 0.07 mmol) in dichloromethane (2 mL) were added bromoacetonitrile (15.59 mg, 0.13 mmol) and N,N-diisopropylamine (42.01 mg, 0.325 mmol). The reaction mixture was left to react at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10%) to obtain 25 mg of a crude product. The crude product was then purified by reverse phase purification (ACN:H2O = 0%-50%) to obtain the target product (S)-2-(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-yl)acetonitrile (20 mg, 0.04 mmol, 61%) as a white solid. LC / MS (ESI) M / Z: 501.2 [M+H] + .

[0828] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.6Hz,1H),8.49(d,J=1.0Hz,1H),8.22(s,1H ),7.79-7.73(m,2H),7.05(d,J=1.0Hz,1H),5.67(dd,J=6.0,4.4Hz,1H),5.08(t ,J=5.6Hz,1H),4.52-4.42(m,1H),4.21(s,1H),4.00-3.90(m,2H),3.81(s,2H), 2.95(d,J=11.1Hz,2H),2.47-2.40(m,5H),2.19-2.09(m,2H),2.07-2.00(m,2H).

[0829] Example 99: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-5-nitropyrazolo[1, 5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0830]

[0831] Steps:

[0832] Step 1: 4-(4-(4-hydroxy-5-nitropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol- tert-Butyl oxazol-1-yl)piperidine-1-carboxylate

[0833] To a solution of ...

Claims

1. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof; wherein The compound is as shown in formula (A); in R1 is selected from the group consisting of: none, H, cyano, -alkylene-cyano, R 11 -SO2- and -alkylene-SO2-R 11 , where R 11 is hydrogen, alkyl, heterocyclyl, aryl or heteroaryl; is a 4- to 10-membered heterocyclic ring or C 4-10 Cycloalkanes, among which X1 is a carbon atom or a nitrogen atom, X2 is selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom, S, SO and SO2, m is 0, 1, 2, 3, or 4; and R2 is each independently selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or two R2 substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-, 4-, 5-, or 6-membered spirocyclic ring, or two R2 substituted on adjacent carbon atoms together with the carbon atom to which they are attached form a 3-, 4-, 5-, or 6-membered fused ring; and when X2 is an oxygen atom (O), S, SO or SO2, R1 is absent; Z1, Z2 and Z3 are each independently a carbon atom or a nitrogen atom; Z4 is absent or is a carbon atom or a nitrogen atom, provided that when Z4 is absent, Z1 is directly connected to the carbon atom to which R3 is attached, The prerequisite is in It is aromatic and Also optionally one or more (preferably one) R 31 replace; R3 is hydrogen, cycloalkyl, alkyl, deuterated alkyl or deuterated cycloalkyl; R 31 Selected from the group consisting of cyano, halogen, cycloalkyl, alkyl, deuterated alkyl or deuterated cycloalkyl; for in Asterisk * indicates The asterisk ** indicates the site of attachment to Y, and R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -COOR 4a 、-COR 4a , nitro, -N(R 4b )R 4a 、-N(R 4a )COR 4b 、-N(R 4a )SOR 4b 、-N(R 4a )SO2R 4b , -alkylene-R 4b , -alkenylene-R 4b or -alkynylene-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 heterocyclyl or optionally substituted heteroaryl, wherein the optional substitution refers to the replacement of hydrogen on the group by one or more R 4c replaced by; among them, R 4c Select the following group: halogen, cyano, alkyl, hydroxy, -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, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino); p1 and p2 are each independently 0, 1, 2 or 3, provided that the chemical valence bond theory is satisfied; Y is -O-, -S- or -NR8-, wherein R8 is hydrogen or alkyl; R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein the alkyl is unsubstituted or further substituted with hydroxy, halogen, alkoxy, alkenyl, alkynyl, phosphinoylalkoxy, aryl, heteroaryl, heterocyclyl, or cycloalkyl, and the alkenyl and alkynyl are unsubstituted or further substituted with alkyl or cycloalkyl; and the aryl, heteroaryl, heterocyclyl, and cycloalkyl are further optionally substituted with one or more substituents selected from the group consisting of alkyl, oxo, aryl, heteroaryl, heterocyclyl, or cycloalkyl; does not exist or middle is a six-membered heteroaryl, phenyl, cycloalkyl or heterocyclyl, q is 0, 1, 2, 3 or 4, and R7 is halogen, alkyl, hydroxyalkyl or haloalkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof; characterized in that The compound is a compound of formula (I); wherein X1, Z1, Z2, Z3, Z4, R1, R2, R3, R4, R5, R6, R7, m, p1, p2, Cy1, Cy2, and ring A are as defined in claim 1.

3. The compound according to claim 2, wherein The compound is a compound of formula (IA), wherein X1, Z1, Z2, Z3, Z4, R1, R2, R3, R4, R5, R6, R7, m, p1, p2, Cy1, Cy2, and ring A are as defined in claim 2.

4. The compound according to claim 3, wherein for Asterisks** indicate sites linked to Y R4 is selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, -N(R 4b )R 4a , where R 4a and R 4b are each independently selected from the group consisting of hydrogen, alkyl; R5 is ethynyl or -ethynylene-R 4b , where R 4b Selected from the following group: cyano, optionally substituted alkyl, optionally substituted cycloalkyl, wherein the optional substitution means that the hydrogen on the group is replaced by one or more R 4c replaced by; among them, R 4c Select from the following group: halogen, cyano, alkyl, hydroxy, -SH, alkoxy, alkylthio.

5. The compound according to claim 1, wherein The compound is a compound of formula (IA), in, R1 is cyano; is a 4- to 10-membered heterocyclic ring, wherein X1 is a carbon atom or a nitrogen atom, m is 0, 1, 2, 3, or 4; and R2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two R2 substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-, 4-, 5-, or 6-membered spirocyclic ring, or two R2 substituted on adjacent carbon atoms together with the carbon atom to which they are attached form a 3-, 4-, 5-, or 6-membered fused ring; Z1, Z2 and Z3 are nitrogen atoms; Z4 does not exist, and Z1 is directly connected to the carbon atom to which R3 is attached, R3 is hydrogen, cycloalkyl, alkyl, deuterated alkyl or deuterated cycloalkyl; for in Asterisk * indicates The asterisk ** indicates the site of attachment to Y, and R4 is selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, -N(R 4b )R 4a , where R 4a and R 4b are each independently selected from the group consisting of hydrogen, alkyl; R5 is ethynyl or -ethynylene-R 4b , where R 4b Selected from the following group: optionally substituted alkyl, wherein the optional substitution refers to the hydrogen on the group being replaced by one or more R 4c replaced by; among them, R 4c Select the following group: halogen, cyano, alkyl, hydroxy, -SH, -alkylthio; Y is -O- or -NH-; R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein the alkyl is unsubstituted or further substituted with hydroxy, halogen, alkoxy, alkenyl, alkynyl, phosphinoylalkoxy, aryl, heteroaryl, heterocyclyl, or cycloalkyl, and the alkenyl and alkynyl are unsubstituted or further substituted with alkyl or cycloalkyl; and the aryl, heteroaryl, heterocyclyl, and cycloalkyl are further optionally substituted with one or more substituents selected from the group consisting of alkyl, oxo, aryl, heteroaryl, heterocyclyl, or cycloalkyl; does not exist or middle is a six-membered heteroaryl, phenyl, cycloalkyl or heterocyclyl, q is 0, 1, 2, 3 or 4, and R7 is halogen, alkyl, hydroxyalkyl or haloalkyl.

6. The compound according to claim 1, wherein The compounds are selected from Table B.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof and a pharmaceutically acceptable excipient.

8. Use of the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer or prodrug thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating or preventing a disease.

9. The use according to claim 8, characterized in that The disease is selected from the group consisting of cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome, or a combination thereof.

10. The use according to claim 9, characterized in that The cancer is selected from the group consisting of urothelial carcinoma, urothelial carcinoma, urothelial bladder cancer, upper urinary tract cancer, urothelial upper urinary tract cancer, urethral cancer, 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, bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

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