New FGFR3 inhibitor compound

Abstract

The present invention relates to an FGFR3 selective inhibitor compound or a pharmaceutically acceptable salt thereof. The compound can be used for treating cancer such as urothelial cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, or Muenke syndrome.

Description

Novel fgfr3 inhibitor compounds TECHNICAL FIELD

[0001] The present invention belongs to the field of medicinal chemistry, in particular to novel FGFR3 selective inhibitor compounds. The present invention provides novel FGFR3 selective inhibitor compounds or pharmaceutically acceptable salts, isotopologues, tautomers, stereoisomers or prodrugs thereof, and uses thereof as medicaments. The compounds can be used for treating cancer such as urothelial carcinoma, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delays and acrogeria or muenke syndrome. BACKGROUND

[0002] Fibroblast Growth Factors (FGFs) play a critical 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 through interaction with specific receptors, and thus affect the development of an organism and the maintenance of tissue homeostasis. The Fibroblast Growth Factor Receptors (FGFRs) family consists of five members, four of which, 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] Binding of FGF to FGFR triggers receptor dimerization and autophosphorylation, which in turn activates the tyrosine kinase activity of the receptor. This receptor activation process is able to recruit and activate specific downstream signaling molecules, thus participating in the regulation of a variety of important biological processes such as cell growth, metabolism, and survival. Activation of the FGF / FGFR signaling pathway is closely related to the changes in biological behaviors of tumor cells such as proliferation, migration, invasion, and angiogenesis.

[0004] Given the role of the FGF / FGFR signaling pathway in a variety of biological processes, especially in the important position in tumorigenesis, research and regulation of the FGF / FGFR signaling pathway has become a hot field of biomedical research. The development of compounds or drugs that can selectively regulate the FGF / FGFR signaling pathway has important clinical significance and application prospects for the treatment of related diseases, especially tumors. SUMMARY

[0005] The present application aims to provide a new FGFR3 inhibitor, which regulates FGF / FGFR signaling pathway by selectively inhibiting the activity of FGFR3, and provides a new strategy and means for the treatment of FGFR3 related diseases. The FGFR3 inhibitor of the present application has high selectivity, good bioavailability and pharmacokinetic characteristics, and low side effects, and has important clinical application prospects.

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

[0007] wherein each variable 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.

[0008] In some embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof, as an FGFR3 inhibitor

[0009] wherein each variable R1, R2, m, X1, Z1, Z2, Z3, Z4, R3, Cy1-Cy2, R4, p1, R5, p2, Y, R6, R7, and q are as defined herein.

[0010] In a second aspect of the present application, there is provided a pharmaceutical composition comprising a compound of the present application, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0011] In a third aspect of the present application, there is provided use of a compound of the present application, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof, in the manufacture of a medicament for treating or preventing a disease (such as uroepithelial cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delays and acrocephaly (SADDAN), muenke syndrome, or cancer).

[0012] In a fourth aspect of the present application, there is provided a method of treating or preventing a disease (such as cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delays and acrocephaly (SADDAN), muenke syndrome, or a combination thereof), the method comprising administering to a subject in need thereof a compound of the present application, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof.

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

[0014] The present invention is described below with reference to specific implementation schemes and embodiments, but the scope of the present invention should not be limited thereto. Attached Figure Description

[0015] Figure 1 shows the tumor growth curve (left) and body weight change trend (right) of the mouse RT112 model in test case 4. Detailed Implementation Plan

[0016] definition

[0017] Unless specifically defined in this application, all technical and scientific terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0018] Unless the context clearly indicates otherwise, the singular forms of the terms “a / an” and “the” as used in this application (including the claims) include their respective plural references.

[0019] Unless otherwise expressly stated, the connection direction of groups or segments in this invention is read from left to right. For example, The left end of the segment is connected to R1, and its right end is connected to... Link; other groups or segments are interpreted in a similar manner.

[0020] Unless otherwise stated, bonds marked with wavy lines or dashed lines in the structure of this application represent positions where they are connected to other parts of the molecule.

[0021] The term "alkyl" includes those selected from those containing 1 to 18 carbon atoms. 1-18 Alkyl groups (e.g., 1 to 12 C) 1-12 Alkyl groups, further such as 1 to 10 C16 groups. 1-10 Alkyl groups, and even more specifically, those with 1 to 8 carbon atoms. 1-8 Alkyl groups, or 1 to 6 C16 groups 1-6 Alkyl groups, or 1 to 4 C16 groups 1-4 Alkyl groups are straight-chain and branched saturated hydrocarbon groups containing carbon atoms, either substituted or unsubstituted. Alkyl groups (i.e., C164-C65) are alkyl groups containing 1 to 6 carbon atoms. 1-6Examples 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.

[0022] The term "alkenyl" includes substituted or unsubstituted hydrocarbyl radicals selected from straight and branched chain hydrocarbon groups with at least one C=C double bond and 2 to 18, i.e., C2-C18alkenyl groups. 2-18 alkenyl groups (e.g., 2 to 8, i.e., C2-C8alkenyl groups). 2-8 alkenyl groups (e.g., 2 to 6, i.e., C2-C6alkenyl groups). 2-6 alkenyl groups (e.g., 2 to 4, i.e., C2-C4alkenyl groups). 2-4 alkenyl groups (e.g., 2 to 4, i.e., C2-C4alkenyl groups). Examples of alkenyl groups include ethenyl (C2alkenyl), 1 -propenyl (C3alkenyl), 2-propenyl (C3alkenyl), 1 -butenyl (C4alkenyl), 2-butenyl (C4alkenyl), butadienyl (C4alkenyl), pentenyl (C5alkenyl), pentadienyl (C5alkenyl), hexenyl (C6alkenyl), and the like.

[0023] The term "alkynyl" includes substituted or unsubstituted hydrocarbyl radicals selected from straight and branched chain hydrocarbon groups with at least one CºC triple bond and 2 to 18, i.e., C2-C18alkynyl groups. 2-18 alkynyl groups (e.g., 2 to 8, i.e., C2-C8alkynyl groups). 2-8 alkynyl groups (e.g., 2 to 6, i.e., C2-C6alkynyl groups). 2-6 alkynyl groups (e.g., 2 to 4, i.e., C2-C4alkynyl groups). 2-4 alkynyl groups (e.g., 2 to 4, i.e., C2-C4alkynyl groups). Examples of alkynyl groups include ethynyl (C2alkynyl), 1 -propynyl (C3alkynyl), 2-propynyl (C3alkynyl), 1 -butynyl (C4alkynyl), 2-butynyl (C4alkynyl), pentynyl (C5alkynyl), hexynyl (C6alkynyl), and the like. 2-6 alkynyl groups (e.g., 2 to 4, i.e., C2-C4alkynyl groups). Examples of alkynyl groups include ethynyl (C2alkynyl), 1 -propynyl (C3alkynyl), 2-propynyl (C3alkynyl), 1 -butynyl (C4alkynyl), 2-butynyl (C4alkynyl), pentynyl (C5alkynyl), hexynyl (C6alkynyl), and the like.

[0024] The term "halogen" means fluorine (F), chlorine (CI), bromine (Br), and iodine (I).

[0025] The term "halo-substituted" or "halo" means substituted with F, Cl, Br, or I, including but not limited to substituted with one to ten substituents selected from F, Cl, Br, or I, substituted with one to six substituents selected from F, Cl, Br, or I, substituted with one to four substituents selected from F, Cl, Br, or I.

[0026] The term "haloalkyl" means an alkyl group as defined above substituted with one or more halo groups. In some embodiments, a "haloalkyl" is a C 1-2 haloalkyl, C 1-4 haloalkyl, or C 1-6 haloalkyl. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CC13, -CH2C1, -CHC12, 2,2,2-trifluoro-l,l-dimethyl-ethyl, and the like.

[0027] The term "alkoxy" means substituted or unsubstituted -O-alkyl, alkyl being as previously defined. Non-limiting examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. Similarly, the term "alkylthio" means substituted or unsubstituted -S-alkyl, alkyl being as previously defined. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, cyclopropylthio, and the like.

[0028] The term "amino" means -NH2.

[0029] The terms "alkylamino" and "dialkylamino" mean an amino group substituted with one or two alkyl groups, respectively, i.e., -NH(alkyl) and -N(alkyl)2, alkyl being as previously defined.

[0030] The terms "cycloalkyl" or "cycloalkane" are used interchangeably and mean a substituted or unsubstituted saturated carbocyclic ring radical, typically having from 3 to 12 carbon atoms, i.e., C 3-12 cycloalkyl. Cycloalkyl includes monocyclic C 3-8 , for example monocyclic C 3-6 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like; cycloalkyl also includes bicyclic cycloalkyl, for example 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, and the like. Cycloalkyl groups appearing in the present application are as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0031] The terms "heterocyclyl" or "heterocycle" are used interchangeably and include non-aromatic heterocyclyl groups whose ring members include one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spirocyclic, i.e., containing monocyclic heterocyclyl groups, bridged heterocyclyl groups, spiroheterocyclyl groups, and fused heterocyclyl groups. Monocyclic heterocyclyl groups include 3- to 8-membered heterocyclyl groups containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur, such as azirdinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, cyclobutone, pyranyl, thiopyranyl, morpholinyl, or azepinyl. Bridged heterocyclyl groups include 7- to 14-membered bridged heterocyclyl groups that are ring systems co-containing 7- to 14- atoms, including at least one heteroatom selected from nitrogen, oxygen, or sulfur, formed by two non-adjacent rings sharing two or more atoms. Spiroheterocyclyl groups include 5- to 14-membered spiroheterocyclyl groups that are cyclic structures containing carbon atoms formed by at least two rings sharing one carbon atom. SpiroC 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[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]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 heterocyclyl groups include bicyclic 6- to 14-membered heterocyclyl groups comprising 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur, and formed by two or more rings sharing two adjacent atoms. 7- to 14-membered fused heterocyclyl groups include, but are not limited to, octahydroquinoline, indoline, or tetrahydropyrrolizine.

[0032] The term "aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group. Aryl groups preferably have 6 to 10 carbon ring atoms, i.e., C6-C10 aryl groups. Aryl groups include phenyl and naphthyl groups. In some embodiments, the aryl group is phenyl. 10 Aryl. Aryl groups include phenyl and naphthyl groups. In some embodiments, the aryl group is phenyl.

[0033] The term "heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 heteroatoms or heteroatom-containing groups (including, but not limited to, N, O, or S (=O)2) in the ring. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, and the like. n, n is 0, 1, 2). In some embodiments, heteroaryl refers to a 5-14 membered, e.g., 5-10 membered, monocyclic or bicyclic ring containing ring carbon atoms and 1-4 ring heteroatoms. Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, 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 to the heteroaryl ring.

[0034] Unless otherwise specifically defined, each group (e.g., alkyl, alkylene, alkenyl, alkynyl, cycloalkane or cycloalkyl, heterocycle, aryl, or heteroaryl) in a compound of a formula (e.g., Formula A, Formula I, Formula IA, Formula IB, Formula II) of the present application includes unsubstituted or substituted forms, and when substituted, one or more (e.g., 1, 2, or 3) hydrogens on the group are replaced with a substituent group as defined herein. Unless otherwise defined, substituents of alkyl groups (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 quantities ranging from zero to (2M+1), where M is the total number of carbon atoms in this group. R a R b and R c Each independently represents hydrogen, an unsubstituted C1-8 alkyl, an unsubstituted aryl, an aryl substituted with 1-3 halogens, a C1-8 alkoxy or C1-8 thioalkoxy, or an unsubstituted -C1-4 alkylene-aryl. When R a and R b When attached to the same nitrogen atom, they can combine with the nitrogen atom to form 3-, 4-, 5-, 6-, or 7-membered rings. For example, -NR a R b This refers to the inclusion of 1-pyrrolidinyl and 4-morpholinyl groups. Similarly, unless otherwise defined, the substituents of aryl and heteroaryl groups are diverse and are generally selected from: halogens, -OR... a -OC(O)R a -NR a R b -SR a -R a -CN, -NO2, -CO2R a CONR a R b C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R a -NR a -C(O)NR b Rc, NH C(NH2)=NH, -NR aC(NH2)=NH, -NH-C(NH2)=NR a , -S(O)R a , -S(O)2R a , S(O)2NR a R b , NR a S(O)2R b , -N3, perfluoro(Ci-C4)alkoxy, and perfluoro(Ci-C4)alkyl, the number of which is zero to the total number of open valences on the aromatic ring system; wherein R a , R b and Rc are independently selected from the group consisting of hydrogen, Ci-8alkyl, C3-6cycloalkyl, C2-8alkenyl, C2-8alkynyl, unsubstituted aryl and heteroaryl, unsubstituted -Ci-4alkylene-aryl or heteroaryl and unsubstituted -Ci-4alkylene-aryloxy.

[0035] When a numerical range is listed, the range is intended to include each and every value and sub-range within the range. For example, "C 1-6 alkyl" or "Ci-C6alkyl" 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.

[0036] 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 that provides attachment at any available vertex of the aromatic ring. In some embodiments, this description also includes attachment on a ring fused to the aromatic ring. For example, a bond drawn to the center of an indole benzene moiety would represent a bond attached to any available vertex of the six- or five-membered ring portion of the indole.

[0037] "Pharmaceutically acceptable salt" means 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 of the disclosure, or separately by reacting a free base function with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0038] Additionally, if the compounds disclosed herein are obtained as acid addition salts, the free bases can be obtained by basifying these salt solutions. Conversely, if the products are the free bases, the addition salts (e.g., the pharmaceutically acceptable addition salts) can be produced by dissolving the free base in a suitable organic solvent and treating that solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those of ordinary skill in the art will recognize a variety of synthetic methodologies that can be employed without undue experimentation to produce the nontoxic pharmaceutically acceptable addition salts.

[0039] A "subject" for administration includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a bovine, a porcine, a equine, an ovine, a caprine, a rodent, a feline, and / or a canine. 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.

[0040] "Disease," "disorder," and "condition" are used interchangeably herein.

[0041] The term "treatment" means inhibiting, slowing, stopping, or reversing the progression or severity of an existing symptom, condition, or disorder.

[0042] Generally, an "effective amount" of a compound refers to an amount that is sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the application can vary depending on such factors 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 therapeutic and prophylactic effective amounts.

[0043] The compounds of the application can include one or more asymmetric centers and can therefore occur as various stereoisomeric forms, e.g., enantiomeric and / or diastereomeric forms. For example, the compounds of the application can be individual enantiomers, diastereomers or geometric isomers (e.g., cis- and trans-isomers), or can be mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be separated from mixtures 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 the preferred isomer can be prepared by asymmetric synthesis.

[0044] The compounds of the present application can also exist in tautomeric forms. Where tautomers exist, one of the compounds described is not intended to be limited to any particular tautomer, but rather is intended to encompass all tautomers.

[0045] The present application also includes isotopically-labeled compounds (isotopic variants) which are identical to those recited in Formula (I) or (II) but for the fact that 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 heteroatoms in the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. The present application also includes the prodrugs of the compounds of the present application that contain the foregoing isotopes and / or other isotopes of other atoms are within the scope of the present application. Certain isotopically-labeled compounds of the present application, for example, those into which radioactive isotopes such as 3 H and 14 C) are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled general formula compounds of the present application, such as compounds of Formula (A), and the like, and prodrugs thereof, can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0046] The term "prodrug" means a compound which, upon administration, is metabolized to yield an active drug substance. Examples of prodrugs include, but are not limited to, esters (e.g., phosphate, phosphonate, acetate, formate, and benzoate), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), and the like.

[0047] The term "deuterium (D or 2H) is a stable isotope of hydrogen, which occurs in nature with an abundance of 0.015 mole percent. The term "deuterated" means that one or more hydrogen atoms H in a group or compound are replaced by D.

[0048] Isotopic variants of the present application include deuterated compounds. A "deuterated compound" means a compound in which one or more hydrogen atoms bonded to carbon are replaced by one or more deuterium atoms. Likewise, "deuterated" means a chemical structure or organic group in which one or more hydrogen atoms bonded to carbon are replaced by one or more deuterium atoms, e.g., "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated aryl," and the like. For example, "deuterated alkyl" means an alkyl group as defined herein in which at least one hydrogen atom bonded to carbon is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to one deuterium; one carbon atom can be bonded to multiple deuterium; multiple carbon atoms in an alkyl group can be bonded to deuterium. For example, deuterated methyl includes methyl-D3, in which three hydrogen atoms are replaced by deuterium; it also includes monodeuterated methyl and di-deuterated methyl. For example, deuterated piperazinyl means that one or more hydrogen atoms in a piperazinyl group are replaced by deuterium, including piperazinyl in which all eight hydrogen atoms are replaced by deuterium. In some embodiments, compounds of the present application include deuterated compounds.

[0049] Compounds of the present application

[0050] As used herein, the term "compounds of the present application" refers to compounds as illustrated in Formula (A), (I), (IA), (IB), or (II) herein. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of the compounds of Formula (A), (I), (IA), (IB), or (II).

[0051] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is salts of acids with compounds of the present application. Suitable acids for salt formation include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, and the like; organic acids such as formic, acetic, trifluoroacetic, propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric, citric, picric, benzoic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic, and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and the like. Another preferred class of salts is salts of bases with compounds of the present application, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkylammonium salts and other pharmaceutically acceptable amine salts), such as methylammonium, ethylammonium, propylammonium, dimethylammonium, trimethylammonium, diethylammonium, triethylammonium, t-butylammonium, ethylenediammonium, hydroxyethylammonium, dihydroxyethylammonium, trihydroxyethylammonium, and amine salts of morpholine, piperazine, lysine, respectively.

[0052] The term "solvate" refers to a compound of the present application coordinated with solvent molecules in a specific stoichiometry. A "hydrate" is a solvate with water.

[0053] In addition, the compounds of the present application also include prodrugs of the compounds of Formula (A), (I), (IA), (IB), or (II). The term "prodrug" includes a compound that can itself be biologically active or inactive, which, when administered to a human, is metabolized or chemically converted within the body to form a compound of Formula (A), (I), (IA), (IB), or (II), or a salt or solution of a compound of Formula (A), (I), (IA), (IB), or (II). The prodrugs include, but are not limited to, carboxylate esters, carbonates, phosphates, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like of the compounds.

[0054] In a first aspect of the present application, the present application provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof; wherein the compound is of Formula (A);

[0055] wherein,

[0056] R1is selected from the group consisting of null, H, cyano, -alkylene-cyano (such as - methylene-cyano), R 11 -SO2- and -alkylene-SO2-R 11 wherein R 11 is hydrogen, alkyl, heterocyclyl, aryl, or heteroaryl;

[0057] wherein, is a 4- to 10-membered heterocyclic ring or C 4-10 cycloalkane, wherein

[0058] X1is a carbon atom (CH) or a nitrogen atom (N),

[0059] X2is selected from the group consisting of a carbon atom (CH), a nitrogen atom (N), an oxygen atom (O), S, SO, and SO2,

[0060] m is 0, 1, 2, 3, or 4; and

[0061] R2is each independently selected from the group consisting of hydrogen, hydroxyl, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two R2substituents on the same carbon atom, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered spirocycle (the 3-, 4-, 5-, and 6- refer to the number of ring atoms of the ring formed by the two R2substituents on the same carbon atom and the carbon atom to which they are attached), or two R2substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, or 6-membered fused (or annelated) ring (the 3-, 4-, 5-, and 6- refer to the number of ring atoms of the ring formed by the two R2substituents on adjacent carbon atoms and the carbon atoms to which they are attached);

[0062] and R1is null when X2is an oxygen atom (O), S, SO, or SO2;

[0063] Z1, Z2, and Z3are each independently a carbon atom or a nitrogen atom;

[0064] Z4is absent or is a carbon atom or a nitrogen atom, provided that when Z4is absent, Z1is directly connected to the carbon atom to which R3is attached,

[0065] with the proviso that is aromatic and is optionally substituted with one or more (preferably, one) R 31 ;

[0066] R3is hydrogen, cycloalkyl, alkyl, deuterated alkyl, or deuterated cycloalkyl;

[0067] R 31 is selected from the group consisting of cyano, halogen, cycloalkyl, alkyl, deuterated alkyl, or deuterated cycloalkyl (preferably, R 31 is cyano or halogen);

[0068] is wherein

[0069] the asterisk * indicates the point of attachment to , and the asterisk ** indicates the point of attachment to Y, and

[0070] R4and R5are each independently selected from the group consisting of hydrogen, halogen (such as F, Cl, Br), CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkenyl, alkynyl (such as ethynyl), 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 (e.g., methylene-R) 4b ), --alkenyl-R 4b (e.g. - vinylidene-R) 4b ) or -ethynyl-R 4b (e.g. - vinylidene-R) 4b ), where R 4a and R 4b Each is independently selected from the group consisting of: hydrogen, cyano, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclic or optionally substituted heteroaryl, wherein the optional substitution refers to the hydrogen on the group being replaced by one or more (e.g., 1, 2 or 3) R 4c Replaced; of which, R 4c Select the following group: halogen, cyano, alkyl, hydroxyl, -SH, -alkylthio, -C(O)H, -C(O)alkyl, -S(O) 1-2 H, -S(O) 1-2 Alkyl, amino, alkylamino, dialkylamino, -C(O)amino, -C(O)-(alkylamino), -C(O)-(dialkylamino), -S(O) 1-2 Amino group, -S(O) 1-2 -(alkylamino) and -S(O) 1-2 -(dialkylamino); or alternatively, R4 and R5 are each independently selected from the group consisting of: hydrogen, halogens (e.g., F, Cl, Br), CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, -COOR 4a -COR 4a nitro (NO2), -N (R) 4b )R 4a -N(R) 4a )COR 4b -N(R) 4a SOR 4b -N(R) 4a SO2R 4b ,-alkylene-R 4b (e.g., methylene-R) 4b ), --alkenyl-R 4b (e.g. - vinylidene-R) 4b ) or -ethynyl-R 4b (e.g., -ethynyl-R) 4b ), where R 4aand R 4b each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl,

[0071] each of pi and p2 is independently 0, 1, 2, or 3, provided that the theory of valency is satisfied;

[0072] Y is -0-, -S-, or -NR8-, wherein R8 is hydrogen or alkyl;

[0073] R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein the alkyl is unsubstituted or further substituted with hydroxyl, halogen, alkoxy, alkenyl, alkynyl, phosphonooxyalkoxy, 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 further substituted with one or more substituents selected from the group consisting of alkyl (such as methyl), oxo (=0), aryl, heteroaryl, heterocyclyl, or cycloalkyl;

[0074] is absent 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.

[0075] In some embodiments, R1 is cyano or R 11 -SO2-, wherein R 11 is hydrogen, alkyl, heterocyclyl, aryl, or heteroaryl.

[0076] In some embodiments, R1 is cyano.

[0077] In some embodiments, X1 and X2 are separated by at least one ring atom; preferably, X1 and X2 are separated by one, two, or three ring atoms.

[0078] In some embodiments, wherein the heterocycle or cycloalkane can be monocyclic or spirocyclic.

[0079] In some embodiments, when the heterocycle is a 4- to 10-membered heterocycle, only X1 and X2 can be heteroatoms.

[0080] In some embodiments, when X2 is a nitrogen atom, is a nitrogen-containing 5- or 6-membered heterocycle or a nitrogen-containing spirocycle (such as a 7- to 9-membered spirocycle). In some embodiments, when X2 is a carbon atom (CH), is a 4-, 5-, or 6-membered heterocycle or C 4-6 cycloalkane (such as cyclohexane) or spirocycle (such as a C 7-9spirocyclic). In some embodiments, X2 is an oxygen atom (O), S, SO, or SO2, is a 4-, 5-, or 6-membered heterocyclic or spirocyclic ring (e.g., a 7- to 9-membered spirocyclic ring).

[0081] In some embodiments, is selected from the group consisting of:

[0082] wherein each of n1, n2, n3, and n4 is independently 1, 2, 3, or 4, and R2and m are as defined above; preferably, each of n1, n2, n3, and n4 is independently 1 or 2.

[0083] In some embodiments, X2 is selected from the group consisting of a carbon atom, a nitrogen atom, and an oxygen atom. In some embodiments, R1is cyano or -alkylene-cyano (e.g., -methylene-cyano), and is selected from the group consisting of:

[0084] In some embodiments, R6is hydrogen or alkyl, wherein the alkyl is unsubstituted or further substituted with hydroxy, halo, alkoxy, phosphonooxyalkoxy, aryl, heteroaryl, or cycloalkyl.

[0085] In some embodiments, the carbon on which R6is located is a chiral carbon.

[0086] In some embodiments, the carbon on which R6is located is a chiral carbon in the S configuration or the R configuration; preferably, in the S configuration.

[0087] In some embodiments, wherein ring A is a six-membered heteroaryl, cycloalkyl, or heterocyclyl group, wherein q is 0, 1, 2, 3, or 4, and R7is halo, alkyl, hydroxyalkyl, or haloalkyl.

[0088] In some embodiments,

[0089] Z1, Z2, Z3, Z4, R3, R4, p1, Y, R6, R7, and q are as previously defined;

[0090] is a 4- to 10-membered heterocyclic or C 4-10 cycloalkane, wherein

[0091] X1is a carbon atom (CH) or a nitrogen atom (N),

[0092] X2is selected from the group consisting of a carbon atom (CH), a nitrogen atom (N),

[0093] m is 0, 1, 2, 3, or 4; and

[0094] R2is selected from the group consisting of hydrogen, hydroxyl, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two R2substituents on the same carbon atom, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered spiro ring, or two R2substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, or 6-membered fused ring;

[0095] R1is cyano;

[0096]

[0097] (Preferably, ) wherein

[0098] The asterisk * indicates the site of attachment to The asterisk ** indicates the site of attachment to Y, and

[0099] R4is selected from the group consisting of hydrogen, halogen (such as F, CI, Br), CN, alkyl, haloalkyl, hydroxyl, 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 -ethenylene-R 4b ), or -alkynylene-R 4b (such as -ethynylene-R 4b ), wherein R 4a and R 4b are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl; pi is 0, 1, or 2, provided that the theory of valency is satisfied;

[0100] R5is alkynyl (such as ethynyl) or -alkynylene-R 4b (such as -ethynylene-R 4b ), wherein R 4b is selected from the group consisting of hydrogen, cyano, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl, p2 is 1.​

[0101] In some embodiments, R4is 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 -vinylene-R 4b ), or -alkynylene-R 4b (such as -acetylene-R 4b ), wherein R 4a and R 4b are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl; and p1 is 0, 1, or 2, provided that the theory of valency is satisfied.

[0102] In some embodiments, R5is -alkynylene-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 means that a hydrogen on the group is replaced by one or more R 4c ; wherein, optionally, R 4c is selected from the group consisting of 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).

[0103] In some embodiments, R5is -alkynylene-R 4b ; optionally, R 4b is selected from the group consisting of cyano, optionally substituted alkyl, optionally substituted cycloalkyl, wherein the optional substitution means that a hydrogen on the group is replaced by one or more R 4c ; wherein, optionally, R 4chalogen, cyano, alkyl, hydroxy, -SH, alkoxy, alkylthio.

[0104] In some embodiments, R5is -ethynylene-R 4b ; optionally, R 4b is selected from the group consisting of cyano, alkyl, cycloalkyl.

[0105] In some embodiments, R5is ethynyl.

[0106] In some embodiments, R4is selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, -N(R 4b )R 4a , wherein R 4a and R 4b are each independently selected from the group consisting of hydrogen, alkyl; and / or R5is ethynyl or -ethynylene-R 4b , wherein 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 means that a hydrogen on the group is replaced with one or more (such as 1, 2, or 3) R 4c ; wherein R 4c is selected from the group consisting of 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).

[0107] In some embodiments, is preferably,

[0108] In some embodiments, R2is 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, R2is selected from the group consisting of hydrogen, hydroxy, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy. In some embodiments, R2is hydrogen.

[0109] In some embodiments, m is 0.

[0110] In some embodiments, In some embodiments, is a 4- to 6-membered heterocyclic ring or C 4-6 cycloalkane.

[0111] In some embodiments, X1is a carbon atom.

[0112] In some embodiments, is selected from the group consisting of:

[0113] In some embodiments, X2is a nitrogen atom. In some embodiments, is In some embodiments, the compound is represented by Formula (I);

[0114] wherein each variable (e.g., X1, Z1, Z2, Z3, Z4, R1, R2, R3, R4, R5, R6, R7, m, p1, p2, Cy1, Cy2, ring A are as defined in Formula (A).

[0115] In some embodiments, Z1is -CH-, -C=, or -N-; and / or, Z2is -CH2-, -CH=, -N=, or -NH-; and / or, Z3is -CH2-, -CH=, -N=, or -NH-; and / or, Z4is absent or -CH2-, -CH=, -N=, or -NH-.

[0116] In some embodiments, at least one of Z1, Z2, Z3, and Z4is a nitrogen atom.

[0117] In some embodiments, R4and R5are each independently hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, -COOR 4a , -COR 4a , or -NHR 4a COR 4b , wherein R 4a and R 4b are each independently hydrogen, alkyl, haloalkyl, hydroxylalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl, p1and p2are each independently 0, 1, 2, or 3, provided that the theory of chemical valence is satisfied.

[0118] In some embodiments, provided is a compound of Formula (I), or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, or prodrug thereof

[0119] wherein

[0120] R1 is a cyano group or R 11 -SO2-, where R 11 It can be hydrogen, alkyl, heterocyclic, aryl, or heteroaryl;

[0121] It is a nitrogen-containing 5- or 6-membered heterocyclic ring or a nitrogen-containing spirocyclic ring, wherein X1 is a carbon atom or a nitrogen atom, and m is 0, 1, 2, 3 or 4; and R2 is hydrogen, hydroxyl, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, or two R2s substituted on the same carbon atom together with the carbon atoms to which they are attached form a 3-, 4-, 5- or 6-membered spirocyclic ring, or two R2s substituted on adjacent carbon atoms together with the carbon atoms to which they are attached form a 3-, 4-, 5- or 6-membered fused ring;

[0122] Z1 is -CH-, -C=, or -N-

[0123] Z2 is -CH2-, -CH=, -N=, or -NH-

[0124] Z3 is -CH2-, -CH=, -N=, or -NH-

[0125] Z4 either does not exist or is -CH2-, -CH=, -N=, or -NH-, provided that when Z4 does not exist, the carbon atom of Z1 is directly bonded to R3.

[0126] The prerequisite is In It is aromatic, and at least one of Z1, Z2, Z3 and Z4 is a nitrogen atom;

[0127] R3 is hydrogen, cycloalkyl, alkyl, deuterated alkyl, or deuterated cycloalkyl;

[0128] for

[0129] The asterisk * indicates a parallelism. The sites connected, with asterisks ** indicating sites connected to Y, and

[0130] R4 and R5 are each independently hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, -COOR 4a -COR 4a or -NHR 4a COR 4b , where R 4a and R 4beach independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl, each of p1 and p2 independently is 0, 1, 2, or 3, provided that the theory of valency is satisfied;

[0131] Y is -O-, -S-, or -NR8-, wherein R8is hydrogen or alkyl;

[0132] R6is hydrogen or alkyl, wherein the alkyl is unsubstituted or further substituted by hydroxyl, halogen, alkoxy, phosphonooxyalkoxy, aryl, heteroaryl, or cycloalkyl;

[0133] Ring A is a six-membered heteroaryl, cycloalkyl, or heterocyclyl, wherein q is 0, 1, 2, 3, or 4, and R7is halogen, alkyl, hydroxyalkyl, or haloalkyl.

[0134] In some embodiments, X1is a carbon atom. In some embodiments, X1is a nitrogen atom.

[0135] In some embodiments, is selected from the group consisting of:

[0136] wherein each of n1, n2, n3, and n4 is independently 1, 2, 3, or 4, and R2and m are as defined above; preferably, each of n1, n2, n3, and n4 is independently 1 or 2.

[0137] In some embodiments, is wherein m is 2; and R2is substituted on the same carbon atom, the two R2together with the carbon atom to which they are attached form a 3-, 4-, 5-, or 6-membered spiro ring; preferably, is

[0138] In some embodiments, is wherein m is 2; and R2is substituted on adjacent carbon atoms. The two R2together with the carbon atoms to which they are attached form a 3-, 4-, 5-, or 6-membered fused ring; preferably, is

[0139] In some embodiments, is wherein R2and m are as defined above. In some embodiments, is wherein each of n1, n2, n3, and n4 is independently 1, 2, 3, or 4, and R2and m are as defined above; preferably, each of n1, n2, n3, and n4 is independently 1 or 2. In some embodiments, wherein R2and m are as defined above. wherein R2and m are as defined above.

[0140] In some embodiments, is selected from the group consisting of:

[0141] In some embodiments, is

[0142] In some embodiments, the compound or compound of Formula (I) is a compound of Formula (IA) or (IB), or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, or prodrug thereof:

[0143] In some embodiments, Z4is a carbon atom or a nitrogen atom (i.e., Z4is -CH=, -CR 31 =, or -N=).

[0144] In some embodiments, R1is attached to Z1.

[0145] In some embodiments, is

[0146] In some embodiments, the compound is a compound of Formula (IA). In some embodiments, R1is attached to Z1, Z1is a nitrogen atom or a carbon atom (Z1is -N= or =C=), Z2is a carbon atom or a nitrogen atom (i.e., Z2is -CH=, -CR 31 =, or -N=), Z3is a carbon atom or a nitrogen atom (i.e., Z3is -CH=, -CR 31 =, or -N=), and Z4is absent or is a carbon atom or a nitrogen atom (i.e., Z4is absent or -CH=, -CR 31 =, or -N=). In some embodiments, R1is attached to Z1, Z1is a nitrogen atom or a carbon atom, Z2is a carbon atom or a nitrogen atom, Z3is a carbon atom or a nitrogen atom, and Z4is absent. In some embodiments, R1is attached to Z1, Z1is a carbon atom, Z2is a carbon atom or a nitrogen atom, Z3is a carbon atom or a nitrogen atom, and Z4is a nitrogen atom. In some embodiments, R1is attached to Z1, Z1is a carbon atom, Z2is a carbon atom or a nitrogen atom, Z3is a carbon atom, and Z4is a carbon atom or a nitrogen atom.

[0147] In some embodiments, Z1, Z2, and Z3are nitrogen atoms; Z4is absent, and Z1is directly connected to the carbon atom to which R3is attached.

[0148] In some embodiments, is selected from the group consisting of:

[0149] In some embodiments, is preferably is

[0150] In some embodiments, is

[0151] In some embodiments, is preferably

[0152] In some embodiments, is selected from the group consisting of: In some embodiments, R 31 is hydrogen or cyano. In some embodiments, R3is hydrogen or alkyl.

[0153] In some embodiments, R3is H.

[0154] In some embodiments, R3is C 3-8 cycloalkyl. In some embodiments, R3is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R3is 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, for example methyl or methyl-d3. In some embodiments, R3is

[0155] In some embodiments, is wherein Z1, Z2, and Z3are carbon atoms or nitrogen atoms, provided that at least one of Z1, Z2, and Z3is a nitrogen atom. In some embodiments, is In the above embodiments, Z1, Z2, and Z3are nitrogen atoms, or Z1and Z2are nitrogen atoms and Z3is a carbon atom.

[0156] In some embodiments, R2is attached to Z4.

[0157] In some embodiments, In some embodiments,

[0158] In some embodiments, R2is attached to Z4, Z1is a nitrogen atom (e.g., -N=) or a carbon atom (e.g., -CH=), Z2is a carbon atom (e.g., -CH=) or a nitrogen atom (e.g., -N=), Z3is a carbon atom (e.g., -CH=) or a nitrogen atom (e.g., -N=), and Z4is a carbon atom (e.g., =CH=) or a nitrogen atom (e.g., -N=).

[0159] In some embodiments, is selected from the group consisting of:

[0160] In some embodiments, In some embodiments, wherein Z1, Z2, Z3, and R3are as defined in formula (I). In some embodiments, In some embodiments, In some embodiments, R3is C 1- 6alkyl.

[0161] In some embodiments, In some embodiments,

[0162] In some embodiments, at least one of pi and p2 is 1. In some embodiments, one of pi and p2 is 1 and the other is 0 or 1.

[0163] In some embodiments, R4and R5are each independently selected from the group consisting of hydrogen, halogen (e.g., F, CI, Br), CN, alkyl, haloalkyl, hydroxyl, alkynyl, cycloalkyl, -COOR 4a , -COR 4a , nitro, -N(R 4b )R 4a (e.g., -NH2), -NHSO2R 4b , -alkylene-R 4b , -alkenylene-R 4b , or -alkynylene-R 4b . In some embodiments, R 4a and R 4b are each independently selected from the group consisting of hydrogen, cyano, alkyl, or cycloalkyl (e.g., cyclopropyl).

[0164] In some embodiments, R4and R5are each independently selected from the group consisting of hydrogen, F, CI, Br, CN, alkyl, haloalkyl, or -COOR 4a . In some embodiments, R 4b is hydrogen or alkyl.

[0165] In some embodiments, R4and R5are 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, R5is selected from the group consisting of nitro, -NH2, and -NHSO2R 4b . In some embodiments, R 4b is alkyl.

[0166] In some embodiments, R4and R5are each independently selected from the group consisting of -vinyl-R 4b or -ethynylene-R 4b . In some embodiments, R 4b is each independently selected from the group consisting of hydrogen, cyano, alkyl (such as methyl), or cycloalkyl (such as cyclopropyl).

[0167] In some embodiments, R4is selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, -N(R 4b )R 4a , wherein R 4a and R 4b are each independently selected from the group consisting of hydrogen, alkyl. In some embodiments, R4is hydrogen and / or p1is 0. In some embodiments, p2is 1.

[0168] In some embodiments, R5is selected from the group consisting of hydrogen, halogen (such as F, Cl, Br), CN, alkyl, haloalkyl, hydroxyl, 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 are each independently selected from the group consisting of hydrogen, alkyl, or cycloalkyl (such as cyclopropyl).

[0169] In some embodiments, R5is 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.

[0170] In some embodiments, R5is 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, R5is selected from the group consisting of nitro, -N(R 4b )R 4a , and -NHSO2R 4b . In some embodiments, R 4a is hydrogen or alkyl (e.g., C 1-4 alkyl), and R 4b is selected from the group consisting of hydrogen, alkyl (e.g., C 1-4 alkyl), cycloalkyl (e.g., C 3-6 cycloalkyl), and heterocyclyl (e.g., 3- to 6-membered heterocyclyl). In some embodiments, R 4a is hydrogen or alkyl (e.g., C 1-4 alkyl), and R 4b is hydrogen or alkyl (e.g., C 1-4 alkyl). In some embodiments, R 4a is hydrogen, and R 4b is selected from the group consisting of hydrogen, alkyl (e.g., C 1-4 alkyl), cycloalkyl (e.g., C 3-6 cycloalkyl), and heterocyclyl (e.g., 3- to 6-membered heterocyclyl).

[0171] In some embodiments, R5is 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 optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, more preferably, R 4b is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, most preferably, R 4b is selected from the group consisting of alkyl, cycloalkyl); wherein the optional substitution means that a hydrogen on the group is replaced with one or more (e.g., 1, 2, or 3) R 4c ; optionally wherein R 4c is selected from the group consisting of 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) (preferably, R 4c halogen, cyano, alkyl, hydroxy, -SH, alkoxy, alkylthio.

[0172] In some embodiments, R5is selected from the group consisting of -vinyl-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).

[0173] In some embodiments,

[0174] In some embodiments, wherein R5is hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, or -COOR 4a wherein R 4a and R 4b each is independently hydrogen or alkyl.

[0175] In some embodiments, wherein R5is hydrogen or alkyl.

[0176] In some embodiments, wherein R5is 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 .

[0177] In some embodiments, wherein R5is selected from the group consisting of nitro, -NH2, and -NHSO2R 4b .

[0178] In some embodiments, R5is hydrogen and / or p2is 0. In some embodiments, p1is 1. ​​​​​

[0179] In some embodiments, R4is 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, R5is selected from the group consisting of nitro, -NH2.

[0180] In some embodiments, is selected from the group consisting of: preferably

[0181] In some embodiments, pi is 1 and p2 is 1.

[0182] In some embodiments, R4is 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, R5is selected from the group consisting of R5is selected from the group consisting of halogen (such as F, Cl, Br), CN, alkyl.

[0183] In some embodiments, is selected from the group consisting of: preferably

[0184] In some embodiments,

[0185] is (preferably ); optionally R5is R5is alkynyl or -alkynylene-R 4b (ethynyl or -ethynylene-R 4b ); the asterisk ** indicates the site of attachment to Y

[0186] Optionally, R4is selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, -N(R 4b )R 4a , wherein R 4a and R 4b are each independently selected from the group consisting of hydrogen, alkyl;

[0187] Optionally, R5is ethynyl or -ethynylene-R 4b , wherein, R4b selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, wherein the optional substitution means that a hydrogen on the group is replaced by one or more (such as 1, 2, or 3) R 4c substituents; wherein R 4c is selected from the group consisting of 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).

[0188] In some embodiments, is selected from the group consisting of:

[0189] In some embodiments, is selected from the group consisting of: and the like.

[0190] In some embodiments, is (preferably ), and is wherein R5 is hydrogen or alkyl (preferably hydrogen).

[0191] In some embodiments, Y is O.

[0192] In some embodiments, in R6, the alkyl is C 1-4 alkyl, and / or the alkenyl is C 2-4 alkenyl, and / or the alkynyl is C 2-4 alkynyl. In some embodiments, in R6, the aryl is phenyl, and / or the heteroaryl is 5- or 6-membered heteroaryl. In some embodiments, in R6, the heterocyclyl is 4- to 6-membered heterocyclyl, and / or the cycloalkyl is C 3-6 cycloalkyl.

[0193] In some embodiments, R6 is C 1-4 alkyl, hydroxyC 1-4 alkyl, or phosphonooxyC 1-4 alkyl(-C 1-4 alkyl(-C 1-4 alkyl(-C 1-4Alkylene-OP(=O)(OH)2). In some embodiments, R6 is methyl, hydroxymethyl (-CH2OH) or phosphonomethoxymethyl (-CH2OCH2O-P(=O)(OH)2).

[0194] In some implementations, R6 is an alkyl group (such as C6). 1-4 The alkyl group is alkyl, alkenyl, or alkynyl, wherein the alkyl group is further substituted with an alkenyl or alkynyl group and the alkenyl or alkynyl group is unsubstituted or further substituted with an alkyl or cycloalkyl group. In some embodiments, R6 is selected from the group consisting of: -methylene-C 2-4 alkenyl, -methylene-C 2-4 alkynyl, -ethynyl-C 1-4 Alkyl, -ethynyl-C 3-6 cycloalkyl, -vinylidene-C 1-4 Alkyl and -vinyl-C 3-6 Cycloalkyl. In some embodiments, R6 is selected from the group consisting of:

[0195] In some implementations, R6 is an alkyl group (such as C6). 1-4 The alkyl group is further substituted with an aryl, heteroaryl, heterocyclic, or cycloalkyl group (preferably substituted with a heterocyclic group, more preferably substituted with a morpholine or piperazine group), and the aryl, heteroaryl, heterocyclic, and cycloalkyl groups are optionally substituted with one or more substituents selected from the group consisting of: alkyl (e.g., methyl), oxo (=O), aryl, heteroaryl, heterocyclic, or cycloalkyl. In some embodiments, R6 is methyl, wherein the methyl group is further substituted with a morpholine or piperazine group, and the morpholine and piperazine groups are optionally substituted with one or more substituents selected from the group consisting of: alkyl (e.g., methyl), oxo, and heterocyclic (e.g., oxetyl). In some embodiments, R6 is selected from the group consisting of:

[0196] In some implementation schemes, ring A middle, It is a pyridine ring, a pyrimidine ring, or a monocyclic C 3-8 cycloalkyl, bicyclic C 6-11 Cycloalkyl or bicyclic heterocyclic groups, where R7 is independently a halogen or alkyl group, and q is 0, 1, or 2. In some embodiments, cycloA... middle, It is a pyridine ring, a bicyclic [3.3.0]octyl, a bicyclic [3.2.0]heptyl, a bicyclic [2.2.1]heptyl, a bicyclic [2.2.0]hexyl, a bicyclic [3.1.1]heptyl, or a tetrahydro-1H-pyrrolazinyl (e.g., tetrahydro-1H-pyrrolazin-7-yl). ), each R7is independently halogen, and q is 0, 1, or 2, wherein the group is unsubstituted or substituted with one or two halogens.

[0197] In some embodiments, ring A is 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-lH-pyrrolizine (e.g., tetrahydro-lH-pyrrolizin-7-yl ), wherein the group is unsubstituted or substituted with one or two halogens.

[0198] In some embodiments, is selected from the group consisting of:

[0199] In some embodiments, 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-lH-pyrrolizine (e.g., tetrahydro-lH-pyrrolizin-7-yl 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-lH-pyrrolizine (e.g., tetrahydro-lH-pyrrolizin-7-yl

[0200] In some embodiments, is selected from the group consisting of:

[0201] In some embodiments, ring A is 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-lH-pyrrolizine (e.g., tetrahydro-lH-pyrrolizin-7-yl

[0202] In some embodiments, the compound is according to Formula (II), wherein the variables are defined as in Formula (A) or (I); or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, or prodrug thereof.

[0203] In some embodiments, a compound of Formula (II) is provided, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, or prodrug thereof

[0204] wherein

[0205] R1is cyano or R 11 -SO2-, wherein R 11 is hydrogen, alkyl, heterocyclyl, aryl, or heteroaryl;

[0206] R2is hydrogen, hydroxyl, amino (NH2), alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or two R2substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-, 4-, 5-, or 6-membered spirocycle, or two R2substituted on adjacent carbon atoms together with the carbon atoms to which they are attached form a 3-, 4-, 5-, or 6-membered fused ring;

[0207] Z1is -CH-, -C=, or -N-

[0208] Z2is -CH2-, -CH=, -N=, or -NH-

[0209] Z3is -CH2-, -CH=, -N=, or -NH-

[0210] with the proviso that is not aromatic, and at least one of Z1, Z2, and Z3is a nitrogen atom;

[0211] is wherein the asterisk * indicates the point of attachment to , the asterisk ** indicates the point of attachment to Y, and R4and R5are each independently hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, -COOR 4a , -COR 4a , or -NHR 4a COR 4b , wherein R 4a and R 4b are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl, p1and p2are each independently 0, 1, 2, or 3, provided that the rules of chemical valence are satisfied;

[0212] Y is -O-, -S-, or -NR8-, wherein R8is hydrogen or alkyl;

[0213] R6is hydrogen or alkyl, wherein the alkyl is unsubstituted or further substituted by hydroxyl, halogen, alkoxy, phosphonooxyalkoxy, aryl, heteroaryl, or cycloalkyl;

[0214] Ring A is a six-membered heteroaryl, cycloalkyl, or heterocyclyl, wherein q is 0, 1, 2, 3, or 4, and R7is halogen, alkyl, hydroxyalkyl, or haloalkyl.

[0215] In some embodiments, X1is a carbon atom. In some embodiments, X1is a nitrogen atom. In some embodiments, wherein n1, n2, n3, and n4 are each independently 1, 2, 3, or 4, and R2and m are as defined above; preferably, n1, n2, n3, and n4 are each independently 1 or 2.

[0216] In some embodiments, wherein m is 2; and R2are substituted on the same carbon atom, the two R2together with the carbon atom to which they are attached form a 3-, 4-, 5-, or 6-membered spiro ring.

[0217] In some embodiments, wherein m is 2; and R2are substituted on adjacent carbon atoms. The two R2together with the carbon atoms to which they are attached form a 3-, 4-, 5-, or 6-membered fused ring.

[0218] In some embodiments, wherein R2and m are as defined above. In some embodiments, wherein n1, n2, n3, and n4 are each independently 1, 2, 3, or 4, and R2and m are as defined above; preferably, n1, n2, n3, and n4 are each independently 1 or 2. In some embodiments, wherein R2and m are as defined above.

[0219] In some embodiments,

[0220] In some embodiments, In the above embodiments, Z1, Z2, and Z3are nitrogen atoms, or Z1and Z2are nitrogen atoms, and Z3is a carbon atom.

[0221] In some embodiments, wherein R5is hydrogen, F, Cl, Br, CN, alkyl, haloalkyl, or -COOR 4a wherein R 4a and R 4b are each independently hydrogen or alkyl;​​​​​​​​​

[0222] In some embodiments, For

[0223] In some embodiments, Y is O.

[0224] In some embodiments, R6is C 1-4 alkyl, hydroxy C 1-4 alkyl or phosphonooxy C 1-4 alkoxy-C 1-4 alkyl. In some embodiments, R6is methyl, hydroxymethyl or phosphonooxymethoxymethyl.

[0225] In some embodiments, In some embodiments, ring A is a pyridine ring, a pyrimidine ring, a monocyclic C3-8cycloalkyl, a bicyclic C 6-11 cycloalkyl or bicyclic heterocyclyl, wherein R7is halo or alkyl, and q is 0, 1 or 2.

[0226] In some embodiments, In some embodiments, ring A is a pyridine ring, a bicyclo[3.3.0]octyl, a bicyclo[3.2.0]heptyl, a bicyclo[2.2.1]heptyl, a bicyclo[2.2.0]hexyl, a bicyclo[3.1.1]heptyl or a tetrahydro-lH-pyrrolizinyl (e.g., tetrahydro-lH-pyrrolizin-7-yl ), wherein the group is unsubstituted or substituted with one or two halogens. In some embodiments, ring A For

[0227] In some embodiments, X1, X2, Y, Z1, Z2, Z3, Z4, R1, R2, R3, R4, R5, R6, R7, subscript m, subscript p1, subscript p2, subscript q, Cy1, Cy2and and each independently is the corresponding group in a specific compound of the application (e.g., a specific compound as shown in Tables A and B).

[0228] In some embodiments, the compound is a compound selected from Table B below, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer or prodrug thereof:

[0229] Table B

[0230] Pharmaceutical compositions and methods of administration

[0231] Since the compounds of the present application have excellent FGFR3 and / or in vitro inhibitory activity against tumor cells, the compounds of the present application and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compounds of the present application as an active ingredient can be used for treating, preventing, and alleviating FGFR3-related or FGFR3-mediated diseases and tumors. According to the prior art, the compounds of the present application can be used for treating the following diseases: cancer such as uroepithelial cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delays and acrocephaly or Muenke syndrome, etc.; cancer, for example, uroepithelial cancer, bladder cancer (e.g., uroepithelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper urinary tract cancer (e.g., uroepithelial 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, renal cancer (e.g., renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0232] In a second aspect of the present application, there is provided a pharmaceutical composition comprising a compound of the first aspect, or a pharmaceutically acceptable salt, isotopologue, tautomer, stereoisomer or prodrug thereof, and a pharmaceutically acceptable excipient.

[0233] The pharmaceutical composition of the present application comprises a safe and effective amount of the compound of the present application or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present application per dose, more preferably, 10-500 mg of the compound of the present application per dose. Preferably, the "one dose" is one capsule or tablet.

[0234] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler substances or gel materials, which are suitable for human use and which are of sufficient purity and sufficiently low toxicity. By "compatible" it is meant that the components of the composition are capable of being commingled with the compounds of the application, with each other, and with other ingredients, and that the resulting mixture is stable enough to be manufactured, used, and / or stored. Examples of suitable pharmaceutically acceptable carriers are celluloses and their derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., lecithin), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like. ), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0235] The mode of administration of the compounds or pharmaceutical compositions of the present application is not narrowly critical and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0236] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as binders, (a) fillers or solubilizers, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) humectants, e.g., hydroxymethylcellulose; (c) gelling agents, e.g., alginic acid; (d) absorbents, e.g., kaolin; (e) lubricants, e.g., magnesium stearate; (f) preservatives, e.g., sodium benzoate; (g) antioxidants, e.g., ascorbic acid; (h) chelating agents, e.g., ethylenediaminetetraacetic acid; and (i) pH adjusting agents, e.g., sodium hydroxide. In addition, the following agents can be present: (a) wetting agents, e.g., propylene glycol monostearate; (b) emulsifying agents, e.g., acacia; (c) coloring agents; (d) flavoring agents; (e) sweetening agents; and (f) salivating agents.

[0237] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They can contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0238] Liquid dosage forms for oral administration include pharmaceutically- acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, and the like, citric acids, and / or sodium benzoate, and / or sorbic acid, and / or flavoring agents.

[0239] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0240] Suspensions, in addition to the active compounds, can contain suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, and the like.

[0241] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyol, and suitable mixtures thereof.

[0242] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalers. The active component is admixed with a carrier, which can be a sterile

[0243] A compound of the application can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0244] In using the pharmaceutical compositions, therapeutically effective amounts of a compound of the application are administered to a mammal (e.g., human) in need of such treatment in dosages, and the dosages are determined by the judgment of the practitioner, taking into account a variety of factors, including the age, weight, health, medical history, and the like, of the patient. Generally, oral dosages in the range of 1 to 2000 mg, preferably 20 to 500 mg, per day are appropriate for a 60 kg subject. Of course, the specific dose will depend on the route of administration, the patient's health status, and the like, and will be adjusted in the judgment of the practitioner.

[0245] In a third aspect of the application, there is provided the use of a compound of the first aspect, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer or prodrug thereof, or a pharmaceutical composition of the second aspect, in the manufacture of a medicament for the treatment or prevention of a disease.

[0246] In some embodiments, the disease is an FGFR3 -associated disease.

[0247] In some embodiments, the FGFR3-related disease is associated with a FGFR3 gene, a FGFR3 kinase protein, or a modulation abnormality associated with expression or activity or level of any of them.

[0248] 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 delays and acrogeria (SADDAN), Muenke syndrome, or a combination thereof.

[0249] In some embodiments, the disease is cancer.

[0250] In some embodiments, the cancer is selected from the group consisting of urothelial cancer, uroepithelial cancer, bladder cancer (e.g., uroepithelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g., uroepithelial upper 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, renal cancer (e.g., renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0251] In some embodiments, the cancer is selected from breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, uroepithelial cancer, bladder cancer, uroepithelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper tract cancer, uroepithelial upper tract cancer, and glioblastoma.

[0252] In some embodiments, the cancer is selected from bladder cancer, uroepithelial bladder cancer, non-muscle invasive bladder cancer, and muscle invasive bladder cancer.

[0253] In some embodiments, the cancer is urothelial cancer.

[0254] In some embodiments, the disease is FGFR3-related cancer.

[0255] In a fourth aspect of the present application, there is provided a method of treating or preventing a disease, comprising the step of administering to a subject in need thereof a compound of the first aspect of the present application, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, or prodrug thereof, or a pharmaceutical composition of the second aspect.

[0256] In some embodiments, the disease is as defined in the third aspect.

[0257] 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 delays and acrocephaly, Muenke syndrome, or a combination thereof.

[0258] In some embodiments, the present application provides a method of treating or preventing a disease, such as cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delays and acrocephaly, Muenke syndrome, or a combination thereof, the method comprising administering to a subject in need thereof a compound of the present application, or a pharmaceutically acceptable salt, isotopologue, tautomer, stereoisomer, or prodrug thereof.

[0259] In some embodiments, the cancer described herein is an FGFR3-associated cancer, which is associated with a dysregulation of FGFR3 gene, FGFR3 kinase protein, or expression or activity or level of any of the same. Examples of FGFR3-associated cancers include, but are not limited to, urothelial cancer, uroepithelial cancer, bladder cancer (e.g., uroepithelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g., uroepithelial upper 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, renal cancer (e.g., renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0260] The main advantages of the present application include

[0261] (a) The compounds of the present application have superior anti-tumor cell proliferation activity.

[0262] (b) The compounds of the present application have superior selectivity, especially, selectivity for FGFR3 in the family of fibroblast growth factor receptors (FGFRs). The preferred compounds of the present application exhibit superior inhibitory activity against FGFR3 compared to the inhibitory activity against other members of the FGFRs family, such as FGFR1.

[0263] (c) The preferred compounds of the present application exhibit significantly superior anti-tumor effects in animal models.

[0264] (d) The compounds of the present application have low toxicity.

[0265] The application will be further described in conjunction with specific examples. It should be understood that these examples are intended to illustrate but not limit the scope of this application. The experimental procedures in the following examples, unless otherwise specified, were generally in accordance with conventional procedures, for example, as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Percentages and parts are weight percentages and parts by weight, unless otherwise specified.

[0266] The reagents employed in the present application are either commercially available or synthesized by conventional methods well known in the art. Unless otherwise specified, the ee value of the chiral carbon contained in the (1S)-1-(5-fluoropyridin-2-yl) substituent contained in the examples ranges from 76% to 90%.

[0267] Preparation Examples

[0268] The reagents employed in the present application are either commercially available or synthesized by conventional methods well known in the art.

[0269] Example 1: 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

[0270] Step 1: 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridine

[0271] Dissolve 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (20 g, 88.08 mmol), bis(pinacolato)diboron (44.7 g, 176.1 mmol) and potassium acetate (25.9 g, 264.2 mmol) in 1,4-dioxane (200 mL), and add 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (3.22 g, 4.404 mmol) under nitrogen protection, heat to 85 °C and stir for 4 hours. Cool the reaction solution to room temperature, filter and concentrate. Purify the residue 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] + .

[0272] Step 2: 4-(5-cyclopropyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0273] tert-Butyl 4-azidopiperidine-l-carboxylate (24 g, 106.1 mmol), ethyl 3-cyclopropyl-3-oxopropylate (19.88 g, 127.3 mmol) and potassium carbonate (43.97 g, 318.2 mmol) were dissolved in dimethyl sulfoxide (200 mL) and the reaction was heated to 85 °C under nitrogen protection for 5 hours. The reaction was cooled to room temperature, water (500 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: 20% to 40% ethyl acetate) to give the title compound (17.1 g, 46.92 mmol, yield: 44.24%). LC / MS (ESI) M / Z: 365.3 [M+H] + .

[0274] Step 3: tert-Butyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-cyclopropyl-1H-1,2,3- triazole-4-carboxylate

[0275] tert-Butyl 4-(5-cyclopropyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1- carboxylate (17.1 g, 46.92 mmol) was dissolved in water (150 mL) and methanol (30 mL) and potassium hydroxide (5.27 g, 93.84 mmol) was added. The reaction was heated to 50 °C and stirred for 2 hours. The reaction was cooled to room temperature, water (50 mL) was added and the pH of the reaction was adjusted to 4 using 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (3 * 200 mL) and the organic phase was washed with water and saturated brine, dried under reduced pressure to give the title compound (15.4 g, 45.78 mmol, yield: 97.57%). LC / MS (ESI) M / Z: 337.2 [M+H] + .

[0276] Step 4: tert-Butyl 4-(4-bromo-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0277] To a solution of 4-(5-cyclopropyl-4-(4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3- triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (16.2 g, 27.71 mmol) in DCM (300 mL) was added TFA (30 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (300 mL) and water (100 mL) was added. The organic phase was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: DCM / MeOH, gradient: 100% DCM to 95% DCM / 5% MeOH) to give the title compound (12.0 g, 26.71 mmol, yield: 97.34%). LC / MS (ESI) M / Z: 395.3 [M+H] + .

[0278] Step 5: 4-(5-cyclopropyl-4-(4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1- yl)piperidine-1-carboxylic acid tert-butyl ester

[0279] To a solution of 4-(4-bromo-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (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) in 1,4-dioxane (150 mL) and water (30 mL) was added 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (2.26 g, 3.50 mmol) under nitrogen and heated to 85 °C 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 over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 50% to 70% ethyl acetate) to give the title compound (16.2 g, 27.71 mmol, yield: 79.13%). LC / MS (ESI) M / Z: 439.3 [M+H] + .

[0280] Step 6: 4-(5-cyclopropyl-4-(4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3-triazol-1- yl)piperidine-1-carboxylic acid tert-butyl ester

[0281] Dodecan-1-thiol (2076.94 mg, 10.262 mmol) was added to a solution containing 2-methyl-2-propyl-4-[5-cyclopropyl-4-(4-methoxy-pyrazolo[1,5-a]pyridine-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-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) and the reaction stirred at 100 °C under nitrogen for 2 hours. The reaction was also allowed to cool to room temperature, water (10 mL) and petroleum ether (3 mL) were added and the pH of the reaction adjusted to 4 with formic acid. Stirring was continued for 3 hours. The reaction was filtered under reduced pressure and the solid washed with water and then petroleum ether. The product, 2-methyl-2-propyl-4-[5-cyclopropyl-4-(4-hydroxy-pyrazolo[1,5-a]pyridine-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylate (365 mg, 0.860 mmol, 83.79% yield) was obtained by drying under reduced pressure. LC / MS (ESI) M / Z: 425.4 [M+H] + .

[0282] Step 7: 4-[5-cyclopropyl-4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl]oxy}pyrazolo[1,5-a]pyridine-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylate

[0283] To a solution of 2-methyl-2-yl 4-[5-cyclopropyl-4-(4-hydroxypyrazolo[l,5- a]pyridin-6-yl)-l,2,3-triazol-l-yl]hexahydropyridine-l-carboxylate (290 mg, 0.683 mmol), l-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-l-ylmethanesulfonate (262.63 mg, 0.751 mmol) and cesium carbonate (667.76 mg, 2.049 mmol) in N,N-dimethylformamide (1 mL) was heated to 110 °C for 30 minutes. The reaction was allowed to cool to room temperature, water (10 mL) was added and the mixture was extracted twice with ethyl acetate. The organic phase was washed with water (3*30 mL) and then 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% - 50%) to give the product 4-[5-cyclopropyl-4-(4-{[l-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-l-yl]oxy}pyrazolo[l,5-a]pyridin-6-yl)-l,2,3-triazol-l-yl]hexahydropyridine-l-carboxylate (217 mg). Yield: 45%. LC / MS (ESI) M / Z: 678.3 [M+H] + .

[0284] Step 8: tert-Butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2- yl)ethoxy)-3-chloropyrazolo[l,5-a]pyridin-6-yl)-5-cyclopropyl-lH-l,2,3-triazol-l- yl)piperidine-l-carboxylate

[0285] 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-silano-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1 -yl]hexahydropyridine-1 -carboxylate (186 mg, 0.274 mmol) in dichloromethane (1 mL) was added N-chlorosuccinimide (34.81 mg, 0.261 mmol) at room temperature and the reaction stirred at room temperature for 16 hours. To the reaction was added water (20 mL) and extracted with dichloromethane (3*20 mL), the organic phases combined and washed with saturated sodium chloride, the organic phase 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 product tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1 H-1,2,3-triazol-1-yl)piperidine-1 -carboxylate (203 mg). Yield: 93%. LC / MS (ESI) M / Z: 712.4 [M+H] + .

[0286] Step 9: 2-((3-chloro-6-(5-cyclopropyl-1-(piperidin-4-yl)-1 H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1 -ol

[0287] tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1 H-1,2,3-triazol-1-yl)piperidine-1 -carboxylate (180 mg, 0.253 mmol) and hydrochloric acid in dioxane (4M in dioxane, 5 mL) were stirred at room temperature for 1 hour. The reaction was evaporated under pressure to dryness to give crude 2-((3-chloro-6-(5-cyclopropyl-1-(piperidin-4-yl)-1 H-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] + .

[0288] Step 10: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1 H-1,2,3-triazol-1-yl)piperidine-1 -carbonitrile

[0289] 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 was stirred at room temperature for 1 h. The reaction was extracted with dichloromethane and water, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate and filtered. The residue was purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0% to 10%) to give product 80 mg, which was further purified by reverse phase (ACN:H20 = 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 (60 mg). Yield: 35%. LC / MS (ESI) M / Z: 523.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.51 (s, 1H), 8.12 (s, 1H), 7.78 (td, J = 8.8, 2.9 Hz, 1H), 7.64 (dd, J = 8.8, 4.5 Hz, 1H), 6.99 (s, 1H), 5.60 (t, J = 5.2 Hz, 1H), 5.15 (t, J = 5.7 Hz, 1H), 4.85 - 4.68 (m, 1H), 3.94 (t, J = 5.4 Hz, 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).

[0290] Example 2: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0291] Step 1: tert-Butyl 4-(5-cyclobutyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1- carboxylate

[0292] tert-Butyl 4-azidopiperidine-l-carboxylate (3.6 g, 15.9 mmol), ethyl 3-cyclobutyl-3-oxopropionate (3.0 g, 17.5 mmol) and potassium carbonate (6.6 g, 47.7 mmol) were dissolved in dimethyl sulfoxide (36 mL) and the reaction was heated to 80 °C under nitrogen for 6 hours. After completion of the reaction, the reaction was cooled to room temperature, water (100 mL) was added and the reaction was extracted with ethyl acetate (3 * 200 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 20% to 40% ethyl acetate) to give the target compound as a light yellow oil (3.6 g, 9.5 mmol, yield: 60%). LC / MS (ESI) M / Z: 379.2 [M+H] + .

[0293] Step 2: tert-Butyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-cyclobutyl-1H-1,2,3- triazole-4-carboxylate

[0294] tert-Butyl 4-(5-cyclobutyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1- carboxylate (3.6 g, 9.5 mmol) was dissolved in water (30 mL) and methanol (30 mL) and potassium hydroxide (1.1 g, 19.0 mmol) was added. The reaction was heated to 50 °C and stirred for 2 hours. After completion of the reaction, the reaction was cooled to room temperature, the pH of the reaction was adjusted to 4 using 1 M hydrochloric acid and the reaction was extracted with ethyl acetate (3 * 50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to give the target compound as a yellow oil (2.3 g, 6.6 mmol, yield: 69%). LC / MS (ESI) M / Z: 295.2 [M+H-56] + .

[0295] Step 3: tert-Butyl 4-(4-bromo-5-cyclobutyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0296] To a solution of tert-butyl 4-(5-cyclobutyl-4-(4-methoxy-pyrazolo[1,5- a]pyridin-6-yl)-1 H-1,2,3-triazol-1 -yl)piperidine-1 -carboxylate (400 mg, 0.9 mmol) in 1,4-dioxane (10 mL) was added 4M HCI in dioxane (10 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water (20 mL) and the resulting solid was collected by filtration to give the title compound as a white solid (350 mg, 0.9 mmol, 100% yield). LC / MS (ESI) M / Z: 405.3 [M+H] + .

[0297] Step 4: tert-Butyl 4-(5-cyclobutyl-4-(4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-1 H-1,2,3- triazol-1 -yl)piperidine-1 -carboxylate

[0298] To a solution of tert-butyl 4-(5-cyclobutyl-4-(4-methoxy-pyrazolo[1,5- a]pyridin-6-yl)-1 H-1,2,3-triazol-1 -yl)piperidine-1 -carboxylate (400 mg, 0.9 mmol) in 1,4-dioxane (10 mL) was added 4M HCI in dioxane (10 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water (20 mL) and the resulting solid was collected by filtration to give the title compound as a white solid (350 mg, 0.9 mmol, 100% yield). LC / MS (ESI) M / Z: 405.3 [M+H] + .

[0299] Step 5: tert-Butyl 4-(5-cyclobutyl-4-(4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-1 H-1,2,3- triazol-1 -yl)piperidine-1 -carboxylate

[0300] To a solution of tert-butyl 4-(5-cyclobutyl-4-(4-methoxy-pyrazolo[1,5- a]pyridin-6-yl)-1 H-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) was added dodecan-1 -thiol (716 mg, 3.5 mmol) and the reaction stirred at 100 °C for 3 hours under nitrogen. After completion of the reaction, the reaction was allowed to cool to room temperature, water (30 mL) was added and the reaction was extracted with ethyl acetate (3*100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3-7% methanol) to give the target compound as a white solid (305 mg, 0.7 mmol, yield: 79%). LC / MS (ESI) M / Z: 439.2 [M+H] + .

[0301] Step 6: tert-butyl 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1 -(5-fluoropyridin-2-yl)ethoxy)- 3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-cyclobutyl-1 H-1,2,3-triazol-1 -yl)piperidine-1 - carboxylate

[0302] To a solution of tert-butyl 4-(5-cyclobutyl-4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1 H- 1,2,3-triazol-1 -yl)piperidine-1 -carboxylate (305 mg, 0.7 mmol), 2-((tert- butyldimethylsilyl)oxy)-1 -(5-fluoropyridin-2-yl)ethanesulfonic acid ethyl ester (242 mg, 0.7 mmol) and cesium carbonate (226 mg, 2.1 mmol) in N,N-dimethylformamide (5 mL) was added was heated to 110 °C and stirred for 10 minutes. The reaction was allowed to cool to room temperature, water (20 mL) was added and the reaction was extracted with ethyl acetate (3*50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3-7% methanol) to give the target product as a white solid (240 mg, 0.35 mmol, yield: 50%). LC / MS (ESI) M / Z: 636.4 [M+H-56] + .

[0303] Step 7: tert-butyl 4-(4-(2-(tert-butyldimethylsilyl)oxy)-1 -(5-fluoropyridin-2-yl)ethoxy)- 3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-cyclobutyl-1 H-1,2,3-triazol-1 -yl)piperidine-1 - carboxylate

[0304] To a solution of tert-butyl 4-(4-(2-(tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2- yl)ethoxy)-5-cyclobutyl-lH-l,2,3-triazol-l-yl)piperidin-l-yl)carbamate (240 mg, 0.35 mmol) in dichloromethane (5 mL) was added N-chlorosuccinimide (46 mg, 0.3 mmol) at room temperature. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, water (10 mL) was added to the reaction, extracted with dichloromethane (3*30 mL), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3% to 7% methanol) to obtain the target product (190 mg, 0.26 mmol, yield: 75%) as a yellow solid. LC / MS (ESI) M / Z: 726.3 [M+H] + .

[0305] Step 8: 2-((3-chloro-6-(5-cyclobutyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-l-ol

[0306] To a solution of tert-butyl 4-(4-(2-(tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2- yl)ethoxy)-5-cyclobutyl-lH-l,2,3-triazol-l-yl)piperidin-l-yl)carbamate (240 mg, 0.35 mmol) in dichloromethane (5 mL) was added N-chlorosuccinimide (46 mg, 0.3 mmol) at room temperature. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, water (10 mL) was added to the reaction, extracted with dichloromethane (3*30 mL), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3% to 7% methanol) to obtain the target product (190 mg, 0.26 mmol, yield: 75%) as a yellow solid. LC / MS (ESI) M / Z: 726.3 [M+H] + .

[0307] Step 9: 4-(4-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6- yl)-5-cyclobutyl-lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile

[0308] 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 was stirred at room temperature for 1 h. After completion of the reaction, the reaction was evaporated under reduced pressure and the residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0-10%) to get 100 mg of crude product which was further purified by reverse phase purification (ACN:H20 = 0-50%) to get the target 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 (400 MHz, DMSO-d6) δ 8.61 (d, J = 2.8 Hz, 1H), 8.30 (d, J = 1.0 Hz, 1H), 8.12 (s, 1H), 7.78 (td, J = 8.8, 2.8 Hz, 1H), 7.64 (dd, J = 8.8, 4.4 Hz, 1H), 6.63 (d, J = 1.0 Hz, 1H), 5.60 (t, J = 5.2 Hz, 1H), 5.13 (t, J = 5.6 Hz, 1H), 4.47 - 4.37 (m, 1H), 3.92 (t, J = 5.4 Hz, 2H), 3.78 (t, J = 8.4 Hz, 1H), 3.55 (d, J = 12.6 Hz, 2H), 3.28 (d, J = 13.6 Hz, 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).

[0309] Example 3: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0310] Step 1: tert-butyl 4-(5-cyclopentyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1- carboxylate

[0311] tert-Butyl 4-azidopiperidine-l-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) were dissolved in dimethyl sulfoxide (50 mL) and the reaction was heated to 80 °C under nitrogen for 5 h. The reaction was cooled to room temperature, water (200 mL) was added and the mixture was extracted with ethyl acetate (3 * 150 mL). The organic phase was 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% to 50% ethyl acetate) to give the title compound (2.1 g, 5.35 mmol, 40.36% yield). LC / MS (ESI) M / Z: 393.4 [M+H] + .

[0312] Step 2: tert-Butyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-cyclopentyl-1H-1,2,3- triazole-4-carboxylate

[0313] tert-Butyl 4-(5-cyclopentyl-4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1- carboxylate (2.1 g, 5.350 mmol) was dissolved in water (20 mL) and methanol (4 mL), potassium hydroxide (0.60 g, 10.70 mmol) was added and the reaction was heated to 50 °C for 3 h. The reaction was cooled to room temperature, water (20 mL) was added and the pH of the reaction was adjusted to 4 using 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (3 * 50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (1.8 g, 4.939 mmol, 92.31% yield). LC / MS (ESI) M / Z: 363.2 [M-H] - .

[0314] Step 3: tert-Butyl 4-(4-bromo-5-cyclopentyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0315] To a solution of tert-butyl 4-(5-cyclopentyl-4-(4-methoxy-pyrazolo[1,5- a]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (230 mg, 0.493 mmol) in DCM (5 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (5 mL) and water (5 mL) was added. The organic phase was separated and the aqueous phase was extracted with DCM (3*5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-50% ethyl acetate) to give the title compound (180 mg, 0.493 mmol, yield: 100%). LC / MS (ESI) M / Z: 395.3 [M+H] + .

[0316] Step 4: tert-Butyl 4-(5-cyclopentyl-4-(4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3- triazol-1-yl)piperidine-1-carboxylate

[0317] To a solution of tert-butyl 4-(5-cyclopentyl-4-(4-methoxy-pyrazolo[1,5- a]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (230 mg, 0.493 mmol) in DCM (5 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (5 mL) and water (5 mL) was added. The organic phase was separated and the aqueous phase was extracted with DCM (3*5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-50% ethyl acetate) to give the title compound (180 mg, 0.493 mmol, yield: 100%). LC / MS (ESI) M / Z: 395.3 [M+H] + .

[0318] Step 5: tert-Butyl 4-(5-cyclopentyl-4-(4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-1H-1,2,3- triazol-1-yl)piperidine-1-carboxylate

[0319] 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) was dissolved in N,N- dimethylacetamide (4 mL), dodecan-1-thiol (798 mg, 3.944 mmol) and aqueous sodium hydroxide (236 mg, 5.915 mmol, 50% aqueous solution) were added and the reaction was heated to 100 °C under nitrogen for 2 h. The reaction was allowed to cool to room temperature, water (10 mL) and ethyl acetate (3 mL) were added and the pH of the reaction was adjusted to 4 with formic acid and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, 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% to 10% methanol) to give the title compound (200 mg, 0.442 mmol, 86.66% yield). LC / MS (ESI) M / Z: 453.4 [M+H] + .

[0320] Step 6: 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

[0321] 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) and the reaction was heated to 110 °C for 30 min. The reaction was allowed to cool to room temperature, water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, 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% to 10% methanol) to give the title compound (124 mg, 0.176 mmol, 39.75% yield).

[0322] Step 7: 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

[0323] Step 8: 2-((3-chloro-6-(5-cyclopentyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-l-ol

[0324] Step 8: 2-((3-chloro-6-(5-cyclopentyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-l-ol

[0325] Step 8: 2-((3-chloro-6-(5-cyclopentyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-l-ol + .

[0326] Step 8: 2-((3-chloro-6-(5-cyclopentyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-l-ol

[0327] In a round bottom flask, 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), N,N-diisopropylethylamine (234 mg, 1.813 mmol) and cyanogen bromide (25 mg, 0.242 mmol) were added and the reaction was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction and extracted with dichloromethane (20 mL X 3), the organic phase was combined, 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% to 10% methanol) to give 50 mg of crude product which was further purified by reverse phase (ACN:H20 = 0% to 50%) to give the title compound (white solid, 10 mg, 0.018 mmol, 13.4% yield). LC / MS (ESI) M / Z: 551.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 2.9 Hz, 1H), 8.28 (d, J = 1.0 Hz, 1H), 8.13 (s, 1H), 7.77 (td, J = 8.8, 2.9 Hz, 1H), 7.61 (dd, J = 8.8, 4.5 Hz, 1H), 6.56 (s, 1H), 5.58 (t, J = 5.2 Hz, 1H), 5.13 (t, J = 5.6 Hz, 1H), 4.62 - 4.54 (m, 1H), 3.91 (t, J = 5.3 Hz, 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).

[0328] Example 4: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2- a]pyridin-6-yl)-5-methyl-1,2,3-triazazol-1-yl]hexahydropyridine-1-carbonitrile

[0329] Step 1: 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2- a]pyridine

[0330] Dissolve 6-bromo-8-methoxyimidazo[l,2-a]pyridine (500 mg, 2.20 mmol), bis(pinacolato)diboron (1678 mg, 6.61 mmol) and potassium acetate (649 g, 6.61 mmol) in 1,4-dioxane (10 mL) and add palladium(II) chloride, 1,1'-bis(diphenylphosphino)ferrocene (162 mg, 0.220 mmol) under nitrogen. Stir at 80 °C for 2 h. Cool the reaction to room temperature, filter and concentrate under reduced pressure. Purify the residue by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0% to 100% ethyl acetate) to give the title compound (360 mg, 1.32 mmol, 59.64% yield). LC / MS (ESI) M / Z: 275.2 [M+H] + .

[0331] Step 2: 4-[4-(8-methoxyimidazo[l,2-a]pyridin-6-yl)-5-methyl-l,2,3-triazol-l- yl]hexahydropyridine-1-carboxylic acid 2-methylprop-2-yl ester

[0332] Dissolve 8-methoxy-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2- a]pyridine (360 mg, 1.31 mmol), 4-(4-bromo-5-methyl-l,2,3-triazol-l-yl)hexahydropyridine- 1-carboxylic acid 2-methylprop-2-yl ester (499 mg, 1.45 mmol) and potassium carbonate (545 mg, 3.94 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) and add palladium(II) chloride, 1,1'-bis(di-tert-butylphosphino)ferrocene (85 mg, 0.13 mmol) under nitrogen. Stir at 80 °C for 3 h. Cool the reaction to room temperature, concentrate the 1,4-dioxane, add water (20 mL) and extract with ethyl acetate (3 x 20 mL). Dry the organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0% to 10% anhydrous methanol) to give the title compound (500 mg, 1.12 mmol, 92.30% yield). LC / MS (ESI) M / Z: 413.4 [M+H] + .

[0333] Step 3: 4-[4-(8-hydroxyimidazo[l,2-a]pyridin-6-yl)-5-methyl-l,2,3-triazol-l- yl]hexahydropyridine-1-carboxylic acid 2-methylprop-2-yl ester

[0334] To a solution of 4-[4-(8-methoxy-imidazo[l,2-a]pyridin-6-yl)-5-methyl- 1,2,3-triazol-l-yl]hexahydropyridine-l-carboxylic acid-2-methylprop-2-yl ester (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 was allowed to cool to room temperature, water (100 mL) and ethyl acetate (10 mL) were added and the pH of the reaction was adjusted to 4 with formic acid. The reaction 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 give the title compound (270 mg, 0.678 mmol, yield: 55.90%). LC / MS (ESI) M / Z: 399.4 [M+H] + .

[0335] Step 4: 4-[4-(8-{[l-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4- silahex-l-yl]oxy}imidazo[l,2-a]pyridin-6-yl)-5-methyl-l,2,3-triazol-l-yl]hexahydropyridine-l- carboxylic acid-2-methylprop-2-yl ester

[0336] To a solution of 4-[4-(8-hydroxy-imidazo[l,2-a]pyridin-6-yl)-5-methyl-l,2,3- triazol-l-yl]hexahydropyridine-l-carboxylic acid-2-methylprop-2-yl ester (270 mg, 0.678 mmol), l-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-l-ylmethanesulfonate (174 mg, 0.50 mmol) and cesium carbonate (221 mg, 0.678 mmol) in N,N-dimethylformamide (4 mL) was heated to 110 °C for 30 minutes. The reaction was allowed to cool to room temperature, water (40 mL) was added and the reaction 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 give the title compound (180 mg, 0.276 mmol, yield: 40.75%). LC / MS (ESI) M / Z: 652.6 [M+H] + .

[0337] Step 5: 2-(5-fluoropyridin-2-yl)-2-({6-[l-(hexahydropyridin-4-yl)-5-methyl- l,2,3-triazin-4-yl]imidazo[l,2-a]pyridin-8-yl}oxy)ethan-l-ol

[0338] A solution of 4-[4-(8-{[l-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4- silahex-l-yl]oxy}imidazo[l,2-a]pyridin-6-yl)-5-methyl-l,2,3-triazin-l-yl]hexahydropyridine- 1-carboxylic acid-2-methylprop-2-yl ester (180 mg, 0.276 mmol) and hydrochloric acid in dioxane (4 M in dioxane, 10 mL) was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to give crude 2-(5-fluoropyridin-2-yl)-2-({6-[l-(hexahydropyridin-4-yl)-5-methyl-l,2,3-triazin-4- yl]imidazo[l,2-a]pyridin-8-yl}oxy)ethan-l-ol (120 mg, 0.274 mmol). LC / MS (ESI) M / Z: 438.4 [M+H] + .

[0339] Step 6: 4-[4-(8-{[l-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[l,2-a]pyridin-6- yl)-5-methyl-l,2,3-triazin-l-yl]hexahydropyridine-l-carbonitrile

[0340] To a solution of 2-(5-fluoropyridin-2-yl)-2-({6-[l-(hexahydropyridin-4-yl)-5-methyl- l,2,3-triazin-4-yl]imidazo[l,2-a]pyridin-8-yl}oxy)ethan-l-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 stirred for 1 h. The reaction was extracted with dichloromethane and water, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate and filtered. The residue was purified by column chromatography (eluent: anhydrous methanol / dichloromethane, gradient: 0% to 10% anhydrous methanol) to give crude product, which was further purified by reverse phase (ACN:H20 = 5% to 95%) to give 4-[4-(8-{[l-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[l,2-a]pyridin-6-yl)-5- methyl-l,2,3-triazin-l-yl]hexahydropyridine-l-carbonitrile (30 mg, 0.065 mmol, yield: 23.65%). LC / MS (ESI) M / Z: 463.4 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 2.8 Hz, 1H), 8.46 (d, J = 1.3 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 7.72 (td, J = 8.8, 2.9 Hz, 1H), 7.62 (dd, J = 8.7, 4.5 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 6.88 (d, J = 1.4 Hz, 1H), 5.74 (t, J = 5.2 Hz, 1H), 5.25 (t, J = 5.8 Hz, 1H), 4.59 (tt, J = 10.9, 4.1 Hz, 1H), 3.94 (t, J = 5.5 Hz, 2H), 3.56 (dt, J = 13.0, 3.7 Hz, 2H), 3.26 (dd, J = 12.6, 2.9 Hz, 2H), 2.38 (s, 3H), 2.20 - 2.03 (m, 4H).

[0341] Example 5: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-(6-(6-(methylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole

[0342] Step 1: 5-Bromo-7-fluoro-1H-indazole-1-carboxylic acid tert-butyl ester

[0343] 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), slowly add 4-dimethylaminopyridine (227 mg, 1.86 mmol), stir at room temperature for 18 hours. Add water (30 mL) and extract, the aqueous phase is extracted with (2 x 30 mL) dichloromethane, the organic phases are combined, 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 give the title compound (white solid, 1.7 g, 5.39 mmol, yield: 58.0%). LC / MS (ESI) M / Z: 314.9 [M+H] + .

[0344] Step 2: 7-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylic acid tert-butyl ester

[0345] Dissolve 5-bromo-7-fluoro-lH-indazole-l-carboxylic acid tert-butyl ester (1.7 g, 5.39 mmol), bis(pinacolato)diboron (2.74 g, 10.8 mmol), potassium acetate (2.12 g, 21.6 mmol) in 1,4-dioxane (20 mL), add l, l'-bis(diphenylphosphino)ferrocene palladium dichloride (790 mg, 1.08 mmol), and react at 90 °C for 3 hours. Concentrate the reaction under reduced pressure, add silica gel to the residue, and purify the mixture by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0% to 40% ethyl acetate) to obtain the title compound (colorless oil, 1.95 g, 5.39 mmol, yield: 100%). LC / MS (ESI) M / Z: 363.2 [M+H] + .

[0346] Step 3: 7-Fluoro-5-hydroxy-lH-indazole-l-carboxylic acid tert-butyl ester

[0347] Dissolve 7-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole-l- carboxylic acid tert-butyl ester

[0348] (1.95 g, 5.39 mmol) in anhydrous methanol (30 mL), slowly add 30% aqueous hydrogen peroxide solution (3.05 g, 26.9 mmol) under ice bath, remove the ice bath after the addition is complete, and react at room temperature overnight. Quench by slowly adding sodium sulfite solution. Extract with ethyl acetate (3 x 30 mL), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (1.3 g, 5.15 mmol, yield: 95.7%). LC / MS (ESI) M / Z: 253.1 [M+H] + .

[0349] Step 4: 7-Fluoro-lH-indazol-5-ol hydrochloride

[0350] Dissolve 7-fluoro-5-hydroxy-lH-indazole-l-carboxylic acid tert-butyl ester (1.3 g, 5.15 mmol) in 4 M hydrochloric acid in 1,4-dioxane (25 mL) at room temperature, and stir the reaction at room temperature for 4 hours. Concentrate the reaction under reduced pressure, add saturated sodium bicarbonate solution until no gas is generated, extract the aqueous phase with dichloromethane (3 x 30 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (988 mg, crude). LC / MS (ESI) M / Z: 152.9 [M+H] + .

[0351] Step 5: 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-lH-indazole

[0352] Step 1 : 7-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole Step 2: 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole + .

[0353] Step 6: 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole

[0354] Step 6: 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole + .

[0355] Step 7: 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole

[0356] Step 6: 5-((tert-butyldimethylsilyl)oxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole

[0357] (1.2 g, 3.06 mmol) was dissolved in dichloromethane (15 mL), and p-toluenesulfonic acid (158 mg, 0.92 mmol) and 3,4-dihydro-2H-pyran (515 mg, 6.12 mmol) were added. The reaction was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium bicarbonate (20 mL) was added, and the mixture was extracted with dichloromethane (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–20% ethyl acetate) to give the title compound (980 mg, 2.06 mmol, yield: 67.3%). LC / MS (ESI) M / Z: 477.1 [M+H] + .

[0358] Step 8: 7-Fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-ol

[0359] 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 solution of sodium bicarbonate (20 mL) was added, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%–10% anhydrous methanol) to give the title compound (460 mg, 1.27 mmol, yield: 61.7%). LC / MS (ESI) M / Z: 363.2 [M+H] + .

[0360] Step 9: 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0361] Methanesulfonic acid-(lS)-l-(3,5-dichloropyridin-4-yl)ethyl ester (508 mg, 1.88 mmol) was dissolved in N,N-dimethylformamide (8 mL) at room temperature, 7-fluoro-3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-ol (680 mg, 1.88 mmol) and cesium carbonate (1.84 g, 5.64 mmol) were added and stirred at 110 °C for 6 hours. The reaction was cooled to room temperature, water (30 mL) was added and extracted with ethyl acetate (3 x 30 mL), the organic phase was washed with saturated sodium chloride and 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% - 40% ethyl acetate) to give the title compound (white solid, 560 mg, 1.04 mmol, yield: 55.3%). LC / MS (ESI) M / Z: 535.9 [M+H] + .

[0362] Step 10: (R)-5-(l-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-iodo-lH-indazole

[0363] Methanesulfonic acid-(lS)-l-(3,5-dichloropyridin-4-yl)ethyl ester (508 mg, 1.88 mmol) was dissolved in N,N-dimethylformamide (8 mL) at room temperature, 7-fluoro-3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-ol (680 mg, 1.88 mmol) and cesium carbonate (1.84 g, 5.64 mmol) were added and stirred at 110 °C for 6 hours. The reaction was cooled to room temperature, water (30 mL) was added and extracted with ethyl acetate (3 x 30 mL), the organic phase was washed with saturated sodium chloride and 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% - 40% ethyl acetate) to give the title compound (white solid, 560 mg, 1.04 mmol, yield: 55.3%). LC / MS (ESI) M / Z: 535.9 [M+H] + .

[0364] Step 11: 3-(6-fluoropyridin-3-yl)-5-{[(lR)-l-(3,5-dichloropyridin-4-yl)ethyl]oxy}-lH-indazole

[0365] Step 1 : (R)-5-{[(1 R)-1 -(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-iodo-1 H- indazole + .

[0366] Step 12: (R)-6-(5-(5-(1 -(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-1 H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0367] Step 1 : (R)-5-{[(1 R)-1 -(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-iodo-1 H- indazole + .

[0368] Step 13: (R)-3-(6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-5-(1 -(3,5- dichloropyridin-4-yl)ethoxy)-7-fluoro-1 H-indazole

[0369] (R)-6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-1H-indazol-3-yl)pyridin-2- yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (180 mg, 0.30 mmol) was dissolved in dichloromethane (10 mL) at room temperature, trifluoroacetic acid (5 mL) was added. The reaction was stirred at room temperature for 1 hour, concentrated under reduced pressure, the residue was added to saturated sodium bicarbonate solution until no gas was produced, the aqueous phase was extracted with dichloromethane (2 x 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound which was concentrated under reduced pressure to give the target compound (130 mg, 0.26 mmol, 87% yield). LC / MS (ESI) M / Z: 499.1 [M+H] + .

[0370] Step 14: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-3-(6-(6-(methylsulfonyl)- 2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole

[0371] (R)-3-(6-(2,6-diazaspiro[3.3]heptan-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) at room temperature, triethylamine (79 mg, 0.78 mmol) and methylsulfonyl chloride (45 mg, 0.39 mmol) were added, stirred at room temperature for 1 hour. Water (10 mL) was added, extracted with dichloromethane (3 x 10 mL), the organic phase was washed with saturated sodium chloride and 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 purified by reverse phase (ACN:H20 = 5% to 95%) to give 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-{6-[2-(methyl dioxido-λ6-sulfanyl)-2,6-diazaspiro[3.3]heptan-6-yl]pyridin-3-yl}-1H-indazole (40 mg, 0.069 mmol, 26.5% yield). LC / MS (ESI) M / Z: 577.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.60 (s, 2H), 8.50 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 8.6, 2.4 Hz, 1H), 7.01 (dd, J = 14.0, 2.2 Hz, 2H), 6.55 (d, J = 8.6 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 4.18 (s, 4H), 4.12 (s, 4H), 3.03 (s, 3H), 1.76 (d, J = 6.6 Hz, 3H).

[0372] Example 6: 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)-5-(methyl-d3)-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0373] Step 1: Ethyl 4,4,4-trideuterio-3-oxoacetoate

[0374] Ethyl acetate (0.56 mL, 5.68 mmol) was dissolved in 1.5 mL of tetrahydrofuran and added slowly dropwise to a solution of lithium bis(trimethylsilyl)amide (12.5 mL, 12.5 mmol) (1 M in THF) at -70 °C and stirred for 1 hour. Then 2,2,2-trideuterioacetyl chloride (463 mg, 5.68 mmol) was added slowly dropwise and the reaction was allowed to react at -70 °C for 2 hours. The reaction was allowed to warm to room temperature and quenched with 6 N hydrochloric acid solution and extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with 3 N hydrochloric acid and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude ethyl 4,4,4-trideuterio-3-oxoacetoate (400 mg, 3.00 mmol).

[0375] Step 2: 4-[4-(Ethoxycarbonyl)-5-(trideuteriomethyl)-1,2,3-triazol-1-yl]hexahydropyridine-1- carboxylic acid-2-methylprop-2-yl ester

[0376] tert-Butyl 4-azidopiperidine-l-carboxylate (570 mg, 2.52 mmol), ethyl 4,4,4-trideuterio-3-oxo butanoate (400 mg, 3.00 mmol) and potassium carbonate (1044 mg, 7.56 mmol) were dissolved in dimethyl sulfoxide (10 mL) and the reaction was heated to 85 °C under nitrogen for 5 hours. The reaction was cooled to room temperature, water (50 mL) was added and the reaction 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% to 60% ethyl acetate) to give the title compound (240 mg, 0.703 mmol, 27.90% yield). LC / MS (ESI) M / Z: 342.1 [M+H] + .

[0377] Step 3: 1-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-5- (trideuteriomethyl)-1,2,3-triazole-4-carboxylic acid

[0378] tert-Butyl 4-[4-(ethoxycarbonyl)-5-(trideuteriomethyl)-1,2,3-triazol-1-yl]hexahydropyridine- 1 -carboxylate (240 mg, 0.70 mmol) was dissolved in water (2 mL) and methanol (2 mL), potassium hydroxide (78.9 mg, 1.40 mmol) was added and the reaction was heated to 50 °C for 2 hours. The reaction was cooled to room temperature, water (10 mL) was added and the pH of the reaction was adjusted to 4 using 1 N hydrochloric acid. The reaction was extracted with ethyl acetate (3 x 20 mL), the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (200 mg, 0.64 mmol). LC / MS (ESI) M / Z: 314.2 [M+H] + .

[0379] Step 4: 4-[4-Bromo-5-(trideuteriomethyl)-1,2,3-triazol-1-yl]hexahydropyridine-1- carboxylic acid-2-methylpropan-2-yl ester

[0380] Dissolve 1-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-5- (trideuteromethyl)-1,2,3-triazol-4-carboxylic acid (200 mg, 0.64 mmol) in water (5 mL), add potassium hydroxide (86 mg, 1.53 mmol) and bromine (245 mg, 1.53 mmol), stir the reaction at room temperature for 3 hours. Quench the reaction with saturated sodium sulfite solution, extract with ethyl acetate (3 x 20 mL), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the residue 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] + .

[0381] Step 5: 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteromethyl)-1,2,3- triazol-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropan-2-yl ester

[0382] Dissolve 4-[4-bromo-5-(trideuteromethyl)-1,2,3-triazol-1-yl]hexahydropyridine-1- carboxylic acid-2-methylpropan-2-yl ester (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) in 1,4-dioxane (4 mL) and water (1 mL), add 1,1'- bis(di-tert-butylphosphino)ferrocene palladium dichloride (31.5 mg, 0.05 mmol) under nitrogen, heat to 85 °C and stir for 3 hours. Cool the reaction to room temperature, concentrate the 1,4-dioxane, add water (20 mL), extract with ethyl acetate (3 x 20 mL), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the residue 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] + .

[0383] Step 6: 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteromethyl)-1,2,3- triazol-1-yl]hexahydropyridine-1-carboxylic acid-2-methylpropan-2-yl ester

[0384] To a solution of 4-[4-(4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteromethyl)-1,2,3- triazol-1-yl]hexahydropyridine-1-carboxylic acid-2-methylprop-2-yl ester (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 water) and dodecan-1-thiol (614 mg, 3.03 mmol). The reaction was stirred at 110 °C for 2 hours under nitrogen protection. The reaction was cooled to room temperature, water (40 mL) and ethyl acetate (10 mL) were added, and the pH of the reaction was adjusted to 4 with formic acid. The reaction 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% to 10% anhydrous methanol) to give the title compound (170 mg, 0.423 mmol, 83.78% yield). LC / MS (ESI) M / Z: 402.4 [M+H] + .

[0385] Step 7: 4-[4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahex-1-yl]oxy}pyrazolo[1,5- a]pyridin-6-yl)-5-(trideuteromethyl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid-2- methylprop-2-yl ester

[0386] Step 1 : 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteromethyl)-1,2,3- triazol-1 -yl]hexahydropyridine-1 -carboxylic acid 2-methylprop-2-yl ester

[0387] 1 H NMR (400 MHz, CDC13) δ 8.46 (d, J = 2.8 Hz, 1H), 8.41 (s, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.49 (dd, J = 8.7, 4.4 Hz, 1H), 7.37 (td, J = 8.4, 2.8 Hz, 1H), 6.80 (dd, J = 2.4, 0.8 Hz, 1H), 6.76 (d, J = 1.1 Hz, 1H), 5.63 (dd, J = 5.9, 3.5 Hz, 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 = 4.2 Hz, 3H).

[0388] Step 1 : 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteromethyl)-1,2,3- triazol-1 -yl]hexahydropyridine-1 -carboxylic acid 2-methylprop-2-yl ester

[0389] To a solution of 4-[4-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4- silahex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteromethyl)-1,2,3-triazin-1 - yl]hexahydropyridine-1 -carboxylic acid-2-methylprop-2-yl ester (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 was stirred at room temperature for 1 h. To the reaction was added water (20 mL) and extracted with dichloromethane (3 x 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-silahex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-(trideuteromethyl)-1,2,3-triazin-1 - yl]hexahydropyridine-1 -carboxylic acid-2-methylprop-2-yl ester (100 mg, 0.145 mmol, 75.40% yield). 1 H NMR (400 MHz, CDC13) δ 8.45 (d, J = 2.7 Hz, 1H), 8.27 (s, 1H), 7.84 (s, 1H), 7.71 (dd, J = 8.7, 4.4 Hz, 1H), 7.47 (td, J = 8.4, 2.7 Hz, 1H), 6.82 (s, 1H), 5.76 (dd, J = 5.5, 3.5 Hz, 1H), 4.37 - 4.18 (m, 5H), 2.94 (t, J = 12.6 Hz, 2H), 2.38 (t, J = 2.3 Hz, 1H), 2.32 - 2.19 (m, 2H), 2.00 (s, 1H), 1.49 (s, 9H), 0.79 (s, 9H), -0.00 (d, J = 2.2 Hz, 3H), -0.06 (s, 3H).

[0390] Step 9: 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

[0391] tert-Butyl 4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3- chloropyrazolo[l,5-a]pyridin-6-yl)-5-(methyl-d3)-lH-l,2,3-triazol-l-yl)piperidine-l- carboxylate (100 mg, 0.145 mmol) was dissolved in 4 M hydrochloric acid in dioxane (10 mL) and stirred for 1 h at room temperature. The reaction was concentrated under reduced pressure, saturated sodium bicarbonate solution was added until no gas was evolved, and 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)-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-l-ol (50 mg, 0.105 mmol, 72.4% yield). LC / MS (ESI) M / Z: 476.1 [M+H] + .

[0392] Step 10: 4-(4-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5- a]pyridin-6-yl)-5-(methyl-d3)-lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile

[0393] To a solution of 2-((3-chloro-6-(5-(methyl-d3)-l-(piperidin-4-yl)-lH-l,2,3-triazol-4- yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-l-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 was stirred for 1 h at room temperature. The reaction was extracted with dichloromethane and water, the organic phase was washed with saturated sodium chloride and 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 purified by reverse phase (ACN:H20 = 30% to 80%) to give 4-(4-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-cyclopropyl-lH-l,2,3-triazol-l-yl)piperidine-l- carbonitrile (30 mg, 0.06 mmol). Yield: 57.1%. LC / MS (ESI) M / Z: 526.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 1.0 Hz, 1H), 8.12 (s, 1H), 7.77 (td, J = 8.8, 3.0 Hz, 1H), 7.64 (dd, J = 8.8, 4.4 Hz, 1H), 6.90 (d, J = 1.0 Hz, 1H), 5.63 (t, J = 5.2 Hz, 1H), 5.15 (t, J = 5.6 Hz, 1H), 4.66 - 4.56 (m, 1H), 3.94 (t, J = 5.4 Hz, 2H), 3.56 (d, J = 12.6 Hz, 2H), 3.31 - 3.24 (m, 2H), 2.20 - 2.09 (m, 2H), 2.03 (s, 2H).

[0394] Example 7: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2- a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carbonitrile

[0395] Step 1: 4-bromo-2-methyl-6-(trifluoromethyl)aniline

[0396] 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) portion wise. The reaction mixture was stirred at room temperature for 2 h. The mixture was washed with NaHC03(aq, saturated solution) and brine, the organic layer was dried over Na2S04and filtered. The solvent was removed to get the crude product. Purification by column chromatography (petroleum ether: ethyl acetate = 25: 1) to get 4-bromo-2-methyl-6-(trifluoromethyl)aniline 6.5 g, yield: 91.5%. LC / MS (ESI) M / Z: 254.2 [M+H] + .

[0397] Step 2: 5-bromo-7-(trifluoromethyl)-1H-indazole

[0398] 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 h. The reaction mixture was heated to 60 °C and stirred at 60 °C for 2 h, 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 with DCM twice. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was dissolved in MeOH (50 mL) and 6 N HCl (50 mL). The mixture was stirred at room temperature for 4 h, basified with 10 N aqueous NaOH solution and extracted with DCM twice. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4and 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] + .

[0399] Step 3: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)-1H-indazole

[0400] 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'-bi(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 h under nitrogen. The reaction mixture was filtered to give a liquid which was rotary evaporated to give the crude product. This crude product was immediately subjected to the next step without purification. LC / MS (ESI) M / Z: 313.2 [M+H] + .

[0401] Step 4: 7-(trifluoromethyl)-1H-indazol-5-ol

[0402] To a reaction mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7- (trifluoromethyl)-lH-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. To the reaction mixture was added sodium sulfite (saturated aqueous solution, 30 mL) 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 Na2S04, filtered, and the organic phase was removed under reduced pressure to give a crude product. The crude product was purified by column chromatography (dichloromethane: ethyl acetate = 1:2) to give 7-(trifluoromethyl)-lH-indazol-5-ol 5.4 g of crude product. LC / MS (ESI) M / Z: 203.1 [M+H] + .

[0403] Step 5: 5-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-7-(trifluoromethyl)-lH-indazole

[0404] To a reaction mixture of 7-(trifluoromethyl)-lH-indazol-5-ol (5.4 g, 26.714 mmol) and imidazole (2.73 g, 40.071 mmol) in DMF (100 mL) was added TBSC1 (6.04 g, 40.071 mmol) dropwise at 0 °C, and then 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 saturated aqueous sodium chloride solution, dried over Na2S04, filtered, and the organic phase was removed under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 5-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-7-(trifluoromethyl)-lH-indazole 3.5 g of pure product and 2.5 g of crude product. LC / MS (ESI) M / Z: 317.2 [M+H] + .

[0405] Step 6: 5-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-3-iodo-7-(trifluoromethyl)-lH-indazole

[0406] To a reaction mixture of 5-{[dimethyl(2-methylpropan-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. To the reaction mixture was added water (20 mL) and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2S04, filtered. The solvent was removed to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 5-{[dimethyl(2-methylpropan-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] + .

[0407] Step 7: 3-Iodo-7-(trifluoromethyl)-1H-indazol-5-ol

[0408] To a reaction mixture of 5-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-3-iodo-7- (trifluoromethyl)-1H-indazole (2 g, 4.522 mmol) in THF (3 mL) was added TBAF solution (6.783 mL, 6.783 mmol) at room temperature 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 saturated aqueous sodium chloride solution, dried over Na2S04, filtered, and the organic phase was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 0% to 20%) to obtain 3-iodo-7-(trifluoromethyl)-1H-indazol-5-ol 1.2 g, yield: 80.9%. LC / MS (ESI) M / Z: 329.1 [M+H] + .

[0409] Step 8: 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-iodo-7-(trifluoromethyl)-1H- indazole

[0410] To a solution of 3-iodo-7-(trifluoromethyl)-lH-indazol-5-ol (500 mg, 1.52 mmol) in N,N-dimethylformamide (10 mL) was added (1S)-1-(3,5-dichloropyridin-4-yl) ethyl methanesulfonate (412 mg, 1.52 mmol) and potassium carbonate (632 mg, 4.57 mmol) and heated to 80 °C for 30 min. After completion of the reaction, the reaction was cooled to room temperature, water (30 mL) was added and extracted with ethyl acetate (3 x 20 mL). The organic layer 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 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-iodo-7-(trifluoromethyl)-lH-indazole (200 mg, 0.40 mmol, 26.13% yield). LC / MS (ESI) M / Z: 501.9 [M+H] + .

[0411] Step 9: 3-(6-Fluoropyridin-3-yl)-5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-7- (trifluoromethyl)-lH-indazole

[0412] To a solution of 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-iodo-7- (trifluoromethyl)-lH-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) in 1,4-dioxane (8 mL) and water (0.4 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol) under nitrogen and heated to 90 °C for 2 h. After completion of the reaction, the reaction was cooled to room temperature, 1,4-dioxane was concentrated and water (20 mL) was added and extracted with ethyl acetate (3 x 10 mL). The organic layer 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 3-(6-fluoropyridin-3-yl)-5-{[(1R)-1-(3,5-dichloropyridin-4- yl)ethyl]oxy}-7-(trifluoromethyl)-lH-indazole (100 mg, 0.21 mmol, 71.03% yield). LC / MS (ESI) M / Z: 471.0 [M+H] + .

[0413] 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

[0414] 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-methylpyrrolidine (5 mL) was added 2-methylprop-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 for 6 hours under nitrogen protection. After the reaction was completed, the reaction 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-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 (80 mg, 0.123 mmol, yield: 58.04%). 1 H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.61 (s, 2H), 8.52 (d, J = 2.3 Hz, 1H), 7.90-7.85 (m, 1H), 7.47 (d, J = 14.5 Hz, 2H), 6.55 (d, J = 8.6 Hz, 1H), 6.22 (d, J = 6.7 Hz, 1H), 4.16 (s, 4H), 4.07 (s, 4H), 1.78 (d, J = 6.5 Hz, 3H), 1.40 (s, 9H).

[0415] Step 11: 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl]-5-{[(1R)-1-(3,5-dichloropyridin-4- yl)ethyl]oxy}-7-(trifluoromethyl)-1H-indazole

[0416] To a solution of 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) in dichloromethane (40 mL) was added hydrochloric acid in dioxane (5 mL). After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the title compound 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl]-5-{[(1R)-1-(3,5- dichloropyridin-4-yl)ethyl]oxy}-7-(trifluoromethyl)-1H-indazole (60 mg, 0.11 mmol, yield: 88.67%) as a yellow solid. LC / MS (ESI) M / Z: 549.2 [M+H] + .

[0417] Step 12: 5-{[(1R)-1-(3,5-dichloropyridin-4-yl)ethyl]oxy}-3-{6-[2-(methyldioxy-1<6- sulfanyl)-2,6-diazaspiro[3.3]heptan-6-yl]pyridin-3-yl}-7-(trifluoromethyl)-1H-indazole

[0418] To a solution of 3-[6-(2,6-diazaspiro[3.3]heptan-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 methylsulfonyl chloride (19 mg, 0.16 mmol) at room temperature and stirred for 1 h at room temperature. The reaction mixture was extracted with dichloromethane and water, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate and filtered. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0% to 70% ethyl acetate) to obtain the crude product which was further purified by reverse phase (ACN:H20 = 5% to 95%) to obtain 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]heptan-6-yl]pyridin-3-yl}-7-(trifluoromethyl)-1H-indazole (10 mg, 0.02 mmol, yield: 14.59%) as a yellow solid. LC / MS (ESI) M / Z: 627.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H), 8.61 (s, 2H), 8.53 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 8.6, 2.4 Hz, 1H), 7.47 (d, J = 13.5 Hz, 2H), 6.57 (d, J = 8.7 Hz, 1H), 6.22 (q, J = 6.6 Hz, 1H), 4.19 (s, 4H), 4.12 (s, 4H), 3.03 (s, 3H), 1.78 (d, J = 6.6 Hz, 3H).

[0419] Example 8: 4-(4-(8-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)imidazo[1,5- a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0420] Step 1: tert-Butyl (5-bromo-3-fluoropyridin-2-yl)methylcarbamate

[0421] tert-Butyl (5-bromo-3-fluoropyridin-2-yl)methylcarbamate (2.6 g, 8.5 mmol) was dissolved in 1,4-dioxane (15 mL), and 4 M hydrochloric acid 1,4-dioxane solution (5 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was distilled under reduced pressure to obtain the crude target compound (1.8 g, 8.5 mmol) as a yellow oil. LC / MS (ESI) M / Z: 205.1 [M+H] + .

[0422] Step 2: (5-Bromo-3-fluoropyridin-2-yl)methanamine

[0423] tert-Butyl (5-bromo-3-fluoropyridin-2-yl)methylcarbamate (2.6 g, 8.5 mmol) was dissolved in 1,4-dioxane (15 mL), and 4 M hydrochloric acid 1,4-dioxane solution (5 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was distilled under reduced pressure to obtain the crude target compound (1.8 g, 8.5 mmol) as a yellow oil. LC / MS (ESI) M / Z: 205.1 [M+H] + .

[0424] Step 3: N-((5-bromo-3-fluoropyridin-2-yl)methyl)formamide

[0425] The crude (5-bromo-3-fluoropyridin-2-yl)methanamine (1.8 g, 8.5 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (3 mL) and ethyl formate (20 mL) were added, the reaction was heated to 65 °C and stirred overnight. After the reaction was completed, the reaction was cooled to room temperature and dried under reduced pressure to obtain the red-brown crude target compound (1.8 g, 7.7 mmol). LC / MS (ESI) M / Z: 233.0 [M+H] + .

[0426] Step 4: 6-bromo-8-fluoroimidazo[l,5-a]pyridine

[0427] 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 was stirred at room temperature under nitrogen protection for 3 hours. After the reaction was completed, saturated sodium bicarbonate was added at 0 °C to adjust the pH of the reaction mixture to basic, extracted with dichloromethane (50 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to obtain the target compound (600 mg, 2.8 mmol, three-step yield: 33%). LC / MS (ESI) M / Z: 215.1 [M+H] + .

[0428] Step 5: 6-bromo-8-(l-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)imidazo[l,5- a]pyridine

[0429] 1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethanol-1-ol (875 mg, 2.8 mmol) was dissolved in N,N-dimethylformamide (6 mL). The reaction mixture was kept at 0 °C, and sodium hydride (112 mg, 2.8 mmol) was added. The reaction mixture was stirred at 0 °C for 20 minutes. Then, 6-bromo-8-fluoroimidazolo[1,5-a]pyridine (600 mg, 2.8 mmol) dissolved in N,N-dimethylformamide (3 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with ice water, extracted with ethyl acetate (50 mL * 3), the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and distilled under reduced pressure. The residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to give the target compound (740 mg, 1.5 mmol, yield: 52%). LC / MS (ESI) M / Z: 508.2 [M+H] + .

[0430] Step 6: 8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,5-a]pyridine

[0431] 6-Bromo-8-(1-(5-fluoropyridin-2-yl)-2-((triisopropylsilyl)oxy)ethoxy)imidazo[1,5-a]pyridine (740 mg, 1.5 mmol) was dissolved in 1,4-dioxane (8 mL), and pinacol diboronate (740 mg, 2.9 mmol), potassium acetate (427 mg, 4.4 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (106 mg, 0.1 mmol) were added under a nitrogen atmosphere and the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to give a colorless oily target compound (300 mg, 0.5 mmol, yield: 37%). LC / MS (ESI) M / Z: 508.2 [M+H] + .

[0432] Step 7: 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-carboxylic acid tert-butyl ester

[0433] To a solution of 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) in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (29 mg, 0.05 mmol) was added under nitrogen protection, and the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to obtain the target compound (120 mg, 0.2 mmol, yield: 38%) as a light yellow oil. LC / MS (ESI) M / Z: 694.3 [M+H] + .

[0434] Step 8: 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

[0435] 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 4M hydrochloric acid in 1,4-dioxane (2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure to obtain the target compound (60 mg, 0.1 mmol) as a light yellow oil. LC / MS (ESI) M / Z: 438.2 [M+H] + .

[0436] Step 9: 4-(4-(8-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)imidazo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0437] 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)ethan-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 was stirred at room temperature for 1 hour. After completion of the reaction, the reaction was spin dried under reduced pressure and purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0% to 10%) to give 40 mg of crude product which was further purified by reverse phase (ACN:H20 = 0% to 50%) to give the target product as a white solid (5 mg, 0.01 mmol, 6% over two steps). LC / MS (ESI) M / Z: 463.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 3.0 Hz, 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 = 5.0 Hz, 1H), 5.24 (t, J = 6.0 Hz, 1H), 4.66 - 4.53 (m, 1H), 3.91 (t, J = 5.6 Hz, 2H), 3.56 (d, J = 12.8 Hz, 2H), 3.29 - 3.22 (m, 2H), 2.35 (s, 3H), 2.19 - 2.10 (m, 2H), 2.07 - 2.01 (m, 2H).

[0438] Example 9: 2-(5-fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxyλ6-sulfanyl)-2,6- diazaspiro[3.3]heptan-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]ethan-1-ol

[0439] Step 1: 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2- methylpropan-2-yl ester

[0440] Dissolve 5-bromo-2-fluoropyridine (487 mg, 2.77 mmol) in dimethyl sulfoxide (8.0 mL), add 2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylprop-2-yl ester (549 mg, 2.77 mmol) and N,N-diisopropylethylamine (1.79 g, 13.8 mmol) and stir at 90 °C for 4 hours. Add water (80 mL) and extract with ethyl acetate (3 x 20 mL), dry the organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0% to 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] + .

[0441] Step 2: 2-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane

[0442] Dissolve 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2- methylprop-2-yl ester (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 give crude 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] + .

[0443] Step 3: 6-(5-bromopyridin-2-yl)-2-(methyldioxido-λ6-sulfanyl)-2,6-diazaspiro[3.3]heptane

[0444] Dissolve 2-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane (500 mg, 1.97 mmol) in tetrahydrofuran (5 mL), add triethylamine (0.55 mL, 3.94 mmol) and methylsulfonyl chloride (338 mg, 2.95 mmol). Stir the reaction at room temperature for 1 hour. Add saturated aqueous sodium bicarbonate solution (20 mL) and extract with dichloromethane (3 x 10 mL), dry the organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Purify the residue 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] + .

[0445] Step 4: 6-bromopyrazolo[1,5-a]pyridine-4-ol

[0446] 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 was cooled to room temperature, water (20 mL) and ethyl acetate (10 mL) were added and the pH of the reaction was adjusted to 4 with formic acid. The reaction 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% to 50% ethyl acetate) to give the title compound (300 mg, 1.41 mmol, 63.96%). LC / MS (ESI) M / Z: 213.0 [M+H] + .

[0447] Step 5: 6-bromo-4-{[1 -(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4- silahex-1 -yl]oxy}pyrazolo[1,5-a]pyridine

[0448] To a solution of 6-bromopyrazolo[1,5-a]pyridine-4-ol (300 mg, 1.41 mmol) in N,N-dimethylformamide (4 mL) was added cesium carbonate (345 mg, 1.06 mmol) and 1 -(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahexan-1 -yl methanesulfonate (271 mg, 0.78 mmol) at room temperature. The reaction was stirred at 110 °C for 30 minutes. The reaction was cooled to room temperature, water (10 mL) was added and the reaction 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% to 20% ethyl acetate) to give the title compound (300 mg, 0.642 mmol, 64.93%). LC / MS (ESI) M / Z: 466.1 [M+H] + .

[0449] Step 6: 4-{[1 -(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahex-1 -yl]oxy}- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

[0450] Dissolve 6-bromo-4-{[l-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4- silahex-l-yl]oxy}pyrazolo[l,5-a]pyridine (300 mg, 0.642 mmol), bis(pinacolato)diboron (327 mg, 1.29 mmol) and potassium acetate (190 mg, 1.93 mmol) in 1,4-dioxane (4.0 mL), add l,l'-bis(diphenylphosphino)ferrocenedichloropalladium (48 mg, 0.064 mmol) under nitrogen and stir at 80 °C for 1 h. Cool the reaction to room temperature, filter and concentrate under reduced pressure. Purify the residue by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0% to 20% ethyl acetate) to give the title compound (270 mg, 0.526 mmol, 81.57% yield). LC / MS (ESI) M / Z: 514.3 [M+H] + .

[0451] Step 7: 4-{[l-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahex-l-yl]oxy}-6-{2- [2-(methyldioxido-λ6-sulfanyl)-2,6-diazaspiro[3.3]heptan-6-yl]pyridin-5-yl}pyrazolo[l,5- a]pyridine

[0452] Dissolve 4-{[l-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahex-l-yl]oxy}-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (270 mg, 0.526 mmol), 6-(5- bromopyridin-2-yl)-2-(methyldioxido-λ6-sulfanyl)-2,6-diazaspiro[3.3]heptane (159 mg, 0.478 mmol), potassium carbonate (199 mg, 1.44 mmol) in 1,4-dioxane (4 mL) and water (1 mL), add l,l'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (31 mg, 0.046 mmol) under nitrogen and stir at 80 °C for 1 h. Cool the reaction to room temperature, concentrate the 1,4-dioxane, add water (10 mL) and extract with ethyl acetate (3 x 10 mL). Dry the organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0% to 60% ethyl acetate) to give the title compound (130 mg, 0.203 mmol, 38.69% yield). LC / MS (ESI) M / Z: 639.3 [M+H] + .

[0453] Step 8: 2-(5-fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxido-i6-sulfido)-2,6- diazaspiro[3.3]heptan-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]ethan-1 -ol

[0454] Step 8: 2-(5-fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxido-i6-sulfido)-2,6- diazaspiro[3.3]heptan-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]ethan-1 -ol + . 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.55 (d, J = 1.0 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.6, 2.5 Hz, 1H), 7.72 (td, J = 8.7, 2.9 Hz, 1H), 7.61 (dd, J = 8.8, 4.5 Hz, 1H), 6.78 - 6.74 (m, 2H), 6.48 (d, J = 8.7 Hz, 1H), 5.74 (t, J = 5.2 Hz, 1H), 5.22 (t, J = 5.9 Hz, 1H), 4.13 (s, 4H), 4.09 (s, 4H), 3.95 (t, J = 5.5 Hz, 2H), 3.01 (s, 3H).

[0455] Example 10: 4-[4-(8-{[l-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[l,2- a]pyridin-6-yl)-5-methyl-l,2,3-triazol-l-yl]hexahydropyridine- 1 -carbonitrile

[0456] Step 1: 5-Fluoro-2-vinylpyridine

[0457] To a solution of 8-methoxy-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2- a]pyridine (2.0 g, 11.4 mmol) in ethanol (20 mL) was added potassium vinyltrifluoroborate (1.83 g, 13.6 mmol), triethylamine (1.72 g, 17 mmol) and [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (470 mg, 0.57 mmol). The reaction was heated at 85 °C under nitrogen for 3 h. After completion of the reaction, the reaction was cooled to room temperature, water (40 mL) was added and the reaction was extracted with methyl tert-butyl ether (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 15 °C to obtain the crude compound 5-fluoro-2-vinylpyridine (8 g, 65 mmol) as a yellow oil. LC / MS (ESI) M / Z: 124.2 [M+H] + .

[0458] Step 2: (lS)-l-(5-fluoropyridin-2-yl)ethane-l,2-diol

[0459] To a solution of 5-fluoro-2-vinylpyridine (8 g, 65 mmol) in tert-butanol (4 mL) and water (4 mL) was added methylsulfonamide (6.18 g, 65 mmol) and AD-mix-a (91 g, 117 mmol) and the reaction was stirred at room temperature overnight. After completion of the reaction, saturated aqueous sodium sulfite solution (100 mL) was added and the reaction was extracted with ethyl acetate / isopropanol (1:1) (3 x 50 mL). The organic layer 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 the compound (lS)-l-(5-fluoropyridin-2-yl)ethane-l,2-diol (800 mg, 5.1 mmol, 7.84% yield) as a colorless oil. LC / MS (ESI) M / Z: 158.2 [M+H] + .

[0460] Step 3: (lS)-l-(5-fluoropyridin-2-yl)-2-{[tris(propan-2-yl)silyl]oxy}ethan-l-ol

[0461] (1S)-1-(5-fluoropyridin-2-yl)ethane-1,2-diol (800 mg, 5.1 mmol) was dissolved in dichloromethane (10 mL), imidazole (1.04 g, 15.3 mmol) and triisopropylchlorosilane (1.08 g, 5.6 mmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, water (20 mL) was added and extracted with ethyl acetate (3 x 20 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0% to 20% ethyl acetate) to obtain the target compound (1S)-1-(5-fluoropyridin-2-yl)-2-{[tris(propan-2-yl)silyl]oxy}ethan-1-ol (1.5 g, 4.8 mmol, yield: 94%) as a colorless oil. LC / MS (ESI) M / Z: 314.3 [M+H] + .

[0462] Step 4: tert-butyl (5-bromo-3-fluoropyridin-2-yl)methyl)carbamate

[0463] 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 in portions 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 extracted with ethyl acetate (200 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 5% to 15% ethyl acetate) to obtain the target compound (2.6 g, 8.5 mmol, yield: 17%) as a colorless oil. LC / MS (ESI) M / Z: 305.0 [M+H] + .

[0464] Step 5: (5-bromo-3-fluoropyridin-2-yl)methanamine

[0465] tert-butyl (5-bromo-3-fluoropyridin-2-yl)methyl)carbamate (2.6 g, 8.5 mmol) was dissolved in 1,4-dioxane (15 mL), 4M hydrochloric acid 1,4-dioxane solution (5 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was distilled under reduced pressure to obtain the target compound (1.8 g, 8.5 mmol) as a yellow oil. LC / MS (ESI) M / Z: 205.1 [M+H] + .

[0466] Step 6: N-((5-bromo-3-fluoropyridin-2-yl)methyl)formamide

[0467] The crude (5-bromo-3-fluoropyridin-2-yl)methanamine (1.8 g, 8.5 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (3 mL) and ethyl formate (20 mL) were added, and the reaction was heated to 65 °C and stirred overnight. After the reaction was completed, the reaction was cooled to room temperature and dried under reduced pressure to obtain the crude target compound (1.8 g, 7.7 mmol) as a reddish brown solid. LC / MS (ESI) M / Z: 233.0 [M+H + ].

[0468] Step 7: 6-bromo-8-fluoroimidazo[l,5-a]pyridine

[0469] 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, and the reaction was stirred at room temperature under nitrogen protection for 3 h. After the reaction was completed, saturated sodium bicarbonate was added at 0 °C to adjust the pH of the reaction mixture to basic, and extracted with dichloromethane (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to obtain the target compound (600 mg, 2.8 mmol, three-step yield: 33%). LC / MS (ESI) M / Z: 215.1 [M+H] + .

[0470] Step 8: 6-bromo-8-{[(lS)-l-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(prop-2-yl)-3-oxa-4- silahex-l-yl]oxy}imidazo[l,5-a]pyridine

[0471] (1S)-1-(5-fluoropyridin-2-yl)-2-{[tris(propan-2-yl)silyl]oxy}ethan-1-ol (1093 mg, 3.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), the reaction was placed at 0 °C, 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, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with ice water, extracted with ethyl acetate (50 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure, the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10%-15% ethyl acetate) to obtain the target compound 6-bromo-8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propan-2-yl)-3-oxa-4-silahex-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] + .

[0472] Step 9: 8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propan-2-yl)-3-oxa-4-silahex-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine

[0473] Step 1: 6-Bromo-8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propan-2-yl)-3-oxa-4- silahex-1-yl]oxy}imidazo[1,5-a]pyridine + .

[0474] Step 10: 2-Methylprop-2-yl 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(propan-2- yl)-3-oxa-4-silahex-1-yl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine- 1-carboxylate

[0475] To a solution of 8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(prop-2-yl)-3-oxa-4- silahex-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), 4-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (229 mg, 0.66 mmol) and potassium carbonate (276 mg, 2.0 mmol) in a mixed solvent of 1,4-dioxane (8 mL) and water (2 mL) under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (44 mg, 0.07 mmol) was added and heated to 80 °C 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 ethyl acetate (50 mL*3) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5%-7% methanol) to obtain the target compound 2-methylprop-2-yl 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-5-methyl-4,4-di(prop-2-yl)-3-oxa-4-silahex-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, yield: 72.9%) as a light yellow oil. LC / MS (ESI) M / Z: 694.3 [M+H] + .

[0476] 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-yl}oxy)ethan-1-ol

[0477] 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-yl}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 mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure and the crude product was purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0% to 10%) followed by reverse phase purification (ACN:H20 = 0% to 95%) to give the target product 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-2- hydroxyethyl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1- carbonitrile (25 mg, 0.05 mmol, yield: 13.14%) as a white solid. LC / MS (ESI) M / Z: 463.2 [M+H] + .

[0478] Step 12: 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

[0479] 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-yl}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 mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure and the crude product was purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0% to 10%) followed by reverse phase purification (ACN:H20 = 0% to 95%) to give the target product 4-[4-(8-{[(1S)-1-(5-fluoropyridin-2-yl)-2- hydroxyethyl]oxy}imidazo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1- carbonitrile (25 mg, 0.05 mmol, yield: 13.14%) as a white solid. LC / MS (ESI) M / Z: 463.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.43 (d, J = 1.0 Hz, 1H), 8.27 (s, 1H), 7.72 (td, J = 8.7, 2.9 Hz, 1H), 7.55 (q, J = 4.3 Hz, 2H), 6.34 (s, 1H), 5.55 (t, J = 5.1 Hz, 1H), 5.25 (t, J = 6.0 Hz, 1H), 4.59 (td, J = 11.1, 5.6 Hz, 1H), 3.91 (t, J = 5.6 Hz, 2H), 3.56 (d, J = 12.7 Hz, 2H), 3.27 (t, J = 11.1 Hz, 2H), 2.35 (s, 3H), 2.16 - 2.02 (m, 4H).

[0480] 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

[0481] 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 stirred at room temperature overnight. After the reaction was completed, water (10 mL) was added and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by reverse phase purification (ACN:H2O = 0% to 95%) to obtain the crude product, which was purified by column chromatography (eluent: dichloromethane / ethyl acetate, gradient: 0%-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 (5 mg, 0.01 mmol, yield: 23.27%) as a white solid. LC / MS (ESI) M / Z: 497.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.37 (s, 1H), 8.24 (d, J = 0.9 Hz, 1H), 7.76 (td, J = 8.8, 2.9 Hz, 1H), 7.63 - 7.58 (m, 1H), 6.46 (s, 1H), 5.57 (t, J = 5.2 Hz, 1H), 5.13 (t, J = 5.6 Hz, 1H), 4.63 - 4.55 (m, 1H), 3.92 (t, J = 5.1 Hz, 2H), 3.56 (d, J = 13.1 Hz, 2H), 3.30 - 3.24 (m, 2H), 2.38 (s, 3H), 2.15 - 2.03 (m, 4H).

[0482] Example 11: 2-(5-fluoropyridin-2-yl)-2-[(6-{2-[2-(methyldioxido-λ6-sulfanyl)-2,6- diazaspiro[3.3]heptan-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridin-4-yl)oxy]ethan-1-ol

[0483] Step 1: 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane- 2-carboxylic acid-2-methylprop-2-yl ester

[0484] Step 1: 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane- 2-carboxylic acid-2-methylprop-2-yl ester

[0485] Step 1: 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane- 2-carboxylic acid-2-methylprop-2-yl ester Step 1: 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane- 2-carboxylic acid-2-methylprop-2-yl ester + .

[0485] Step 1: 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane- 2-carboxylic acid-2-methylprop-2-yl ester Step 1: 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane- 2-carboxylic acid-2-methylprop-2-yl ester

[0486] To a solution of 6-[5-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester (191 mg, 0.453 mmol) in N,N-dimethylacetamide (5 mL), sodium hydroxide (91 mg, 2.27 mmol) (dissolved in 0.2 mL of water) and dodecane-1-thiol (551 mg, 2.72 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 110 °C for 3 hours. The reaction solution was cooled to room temperature, and water (20 mL) and ethyl acetate (10 mL) were added. The pH of the reaction system was adjusted to 4 with formic acid. Extracted with ethyl acetate (3 x 20 mL), the organic phase was washed with water and saturated brine, dried under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-100% ethyl acetate) to give the title compound (150 mg, 0.368 mmol, yield 81.2%). LC / MS (ESI) M / Z: 408.2 [M+H] + .

[0487] Step 3: 6-[5-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester

[0488] At room temperature, 6-{2-[2-(methyldioxane-λ6-thio)-2,6-diazaspiro[3.3]heptane-6-yl]pyridin-5-yl}pyrazolo[1,5-a]pyridine-4-phenol (150 mg, 0.368 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (180 mg, 0.552 mmol) and methanesulfonic acid-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhe-1-yl ester (142 mg, 0.405 mmol) were added. The reaction was carried out at 80 °C for 30 min. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%–30% ethyl acetate) to give the title compound (170 mg, 0.257 mmol, yield 69.9%). LC / MS (ESI) M / Z: 661.3 [M+H] + .

[0489] Step 4: 2-(5-fluoropyridin-2-yl)-2-({6-[2-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-5-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)ethanol-1-ol

[0490] 6-[5-(4-{[1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL, 26.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give the crude compound 2-(5-fluoropyridin-2-yl)-2-({6-[2-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-5-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)ethanol-1-ol (110 mg, 0.246 mmol). LC / MS(ESI)M / Z:447.2[M+H] + .

[0491] Step 5: 6-[5-(4-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxynitrile

[0492] At room temperature, cyanogen bromide (52.2 mg, 0.493 mmol) was added to a solution of dichloromethane (3 mL) containing 2-(5-fluoropyridin-2-yl)-2-({6-[2-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-5-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)ethanol (110 mg, 0.246 mmol) and N,N-diisopropylethylamine (637 mg, 4.93 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (3 x 10 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: methanol / dichloromethane, gradient: 0%-10%) to obtain a crude product, which was then purified by reverse-phase chromatography (ACN:H2O = 5% to 95%) to give 6-[5-(4-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxynitrile (30 mg, 0.082 mmol, 24.74%). LC / MS (ESI) M / Z: 472.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.56 (s, 1H), 8.37 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.6, 2.5 Hz, 1H), 7.73 (td, J = 8.7, 2.9 Hz, 1H), 7.62 (dd, J = 8.7, 4.5 Hz, 1H), 6.78 (d, J = 2.3 Hz, 1H), 6.75 (d, J = 1.2 Hz, 1H), 6.47 (d, J = 8.7 Hz, 1H), 5.75 (t, J = 5.1 Hz, 1H), 4.38 (s, 4H), 4.12 (s, 4H), 3.96 (d, J = 5.1 Hz, 2H).

[0493] Example 12: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2- a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carbonitrile

[0494] Step 1: (1R)-2-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-1-(5-fluoropyridin-2- yl)ethan-1-ol

[0495] To a solution of (1R)-2-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-1-(5- fluoropyridin-2-yl)ethan-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 was stirred at 0 degrees for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution (20 mL) was added and the reaction mixture was extracted with ethyl acetate (3 x 10 mL). 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: 0-20% ethyl acetate) to give compound (1R)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahex-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] + .

[0496] Step 2: 6-bromopyrazolo[1,5-a]pyridin-4-ol

[0497] 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 water) and dodecanethiol (21.3 g, 105 mmol). The reaction was stirred at 60 °C for 4 h. After the reaction was completed, the reaction was cooled to room temperature, water (300 mL) was added, formic acid was added to adjust the pH of the reaction to 3-4, 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 give compound 6-bromopyrazolo[1,5-a]pyridin-4-ol (3 g, 14.1 mmol, 79.9% yield) as a white solid. LC / MS (ESI) M / Z: 213.0 [M+H] + .

[0498] Step 3: 6-bromo-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4- silahex-1-yl]oxy}pyrazolo[1,5-a]pyridine

[0499] To a solution of 6-bromopyrazolo[1,5-a]pyridin-4-ol (3 g, 14.1 mmol) in N,N- dimethylformamide (30 mL) was added cesium carbonate (6.88 g, 21.1 mmol) and (1R)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahexan-1-yl methanesulfonate (5.41 g, 15.5 mmol) at room temperature. The reaction was stirred at 110 °C for 30 min. After the reaction was completed, the reaction was cooled to room temperature, water (200 mL) was added, extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0%-50% ethyl acetate) to give the title compound 6-bromo-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahex-1-yl]oxy}pyrazolo[1,5-a]pyridine (2.84 g, 6.09 mmol, 43.24% yield). LC / MS (ESI) M / Z: 466.1 [M+H] + .

[0500] Step 4: 4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahex-1-yl]oxy}- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

[0501] To a solution of 6-bromo-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4- silahex-1-yl]oxy}pyrazolo[1,5-a]pyridine (2.84 g, 6.09 mmol), bis(pinacolato)diboron (3.1 g, 12.2 mmol) and potassium acetate (1.8 g, 18.3 mmol) in 1,4-dioxane (4.0 mL) was added 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium (450 mg, 0.61 mmol) under nitrogen and heated to 80 °C for 2 h. After completion of the reaction, 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 give the title compound 4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahex-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, 38.38% yield). LC / MS (ESI) M / Z: 514.3 [M+H] + .

[0502] Step 5: Step 1: 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2- methylprop-2-yl ester

[0503] To a solution of 5-bromo-2-fluoropyridine (200 mg, 1.14 mmol) in dimethyl sulfoxide (3 mL) was added 2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylprop-2-yl ester (338 mg, 1.7 mmol) and N,N-diisopropylethylamine (735 mg, 5.68 mmol) and stirred at 90 °C for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature, water (30 mL) was added and extracted with ethyl acetate (3 x 10 mL). The organic layer 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 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2- methylprop-2-yl ester (400 mg, 1.13 mmol, 99.36% yield). LC / MS (ESI) M / Z: 354.2 [M+H] + .

[0504] Step 6: 2-Methylpropyl-2-yl-6-[5-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhexyl]oxy}pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester

[0505] At room temperature, 200 mg (0.57 mmol) of 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester (200 mg, 0.57 mmol) and (4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-siloxane-1-yl]oxy}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazole[1,5- [a] Pyridine (348 mg, 0.68 mmol) and potassium carbonate (234 mg, 1.69 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Under nitrogen protection, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (37 mg, 0.06 mmol) was added, and the mixture was heated to 80 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, and water (10 mL) was added. The solution was then diluted with ethyl acetate (3x... Extracted by 10 mL, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to give the title compound 2-methylpropyl-2-yl-6-[5-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhex-1-yl]oxy}pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester (294 mg, 0.45 mmol, yield: 78.8%). LC / MS (ESI) M / Z: 661.4 [M+H] + .

[0506] Step 7: 2-Methylpropyl-2-yl-6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silylhex-1-yl]oxy}pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester

[0507] To a solution of 2-methylpropan-2-yl 6-[5-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5- tetramethyl-3-oxa-4-silahex-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) in dichloromethane (3 mL) was added N-chlorosuccinimide (56 mg, 0.42 mmol) and stirred at room temperature for 1 h. After completion of the reaction, water (10 mL) was added and extracted with dichloromethane (3 x 10 mL). The organic layer 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 2-methylpropan-2-yl 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5- tetramethyl-3-oxa-4-silahex-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, 48.5% yield). LC / MS (ESI) M / Z: 695.3 [M+H] + .

[0508] Step 8: (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-5-yl]pyrazolo[1,5- a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol

[0509] To a solution of 2-methylpropan-2-yl 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5- tetramethyl-3-oxa-4-silahex-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) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) and stirred at room temperature for 1 h. After completion of the reaction, it was concentrated under reduced pressure to give the title compound (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-5-yl]pyrazolo[1,5- a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol (80 mg, 0.17 mmol, 77.11 % yield). LC / MS (ESI) M / Z: 481.3 [M+H] + .

[0510] Step 9: 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5- a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carbonitrile

[0511] (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-5-yl]pyrazolo[1,5- a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (80 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), N,N-diisopropylethylamine (65 mg, 0.5 mmol) and cyanogen bromide (35 mg, 0.33 mmol) were added and stirred at room temperature for 1 hour. After completion of the reaction, water (10 mL) was added and extracted with dichloromethane (3 x 10 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0% to 100% ethyl acetate) to obtain the title compound 6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5- a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carbonitrile (35.7 mg, 0.07 mmol, 42.42% yield). LC / MS (ESI) M / Z: 506.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.54 (d, J = 1.1 Hz, 1H), 8.37 (dd, J = 2.5, 0.8 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 8.7, 2.5 Hz, 1H), 7.77 (td, J = 8.8, 2.9 Hz, 1H), 7.69 (dd, J = 8.8, 4.6 Hz, 1H), 6.91 (d, J = 1.3 Hz, 1H), 6.47 (d, J = 8.7 Hz, 1H), 5.80 (t, J = 5.0 Hz, 1H), 5.11 (t, J = 5.7 Hz, 1H), 4.37 (s, 4H), 4.11 (s, 4H), 4.00 - 3.91 (m, 2H).

[0512] 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

[0513] Step 1 : 5-Fluoro-2-vinylpyridine

[0514] 2-Bromo-5-fluoropyridine (50 g, 284.107 mmol), vinylpotassium 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) and the reaction was stirred at 80 °C under nitrogen for 3 h. The reaction was cooled to room temperature and filtered through methyl tert-butyl ether. The resulting solution was washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine. The ethanol was removed from the reaction mixture and the resulting organic phase was dried over anhydrous sodium sulfate and filtered. The methyl tert-butyl ether was removed by distillation under reduced pressure (temperature controlled at below 15 °C during distillation) to give 43.5 g of crude 5-fluoro-2-vinylpyridine. This material was used immediately in the next step. This material did not give an ion current in LCMS.

[0515] Step 2: (R)-1-(5-Fluoropyridin-2-yl)ethane-1,2-diol

[0516] To a solution of 5-fluoro-2-vinylpyridine (43 g, 296.841 mmol) and methanesulfonamide (28.24 g, 296.841 mmol) in a mixture of tert-butanol and water (100 mL, 1 / 1 v / v) was added AD-mix-β (416.22 g, 534.313 mmol) in portions under nitrogen. The reaction was stirred at room temperature for 16 h. The reaction was quenched by the addition of aqueous sodium sulfite solution and stirred at room temperature for 1 h. The mixture was extracted with a mixture of isopropanol and ethyl acetate (1:1) (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0-8%) to give the title compound (R)-1-(5-fluoropyridin-2-yl)ethane-1,2-diol (35.8 g, crude). LC / MS (ESI) M / Z: 158.1 [M+H] + .

[0517] Step 3: (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol

[0518] To a solution of compound (R)-1-(5-fluoropyridin-2-yl)ethane-1,2-diol (35.8 g, 227.822 mmol) 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 was also allowed to warm to room temperature and stirred for 3 h. After completion of the reaction, it was extracted with ethyl acetate and the organic phase was washed with water (200 mL X 4) and saturated brine. It was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate / pet. ether, gradient: 0-20%) to afford 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] + .

[0519] Step 4: tert-Butyl 4-(4-bromo-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[0520] To a solution of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-cyclopropyl-1H-1,2,3- triazole-4-carboxylic acid (15.4 g, 45.78 mmol) in water (150 mL) was added sodium acetate (4.51 g, 54.94 mmol) and N-bromosuccinimide (20.37 g, 114.5 mmol) and the reaction was heated to 80 °C and stirred for 3 h. The reaction was cooled to room temperature, water (50 mL) was added and it was extracted with ethyl acetate (200*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: pet. ether / ethyl acetate, gradient: 30-50% ethyl acetate) to afford the title compound (13.0 g, 35.01 mmol, yield: 76.48%). LC / MS (ESI) M / Z: 371.2 / 373.3 [M+H] + .

[0521] 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-silinan-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1- carboxylate

[0522] A solution of 2-methyl-2-yl 4-[5-cyclopropyl-4-(4-hydroxypyrazolo[l,5- a]pyridin-6-yl)-l,2,3-triazol-l-yl]hexahydropyridine-l-carboxylate (5.07 g, 11.943 mmol), l-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-l- ylmethanesulfonate (4.59 g, 13.138 mmol) and cesium carbonate (11.67 g, 35.830 mmol) in N,N-dimethylformamide (50 mL) was stirred at 110 °C for 30 min. The reaction was cooled to room temperature and extracted with ethyl acetate and water. The organic phase was washed with water (100 mL X 3), saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0-50%) to give the title compound 2-methylprop-2-yl 4-[5-cyclopropyl-4-(4-{[(lS)-l-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-l-yl]oxy}pyrazolo[l,5-a]pyridin-6-yl)-l,2,3-triazol-l-yl]hexahydropyridine-l-carboxylate (5.7 g, 8.408 mmol, yield: 70.40%). LC / MS (ESI) M / Z: 678.4 [M+H] + .

[0523] Step 6: 2-methyl-2-yl 4-[4-(3-chloro-4-{[(lS)-l-(5-fluoropyridin-2-yl)-4,4,5,5- tetramethyl-3-oxa-4-silane-l-yl]oxy}pyrazolo[l,5-a]pyridin-6-yl)-5-cyclopropyl- l,2,3-triazol-l-yl]hexahydropyridine-l-carboxylate

[0524] 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-silane-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1- yl]hexahydropyridine-1-carboxylate (5.7 g, 8.408 mmol) in dichloromethane (90 mL) was added N-chlorosuccinimide (1.10 g, 8.240 mmol) and the reaction was stirred at room temperature for 16 hours. To the reaction was added 150 mL of water and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 0-20%) to give the title compound 2-methylpropan-2-yl 4-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silane-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-cyclopropyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylate (4.4 g, 6.177 mmol, 73.46%) LC / MS (ESI) M / Z: 712.3 [M+H] + .

[0525] Step 7: (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

[0526] 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-silane-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-1,2,3-triazol-1- yl]hexahydropyridine-1-carboxylate (4.4 g, 6.177 mmol) and hydrogen chloride in dioxane (4 M, 4.6 mL) in dioxane (60 mL) was stirred at room temperature for one hour. The reaction was distilled under reduced pressure using a rotary evaporator to give the title compound (2S)-2-({3-chloro-6-[5-cyclopropyl-1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol (3.8 g, yield: 98.84%). LC / MS (ESI) M / Z: 498.2 [M+H] + .

[0527] Step 8: 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

[0528] 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 was stirred at room temperature for 1 h. The reaction was extracted with dichloromethane and water, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate and filtered. The residue was purified by column chromatography (eluent: methanol / dichloromethane, gradient: 0% to 10%) to give crude product 2.8 g, which was further purified by reverse phase (ACN:H20 = 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 (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.51 (s, 1H), 8.12 (s, 1H), 7.78 (td, J = 8.8, 2.9 Hz, 1H), 7.64 (dd, J = 8.8, 4.5 Hz, 1H), 6.99 (s, 1H), 5.60 (t, J = 5.2 Hz, 1H), 5.15 (s, 1H), 4.85 - 4.68 (m, 1H), 3.94 (d, J = 4.9 Hz, 2H), 3.58 (d, J = 12.1 Hz, 2H), 3.36 (d, J = 3.5 Hz, 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).

[0529] Example 14: (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

[0530] Step 1: (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

[0531] A solution of sodium hydride (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. Then the mixture was cooled to <5 degrees and (chloromethyl)(methyl)sulfane (184.66 mg, 1.912 mmol) was added, keeping the temperature at <5 degrees. The mixture was stirred at this temperature for 3 hours and then the temperature was slowly increased to room temperature and stirring was continued for 13 hours. At temperature <5 degrees, ethyl acetate (20 mL) and saturated aqueous NH4Cl (20 mL) were added to the reaction and stirred. After warming to ambient temperature, the layers were separated and the organic layer was washed with saturated aqueous sodium chloride (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 give the title compound (S)-4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-((methylthio)methoxy)ethoxy)pyrazolo[1,5- a]pyridin-6-yl)-5-cyclopropyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile (280 mg, yield: 50%). LC / MS (ESI) M / Z: 583.2 [M+H] + .

[0532] Step 2: (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

[0533] A solution of 4-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-3-oxa-5- thia-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 min. The mixture was cooled to 0 °C and N-iodosuccinimide (162.06 mg, 0.720 mmol) was added immediately. After the mixture was stirred for 35 min, 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 aqueous layer was separated and back-extracted with ethyl acetate (10 mL). The combined organic layers were concentrated to give the crude product, which was purified by reverse-phase HPLC (ACN / H2O: 5% to 45%) to give (S)-(2-((3-chloro-6-(1-(1-cyanopiperidin-4-yl)-5-cyclopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)methyl dihydrogen phosphate (44.2 mg, yield: 14.54%). LC / MS (ESI) M / Z: 633.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 2.8 Hz, 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 = 5.1 Hz, 1H), 5.17 - 5.09 (m, 2H), 4.86 - 4.71 (m, 1H), 4.16 (d, J = 5.1 Hz, 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).

[0534] 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

[0535] Reaction Scheme:

[0536] Procedure:

[0537] Step 1: 4-hydroxy-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0538] Benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (4.5 g, 19.4 mmol) was dissolved in methanol (50 mL), cerium (III) chloride heptahydrate (10.9 g, 29.2 mmol) was added, sodium borohydride (1.1 g, 29.2 mmol) was added at 0 degree, stirred for 2 hours. After the reaction was completed, concentrated under reduced pressure, water (100 mL) was added, extracted with ethyl acetate (3*10 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to obtain compound 4-hydroxy-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester (3.4 g, 14.6 mmol, yield: 74.9%). LC / MS (ESI) M / Z: 234.2 [M+H] + .

[0539] Step 2: 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester

[0540] Benzyl 4-hydroxy-3,4-dihydropyridine-1(2H)-carboxylate (3.4 g, 14.6 mmol), diethylzinc (14.6 ml, 1M, 146 mmol) were dissolved in dichloromethane (40 mL), methyl iodide (39 g, 146 mmol) was added at 0 degree, stirred for 3 hours. After the reaction was completed, water (100 mL) was added, extracted with dichloromethane (3*50 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to obtain 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (2 g, 8.1 mmol, yield: 55.5%). LC / MS (ESI) M / Z: 248.2 [M+H] + .

[0541] Step 3: 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester

[0542] To a solution of 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (2 g, 8.1 mmol) in methanol (20 mL), palladium on carbon (200 mg), di-tert-butyl dicarbonate (2.65 g, 12.2 mmol) was added. The reaction was stirred under hydrogen atmosphere overnight. After completion of the reaction, water (50 mL) was added and extracted with ethyl acetate (3*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 give 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] + .

[0543] Step 4: tert-Butyl 5-((methylsulfonyl)oxy)-2-azabicyclo[4.1.0]heptane-2-carboxylate

[0544] 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), triethylamine (1.56 g, 15.5 mmol) and p-toluenesulfonyl chloride (10.3 mmol) were added at 0°C and stirred at room temperature for 1 h. After completion of the reaction, water (30 mL) was added and extracted with dichloromethane (3*20 mL), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 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] + .

[0545] Step 5: tert-Butyl 5-azido-2-azabicyclo[4.1.0]heptane-2-carboxylate

[0546] tert-butyl 5-((methylsulfonyl)oxy)-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.15 g, 3.95 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium azide (513 mg, 7.9 mmol) was added, and the mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 * 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% to 20% ethyl acetate) to obtain the title compound (780 mg, 3.28 mmol, 83% yield). LC / MS (ESI) M / Z: 239.4 [M+H] + .

[0547] 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 was obtained by the synthetic route and steps of Example 2. LC / MS (ESI) M / Z: 509.9 [M+H] + .

[0548] Example 24: (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

[0549] The compound Example 24 was synthesized using the synthetic route and steps of Example 115, replacing ethyl 3-oxobutanoate-4,4,4-d3 with ethyl 3-oxobutanoate.

[0550] Procedure:

[0551] 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

[0552] To a solution of (2S)-2-((3-chloro-6-(5-(methyl-d 3)To a solution of (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 (30 mg, 0.06 mmol) in dichloromethane DCM (2 mL), cyanogen bromide (12 mg, 0.12 mmol) and N,N-diisopropylamine (38 mg, 0.29 mmol) were added. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction solution was added to water (5 mL) and 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 the crude product, which was further purified by reverse phase purification (ACN:H2O=10%-50%) to obtain the target product as a white solid (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] + .

[0553] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.8 Hz, 1H), 8.44 (s, 1H), 8.12 (s, 1H), 7.77 (td, J = 8.8, 2.8 Hz, 1H), 7.64 (dd, J = 8.8, 4.4 Hz, 1H), 6.95-6.86 (m, 1H), 5.63 (dt, J = 5.8, 2.8 Hz, 1H), 5.15 (t, J = 5.6 Hz, 1H), 4.65-4.52 (m, 1H), 3.94 (t, J = 5.4 Hz, 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).

[0554] Example 36: (S)-6-(1-(1-cyanopiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0555] Step 1: (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5- fluoropyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l- yl)piperidine-l-carboxylate

[0556] To a mixture solution of tert-butyl 4-(4-bromo-5-methyl-lH-l,2,3-triazol-l- yl)piperidine-l-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)-l-(5-fluoropyridin-2-yl)ethoxy)- 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (446 mg, 0.9 mmol), [l,l'-bis(ditert-butylphosphino)ferrocene]dichloropalladium (56 mg, 0.1 mmol) and potassium carbonate (357 mg, 2.6 mmol) under nitrogen atmosphere at room temperature. The reaction was stirred at 90 °C for 2 hours. After completion of the reaction, the reaction was cooled to room temperature, water (30 mL) was added and extracted with ethyl acetate (100 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40% to 60% ethyl acetate) to give (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (260 mg, 0.4 mmol, yield: 46%) as a light yellow oil. LC / MS (ESI) M / Z: 652.3 [M+H] + .

[0557] Step 2: (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l- yl)piperidine-l-carboxylate

[0558] (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,5- a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylic acid tert-butyl ester (260 mg, 0.4 mmol) was dissolved in dichloromethane (5 mL), N-iodosuccinimide (68 mg, 0.4 mmol) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, water (10 mL) was added to the reaction system, and extraction was performed with dichloromethane (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40% to 60% ethyl acetate) to obtain (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3- iodopyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylic acid tert-butyl ester (250 mg, 0.3 mmol, yield: 81%) as a light yellow oil. LC / MS (ESI) M / Z: 778.2 [M+H] + .

[0559] Step 3: (S)-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-5-methyl-lH-l,2,3-triazol-4-yl)-4-(2- ((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridine-3- carboxylic acid methyl ester

[0560] (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3- iodopyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l- carboxylic acid tert-butyl ester (250 mg, 0.3 mmol) was dissolved in dioxane (10 mL) and methanol (5 mL), palladium acetate (2 mg, 0.01 mmol), 4,5- bisdiphenylphosphino-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 and the reaction mixture was stirred at 90 °C under nitrogen atmosphere for 2 hours. After the reaction was completed, the reaction was cooled to room temperature, water (30 mL) was added and the reaction was extracted with ethyl acetate (100 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40%-60% ethyl acetate) to give (S)-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-5-methyl-lH-l,2,3-triazol-4-yl)-4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid methyl ester (44 mg, 0.06 mmol, yield: 19%) as a yellow oil. LC / MS (ESI) M / Z: 710.3 [M+H] + .

[0561] Step 4: (S)-4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(5-methyl-l-(piperidin-4-yl)- lH-l,2,3-triazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxylic acid methyl ester

[0562] To a solution of (S)-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-5-methyl-lH- 1,2,3-triazol-4-yl)-4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy) pyrazolo[l,5-a]pyridine-3-carboxylic acid methyl ester (44 mg, 0.06 mmol) in dichloromethane (2 mL) was added 4M hydrochloric acid in dioxane (2 mL) and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was concentrated to dryness to give crude (S)-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)-6-(5-methyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5- a]pyridine-3-carboxylic acid methyl ester (20 mg, 0.04 mmol, yield: 65%) as a white solid which was used directly in the next step without further purification. LC / MS (ESI) M / Z: 496.2 [M+H] + .

[0563] Step 5: (S)-6-(l-(l-cyanopiperidin-4-yl)-5-methyl-lH-l,2,3-triazol-4-yl)-4-(l-(5- fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid methyl ester

[0564] To a solution of (S)-4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(5-methyl-l- (piperidin-4-yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxylic acid methyl ester (20 mg, 0.04 mmol) in dichloromethane (3 mL) was added N,N- diisopropylamine (104 mg, 0.8 mmol) and cyanogen bromide (13 mg, 0.1 mmol) and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, water (5 mL) was added and the reaction was extracted with dichloromethane (15 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 60%-80% ethyl acetate) to give (S)-6-(l-(l-cyanopiperidin-4-yl)-5-methyl-lH-l,2,3-triazol-4-yl)-4-(l-(5- fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,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 (400 MHz, DMSO-d6) δ 8.67-8.57 (m, 2H), 8.47 (s, 1H), 7.75 (td, J = 8.6, 2.8 Hz, 1H), 7.67 (dd, J = 8.8, 4.6 Hz, 1H), 7.07 (d, J = 1.2 Hz, 1H), 5.65 (t, J = 5.2 Hz, 1H), 5.03 (t, J = 6.0 Hz, 1H), 4.67-4.57 (m, 1H), 3.94 (t, J = 5.6 Hz, 2H), 3.86 (s, 3H), 3.56 (d, J = 13.0 Hz, 2H), 3.26 (d, J = 10.8 Hz, 2H), 2.39 (s, 3H), 2.19-2.10 (m, 2H), 2.05-1.96 (m, 2H).

[0565] Example 50: (S)-6-(5-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6-methylpyridin-2-yl]-2,6- diazaspiro[3.3]heptane-2-carbonitrile

[0566] Step 1: 6-(5-bromo-6-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester

[0567] To 3-bromo-6-fluoro-2-methylpyridine (150 mg, 0.8 mmol) in dimethyl sulfoxide (5 mL) was added 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (157 mg, 0.8 mmol) and N,N-diisopropylethylamine (306 mg, 2.4 mmol) and the reaction was stirred at 90 °C for 3 hours. After completion of the reaction, the reaction was cooled to room temperature, water (15 mL) was added and the reaction was extracted with ethyl acetate (50 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 20%-35% ethyl acetate) to give 6-(5-bromo-6-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 0.5 mmol, yield: 69%) as a light yellow solid. LC / MS (ESI) M / Z: 368.1 [M+H] + .

[0568] Step 2: (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6-methylpyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0569] To a mixture solution of 6-(5-bromo-6-methylpyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (200 mg, 0.5 mmol) in dioxane (4 mL) and water (0.4 mL) was added (S)-4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (279 mg, 0.5 mmol), [l,l'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 0.05 mmol) and potassium carbonate (225 mg, 1.6 mmol) under nitrogen atmosphere at room temperature. The reaction was heated to 90 °C and stirred for 2 hours. After completion of the reaction, the reaction was cooled to room temperature, water (10 mL) was added and extracted with ethyl acetate (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-45% ethyl acetate) to give (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,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] + .

[0570] Step 3: (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3- chloropyrazolo[l,5-a]pyridin-6-yl)-6-methylpyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester

[0571] (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3- chloropyrazolo[l,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) 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 extraction was performed with dichloromethane (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30% to 45% ethyl acetate) to obtain (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3- chloropyrazolo[l,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 light yellow oil. LC / MS (ESI) M / Z: 709.3 [M+H] + .

[0572] Step 4: (S)-2-((3-chloro-6-(2-methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0573] To a solution of (S)-6-(5-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3- chloropyrazolo[l,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 mixture was stirred at room temperature for 16 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to basic with saturated sodium bicarbonate, and extraction was performed with dichloromethane (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain (S)-2-((3-chloro-6-(2-methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (80 mg, 0.2 mmol, yield: 57%) as a light yellow solid. LC / MS (ESI) M / Z: 495.1 [M+H] + .

[0574] 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

[0575] To a solution of (S)-2-((3-chloro-6-(2-methyl-6-(2,6-diazaspiro[3.3]heptan-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) was added N,N-diisopropylethylamine (104 mg, 0.8 mmol) and cyanogen bromide (41 mg, 0.3 mmol), 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 distilled under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-45% ethyl acetate) to obtain (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 (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.8 Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.77 (td, J = 8.8, 2.8 Hz, 1H), 7.64 (dd, J = 8.8, 4.4 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 6.50 (s, 1H), 6.28 (d, J = 8.4 Hz, 1H), 5.60 (t, J = 5.0 Hz, 1H), 5.09 (t, J = 5.6 Hz, 1H), 4.36 (s, 4H), 4.08 (s, 4H), 3.93 (t, J = 5.4 Hz, 2H), 2.08 (s, 3H).

[0576] Example 51: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2-a]pyridin-6-yl)- 5-methyl-1,2,3-triazepan-1-yl]hexahydropyridine-1-carbonitrile

[0577] Step 1: 6-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid 2- methylpropan-2-yl ester

[0578] To a solution of 4,6-dichloro-5-methylpyrimidine (200 mg, 1.23 mmol) in 1,4- dioxane (5 mL) was 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 °C for 2 h. After the reaction was completed, the reaction 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 give 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, 97.9% yield). LC / MS (ESI) M / Z: 325.2 [M+H] + .

[0579] Step 2: 2-methylpropan-2-yl 6-[6-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5-tetramethyl-3-oxa-4-silahex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]- 2,6-diazaspiro[3.3]heptane-2-carboxylate

[0580] Step 2: 2-methylprop-2-yl 6-(6-chloro-5-methylpyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate + .

[0581] 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-silahex-1-yl]oxy}pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrimidin-4-yl]-2,6- diazaspiro[3.3]heptane-2-carboxylate

[0582] To a solution of 2-methylprop-2-yl 6-[6-(4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5- tetramethyl-3-oxa-4-silahex-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 oxalyl chloride (45 mg, 0.34 mmol). The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL*3), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-60% ethyl acetate) to give the product 2-methylprop-2-yl 6-[6-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5- tetramethyl-3-oxa-4-silahex-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] + .

[0583] Step 4: (2S)-2-({3-chloro-6-[4-(2,6-diazaspiro[3.3]heptan-2-yl)-5-methylpyrimidin-6-yl]pyrazolo[1,5- a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0584] To a solution of 2-methylprop-2-yl 6-[6-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-4,4,5,5- tetramethyl-3-oxa-4-silahex-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) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL). Stirring at room temperature overnight. After the reaction was completed, concentrated under reduced pressure to give the title compound (2S)-2-({3-chloro-6-[4-(2,6-diazaspiro[3.3]heptan-2-yl)-5-methylpyrimidin-6-yl]pyrazolo[1,5- a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (120 mg, 0.24 mmol). LC / MS (ESI) M / Z: 496.2 [M+H] + .

[0585] 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

[0586] (2S)-2-({3-chloro-6-[4-(2,6-diazaspiro[3.3]heptan-2-yl)-5-methylpyrimidin-6-yl]pyrazolo[1,5- a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (120 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL), N,N-diisopropylethylamine (94 mg, 0.73 mmol) and cyanogen bromide (51 mg, 0.48 mmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, water (10 mL) was added and extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to obtain 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 (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.44-8.38 (m, 2H), 8.15 (s, 1H), 7.77 (td, J = 8.8, 3.0 Hz, 1H), 7.65 (dd, J = 8.8, 4.5 Hz, 1H), 6.74 (d, J = 1.0 Hz, 1H), 5.61 (t, J = 5.1 Hz, 1H), 5.13 (t, J = 5.6 Hz, 1H), 4.41-4.35 (m, 8H), 3.93 (td, J = 5.2, 2.4 Hz, 2H), 1.98 (s, 3H).

[0587] Example 52: 6-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5- a]pyridin-6-yl)-2-cyanophenyl]-2,6-diazaspiro[3.3]heptane-2-carbonitrile

[0588] Reference to the experimental procedure of Example 51. LC / MS (ESI) M / Z: 530.15 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 1.1 Hz, 1H), 8.59 (d, J = 2.9 Hz, 1H), 8.06 (s, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.77 (td, J = 9.0, 2.6 Hz, 2H), 7.70 (dd, J = 8.8, 4.6 Hz, 1H), 7.01 (s, 1H), 6.63 (d, J = 8.9 Hz, 1H), 5.90 (t, J = 5.1 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.39 (s, 4H), 4.32 (s, 4H), 4.01 - 3.89 (m, 2H).

[0589] Example 53: 4-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5- a]pyridin-6-yl)-2-cyanophenyl]piperazine-1-carbonitrile

[0590] Reference the experimental procedure of Example 51. LC / MS (ESI) M / Z: 518.14 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 1.1 Hz, 1H), 8.59 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.10 (s, 1H), 7.97 (dd, J = 8.7, 2.4 Hz, 1H), 7.77 (td, J = 8.8, 2.9 Hz, 1H), 7.71 (dd, J = 8.8, 4.6 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 1.2 Hz, 1H), 5.93 (dd, J = 6.0, 3.9 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.02 (ddd, J = 11.7, 5.5, 3.9 Hz, 1H), 3.93 (dt, J = 11.7, 5.9 Hz, 1H), 3.46 - 3.39 (m, 4H), 3.29 - 3.22 (m, 4H).

[0591] 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

[0592] The synthetic route and procedure of Example 50 were used to synthesize compound Example 54 by replacing 3-bromo-6-fluoro-2-methylpyridine with 5-bromo-2-fluoro-4- methylpyridine in the following table. LC / MS (ESI) M / Z: 520.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 2.8 Hz, 1H), 8.19 (d, J = 1.0 Hz, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.76 (td, J = 8.8, 3.0 Hz, 1H), 7.64 (dd, J = 8.8, 4.4 Hz, 1H), 6.50 (d, J = 1.0 Hz, 1H), 6.31 (s, 1H), 5.60 (t, J = 5.2 Hz, 1H), 5.09 (t, J = 5.6 Hz, 1H), 4.36 (s, 4H), 4.08 (s, 4H), 3.92 (t, J = 5.4 Hz, 2H), 1.96 (s, 3H).

[0593] Example 55: (S)-4-(6-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5- a]pyridin-6-yl)-5-methylpyrimidin-4-yl)piperazine-l-carbonitrile

[0594] Step 1: 4-(6-chloro-5-methylpyrimidin-4-yl)piperazine-l-carboxylate

[0595] To a solution of 4,6-dichloro-5-methyl-pyrimidine (200 mg, 1.2 mmol) in dimethyl sulfoxide (5 mL) was added tert-butyl piperazine-l-carboxylate (229 mg, 1.2 mmol) and N,N- diisopropylethylamine (476 mg, 3.7 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated to 90 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water (15 mL) was added and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 1% to 3% methanol) to obtain 4-(6-chloro-5-methylpyrimidin-4-yl)piperazine-l-carboxylate (300 mg, 1.0 mmol, yield: 78%) as a light yellow solid. LC / MS (ESI) M / Z: 313.1 [M+H] + .

[0596] The subsequent steps refer to the synthetic route of Example 50. LC / MS (ESI) M / Z: 509.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.59 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 1.0 Hz, 1H), 8.17 (s, 1H), 7.78 (td, J = 8.8, 2.8 Hz, 1H), 7.67 (dd, J = 8.8, 4.4 Hz, 1H), 6.93 (d, J = 1.0 Hz, 1H), 5.67 (dd, J = 6.0, 4.0 Hz, 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)

[0597] Example 56: (S)-6-(5-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-cyanopyridin-2-yl]-2,6- diazaspiro[3.3]heptane-2-carbonitrile

[0598] The compound Example 56 was synthesized using the synthetic route and procedure of Example 50, replacing 3-bromo-6-fluoro-2-methylpyridine with 5-bromo-2- chloronicotinonitrile in the following table. LC / MS (ESI) M / Z: 531.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.72 - 8.68 (m, 2H), 8.59 (d, J = 2.8 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.08 (s, 1H), 7.81 - 7.75 (m, 1H), 7.73 - 7.69 (m, 1H), 7.06 (d, J = 1.2 Hz, 1H), 5.91 (dd, J = 6.0, 3.8 Hz, 1H), 5.09 (t, J = 5.6 Hz, 1H), 4.43 (s, 4H), 4.39 (s, 4H), 4.04 - 3.98 (m, 1H), 3.98 - 3.89 (m, 1H).

[0599] Example 57: (S)-6-(5-(3-bromo-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane- 2-carbonitrile

[0600] The compound Example 57 was synthesized using the synthetic route and procedure of Example 50, replacing 3-bromo-6-fluoro-2-methylpyridine with 5-bromo-2- fluoropyridine in the following table, while replacing NCS with NBS. LC / MS (ESI) M / Z: 550.1 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.8 Hz, 1H), 8.58 (d, J = 1.0 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.04 (s, 1H), 7.83 (dd, J = 8.6, 2.4 Hz, 1H), 7.79 - 7.69 (m, 2H), 6.91 (d, J = 1.2 Hz, 1H), 6.47 (d, J = 8.6 Hz, 1H), 5.80 (t, J = 5.2 Hz, 1H), 5.09 (t, J = 5.6 Hz, 1H), 4.37 (s, 4H), 4.11 (s, 4H), 4.01 - 3.92 (m, 2H).

[0601] Example 58: (S)-4-(6-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)pyrimidin-4-yl)piperazine-l-carbonitrile

[0602] Example 58 was synthesized using the synthetic route and procedure of Example 50, replacing 3-bromo-6-fluoro-2-methylpyridine with 4,6-dichloropyrimidine in the table below. LC / MS (ESI) M / Z: 507.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 1.0 Hz, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.51 (d, J = 1.0 Hz, 1H), 8.18 (s, 1H), 7.77 (td, J = 8.8, 2.8 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.32 (s, 1H), 6.98 (d, J = 1.2 Hz, 1H), 5.76 (t, J = 5.0 Hz, 1H), 5.14 (t, J = 5.6 Hz, 1H), 4.39 (s, 4H), 4.24 (s, 4H), 4.00 - 3.90 (m, 2H).

[0603] Example 59: (S)-6-(4-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2- carbonitrile

[0604] Step 1: 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0605] To a solution of (4-bromophenyl)boronic acid (200 mg, 1.0 mmol) in dichloromethane (5 mL) was 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) at room temperature under nitrogen atmosphere. The reaction mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 15-20% ethyl acetate) to give the target compound tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (130 mg, 0.4 mmol, 84% yield) as a white solid. LC / MS (ESI) M / Z: 353.0 [M+H] + .

[0606] The subsequent steps refer to the synthetic route of Example 50. LC / MS (ESI) M / Z: 505.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.45 (d, J = 1.1 Hz, 1H), 8.03 (s, 1H), 7.80-7.73 (m, 1H), 7.67 (dd, J = 8.8, 4.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 6.87 (s, 1H), 6.49 (d, J = 8.6 Hz, 2H), 5.77 (t, J = 5.1 Hz, 1H), 5.11 (t, J = 5.6 Hz, 1H), 4.36 (s, 4H), 3.98 (s, 4H), 3.97-3.90 (m, 2H).

[0607] Example 60: (S)-6-(4-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5- a]pyridin-6-yl)-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carbonitrile

[0608] Reaction Scheme:

[0609] Procedure:

[0610] Step 1: tert-butyl 6-(4-bromo-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0611] To a solution of 4-bromo-2-fluoro-l-iodobenzene (150 mg, 0.5 mmol) in 1,4-dioxane (5 mL) was 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) under nitrogen at room temperature. The reaction mixture was heated at 100 °C for 2 h. After completion of the reaction, the reaction mixture was distilled under reduced pressure and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 15-20% ethyl acetate) to give the target compound tert-butyl 6-(4-bromo-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (140 mg, 0.4 mmol, 76% yield) as a white solid. LC / MS (ESI) M / Z: 371.0 [M+H] + .

[0612] Subsequent steps refer to the synthetic route of Example 50. LC / MS (ESI) M / Z: 523.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.8 Hz, 1H), 8.55 (d, J = 1.0 Hz, 1H), 8.05 (s, 1H), 7.77 (td, J = 8.6, 2.8 Hz, 1H), 7.69 (dd, J = 8.8, 4.6 Hz, 1H), 7.48 (dd, J = 14.0, 2.0 Hz, 1H), 7.35 (dd, J = 8.2, 2.0 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H), 6.59 (dd, J = 9.6, 8.4 Hz, 1H), 5.88 - 5.81 (m, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.36 (s, 4H), 4.08 (d, J = 2.0 Hz, 4H), 4.02 - 3.90 (m, 2H).

[0613] Example 61: 4-(4-(3-chloro-4-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-yl)methoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile

[0614] Step 1: ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-yl)methyl methanesulfonate

[0615] To a solution of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methanol (200 mg, 1.3 mmol) in dichloromethane (5 mL) was added triethylamine (385 mg, 3.8 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred in an ice bath for 5 minutes, then methylsulfonyl chloride (216 mg, 1.9 mmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture obtained a colorless oily crude product of the target compound ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methyl methanesulfonate (200 mg, 0.4 mmol, yield: 68%), and the structure of the intermediate was confirmed in the next step. The crude target product was directly used in the next step without further purification.

[0616] Step 2: tert-Butyl 4-(4-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate

[0617] To a solution of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methyl methanesulfonate (134 mg, 0.6 mmol) in N,N-dimethylformamide (5.00 mL) was added tert-butyl 4-(4-(4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (150 mg, 0.4 mmol) and cesium carbonate (368 mg, 1.1 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was placed in a 90 °C reactor for 15 minutes. After the reaction was completed, water (10 mL) was added to the reaction mixture, and the organic phase was extracted with ethyl acetate (30 mL*3), 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% to 6% methanol) to obtain the target product tert-butyl 4-(4-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (120 mg, 0.2 mmol, yield: 60%) as a yellowish oily substance. LC / MS (ESI) M / Z: 540.3 [M+H] + .

[0618] The subsequent steps refer to the synthetic route of Example 50. LC / MS (ESI) M / Z: 499.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 1.0 Hz, 1H), 8.11 (s, 1H), 7.19 (d, J = 1.2 Hz, 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), 3.07 - 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).

[0619] Example 62: (S)-4-(4-(3-ethynyl-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l- yl)piperidine-l-carbonitrile

[0620] Step 1: (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5- fluoropyridin-2-yl)ethoxy)-3-((trimethylsilyl)ethynyl)pyrazolo[l,5-a]pyridin-6- yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate

[0621] To a solution of (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5- fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3- triazol-l-yl)piperidine-l-carboxylate (400 mg, 0.5 mmol) in tetrahydrofuran (10 mL) was added trimethylsilylacetylene (151 mg, 1.5 mmol), palladium dichloride bis(triphenylphosphine) Pd(PPh3)2Cl2(36 mg, 0.05 mmol), triethylamine (260 mg, 2.5 mmol) and cuprous iodide (10 mg, 0.05 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was heated at 60 °C for 4 h. After the reaction was completed, the reaction mixture 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 distilled under reduced pressure. The residue was purified by reverse phase purification (ACN:H2O = 0%-50%) to give the target compound (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3-((trimethylsilyl)ethynyl)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (270 mg, 0.4 mmol, 70%) as a yellow oil. LC / MS (ESI) M / Z: 748.3 [M+H] + .

[0622] Step 2: (S)-tert-butyl 4-(4-(3-ethynyl-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l- carboxylate

[0623] To a solution of (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5- fluoropyridin-2-yl)ethoxy)-3-((trimethylsilyl)ethynyl)pyrazolo[l,5-a]pyridin-6-yl)-5- methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (80 mg, 0.1 mmol) in dichloromethane (2 mL) was added 1 mol / L tetrabutylammonium fluoride (0.3 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was added to water (5 mL) and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3% to 5% methanol) to obtain the target compound (S)-tert-butyl 4-(4-(3-ethynyl-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l- carboxylate (40 mg, 0.07 mmol, 67%) as a yellow oil. LC / MS (ESI) M / Z: 562.2 [M+H] + .

[0624] Step 3: (S)-2-((3-ethynyl-6-(5-methyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0625] To a solution of (S)-tert-butyl 4-(4-(3-ethynyl-4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l- carboxylate (40 mg, 0.07 mmol) in dichloromethane (2 mL) was added zinc bromide (48 mg, 0.2 mmol) at room temperature. 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-l-(piperidin-4-yl)-lH-l,2,3-triazol-4- yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol (20 mg, 0.04 mmol) as a light brown solid. LC / MS (ESI) M / Z: 462.2 [M+H] + .

[0626] 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

[0627] 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), cyanogen bromide (9 mg, 0.09 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction was spin dried under reduced pressure, the residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10%) to get 15 mg of crude product which was further purified by reverse phase (ACN:H2O = 0%-50%) to get 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 (400 MHz, DMSO-d6) δ 8.59 (d, J = 3.0 Hz, 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).

[0628] Example 63: (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 (ee: 77.14%)

[0629] Procedure:

[0630] Step 1: (R)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethanol

[0631] Dissolve (lR)-2-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-l-(5-fluoropyridin-2- yl)ethanol (17.82 g, 65.756 mmol) in dichloromethane (300 mL), add DIEA (25.447 mL, 197.268 mmol), cool the reaction to 0 °C, and add MsCl (5.57 mL, 72.331 mmol) dropwise. Allow the reaction to warm to room temperature and stir for 1 h. Dilute the reaction with 300 mL of water, extract the reaction with 300 mL of dichloromethane three times, combine the organic layers, wash the organic layer with 300 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. This gives crude (R)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethanol (25 g, crude) as a yellow oil. LC / MS (ESI) M / Z: 272.1 [M+H] + .

[0632] Step 2: (S)-6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2- yl)ethoxy)pyrazolo[l,5-a]pyridine

[0633] Dissolve (R)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethanol (25 g) in DMF (250 mL), add 6-bromopyrazolo[l,5-a]pyridin-4-ol (15.334 g, 72.331 mmol), and cesium carbonate (64.309 g, 197.268 mmol), and allow the reaction to warm to 80 °C and stir for 1 h. Dilute the reaction with 300 mL of water, extract the reaction with 300 mL of ethyl acetate three times, combine the organic layers, wash the organic layer with 300 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify the crude product on a silica gel column (PE / EA = 10: 1) to give (S)-6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridine (19.55 g, 44.043 mmol, 63.9%) as a yellow oil. LC / MS (ESI) M / Z: 466.1 [M+H] + .

[0634] Step 3: (S)-4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine

[0635] (S)-6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,5- a]pyridine (17.72 g, 38.108 mmol) was dissolved in dioxane (400 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,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) were added, the reaction was protected by nitrogen, and the reaction was heated to 90 °C for 5 h. Without further treatment, the reaction solution was directly used for the next step. LC / MS (ESI) M / Z: 514.2 [M+H] + .

[0636] Step 4: (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,5- a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate

[0637] The reaction solution of the previous step was added with H2O (10 mL), tert-butyl 4-(4-bromo-5-methyl-l,2,3-triazol-l-yl)hexahydropyridine-l-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 solution was protected by nitrogen, and the reaction was heated to 100 °C for 4 h. The reaction solution was diluted with 200 mL of water, the reaction solution was extracted with 200 mL of ethyl acetate for 3 times, the organic phase was combined, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated. The crude product was subjected to silica gel column chromatography (PE / (EA:EtOH = 3: 1) = 3: 1) to obtain (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,5- a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (14.8 g, 22.734 mmol, 59.91%) as a yellow oil. LC / MS (ESI) M / Z: 652.3 [M+H] + .

[0638] Step 5: (S)-2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5- a]pyridin-4-yl)oxy)ethanol

[0639] (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[l,5- a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylic acid tert-butyl ester (7.5 g, 11.521 mmol) was dissolved in dichloromethane (30 mL), HCl (30 mL, 120.000 mmol) was added, and the reaction was stirred at room temperature for 1 hour. It was directly rotary evaporated to give yellow solid (S)-2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4- yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)ethanol (6 g, crude). LC / MS (ESI) M / Z: 438.2 [M+H] + .

[0640] Step 6: (S)-4-(4-(4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5- methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile

[0641] (S)-2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4- yl)pyrazolo[l,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, and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with 100 mL of water, and the reaction was extracted with 100 mL of ethyl acetate three times, the organic phase was combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10: 1) to give yellow oil (S)-4-(4-(4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5- methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile (3.05 g, 6.595 mmol, 48.08 %). LC / MS (ESI) M / Z: 463.2 [M+H] + .

[0642] Step 7: (S)-4-(4-(4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-iodopyrazolo[l,5-a]pyridin-6- yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile

[0643] (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) was dissolved in dichloromethane (50 mL), N-iodosuccinimide (1.48 g, 6.595 mmol) was added, and the reaction solution was allowed to react at room temperature for 18 hours. The reaction solution was directly spin-dried. The crude product was subjected to silica gel column chromatography (DCM / MeOH = 10:1) to obtain (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] + .

[0644] Step 8: (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

[0645] (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 bis(triphenylphosphine)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, and the reaction solution was allowed to react at 50°C under nitrogen protection while dropwise adding ethynylcyclopropane (1.31 g, 19.783 mmol) for 3 hours. The reaction solution was diluted with 50 mL of water, and the reaction solution was extracted with 50 mL of ethyl acetate three times, and the organic phases were combined and washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The crude product was subjected to silica gel column chromatography (PE / (EA:EtOH = 3:1) = 1:1) to obtain (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] + .

[0646] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 1.0 Hz, 1H), 8.09 (s, 1H), 7.79 (td, J = 8.8, 2.8 Hz, 1H), 7.72 (dd, J = 8.6, 4.6 Hz, 1H), 6.97 (d, J = 1.2 Hz, 1H), 5.65 (dd, J = 6.2, 4.2 Hz, 1H), 5.11 (t, J = 5.6 Hz, 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, 2.6 Hz, 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).

[0647] Example 64: (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 (ee: 79%)

[0648] Step 1 : (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

[0649] To a solution of trimethyl(prop-1-yn-1-yl)silane (108 mg, 1.0 mmol) in methanol (3 mL) was added potassium carbonate (133 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium (37 mg, 0.03 mmol), copper(I) iodide (6 mg, 0.03 mmol) and triethylamine (162 mg, 1.6 mmol) under nitrogen atmosphere at room temperature. The mixture was stirred at room temperature for 30 minutes, then a solution of (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) in tetrahydrofuran (3 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, 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 distilled under reduced pressure. The residue was purified by reverse phase purification (ACN:H2O = 0%-50%) to give 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 light yellow oil. LC / MS (ESI) M / Z: 690.3 [M+H] + .

[0650] Step 2: (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

[0651] To a solution of (S)-tert-butyl 4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5- fluoropyridin-2-yl)ethoxy)-3-(prop-l-yn-l-yl)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl- lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (80 mg, 0.1 mmol) in dichloromethane (2 mL) was added 1 mol / L tetrabutylammonium fluoride (0.7 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was added to water (5 mL) and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 3% to 5% methanol) to obtain the target compound (S)-tert-butyl 4-(4-(4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-l-yn-l-yl)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (50 mg, 0.09 mmol, yield: 60%) as a yellow oil. LC / MS (ESI) M / Z: 576.2 [M+H] + .

[0652] Step 3: (S)-2-(5-fluoropyridin-2-yl)-2-(6-(5-methyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-3-(prop-l-yn-l-yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)ethan-l-ol

[0653] To a solution of (S)-tert-butyl 4-(4-(4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-l-yn-l-yl)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (50 mg, 0.09 mmol) in dichloromethane (2 mL) was added zinc bromide (59 mg, 0.3 mmol) at room temperature. 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-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-3-(prop-l-yn-l-yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)ethan-l-ol (25 mg, 0.05 mmol) as a light brown solid. LC / MS (ESI) M / Z: 476.2 [M+H] + .

[0654] Step 4: (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

[0655] 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)ethan-1-ol (25 mg, 0.05 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylamine (34 mg, 0.3 mmol), cyanogen bromide (11 mg, 0.1 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction was spin dried under reduced pressure, the residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0%-10%) to give crude product 15 mg, which was further purified by reverse phase (acetonitrile: water = 0%-50%) to give 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 (400 MHz, DMSO-d6) d 8.59 (d, J = 2.9 Hz, 1H), 8.45 (d, J = 1.0 Hz, 1H), 8.09 (s, 1H), 7.81 (td, J = 8.6, 2.8 Hz, 1H), 7.74 (dd, J = 8.6, 4.6 Hz, 1H), 7.00 (s, 1H), 5.66 - 5.61 (m, 1H), 5.09 (t, J = 5.6 Hz, 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).

[0656] Example 65: ({1-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5- a]pyridin-6-yl)-2-cyanophenyl]-3-(hydroxymethyl)azetidin-3-yl}methyl)azidine

[0657] Reference Example 51 experimental procedure. LC / MS (ESI) M / Z: 548.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, J = 4.0, 2.0 Hz, 2H), 8.05 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.77 (ddd, J = 11.4, 8.8, 2.5 Hz, 2H), 7.71 (dd, J = 8.8, 4.7 Hz, 1H), 7.07 - 6.94 (m, 2H), 6.53 (t, J = 6.0 Hz, 1H), 5.96 - 5.76 (m, 1H), 5.33 (t, J = 5.1 Hz, 1H), 5.09 (t, J = 5.6 Hz, 1H), 4.06 - 3.87 (m, 6H), 3.59 (d, J = 5.1 Hz, 2H), 3.49 (d, J = 6.1 Hz, 2H).

[0658] Example 66: 4-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5- a]pyridin-6-yl)-3-cyanopyridin-2-yl]piperazine-1-carbonitrile

[0659] Reference Example 51 experimental procedure. LC / MS (ESI) M / Z: 519.14 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 2.5 Hz, 1H), 8.78 (d, J = 1.1 Hz, 1H), 8.59 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.11 (s, 1H), 7.78 (td, J = 8.7, 2.9 Hz, 1H), 7.72 (dd, J = 8.7, 4.7 Hz, 1H), 7.13 (d, J = 1.2 Hz, 1H), 5.94 (dd, J = 5.9, 3.9 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.07 - 3.99 (m, 2H), 3.93 (dt, J = 11.7, 5.9 Hz, 1H), 3.76 - 3.71 (m, 4H), 3.42 - 3.37 (m, 4H).

[0660] Example 67: 6-[4-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5- a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carbonitrile

[0661] Reference Example 51 experimental procedure. LC / MS (ESI) M / Z: 506.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 1.1 Hz, 1H), 8.62 (d, J = 2.9 Hz, 1H), 8.14 (s, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.79 (td, J = 8.7, 2.9 Hz, 1H), 7.70 (dd, J = 8.7, 4.5 Hz, 1H), 6.96 (dd, J = 5.4, 1.5 Hz, 2H), 6.61 (d, J = 1.5 Hz, 1H), 5.83 (t, J = 5.1 Hz, 1H), 5.14 (t, J = 5.6 Hz, 1H), 4.38 (s, 4H), 4.13 (s, 4H), 4.00 - 3.94 (m, 2H).

[0662] Example 68: 1-{6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2- hydroxyethyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptan- 2-yl}ethan-1-one

[0663] Reference Example 51 experimental procedure. LC / MS (ESI) M / Z: 506.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 1.1 Hz, 1H), 8.62 (d, J = 2.9 Hz, 1H), 8.14 (s, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.79 (td, J = 8.7, 2.9 Hz, 1H), 7.70 (dd, J = 8.7, 4.5 Hz, 1H), 6.96 (dd, J = 5.4, 1.5 Hz, 2H), 6.61 (d, J = 1.5 Hz, 1H), 5.83 (t, J = 5.1 Hz, 1H), 5.14 (t, J = 5.6 Hz, 1H), 4.38 (s, 4H), 4.13 (s, 4H), 4.00 - 3.94 (m, 2H).

[0664] Example 69: (2S)-2-({6-[2-(6-aza-2-oxaspiro[3.3]heptan-6-yl)pyridin-5-yl]-3- chloropyrazolo[1,5-a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol

[0665] The experimental procedure of Reference Example 51 was followed. LC / MS (ESI) M / Z: 482.13 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.54 (d, J = 1.0 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 8.7, 2.5 Hz, 1H), 7.77 (td, J = 8.7, 2.9 Hz, 1H), 7.69 (dd, J = 8.8, 4.6 Hz, 1H), 6.91 (s, 1H), 6.47 (d, J = 8.7 Hz, 1H), 5.80 (dd, J = 6.0, 4.2 Hz, 1H), 5.11 (t, J = 5.7 Hz, 1H), 4.73 (s, 4H), 4.14 (s, 4H), 4.01 - 3.91 (m, 2H).

[0666] Example 70: 1-{6-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2- hydroxyethyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,6-diazaspiro[3.3]heptan- 2-yl}prop-2-en-1-one

[0667] The experimental procedure of Reference Example 51 was followed. LC / MS (ESI) M / Z: 535.16 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.54 (d, J = 1.0 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 8.7, 2.5 Hz, 1H), 7.77 (td, J = 8.7, 2.9 Hz, 1H), 7.69 (dd, J = 8.8, 4.6 Hz, 1H), 6.91 (s, 1H), 6.47 (d, J = 8.7 Hz, 1H), 5.80 (dd, J = 6.0, 4.2 Hz, 1H), 5.11 (t, J = 5.7 Hz, 1H), 4.73 (s, 4H), 4.14 (s, 4H), 4.01 - 3.91 (m, 2H).

[0668] Example 71: 2-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2- hydroxyethyl]oxy}pyrazolo[1,5-a]pyridin-6-yl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane-7- carbonitrile

[0669] Reference to the experimental procedure of Example 51. LC / MS (ESI) M / Z: 534.17 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.54 (d, J = 1.1 Hz, 1H), 8.36 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 8.7, 2.5 Hz, 1H), 7.77 (td, J = 8.8, 2.9 Hz, 1H), 7.69 (dd, J = 8.8, 4.6 Hz, 1H), 6.91 (s, 1H), 6.44 (d, J = 8.7 Hz, 1H), 5.80 (t, J = 5.1 Hz, 1H), 5.11 (t, J = 5.6 Hz, 1H), 4.01 - 3.91 (m, 2H), 3.22 - 3.17 (m, 4H), 1.84 - 1.77 (m, 4H).

[0670] Example 72: (2S)-2-({3-chloro-6-[2-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-5-yl]pyrazolo[1,5- a]pyridin-4-yl}oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0671] Reference to the experimental procedure of Example 51. LC / MS (ESI) M / Z: 481.93 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.61 - 8.55 (m, 3H), 8.37 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.77 (td, J = 8.8, 2.9 Hz, 1H), 7.69 (dd, J = 8.8, 4.6 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.82 (t, J = 5.1 Hz, 1H), 4.23 - 4.17 (m, 8H), 3.99 - 3.93 (m, 2H).

[0672] Example 73: (S)-2-((3-chloro-6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1 -ol

[0673] Reference to the experimental procedure of Example 51. LC / MS (ESI) M / Z: 559.13 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1 H), 8.55 (d, J = 1.1 Hz, 1 H), 8.38 (d, J = 2.5 Hz, 1 H), 8.05 (s, 1 H), 7.85 (dd, J = 8.6, 2.5 Hz, 1 H), 7.77 (td, J = 8.8, 2.9 Hz, 1 H), 7.69 (dd, J = 8.7, 4.6 Hz, 1 H), 6.92 (s, 1 H), 6.49 (d, J = 8.7 Hz, 1 H), 5.81 (t, J = 5.0 Hz, 1 H), 5.1 1 (s, 1 H), 4.14 (s, 4H), 4.09 (s, 4H), 4.00 - 3.91 (m, 2H), 3.01 (s, 3H).

[0674] Example 74: (S)-5-(3-chloro-4-(1 -(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5- a]pyridin-6-yl)-2-(4-(methylsulfonyl)piperazin-1 -yl)nicotinamide

[0675] Reference to the experimental procedure of Example 51. LC / MS (ESI) M / Z: 572.12 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1 H), 8.55 (d, J = 1.1 Hz, 1 H), 8.38 (d, J = 2.5 Hz, 1 H), 8.05 (s, 1 H), 7.85 (dd, J = 8.6, 2.5 Hz, 1 H), 7.77 (td, J = 8.8, 2.9 Hz, 1 H), 7.69 (dd, J = 8.7, 4.6 Hz, 1 H), 6.92 (s, 1 H), 6.49 (d, J = 8.7 Hz, 1 H), 5.81 (t, J = 5.0 Hz, 1 H), 5.1 1 (s, 1 H), 4.14 (s, 4H), 4.09 (s, 4H), 4.00 - 3.91 (m, 2H), 3.01 (s, 3H).

[0676] Example 75: 4-[4-(8-{[1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}imidazo[1,2- a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carbonitrile

[0677] Reference to the experimental procedure of Example 51. LC / MS (ESI) M / Z: 521.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.54 (d, J = 1.1 Hz, 1H), 8.36 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.82 (dd, J = 8.7, 2.5 Hz, 1H), 7.77 (td, J = 8.8, 2.9 Hz, 1H), 7.69 (dd, J = 8.8, 4.6 Hz, 1H), 6.91 (s, 1H), 6.44 (d, J = 8.7 Hz, 1H), 5.80 (t, J = 5.1 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.02 - 3.90 (m, 6H), 2.68 - 2.52 (m, 5H).

[0678] Example 76: 2-[5-(3-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethyl]oxy}pyrazolo[1,5- a]pyridin-6-yl)pyridin-2-yl]-2-azaspiro[3.3]heptane-6-carbonitrile

[0679] Reference to the experimental procedure of Example 51. LC / MS (ESI) M / Z: 505.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.9 Hz, 1H), 8.54 (d, J = 1.1 Hz, 1H), 8.36 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.82 (dd, J = 8.7, 2.5 Hz, 1H), 7.77 (td, J = 8.8, 2.9 Hz, 1H), 7.69 (dd, J = 8.8, 4.6 Hz, 1H), 6.91 (s, 1H), 6.44 (d, J = 8.7 Hz, 1H), 5.80 (t, J = 5.1 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.02 - 3.90 (m, 6H), 2.68 - 2.52 (m, 5H).

[0680] Example 77: (S)-2-((3-chloro-6-(6-(7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-2- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethanol-1-ol

[0681] Referring to the experimental procedure of Example 51. LC / MS (ESI) M / Z: 587.16 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.60 (d, J = 2.9 Hz, 1H), 8.54 (d, J = 1.1 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 8.7, 2.5 Hz, 1H), 7.77 (td, J = 8.7, 2.9 Hz, 1H), 7.69 (dd, J = 8.7, 4.6 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H), 6.45 (d, J = 8.7 Hz, 1H), 5.81 (dd, J = 6.0, 4.2 Hz, 1H), 5.11 (t, J = 5.7 Hz, 1H), 4.02 - 3.91 (m, 2H), 3.74 (s, 4H), 3.13 (t, J = 5.5 Hz, 4H), 2.87 (s, 3H), 1.85 (t, J = 5.6 Hz, 4H).

[0682] Example 81: (R)-4-(4-(5-(l-(3,5-dichloropyridin-4-yl)ethoxy)-lH-indazol-3-yl)-5- methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile

[0683] Procedure steps:

[0684] Step 1: 5-((tert-butyldimethylsilyl)oxy)-3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH- indazole

[0685] 3-Iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-1H-indazole-5-ol (5 g, 14.528 mmol) was dissolved in dichloromethane (50 mL), and imidazole (2.97 g, 43.585 mmol) and TBSCl (2.63 g, 17.434 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 50 mL of water and extracted three times with 50 mL of dichloromethane. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a yellow solid 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.3 g, 12.369 mmol, 85.13%). LC / MS (ESI) M / Z: 459.1 [M+H] + .

[0686] Step 2: 5-[(tert-butyldimethylsilyl)oxy]-1-(tetrahydro-2H-pyran-2-yl)-3-(trimethyltinyl)-1H-indazole

[0687] 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2 g, 4.367 mmol) was dissolved in dioxane (3 mL), and hexamethyldistin (4.29 g, 13.100 mmol) and tetraphenylphosphine palladium (0.50 g, 0.437 mmol) were added. Under nitrogen protection, the reaction solution was heated to 115 °C and reacted for 8 hours. The reaction solution was quenched with 50 mL of 1 M KF aqueous solution and extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. A yellow solid crude 5-[(tert-butyldimethylsilyl)oxy]-1-(tetrahydro-2H-pyran-2-yl)-3-(trimethylstanyl)-1H-indazole (3 g, 6.048 mmol, 138.51%) was obtained. LC / MS(ESI)M / Z:497.1[M+H] + .

[0688] Step 3: 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-carboxylic acid tert-butyl ester

[0689] To a solution of 5-[(tert-butyldimethylsilyl)oxy]-1-(tetrahydro-2H-pyran-2-yl)-3- (trimethylstannyl)-1H-indazole (1436.68 mg, 1.738 mmol) in toluene (20 mL) was added 4- (4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate tert-butyl (600 mg, 1.738 mmol) and Pd(dtbpf)Cl2(113.14 mg, 0.174 mmol). The reaction was heated to 125 °C for 8 h. The reaction was directly concentrated and the crude product was purified by silica gel column (PE / (EA:EtOH = 3:1) = 3:1) to give 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 tert-butyl (650 mg, 1.091 mmol, 62.75%) as a yellow solid. LC / MS (ESI) M / Z: 597.3 [M+H] + .

[0690] Step 4: 4-(4-(5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3- triazol-1-yl)piperidine-1-carboxylate tert-butyl

[0691] To a solution of 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 tert-butyl (300 mg, 0.503 mmol) in THF (10 mL) was added 1M TBAF in tetrahydrofuran (1.007 mL, 1.007 mmol). The reaction was stirred at room temperature for 1 h. The reaction was diluted with 30 mL of water and extracted with 30 mL of ethyl acetate for 3 times. The organic phase was combined and washed with 50 mL of saturated brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column (PE / EA = 1:1) to give 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 tert-butyl (230 mg, 0.477 mmol, 94.68%) as a yellow oil.

[0692] LC / MS (ESI) M / Z: 482.3 [M+H] + .

[0693] Step 5: (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate

[0694] (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, MsCl (178.93 mg, 1.562 mmol) was added dropwise, and the reaction solution was reacted at 0 °C for 1 hour. The reaction solution was diluted with 30 mL of water, the reaction solution was extracted with 30 mL of dichloromethane three times, the organic phases were combined, the organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated. A yellow oil of (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (500 mg, 1.859 mmol, 118.98%) was obtained.

[0695] LC / MS (ESI) M / Z: 270.1 [M+H] + .

[0696] Step 6: 4-(4-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0697] 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), (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, and the reaction solution was raised to 100 °C and reacted for 5 hours. The reaction solution was diluted with 20 mL of water, the reaction solution was extracted with 20 mL of ethyl acetate three times, the organic phases were combined, the organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated. A yellow oil of crude 4-(4-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.198 mmol, 53.26%) was obtained. LC / MS (ESI) M / Z: 656.2 [M+H] + .

[0698] 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

[0699] 4-(4-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (130 mg, 0.198 mmol) was dissolved in DCM (2 mL), and a 4M HCl solution of dioxane (1 mL, 4.000 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was directly evaporated to dryness to give (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (150 mg, 0.318 mmol, 109.74%). LC / MS (ESI) M / Z: 472.1 [M+H] + .

[0700] Step 8: (R)-4-(4-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile

[0701] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (150 mg, 0.318 mmol) was dissolved in DMF (2 mL), and DIEA (205.21 mg, 1.588 mmol) and cyanogen bromide (33.63 mg, 0.318 mmol) were added. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction solution was directly filtered and passed through a C18 reversed-phase column (0.1% aqueous FA / ACN) to give a white solid (R)-4-(4-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (24.32 mg, 0.049 mmol, 15.40%). LC / MS (ESI) M / Z: 497.1 [M+H] + .

[0702] 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.57 (s, 2H), 7.67 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 6.06 (q, J = 6.6 Hz, 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 = 6.6 Hz, 3H).

[0703] Example 82: (S)-4-(4-(5-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-lH-indazol-3-yl)-5- methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile

[0704] Procedure:

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

[0706] Dissolve (R)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethanol (200 mg, 0.737 mmol) in dichloromethane (5 mL), add DIEA (285.73 mg, 2.211 mmol), cool the reaction to 0 °C, add MsCl (0.063 mL, 0.811 mmol) dropwise, and allow the reaction to warm to room temperature for 1 hour. Dilute the reaction with 10 mL water, extract the reaction with 10 mL dichloromethane three times, combine the organic layers, wash the organic layer with 20 mL saturated brine, dry over sodium sulfate, and concentrate. This gives crude (R)-2-((tert-butyldimethylsilyl)oxy)-l-(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] + .

[0707] Step 2: 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l- carboxylic acid tert-butyl ester

[0708] (R)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethyl methanesulfonate (235 mg, 0.673 mmol) was dissolved in DMF (2 mL), 4-(4-(5-hydroxy-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)-5-methyl- lH-l,2,3-triazol-l-yl)piperidine-l-carboxylic acid tert-butyl ester (100 mg, 0.207 mmol) and cesium carbonate (202.55 mg, 0.622 mmol) were added, the reaction was heated to 100 °C for 2 hours. The reaction was diluted with 20 mL water, the reaction was extracted with 20 mL ethyl acetate for 3 times, the organic phase was combined, washed with 50 mL saturated brine, dried over sodium sulfate, and concentrated. The crude product was obtained as yellow oil. The crude product was purified by silica gel column chromatography (PE / EA = 1:1) to obtain 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylic acid tert-butyl ester (90 mg, 0.122 mmol, 59.06%) as yellow oil. LC / MS (ESI) M / Z: 736.4 [M+H] + .

[0709] Step 3: 5-((S)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3-(5- methyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole

[0710] 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l- carboxylic acid tert-butyl ester (70 mg, 0.095 mmol) was dissolved in dichloromethane (5 mL), zinc bromide (107.09 mg, 0.476 mmol) was added, the reaction was stirred at room temperature for 24 hours. The reaction was directly concentrated to obtain 5-((S)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3-(5-methyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (130 mg, 0.204 mmol, 214.96%) as yellow solid. LC / MS (ESI) M / Z: 636.3 [M+H] + .

[0711] Step 4: 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-indazol-3 -yl)-5 -methyl- 1 H- 1,2,3 -triazol- 1 -yl)piperidine- 1 - carbonitrile

[0712] Step 4: 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-indazol-3 -yl)-5 -methyl- 1 H- 1,2,3 -triazol- 1 -yl)piperidine- 1 - carbonitrile + .

[0713] Step 5: (S)-4-(4-(5-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-lH-indazol-3-yl)-5-methyl- lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile

[0714] 4-(4-(5-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxynitrile (94 mg, 0.142 mmol) was dissolved in dichloromethane (2 mL) and methanol (0.3 mL), and a 4M HCl solution of dioxane (2 mL, 8.000 mmol) was added. The reaction was carried out at room temperature for 18 hours. The reaction solution was evaporated to dryness and then passed through a reverse-phase column (C18) in a (1 / 1000 ammonium bicarbonate aqueous solution: acetonitrile) system to give a white solid (S)-4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-1H-indazol-3-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxynitrile (9.09 mg, 0.020 mmol, 13.80%). LC / MS (ESI) M / Z: 463.2 [M+H] + .

[0715] 1 H 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).

[0716] Example 84: 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)piperidin-1-carboxynitrile

[0717] Step 1: 1-(4-fluorophenyl)but-2-yn-1-ol

[0718] 4-Fluorobenzaldehyde (2 g, 16.129 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction temperature was lowered to 0 °C, and a tetrahydrofuran solution of magnesium 1-propyne bromide (35 mL, 17.742 mmol, 0.5 M) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL * 3), and the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was obtained. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give 1-(4-fluorophenyl)but-2-yn-1-ol (2.4 g, 14.634 mmol, yield: 90.90%). LC / MS (ESI) M / Z: 165.1 [M+H] + .

[0719] Step 2: 1-(4-fluorophenyl)but-2-yn-1-ylmethanesulfonate

[0720] 1-(4-fluorophenyl)but-2-yn-1-ol (400 mg, 2.436 mmol) was dissolved in DCM (8 mL), and DIEA (314.90 mg, 2.436 mmol) was added. The reaction solution was cooled to 0 °C, and MsCl (279.06 mg, 2.436 mmol) was added dropwise. The reaction solution was reacted at 0 °C for 1 hour. The reaction solution was diluted with 50 mL of water, and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. A yellow oily crude product, 1-(4-fluorophenyl)but-2-yn-1-yl methanesulfonate (496 mg, 2.050 mmol, 84.12%), was obtained. It was not purified and proceeded directly to the next step. LC / MS (ESI) M / Z: 243.0 [M+H] +

[0721] Step 3: 1-tert-butyl-4-(4-(4-((1-(4-fluorophenyl)but-2-yn-1-yl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid ester

[0722] Dissolve 2-methyl-2-propanolyl 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl- 1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylate (500 mg, 1.255 mmol) 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), and the reaction solution is raised to 40 °C and reacted for 3 hours. Dilute the reaction solution with 30 mL of water, extract the reaction solution with ethyl acetate (30 mL*3), combine the organic phases, wash the organic phase with 50 mL of saturated brine, dry over anhydrous sodium sulfate, and spin dry. The crude product is subjected to silica gel column chromatography (DCM / MeOH = 20:1) to obtain a crude product. The crude product is subjected to reverse phase column chromatography (0.05% FA in H2O / ACN) to obtain tert-butyl 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] +

[0723] 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

[0724] Dissolve tert-butyl 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) in DCM (5 mL), add NCS (20.26 mg, 0.152 mmol), and the reaction solution is reacted at room temperature for 8 hours. Spin dry the reaction solution to obtain a crude product. Subject the crude product to silica gel column chromatography (PE / EA = 3:1) to obtain yellow solid 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%). LC / MS (ESI) M / Z: 579.2 [M+H] + .

[0725] Step 5: 3-chloro-4-((l-(4-fluorophenyl)but-2-yn-l-yl)oxy)-6-(5-methyl-l-(piperidin-4- yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5-a]pyridine

[0726] Step 5: 3-chloro-4-((l-(4-fluorophenyl)but-2-yn-l-yl)oxy)-6-(5-methyl-l-(piperidin-4- yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5-a]pyridine + .

[0727] Step 6: 4-(4-(3-chloro-4-((l-(4-fluorophenyl)but-2-yn-l-yl)oxy)pyrazolo[l,5-a]pyridin-6- yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile

[0728] Step 5: 3-chloro-4-((l-(4-fluorophenyl)but-2-yn-l-yl)oxy)-6-(5-methyl-l-(piperidin-4- yl)-lH-l,2,3-triazol-4-yl)pyrazolo[l,5-a]pyridine + . 1HNMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.11 (s, 1H), 7.62-7.58 (m, 2H), 7.25 (t, J = 8.8 Hz, 2H), 6.06 (d, J = 4.2 Hz, 1H), 5.87-5.86 (d, J = 4.6 Hz, 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).

[0729] Example 90: (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

[0730] Procedure:

[0731] Step 1: (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

[0732] 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 (Refer to Example 62, 30 mg, 0.07 mmol) in dichloromethane (2 mL) was added bromoacetonitrile (15.59 mg, 0.13 mmol) and N,N-diisopropylamine (42.01 mg, 0.325 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the reaction was evaporated under reduced pressure and the residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0-10%) to get 25 mg of crude product which was further purified by reverse phase (ACN:H20 = 0-50%) to get 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] + .

[0733] 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.6 Hz, 1H), 8.49 (d, J = 1.0 Hz, 1H), 8.22 (s, 1H), 7.79-7.73 (m, 2H), 7.05 (d, J = 1.0 Hz, 1H), 5.67 (dd, J = 6.0, 4.4 Hz, 1H), 5.08 (t, J = 5.6 Hz, 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 = 11.1 Hz, 2H), 2.47-2.40 (m, 5H), 2.19-2.09 (m, 2H), 2.07-2.00 (m, 2H).

[0734] Example 99: (S)-4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-5-nitro pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

[0735] Procedure:

[0736] Step 1: tert-Butyl 4-(4-(4-hydroxy-5-nitropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3- triazol-1-yl)piperidine-1-carboxylate

[0737] To a solution of tert-butyl 4-(4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3- triazol-1-yl)piperidine-1-carboxylate (400 mg, 1.00 mmol) in dichloromethane (10 mL) was added dropwise nitric acid (63.25 mg, 1.00 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 2 h. After completion of the reaction, the reaction 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 give the target compound tert-butyl 4-(4-(4-hydroxy-5-nitropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (120 mg, 0.27 mmol, 27%) as a black solid. LC / MS (ESI) M / Z: 444.2 [M+H] + .

[0738] Step 2: (S)-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-5- nitropyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylic acid tert-butyl ester

[0739] To a solution of (S)-tert-butyl 4-(4-(4-hydroxy-5-nitropyrazolo[l,5-a]pyridin-6-yl)-5- methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (100 mg, 0.23 mmol) in N,N- dimethylformamide (3 mL) was added (R)-ethyl 2-((tert-butyldimethylsilyl)oxy)-l-(5- fluoropyridin-2-yl)methanesulfonate (78.81 mg, 0.23 mmol) and cesium carbonate (220.41 mg, 0.68 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, water (10 mL) was added and extracted with ethyl acetate (15 mL*3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40% to 60% ethyl acetate) to give the target product (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-5- nitropyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (25 mg, 0.04 mmol, 16%) as yellow oil. LC / MS (ESI) M / Z: 697.3 [M+H] + .

[0740] Step 3: (S)-2-(5-fluoropyridin-2-yl)-2-(6-(5-methyl-l-(piperidin-4-yl)-lH-l,2,3-triazol-4-yl)-5- nitropyrazolo[l,5-a]pyridin-4-yl)oxy)ethan-l-ol

[0741] To a solution of (S)-tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5- fluoropyridin-2-yl)ethoxy)-5-nitropyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3- triazol-l-yl)piperidine-l-carboxylate (25 mg, 0.04 mmol) in dichloromethane (2 mL) was added 4M hydrochloric acid in dioxane (1 mL) at room temperature under nitrogen atmosphere. The reaction mixture was allowed to react at room temperature for 5 hours. After the reaction was completed, the reaction solution was added to sodium bicarbonate to adjust the pH to basic, extracted with dichloromethane (20 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5% to 15% methanol) to obtain the target compound (S)-2-(5-fluoropyridin-2-yl)-2-(6-(5-methyl-l-(piperidin-4-yl)-lH-l,2,3- triazol-4-yl)-5-nitropyrazolo[l,5-a]pyridin-4-yl)oxy)ethan-l-ol (15 mg, 0.03 mmol, yield: 87%) as a light yellow oil. LC / MS (ESI) M / Z: 483.2 [M+H] + .

[0742] Step 4: (S)-4-(4-(4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-5-nitropyrazolo[l,5- a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine-l-carbonitrile

[0743] To a solution of (S)-2-(5-fluoropyridin-2-yl)-2-(6-(5-methyl-l-(piperidin-4-yl)-lH-l,2,3- triazol-4-yl)-5-nitropyrazolo[l,5-a]pyridin-4-yl)oxy)ethan-l-ol (15 mg, 0.03 mmol) in dichloromethane (2 mL) was added cyanogen bromide (6.59 mg, 0.06 mmol) and N,N- diisopropylamine (20.09 mg, 0.16 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction solution was added to water (5 mL), extracted with dichloromethane (3*15 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the residue was purified by reverse phase (ACN:H20=0% to 50%) to obtain the target product (S)-4-(4-(4-(l-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)-5-nitropyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)piperidine- l-carbonitrile (7 mg, 0.01 mmol, 44%) as a white solid. LC / MS (ESI) M / Z: 508.2 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.8 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.76 (td, J = 8.6, 2.8 Hz, 1H), 7.63 (dd, J = 8.8, 4.4 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 6.64 (s, 1H), 5.75 (t, J = 5.0 Hz, 1H), 5.31 (t, J = 5.8 Hz, 1H), 4.65 - 4.55 (m, 1H), 3.96 (t, J = 5.4 Hz, 2H), 3.56 (d, J = 13.0 Hz, 2H), 3.30 - 3.22 (m, 2H), 2.15 (s, 3H), 2.14 - 2.02 (m, 4H).

[0744] Example 100-P1 and 100-P2: (4-(4-((S)-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)cyclohexane-1-carbonitrile (cis and trans isomers)

[0745] Example 100-P1 and 100-P2

[0746] The synthetic route and procedure of Example 115 was used to synthesize compounds Example 100-P1 and Example 100-P2 using 4-hydroxycyclohexane-1-carbonitrile in place of 8-hydroxy-5-azaspiro[3.5]nonane-5-carboxylic acid tert-butyl ester.

[0747] Procedure:

[0748] Step 1: (4-(4-((S)-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)cyclohexane-1-carbonitrile (Example 100-P1) and (4-(4-((S)-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)cyclohexane-1-carbonitrile (Example 100-P2)

[0749] To a solution of (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)cyclohexane-1-carbonitrile (100 mg, 0.17 mmol) in N,N-dimethylformamide (5 mL) was added trimethyl(prop-1-yn-1-yl)silane (57 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium (20 mg, 0.02 mmol), cesium carbonate (167 mg, 0.51 mmol) and cuprous iodide (3 mg, 0.02 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was heated at 50 °C for 2 hours. After completion of the reaction, the reaction mixture was added to water (10 mL) and extracted with ethyl acetate (3*30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 70% to 100% ethyl acetate) to give two crude target compounds (Example 100-P1, later eluted) and (Example 100-P2, earlier eluted) as light yellow solids. The two crude products were purified separately by reverse phase purification (ACN:H2O = 10% to 50%) to give the target product (4-(4-((S)-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)cyclohexane-1-carbonitrile (Example 100-P1) (12.56 mg, 0.03 mmol, 15% yield) as a white solid, LC / MS (ESI) M / Z: 500.2 [M+H] + and the target product (4-(4-((S)-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)cyclohexane-1-carbonitrile (Example 100-P2) (6.16 mg, 0.01 mmol, 7% yield) as a white solid, LC / MS (ESI) M / Z: 500.2 [M+H] + Example 100-P1: 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 1.0 Hz, 1H), 8.09 (s, 1H), 7.81 (td, J = 8.6, 2.8 Hz, 1H), 7.74 (dd, J = 8.6, 4.6 Hz, 1H), 7.01 (d, J = 1.0 Hz, 1H), 5.65 (t, J = 5.0 Hz, 1H), 5.08 (t, J = 5.6 Hz, 1H), 4.52 - 4.43 (m, 1H), 4.02 - 3.90 (m, 2H), 3.29 - 3.24 (m, 1H), 2.42 (s, 3H), 2.10 (s, 3H), 2.09 - 1.99 (m, 6H), 1.89 - 1.80 (m, 2H). Example 100-P2: 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 1.0 Hz, 1H), 8.09 (s, 1H), 7.85 - 7.72 (m, 2H), 7.00 (d, J = 1.0 Hz, 1H), 5.72 - 5.63 (m, 1H), 5.08 (t, J = 5.6 Hz, 1H), 4.51 - 4.43 (m, 1H), 3.99 - 3.91 (m, 2H), 2.95 - 2.84 (m, 1H), 2.41 (s, 3H), 2.22 - 2.14 (m, 2H), 2.10 (s, 3H), 2.07 - 1.96 (m, 4H), 1.84 - 1.73 (m, 2H).

[0750] Example 101: 4-[4-(4-{[1-(4-fluorophenyl)-2-(1,4-oxazin-4-yl)ethyl]oxy}-3-(prop-1-ynyl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1,2,3-triazol-1-yl]hexahydropyridine-1-carbonitrile

[0751] Procedure:

[0752] Step 1: 1-(4-fluorophenyl)-2-(1,4-oxazin-4-yl)ethan-1-one

[0753] To a solution of 2-bromo-l-(4-fluorophenyl)ethan-l-one (1 g, 4.608 mmol) in tetrahydrofuran (10 mL), morpholine (3.226 mL, 36.860 mmol) was added dropwise. White solid was produced during the addition. After the addition, the reaction was heated to 60 °C and stirred for 2 h. The reaction was filtered, the filter cake was washed with tetrahydrofuran, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 50%) to give the target product l-(4-fluorophenyl)-2-(l,4-oxazin-4-yl)ethan-l-one (1.1 g, 4.927 mmol, 106.94%). LC / MS (ESI) M / Z: 224.1 [M+H] + .

[0754] Step 2: l-(4-Fluorophenyl)-2-(l,4-oxazin-4-yl)ethanol-1-ol

[0755] To a solution of l-(4-fluorophenyl)-2-(l,4-oxazin-4-yl)ethan-l-one (1 g, 4.479 mmol) in methanol (2 mL), sodium borohydride (0.51 g, 13.438 mmol) was added at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction was concentrated to give the crude product. The crude product was extracted with dichloromethane and water. The aqueous phase was washed with dichloromethane. The combined organic phase was concentrated to give the crude product l-(4-fluorophenyl)-2-(l,4-oxazin-4-yl)ethanol-1-ol (900 mg, 3.596 mmol, 80.28%). LC / MS (ESI) M / Z: 226.1 [M+H] + .

[0756] Step 3: 4-[2-Chloro-2-(4-fluorophenyl)ethyl]-l,4-oxazinane

[0757] To a solution of l-(4-fluorophenyl)-2-(l,4-oxazin-4-yl)ethanol-1-ol (710 mg, 3.152 mmol) and DIEA (814.76 mg, 6.304 mmol) in dichloromethane (20 mL), MsCl (469.32 mg, 4.097 mmol) was added. The reaction was stirred at room temperature for 2 h. The reaction was extracted with dichloromethane and water. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product 4-[2-chloro-2-(4-fluorophenyl)ethyl]-l,4-oxazinane (750 mg, 3.077 mmol, 97.64%). No purification was performed and the product was used dir...

Claims

1. A compound, or a pharmaceutically acceptable salt, isotopologue, tautomer, stereoisomer, or prodrug thereof; wherein, The compound is represented by formula (A); wherein R1is selected from the group consisting of null, H, cyano, -alkylene-cyano, R 11 -SO2- and -alkylene-SO2-R 11 wherein R 11 is hydrogen, alkyl, heterocyclyl, aryl, or heteroaryl; R is 4- to 10-membered heterocycle or C 4-10 cycloalkane, wherein X1is a carbon atom or a nitrogen atom, X2is 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 R2is each independently selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or two R2substituents on the same carbon atom, together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered spiro ring, or two R2substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a 3-, 4-, 5- or 6-membered fused ring; and R1is null when X2is an oxygen atom (O), S, SO or SO2; Z1, Z2and Z3are each independently a carbon atom or a nitrogen atom; Z4is absent or is a carbon atom or a nitrogen atom, provided that when Z4is absent, Z1is directly connected to the carbon atom to which R3is attached, provided that in the is aromatic and optionally substituted with one or more (preferably, one) R 31 substituted; R3is hydrogen, cycloalkyl, alkyl, deuterated alkyl or deuterated cycloalkyl; R 31 selected from the group consisting of cyano, halo, cycloalkyl, alkyl, deuterated alkyl, or deuterated cycloalkyl; For wherein The asterisk * indicates that the site of attachment, the asterisk ** indicates the site of attachment to Y, and R4and R5are each independently selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxyl, 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 , wherein R 4a and R 4b are 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 means that a hydrogen on the group is replaced with one or more R 4c ; wherein R 4c is selected from the group consisting of halogen, cyano, alkyl, hydroxyl, -SH, alkoxy, alkylthio, -C(O)H, -C(O)alkyl, -S(O) 1-2 H, -S(O) 1-2 alkyl, amino, alkylamino, dialkylamino, -C(O)amino, -C(O)-(alkylamino), -C(O)-(dialkylamino), -S(O) 1-2 amino, -S(O) 1-2 -(alkylamino), and -S(O) 1-2 -(dialkylamino); p1and p2are each independently 0, 1, 2 or 3, provided that the theory of valency is satisfied; Y is -O-, -S- or -NR8-, wherein R8is hydrogen or alkyl; R6is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein the alkyl is unsubstituted or further substituted by hydroxyl, halogen, alkoxy, alkenyl, alkynyl, phosphonooxyalkoxy, aryl, heteroaryl, heterocyclyl or cycloalkyl, and the alkenyl and alkynyl are unsubstituted or further substituted by alkyl or cycloalkyl; and the aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally further substituted by one or more substituents selected from the group consisting of alkyl, oxo, aryl, heteroaryl, heterocyclyl or cycloalkyl; absent or In is a six-membered heteroaryl, phenyl, cycloalkyl or heterocyclyl, q is 0, 1, 2, 3 or 4, and R7is halogen, alkyl, hydroxyalkyl or haloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof; wherein, 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, ring A are as defined in claim 1.

3. The compound of 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, ring A are as defined in claim 2.

4. The compound of claim 3, wherein For the asterisk ** indicates the site of attachment to Y; R4is selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, -N(R 4b )R 4a , wherein R 4a and R 4b are each independently selected from the group consisting of hydrogen, alkyl; R5is ethynyl or -ethynylene-R 4b wherein R 4b is selected from the group consisting of cyano, optionally substituted alkyl, optionally substituted cycloalkyl, wherein the optional substitution means that a hydrogen on the group is replaced by one or more R 4c wherein R 4c is selected from the group consisting of halogen, cyano, alkyl, hydroxy, -SH, alkoxy, alkylthio.

5. The compound of claim 1, wherein The compound is a compound of formula (IA); wherein R1is cyano; is a 4- to 10-membered heterocyclyl, wherein X1is a carbon atom or a nitrogen atom, m is 0, 1, 2, 3 or 4; and R2is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino, dialkylamino, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or two R2substituents on the same carbon atom, together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered spiro ring, or two R2substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a 3-, 4-, 5- or 6-membered fused ring; Z1, Z2, and Z3 are nitrogen atoms; Z4 is absent 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 wherein The asterisk * indicates that the site of attachment, the asterisk ** indicates the site of attachment to Y, and R4is selected from the group consisting of hydrogen, halogen, CN, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, -N(R 4b )R 4a , wherein R 4a and R 4b are each independently selected from the group consisting of hydrogen, alkyl; R5is ethynyl or -ethynylene-R 4b wherein R 4b is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, wherein the optional substitution means that a hydrogen on the group is replaced by one or more R 4c wherein R 4c is selected from the group consisting of 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 hydroxyl, halo, alkoxy, alkenyl, alkynyl, phosphonooxyalkoxy, 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 further substituted with one or more substituents selected from the group consisting of alkyl, oxo, aryl, heteroaryl, heterocyclyl, or cycloalkyl; absent or In is a six-membered heteroaryl, phenyl, cycloalkyl, or heterocyclyl, q is 0, 1, 2, 3, or 4, and R7 is halo, alkyl, hydroxyalkyl, or haloalkyl.

6. The compound of claim 1, wherein, The compound is selected from Table B.

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

8. Use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, isotopically enriched variant, tautomer, stereoisomer, or prodrug thereof, or a pharmaceutical composition of claim 7, in the manufacture of a medicament for the treatment or prevention of a disease.

9. 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 delays and acrocephalosyndactyly syndrome (SADDAN), muenke syndrome, or a combination thereof.

10. Use according to claim 9, characterized in that, The cancer is selected from the group consisting of urothelial cancer, urothelial carcinoma, urothelial carcinoma of the bladder, upper tract cancer, urothelial carcinoma of the upper tract, urethral cancer, breast cancer, invasive ductal carcinoma of the breast, invasive lobular carcinoma of the breast, 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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