TW202222797A - Pyrazolo[1,5-a]pyridine compound, preparation method therefor and use thereof - Google Patents

Abstract

Disclosed are a pyrazolo[1,5-a]pyridine compound, a preparation method therefor and a use thereof. Also disclosed is a pharmaceutical composition containing the compound as an active ingredient or a pharmaceutically acceptable salt thereof. The present invention further relates to the use of a compound of formula (I) for treating and preventing diseases that can be treated with wild-type, gene fusion-type and mutant (including but not limited to G804 and G810) RET kinase inhibitors, including diseases or conditions mediated by an RET kinase.

Description

Pyrazolo[1,5-a]pyridine compounds and preparation method and application thereof

The invention belongs to the field of medicine, in particular to a pyrazolo[1,5-a]pyridine compound and a preparation method and application thereof.

Transfection rearrangement (RET) kinase is a single-pass transmembrane receptor tyrosine kinase that plays an important role in the development of the kidney and enteric nervous system, and the maintenance of homeostasis in the nervous, endocrine, hematopoietic, and male reproductive systems. The structure of RET is divided into extracellular domain, transmembrane domain and intracellular kinase domain. Its ligand neurotrophic factor (GDNF) family does not directly bind to RET, but first forms a complex GFL-GFRα with the GDNF family receptor α, and then catalyzes the homodimerization of RET to autophosphorylate RET in the intracellular region, In turn, adaptor proteins and pathway proteins are recruited to activate multiple signaling pathways including MAPK, PI3K, JAK-STAT, PKA, and PKC, which are involved in cell proliferation, nerve conduction, cell migration, and cell differentiation (Alexander Drilon, Nature Reviews Clinical Oncology, 2018, 15:151–167).

The gene encoding the RET protein is located on the long arm of human chromosome 10, and its abnormalities (gene fusions, mutations, etc.) can cause a variety of diseases, including papillary thyroid cancer (PTC), medullary thyroid cancer (MTC), Hirschsprung's disease, pulmonary Adenocarcinoma, irritable bowel syndrome, etc.

The chromosomal rearrangement of the RET gene may lead to the breakage of the RET gene. After the break, the 3' end of the RET gene can be fused with different genes such as KIF5B, TRIM33, CCDC6 or NCOA4 to form a fusion gene. The expressed fusion protein shows continuous activation, driving tumorigenesis. RET gene fusions have been reported to be present in approximately 10-20% of PTC patients, mainly CCDC6-RET and NCOA4-RET fusions. About 1% to 2% of lung adenocarcinoma patients have RET fusion genes, mainly KIF5B-RET, CCDC6-RET, TRIM33-RET, NCOA4-RET, among which KIF5B-RET is the most common (Rosell R, and Karachaliou N, Lancet Oncol., 2016, 17:1623-1625).

Activating mutations in the RET gene caused by point mutations can cause multiple endocrine neoplasia type 2 (MEN2), which manifests as hyperplasia or tumor of neuroendocrine cells in the thyroid, adrenal medulla, and parathyroid glands (Mulligan LM, Nat Rev Cancer ., 2014, 14:173-86). About 60% of MTC patients have RET mutations.

Therefore, compounds that inhibit gene fusions or mutated RET kinases are very useful for the prevention and treatment of RET-driven tumors.

Several multi-target kinase inhibitors have certain inhibitory activity against RET, such as Cabozantinib, Vandetanib, Lenvatini and Ponatinib, but All are nonspecific RET inhibitors. In addition, due to the large homology between RET and the kinase domain of VEGFR2, these compounds not only inhibit RET, but also have a certain inhibitory effect on multiple targets including VEGFR2, which leads to a high risk of off-target toxicity and is difficult to exert. satisfactory curative effect.

Two RET-targeted drugs are currently on the market, namely LOXO-292 (selpercatinib/LY3527723) from Loxo Oncology and BLU-667 (pralsetinib/Gavreto) from Blurprint. These two targeted drugs show ideal efficacy and safety for RET fusion or mutation-positive patients, especially RET fusion-positive non-small cell lung cancer (NSCLC) and RET mutation-positive medullary thyroid Cancer (medullary thyroid cancer, MTC).

In the process of using selpercatinib to treat RET fusion-positive NSCLC and RET mutation-positive MTC, some patients developed drug resistance. Through the detection of circulating tumor DNA (ctDNA), it was found that RET G810R, G810S and RET appeared in these patients. Solvent domain frontier mutation of G810C. In phase 1 and 2 clinical trials of selpercratinib, an acquired mutation of RET G810 was found in the tumor tissue of one patient with CCDC6-RET fusion-positive NSCLC and the plasma of another patient with RET fusion-positive NSCLC. Preclinical studies have reported the presence of the RET G810R mutation in a CCDC6-RET patient-derived xenograft model of acquired resistance to selpercatinib. Structural models predicted that mutations at G810 would sterically hinder selpercatinib binding, and in vitro assays confirmed the loss of RET activity of anti-RET multikinase inhibitors and selective RET inhibitors against G810 mutations (Solomon BJ, Tan L, Lin JJ et al ., J Thorac Oncol. 2020 Apr;15(4):541-549.).

Therefore, there is an urgent need in the art to develop drugs with high specificity and high efficiency for inhibiting wild-type, fusion and mutant (including but not limited to V804 and G810) RET kinases.

The object of the present invention is to provide a new class of compounds with RET kinase inhibitory activity and/or good pharmacodynamic/pharmacokinetic properties and uses thereof.

其中， A選自下組：-CN、-COOR ₁(

)、-CONR ₂R ₃(

)、-NHCOR ₄(

)或-NHCONR ₂R ₃(

)； B選自下組：R ₇、-O-(L ₁) _m1-R ₈、-OCOR ₉(

)、-NR ₁₀R ₁₁(

)、-COOR ₁₂(

)、-CONR ₁₀R ₁₁(

)、-(L ₂) _m2-R ₁₂、-(L ₂) _m2-NR ₁₀R ₁₁(

)；其中，各L ₁獨立地選自下組：-CR _fR _g-(

)、-CO-；各L ₂獨立地選自下組：-CR _fR _g(

)、-CO-； X ₁和X ₂各自獨立地為CR或N；其中，R選自取代或未取代的下組基團：C1-C6烷基、H、鹵素或氰基；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、鹵素、氰基、羥基、胺基； Z選自取代或未取代的下組基團：C1-C6烷基、C1-C6烷氧基、C1-C6鹵烷基、C3-C8環烷基、C3-C8環烷氧基、C1-C6鹵代烷氧基、C1-C6烷胺基、C1-C6烷硫基；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、鹵素、氰基、羥基、胺基； R ₁、R ₂、R ₃和R ₄各自獨立地選自取代或未取代的下組基團：H、C1-C6烷基、C3-C8環烷基、3-8元環雜烷基、C2-C6烯基、C5-C10芳基或5-10元雜芳基；或者R ₂和R ₃與其連接的N原子一起構成取代或未取代的3-12元雜環基；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、鹵素、氰基、羥基、胺基； R ₇為取代或未取代的5-10雜芳基；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、鹵素、氰基、羥基、胺基； R ₈選自取代或未取代的下組基團：-C1-C6烷基-E、C5-C12稠合雙環、5-12元稠合雜雙環、C5-C12元螺雙環或5-12元螺雜雙環，E選自下組：-CN、-COOR ₁(

)、-OCOR ₁(

)、-CONR ₂R ₃(

)、-NHCOR ₄(

)或-NHCONR ₂R ₃(

)；其中，所述取代是指被1、2、3或4個選自下組的基團取代：H、氧代(=O)、鹵素、氰基、羥基、C1-C6烷基、C3-C8環烷基、C1-C6鹵烷基、C1-C6烷氧基、C3-C8環烷氧基、C1-C6鹵烷氧基、C1-C6烷胺基、C1-C6烷硫基； R ₉選自取代或未取代的下組基團：C1-C6烷氧基、C1-C6鹵烷氧基、-NR ₁₀R ₁₁(

)、-(L ₃) _m3-(3-8元環雜烷基)、-(L ₃) _m3-(C5-C10芳基)、-(L ₃) _m3-(5-10元雜芳基)，其中，各L ₃獨立地選自下組：-CR _fR _g-(

)、-NR _h-(

)；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、鹵素、氰基、羥基、胺基； R ₁₀和R ₁₁各自獨立選自取代或未取代下組基團：H、C1-C6烷基、-(L ₂) _m2-NQ ₁Q ₂(

)、C3-C8環烷基、3-8元環雜烷基、C6-C10芳基、5-10元雜芳基；或者，R ₁₀和R ₁₁與相連的N一起構成3-12元的取代或未取代的雜環，所述雜環含有1-3個N原子和0、1或2個O或S原子；其中，Q ₁、Q ₂各自獨立選自：H、取代或未取代的C1-C6烷基，或者Q ₁和Q ₂與相連的N構成一個3-10元的取代或未取代的雜環，所述雜環含有1-3個N原子和0、1或2個O或S原子；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、氰基、鹵素、羥基、C3-C8環烷基、3-8元環雜烷基、C6-C10芳基、5-10元雜芳基； 各R ₁₂獨立地選自取代或未取代的下組基團：C1-C6烷基、C3-C8環烷基、3-8元環雜烷基、C6-C10芳基、5-10元雜芳基；其中，所述取代是指被選自下組的一個或多個基團：C1-C6烷基、氰基、鹵素、羥基、C3-C8環烷基、3-8元環雜烷基、C6-C10芳基、5-10元雜芳基； R _f和R _g各自獨立地選自下組：H、鹵素、C1-C4烷基、C1-C4鹵代烷基、OH、-NH ₂、C3-C6環烷基； R _h獨立地選自下組：H、C1-C4烷基、C1-C4鹵代烷基、C3-C6環烷基； n為0、1、2； m ₁為1、2、3、4、5或6； m ₂為1、2、3、4、5或6； m ₃為0、1或2； 限定條件為，當B為R ₇時，A選自下組：-COOR ₁、-CONR ₂R ₃(

)、-NHCOR ₄(

)、-NHCONR ₂R ₃(

)。 The first aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof;

Wherein, A is selected from the following group: -CN, -COOR ₁ (

), -CONR ₂ R ₃ (

), -NHCOR ₄ (

) or -NHCONR ₂ R ₃ (

); B is selected from the following group: R ₇ , -O-(L ₁ ) _m1 -R ₈ , -OCOR ₉ (

), -NR ₁₀ R ₁₁ (

), -COOR ₁₂ (

), -CONR ₁₀ R ₁₁ (

), -(L ₂ ) _m2 -R ₁₂ , -(L ₂ ) _m2 -NR ₁₀ R ₁₁ (

); wherein, each L is independently selected from the group consisting _of -CR _f R _g -(

), -CO-; each L _{is independently selected from the group consisting of -CR f R g} (

), -CO-; X ₁ and X ₂ are each independently CR or N; wherein, R is selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkyl, H, halogen or cyano; wherein, the The substitution refers to being substituted by one or more groups selected from the following group: C1-C6 alkyl, halogen, cyano, hydroxyl, amine group; Z is selected from the substituted or unsubstituted group of the following group: C1-C6 Alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 alkane Sulfanyl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of C1-C6 alkyl, halogen, cyano, hydroxyl, amine; R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C2-C6 alkenyl, C5-C10 aryl or a 5-10-membered heteroaryl group; or R ₂ and R ₃ together with the N atom to which they are attached constitute a substituted or unsubstituted 3-12-membered heterocyclic group; wherein, the substitution refers to one selected from the following group or multiple groups are substituted: C1-C6 alkyl, halogen, cyano, hydroxyl, amino; R ₇ is a substituted or unsubstituted 5-10 heteroaryl; wherein, the substitution refers to being selected from the group One or more groups of substituted: C1-C6 alkyl, halogen, cyano, hydroxyl, amine group; R ₈ is selected from substituted or unsubstituted following groups: -C1-C6 alkyl-E, C5- C12 fused bicyclic ring, 5-12 membered fused heterobicyclic ring, C5-C12 membered spirobicyclic ring or 5-12 membered spiro heterobicyclic ring, E is selected from the following group: -CN, -COOR ₁ (

), -OCOR ₁ (

), -CONR ₂ R ₃ (

), -NHCOR ₄ (

) or -NHCONR ₂ R ₃ (

); wherein, the substitution refers to being substituted by 1, 2, 3 or 4 groups selected from the group consisting of H, oxo (=O), halogen, cyano, hydroxyl, C1-C6 alkyl, C3 -C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 alkylthio; R ₉ is selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkoxy, C1-C6 haloalkoxy, -NR ₁₀ R ₁₁ (

), -(L ₃ ) _m3 -(3-8 membered cycloheteroalkyl), -(L ₃ ) _m3 -(C5-C10 aryl), -(L ₃ ) _m3 -(5-10 membered heteroaryl) ), wherein each _L is independently selected from the group consisting of -CR _f R _g -(

), -NR _h -(

); wherein, the substitution refers to being substituted by one or more groups selected from the following group: C1-C6 alkyl, halogen, cyano, hydroxyl, amino; R ₁₀ and R ₁₁ are independently selected from substituted or Unsubstituted groups of the following group: H, C1-C6 alkyl, -(L ₂ ) _m2 -NQ ₁ Q ₂ (

), C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl; or, R ₁₀ and R ₁₁ together with the attached N form a 3-12 membered A substituted or unsubstituted heterocycle containing 1-3 N atoms and 0, 1 or 2 O or S atoms; wherein Q ₁ and Q ₂ are each independently selected from: H, substituted or unsubstituted C1-C6 alkyl, or Q1 and _Q2 and the attached N form a 3-10 membered substituted or unsubstituted heterocycle containing 1-3 N atoms and 0, 1 or ₂ O or S atom; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of C1-C6 alkyl, cyano, halogen, hydroxyl, C3-C8 cycloalkyl, 3-8 membered ring Heteroalkyl, C6-C10 aryl, 5-10-membered heteroaryl; each R ₁₂ is independently selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkyl, C3-C8 cycloalkyl, 3- 8-membered ring heteroalkyl, C6-C10 aryl, 5-10-membered heteroaryl; wherein, the substitution refers to one or more groups selected from the group consisting of C1-C6 alkyl, cyano, halogen, hydroxy, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl; R _f and R _g are each independently selected from the group consisting of H, halogen , C1-C4 alkyl, C1-C4 haloalkyl, OH, -NH ₂ , C3-C6 cycloalkyl; R is independently selected from the group consisting of _H , C1-C4 alkyl, C1-C4 haloalkyl, C3 -C6 cycloalkyl; n is 0, 1, 2; m ₁ is 1, 2, 3, 4, 5 or 6; m ₂ is 1, 2, 3, 4, 5 or 6; m ₃ is 0, 1 or 2; with the limitation that, when B is R ₇ , A is selected from the following group: -COOR ₁ , -CONR ₂ R ₃ (

), -NHCOR ₄ (

), -NHCONR ₂ R ₃ (

).

In another preferred embodiment, R ₁₂ is independently selected from the group consisting of substituted or unsubstituted groups: C1-C3 alkyl, C3-C6 cycloalkyl, 3-6 membered cycloheteroalkyl, phenyl, pyrazole , pyridine, furan, thiophene, oxazole, isoxazole, triazole; wherein, the substitution refers to being substituted by one or more groups selected from the group of C1-C3 alkyl, cyano, halogen, hydroxyl .

In another preferred example, the "-(L ₂ ) _m2 -" is -CH ₂ -; wherein the definitions of L ₂ and m ₂ are as described above.

)或-(L ₂) _m2-NR ₁₀R ₁₁(

)；其中，R ₁₀、R ₁₁、L ₂和m ₂的定義如上所述。 In another preferred embodiment, B is selected from the following group: -NR ₁₀ R ₁₁ (

) or -(L ₂ ) _m2 -NR ₁₀ R ₁₁ (

); wherein R ₁₀ , R ₁₁ , L ₂ and m ₂ are as defined above.

In another preferred embodiment, B is selected from the following group: -NH-(C1-C8 alkyl) or -NH-(C3-C8 cycloalkyl).

)，其中，L ₁、m1、R ₈和R ₉的定義如上所述。 In another preferred embodiment, B is selected from the following group: -O-(L ₁ ) _m1 -R ₈ or -OCOR ₉ (

), wherein L ₁ , m1 , R ₈ and R ₉ are as defined above.

In another preferred example, m ₁ is 1, 2, 3 or 4.

In another preferred embodiment, B is selected from the following group: -O-(CH ₂ ) _m1 -R ₈ , wherein m ₁ is 1, 2, or 3; the definition of R ₈ is as described above.

)、-(L ₂) _m2-R ₁₂，其中，R ₁₀、R ₁₁、R ₁₂、L ₂和m ₂的定義如上所述。 In another preferred embodiment, B is selected from the following group: -COOR ₁₂ , -CONR ₁₀ R ₁₁ (

), -(L ₂ ) _m2 -R ₁₂ , wherein R ₁₀ , R ₁₁ , R ₁₂ , L ₂ and m ₂ are as defined above.

)、-NR ₁₀R ₁₁(

)；其中，L ₁、m1、R ₈、R ₉、R ₁₀和R ₁₁的定義如上所述。 In another preferred embodiment, B is selected from the following group: -O-(L ₁ ) _m1 -R ₈ , -OCOR ₉ (

), -NR ₁₀ R ₁₁ (

); wherein L ₁ , m1 , R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined above.

)、C3-C6環烷基、3-6元環雜烷基、苯基、吡唑、吡啶、呋喃、噻吩、噁唑、異噁唑、三氮唑；或者，R ₁₀和R ₁₁與相連的N一起構成3-12元的取代或未取代的雜環，所述雜環含有1-3個N原子和0、1或2個O或S原子；Q ₁、Q ₂各自獨立選自：H、C1-C3烷基；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C3烷基、氰基、鹵素、羥基、環丙基、環丁基、環戊基、環己基、苯基、吡唑、吡啶、呋喃、噻吩、噁唑、異噁唑、三氮唑。 In another preferred example, B is -NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C3 alkyl, -(CH ₂ ) ₂ - NQ ₁ Q ₂ (

), C3-C6 cycloalkyl, 3-6 membered cycloheteroalkyl, phenyl, pyrazole, pyridine, furan, thiophene, oxazole, isoxazole, triazole; or, R ₁₀ and R ₁₁ are connected to The N together form a 3-12-membered substituted or unsubstituted heterocyclic ring containing 1-3 N atoms and 0, 1 or 2 O or S atoms; Q ₁ , Q ₂ are each independently selected from: H, C1-C3 alkyl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of C1-C3 alkyl, cyano, halogen, hydroxyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, phenyl, pyrazole, pyridine, furan, thiophene, oxazole, isoxazole, triazole.

為

。 In another preferred example, when n is 0, the

for

.

。 In another preferred embodiment, R ₇ is

.

， 其中，A、B、X ₁、X ₂和n的定義如上所述。 In another preferred embodiment, the compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof has the structure described in formula I':

, wherein A, B, X ₁ , X ₂ and n are defined as above.

In another preferred embodiment, A is selected from the following group: -CN, -COOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ or -NHCONR ₂ R ₃ ; wherein, R ₁ , R ₂ and R ₃ are each independently selected From the following group: H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C2-C6 alkenyl, C5-C10 aryl or 5-10 membered heteroaryl; R ₄ Selected from substituted or unsubstituted groups from the following group: C1-C3 alkyl, C3-C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C2-C4 alkenyl, phenyl, pyrazole, pyridine, furan, Thiophene, oxazole, isoxazole, triazole; wherein, the substitution refers to being substituted by a C1-C3 alkyl group.

In another preferred embodiment, B is selected from the following group: R ₇ , -O-(L ₁ ) _m1 -R ₈ , -NR ₁₀ R ₁₁ , -CONR ₁₀ R ₁₁ , -(L ₂ ) _m2 -R ₁₂ , -(L ₂ ) _m2 -NR ₁₀ R ₁₁ ; with the proviso that, when B is R ₇ , A is selected from the group consisting of: -COOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ , -NHCONR ₂ R ₃ ; wherein , R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , L ₁ , L ₂ , m ₁ , m ₂ , R ₈ , R ₁₀ , R ₁₁ and R ₁₂ are as defined above.

In another preferred embodiment, -(L ₁ ) _m1 - is selected from the following group: -(CH ₂ ) ₂ -, -CO-, -CO-NH-.

In another preferred example, -(L ₂ ) _m2 - is selected from the group consisting of -(CH ₂ ) ₂ -, -CO-, -O-CO-.

In another preferred example, R ₈ is selected from the group consisting of substituted or unsubstituted groups: -C1-C6 alkyl-E, 5-12-membered condensed heterobicycle or 5-12-membered spiroheterobicycle, wherein E is selected from the group consisting of -CN, -COOR ₁ , -OCOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ or -NHCONR ₂ R ₃ ; the heterobicycle contains 1-3 N atoms and 0, 1 or 2 O or S atom is used as a ring atom, and the N atom in the heterobicyclic ring is connected to the L ₁ part; wherein, the substitution refers to being substituted by 1, 2, 3 or 4 groups selected from the group consisting of H, oxo ( =O), halogen, cyano, hydroxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 halogen Alkoxy, C1-C6 alkylamino, C1-C6 alkylthio; R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

In another preferred embodiment, R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C2-C6 alkenyl, C5-C10 aryl or 5-10 membered heteroaryl.

。 In another preferred embodiment, R ₈ is selected from the following group:

.

或

，其中，G為C1-C6烷基。 In another preferred embodiment, R ₉ is selected from the following group: C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamino,

or

, where G is a C1-C6 alkyl group.

In another preferred embodiment, R ₁₀ and R ₁₁ are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C3 alkyl, -(CH ₂ ) ₂ -NQ ₁ Q ₂ , C3-C6 cycloalkane base, 3-6 membered cycloheteroalkyl, phenyl, pyrazole, pyridine, furan, thiophene, oxazole, isoxazole, triazole; alternatively, R ₁₀ and R ₁₁ together with the attached N form 3-8 A substituted or unsubstituted heterocyclic ring containing 1-3 N atoms and 0, 1 or 2 O or S atoms; wherein Q ₁ and Q ₂ are each independently selected from: H, C1-C3 Alkyl; or Q ₁ and Q ₂ and the attached N form a 3-10 membered substituted or unsubstituted heterocycle containing 1-3 N atoms and 0, 1 or 2 O or S atoms , the substitution refers to the substitution of C1-C3 alkyl, cyano, halogen, and hydroxyl by one or more groups selected from the following group.

； R ₉選自下組：C1-C3烷氧基、C1-C3鹵烷氧基、C1-C3烷胺基、

或

，其中，G為C1-C6烷基； R ₁₀和R ₁₁各自獨立選自取代或未取代下組基團：H、C1-C3烷基、-(CH ₂) ₂-NQ ₁Q ₂、C3-C6環烷基、3-6元環雜烷基、苯基、吡唑、吡啶、呋喃、噻吩、噁唑、異噁唑、三氮唑；其中，Q ₁、Q ₂各自獨立選自：H、C1-C3烷基；所述取代是指被選自下組的一個或多個基團取代C1-C3烷基、氰基、鹵素、羥基； R ₁₂各自獨立地選自取代或未取代的下組基團：C1-C3烷基、C3-C6環烷基、3-6元環雜烷基、苯基、吡唑、吡啶、呋喃、噻吩、噁唑、異噁唑、三氮唑；其中，所述取代是指被選自下組的一個或多個基團取代C1-C3烷基、氰基、鹵素、羥基； m為1、2、3； 限定條件： 當B為R ₇時，A選自下組：-COOR ₁、-CONR ₂R ₃、-NHCOR ₄、-NHCONR ₂R ₃。 In another preferred embodiment, B is selected from the following group: R ₇ , -O-(CH ₂ ) _m -R ₈ , -OCOR ₉ , -NR ₁₀ R ₁₁ , -COOR ₁₂ , -CONR ₁₀ R ₁₁ , -CH ₂ R ₁₂ , -CH ₂ NR ₁₀ R ₁₁ ; wherein, R ₇ is selected from the group consisting of substituted or unsubstituted groups: C5-C10 heteroaryl; wherein, the substitution refers to C1-C6 alkyl, halogen, cyano group, hydroxyl group, amine group; R ₈ is selected from the following group:

; R ₉ is selected from the group consisting of C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamino,

or

, wherein, G is a C1-C6 alkyl group; R ₁₀ and R ₁₁ are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C3 alkyl, -(CH ₂ ) ₂ -NQ ₁ Q ₂ , C3 -C6 cycloalkyl, 3-6 membered cycloheteroalkyl, phenyl, pyrazole, pyridine, furan, thiophene, oxazole, isoxazole, triazole; wherein, Q ₁ and Q ₂ are each independently selected from: H, C1-C3 alkyl; Said substitution means that C1-C3 alkyl, cyano, halogen, and hydroxyl are substituted by one or more groups selected from the following group; R ₁₂ is independently selected from substituted or unsubstituted The following groups of: C1-C3 alkyl, C3-C6 cycloalkyl, 3-6 membered cycloheteroalkyl, phenyl, pyrazole, pyridine, furan, thiophene, oxazole, isoxazole, triazole ; Wherein, the substitution refers to the substitution of C1-C3 alkyl, cyano, halogen, and hydroxyl by one or more groups selected from the following group; m is 1, 2, 3; Restrictions: When B is R ₇ , A is selected from the group consisting of -COOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ , -NHCONR ₂ R ₃ .

In another preferred example, B is the corresponding group in each specific compound prepared in the examples.

In another preferred example, A is the corresponding group in each specific compound prepared in the examples.

式中， R _m和R _n各自獨立地選自取代或未取代的下組基團：H、C1-C3烷基；其中，所述取代是指被1-2個鹵素原子取代； X ₁和X ₂各自獨立地為CH或N。 In another preferred example, the compound has the structure shown in formula II

In the formula, R _m and R _n are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C3 alkyl; wherein, the substitution refers to being substituted by 1-2 halogen atoms; X ₁ and X ₂ is each independently CH or N.

In another preferred embodiment, R _m and R _n are each independently selected from: H, methyl, ethyl, n-propyl, -CH ₂ F, -CHF ₂ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , _{-CHFCH3 , -CHFCH2F} , _{-CH2CH2CH2F or -CH2CHFCH2F .}

R _m選自：H、甲基、乙基、正丙基、-CH ₂F、-CHF ₂、-CH ₂CH ₂F、-CH ₂CHF ₂、-CHFCH ₃、-CHFCH ₂F、-CH ₂CH ₂CH ₂F或-CH ₂CHFCH ₂F。 In another preferred example, the compound has the structure shown in formula III

_Rm is selected from: H, methyl, ethyl, n _{- propyl} , _-CH2F , _-CHF2 , _-CH2CH2F , _-CH2CHF2 , _-CHFCH3 , _-CHFCH2F , -CH _{2CH2CH2F or -CH2CHFCH2F . _}

In another preferred example, R _{n is} selected from: H or methyl; R _m is selected from: H, methyl, ethyl, n-propyl, -CH ₂ F, CHF ₂ , -CH ₂ CH ₂ F, - _CH2CHF2 , _{-CHFCH3 , -CHFCH2F , -CH2CH2CH2F or -CH2CHFCH2F .}

式中， R _A和R _B各自獨立地選自：H、F、甲基。 In another preferred embodiment, the compound has the structure shown in formula IV

In the formula, R _A and R _B are each independently selected from: H, F, methyl.

。 In another preferred embodiment, the compound or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof is selected from the following group:

.

。 In another preferred embodiment, the compound or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof is selected from the following group:

.

。 In another preferred embodiment, the compound or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof is selected from the following group:

.

。 In another preferred embodiment, the compound or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, the compound is selected from the following group:

.

In another preferred embodiment, the compound or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein the pharmaceutically acceptable salt is acetate, adipic acid Salt, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclamate Pentane propionate, diglycolate, lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, Hydrochloride, Hydrobromide, Hydroiodide, Isethionate, Lactate, Maleate, Mesylate, Naphthalene Sulfonate, Nicotinate, Nitrate, Oxalate, Fruit Gelates, persulfates, phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates, tartrates, thiocyanate acid salt, tosylate, dodecanoate.

The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof; and a pharmaceutically acceptable carrier or diluent.

In another preferred embodiment, the pharmaceutical composition further includes a second cancer therapeutic agent.

In another preferred embodiment, the second cancer therapeutic agent includes radioactive agents, cytotoxic agents, kinase inhibitors, immune targeting inhibitors and angiogenesis inhibitors.

In another preferred embodiment, the second cancer therapeutic agent is one or more selected from the group consisting of: PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105 , LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, tositumumab, Tilimumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lolatinib, ocaltinib), PI3K inhibitors (such as idelaris, Dactolisib, Taselisib, Buparlisib, etc. ), BTK inhibitors (such as ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, ike tinib, canetinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, rivatinib, cabozantinib, sunitinib, donafenib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, entinostat, darxilast, tecdinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Lerociclib, etc.), MEK inhibitors (such as Division Metinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.) , mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, ocaltinib, linsitinib, BMS-754807, GSK1838705A, etc.) or a combination thereof.

A third aspect of the present invention provides use of the compound of the first aspect or the pharmaceutical composition of the second aspect in the preparation of a medicament for inhibiting RET kinase activity in a cell or a subject.

In another preferred embodiment, the RET kinase is wild type, gene fusion type and mutant type.

In another preferred example, the RET kinase is a mutant type, preferably M918T, V804M, V804L, G810S and G810R.

In another preferred embodiment, the medicament is used to treat RET-related diseases and the following disorders: the expression or activity or level of RET gene, RET kinase, or any one of them.

In another preferred embodiment, the disease is selected from the group consisting of eye disease, rheumatoid arthritis, pulmonary fibrosis, liver fibrosis, and tumors, and the tumors include bladder cancer, ovarian cancer, adenocarcinoma, gastric cancer, and pancreas. Cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophagus cancer, lip cancer, throat cancer Cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchyma cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, chorionic villus Membranous cancer, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small Cell lung cancer, non-small cell lung cancer, multiple myeloma.

A fourth aspect of the present invention provides a method for treating a RET-related disease, the method comprising administering to a subject identified or diagnosed as having a RET-related disease a therapeutically effective amount of the compound described in the first aspect or a pharmaceutically acceptable amount thereof. An acceptable salt or solvate, or a pharmaceutical composition as described in the second aspect.

In a fifth aspect of the present invention, the present invention provides a method for inhibiting RET kinase activity in a cell or a subject, the method comprising contacting the cell or administering to the subject a compound as described above or The steps of the pharmaceutical composition.

In another preferred embodiment, the cells are mammalian cells.

In another preferred embodiment, the subject is a mammal, preferably a human.

(i-1)在惰性溶劑中，鹼性條件下(例如，Cs ₂CO ₃等)，化合物3-1和羥基保護試劑(例如，苄基溴)反應，得到化合物3-2； (i-2)在惰性溶劑中，鹼性條件(例如，K ₃PO ₄)和催化劑(例如，碘化亞銅和L-脯氨酸)存在下，化合物3-2與胺化合物NHR _mR _n反應，得到化合物3-3； (i-3)在惰性溶劑中，酸性條件(例如，HBr)下，化合物3-3脫保護，得到化合物3-4； (i-4)在惰性溶劑中，化合物3-4與PhNTf ₂反應，得到化合物3-5； (i-5)在惰性溶劑中，催化劑存在(例如，鈀催化劑和鹵化亞銅)下，化合物3-5與化合物3-6反應，得到式II化合物； 式中，R _m、R _n的定義如上所述。 A sixth aspect of the present invention provides a preparation method of a compound of formula II, comprising the following steps:

(i-1) In an inert solvent, under basic conditions (eg, Cs ₂ CO ₃ , etc.), compound 3-1 is reacted with a hydroxyl protection reagent (eg, benzyl bromide) to obtain compound 3-2; (i- 2) In an inert solvent, in the presence of basic conditions (eg, K ₃ PO ₄ ) and a catalyst (eg, cuprous iodide and L-proline), compound 3-2 is reacted with an amine compound NHR _m R _n , Compound 3-3 is obtained; (i-3) In an inert solvent, under acidic conditions (eg, HBr), compound 3-3 is deprotected to obtain compound 3-4; (i-4) In an inert solvent, compound 3 -4 reacts with PhNTf ₂ to give compound 3-5; (i-5) In an inert solvent, in the presence of a catalyst (eg, palladium catalyst and cuprous halide), compound 3-5 reacts with compound 3-6 to give formula Compound II; In the formula, the definitions of R _m and R _n are as described above.

(i')在惰性溶劑(例如DMF)中，鹼性條件下(例如，K ₂CO ₃、Na ₂CO ₃、Cs ₂CO ₃等)，化合物3'-1和化合物3'-2反應，得到化合物3'-3； (ii')在惰性溶劑(如二氧六環)中，在酸性條件(例如，三氟乙酸、HCl)下，化合物3'-3脫胺保護得到化合物3'-4； (iii')在惰性溶劑(如DCM)中，還原劑(例如，NaBH(OAc) ₃)存在下，化合物3'-4與化合物3'-5進行還原胺化，得到化合物3'-6； (iv')在惰性溶劑(如DMF)中，催化劑作用(例如，鈀催化劑)下，化合物1-6與聯硼頻哪醇酯3'-7反應，得到化合物3-6。 In another preferred embodiment, the preparation of the compound of formula II further comprises the following steps:

(i') in an inert solvent (eg DMF), under basic conditions (eg, K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , etc.), compound 3'-1 and compound 3'-2 are reacted, Compound 3'-3 is obtained; (ii') in an inert solvent (such as dioxane), under acidic conditions (for example, trifluoroacetic acid, HCl), deamination of compound 3'-3 is protected to obtain compound 3'- 4; (iii') Reductive amination of compound 3'-4 with compound 3'-5 in the presence of a reducing agent (eg, NaBH(OAc) ₃ ) in an inert solvent (such as DCM) to obtain compound 3'- 6; (iv') In an inert solvent (such as DMF), under the action of a catalyst (eg, a palladium catalyst), compound 1-6 is reacted with biboron pinacol ester 3'-7 to obtain compound 3-6.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

After extensive and in-depth research, the inventors have discovered a class of compounds with better RET kinase activity (wild type, gene fusion type and various mutant RET kinases) and better selectivity for VEGFR2 kinase through rational design. . In addition, the compounds have excellent inhibitory activity against RET kinase-sensitive cells, and have good pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been completed.

the term

In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art.

When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-C6 refers to one to six carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkanes base. One or more positions in the alkyl group are substituted, especially 1 to 4 substituents, which can be substituted at any position.

The term "C1-C6 alkoxy" refers to a straight or branched chain or cyclic alkoxy group (such as C3-C6 cycloalkoxy) having 1 to 6 carbon atoms, representative examples include (but not Limited to): methoxy, ethoxy, propoxy, isopropoxy and butoxy and the like. Preferably it is C1-C3 alkoxy.

、

、

、

、

、

、

、

等。C5-C12螺雙環指包括C5、C6、C7、C8、C9、C10、C11、C12雙環烷基，其包括但不限於：

、

、

、

、

、

、

、

等。 The term "cycloalkyl" is meant to include saturated monocyclic, bicyclic or polycyclic cyclic alkyl groups, such as C3-C8 or C3-C12 cycloalkyl groups. C3-C8 cycloalkyl is meant to include C3, C4, C5, C6, C7, or C8 cycloalkyl. Cycloalkyl groups may also include cycloalkyl groups with structures such as spiro, bridged, and paracyclic structures. Representative cycloalkyl groups of the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. It is understood that substituted or unsubstituted cycloalkyl groups, such as branched cycloalkyl groups (eg, 1-methylcyclopropyl and 2-methylcyclopropyl), are included in the definition of "cycloalkyl". C5-C12 fused bicyclic refers to include C5, C6, C7, C8, C9, C10, C11, C12 bicycloalkyl, including but not limited to:

,

,

,

,

,

,

,

Wait. C5-C12 spirobicyclic refers to include C5, C6, C7, C8, C9, C10, C11, C12 bicycloalkyl, including but not limited to:

,

,

,

,

,

,

,

Wait.

The term "cycloalkoxy" refers to a group in which H on a cycloalkyl group is substituted by -O- and an oxygen is used as a bond, preferably C3-C8 cycloalkoxy, including but not limited to cyclopropoxy, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, etc.

The term "cycloheteroalkyl" refers to having the specified number of ring vertices (or members) and having one to five heteroatoms selected from N, O and S, respectively substituted for carbon atoms in the ring skeleton, and wherein the nitrogen and sulfur atoms are any A cycloalkyl ring that is optionally oxidized and the nitrogen atom is optionally quaternized. Cycloheteroalkyl is usually a 4-12 membered ring. Cycloheteroalkyl can be a monocyclic, bicyclic or polycyclic ring system. Examples of cycloheteroalkyl include, but are not limited to: pyrrolidinyl, imidazolidinyl, pyrazolidinyl, butyrolactamyl, valerolactamido, imidazolidinone, hydantoin, dioxa Cyclopentyl, phthalimido, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thio Morpholine-S,S-oxide, piperazinyl, piperanyl, pyridone, 3-pyrrolinyl, thiopyranyl, pyranone, tetrahydrofuranyl, tetrahydrothienyl, quinuclidine and their analog.

The term "haloalkyl" is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl propyl and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups" having branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more fluorine atoms.

)，R ₁’和R ₂’各自獨立地為H、烷基，優選地烷基為C1-C6烷基，更優選地為C1-C3烷基，且R ₁’和R ₂’不同時為H。 The term "alkylamino" refers to -NR ₁ 'R ₂ '(

), R ₁ ' and R ₂ ' are each independently H, alkyl, preferably alkyl is C1-C6 alkyl, more preferably C1-C3 alkyl, and R ₁ ' and R ₂ ' are not simultaneously H.

The term "alkylthio" refers to -SR ₁ ', where R ₁ ' is an alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group.

The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms (or C2-C8) in length. For example, in the present invention, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a single ring having a total of 5 to 15 ring members , bicyclic or tricyclic ring systems (preferably 6-10 membered aromatic rings), wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. "Aryl" may be substituted or unsubstituted. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl or aromatic ring. The connecting lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom.

The term "heteroaryl" refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc. "Heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamine, halogen, amine, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, Cycloalkylthio, oxo, carboxyl and carboxylate.

The term "heterocycle", "heterocyclyl" or "heterocyclic group" refers to a stable 3-, 4-, 5-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-membered , 11-, 12-, 13-, or 14-membered polycyclic heterocycles, including fused, spiro, and/or bridged ring structures, which are saturated, partially unsaturated, or fully unsaturated, and which contain carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. The term also includes polycyclic groups formed by the fusion of a heterocyclic ring with an aromatic ring (eg, a benzene ring). A "heterocycle" may be substituted or unsubstituted. Nitrogen and sulfur heteroatoms as ring atoms can be optionally oxidized. Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or, if defined, another substituent). Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogens in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one. When the term "heterocycle" is used, it is intended to include heteroaryl groups. Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazole base, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH -carbazolyl, carboline, chromanyl, chromenyl, cinnoline, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 -b] tetrahydrofuranyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolenyl, indolyl, indolyl Azinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinoline olinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, naphthinyl, octahydroisoquinolinyl , oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, rylene, oxindole, pyrimidinyl, phenanthridine, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxthiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidinyl, piperonyl, pteridyl, purinyl, pyridine pyrazolyl, pyrazinyl, pyrazolidine, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, Pyrimidyl, pyrrolidinyl, pyrrolidyl, 2-pyrrolidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetra azolyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazinyl oxadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxazole base, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4- triazolyl and xanthyl. The present invention also includes fused and spiro compounds containing, for example, the heterocycles described above.

The terms "spiro", "fused ring" indicate that one ring originates from a particular cyclic carbon on another ring, for example, a saturated bridged ring system (ring B and ring B' sharing two carbon atoms) is called "Fused rings" where Ring B and Ring B' share a carbon atom in two saturated ring systems are called "spiro rings". "Spirocyclic" "fused ring" systems can be attached to the main structure at any ring heteroatom or ring carbon atom to form stable compounds. In some embodiments, the fused ring is a 5-12 membered fused ring.

As used herein, the term "fused bicyclic heterocycle" or "bicyclic heterocycle" group refers to a stable 5-12 membered heterocyclic ring system containing two fused rings consisting of carbon atoms and 1, 2, 3 one or four heteroatoms independently selected from N, O and S. Among the two fused rings, one ring is a C3-C8 membered alkane ring, which is fused to the second ring. The second ring is a saturated, partially unsaturated or unsaturated C3-C8 monocyclic and bicyclic heterocyclic group can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The bicyclic heterocyclic groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. When the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other.

The term "hydroxy" refers to -OH.

In the present invention, each of the above-mentioned alkyl groups, haloalkyl groups, alkoxy groups, cycloalkyl groups, aryl groups, heteroaryl groups, cycloheteroalkyl groups, alkenyl groups, heterocycle groups, heterocyclic groups, etc. may be substituted substituted or unsubstituted.

)、-NR _bS(=O) ₂R _e(

)、-NR _bP(=O) ₂R _e(

)、-S(=O) ₂NR _bR _c(

)、-P(=O) ₂NR _bR _c(

)、-C(=O)OR _d(

)、-C(=O)R _a(

)、-C(=O)NR _bR _c(

)、-OC(=O)R _a(

)、-OC(=O)NR _bR _c(

)、-NR _bC(=O)OR _e(

)、-NR _dC(=O)NR _bR _c(

)、-NR _dS(=O) ₂NR _bR _c(

)、-NR _dP(=O) ₂NR _bR _c(

)、-NR _bC(=O)R _a(

₎、或-NR _bP(=O) ₂R _e(

)，其中，R _a可以獨立表示氫、氘、烷基、環烷基、烯基、炔基、雜環或芳環，R _b、R _c和R _d可以獨立表示氫、氘、烷基、環烷基、雜環或芳環，或者R _b和R _c與N原子一起可以形成雜環；R _e可以獨立表示氫、烷基、環烷基、烯基、炔基、雜環或芳環。上述典型的取代基，如烷基、環烷基、烯基、環烯基、炔基、雜環或芳環可以任選取代。所述取代基例如(但並不限於)：鹵素、羥基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8環烷基、3-12元雜環基、芳基、雜芳基、C1-C8醛基、C2-C10醯基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺醯基、及C1-C6脲基等。 In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing _Cl ), nitrile base, nitro, oxo (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocycle, aromatic ring, -OR _a , -SR _a , -S (=O)R _e , -S(=O) ₂ R _e , -P(=O) ₂ R _e , -S(=O) ₂ OR _e , -P(=O) ₂ OR _e , -NR _b R _c (

), -NR _b S(=O) ₂ R _e (

), -NR _b P(=O) ₂ R _e (

), -S(=O) ₂ NR _b R _c (

), -P(=O) ₂ NR _b R _c (

), -C(=O)OR _d (

), -C(=O)R _a (

), -C(=O)NR _b R _c (

), -OC(=O)R _a (

), -OC(=O)NR _b R _c (

), -NR _b C(=O)OR _e (

), -NR _d C(=O)NR _b R _c (

), -NR _d S(=O) ₂ NR _b R _c (

), -NR _d P(=O) ₂ NR _b R _c (

), -NR _b C(=O)R _a (

₎ , or -NR _b P(=O) ₂ R _e (

), wherein R _a can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring, and R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, heterocycle or aromatic ring, or _Rb and _Rc together with N atom may form a heterocycle; _Re may independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring . The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted. The substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, And C1-C6 ureido and so on.

Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has enough hydrogen atoms to replenish its valence state.

When a substituent is a non-terminal substituent, it is an extension of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, and alkoxy corresponds to Alkyleneoxy, etc.

The term "halo" or "halogen" includes fluorine, chlorine, bromine and iodine.

The term "cyano" refers to -CN.

Active ingredient

As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (eg, a deuterated compound) thereof ) or prodrugs. The term also includes racemates, optical isomers.

式中，A選自下組：-CN、-COOR ₁、-CONR ₂R ₃、-NHCOR ₄或-NHCONR ₂R ₃； B選自下組：R ₇、-O-(L ₁) _m1-R ₈、-OCOR ₉、-NR ₁₀R ₁₁、-COOR ₁₂、-CO-NR ₁₀R ₁₁、-(L ₂) _m2-R ₁₂、-(L ₂) _m2-NR ₁₀R ₁₁；其中，各L ₁獨立地選自下組：-CR _fR _g-、-CO-、-CO-NH-；各L ₂獨立地選自下組：-CR _fR _g-、-CO-、-O-CO-； X ₁和X ₂各自獨立地為CR或N；其中，R選自取代或未取代的下組基團：C1-C6烷基、H、鹵素或氰基；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、鹵素、氰基、羥基、胺基； Z選自取代或未取代的下組基團：C1-C6烷基、C1-C6烷氧基、C1-C6鹵烷基、C3-C8環烷基、C3-C8環烷氧基、C1-C6鹵代烷氧基、C1-C6烷胺基、C1-C6烷硫基；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、鹵素、氰基、羥基、胺基； R ₁、R ₂、R ₃和R ₄各自獨立地選自取代或未取代的下組基團：H、C1-C6烷基、C3-C8環烷基、3-8元環雜烷基、C2-C6烯基、C5-C10芳基或5-10元雜芳基；或者R ₂和R ₃與其連接的N原子一起構成取代或未取代的3-12元雜環基；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、鹵素、氰基、羥基、胺基； R ₇為取代或未取代的5-10雜芳基；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、鹵素、氰基、羥基、胺基； R ₈選自取代或未取代的下組基團： -C1-C6烷基-E、C5-C12稠合雙環、5-12元稠合雜雙環、C5-C12元螺雙環或5-12元螺雜雙環，E選自下組：-CN、-COOR ₁、-OCOR ₁、-CONR ₂R ₃、-NHCOR ₄或-NHCONR ₂R ₃；其中，所述取代是指被1、2、3或4個選自下組的基團取代：H、氧代(=O)、鹵素、氰基、羥基、C1-C6烷基、C3-C8環烷基、C1-C6鹵烷基、C1-C6烷氧基、C3-C8環烷氧基、C1-C6鹵烷氧基、C1-C6烷胺基、C1-C6烷硫基； R ₉選自取代或未取代的下組基團：C1-C6烷氧基、C1-C6鹵烷氧基、-NR ₁₀R ₁₁、-(L ₃) _m3-(3-8元環雜烷基)、-(L ₃) _m3-(C5-C10芳基)、-(L ₃) _m3-(5-10元雜芳基)，其中，各L ₃獨立地選自下組：-CR _fR _g-、-NR _h-；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、鹵素、氰基、羥基、胺基； R ₁₀和R ₁₁各自獨立選自取代或未取代下組基團：H、C1-C6烷基、-(L ₂) _m2-NQ ₁Q ₂、C3-C8環烷基、3-8元環雜烷基、C6-C10芳基、5-10元雜芳基；其中，Q ₁、Q ₂各自獨立選自：H、取代或未取代的C1-C6烷基，或者Q ₁和Q ₂與相連的N構成一個3-10元的取代或未取代的雜環，所述雜環含有1-3個N原子和0、1或2個O或S原子；其中，所述取代是指被選自下組的一個或多個基團取代：C1-C6烷基、氰基、鹵素、羥基、C3-C8環烷基、3-8元環雜烷基、C6-C10芳基、5-10元雜芳基； 各R ₁₂獨立地選自取代或未取代的下組基團：C1-C6烷基、C3-C8環烷基、3-8元環雜烷基、C6-C10芳基、5-10元雜芳基；其中，所述取代是指被選自下組的一個或多個基團：C1-C6烷基、氰基、鹵素、羥基、C3-C8環烷基、3-8元環雜烷基、C6-C10芳基、5-10元雜芳基； R _f和R _g各自獨立地選自下組：H、鹵素、C1-C4烷基、C1-C4鹵代烷基、OH、NH ₂、C3-C6環烷基； R _h獨立地選自下組：H、C1-C4烷基、C1-C4鹵代烷基、C3-C6環烷基； n為0、1、2； m ₁為1、2、3、4、5或6； m ₂為1、2、3、4、5或6； m ₃為0、1或2； 限定條件為，當B為R ₇時，A選自下組：-COOR ₁、-CONR ₂R ₃、-NHCOR ₄、-NHCONR ₂R ₃。 A、B、Z、X ₁、X ₂、n的定義如上所述。 The compound of the present invention has the structure shown in formula I

In the formula, A is selected from the following group: -CN, -COOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ or -NHCONR ₂ R ₃ ; B is selected from the following group: R ₇ , -O-(L ₁ ) _m1 - R ₈ , -OCOR ₉ , -NR ₁₀ R ₁₁ , -COOR ₁₂ , -CO-NR ₁₀ R ₁₁ , -(L ₂ ) _m2 -R ₁₂ , -(L ₂ ) _m2 -NR ₁₀ R ₁₁ ; wherein each L ₁ is independently selected from the following group: -CR _f R _g -, -CO-, -CO-NH-; each L ₂ is independently selected from the following group: -CR _f R _g -, -CO-, -O- CO-; X ₁ and X ₂ are each independently CR or N; wherein, R is selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkyl, H, halogen or cyano; wherein, the substitution is Refers to being substituted by one or more groups selected from the following group: C1-C6 alkyl, halogen, cyano, hydroxyl, amino; Z is selected from substituted or unsubstituted groups: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 alkylthio; Wherein, the substitution refers to being substituted by one or more groups selected from the following group: C1-C6 alkyl, halogen, cyano, hydroxyl, amine; R ₁ , R ₂ , R ₃ and R ₄ are each independently is selected from the group consisting of substituted or unsubstituted groups: H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C2-C6 alkenyl, C5-C10 aryl or 5 -10-membered heteroaryl; or R ₂ and R ₃ together with the N atom to which they are attached constitute a substituted or unsubstituted 3-12-membered heterocyclic group; wherein, the substitution refers to one or more selected from the group below Group substitution: C1-C6 alkyl, halogen, cyano, hydroxyl, amino; R ₇ is a substituted or unsubstituted 5-10 heteroaryl; wherein, the substitution refers to being selected from one of the following groups or Multiple group substitutions: C1-C6 alkyl, halogen, cyano, hydroxyl, amine; R ₈ is selected from the following groups of substituted or unsubstituted groups: -C1-C6 alkyl-E, C5-C12 condensed Bicyclic, 5-12 membered fused heterobicyclic, C5-C12 membered spirobicyclic or 5-12 membered spiroheterobicyclic, E is selected from the group consisting of: -CN, -COOR ₁ , -OCOR ₁ , -CONR ₂ R ₃ , - NHCOR ₄ or -NHCONR ₂ R ₃ ; wherein the substitution refers to substitution with 1, 2, 3 or 4 groups selected from the group consisting of H, oxo (=O), halogen, cyano, hydroxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 alkylthio group; R ₉ is selected from the group consisting of substituted or unsubstituted groups Group: C1-C6 alkoxy, C1-C6 haloalkoxy, -NR ₁₀ R ₁₁ , -(L ₃ ) _m3 -(3-8 membered cycloheteroalkyl), -(L ₃ ) _m3 -(C5 -C10 aryl), -(L ₃ ) _m3 -(5-10-membered heteroaryl), wherein each L ₃ is independently selected from the following group: -CR _f R _g -, -NR _h -; wherein, the The substitution refers to being substituted by one or more groups selected from the following group: C1-C6 alkyl, halogen, cyano, hydroxyl, amino; R ₁₀ and R ₁₁ are independently selected from substituted or unsubstituted groups Group: H, C1-C6 alkyl, -(L ₂ ) _m2 -NQ ₁ Q ₂ , C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl wherein, Q ₁ and Q ₂ are each independently selected from: H, substituted or unsubstituted C1-C6 alkyl, or Q ₁ and Q ₂ and the connected N form a 3-10-membered substituted or unsubstituted heterocyclic ring, the heterocycle contains 1-3 N atoms and 0, 1 or 2 O or S atoms; wherein the substitution refers to substitution by one or more groups selected from the group consisting of C1-C6 alkanes group, cyano group, halogen, hydroxyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl; each R ₁₂ is independently selected from substituted or unsubstituted The following group of groups: C1-C6 alkyl, C3-C8 cycloalkyl, 3-8-membered ring heteroalkyl, C6-C10 aryl, 5-10-membered heteroaryl; wherein, the substitution refers to being replaced by One or more groups selected from the group consisting of C1-C6 alkyl, cyano, halogen, hydroxyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl; R _f and R _g are each independently selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, OH, NH ₂ , C3-C6 cycloalkyl; R _h independently is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl; n is 0, 1, 2; m ₁ is 1, 2, 3, 4, 5 or 6; m ₂ is 1, 2, 3, 4, 5 or 6; m ₃ is 0, 1 or 2; with the proviso that, when B is R ₇ , A is selected from the group consisting of -COOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ , -NHCONR ₂ R ₃ . The definitions of A, B, Z, X ₁ , X ₂ , and n are as described above.

Preferably, in formula I, B is -NR ₁₀ R ₁₁ ; wherein, R ₁₀ and R ₁₁ are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C3 alkyl; wherein, the substitution refers to Substituted with one or more (eg 2, 3 or 4) groups selected from the group consisting of C1-C3 alkyl, halogen (preferably F).

， 其中，A、B、X ₁、X ₂和n的定義如上所述。 Preferably, the compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof has the structure described in formula I':

, wherein A, B, X ₁ , X ₂ and n are defined as above.

式中， R _m和R _n各自獨立地選自取代或未取代的下組基團：H、C1-C3烷基；其中，所述取代是指被1-2個鹵素原子取代；優選地，R _m和R _n各自獨立地選自：H、甲基、乙基、正丙基、-CH ₂F、-CHF ₂、-CH ₂CH ₂F、-CH ₂CHF ₂、-CHFCH ₃、-CHFCH ₂F、-CH ₂CH ₂CH ₂F或-CH ₂CHFCH ₂F； X ₁和X ₂各自獨立地為CH或N。 Preferably, the compound has the structure shown in formula II

In the formula, R _m and R _n are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C3 alkyl; wherein, the substitution refers to being substituted by 1-2 halogen atoms; preferably, _Rm and _Rn are each independently selected from: H, methyl, ethyl, n _{- propyl} , _-CH2F , -CHF2, _-CH2CH2F , _-CH2CHF2 , _-CHFCH3 , _- CHFCH ₂ F, -CH ₂ CH ₂ CH ₂ F or -CH ₂ CHFCH ₂ F; X ₁ and X ₂ are each independently CH or N.

Preferably, in formula I-II, X ₂ is N.

Preferably, in formula I-II, X ₁ is N.

Preferably, in formula I-II, X ₁ and X ₂ are N.

Preferably, in formula I-II, X ₁ is CH, and X ₂ is N.

Preferably, R _{n is} selected from: H or methyl; R _m is selected from: H, methyl, ethyl, n-propyl, -CH ₂ F, CHF ₂ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CHFCH ₃ , -CHFCH ₂ F, -CH ₂ CH ₂ CH ₂ F, or -CH ₂ CHFCH ₂ F.

R _m選自：H、甲基、乙基、正丙基、-CH ₂F、-CHF ₂、-CH ₂CH ₂F、-CH ₂CHF ₂、-CHFCH ₃、-CHFCH ₂F、-CH ₂CH ₂CH ₂F或-CH ₂CHFCH ₂F。 Preferably, the compound has the structure shown in formula III

_Rm is selected from: H, methyl, ethyl, n _{- propyl} , _-CH2F , _-CHF2 , _-CH2CH2F , _-CH2CHF2 , _-CHFCH3 , _-CHFCH2F , -CH _{2CH2CH2F or -CH2CHFCH2F . _}

式中， R _A和R _B各自獨立地選自：H、F、甲基。 Preferably, the compound has the structure shown in formula IV

In the formula, R _A and R _B are each independently selected from: H, F, methyl.

The salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts. As used herein, the term "salt" refers to salts formed with inorganic or organic acids and bases in the acid or basic form. In addition, when a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion ("inner salt") that may be formed is contained in within the scope of the term "salt". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, eg, in isolation or purification steps in the manufacturing process. The compounds of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.

The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, Benzenesulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphorate, Camphorsulfonate, Cyclopentane Propionate, Diglycolate, Lauryl Sulfate, Ethane Sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (as , 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, fruit Gelates, persulfates, phenylpropionates (such as 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates ( as formed with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates such as p-toluenesulfonates, dodecanoates, and the like.

Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (eg, organic amines) such as benzathine, dicyclohexylamine , Hypamine (salt with N,N -di(dehydroabietyl)ethylenediamine), N -methyl-D-glucosamine, N -methyl-D-glucosamine, third Butylamine, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be combined with halide fourth ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl sulfate Salts (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromine compounds and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.

Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.

Stereoisomers of all compounds (eg, those due to asymmetric carbon atoms that may exist for various substitutions), including their enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof. The chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC). The racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.

The compound of the present invention, the compound obtained by successively preparing, isolating and purifying the compound has a weight content equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.

All configurational isomers of the compounds of the present invention are contemplated, whether in admixture, pure or very pure form. The definition of compounds in the present invention includes both cis ( Z ) and trans ( E ) olefin isomers, as well as carbocyclic and heterocyclic cis and trans isomers.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are detailed below. For purposes of the present invention, chemical elements are as defined in Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics , ^75th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.

In accordance with the present invention, a mixture of isomers may contain isomers in various ratios. For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of 2, 99:1, or 100:0, isomers are within the scope of the present invention. Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.

The present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, respectively , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the aforementioned compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioisotopes ^{of3H and14C} , are also among them and are useful in drug and substrate tissue distribution experiments. Tritium, ie ³ H and carbon-14, ie ¹⁴ C, are relatively easy to prepare and detect. Is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie ² H, may be preferred in some cases due to their good metabolic stability in certain therapeutics, such as increased half-life or reduced dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.

If a synthesis of a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then the diastereoisomeric salt can be formed by separation crystallization or Separation by conventional means, such as chromatography, then yields the pure enantiomers.

As described herein, the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope. Generally, whether the term "substituted" appears before or after the term "optional", the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent. When multiples of a particular structure are substituted at positions with multiple specified substituents, the substituents may be the same or different at each position. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, eg heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence. Furthermore, the present invention is not intended to limit in any way the permissible substituted organic compounds. The present invention contemplates that the combination of substituents and variable groups is well suited for the treatment of diseases in the form of stable compounds. As used herein, the term "stable" refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.

The metabolites of the compounds involved in the application and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the application and their pharmaceutically acceptable salts in vivo, are also included in the claims of the application. middle.

Preparation

The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.

Usually, in the preparation process, each reaction is usually carried out at room temperature to 90° C. under the protection of inert gas and in a suitable solvent, and the reaction time is usually 2-24 hours.

方法一中：Y可以是Cl、Br、I；A、X ₁、X ₂、n、Z、L ₁、m ₁、R ₈具有本發明所述的定義。所述方法包括以下步驟： (i)在惰性溶劑(例如DMSO)中，鹼性條件下(例如，K ₂CO ₃、Na ₂CO ₃、Cs ₂CO ₃等)，化合物1-01和化合物1-02反應，得到化合物1-2； (ii)在惰性溶劑中，在酸性條件(例如，三氟乙酸)下，化合物1-2脫胺保護得到化合物1-3； (iii)在惰性溶劑中，還原劑(例如，NaBH(OAc) ₃)存在下，化合物1-3與化合物1-03進行還原胺化，得到化合物1-4； (iv)在惰性溶劑(例如，DMF)中，催化劑作用(例如，鈀催化劑)下，化合物1-4與錫試劑反應，得到化合物1-5； (v)在惰性溶劑中，催化劑作用(例如，鈀催化劑)下，化合物1-5與化合物1-04反應，得到化合物1-6； (vi)在惰性溶劑(例如，二甲苯)中，在酸性條件(例如，氫氟酸吡啶鹽)下，化合物1-6脫保護，得到化合物1-7； (vii)在惰性溶劑(例如，DMSO)中，鹼性條件下(例如，Cs ₂CO ₃)，化合物1-7與化合物Y-(L ₁)m ₁-R ₈反應得到化合物1-8。 以上反應步驟中，反應溶劑、反應溫度、反應時間、催化劑等可以根據具體的反應物進行選擇。 method one:

In the first method: Y can be Cl, Br, I; A, X ₁ , X ₂ , n, Z, L ₁ , m ₁ , R ₈ have the definitions described in the present invention. The method includes the following steps: (i) Compound 1-01 and Compound 1 in an inert solvent (eg, DMSO) under basic conditions (eg, K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , etc.) -02 reaction to obtain compound 1-2; (ii) in an inert solvent, under acidic conditions (eg, trifluoroacetic acid), deamination of compound 1-2 to obtain compound 1-3; (iii) in an inert solvent , in the presence of a reducing agent (eg, NaBH(OAc) ₃ ), compound 1-3 is subjected to reductive amination with compound 1-03 to obtain compound 1-4; (iv) in an inert solvent (eg, DMF), the catalyst acts (for example, palladium catalyst), compound 1-4 reacts with tin reagent to obtain compound 1-5; (v) in inert solvent, under the action of catalyst (for example, palladium catalyst), compound 1-5 and compound 1-04 reaction to obtain compound 1-6; (vi) in an inert solvent (eg, xylene) under acidic conditions (eg, pyridinium hydrofluoride), deprotection of compound 1-6 to obtain compound 1-7; ( vii) Compound 1-7 is reacted with compound Y-(L ₁ )m ₁ -R ₈ in an inert solvent (eg, DMSO) under basic conditions (eg, Cs ₂ CO ₃ ) to give compound 1-8. In the above reaction steps, the reaction solvent, reaction temperature, reaction time, catalyst, etc. can be selected according to the specific reactants.

方法二中：A、X ₁、X ₂、n、Z、R ₁₀、R ₁₁具有本發明所述的定義。所述方法包括以下步驟： (i)在惰性溶劑中，鹼性條件下(例如，Cs ₂CO ₃等)，化合物2-01和羥基保護試劑(例如，苄基溴)反應，得到化合物2-2； (ii)在惰性溶劑中，鹼性條件(例如，K ₃PO ₄)和催化劑(例如，碘化亞銅和L-脯氨酸)作用下，化合物2-2與胺化合物NHR ₁₀R ₁₁反應，得到化合物2-3； (iii)在惰性溶劑中，酸性條件(例如，HBr)下，化合物2-3脫保護，得到化合物2-4； (iv)在惰性溶劑中，化合物2-4與PhNTf ₂反應，得到化合物2-5； (v)在惰性溶劑中，催化劑作用(例如，鈀催化劑和鹵化亞銅)下，化合物2-5與化合物1-5反應，得到化合物2-6。 Method Two:

In the second method: A, X ₁ , X ₂ , n, Z, R ₁₀ and R ₁₁ have the definitions described in the present invention. The method includes the following steps: (i) in an inert solvent, under basic conditions (eg, _Cs2CO3 , etc. ₎ , compound 2-01 is reacted with a hydroxyl protecting reagent (eg, benzyl bromide) to obtain compound 2- 2; (ii) in an inert solvent, under the action of basic conditions (eg, K ₃ PO ₄ ) and catalysts (eg, cuprous iodide and L-proline), compound 2-2 and amine compound NHR ₁₀ R ₁₁ Reaction to obtain compound 2-3; (iii) In an inert solvent, under acidic conditions (for example, HBr), compound 2-3 is deprotected to obtain compound 2-4; (iv) In an inert solvent, compound 2- 4 reacts with PhNTf ₂ to give compound 2-5; (v) in an inert solvent, under the action of a catalyst (eg, palladium catalyst and cuprous halide), reacts compound 2-5 with compound 1-5 to give compound 2-6 .

(i-1)在惰性溶劑中，鹼性條件下(例如，Cs ₂CO ₃等)，化合物3-1和羥基保護試劑(例如，苄基溴)反應，得到化合物3-2； (i-2)在惰性溶劑中，鹼性條件(例如，K ₃PO ₄)和催化劑(例如，碘化亞銅和L-脯氨酸)存在下，化合物3-2與胺化合物NHR _mR _n反應，得到化合物3-3； (i-3)在惰性溶劑中，酸性條件(例如，HBr)下，化合物3-3脫保護，得到化合物3-4； (i-4)在惰性溶劑中，化合物3-4與PhNTf ₂反應，得到化合物3-5； (i-5)在惰性溶劑中，催化劑存在(例如，鈀催化劑和鹵化亞銅)下，化合物3-5與化合物3-6反應，得到式II化合物； 式中，R _m、R _n的定義如上所述。 Preferably, the compound of the present invention is prepared by the following method:

(i-1) In an inert solvent, under basic conditions (eg, Cs ₂ CO ₃ , etc.), compound 3-1 is reacted with a hydroxyl protection reagent (eg, benzyl bromide) to obtain compound 3-2; (i- 2) In an inert solvent, in the presence of basic conditions (eg, K ₃ PO ₄ ) and a catalyst (eg, cuprous iodide and L-proline), compound 3-2 is reacted with an amine compound NHR _m R _n , Compound 3-3 is obtained; (i-3) In an inert solvent, under acidic conditions (eg, HBr), compound 3-3 is deprotected to obtain compound 3-4; (i-4) In an inert solvent, compound 3 -4 reacts with PhNTf ₂ to give compound 3-5; (i-5) In an inert solvent, in the presence of a catalyst (eg, palladium catalyst and cuprous halide), compound 3-5 reacts with compound 3-6 to give formula Compound II; In the formula, the definitions of R _m and R _n are as described above.

(i')在惰性溶劑(例如DMF)中，鹼性條件下(例如，K ₂CO ₃、Na ₂CO ₃、Cs ₂CO ₃等)，化合物3'-1和化合物3'-2反應，得到化合物3'-3； (ii')在惰性溶劑(如二氧六環)中，在酸性條件(例如，三氟乙酸、HCl)下，化合物3'-3脫胺保護得到化合物3'-4； (iii')在惰性溶劑(如DCM)中，還原劑(例如，NaBH(OAc) ₃)存在下，化合物3'-4與化合物3'-5進行還原胺化，得到化合物3'-6； (iv')在惰性溶劑(如DMF)中，催化劑作用(例如，鈀催化劑)下，化合物1-6與聯硼頻哪醇酯3'-7反應，得到化合物3-6。 以上反應步驟中，反應溶劑、反應溫度、反應時間、催化劑等可以根據具體的反應物進行選擇。 Preferably, the preparation of the compound of formula II further comprises the steps of:

(i') in an inert solvent (eg DMF), under basic conditions (eg, K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , etc.), compound 3'-1 and compound 3'-2 are reacted, Compound 3'-3 is obtained; (ii') in an inert solvent (such as dioxane), under acidic conditions (for example, trifluoroacetic acid, HCl), deamination of compound 3'-3 is protected to obtain compound 3'- 4; (iii') Reductive amination of compound 3'-4 with compound 3'-5 in the presence of a reducing agent (eg, NaBH(OAc) ₃ ) in an inert solvent (such as DCM) to obtain compound 3'- 6; (iv') In an inert solvent (such as DMF), under the action of a catalyst (eg, a palladium catalyst), compound 1-6 is reacted with biboron pinacol ester 3'-7 to obtain compound 3-6. In the above reaction steps, the reaction solvent, reaction temperature, reaction time, catalyst, etc. can be selected according to the specific reactants.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.

The compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When co-administered, the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently. When the compound of formula I is administered concomitantly with one or more other drugs, a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used. Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods. When a compound of formula I is administered in pharmaceutical combination with one or more other drugs, the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.

Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab , Atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibody (such as Tuximab, Obinutuzumab, Ofatumumab, Tositumumab, Tiimumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI -622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lola PI3K inhibitors (such as Idelaris, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as Alpha Titinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canetinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, Rivatinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, entinostat, Darxilast, Tycodinaline, etc.), CDK inhibition Agents (such as palbociclib, ribociclib, Abemaciclib, Lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 ( CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc. ), an IGF-1R inhibitor (eg, Ceritinib, ocatinib, linsitinib, BMS-754807, GSK1838705A, etc.), or a combination thereof.

The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, drop pills, external liniments, controlled-release or sustained-release or nano-formulations .

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moisturizing Wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) fillers or extenders, for example, starches , lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants such as, Glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption acceleration agents such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, stearin Calcium acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

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

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

Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

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

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

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

The therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, wherein the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is given. The dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of the general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention The compounds are mixed to form a pharmaceutical composition.

The present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I) described in the present invention, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, to a subject in need of treatment, Or administer the pharmaceutical composition of the present invention for selectively inhibiting RET.

)的6位上為胺基的化合物對G810突變的RET具有較好的抑制活性，尤其是乙基或氟代乙基。 (6)本發明化合物構效關係資料表明，R _m為乙基或氟代乙基(優選CH ₂CH ₂F)，R _n為H或甲基(優選為H)時，本發明化合物對V804和G810突變的RET具有較好的抑制活性。 The present invention has the following main advantages: (1) The compound of the present invention has excellent inhibitory ability to RET kinase, excellent selectivity to RET kinase, and low inhibitory activity to other kinases such as VEGFR2. (2) The compounds of the present invention have lower toxic and side effects. (3) The compounds of the present invention have better pharmacodynamics and pharmacokinetic properties. (4) The compounds of the present invention have desirable inhibitory activity against wild-type, gene fusion and mutant (including but not limited to V804 and G810) RET kinases. (5) The compound of the present invention is in pyrazolo[1,5-a]pyridine (

The compounds with an amine group at the 6-position of ) have better inhibitory activity on G810-mutated RET, especially ethyl or fluoroethyl. (6) The data on the structure-activity relationship of the compound of the present invention shows that when R _m is ethyl or fluoroethyl (preferably CH ₂ CH ₂ F), and R _n is H or methyl (preferably H), the compound of the present invention is not effective for V804 and G810 mutant RET had better inhibitory activity.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental method of unreceipted specific conditions in the following examples, usually according to normal conditions such as people such as Sambrook, molecular colonization: conditions described in laboratory manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to manufacture conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.

The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography mass spectrometry (LC-MS).

NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic instruments, and the determination solvent contained deuterated dimethylsulfoxide (DMSO-d ₆ ), deuterated acetone (CD ₃ COCD ₃ ), deuterated chloroform (CDCl ₃ ) And deuterated methanol (CD ₃ OD), etc., the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in units of one millionth (ppm).

Liquid chromatography mass spectrometry (LC-MS) was detected using an Agilent 1260 mass spectrometer. The HPLC assay was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0 mm chromatography column).

TLC silica gel plate used Qingdao GF254 silica gel plate, TLC used 0.15-0.20 mm, and TLC used 0.4 mm-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by using or according to the literature data reported in the field.

Unless otherwise specified, all the reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperatures are all in degrees Celsius.

The following abbreviations are used throughout the invention THF: tetrahydrofuran MeOH: methanol HCl: hydrochloric acid Pd( _PPh3 ) ₄ : tetrakistriphenylphosphine palladium K2CO3: potassium carbonate _AcOK : potassium acetate _NaOH : sodium hydroxide _H2O : Water TEA: Triethylamine DIEA: N,N-Diisopropylethylamine DMF: N,N-Dimethylformamide DMA: N,N-Dimethylacetamide Py: Pyridine DCE: 1,2 -dichloroethane DMSO: dimethylsulfoxide TFA: trifluoroacetic acid NaBH(AcO) ₃ : sodium triacetoxyborohydride Sn ₂ (Bu-n) ₆ : hexahexylditin AlCl ₃ : aluminum trichloride CuI: cuprous iodide DPPA: diphenyl phosphate azide BuOH: tert-butanol Cs ₂ CO ₃ : cesium carbonate K ₃ PO ₄ : potassium phosphate BnBr: benzyl bromide Pd ₂ (dba) ₃ : tris(dibenzylidene) acetone) Dipalladium X-Phos: 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl EA: Ethyl acetate NaHCO ₃ : Sodium bicarbonate DIPEA: N,N-diisopropylethyl acetate Amine HBr: Hydrogen Bromide

Example

Synthesis of Intermediate 1 :

step 1: synthesis 3-(5- Chloropyrazine -2- base )-3,6- diazabicyclo [3.1.1] Heptane -6- tert-butyl carboxylate

3,6-Diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (6.2 g, 31.3 mmol) was dissolved in dimethylsulfite (40 mL), then 2, 5-Dichloropyrazine (6.02 g, 40.7 mmol) and potassium carbonate (21.6 g, 156.5 mmol), the reaction solution was stirred at 80 °C overnight. After the reaction was completed, it was cooled to room temperature, water (50 mL) and ethyl acetate (100 mL) were added, the organic phase was separated, washed with water, dried, and subjected to column chromatography (PE:EA=3:1) to obtain the third butyl 3-(5-chloropyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester 7 g, yield 72.2%. MS m/z (ESI): 311.2 [M+H] ⁺ .

step 2: synthesis 3-(5- Chloropyrazine -2- base )-3,6- diazabicyclo [3.1.1] Heptane trifluoroacetate

At room temperature, 3-(5-chloropyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (5 g, 16.12 mmol ) was dissolved in dichloromethane (30 mL), then trifluoroacetic acid (30 mL) was added, and the solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction, the reaction solution was concentrated, diethyl ether (150 mL) was added to precipitate a solid, which was filtered to obtain 3-(5-chloropyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane Trifluoroacetate 4.9 g, yield 98.5%. MS m/z (ESI): 211.1 [M+H] ⁺ .

step 3: synthesis 3-(5- Chloropyrazine -2- base )-6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane

3-(5-Chloropyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane trifluoroacetate (4.9 g, 15.96 mmol) was dissolved in dichloromethane (100 mL) ), sodium triacetoxyborohydride (17.2 g, 81.2 mmol) and 6-methoxynicotinic aldehyde (6.66 g, 48.6 mmol) were added, and the reaction was stirred at room temperature for 2 h. After monitoring the completion of the reaction, dichloride was added. Dilute with methane, quench the reaction with ammonium chloride solution (50 mL), extract with dichloromethane (50 mL*2), wash the organic phase with water, dry and concentrate, and perform column chromatography to obtain 3-(5-chloropyrazine-2). -yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane 4.3 g, yield 81.4%. MS m/z (ESI): 332.2 [M+H] ⁺ .

step 4: synthesis 6((6- Methoxypyridine -3- base ) methyl )-3-(5-( tributyltin ) Pyrazine -2- base )-3 , 6- diazabicyclo [3.1.1] Heptane

3-(5-Chloropyrazin-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (4.3 g, 12.99 mmol) was dissolved in DMF (40 mL), hexabutylditin (9.79 g, 16.89 mmol) and tetrakistriphenylphosphine palladium (1.5 g, 1.299 mmol) were added, and the reaction was stirred at 140 °C 16 h, after monitoring the completion of the reaction, the reaction was quenched with ammonium chloride solution (50 mL), extracted with ethyl acetate (30 mL*2.), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 6((6 -Methoxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (intermediate 1) 2g. MS m/z (ESI): 588.3 [M+H] ⁺ .

Synthesis of Intermediate 2 :

step 1: synthesis 4-(5- Bromopyridine -2- base ) Piperazine -1- tert-butyl carboxylate

5-Bromo-2-fluoropyridine (10 g, 56.8 mmol), potassium carbonate (31 g, 227.3 mmol) and tert-butyl tert-butylpiperazine-1-carboxylate (10.6 g, 56.8 mmol) were dissolved In DMF (50 mL), the reaction solution was stirred at 120 °C for 16 h. After monitoring the completion of the reaction, water (50 mL) and EA (30 mL*2) were added for extraction, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 15 g of 4-(5-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester. MS m/z (ESI): 342.5 [M+H] ⁺ .

step 2: synthesis 1-(5- Bromopyridine -2- base ) Piperazine

At room temperature, tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (15 g, 43.99 mmol) was dissolved in dichloromethane (20 mL) followed by the addition of hydrochloric acid Dioxane (80 mL), the solution was reacted at room temperature for 1 hour, and the completion of the reaction was monitored. The reaction solution was concentrated, adjusted to pH=9 with potassium carbonate solution, extracted with ethyl acetate, washed with water for the organic phase, dried, and concentrated. , column chromatography to obtain 1-(5-bromopyridin-2-yl)piperazine 8.5 g. MS m/z (ESI): 242.2 [M+H] ⁺ .

step 3: synthesis 1-(5- Bromopyridine -2- base )-4-((6- Methoxypyridine -3- base ) methyl ) Piperazine

1-(5-Bromopyridin-2-yl)piperazine (8.5 g, 35.3 mmol) was dissolved in dichloromethane (150 mL), sodium triacetoxyborohydride (22.5 g, 105.9 mmol) and 6 were added -Methoxynicotinic aldehyde (9.7 g, 70.6 mmol), then the reaction was stirred at room temperature for 2 h. After monitoring the completion of the reaction, dichloromethane was added to dilute, and the reaction was quenched with ammonium chloride solution (50 mL). 50 mL*2.) was extracted, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 1-(5-bromopyridin-2-yl)-4-((6-methoxypyridin-3-yl)methyl base) piperazine 8.3 g. MS m/z (ESI): 363.3 [M+H] ⁺ .

step 4: synthesis 1-((6- Methoxypyridine -3- base ) methyl )-4-(5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) Pyridine -2- base ) Piperazine

1-(5-Bromopyridin-2-yl)-4-((6-methoxypyridin-3-yl)methyl)piperazine (8.3 g, 22.93 mmol) was dissolved in DMF (40 mL), Add pinacol biboronate (11.65 g, 45.86 mmol), palladium acetate (0.26 g, 1.15 mmol), triphenylphosphine (1.2 g, 4.586 mmol) and potassium acetate (6.74 g, 68.78 mmol). Then, the reaction was stirred at 80 °C for 16 h. After monitoring the completion of the reaction, diluted with water, extracted with ethyl acetate (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 1-((6-methoxypyridine) -3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-yl ) piperazine ( Intermediate 2 ) 4.98 g. MS m/z (ESI): 411.2 [M+H] ⁺ .

Synthesis of Intermediate 3 :

step 1: synthesis 4- bromine -6-(( tert-butyldimethylsilyloxy ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (1.6 g, 6.75 mmol) and tert-butyldimethylchlorosilane (1.12 g, 7.43 mmol) were dissolved in tetrahydrofuran (50 mL), then triethylamine (1.87 mL) was added dropwise, the reaction solution was stirred at room temperature for 2 h, an appropriate amount of water was added, extracted with ethyl acetate, the organic phase was washed with water, dried, concentrated, and subjected to column chromatography to obtain 4 -Bromo-6-((tert-butyldimethylsilyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 1.55 g. MS m/z (ESI): 352.0 [M+H] ] ⁺ .

step 2: synthesis 6-(( tert-butyldimethylsilyl ) Oxygen )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

4-Bromo-6-((tert-butyldimethylsilyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (1.55 g, 4.43 mmol), 6((6-methylcarbonitrile) Oxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (2.6 g, 4.43 g mmol), cuprous iodide (84 mg, 0.443 mmol) and tetrakistriphenylphosphine palladium (512 mg, 0.443 mmol) were dissolved in xylene (40 mL), and the reaction solution was stirred at room temperature for 16 h. After monitoring the completion of the reaction , the reaction was quenched with water (10 mL), extracted with EA (20 mL*3), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 6-((tert-butyldimethylsilyl)oxy)- 4-(5-(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazine-2 -yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 1.57 g. MS m/z (ESI): 569.3 [M+H] ⁺ .

step 3: synthesis 6- hydroxyl -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-((T-butyldimethylsilyl)oxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazo Heterobicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (1.57 g, 2.76 mmol) was dissolved in dichloromethane (40 mL), then pyridine hydrogen fluoride (0.75 mL) was added dropwise, the reaction solution was stirred at room temperature for 2 h, adjusted to neutral pH with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with water, dried, concentrated, Column chromatography to give 6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane -3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( intermediate 3 ) 1 g. MS m/z (ESI): 455.4 [M+H] ⁺ .

Synthesis of Intermediate 4 :

step : synthesis 6- hydroxyl -4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

4-Bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (1.0 mg, 4.2 mmol) was combined with 1-((6-methoxypyridin-3-yl)methyl) -4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-yl)piperazine (2.07 g, 5.04 g mmol) was dissolved in dioxane:water=(3:1, 20 mL), then Pd(PPh ₃ ) ₄ (0.5 g, 0.42 mmol) and sodium carbonate (1.34 g, 12.6 mmol) were added respectively, under nitrogen protection, Stir overnight at 85°C, add water to quench the reaction after the reaction is complete, separate the organic phase, wash with water, dry, and perform column chromatography (PE:EA=1:1) to obtain 6-hydroxy-4-(6-(4- ((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Intermediate 4 ) 0.7 g. MS m/z (ESI): 442.2 [M+H] ⁺ .

Synthesis of Intermediate 5 :

step 1: synthesis 6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- Formic acid

Ethyl 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (7.8 g, 26.17 mmol) was dissolved in tetrahydrofuran (10 mL) and sodium hydroxide solution ( 5 mol/L, 10 mL) and ethanol (10 mL), the reaction solution was stirred at room temperature for 2 h, after monitoring the reaction was complete, concentrated, adjusted to pH 3 with dilute hydrochloric acid, extracted with EA (20 mL*3), organic The phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 6 g of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid. MS m/z(ESI): 271.1[M+H] ⁺

step 2: Synthesis of tertiary butyl (6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- base ) Urethane

6-Bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (6 g, 22.2 mmol), diphenylphosphoryl azide (31 g, 227.3 mmol) were dissolved in third In butanol (50 mL), the reaction solution was stirred at 80 °C for 4 h. After monitoring the completion of the reaction, it was concentrated to obtain tert-butyl(6-bromo-4-methoxypyrazolo[1,5-a]pyridine) The crude -3-yl)carbamate was used in the next step. MS m/z (ESI): 342.5 [M+H] ⁺ .

step 3: synthesis 6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- amine

At room temperature, tert-butyl(6-bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate (crude) was dissolved in dichloromethane (50 mL), then trifluoroacetic acid (50 mL) was added, the solution was reacted at room temperature for 1 hour, the monitoring reaction was complete, the reaction solution was concentrated, adjusted to pH=9 with potassium carbonate solution, extracted with ethyl acetate, the organic phase was Washed with water, dried, concentrated, and subjected to column chromatography to obtain 3.1 g of 6-bromo-4-methoxypyrazolo[1,5-a]pyridin-3-amine ( intermediate 5 ). MS m/z (ESI): 242.3 [M+H] ⁺ .

Example 1 Synthesis of Compound 1

step 1: synthesis 4- hydroxyl -6-(1- methyl -1H- Pyrazole -4- base ) - Pyrazolo [1,5-a] Pyridine -3- Ethyl carboxylate

6-Bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carboxylate ethyl ester (400 mg, 1.4 mmol) was combined with 1-methyl-4-(4,4,5,5 - Tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (351 mg, 1.7 mmol) was dissolved in dioxane:water=(3:1, 20 mL ), and then respectively added Pd(PPh ₃ ) ₄ (145 mg, 0.14 mmol) and sodium carbonate (450 mg, 4.2 mmol), under nitrogen protection, stirred at 85 °C overnight, after the reaction was completed, water was added to quench the reaction, and the organic phase, washed with water, dried, column chromatography (PE:EA=1:1) to obtain 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5 -a]ethyl pyridine-3-carboxylate 250 mg, 62% yield. MS m/z (ESI): 287.4 [M+H] ⁺ .

step 2: 6-(1- methyl -1H- Pyrazole -4- base )-4-( Trifluoromethylsulfonyloxy ) - Pyrazolo [1,5-a] Pyridine -3- Ethyl carboxylate

At room temperature, ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine-3-carboxylate (250 mg, 0.87 mmol) and DIEA (224 mg, 1.74 mmol) were dissolved in DMA (5 mL), then N-phenylbis(trifluoromethanesulfonyl)imide (343 mg, 1.0 mmol) was added, under nitrogen protection, and stirred at room temperature 6 hours. After the reaction was completed, water was added to quench the reaction, the organic phase was separated, washed with water, dried, and subjected to column chromatography (DCM:MeOH=20:1) to obtain 6-(1-methyl-1H-pyrazol-4-yl) -4-(Trifluoromethylsulfonyloxy)-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester 230 mg, yield 63%. MS m/z (ESI): 419.3 [M+H] ⁺ .

step 3: 4-(6-(4-(6- Methoxypyridine -3- base ) Piperazine -1- base ) Pyridine -3- base )-6-(1- methyl -1H- Pyrazole -4- base ) - Pyrazolo [1,5-a] Pyridine -3- Ethyl carboxylate

6-(1-Methyl-1H-pyrazol-4-yl)-4-(trifluoromethylsulfonyloxy)-pyrazolo[1,5-a]pyridine-3-carboxylate at room temperature Ethyl acid (230 mg, 0.55 mmol), 1-(6-methoxypyridin-3-yl)-4-(5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl)pyridin-2-yl)piperazine (293 mg, 0.71 mmol), Pd2(dba _{)3 (} 50 mg, 0.055 mmol), X-phos (45 mg, 0.11 mmol) was dissolved in dioxane:water=(3:1, 20 mL), then sodium carbonate (291 mg, 2.75 mmol) was added, under nitrogen protection, stirred at 85 °C overnight, after the reaction was complete, water was added to quench the reaction, and the mixture was separated. The organic phase was removed, washed with water, dried, and subjected to column chromatography (DCM:MeOH=20:1) to obtain 4(6-(4-(6-methoxypyridin-3-yl)piperazin-1-yl)pyridine -3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester ( Compound 1) 121 mg, yield The rate is 39.9%. MS m/z (ESI): 553.0 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 9.12(s, 1H), 8.41(s, 1H), 8.37(s, 1H), 8.19(d, 1H), 8.09(s, 1H), 8.08(d, 1H) ), 7.66-7.68(m, 2H), 7.56-7.58(m, 1H), 6.68(d, 1H), 6.80(d, 1H), 3.82-3.87(m, 8H), 3.55(s, 4H), 3.47 (s, 2H), 2.49-2.50 (s, 3H), 0.89 (t, 3H).

Example 2 : Synthesis of Compound 2

step 1: 6- bromine -4- Methoxy - Pyrazolo [1,5-a] Pyridine -3- carboxylic acid

At room temperature, ethyl 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (1.56 g, 5.26 mmol) was dissolved in THF/MeOH=(1:1, 20 mL), then added NaOH (4M, 10 mL), stirred at 50 °C for 1 h, the reaction was complete, concentrated under reduced pressure to remove the organic solvent, acidified with hydrochloric acid to pH=2-3, stirred at 0 °C for 0.5 h, the solid was filtered, washed with water, Concentration gave 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylic acid 1.3 g, 92% yield, MS m/z (ESI): 268.9 [MH] ⁺ .

step 2:6- bromine -4- Methoxy - Pyrazolo [1,5-a] Pyridine -3- formyl chloride

Under nitrogen, 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylic acid (400 mg, 1.48 mmol) was dissolved in 20 (mL) DCM and cooled to 0 ℃, added oxalic chloride (282 mg, 2.22 mmol) and 1 drop of DMF, stirred at room temperature overnight, the reaction was complete, the solvent was removed, and used directly in the next step.

step 3: 6- bromine -4- Methoxy -N,N- dimethylpyrazolo [1,5-a] Pyridine -3- carboxamide

At room temperature, a solution of dimethylamine in tetrahydrofuran (0.96 mL, 1.48 mmol) and triethylamine (448 mg, 4.44 mmol) were dissolved in DCM (20 mL), cooled to 0 °C, and then 6-bromo-4-methyl was added Oxy H-pyrazolo[1,5-a]pyridine-3-carboxylate chloride (426 mg, 1.48 mmol), incubated for 0.5 h, the reaction was complete, water was added to quench the reaction, the organic phase was separated, washed with water, It was dried and subjected to column chromatography to obtain 494 mg of 6-bromo-4-methoxy-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide with a yield of 100%. MS m/z (ESI): 297.9 [M+H] ⁺ .

step 4: 6- bromine -4- hydroxyl -N,N- dimethylpyrazolo [1,5-a] Pyridine -3- carboxamide

Under nitrogen protection, 6-bromo-4-methoxy-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide (494 mg, 1.6 mmol) was dissolved in room temperature DCE ( ₂₀ mL) followed by AlCl3 (665 mg, 4.98 mmol). Stir at 50°C for 0.5h, the reaction is complete, the pH of the reaction solution is adjusted to 5-6 with dilute hydrochloric acid, extracted with DCM, the organic phase is separated, washed with water, dried, and subjected to column chromatography (DCM:MeOH=20:1) to obtain 6- Bromo-4-hydroxy-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide 341 mg, yield 91.4%. MS m/z (ESI): 281.9 [M+H] ⁺ .

step 5: 4- hydroxyl -N,N- dimethyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- carboxamide

6-Bromo-4-methoxy-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide (341 mg, 1.2 mmol) was combined with 1-methyl-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (123 mg, 1.44 mmol) was dissolved in dioxane:water = (10:1, 22 mL), then respectively added Pd(Ph ₃ ) ₄ (123 mg, 0.12 mmol) and sodium carbonate (381 mg, 3.6 mmol), under nitrogen protection, stirred at 90 °C overnight, after the reaction was completed, added The reaction was quenched with water, the organic phase was separated, washed with water, dried, and subjected to column chromatography (DCM:MeOH=20:1) to obtain 4-hydroxy-N,N-dimethyl-6-(1-methyl-1H -Pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide 409 mg, 100% yield. MS m/z (ESI): 284.2 [M+H] ⁺ .

step 6: 3-( dimethylaminocarbonyl )-6-(1- methyl -1H- Pyrazole -4- base ) - Pyrazolo [1,5-a] Pyridine -4- triflate

4-Hydroxy-N,N-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate at room temperature The amine (400 mg, 1.4 mmol) and DIEA (310 mg, 2.8 mmol) were dissolved in DMA (5 mL), then N-phenylbis(trifluoromethanesulfonyl)imine (600 mg, 1.68 mmol) was added, Under nitrogen protection, the mixture was stirred at room temperature for 3 hours. After the reaction was completed, water was added to quench the reaction, the organic phase was separated, washed with water, dried, and subjected to column chromatography (DCM:MeOH=20:1) to obtain 3-(dimethylaminocarboxy)-6-(1 -Methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate 300 mg, 85% yield. MS m/z (ESI): 417.9 [M+H] ⁺ .

step 7: 4-(6-(4-(6- Methoxypyridine -3- base ) Piperazine -1- base ) Pyridine -3- base )-N,N- dimethyl -6-(1- methyl -1H- Pyrazole -4- base ) - Pyrazolo [1,5-a] Pyridine -3- carboxamide

3-(Dimethylaminocarbamoyl)-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4-yl at room temperature Triflate (300 mg, 0.72 mmol), 1-(6-methoxypyridin-3-yl)-4-(5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborol-2-yl)pyridin-2-yl)piperazine (383 mg, 0.93 mmol), Pd2(dba) ₃ (65 mg, 0.072 mmol), X-phos (60 mg , 0.144 mmol), dissolved in dioxane:water=(10:1, 20 mL), then sodium carbonate (381 mg, 3.6 mmol) was added, under nitrogen protection, stirred at 90 °C overnight, after the reaction was completed, water was added to quench After the reaction, the organic phase was separated, washed with water, dried, and subjected to column chromatography (DCM:MeOH=10:1) to obtain 4-(6-(4-(6-methoxypyridin-3-yl)piperazine-1) -yl)pyridin-3-yl)-N,N-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine-3- Formamide ( compound 2) 188 mg, 50% yield, MS m/z (ESI): 552.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.34 (s, 1H), 8.24 (d, 1H), 8.07 (t, 1H), 7.66-7.69 (m, 1H), 7.56-7.59 (m, 1H), 6.89(d, 1H), 6.81(d, 1H), 4.14(s, 3H), 3.84(s, 3H), 3.57(s, 4H), 3.48(s, 2H), 2.56( s, 3H), 2.45-2.47 (m, 3H), 2.41 (s, 2H).

Example 3 : Synthesis of Compound 3

step 1: 6- bromine -N- Ethyl -4- Methoxy - Pyrazolo [1,5-a] Pyridine -3- carboxamide

At room temperature, a solution of ethylamine in tetrahydrofuran (1 mL, 1.92 mmol) and DIEA (448 mg, 4.44 mmol) were dissolved in DCM (10 mL), cooled to 0 °C, and then 6-bromo-4-methoxy was added -Pyrazolo[1,5-a]pyridine-3-carbamoyl chloride (426 mg, 1.48 mmol), the reaction was kept for 0.5 h, the reaction was complete, water was added to quench the reaction, the organic phase was separated, washed with water, dried, and put in a tube Column chromatography gave 420 mg of 6-bromo-N-ethyl-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxamide in a yield of 90%.

step 2: 6- bromine -N- Ethyl -4- hydroxyl - Pyrazolo [1,5-a] Pyridine -3- carboxamide

6-Bromo-N-ethyl-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxamide (420 mg, 1.4 mmol) was dissolved in DCE 20 at room temperature under nitrogen protection (mL), then added AlCl ₃ (567 mg, 4.25 mmol), stirred at 50° C. for 2 h, the reaction was complete, the reaction pH was adjusted to 5-6, extracted with DCM, the organic phase was separated, washed with water, dried, and subjected to column chromatography ( PE:EA=5:1) to obtain 6-bromo-N-ethyl-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carboxamide 336 mg with a yield of 83%. MS m/z (ESI): 286.1 [M+H] ⁺ .

step 3: N- Ethyl -4- hydroxyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- carboxamide

6-Bromo-N-ethyl-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carboxamide (336 mg, 1.1 mmol) was combined with 1-methyl-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (324 mg, 1.4 mmol) was dissolved in dioxane:water=(10:1 , 22 mL), and then respectively added Pd(PPh ₃ ) ₄ (124 mg, 0.11 mmol) and sodium carbonate (385 mg, 3.3 mmol), under nitrogen protection, stirred at 90 °C overnight, after the reaction was complete, water was added to quench the reaction, The organic phase was separated, washed with water, dried, and subjected to column chromatography (DCM:MeOH=20:1) to obtain N-ethyl-4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyridine-3-carboxamide 284 mg, yield 77%.

step 4: 3-( Ethylaminocarbonyl )-6-(1- methyl -1H- Pyrazole -4- base ) - Pyrazolo [1,5-a] Pyridine -4- triflate

At room temperature, N-ethyl-4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (284 mg, 1.40 mmol) and DIEA (256 mg, 2.80 mmol) were dissolved in DMA (5 mL), then N-phenylbis(trifluoromethanesulfonyl)imide (428 mg, 1.2 mmol) was added under nitrogen protection, Stir at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, the organic phase was separated, washed with water, dried, and subjected to column chromatography (DCM:MeOH=20:1) to obtain 3-(ethylaminocarboxy)-6-(1- Methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate 360 mg, 87% yield, MS m/z (ESI): 416.0[M+H] ⁺ .

step 5: N- Ethyl -4-(6-(4-(6- Methoxypyridine -3- base ) Piperazine -1- base ) Pyridine -3- base )-6-(1- methyl -1H- Pyrazole -4- base ) - Pyrazolo [1,5-a] Pyridine -3- carboxamide

3-(Ethylaminocarbamoyl)-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4-yltris Fluoromethanesulfonate (200 mg, 0.4 mmol), 1-(6-methoxypyridin-3-yl)-4-(5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol- _{2-yl)pyridin-2-yl)piperazine (256 mg, 0.62) mmol), Pd2(dba)3 (} 37 mg, 0.04 mmol), X-phos (38 mg, 0.04 mmol), dissolved in dioxane:water=(10:1, 20 mL), then sodium carbonate (212 mg, 2.0 mmol) was added, under nitrogen protection, stirred at 90 °C overnight, after the reaction was completed, water was added to quench The reaction was quenched, the organic phase was separated, washed with water, dried, and subjected to column chromatography (DCM:MeOH=10:1) to obtain N-ethyl-4-(6-(4-(6-methoxypyridine-3- yl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine-3-carboxylate Amine ( compound 3) 113 mg, yield 42%. MS m/z (ESI): 552.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.35 (s, 1H), 8.21 (d, 1H), 8.14 (s, 1H), 8.08 (m, 1H), 7.66-7.69 (m , 1H), 6.62-7.64(d, 1H), 7.54-7.59(m, 1H), 7.52(d, 1H), 6.80-6.87(m, 1H), 3.87(s, 3H), 3.85(s, 3H) ), 3.55 (s, 4H), 3.48 (s, 2H), 2.86-2.92 (m, 2H), 2.44-2.47 (m, 4H), 0.79 (m, 3H).

Embodiment 4 : the synthesis of compound 4

step 1: synthesis N-(6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- base ) Acetamide

6-Bromo-4-methoxypyrazolo[1,5-a]pyridin-3-amine (600 mg, 2.49 mmol) and triethylamine (0.517 mL) were dissolved in dichloromethane (15 mL) , then acetonitrile chloride (0.27 mL) was added dropwise in an ice bath, the reaction solution was reacted at room temperature for 1 h, after monitoring the completion of the reaction, cooling, adding water to quench the reaction, extracting with EA (10 mL*3), washing the organic phase with water, It was dried, concentrated, and subjected to column chromatography to obtain 580 mg of N-(6-bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)acetamide. MS m/z (ESI): 284.2 [M+H] ⁺ .

step 2: synthesis N-(4- Methoxy -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base ) Acetamide

N-(6-Bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)acetamide (580 mg, 2.05 mmol), tetrakistriphenylphosphine palladium (237 mg, 0.205 mmol), sodium carbonate (652 mg, 6.15 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- base)-pyrazole (512 mg, 2.46 mmol) was dissolved in dioxane (15 mL) and water (5 mL), and the reaction was stirred at 80 °C for 16 h. After monitoring the completion of the reaction, it was cooled and quenched by adding water. Reaction, EA (30 mL*2) extraction, organic phase washing, drying and concentration, column chromatography to obtain N-(4-methoxy-6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyridin-3-yl)acetamide 520 mg. MS m/z (ESI): 286.0 [M+H] ⁺ .

step 3: synthesis N-(4- hydroxyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base ) Acetamide

N-(4-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)acetamide (520 mg, 1.82 mmol) was dissolved in 1,2-dichloroethane (20 mL), and then aluminum trichloride (850 mg, 6.39 mmol) was added, the reaction solution was stirred at room temperature for 16 h, and water (10 mL) was added. ) quenched the reaction, extracted with EA (20 mL*3), washed the organic phase with water, dried and concentrated, column chromatography to obtain N-(4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl) )pyrazolo[1,5-a]pyridin-3-yl)acetamide 250 mg, MS m/z (ESI): 272.5 [M+H] ⁺ .

step 4: synthesis 3- Acetamide -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -4- triflate

N-(4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)acetamide (250 mg, 0.92 mmol ), N-phenylbis(trifluoromethanesulfonyl)imide (396 mg, 1.11 mmol) and N,N-diisopropylethylamine (0.33 mL, 1.85 mmol) were dissolved in DMA (20 mL), The reaction was stirred at room temperature for 16 h. After monitoring the completion of the reaction, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 3-acetamido-6 -(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate 300 mg. MS m/z (ESI): 404.4 [M+H] ⁺ .

step 5: synthesis N-(4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base ) Acetamide

3-Acetamido-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (150 mg, 0.372 mmol), 1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) Heptan-2-yl)pyridin-2-yl)piperazine (183 mg, 0.447 mmol), sodium carbonate (197 mg, 1.86 mmol), tris(dibenzylideneacetone)dipalladium (34 mg, 0.037 mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (35.5 mg, 0.074 mmol) were dissolved in dioxane (15 mL) and water (5 mL), the reaction was carried out at 80 °C The reaction was stirred for 16 h. After monitoring the completion of the reaction, the reaction was cooled, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain N-(4-(6-(4 -((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazole [1,5-a]pyridin-3-yl)acetamide ( compound 4) 100 mg. MS m/z (ESI): 537.1 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 9.02(s, 1H), 8.91(d, J = 1.4 Hz, 1H), 8.31(s, 1H), 8.23 – 8.18(m, 1H), 8.09(d , J = 2.4 Hz, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.86 (s, 1H), 7.68 (dd, J = 8.5, 2.4 Hz, 1H), 7.58 (dd, J = 8.8, 2.5 Hz, 1H), 7.37 (d, J = 1.4 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.82 (dd, J = 8.4, 0.7 Hz, 1H), 3.87 (s, 3H) , 3.85(s, 3H), 3.57(t, J = 5.0 Hz, 4H), 3.49(s, 2H), 2.47(t, J = 5.0 Hz, 4H), 1.66(s, 3H).

Example 5 : Synthesis of Compound 5

step 1: synthesis 6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- carbonyl chloride

6-Bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (400 mg) was dissolved in dichloromethane (10 mL), and oxalic chloride (282 mL) was slowly added dropwise. mg), then 2 drops of DMF were added, and the reaction solution was stirred at room temperature for 1 h. After monitoring the completion of the reaction by LCMS, it was concentrated to obtain 6-bromo-4-methoxypyrazolo[1,5-a]pyridine- 3-Carbonyl chloride (426 mg).

step 2: synthesis 6- bromine -N- Isopropyl -4- Methoxypyrazolo [1,5-a] Pyridine -3- carboxamide

6-Bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonyl chloride (426 mg) was dissolved in dichloromethane (10 mL), isopropylamine (113 mg) was added, then Triethylamine (448 mg) was added dropwise, and the reaction solution was stirred at room temperature for 1 h. After the reaction was completed as monitored by LCMS, water (10 mL) was added to quench the reaction, washed with water, dried and concentrated, and subjected to column chromatography to obtain 6-bromo -N-Isopropyl-4-methoxypyrazolo[1,5-a]pyridine-3-carboxamide (350 mg). MS m/z (ESI): 312.1 [M+H] ⁺ .

step 3: synthesis 6- bromine -4- hydroxyl -N- isopropylpyrrolo [1,5-a] Pyridine -3- carboxamide

6-Bromo-N-isopropyl-4-methoxypyrazolo[1,5-a]pyridine-3-carboxamide (350 mg) was dissolved in 1,2-dichloroethane (10 mL ), aluminum trichloride (446 mg) was added, and the reaction solution was stirred at room temperature for 16 h. After the reaction was completed as monitored by LCMS, water (20 mL) was added to quench the reaction, extracted with dichloromethane, washed with water, dried and concentrated to obtain 6-Bromo-4-hydroxy-N-isopropylpyrrolo[1,5-a]pyridine-3-carboxamide (300 mg). MS m/z (ESI): 297.2 [M+H] ⁺ .

step 4: synthesis 4- hydroxyl -N- Isopropyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- carboxamide

Combine 6-bromo-4-hydroxy-N-isopropylpyrrolo[1,5-a]pyridine-3-carboxamide (300 mg, 1.01 mmol), tetrakistriphenylphosphine palladium (117 mg, 0.101 mmol) ), sodium carbonate (321 mg, 3.03 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) - Pyrazole (252 mg, 1.21 mmol) was dissolved in dioxane (15 mL) and water (5 mL), the reaction was stirred at 80 °C for 16 h, after monitoring the completion of the reaction, cooling, adding water to quench the reaction, EA (30 mL*2) extraction, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 200 mg of 4-hydroxy-N-isopropyl-6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyridine-3-carboxamide. MS m/z (ESI): 300.1 [M+H] ⁺ .

step 5: synthesis 3-( Isopropylformyl )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -4- triflate

4-Hydroxy-N-isopropyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (200 mg, 0.67 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (287 mg, 0.802 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.34 mmol) were dissolved in DMA (20 mL) , the reaction was stirred at room temperature for 16 h, and after monitoring the completion of the reaction, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 150 mg of 3-(isopropyl) (methylcarbamoyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate. MS m/z (ESI): 432.2 [M+H] ⁺ .

step 6: synthesis N- Isopropyl -4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- carboxamide

3-(Isopropylcarboxylate)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate ( 150 mg, 0.348 mmol), 1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl)pyridin-2-yl)piperazine (171 mg, 0.418 mmol), sodium carbonate (185 mg, 1.74 mmol), tris(dibenzylideneacetone)dipalladium (32 mg, 0.035 mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (33.2 mg, 0.070 mmol) were dissolved in dioxane (15 mL) and water (5 mL), the The reaction was stirred at 80 °C for 16 h. After monitoring the completion of the reaction, the reaction was cooled, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain N-isopropyl-4 -(6-(4-((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole- 4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide ( compound 5) 40 mg. MS m/z (ESI): 566.1 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J = 1.5 Hz, 1H), 8.34 (s, 1H), 8.22 (d, J = 2.5 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 0.8 Hz, 1H), 7.67 (dd, J = 8.5, 2.4 Hz, 1H), 7.57 (dd, J = 8.8, 2.5 Hz, 1H) ), 7.53 – 7.47(m, 2H), 6.85(d, J = 8.9 Hz, 1H), 6.81(d, J = 8.5 Hz, 1H), 3.87(s, 3H), 3.84(s, 3H), 3.63 (dq, J = 13.5, 6.6 Hz, 1H), 3.54(t, J = 5.0 Hz, 4H), 3.48(s, 2H), 2.46(t, J = 5.0 Hz, 4H), 0.86(s, 3H) , 0.85(s, 3H).

Example 6 : Synthesis of Compound 6

step 1: synthesis 6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- formyl chloride

6-Bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (400 mg) was dissolved in dichloromethane (10 mL), and oxalic chloride (282 mL) was slowly added dropwise. mg), then 2 drops of DMF were added, and the reaction solution was stirred at room temperature for 1 h. After monitoring the completion of the reaction by LCMS, it was concentrated to obtain 6-bromo-4-methoxypyrazolo[1,5-a]pyridine- 3-Formyl chloride (430 mg).

step 2: synthesis 6- bromine -4- Methoxy -N- Pyrazolo [1,5-a] Pyridine -3- carboxamide

6-Bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxychloride (430 mg) was dissolved in dichloromethane (10 mL), methylamine (59 mg) tetrahydrofuran was added solution, then triethylamine (448 mg) was added dropwise, and the reaction solution was stirred at room temperature for 1 h. After the reaction was monitored by LCMS, water (10 mL) was added to quench the reaction, washed with water, dried and concentrated, and subjected to column chromatography to obtain 6-Bromo-4-methoxy-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (350 mg). MS m/z (ESI): 284.2 [M+H] ⁺ .

step 3: synthesis 6- bromine -4- hydroxyl -N- Pyrazolopyridine -3- carboxamide

6-Bromo-4-methoxy-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (350 mg) was dissolved in 1,2-dichloroethane (10 mL) Aluminium trichloride (490 mg) was added, and the reaction solution was stirred at room temperature for 16 h. After the completion of the reaction was monitored by LCMS, water (20 mL) was added to quench the reaction, extracted with dichloromethane, washed with water, dried and concentrated to obtain 6 -Bromo-4-hydroxy-N-methylpyrazolopyridine-3-carboxamide (300 mg). MS m/z (ESI): 270.7 [M+H] ⁺ .

step 4: synthesis 4- hydroxyl -N- methyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- carboxamide

6-Bromo-4-hydroxy-N-methylpyrazolopyridine-3-carboxamide (300 mg, 1.12 mmol), tetrakistriphenylphosphine palladium (129 mg, 0.111 mmol), sodium carbonate (355 mg , 3.35 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-pyrazole (279 mg, 1.34 mmol) was dissolved in dioxane (15 mL) and water (5 mL), and the reaction was stirred at 80 °C for 16 h. After monitoring the completion of the reaction, it was cooled, water was added to quench the reaction, and EA (30 mL*2) was extracted. , the organic phase was washed with water, dried, concentrated, and subjected to column chromatography to obtain 4-hydroxy-N-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine-3-carboxamide 260 mg. MS m/z (ESI): 272.4 [M+H] ⁺ .

step 5: synthesis 6-(1- methyl -1H- Pyrazole -4- base )-3-( methylcarbamate ) Pyrazolo [1,5-a] Pyridine -4- triflate

4-Hydroxy-N-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (260 mg, 0.96 mmol ), N-phenylbis(trifluoromethanesulfonyl)imide (411 mg, 1.15 mmol) and N,N-diisopropylethylamine (0.34 mL, 1.92 mmol) were dissolved in DMA (20 mL), The reaction was stirred at room temperature for 16 h. After monitoring the completion of the reaction, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 6-(1-methyl- 1H-pyrazol-4-yl)-3-(methylcarbamate)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate 200 mg. MS m/z (ESI): 404.3 [M+H] ⁺ .

step 6: synthesis 4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base )-N- methyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- carboxamide

6-(1-Methyl-1H-pyrazol-4-yl)-3-(methylcarbamate)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate ( 200 mg, 0.496 mmol), 1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl)pyridin-2-yl)piperazine (244 mg, 0.596 mmol), sodium carbonate (263 mg, 2.48 mmol), tris(dibenzylideneacetone)dipalladium (45 mg) , 0.0496 mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (47 mg, 0.099 mmol) were dissolved in dioxane (15 mL) and water (5 mL), the The reaction was stirred at 80 °C for 16 h. After monitoring the completion of the reaction, the reaction was cooled, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 4-(6-(4 -((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-N-methyl-6-(1-methyl-1H-pyrazole-4 -yl)pyrazolo[1,5-a]pyridine-3-carboxamide ( compound 6) 60 mg. MS m/z (ESI): 538.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 1.5 Hz, 1H), 8.35 (s, 1H), 8.21 (d, J = 2.5 Hz, 1H), 8.16 (s, 1H), 8.09(s, 1H), 8.08(d, J = 0.8 Hz, 1H), 7.68(d, J = 8.5 Hz, 1H), 7.61(d, J = 4.8 Hz, 1H), 7.56(s, 1H), 7.53(d, J = 1.5 Hz, 1H), 6.86(d, J = 8.9 Hz, 1H), 6.82(d, J = 8.4 Hz, 1H), 3.88(s, 3H), 3.85(s, 3H), 3.56(s, 4H), 3.49(s, 2H), 2.47(s, 4H), 2.39(d, J = 4.6 Hz, 3H).

Example 7 : Synthesis of Compound 7

step 1: synthesis 6- bromine -4- Methoxypyrazolopyridine -3- Methyl Carboxylate

6-Bromo-4-hydroxypyrazolopyridine-3-carboxylic acid (1.8 g, 7.04 mmol) was dissolved in DMF (25 mL) and cesium carbonate (4.59 g, 14.08 mmol) was added followed by iodomethane (0.57 mL) , 9.15 mmol), the reaction solution was stirred at room temperature for 16 h, after LCMS monitoring was completed, water (30 mL) was added, extracted with ethyl acetate, washed with water, dried and concentrated to obtain 6-bromo-4-methoxypyrazolo Methyl pyridine-3-carboxylate (1.8 g). MS m/z (ESI): 285.2 [M+H] ⁺ .

step 2: synthesis 4- Methoxy -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- methyl formate

6-Bromo-4-methoxypyrazolopyridine-3-carboxylate methyl ester (600 mg, 2.11 mmol), tetrakistriphenylphosphine palladium (244 mg, 0.211 mmol), sodium carbonate (672 mg, 6.34 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-pyrazole (527 mg, 2.54 mmol ) was dissolved in dioxane (15 mL) and water (5 mL), and the reaction was stirred at 80 °C for 16 h. After monitoring the completion of the reaction, it was cooled, water was added to quench the reaction, and EA (30 mL*2) was extracted. The organic phase was washed with water, dried, concentrated, and subjected to column chromatography to obtain 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- Methyl formate 600 mg. MS m/z (ESI): 287.3 [M+H] ⁺ .

step 3: synthesis 4- hydroxyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- methyl formate

Methyl 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (600 mg, 2.10 mmol) was dissolved in 1 , 2-dichloroethane (20 mL), aluminum trichloride (977 mg, 7.34 mmol) was added, and the reaction solution was stirred at room temperature for 16 h. After the completion of the reaction was monitored by LCMS, water (20 mL) was added to quench Reaction, extraction with dichloromethane, washing with water, drying and concentration to obtain methyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate ester (300 mg). MS m/z (ESI): 273.0 [M+H] ⁺ .

step 4: synthesis 6-(1- methyl -1H- Pyrazole -4- base )-4-(( trifluoromethyl ) Sulfonate ) Oxygen ) Pyrazolo [1,5-a] Pyridine -3- Methyl Carboxylate

4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (300 mg, 1.1 mmol), N-benzene Bis(trifluoromethanesulfonyl)imide (473 mg, 1.32 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.2 mmol) were dissolved in DMA (20 mL) and the reaction was stirred at room temperature The reaction was carried out for 16 h. After monitoring the completion of the reaction, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 6-(1-methyl-1H-pyrazole- 4-yl)-4-((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylate 220 mg. MS m/z (ESI): 405.5 [M+H] ⁺ .

step 5: synthetic methyl 4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- Methyl Carboxylate

6-(1-Methyl-1H-pyrazol-4-yl)-4-((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid Methyl ester (220 mg, 0.54 mmol), 1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborol-2-yl)pyridin-2-yl)piperazine (266 mg, 0.65 mmol), sodium carbonate (286 mg, 2.7 mmol), tris(dibenzylideneacetone)di Palladium (49.5 mg, 0.054 mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (52 mg, 0.109 mmol) were dissolved in dioxane (15 mL) and water (5 mL) ), the reaction was stirred at 80 °C for 16 h. After monitoring the completion of the reaction, the reaction was cooled, water was added to quench the reaction, EA (30 mL*2) was extracted, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain methyl 4 -(6-(4-((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole- 4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate methyl ester ( compound 7) 320 mg. MS m/z (ESI): 539.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J = 1.5 Hz, 1H), 8.42 (s, 1H), 8.36 (d, J = 0.7 Hz, 1H), 8.20 – 8.15 (m, 1H) ), 8.09(d, J = 0.8 Hz, 1H), 8.08 – 8.05(m, 1H), 7.69 – 7.63(m, 2H), 7.55(dd, J = 8.8, 2.5 Hz, 1H), 6.86(d, J = 8.9 Hz, 1H), 6.80(dd, J = 8.5, 0.7 Hz, 1H), 3.86(s, 3H), 3.83(s, 3H), 3.54(t, J = 4.9 Hz, 3H), 3.47( s, 2H), 3.37 (s, 4H), 2.45 (d, J = 5.0 Hz, 4H).

Example 8 : Synthesis of Compound 8

step 1 :synthesis 6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- formyl chloride

6-Bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (0.6 g, 2.23 mmol) was dissolved in dichloromethane (15 mL) and added dropwise at 0 °C Oxalyl chloride (0.56 g, 4.46 mmol), the reaction solution was reacted at room temperature for 2 h, and after monitoring the completion of the reaction, the reaction solution was directly spin-dried and sent to the next step.

step 2 :synthesis 6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- carboxamide

The product 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-yl chloride obtained in the previous step was dissolved in tetrahydrofuran (10 mL), and then ammonia water (1 mL) was added at 0°C. ), stirred at room temperature for 1 hour, and after the reaction was complete, most of the reaction solution was spin-dried, extracted with dichloromethane (30 mL*2.), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 6-bromo- 4-Methoxypyrazolo[1,5-a]pyridine-3-carboxamide 0.4 g. MS m/z (ESI): 270.1 [M+H] ⁺ .

step 3 :synthesis 4- Methoxy -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- carboxamide

6-Bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxamide (400 mg, 1.48 mmol), tetrakistriphenylphosphine palladium (170 mg, 0.148 mmol), carbonic acid Sodium (470 mg, 4.44 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-pyrazole (462 mg, 2.22 mmol) was dissolved in dioxane (15 mL) and water (5 mL), and the reaction was stirred at 80 °C for 16 h. After monitoring the completion of the reaction, it was cooled, and water was added to quench the reaction. EA (30 mL*2) extraction, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a] Pyridine-3-carboxamide 0.2 g. MS m/z (ESI): 272.3 [M+H] ⁺ .

step 4 :synthesis 4- hydroxyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- carboxamide

4-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (0.4 g, 1.47 mmol) was dissolved in 1,2-dichloroethane (20 mL), then aluminum trichloride (0.7 g, 2.98 mmol) was added, the reaction solution was stirred at room temperature for 4 h, and the reaction was quenched with water (10 mL), DCM (30 mL*3) was extracted, the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyridine-3-carboxamide 0.3 g. MS m/z (ESI): 258.3 [M+H] ⁺ .

step 5 :synthesis 3- Aminocarboxy -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -4- triflate

4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (0.2 g, 0.78 mmol), N-benzene Bis(trifluoromethanesulfonyl)imide (0.33 g, 0.93 mmol) and N,N-diisopropylethylamine (0.2 g, 1.56 mmol) were dissolved in DMA (10 mL) and the reaction was stirred at room temperature The reaction was carried out for 8 h. After monitoring the completion of the reaction, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 3-aminocarbamoyl-6-(1- Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate 0.3 g. MS m/z (ESI): 390.2 [M+H] ⁺ .

step 6 :synthesis 4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- carboxamide

3-Aminocarbamoyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.2 g , 0.52 mmol), 1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxo Borolin-2-yl)pyridin-2-yl)piperazine (0.25 g, 0.62 mmol), sodium carbonate (0.17 g, 1.56 mmol), tris(dibenzylideneacetone)dipalladium (48 mg, 0.052 mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (50 mg, 0.104 mmol) in dioxane (15 mL) and water (5 mL), the reaction The reaction was stirred at 80 °C overnight. After monitoring the completion of the reaction, the reaction was cooled, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 4-(6-(4-( (6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[ 1,5-a]pyridine-3-carboxamide ( Compound 8) 120 mg. MS m/z (ESI): 524.3 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.89(s, 1H), 8.35(s, 1H), 8.21(d, J = 2.1 Hz, 1H), 8.12(s, 1H), 8.04(s, 1H), 7.86(s, 1H), 7.65(dd, J = 30.6, 7.0 Hz, 2H), 7.40(d, J = 1.2 Hz, 1H), 7.10(s, 1H), 6.89 – 6.76(m, 2H), 5.72 (d, J = 4.4 Hz, 1H), 3.89 (d, J = 8.8 Hz, 6H), 3.57 (d, J = 30.1 Hz, 5H), 2.50 (d, J = 10.0 Hz, 5H).

Example 9 : Synthesis of Compound 9

step 1 :synthesis 1-(6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- base )-3- methyl urea

6-Bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (0.55 g, 2.04 mmol), diphenylphosphoryl azide (0.84 g, 3.06 mmol), triethyl Amine (1.23 g, 12.24 mmol) was dissolved in toluene (20 mL), the reaction solution was stirred at 50 °C for 6 h, then methylamine hydrochloride (0.55 g, 8.16 mmol) was added, and the mixture was refluxed overnight to monitor the reaction After completion, most of the solvent was concentrated, extracted with DCM (30 mL*2), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 1-(6-bromo-4-methoxypyrazolo[1,5- a] Pyridin-3-yl)-3-methylurea 0.4 g. MS m/z (ESI): 300.0 [M+H] ⁺ .

step 2 :synthesis 1-(4- Methoxy -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base )-3- methyl urea

1-(6-Bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)-3-methylurea (400 g, 1.33 mmol), tetrakistriphenylphosphine palladium ( 153 mg, 0.133 mmol), sodium carbonate (422 mg, 3.99 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl)-pyrazole (332 mg, 1.6 mmol) was dissolved in dioxane (15 mL) and water (5 mL), and the reaction was stirred at 80 °C for 16 h. After monitoring the completion of the reaction, it was cooled and added The reaction was quenched with water, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 1-(4-methoxy-6-(1-methyl-1H-pyrazole-4). -yl)pyrazolo[1,5-a]pyridin-3-yl)-3-methylurea 0.3 g. MS m/z (ESI): 300.1 [M+H] ⁺ .

step 3 :synthesis 1-(4- hydroxyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base )-3- methyl urea

1-(4-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-3-methylurea ( 0.3 g, 1.0 mmol) was dissolved in 1,2-dichloroethane (20 mL), and then aluminum trichloride (0.49 g, 2.0 mmol) was added, and the reaction solution was stirred at room temperature for 4 h, followed by water. (10 mL) quenched the reaction, extracted with DCM (30 mL*3), washed the organic phase with water, dried and concentrated, and column chromatography gave 1-(4-hydroxy-6-(1-methyl-1H-pyrazole- 4-yl)pyrazolo[1,5-a]pyridin-3-yl)-3-methylurea 0.2 g. MS m/z (ESI): 287.3 [M+H] ⁺ .

step 4 :synthesis 6-(1- methyl -1H- Pyrazole -4- base )-3-(3- methyl ureido ) Pyrazolo [1,5-a] Pyridine -4- triflate

1-(4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-3-methylurea (0.2 g , 0.70 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (0.38 g, 1.04 mmol) and N,N-diisopropylethylamine (0.18 g, 1.4 mmol) were dissolved in DMA (10 mL) ), the reaction was stirred at room temperature for 8 h, and after monitoring the completion of the reaction, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 6-(1- Methyl-1H-pyrazol-4-yl)-3-(3-methylureido)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate 0.25 g. MS m/z (ESI): 419.4 [M+H] ⁺ .

step 5 :synthesis 1-(4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base )-3- methyl urea

6-(1-Methyl-1H-pyrazol-4-yl)-3-(3-methylureido)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.25 g, 0.6 mmol), 1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborol-2-yl)pyridin-2-yl)piperazine (0.3 g, 0.72 mmol), sodium carbonate (0.19 g, 1.8 mmol), tris(dibenzylideneacetone)dipalladium ( 55 mg, 0.06 mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (58 mg, 0.12 mmol) were dissolved in dioxane (15 mL) and water (5 mL) , the reaction was stirred at 80 °C overnight, and after monitoring the completion of the reaction, cooling, adding water to quench the reaction, extracting with EA (30 mL*2), washing the organic phase with water, drying and concentrating, and column chromatography to obtain 1-(4-( 6-(4-((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl)-3-methylurea ( compound 9) 100 mg. MS m/z (ESI): 553.1 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.87(s, 1H), 8.30(s, 1H), 8.24(d, J = 2.1 Hz, 1H), 8.10(s, 1H), 8.04(s, 1H), 7.86(s, 1H), 7.65(dd, J = 30.6, 7.0 Hz, 2H), 7.30(d, J = 1.2 Hz, 1H), 7.10(s, 1H), 6.89 – 6.76(m, 2H), 5.72 (d, J = 4.4 Hz, 1H), 3.86(d, J = 8.8 Hz, 6H), 3.52(d, J = 30.1 Hz, 5H), 2.49(d, J = 10.0 Hz, 5H), 2.43(d , J = 4.5 Hz, 3H).

Example 10 : Synthesis of Compound 10

step 1 :synthesis N-(6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- base ) Cyclopropanecarboxamide

6-Bromo-4-methoxypyrazolo[1,5-a]pyridin-3-amine (0.5 g, 2.07 mmol) and triethylamine (0.42 g, 4.14 mmol) were dissolved in dichloromethane (15 mL), and then dropwise added cyclopropanecarbonyl chloride (0.26 g, 2.5 mmol) in an ice bath, the reaction solution was reacted at room temperature for 1 h, after monitoring the completion of the reaction, cooling, adding water to quench the reaction, DCM (20 mL* 2) Extraction, washing the organic phase with water, drying and concentration, and column chromatography to obtain N-(6-bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)cyclopropanecarboxamide 450 mg. MS m/z (ESI): 310.1 [M+H] ⁺ .

step 2 :synthesis N-(4- Methoxy -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base ) Cyclopropanecarboxamide

Combine N-(6-bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)cyclopropanecarboxamide (0.45 g, 1.45 mmol), tetrakistriphenylphosphine palladium (167 g mg, 0.145 mmol), sodium carbonate (0.46 g, 4.35 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-pyrazole (0.36 g, 1.7 mmol) was dissolved in dioxane (15 mL) and water (5 mL), and the reaction was stirred at 80 °C for 16 h. After monitoring the completion of the reaction, it was cooled and water was added. The reaction was quenched, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain N-(4-methoxy-6-(1-methyl-1H-pyrazole-4- yl)pyrazolo[1,5-a]pyridin-3-yl)cyclopropanecarboxamide 0.35 g. MS m/z (ESI): 311.2 [M+H] ⁺ .

step 3 :synthesis N-(4- hydroxyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base ) Cyclopropanecarboxamide

N-(4-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)cyclopropanecarboxamide (0.35 g, 1.1 mmol) was dissolved in 1,2-dichloroethane (20 mL), then aluminum trichloride (0.54 g, 2.2 mmol) was added, the reaction solution was stirred at room temperature for 4 h, and water ( 10 mL) quenched the reaction, extracted with DCM (30 mL*3), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain N-(4-hydroxy-6-(1-methyl-1H-pyrazole-4). -yl)pyrazolo[1,5-a]pyridin-3-yl)cyclopropanecarboxamide 0.25 g. MS m/z (ESI): 298.2 [M+H] ⁺ .

step 4 :synthesis 3-( Cyclopropanecarboxamido )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -4- triflate

N-(4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)cyclopropanecarboxamide (0.25 g, 0.84 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (0.36 g, 1.00 mmol) and N,N-diisopropylethylamine (0.22 g, 1.68 mmol) were dissolved in DMA (10 mL) The reaction was stirred at room temperature for 8 h. After monitoring the completion of the reaction, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 3-(cyclopropanemethane). amido)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate 0.22 g. MS m/z (ESI): 430.1 [M+H] ⁺ .

step 5 :synthesis N-(4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base ) Cyclopropanecarboxamide

3-(Cyclopropanecarboxamido)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.22 g, 0.51 mmol), 1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborol-2-yl)pyridin-2-yl)piperazine (0.25 g, 0.62 mmol), sodium carbonate (0.16 g, 1.53 mmol), tris(dibenzylideneacetone)dipalladium ( 59 mg, 0.051 mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (49 mg, 0.11 mmol) were dissolved in dioxane (15 mL) and water (5 mL) , the reaction was stirred at 80 °C overnight, and after monitoring the completion of the reaction, cooling was performed, water was added to quench the reaction, EA (30 mL*2) was extracted, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain N-(4-( 6-(4-((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl)cyclopropanecarboxamide ( compound 10) 80 mg. MS m/z (ESI): 564.2 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 9.27(s, 1H), 8.90(d, J = 1.3 Hz, 1H), 8.30(s, 1H), 8.19(d, J = 2.4 Hz, 1H), 8.10( s, 1H), 8.04 (s, 1H), 7.86 (s, 1H), 7.68 (dd, J = 8.5, 1.9 Hz, 1H), 7.56 (dd, J = 8.8, 2.4 Hz, 1H), 7.34 (d , J = 1.3 Hz, 1H), 6.90 – 6.75(m, 2H), 3.86(d, J = 11.5 Hz, 6H), 3.64 – 3.39(m, 6H), 2.48(s, 4H), 1.46 – 1.37( m, 1H), 0.57 – 0.48 (m, 2H), 0.46 – 0.36 (m, 2H).

Example 11 : Synthesis of Compound 11

step 1 :synthesis N-(6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- base ) benzamide

6-Bromo-4-methoxypyrazolo[1,5-a]pyridin-3-amine (0.5 g, 2.07 mmol) and triethylamine (0.42 g, 4.14 mmol) were dissolved in dichloromethane (15 mL), then benzyl chloride (0.35 g, 2.5 mmol) was added dropwise in an ice bath, the reaction solution was reacted at room temperature for 1 h, after monitoring the completion of the reaction, cooling, adding water to quench the reaction, DCM (20 mL*2 ) extraction, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 0.5 g of N-(6-bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)benzamide . MS m/z (ESI): 346.5 [M+H] ⁺ .

step 2 :synthesis N-(4- Methoxy -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base ) benzamide

N-(6-Bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)benzamide (0.5 g, 1.45 mmol), tetrakistriphenylphosphine palladium (167 mg , 0.145 mmol), sodium carbonate (0.46 g, 4.35 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-pyrazole (0.36 g, 1.7 mmol) was dissolved in dioxane (15 mL) and water (5 mL), and the reaction was stirred at 80 °C for 12 h. After monitoring the completion of the reaction, it was cooled and quenched by adding water. The reaction was quenched, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain N-(4-methoxy-6-(1-methyl-1H-pyrazol-4-yl) )pyrazolo[1,5-a]pyridin-3-yl)benzamide 0.41 g. MS m/z (ESI): 348.1 [M+H] ⁺ .

step 3 :synthesis N-(4- hydroxyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base ) benzamide

N-(4-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)benzamide (0.42 g , 1.2 mmol) was dissolved in 1,2-dichloroethane (20 mL), then aluminum trichloride (0.58 g, 2.4 mmol) was added, and the reaction solution was stirred at room temperature for 4 h, and water (10 mL) quenched the reaction, extracted with DCM (30 mL*3), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain N-(4-hydroxy-6-(1-methyl-1H-pyrazole-4-) yl)pyrazolo[1,5-a]pyridin-3-yl)benzamide 0.31 g. MS m/z (ESI): 334.2 [M+H] ⁺ .

step 4 :synthesis 3- benzamide -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -4- triflate

N-(4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)benzamide (0.31 g, 0.93 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (0.40 g, 1.12 mmol) and N,N-diisopropylethylamine (0.24 g, 1.86 mmol) were dissolved in DMA (10 mL) , the reaction was stirred at room temperature for 8 h. After monitoring the completion of the reaction, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 3-benzylamino group -6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate 0.26 g. MS m/z (ESI): 466.0 [M+H] ⁺ .

step 5 :synthesis N-(4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base ) benzamide

3-Benzylamino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.26 g , 0.56 mmol), 1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxo Borolin-2-yl)pyridin-2-yl)piperazine (0.28 g, 0.67 mmol), sodium carbonate (0.18 g, 1.68 mmol), tris(dibenzylideneacetone)dipalladium (52 mg, 0.056 mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (49 mg, 0.11 mmol) in dioxane (15 mL) and water (5 mL), the reaction The reaction was stirred at 80 °C overnight. After monitoring the completion of the reaction, the reaction was cooled, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain N-(4-(6-( 4-((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyridin-3-yl)benzamide ( Compound 11) 90 mg. MS m/z (ESI): 601.5 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 9.50 (s, 1H), 8.96 (d, J = 1.3 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.07 ( dd, J = 21.0, 9.0 Hz, 3H), 7.70 – 7.64(m, 1H), 7.64 – 7.57(m, 3H), 7.52(t, J = 7.4 Hz, 1H), 7.40(dd, J = 10.8, 4.6 Hz, 3H), 6.83(d, J = 8.5 Hz, 1H), 6.64(d, J = 8.8 Hz, 1H), 3.86(t, J = 9.6 Hz, 6H), 3.54 – 3.35(m, 6H) , 2.36(s, 4H).

Example 12 : Synthesis of Compound 12

step 1 :synthesis N-(6- bromine -4- Methoxypyrazolo [1,5-a] Pyridine -3- base )-1- methyl -1H- imidazole -5- carboxamide

6-Bromo-4-methoxypyrazolo[1,5-a]pyridin-3-amine (0.5 g, 2.07 mmol) and triethylamine (0.42 g, 4.14 mmol) were dissolved in dichloromethane (15 mL), then 1-methyl-1H-imidazole-5-formyl chloride (0.36 g, 2.5 mmol) was added dropwise in an ice bath, the reaction solution was reacted at room temperature for 1 h, after monitoring the completion of the reaction, cooling, adding water The reaction was quenched, extracted with DCM (20 mL*2), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain N-(6-bromo-4-methoxypyrazolo[1,5-a]pyridine- 3-yl)-1-methyl-1H-imidazole-5-carboxamide 0.52 g. MS m/z (ESI): 350.7 [M+H] ⁺ .

step 2 :synthesis N-(4- Methoxy -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base )-1- methyl -1H- imidazole -5- carboxamide

N-(6-Bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-imidazole-5-carboxamide (0.52 g, 1.48 mmol) ), tetrakistriphenylphosphine palladium (171 mg, 0.148 mmol), sodium carbonate (0.47 g, 4.44 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane-2-yl)-pyrazole (0.37 g, 1.78 mmol) was dissolved in dioxane (15 mL) and water (5 mL), and the reaction was stirred at 80 °C for 12 h , after monitoring the completion of the reaction, cooling, adding water to quench the reaction, extracting with EA (30 mL*2), washing the organic phase with water, drying and concentrating, and column chromatography to obtain N-(4-methoxy-6-(1- Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-imidazole-5-carboxamide 0.4 g. MS m/z (ESI): 352.1 [M+H] ⁺ .

step 3 :synthesis N-(4- hydroxyl -6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base )-1- methyl -1H- imidazole -5- carboxamide

N-(4-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H -Imidazole-5-carboxamide (0.4 g, 1.14 mmol) was dissolved in 1,2-dichloroethane (20 mL), then aluminum trichloride (0.55 g, 2.28 mmol) was added, and the reaction solution was further The reaction was stirred at room temperature for 4 h, quenched with water (10 mL), extracted with DCM (30 mL*3), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain N-(4-hydroxy-6-(1). -Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-imidazole-5-carboxamide 0.26 g. MS m/z (ESI): 338.2 [M+H] ⁺ .

step 4 :synthesis 3-(1- methyl -1H- imidazole -5- formamide )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -4- triflate

N-(4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-imidazole -5-Carboxamide (0.26 g, 0.77 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (0.33 g, 0.93 mmol) and N,N-diisopropylethylamine (0.20 g, 1.54 mmol) was dissolved in DMA (10 mL), and the reaction was stirred at room temperature for 8 h. After monitoring the completion of the reaction, water was added to quench the reaction, EA (30 mL*2) was extracted, the organic phase was washed with water, dried and concentrated. Chromatography to give 3-(1-methyl-1H-imidazol-5-carboxamido)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ] Pyridin-4-yl trifluoromethanesulfonate 0.33 g. MS m/z (ESI): 470.1 [M+H] ⁺ .

step 5 :synthesis N-(4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base )-6-(1- methyl -1H- Pyrazole -4- base ) Pyrazolo [1,5-a] Pyridine -3- base )-1- methyl -1H- imidazole -5- carboxamide

3-(1-Methyl-1H-imidazol-5-carboxamido)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 4-yl trifluoromethanesulfonate (0.33 g, 0.71 mmol), 1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-yl)piperazine (0.35 g, 0.84 mmol), sodium carbonate (0.23 g, 2.13 mmol), tris( Dibenzylideneacetone)dipalladium (65 mg, 0.071 mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (68 mg, 0.14 mmol) were dissolved in dioxane (15 mL) and water (5 mL), the reaction was stirred at 80 °C overnight. After monitoring the completion of the reaction, it was cooled, water was added to quench the reaction, extracted with EA (30 mL*2), the organic phase was washed with water, dried and concentrated, and the column layer analysis to obtain N-(4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl) yl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-imidazole-5-carboxamide ( compound 12) 100 mg. MS m/z (ESI): 605.3 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 9.36 (s, 1H), 8.94 (d, J = 1.3 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.10 ( d, J = 2.1 Hz, 1H), 8.06(s, 1H), 7.99(s, 1H), 7.75 – 7.66(m, 2H), 7.60(dd, J = 8.8, 2.5 Hz, 1H), 7.43(s , 1H), 7.39(d, J = 1.2 Hz, 1H), 6.83(d, J = 8.4 Hz, 1H), 6.62(d, J = 8.8 Hz, 1H), 3.87(d, J = 12.9 Hz, 6H) ), 3.59(s, 3H), 3.43(d, J = 46.0 Hz, 6H), 2.40(s, 4H).

Example 13 : Synthesis of Compound 13

step 1: synthesis 6-(2- Chloroethyl )-2- oxa -6- Azaspiro [3.3] Heptane

2-oxa-6-azaspiro[3.3]heptane (0.3 g, 3.03 mmol), cesium carbonate (2.96 g, 9.09 mmol) were added to DMF (5 mL) followed by 1-bromo-2- Ethyl chloride (1.3 g, 9.09 mmol) was stirred at room temperature overnight and monitored for completion. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 150 mg of 6-(2-chloroethyl)-2-oxa-6-azaspiro[3.3]heptane. MS m/z (ESI): 162.3 [M+H] ⁺ .

step 2: synthesis 6-(2-(2- oxa -6- Azaspiro [3.3] Geng -6- base ) Ethoxy )-4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile (0.1 g, 0.23 mmol), 6-(2-chloroethyl)-2-oxa-6-azaspiro[3.3]heptane (74 mg, 0.45 mmol), carbonic acid Cesium (0.15 g, 0.45 mmol) was dissolved in DMA (5 mL) and stirred at 50 °C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethoxy )-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine -3-carbonitrile ( compound 13) 50 mg. MS m/z (ESI): 567.1 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.64(d, J = 2.1 Hz, 1H), 8.64(d, J = 2.1 Hz, 1H), 8.56(s, 1H), 8.56(s, 1H), 8.32( d, J = 2.5 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.8, 2.5 Hz, 1H), 7.67 (dd, J = 8.5, 2.4 Hz, 1H), 7.26(d, J = 2.1 Hz, 1H), 6.93(d, J = 8.9 Hz, 1H), 6.81(d, J = 8.5 Hz, 1H), 4.59(s, 4H), 4.04(t, J = 5.3 Hz, 2H), 3.84 (s, 3H), 3.55 (dd, J = 29.6, 24.6 Hz, 8H), 2.72 (t, J = 5.2 Hz, 2H), 2.49 – 2.39 (m, 5H), 2.08 – 1.88 (m, 2H).

Example 14 : Synthesis of Compound 14

step 1: synthesis 9-(2- Chloroethyl )-3- oxa -9- Azaspiro [5.5] Undecane

3-oxa-9-azaspiro[5.5]undecane (0.3 g, 1.93 mmol), cesium carbonate (1.88 g, 5.80 mmol) were added to DMF (5 mL) followed by 1-bromo-2 -Chloroethane (0.83 g, 5.80 mmol), stirred at room temperature overnight, monitoring the completion of the reaction. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 180 mg of 9-(2-chloroethyl)-3-oxa-9-azaspiro[5.5]undecane . MS m/z (ESI): 218.5 [M+H] ⁺ .

step 2: synthesis 6-(2-(3- oxa -9- Azaspiro [5.5] 11 carbon -9- base ) Ethoxy )-4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile (0.1 g, 0.23 mmol), 9-(2-chloroethyl)-3-oxa-9-azaspiro[5.5]undecane (98 mg, 0.45 mmol), Cesium carbonate (0.15 g, 0.45 mmol) was dissolved in DMA (5 mL) and stirred at 50 °C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(3-oxa-9-azaspiro[5.5]undec-9-yl)ethane oxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a ]pyridine-3-carbonitrile ( compound 14) 48 mg. MS m/z (ESI): 623.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.73 (s, 1H), 8.58 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H), 7.76 (dd, J = 8.8 , 2.5 Hz, 1H), 7.67(dd, J = 8.4, 1.8 Hz, 1H), 7.31(s, 1H), 6.93(d, J = 8.9 Hz, 1H), 6.80(d, J = 8.4 Hz, 1H) ), 4.23(d, J = 62.7 Hz, 2H), 3.84(s, 3H), 3.66 – 3.42(m, 13H), 2.47(s, 4H), 1.62 – 1.33(m, 11H).

Example 15 : Synthesis of Compound 15

step 1: synthesis 2-(2- Chloroethyl )-2- azabicyclo [2.2.1] Heptane

2-Azabicyclo[2.2.1]heptane (0.2 g, 2.06 mmol), cesium carbonate (2.01 g, 6.18 mmol) were added to DMF (5 mL) followed by 1-bromo-2-chloroethane (0.88 g, 6.18 mmol), stirred overnight at room temperature and monitored for completion. Add water to quench the reaction, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 2-(2-chloroethyl)-2-azabicyclo[2.2.1]heptane 100 mg, MS m /z(ESI):160.7 [M+H] ⁺ .

step 2: synthesis 6-(2-(2- azabicyclo [2.2.1] Geng -2- base ) Ethoxy )-4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile (0.12 g, 0.27 mmol), 2-(2-chloroethyl)-2-azabicyclo[2.2.1]heptane (87 mg, 0.54 mmol), cesium carbonate (0.18 g, 0.54 mmol) was dissolved in DMA (5 mL) and stirred at 50 °C overnight, monitoring the completion of the reaction. Quench by adding water, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(2-azabicyclo[2.2.1]hept-2-yl)ethoxy)-4 -(6-(4-((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3- Formonitrile ( Compound 15) 90 mg. MS m/z (ESI): 565.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.74 (s, 1H), 8.59 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.77 ( dd, J = 8.8, 2.5 Hz, 1H), 7.67(dd, J = 8.5, 2.4 Hz, 1H), 7.33(s, 1H), 6.93(d, J = 8.9 Hz, 1H), 6.81(d, J = 8.5 Hz, 1H), 4.30(s, 2H), 3.84(s, 3H), 3.55(dd, J = 29.6, 24.7 Hz, 8H), 2.49 – 2.40(m, 5H), 1.99(dt, J = 12.5, 7.1 Hz, 1H), 1.84(s, 2H), 1.63 – 1.28(m, 6H).

Example 16 : Synthesis of Compound 16

step 1: synthesis 3-(2- Chloroethyl )-3- azabicycle [3.1.0] Hexane

3-Azabicyclo[3.1.0]hexane (0.2 g, 2.41 mmol), cesium carbonate (1.56 g, 4.82 mmol) were added to DMF (5 mL) followed by 1-bromo-2-chloroethane (0.75 g, 4.82 mmol), stirred overnight at room temperature and monitored for completion. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 110 mg of 3-(2-chloroethyl)-3-azabicyclo[3.1.0]hexane. MS m/z (ESI): 146.6 [M+H] ⁺ .

step 2: synthesis 6-(2-(3- azabicyclo [3.1.0] already -3- base ) Ethoxy )-4-(6-(4-((6- Methoxypyridine -3- base ) methyl ) Piperazine -1- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile (0.1 g, 0.23 mmol), 3-(2-chloroethyl)-3-azabicyclo[3.1.0]hexane (66 mg, 0.45 mmol), cesium carbonate ( 0.15 g, 0.45 mmol) was dissolved in DMA (5 mL) and stirred at 50 °C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(3-azabicyclo[3.1.0]hex-3-yl)ethoxy)-4 -(6-(4-((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3- Formonitrile ( Compound 16) 60 mg. MS m/z (ESI): 551.2 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.68 (s, 1H), 8.57 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.76 ( dd, J = 8.8, 2.5 Hz, 1H), 7.67(dd, J = 8.5, 2.3 Hz, 1H), 7.28(s, 1H), 6.92(d, J = 8.9 Hz, 1H), 6.80(d, J = 8.4 Hz, 1H), 4.15(s, 2H), 3.84(s, 3H), 3.53(d, J = 48.6 Hz, 7H), 2.91(d, J = 97.1 Hz, 4H), 2.48 – 2.30(m , 5H), 1.34(d, J = 10.2 Hz, 2H), 0.56(s, 1H), 0.29(s, 1H).

Example 17 : Synthesis of Compound 17

step 1: tertiary butyl -3-(5- Bromopyrazine -2- base )-3,6- diazabicyclo [3.1.1] Heptane -6- formate

1-Boc-octahydro-pyrrolo[3,4-b]pyridine (350 mg, 1.5 mmol) and cesium carbonate (1.5 g, 4.6 mmol) were dissolved in DMF (5 mL), and 1-bromo was added at room temperature -2-Chloroethane (665 mg, 4.6 mmol), the reaction was stirred at room temperature overnight, and the reaction was complete. Diluted with ethyl acetate, filtered, added water to quench the reaction, extracted, concentrated under reduced pressure to remove the solvent, column chromatography (PE:EA=3:1) to obtain 6-(2-chloroethyl)octahydro-1H-pyrrole and [3,4-b]pyridine-1-carboxylate 3-butyl ester 270 mg, yield 60%. MS m/z (ESI): 289 [M+H] ⁺ .

step 2: 2-(2-((3- cyano group -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Geng -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -6- base ) Oxygen ) Ethyl ) Octahydro -1H- isoindole -4- tert-butyl carboxylate

6-(2-Chloroethyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester (126 mg, 0.44 mmol), 6-hydroxy-4-(5 -(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.22 mmol) was dissolved in DMF (4 mL), cesium carbonate (214 mg, 0.66 mmol) was added, and the reaction was stirred at 50 °C for 3 hours, the reaction was complete . Diluted with DCM, concentrated under reduced pressure to remove solvent, column chromatography (DCM:MeOH=20:1) gave 2-(2-((3-cyano-4-(5-(6-((6-methoxy pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine- 6-yl)oxy)ethyl)octahydro-1H-isoindole-4-carboxylic acid tert-butyl ester 129 mg, 83% yield. MS m/z (ESI): 707 [M+H] ⁺ .

step 3: 4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Geng -3- base ) Pyrazine -2- base )-6-(2-( Octahydro -6H- Pyrrole [3,4-b] Pyridine -6- base ) Ethoxy ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

2-(2-((3-cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1. 1]Hept-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)octahydro-1H-isoindole-4-carboxylic acid The tertiary butyl ester (126 mg, 0.178 mmol) was dissolved in DCM (2 mL), then 2 mL of dioxane hydrochloride was added, and the reaction was stirred for 1 hour, and the reaction was complete. The reaction was quenched with saturated aqueous NaHCO ₃ , extracted with DCM, washed with water, dried, and subjected to column chromatography (DCM:MeOH=10:1) to give 4-(5-(6-((6-methoxypyridin-3-yl) )methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl)-6-(2-(octahydro-6H-pyrrole[3,4- b]Pyridin-6-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 17) 62 mg, yield 57%. MS m/z (ESI): 607 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.73(s, 1H), 8.67(s, 1H), 8.60(s, 1H), 8.29(s, 1H), 8.09(d, 1H), 7.68-7.70(m , 1H), 7.62(d, 2H), 6.76(d, 1H), 4.18(m, 1H), 3.82(m, 3H), 3.79(s, 1H), 3.68(d, 2H), 3.61(d, 2H), 3.54(s, 2H), 3.10-3.13(m, 1H), 2.91-2.95(m, 3H), 2.69-2.79(m, 3H), 2.41-2.47(m, 2H), 2.00-2.04( m, 2H), 1.57-1.63 (m, 3H), 1.23-1.34 (m, 2H).

Example 18 : Synthesis of Compound 18

step 1: tertiary butyl 5-(2- Chloroethyl ) Octahydro -1H- Pyrrole [3,2-c] Pyridine -1- Carboxylate

Octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate 3-butyl ester (350 mg, 1.5 mmol), cesium carbonate (1.5 g, 4.6 mmol) were dissolved in DMF (3 mL) , 1-bromo-2-chloroethane (665 mg, 4.6 mmol) was added at room temperature, the reaction was stirred at room temperature overnight, and the reaction was complete. Diluted with ethyl acetate, filtered, quenched the reaction by adding water, extracted, concentrated under reduced pressure to remove the solvent, column chromatography (PE:EA=3:1) to obtain tert-butyl 5-(2-chloroethyl)8 Hydrogen-1H-pyrrole[3,2-c]pyridine-1-carboxylate 250 mg, 56% yield. MS m/z (ESI): 289 [M+H] ⁺ .

step 2: tertiary butyl 5-(2-((3- cyano group -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -6- base ) Oxygen ) Ethyl ) Octahydro -1H- pyrrolo [3,2-c] Pyridine -1- Carboxylate

The tert-butyl 5-(2-chloroethyl)octahydro-1H-pyrro[3,2-c]pyridine-1-carboxylate (250 mg, 0.86 mmol), 6-hydroxy-4-(5 -(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.22 mmol) was dissolved in DMF (4 mL), cesium carbonate (214 mg, 0.66 mmol) was added, and the reaction was stirred at 50 °C for 18 hours. completely. Diluted with DCM, filtered, concentrated under reduced pressure to remove solvent, column chromatography (DCM:MeOH=20:1) gave tert-butyl 5-(2-((3-cyano-4-(5-(6 -((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[ 1,5-a]pyridin-6-yl)oxy)ethyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 148 mg, 95% yield. MS m/z (ESI): 707 [M+H] ⁺ .

step 3: 4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Geng -3- base ) Pyrazine -2- base )-6-(2-( Octahydro -5H- pyrrolo [3,2-c] Pyridine -5- base ) Ethoxy ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

The tert-butyl 5-(2-((3-cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabis Cyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)octahydro-1H-pyrrolo[ 3,2-c]pyridine-1-carboxylate (148 mg, 0.2 mmol) was dissolved in DCM (3 mL), then 6 mL of dioxane hydrochloride was added, and the reaction was stirred for 1 hour, and the reaction was complete. The solvent was removed, diluted with aq. NaHCO ₃ , extracted with DCM, washed with water, dried, concentrated, column chromatographed (DCM:MeOH=10:1) to give 4-(5-(6-((6-methoxypyridine- 3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl)-6-(2-(octahydro-5H-pyrrolo[ 3,2-c]pyridin-5-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 18) 35 mg, yield 27%. MS m/z (ESI): 607 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.74(s, 1H), 8.67(s, 1H), 8.60(s, 1H), 8.29(s, 1H), 8.09(d, 1H), 7.68-7.70(m , 1H), 7.62(d, 2H), 6.76(d, 1H), 4.23(m, 2H), 3.82(m, 3H), 3.79(s, 1H), 3.68(d, 2H), 3.61(d, 2H), 3.54(s, 2H), 3.92-3.00(m, 2H), 2.78-2.82(m, 1H), 2.70-2.72(m, 2H), 2.53-2.55(m, 2H), 2.40-2.43( m, 2H), 2.16-2.22 (m, 1H), 2.03-2.09 (m, 1H), 1.67-1.76 (m, 2H), 1.57-1.63 (m, 2H), 1.44-1.50 (m, 1H), 1.23 (s, 2H).

Example 19 : Synthesis of Compound 19

step 1: tertiary butyl 2-(2- Chloroethyl )-2,6- Diazaspiro [3.5] Nonane -6-2- formate

Dissolve tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (300 mg, 0.55 mmol) and cesium carbonate (899 mg, 2.76 mmol) in DMF (5 mL) at room temperature 1-Bromo-2-chloroethane (238 mg, 1.66 mmol) was added, and the reaction was stirred at room temperature overnight, and the reaction was complete. Diluted with ethyl acetate, filtered, quenched the reaction by adding water, extracted, concentrated under reduced pressure to remove the solvent, column chromatography (PE:EA=3:1) to obtain tert-butyl 2-(2-chloroethyl)- 2,6-Diazaspiro[3.5]nonane-6-carboxylate 250 mg, 100% yield. MS m/z (ESI): 289 [M+H] ⁺ .

step 2: tertiary butyl 2-(2-((3- cyano group -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -6- base ) Oxygen ) Ethyl )-2,6- Diazaspiro [3.5] Nonane -6- Carboxylate

tert-butyl 2-(2-chloroethyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (126 mg, 0.44 mmol), 6-hydroxy-4-(5 -(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.22 mmol) was dissolved in DMF (2 mL), cesium carbonate (214 mg, 0.66 mmol) was added, and the reaction was stirred at 50 °C for 18 hours. completely. Diluted with DCM, filtered, concentrated under reduced pressure to remove solvent, column chromatography (DCM:MeOH=20:1) gave tert-butyl 2-(2-((3-cyano-4-(5-(6 -((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[ 1,5-a]pyridin-6-yl)oxy)ethyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate 61 mg, 39% yield. MS m/z (ESI): 706 [M+H] ⁺ .

step 3: 6-(2-(2,6- Diazaspiro [3.5] Ren -2- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

The tert-butyl 2-(2-((3-cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabis Cyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-2,6-diazaspiro Cyclo[3.5]nonane-6-carboxylate (61 mg, 0.086 mmol) was dissolved in DCM (3 mL), then TFA (1 mL) was added, and the reaction was stirred for 1 hour. The reaction was complete. The solvent was removed, neutralized with saturated aqueous NaHCO ₃ , extracted with DCM, washed with water, dried, and subjected to column chromatography (DCM:MeOH=10:1) to give 6-(2-(2,6-diazaspiro[3.5]) Non-2-yl)ethoxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1] Heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 19 ) 20 mg, 38% yield. MS m/z (ESI): 607 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.71(d,1H), 8.66(d,1H), 8.61(s,1H), 8.29(d,1H), 8.09(d,1H), 7.68-7.70(m , 1H), 7.57(d, 1H), 6.76(d, 1H), 4.09(m, 2H), 3.82(m, 3H), 3.79(s, 1H), 3.68(d, 2H), 3.61(d, 2H), 3.54(s, 2H), 3.15(d, 2H), 3.00(s, 1H), 2.95(d, 2H), 2.79-2.85(m, 4H), 2.55-2.58(m, 1H), 1.67 -1.70 (t, 2H), 1.61 (d, 1H), 1.51-1.52 (m, 2H), 1.25-1.27 (m, 2H).

Example 20 : Synthesis of Compound 20

step 1: 6-(2- Chloroethyl )-2- oxa -6- nitrogen spiro [3.4] Octane

2-oxa-6-azaspiro[3.4]octane (300 mg, 0.94 mmol) and cesium carbonate (925 mg, 2.84 mmol) were dissolved in DMF (5 mL), and 1-bromo-2- Ethyl chloride (407 mg, 2.84 mmol) was stirred at room temperature overnight, and the reaction was complete. Diluted with ethyl acetate, filtered, added water to quench the reaction, extracted, concentrated under reduced pressure to remove the solvent, and column chromatography (PE:EA=3:1) gave 6-(2-chloroethyl)-2-oxa- 6-Azaspiro[3.4]octane 100 mg, yield 18%. MS m/z (ESI): 176 [M+H] ⁺ .

step 2:6-(2-(2- oxa -6- nitrogen spiro [3.4] pungent -6- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-(2-Chloroethyl)-2-oxa-6-azaspiro[3.4]octane (77 mg, 0.44 mmol), 6-hydroxy-4-(5-(6-((6- Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a ] Pyridine-3-carbonitrile (100 mg, 0.22 mmol) was dissolved in DMF (2 mL), cesium carbonate (214 mg, 0.66 mmol) was added, and the reaction was stirred at 50 °C for 18 hours, and the reaction was complete. Diluted with DCM, filtered, concentrated under reduced pressure to remove solvent, column chromatography (DCM:MeOH=20:1) gave 6-(2-(2-oxa-6-azaspiro[3.4]oct-6-yl) )ethoxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3- yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 20 ) 10 mg, yield 7.6%. MS m/z (ESI): 594 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.71(d,1H), 8.64(d,1H), 8.58(s,1H), 8.27(d,1H), 8.07(d,1H), 7.66-7.68(m , 1H), 7.60(d, 1H), 6.74(d, 1H), 4.21(t, 2H), 3.80(m, 3H), 3.77(s, 1H), 3.66(d, 2H), 3.58-3.61( d, 3H), 3.55 (s, 3H), 2.80 (m, 5H), 2.47-2.57 (m, 5H), 2.01 (t, 2H), 1.59-1.62 (m, 1H).

Example 21 : Synthesis of Compound 21

step 1: tertiary butyl 8-(2- Chloroethyl )-2,8- Diazaspiro [4.5] Decane -2- Carboxylate

Dissolve tert-butyl 2,8-diazaspiro[4.5]decane-2-2-carboxylate (350 mg, 1.45 mmol), cesium carbonate (1.5 g, 4.36 mmol) in DMF (5 mL), 1-Bromo-2-chloroethane (624 mg, 4.36 mmol) was added at room temperature, and the reaction was stirred at room temperature overnight, and the reaction was complete. Diluted with ethyl acetate, filtered, quenched the reaction by adding water, extracted, concentrated under reduced pressure to remove the solvent, column chromatography (PE:EA=3:1) to obtain tert-butyl 8-(2-chloroethyl)- 2,8-Diazaspiro[4.5]decane-2-carboxylate 192 mg, yield 43%.

step 2 : Tertiary butyl 8-(2-((3- cyano group -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -6- base ) Oxygen ) Ethyl )-2,8- Diazaspiro [4.5] Decane -2- Carboxylate

tert-butyl 8-(2-chloroethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (192 mg, 0.66 mmol), 6-hydroxy-4-(5- (6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazole And [1,5-a]pyridine-3-carbonitrile (100 mg, 0.22 mmol) was dissolved in DMF (2 mL), cesium carbonate (214 mg, 0.66 mmol) was added, and the reaction was stirred at 50 °C for 3 hours, the reaction was complete . Diluted with DCM, filtered, concentrated under reduced pressure to remove solvent, column chromatography (DCM:MeOH=20:1) gave tert-butyl 8-(2-((3-cyano-4-(5-(6 -((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[ 1,5-a]pyridin-6-yl)oxy)ethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate 158 mg, 100% yield. MS m/z (ESI): 721 [M+H] ⁺ .

step 3 : 6-(2,8- Diazaspiro [4.5] Gui -8- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

The tert-butyl 8-(2-((3-cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabis Cyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-2,8-diazaspiro [4.5] Decane-2-carboxylate (158 mg, 0.21 mmol) was dissolved in DCM (6 mL), then TFA (2 mL) was added, and the reaction was stirred for 1 hour, and the reaction was complete. The solvent was removed, neutralized with saturated aqueous NaHCO ₃ , extracted with DCM, washed with water, dried, and subjected to column chromatography (DCM:MeOH=10:1) to give 6-(2,8-diazaspiro[4.5]decane-8- yl)ethoxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3 -yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 21 ) 54 mg, yield 39%. MS m/z (ESI): 621 [M+H] ⁺ .

1H NMR (400 MHz, DMSO) δ 8.71(d,1H), 8.64(d,1H), 8.58(s,1H), 8.26(d,1H), 8.07(d,1H), 7.65-7.68(m, 1H), 7.59(d, 1H), 6.73(d, 1H), 4.21(t, 2H), 3.80(m, 3H), 3.77(s, 1H), 3.66(d, 2H), 3.61(d, 2H) ), 3.58(s, 2H), 3.51(s, 2H), 2.98(t, 1H), 271-2.73(m, 3H), 2.54-2.55(m, 1H), 2.39-2.43(m, 4H), 1.54-1.60 (m, 3H), 1..48 (m, 4H).

Example 22 : Synthesis of Compound 22

step 1: synthesis 3-(2- Chloroethyl )-3,6- diazabicyclo [3.1.1] Heptane -6- tert-butyl carboxylate

3,6-Diazabicyclo[3.1.1]heptane-6-carboxylate tert-butyl ester (300.0 mg, 1.51 mmol), cesium carbonate (1.47 g, 4.51 mmol) were dissolved in DMF (3 mL) , 1-bromo-2-chloroethane (650.0 mg, 4.51 mmol) was added, and the mixture was stirred at room temperature overnight, and the completion of the reaction was monitored. Add water, extract with dichloromethane, wash the organic phase with water, dry and concentrate, and perform column chromatography to obtain 3-(2-chloroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid 170 mg of tertiary butyl ester, yield 43%. MS m/z (ESI): 261.0 [M+H] ⁺ .

step 2: synthesis 3-(2-((3- cyano group -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Geng -3- tertiary butyl ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -6- base ) Oxygen ) Ethyl )-3,6- diazabicyclo [3.1.1] Heptane -6- Ethyl carboxylate

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (100.0 mg, 0.22 mmol), 3-(2-chloroethyl)-3,6-diazabicyclo[ 3.1.1] Heptane-6-carboxylate tert-butyl ester (170.0 mg, 0.65 mmol), cesium carbonate (210.0 mg, 0.65 mmol) was dissolved in DMF (3 mL), stirred at 50 °C overnight, monitoring the completion of the reaction . Add water, extract with dichloromethane, wash the organic phase with water, dry and concentrate, and perform column chromatography to obtain 3-(2-((3-cyano-4-(5-(6-((6-methoxypyridine-3 -yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yltert-butyl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-6 -yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ethyl ester 130 mg, yield 87%. MS m/z (ESI): 679.2 [M+H] ⁺ .

step 3: synthesis 6-(2-(3,6- diazabicyclo [3.1.1] Heptane -3- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- formonitrile

3-(2-((3-cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1 ]hept-3-yltert-butyl)pyrazin-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[ 3.1.1] Heptane-6-carboxylate ethyl ester (130.0 mg, 0.20 mmol) was dissolved in dichloromethane (2 mL), 4M HCl/dioxane (5 mL) was added, stirred at room temperature for 2 h, and the completion of the reaction was monitored. . Concentrate the reaction solution, add water, add saturated sodium bicarbonate solution to adjust the pH to neutral or slightly alkaline, extract with dichloromethane, wash the organic phase with water, dry and concentrate, and perform column chromatography to obtain 6-(2-(3,6- Diazabicyclo[3.1.1]heptan-3-yl)ethoxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6- Diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 22 ) 15 mg, yield 14%. MS m/z (ESI): 579.1 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.77(d, J = 2.1 Hz, 1H), 8.67(d, J = 1.4 Hz, 1H), 8.62(s, 1H), 8.30(d, J = 1.4 Hz, 1H), 8.10(d, J = 2.1 Hz, 1H), 7.70(dd, J = 8.5, 2.4 Hz, 1H), 7.63(d, J = 2.1 Hz, 1H), 6.78(d, J = 8.5 Hz, 1H), 4.32(t, J = 5.5 Hz, 2H), 4.00(s, 2H), 3.83(s, 3H), 3.69(d, J = 5.9 Hz, 2H), 3.62(d, J = 12.3 Hz, 2H), 3.54 (s, 2H), 3.26 (d, J = 11.3 Hz, 4H), 3.06 (dd, J = 12.5, 8.4 Hz, 4H), 2.00 (dd, J = 19.4, 8.0 Hz, 2H), 1.62(d, J = 8.7 Hz, 1H), 1.35(d, J = 8.9 Hz, 1H).

Example 23 : Synthesis of Compound 23

step 1: synthesis 5-(2- Chloroethyl )-2,5- Diazaspiro [3.4] Octane -2- tert-butyl carboxylate

2,5-Diazaspiro[3.4]octane-2-carboxylate tert-butyl ester (200.0 mg, 0.94 mmol), cesium carbonate (0.92 g, 2.83 mmol) were dissolved in DMF (3 mL) and added 1-Bromo-2-chloroethane (400.0 mg, 2.83 mmol) was stirred at room temperature overnight and monitored for completion. Add water, extract with dichloromethane, wash the organic phase with water, dry and concentrate, and perform column chromatography to obtain 5-(2-chloroethyl)-2,5-diazaspiro[3.4]octane-2-carboxylic acid third Butyl ester 155mg, yield 60%. MS m/z (ESI): 275.0 [M+H] ⁺ .

step 2: synthesis 5-(2-((3- cyano group -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Geng -3- tertiary butyl ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -6- base ) Oxygen ) Ethyl )-2,5- Diazaspiro [3.4] Octane -2- Methyl Carboxylate

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (100.0 mg, 0.22 mmol), 5-(2-chloroethyl)-2,5-diazaspiro[ 3.4] Octane-2-carboxylate tert-butyl ester (155.0 mg, 0.57 mmol), cesium carbonate (210.0 mg, 0.65 mmol) was dissolved in DMF (3 mL), stirred at 50 °C overnight, and monitored the completion of the reaction. Add water, extract with dichloromethane, wash the organic phase with water, dry and concentrate, and perform column chromatography to obtain 5-(2-((3-cyano-4-(5-(6-((6-methoxypyridine-3 -yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yltert-butyl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-6 -yl)oxy)ethyl)-2,5-diazaspiro[3.4]octane-2-carboxylic acid methyl ester 123 mg, yield 81%. MS m/z (ESI): 693.2 [M+H] ⁺ .

step 3: synthesis 6-(2-(2,5- Diazaspiro [3.4] Octane -5- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

5-(2-((3-cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1 ]hept-3-yltert-butyl)pyrazin-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-2,5-diazaspiro[ 3.4] Methyl octane-2-carboxylate (123.0 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), TFA (0.1 mL) was added, stirred at room temperature for 3 h, and the reaction was monitored for completion. Concentrate the reaction solution, add water, add saturated sodium bicarbonate solution to adjust the pH to neutral or slightly alkaline, extract with dichloromethane, wash the organic phase with water, dry and concentrate, and perform column chromatography to obtain 6-(2-(2,5- Diazaspiro[3.4]octan-5-yl)ethoxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diaza Heterobicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 23 ) 80 mg, yield 76%. MS m/z (ESI): 593.2 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.80 (d, J = 32.2 Hz, 1H), 8.69 (s, 1H), 8.59 (d, J = 5.1 Hz, 1H), 8.28 (s, 1H), 8.14 ( d, J = 23.3 Hz, 1H), 7.69(s, 2H), 6.78(d, J = 7.0 Hz, 1H), 4.26(s, 2H), 3.88(s, 3H), 3.82(d, J = 13.5 Hz, 3H), 3.75 – 3.62(m, 2H), 3.61(d, J = 12.4 Hz, 2H), 3.53(s, 2H), 2.16(d, J = 13.5 Hz, 2H), 1.33(d, J = 8.7 Hz, 1H), 1.25(dd, J = 18.1, 13.5 Hz, 8H), 0.84(d, J = 7.0 Hz, 2H).

Example 24 : Synthesis of Compound 24

step 1: synthesis 3-(2- Chloroethyl )-3- Azaspiro [5.5] Undecane

3-Azaspiro[5.5]undecane (300 mg, 1.96 mmol) and cesium carbonate (1.91 g, 5.87 mmol) were dissolved in DMF (5 mL), and 1-bromo-2-chloroethane was added at room temperature (1.12 g, 7.83 mmol), the reaction was stirred at room temperature overnight, and the reaction was complete. Diluted with ethyl acetate, filtered, added water to quench the reaction, extracted, concentrated under reduced pressure to remove the solvent, column chromatography (PE:EA=3:1) to obtain 3-(2-chloroethyl)-3-azaspiro [5.5]Undecane 192 mg. MS m/z (ESI): 216.1 [M+H] ⁺ .

step 2: synthesis 6-(2-(3- Azaspiro [5.5] Undecane -3- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3 , 6 diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

3-(2-Chloroethyl)-3-azaspiro[5.5]undecane (192 mg, 8.9 mmol), 6-hydroxy-4-(5-(6-((6-methoxypyridine -3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3 - Formonitrile (100 mg, 0.22 mmol) was dissolved in DMF (6 mL), cesium carbonate (215.04 mg, 0.66 mmol) was added, and the reaction was stirred at 50 °C for 3 hours, and the reaction was complete. Diluted with DCM, filtered, concentrated under reduced pressure to remove solvent, column chromatography (DCM:MeOH=20:1) gave 6-(2-(3-azaspiro[5.5]undecan-3-yl)ethane Oxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptan-3-yl)pyrazine -2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 35 mg. MS m/z (ESI): 634.2 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.74 (d, J = 1.9 Hz, 1H), 8.66 (d, J = 1.4 Hz, 1H), 8.60 (s, 1H), 8.28 (d, J = 1.3 Hz, 1H), 8.09(d, J = 2.1 Hz, 1H), 7.69(dd, J = 8.5, 2.4 Hz, 1H), 7.62(d, J = 2.1 Hz, 1H), 6.77(d, J = 8.5 Hz, 1H), 4.23(t, J = 5.4 Hz, 2H), 3.82(s, 4H), 3.82 – 3.77(m, 2H), 3.69(d, J = 5.7 Hz, 2H), 3.62(d, J = 12.2 Hz, 2H), 3.54(s, 2H), 2.78 – 2.68(m, 2H), 2.48 – 2.38(m, 4H), 1.42 – 1.34(m, 10H), 1.32 – 1.26(m, 4H) , 1.24(d, J = 7.2 Hz, 2H), 1.05(t, J = 7.0 Hz, 1H).

Example 25 : Synthesis of Compound 25

step 1: synthesis 8-(2- Chloroethyl )-1- oxa -8- Azaspiro [4.5] Decane

1-oxa-8-azaspiro[4.5]decane (300 mg, 1.69 mmol) and cesium carbonate (1.65 g, 5.07 mmol) were dissolved in DMF (5 mL), and 1-bromo-2 was added at room temperature -Chloroethane (968.01 mg, 6.75 mmol), the reaction was stirred at room temperature overnight, and the reaction was complete. Diluted with ethyl acetate, filtered, quenched the reaction by adding water, extracted, concentrated under reduced pressure to remove the solvent, column chromatography (PE:EA=3:1) to obtain 8-(2-chloroethyl)-1-oxa -8-Azaspiro[4.5]decane 150 mg. MS m/z (ESI): 204.1 [M+H] ⁺ .

step 2: synthesis 6-(2-(1- oxa -8- Azaspiro [4.5] Gui -8- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

8-(2-Chloroethyl)-1-oxa-8-azaspiro[4.5]decane (150 mg, 0.73 mmol), 6-hydroxy-4-(5-(6-((6- Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a ] Pyridine-3-carbonitrile (100 mg, 0.22 mmol) was dissolved in DMF (6 mL), cesium carbonate (215.04 mg, 0.66 mmol) was added, and the reaction was stirred at 50 °C for 3 hours, and the reaction was complete. Diluted with DCM, filtered, concentrated under reduced pressure to remove the solvent, column chromatography (DCM:MeOH=20:1) gave 6-(2-(3-azaspiro[5.5]undecan-3-yl)ethoxy yl)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptan-3-yl)pyrazine- 2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 25 ) 45 mg. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.74 (d, J = 1.9 Hz, 1H), 8.66 (d, J = 1.4 Hz, 1H), 8.60 (s, 1H), 8.28 (d, J = 1.3 Hz, 1H), 8.09(d, J = 2.1 Hz, 1H), 7.69(dd, J = 8.5, 2.4 Hz, 1H), 7.62(d, J = 2.1 Hz, 1H), 6.77(d, J = 8.5 Hz, 1H), 4.23(t, J = 5.4 Hz, 2H), 3.82(s, 4H), 3.82 – 3.77(m, 2H), 3.69(d, J = 5.7 Hz, 2H), 3.62(d, J = 12.2 Hz, 2H), 3.54(s, 2H), 2.78 – 2.68(m, 2H), 2.48 – 2.38(m, 4H), 1.42 – 1.34(m, 10H), 1.32 – 1.26(m, 4H) , 1.24(d, J = 7.2 Hz, 2H), 1.05(t, J = 7.0 Hz, 1H). MS m/z(ESI): 622.1 [M+H] ⁺ .

Example 26 : Synthesis of Compound 26

step 1: synthesis 3- cyano group -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine ) Pyrazolo [1,5-a] Pyridine -6- base 4- Methylpiperazine -1- Carboxylate

At 0 °C, under nitrogen protection, 6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]Heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.22 mmol) was dissolved in THF (10 mL) and added DIPEA (113.8 mg, 0.88 mmol) was slowly added with triphosgene (65.3 mg, 0.22 mmol), and after stirring the reaction for 2 hours, N-methylpiperazine (66.1 mg, 0.66 mmol) was added dropwise to the reaction system and continued stirring overnight, The reaction is complete. Quenched with saturated sodium bicarbonate, extracted with EA (2 * 10 mL), combined the organic phases, washed with saturated brine (20 mL), concentrated under reduced pressure to remove the solvent, column chromatography (DCM:MeOH=10:1), to obtain 3 -Cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine oxazine)pyrazolo[1,5-a]pyridin-6-yl 4-methylpiperazine-1-carboxylate ( compound 26 ) 65 mg. MS m/z (ESI): 581.1 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.10 (d, J = 1.9 Hz, 1H), 8.74 (s, 1H), 8.66 (d, J = 1.4 Hz, 1H), 8.32 (d, J = 1H) 1.3 Hz, 1H), 8.10(s, 1H), 7.83(d, J = 1.9 Hz, 1H), 7.70(dd, J = 8.5, 2.3 Hz, 1H), 6.78(d, J = 8.5 Hz, 1H) , 3.83(s, 4H), 3.80(s, 2H), 3.74 – 3.43(m, 11H), 2.41(d, J = 17.1 Hz, 4H), 2.25(s, 3H).

Example 27 : Synthesis of Compound 27

step 1: synthesis 3- cyano group -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ] Pyrazolo [1,5-a] Pyridine -6- morpholine -4- Carboxylate

At 0 °C, under nitrogen protection, 6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]Heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.22 mmol) was dissolved in THF (10 mL) and added DIPEA (113.8 mg, 0.88 mmol), triphosgene (65.3 mg, 0.22 mmol) was slowly added, and after stirring the reaction for 2 hours, morpholine (57.6 mg, 0.66 mmol) was added dropwise to the reaction system and stirring was continued overnight, and the reaction was completed. Quenched with saturated sodium bicarbonate, extracted with EA (2*10 mL), combined the organic phases, washed with saturated brine (20 mL), concentrated under reduced pressure to remove the solvent, column chromatography (DCM:MeOH=10:1), to obtain 3 -Cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine Azin-2yl]pyrazolo[1,5-a]pyridin-6-ylmorpholine-4-carboxylate ( Compound 27 ) 36 mg. MS m/z (ESI): 721 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.10 (d, J = 1.9 Hz, 1H), 8.73 (s, 1H), 8.65 (d, J = 1.3 Hz, 1H), 8.31 (d, J = 1H) 1.3 Hz, 1H), 8.09(d, J = 1.9 Hz, 1H), 7.84(d, J = 1.9 Hz, 1H), 7.69(dd, J = 8.5, 2.4 Hz, 1H), 6.77(d, J = 8.5 Hz, 1H), 3.81(d, J = 12.0 Hz, 5H), 3.74 – 3.59(m, 11H), 3.54(s, 2H), 3.46(s, 2H), 2.55(d, J = 6.7 Hz, 1H), 1.62 (d, J = 8.5 Hz, 1H). MS m/z (ESI): 568.3 [M+H] ⁺ .

Example 28 : Synthesis of Compound 28

step 1: synthesis 4- Methoxy -6-(( Pyridine -2- methyl group ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

Compound 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (1.0 g, 3.96 mmol), pyridin-2-ylmethanamine (643.4 mg, 5.95 mmol) , CuI (75.4 mg, 0.396 mmol), L-proline (91.3 mg, 0.793 mmol) and K ₃ PO ₄ (1.68 mg, 7.93 mmol), dissolved in DMSO (8 mL), then switched to nitrogen protection, the The reaction solution was stirred at 90 °C overnight. After the reaction was complete, washed with saturated brine (10 mL), the organic phase was concentrated, and purified by column chromatography (PE:EA=3:1) to obtain 4-methoxy-6- ((Pyridin-2-ylmethyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile 300 mg. MS m/z (ESI): 280.1 [M+H] ⁺ .

step 2: synthesis 4- hydroxyl -6-(( Pyridine -2- methyl group ) Amine ) Pyrazolo [1,5-a] Pyridine -3- formonitrile

4-Methoxy-6-((pyridin-2-ylmethyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.2 g, 0.71 mmol) was dissolved in DMF (4 mL), then add n-dodecanethiol (0.34 mL), heat the reaction to 45 °C, slowly add NaOH aqueous solution 12N (0.13 mL) and warm up to 50 °C The reaction solution is stirred overnight under nitrogen protection, after the reaction is complete, add water (10 mL) diluted, adjusted to pH 5-6 with 50% citric acid aqueous solution, EA (2*10 mL), combined with the organic phases and washed with saturated brine (20 mL), concentrated and purified by ISCO column chromatography (DCM/MeOH=10: 1) to obtain 100 mg of 4-hydroxy-6-((pyridin-2-ylmethyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile. MS m/z (ESI): 266.2 [M+H] ⁺ .

step 3: synthesis 3- cyano group -6-(( Pyridine -2- methyl group ) Amine ) Pyrazolo [1,5-a] Pyridine -4- triflate

4-Hydroxy-6-((pyridin-2-ylmethyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.38 mmol) was dissolved in DMA (10 mL) , DIPEA (0.13 mL, 0.76 mmol) was added, N-phenylbis(trifluoromethanesulfonyl)imide (161.7 mg, 0.45 mmol) was slowly added to the reaction solution, and the reaction was stirred at room temperature for 2 h, monitored by LCMS After the completion of the reaction, the reaction was quenched with water (10 mL), extracted with EA (10 mL*3), the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 3-cyano-6-((pyridin-2-ylmethyl) yl)amino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate 88 mg. MS m/z (ESI): 398.2 [M+H] ⁺ .

step 4: synthesis 4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base )-6-(( Pyridine -2- methyl group ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

The compound 3-cyano-6-((pyridin-2-ylmethyl)amino)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonic acid was prepared under nitrogen protection at 0°C Ester (88 mg, 0.22 mmol), 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(tributylstannyl)pyrazin-2-yl)-3,6 - Diazabicyclo[3.1.1]heptane (195.2 mg, 0.33 mmol), Pd(Ph ₃ P) ₄ (25.4 mg, 0.022 mmol) and CuI (4.2 mg, 0.022 mmol), dissolved in 1,4- In xylene (10 mL), the reaction system was stirred evenly, and the temperature was slowly raised to 140 °C, and the reaction was continued to stir overnight. After the reaction was completed as monitored by LCMS, the reaction was quenched with saturated aqueous NaHCO ₃ (10 mL), EA (10 mL*3) Extraction, the organic phase was washed with saturated NaCl water, dried and concentrated, and purified by column chromatography in DCM/MeOH (10:1) to obtain (4-(5-(6-((6-methoxypyridin-3-yl)methyl)) -3,6-Diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)-6-((pyridin-2-ylmethyl)amino)pyrazolo[1, 5-a]pyridine-3-carbonitrile ( Compound 28 ) 32 mg.

1H NMR (400 MHz, DMSO-d6) δ 8.57(d, J = 4.1 Hz, 1H), 8.53(d, J = 1.3 Hz, 1H), 8.39(s, 1H), 8.29(d, J = 1.2 Hz , 1H), 8.10 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.70 (dd, J = 8.4, 2.1 Hz, 1H) , 7.48 (t, J = 4.6 Hz, 2H), 7.30 (dd, J = 6.7, 5.0 Hz, 1H), 6.75 (dd, J = 16.2, 7.3 Hz, 2H), 5.43 – 5.40 (m, 1H), 4.46(d, J = 6.0 Hz, 2H), 3.82(s, 4H), 3.79(s, 2H), 3.74 – 3.48(m, 7H), 2.55(s, 1H), 1.62(d, J = 8.4 Hz , 1H). MS m/z (ESI): 545.3 [M+H] ⁺ .

Example 29 : Synthesis of Compound 29

step 1: synthesis 6- bromine -4-( benzyloxy )- Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (1.0 g, 0.71 mmol) was dissolved in DMF (4 mL) followed by the addition of n-dodecylsulfide alcohol (1.5 mL), heated and reacted to 45 °C, slowly added NaOH aqueous solution 12 N (0.6 mL) and warmed to 50 °C. The reaction solution was stirred overnight under nitrogen protection. After the reaction was complete, add water (10 mL) to dilute, 50% citric acid aqueous solution Adjust the pH to 5-6, EA (2*10 mL), combine the organic phases, wash with saturated brine (20 mL), and concentrate to obtain the product 6-bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3 -0.8 g of formonitrile was directly put into the next reaction. The product was dissolved in (10 mL) DMA solvent, benzyl bromide (1.2 g, 0.67 mmol) and Cs ₂ CO ₃ (3.28 g, 10.08 mmol) were added, heated and stirred overnight, after the reaction was completed, washed with saturated brine (30 mL) , the organic phase was concentrated, and purified by ISCO column chromatography (PE:EA=1:2) to obtain 6-bromo-4-(benzyloxy)-pyrazolo[1,5-a]pyridine-3-carbonitrile 1.0 g. MS m/z (ESI): 328.1 [M+H] ⁺ .

step 2: synthesis 4-( benzyloxy )-6-( Ethylamino ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

Ethylamine hydrochloride (0.92 g, 9.14 mmol) was dissolved in (30 mL) DMSO solvent in advance, K ₂ CO ₃ (0.92 g, 9.14 mmol) was added to neutralize the hydrochloric acid in the system, the reaction was stirred for 2 h and then allowed to stand. The supernatant was collected by centrifugation. In a 100 mL high pressure reaction flask, compound 6-bromo-4-(benzyloxy)-pyrazolo[1,5-a]pyridine-3-carbonitrile (1.0 g, 3.07 mmol), CuI (16.2 mg, 0.61 mmol), L _- proline (141.6 mg, 1.23 mmol) and _K3PO4 (1.3 g, 6.14 mmol), dissolved in ethylamine in DMSO (30 mL), then switched to nitrogen protection, sealed, the reaction The solution was stirred at 90 °C overnight. After the reaction was completed, washed with saturated brine (30 mL), the organic phase was concentrated, and purified by column chromatography (PE:EA=3:1) to obtain 4-(benzyloxy)-6-( (Pyridin-2-ylmethyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile 0.68 g. MS m/z (ESI): 293.2 [M+H] ⁺ .

step 3: synthesis 6-( Ethylamino )-4- Hydroxypyrazolo [1,5-a] Pyridine -3- Formonitrile

4-(Benzyloxy)-6-((pyridin-2-ylmethyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.6 g, 2.05 mmol) was dissolved in HBr (20 mL), slowly heat up to 80 °C and reflux for 2 h. After the reaction is complete, add water (10 mL) to dilute, adjust the pH to 4-5 with 4 N NaOH aqueous solution, EA (2*10 mL), combine the organic phase saturated salt Washed with water (20 mL), concentrated and purified by ISCO column chromatography (DCM/MeOH = 10:1) to obtain 6-(ethylamino)-4-hydroxypyrazolo[1,5-a]pyridine-3- Formonitrile 0.26 g. MS m/z (ESI): 203.5 [M+H] ⁺ .

step 4: 3- cyano group -6-( Ethylamino ) Pyrazolo [1,5-a] Pyridine -4- triflate

6-(Ethylamino)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (160 mg, 0.79 mmol) was dissolved in DMA (10 mL) and DIPEA (0.27 mL) was added , 1.58 mmol), PhNTf ₂ (340 mg, 0.95 mmol) was slowly added to the reaction solution, and then the reaction was stirred at room temperature for 2 h. After the completion of the reaction was monitored by LCMS, the reaction was quenched with water (10 mL), EA (10 mL* 3) Extraction, washing the organic phase with water, drying and concentration, and column chromatography to obtain 3-cyano-6-(ethylamino)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonic acid Ester 270 mg. MS m/z (ESI): 335.2 [M+H] ⁺ .

step 5: synthesis 6-( Ethylamino )-4-(5-(-6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

The compound 3-cyano-6-(ethylamino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (100 mg, 0.30 mmol) was prepared at 0 °C under nitrogen protection. ), 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(tributylstannyl)pyrazin-2-yl)-3,6-diazabicyclo[3.1 .1] Heptane (263.6 mg, 0.45 mmol), Pd(Ph3P _{)4 (} 34.65 mg, 0.03 mmol) and CuI (5.7 mg, 0.03 mmol), dissolved in 1,4-xylene (10 mL) , the reaction system was stirred evenly, slowly heated to 140 ºC, and continued to stir overnight. After the reaction was completed as monitored by LCMS, the reaction was quenched with saturated NaHCO ₃ aqueous solution (10 mL), extracted with EA (10 mL*3), and the organic phase was washed with saturated NaCl water. , dried and concentrated, and purified by column chromatography with DCM/MeOH (10:1) to give 6-(ethylamino)-4-(5-(6-((6-methoxypyridin-3-yl)methyl) ( Compound 29 ) 34 mg. MS m/z (ESI): 482.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (d, J = 1.3 Hz, 1H), 8.40 (s, 1H), 8.28 (d, J = 1.2 Hz, 1H), 8.10 (s, 1H) , 7.97(d, J = 1.8 Hz, 1H), 7.69(d, J = 8.5 Hz, 1H), 7.32(d, J = 1.9 Hz, 1H), 6.76(d, J = 8.4 Hz, 1H), 5.95 (t, J = 5.3 Hz, 1H), 3.81(s, 1H), 3.80(d, J = 8.1 Hz, 1H), 3.74 – 3.47(m, 2H), 3.13 – 2.99(m, 1H), 1.21( t, J = 7.1 Hz, 1H).

Example 30 : Synthesis of Compound 30

step 1: synthesis 7-(2- Chloroethyl )-2- oxa -7- Azaspiro [3.5] Nonane

2-oxa-7-azaspiro[3.5]nonane (0.2 g, 1.57 mmol), cesium carbonate (1.54 g, 4.72 mmol) were added to DMF (5 mL) followed by 1-bromo-2- Ethyl chloride (0.68 g, 4.72 mmol) was stirred at room temperature overnight and monitored for completion. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 7-(2-chloroethyl)-2-oxa-7-azaspiro[3.5]nonane 150 mg . MS m/z (ESI): 190.1 [M+H] ⁺ .

step 2: synthesis 6-(2-(2- oxa -7- Azaspiro [3.5] Ren -7- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.1 g, 0.22 mmol), 7-(2-chloroethyl)-2-oxa-7-aza Spiro[3.5]nonane (84 mg, 0.44 mmol), cesium carbonate (0.15 g, 0.44 mmol) were dissolved in DMA (5 mL) and stirred at 50 °C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(2-oxa-7-azaspiro[3.5]non-7-yl)ethoxy )-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazine- 2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 30 ) 50 mg. MS m/z (ESI): 608.3 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.83 (s, 1H), 8.58 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.67 (dd, J = 8.4 , 1.8 Hz, 1H), 7.31(s, 1H), 6.93(d, J = 8.9 Hz, 1H), 6.80(d, J = 8.4 Hz, 1H), 4.23(d, J = 62.7 Hz, 2H), 3.84(s, 3H), 3.66 – 3.42(m, 13H), 2.27(s, 4H), 1.62 – 1.33(m, 7H).

Example 31 : Synthesis of Compound 31

step 1: synthesis 8-(2- Chloroethyl )-3- oxa -8- azabicyclo [3.2.1] Octane

3-oxa-8-azabicyclo[3.2.1]octane (0.3 g, 2.65 mmol), cesium carbonate (1.72 g, 5.30 mmol) were added to DMF (5 mL) followed by 1-bromo- 2-Chloroethane (0.76 g, 5.30 mmol) was stirred at room temperature overnight and monitored for completion. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 8-(2-chloroethyl)-3-oxa-8-azabicyclo[3.2.1]octane 120 mg. MS m/z (ESI): 176.1 [M+H] ⁺ .

step 2: synthesis 6-(2-(3- oxa -8- azabicyclo [3.2.1] pungent -8- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3 , 6 diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.1 g, 0.22 mmol), 8-(2-chloroethyl)-3-oxa-8-aza Bicyclo[3.2.1]octane (78 mg, 0.44 mmol), cesium carbonate (0.15 g, 0.44 mmol) were dissolved in DMA (5 mL) and stirred at 50 °C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)ethane Oxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptan-3-yl)pyrazine -2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 31 ) 60 mg. MS m/z (ESI): 594.3 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.75 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 1.0 Hz, 1H), 8.61 (s, 1H), 8.30 (s, 1H), 8.10 ( s, 1H), 7.70(d, J = 6.4 Hz, 1H), 7.63(d, J = 2.0 Hz, 1H), 6.78(d, J = 8.5 Hz, 1H), 4.23(s, 2H), 3.81( d, J = 14.3 Hz, 5H), 3.74 – 3.49(m, 8H), 3.42(d, J = 10.0 Hz, 2H), 3.19(s, 2H), 2.68(s, 2H), 2.55(s, 1H) ), 1.88(s, 2H), 1.75(d, J = 7.1 Hz, 2H), 1.63(d, J = 8.5 Hz, 1H).

Example 32 : Synthesis of Compound 32

step 1: synthesis 7-(2- Chloroethyl )-1,7- Diazaspiro [3.5] Ren -2- ketone

1,7-Diazaspiro[3.5]nonan-2-one (0.3 g, 2.12 mmol), cesium carbonate (2.09 g, 6.43 mmol) were added to DMF (5 mL) followed by 1-bromo-2 -Chloroethane (0.91 g, 6.43 mmol), stirred at room temperature overnight, monitoring the completion of the reaction. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 7-(2-chloroethyl)-1,7-diazaspiro[3.5]nonan-2-one 150 mg. MS m/z (ESI): 203.12 [M+H] ⁺ .

step 2: synthesis 4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base )-6-(2-(2- oxo -1,7- Diazaspiro [3.5] Ren -7- base ) Ethoxy ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.15 g, 0.33 mmol), 7-(2-chloroethyl)-1,7-diazaspiro[ 3.5] Nonan-2-one (134 mg, 0.66 mmol), cesium carbonate (0.22 g, 0.66 mmol) were dissolved in DMA (5 mL), stirred at 50 °C overnight, and monitored for completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6 - Diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)-6-(2-(2-oxo-1,7-diazaspiro[3.5]nonan-7 -yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 40 mg. MS m/z (ESI): 621.3 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.74(d, J = 2.1 Hz, 1H), 8.67(d, J = 1.4 Hz, 1H), 8.61(s, 1H), 8.29(d, J = 1.3 Hz, 1H), 8.21(s, 1H), 8.10(d, J = 2.1 Hz, 1H), 7.70(dd, J = 8.5, 2.4 Hz, 1H), 7.62(d, J = 2.1 Hz, 1H), 6.77( d, J = 8.5 Hz, 1H), 4.25 (t, J = 5.6 Hz, 2H), 3.84 – 3.75 (m, 5H), 3.62 (dt, J = 49.8, 10.5 Hz, 7H), 2.77 (t, J = 5.4 Hz, 2H), 2.60(dd, J = 33.9, 6.2 Hz, 4H), 2.42(s, 2H), 1.67(dd, J = 19.3, 11.5 Hz, 4H), 1.47(s, 1H).

Example 33 : Synthesis of Compound 33

step 1: synthesis 2-(2- Chloroethyl )-6- oxa -2- Azaspiro [3.5] Nonane

6-oxa-2-azaspiro[3.5]nonane (0.3 g, 2.36 mmol), cesium carbonate (1.53 g, 4.72 mmol) were added to DMF (5 mL) followed by 1-bromo-2- Ethyl chloride (0.68 g, 4.72 mmol) was stirred at room temperature overnight and monitored for completion. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 120 mg of 2-(2-chloroethyl)-6-oxa-2-azaspiro[3.5]nonane . MS m/z (ESI): 190.2 [M+H] ⁺ .

step 2: synthesis 6-(2-(6- oxa -2- Azaspiro [3.5] Ren -2- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.1 g, 0.22 mmol), 2-(2-chloroethyl)-6-oxa-2-aza Spiro[3.5]nonane (84 mg, 0.44 mmol), cesium carbonate (0.15 g, 0.44 mmol) were dissolved in DMA (5 mL) and stirred at 50 °C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(6-oxa-2-azaspiro[3.5]non-2-yl)ethoxy )-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazine- 2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 33 ) 50 mg. MS m/z (ESI): 608.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.83 (s, 1H), 8.58 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.67 (dd, J = 8.4 , 1.8 Hz, 1H), 7.31(s, 1H), 6.93(d, J = 8.9 Hz, 1H), 6.80(d, J = 8.4 Hz, 1H), 4.23(d, J = 62.7 Hz, 2H), 3.84 (s, 3H), 3.66 – 3.42 (m, 11H), 2.27 (s, 6H), 1.62 – 1.33 (m, 7H).

Example 34 : Synthesis of Compound 34

step 1: synthesis 2-(2- Chloroethyl )-5- oxa -2- Azaspiro [3.4] Octane

5-oxa-2-azaspiro[3.4]octane (0.3 g, 2.65 mmol), cesium carbonate (1.72 g, 5.30 mmol) were added to DMF (5 mL) followed by 1-bromo-2- Ethyl chloride (0.76 g, 5.30 mmol) was stirred at room temperature overnight and monitored for completion. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 130 mg of 2-(2-chloroethyl)-5-oxa-2-azaspiro[3.4]octane . MS m/z (ESI): 176.5 [M+H] ⁺ .

step 2: synthesis 6-(2-(5- oxa -2- Azaspiro [3.4] pungent -2- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.1 g, 0.22 mmol), 2-(2-chloroethyl)-5-oxa-2-aza Spiro[3.4]octane (78 mg, 0.44 mmol), cesium carbonate (0.15 g, 0.44 mmol) were dissolved in DMA (5 mL) and stirred at 50°C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(5-oxa-2-azaspiro[3.4]oct-2-yl)ethoxy )-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazine- 2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 34 ) 50 mg. MS m/z (ESI): 594.3 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.71(d, J = 1.9 Hz, 1H), 8.67(d, J = 1.3 Hz, 1H), 8.61(s, 1H), 8.30(d, J = 1.2 Hz, 1H), 8.10(s, 1H), 7.70(d, J = 7.1 Hz, 1H), 7.61(d, J = 2.0 Hz, 1H), 6.78(d, J = 8.5 Hz, 1H), 4.15(s, 2H), 3.82(d, J = 12.8 Hz, 5H), 3.74 – 3.42(m, 11H), 3.23(s, 2H), 2.94(s, 2H), 2.56(s, 1H), 2.02(t, J = 7.2 Hz, 2H), 1.86 – 1.77(m, 2H).

Example 35 : Synthesis of Compound 35

step 1: synthesis 9-(2- Chloroethyl )-2,9- Diazaspiro [5.5] Undecane -1- ketone

2,9-Diazaspiro[5.5]undecan-1-one (0.4 g, 2.17 mmol), cesium carbonate (2.12 g, 6.51 mmol) were added to DMF (10 mL) followed by 1-bromo -2-Chloroethane (0.94 g, 6.51 mmol) was stirred at room temperature overnight and monitored for completion. Add water to quench the reaction, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 9-(2-chloroethyl)-2,9-diazaspiro[5.5]undecane-1- Ketones 160 mg. MS m/z (ESI): 247.3 [M+H] ⁺ .

step 2: synthesis 4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base )-6-(2-(-1- oxo -2,9- Diazaspiro [5.5] Undecane -9- base ) Ethoxy ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.15 g, 0.33 mmol), 9-(2-chloroethyl)-2,9-diazaspiro[ 5.5] Undecan-1-one (163 mg, 0.66 mmol), cesium carbonate (0.22 g, 0.66 mmol) were dissolved in DMA (5 mL) and stirred at 50°C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6 - Diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)-6-(2-(-1-oxo-2,9-diazaspiro[5.5]undecene Alk-9-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 40 mg. MS m/z (ESI): 649.6 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.77(d, J = 2.1 Hz, 1H), 8.67(d, J = 1.4 Hz, 1H), 8.62(s, 1H), 8.29(d, J = 1.3 Hz, 1H), 8.21(s, 1H), 8.00(d, J = 2.1 Hz, 1H), 7.70(dd, J = 8.5, 2.4 Hz, 1H), 7.62(d, J = 2.1 Hz, 1H), 6.77( d, J = 8.5 Hz, 1H), 4.25 (t, J = 5.6 Hz, 2H), 3.84 – 3.75 (m, 5H), 3.62 (dt, J = 49.8, 10.5 Hz, 7H), 2.77 (t, J = 5.4 Hz, 4H), 2.60(dd, J = 33.9, 6.2 Hz, 6H), 2.42(s, 2H), 1.67(dd, J = 19.3, 11.5 Hz, 4H), 1.57(s, 1H).

Example 36 : Synthesis of Compound 36

step 1: synthesis 6-(2- Chloroethyl )-2- oxa -6- Azaspiro [3.3] Heptane

2-oxa-6-azaspiro[3.3]heptane (0.3 g, 3.03 mmol), cesium carbonate (2.96 g, 9.09 mmol) were added to DMF (5 mL) followed by 1-bromo-2- Ethyl chloride (1.3 g, 9.09 mmol) was stirred at room temperature overnight and monitored for completion. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 180 mg of 6-(2-chloroethyl)-2-oxa-6-azaspiro[3.3]heptane. MS m/z (ESI): 162.3 [M+H] ⁺ .

step 2: synthesis 6-(2-(2- oxa -6- Azaspiro [3.3] Geng -6- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.1 g, 0.22 mmol), 6-(2-chloroethyl)-2-oxa-6-aza Spiro[3.3]heptane (74 mg, 0.44 mmol), cesium carbonate (0.15 g, 0.44 mmol) were dissolved in DMA (5 mL) and stirred at 50 °C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethoxy )-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazine- 2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 36 ) 60 mg. MS m/z (ESI): 580.5 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.66 (dd, J = 7.0, 1.7 Hz, 2H), 8.59 (s, 1H), 8.28 (d, J = 1.3 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.68(dd, J = 8.5, 2.4 Hz, 1H), 7.58(d, J = 2.1 Hz, 1H), 6.76(d, J = 8.5 Hz, 1H), 4.59(s, 4H), 4.05(t, J = 5.2 Hz, 2H), 3.79(d, J = 10.8 Hz, 5H), 3.71 – 3.48(m, 7H), 3.37(s, 5H), 2.73(t, J = 4.9 Hz, 2H ).

Example 37 : Synthesis of Compound 37

step 1: synthesis 9-(2- Chloroethyl )-3- oxa -9- Azaspiro [5.5] Undecane

3-oxa-9-azaspiro[5.5]undecane (0.3 g, 1.93 mmol), cesium carbonate (1.88 g, 5.80 mmol) were added to DMF (5 mL) followed by 1-bromo-2 -Chloroethane (0.83 g, 5.80 mmol), stirred at room temperature overnight, monitoring the completion of the reaction. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 180 mg of 9-(2-chloroethyl)-3-oxa-9-azaspiro[5.5]undecane . MS m/z (ESI): 218.5 [M+H] ⁺ .

step 2: synthesis 6-(2-(3- oxa -9- Azaspiro [5.5] 11 carbon -9- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.1 g, 0.22 mmol), 9-(2-chloroethyl)-3-oxa-9-aza Spiro[5.5]undecane (97 mg, 0.44 mmol), cesium carbonate (0.15 g, 0.44 mmol) were dissolved in DMA (5 mL) and stirred at 50 °C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(3-oxa-9-azaspiro[5.5]undec-9-yl)ethane Oxy)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine Azin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 37 ) 50 mg. MS m/z (ESI): 636.4 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.73 (s, 1H), 8.58 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 8.8, 2.5 Hz, 1H), 7.67(dd, J = 8.4, 1.8 Hz, 1H), 7.31(s, 1H), 6.93(d, J = 8.9 Hz, 1H), 6.80(d, J = 8.4 Hz, 1H), 4.23(d, J = 62.7 Hz, 2H), 3.84(s, 3H), 3.66 – 3.42(m, 13H), 2.47(s, 4H), 1.62 – 1.33(m, 11H).

Example 38 : Synthesis of Compound 38

step 1: synthesis 2-(2- Chloroethyl )-2- azabicyclo [2.2.1] Heptane

2-Azabicyclo[2.2.1]heptane (0.2 g, 2.06 mmol), cesium carbonate (2.01 g, 6.18 mmol) were added to DMF (5 mL) followed by 1-bromo-2-chloroethane (0.88 g, 6.18 mmol), stirred overnight at room temperature and monitored for completion. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 100 mg of 2-(2-chloroethyl)-2-azabicyclo[2.2.1]heptane. MS m/z (ESI): 160.7 [M+H] ⁺ .

step 2: synthesis 6-(2-(2- azabicyclo [2.2.1] Geng -2- base ) Ethoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.1 g, 0.22 mmol), 2-(2-chloroethyl)-2-azabicyclo[2.2.1 ] Heptane (71 mg, 0.44 mmol), cesium carbonate (0.15 g, 0.44 mmol) were dissolved in DMA (5 mL) and stirred at 50 °C overnight, monitoring the completion of the reaction. Quench by adding water, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-(2-azabicyclo[2.2.1]hept-2-yl)ethoxy)-4 -(5-(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl )pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 38 ) 45 mg. MS m/z (ESI): 578.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.69 – 8.60 (m, 2H), 8.29 (d, J = 1.2 Hz, 1H), 8.08 (s, 1H), 7.67 (t, J = 5.1 Hz, 2H), 6.76(d, J = 8.5 Hz, 1H), 5.75(s, 1H), 4.44(s, 2H), 3.79(d, J = 8.8 Hz, 5H), 3.61(dd, J = 28.5, 15.9 Hz, 7H), 2.53(s, 2H), 2.02 – 1.79(m, 2H), 1.68 – 1.21(m, 7H), 0.91 – 0.74(m, 2H).

Example 39 : Synthesis of Compound 39

step 1: synthesis 2- cyano group -2- methylpropyl 4- Methylbenzenesulfonate

3-Hydroxy-2,2-dimethylpropionitrile (1.0 g, 10.1 mmol) and triethylamine (1.53 g, 15.2 mmol) were added to DCM (10 mL), the reaction solution was cooled to 0 °C, and then Then p-toluenesulfonyl chloride (1.92 g, 10.1 mmol) was slowly added, the reaction solution was stirred at room temperature for 2 hours, water was added to quench the reaction, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 2-cyano-2-methylpropyl 4-methylbenzenesulfonate 1.5 g.

step 2: synthesis 6-(2- cyano group -2- Methylpropoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine pyridine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.15 g, 0.33 mmol), 2-cyano-2-methylpropyl 4-methylbenzenesulfonate (170 mg, 0.66 mmol), cesium carbonate (0.22 g, 0.66 mmol) was dissolved in DMF (5 mL) and stirred at 80°C overnight, monitoring the completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain 6-(2-cyano-2-methylpropoxy)-4-(5-(6-((6 -Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazinpyridin-2-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile ( compound 39 ) 60 mg. MS m/z (ESI): 536.1 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.79(d, J = 2.1 Hz, 1H), 8.68(d, J = 1.4 Hz, 1H), 8.62(s, 1H), 8.28(d, J = 1.4 Hz, 1H), 8.08(s, 1H), 7.68(dd, J = 7.4, 2.2 Hz, 2H), 6.75(d, J = 8.5 Hz, 1H), 4.20(s, 2H), 3.79(d, J = 11.5 Hz, 5H), 3.71 – 3.49 (m, 7H), 2.53 (s, 1H), 1.44 (s, 6H).

Example 40 : Synthesis of Compound 40

step 1: synthesis 3-(( Tosyloxy ) methyl )-8- azabicyclo [3.2.1] Octane -8- tert-butyl carboxylate

(1R,5S)-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.5 g, 2.07 mmol), triethylamine (0.32 g , 3.11 mmol) was added to DCM (10 mL), the reaction solution was cooled to 0 °C, then p-toluenesulfonyl chloride (0.4 g, 2.07 mmol) was slowly added, the reaction solution was stirred at room temperature for 2 hours, and water was added. The reaction was quenched, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 3-((toluenesulfonyloxy)methyl)-8-azabicyclo[3.2.1]octane-8 - tert-butyl carboxylate 0.6 g.

step 2: synthesis tertiary butyl 3-(((3- cyano group -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1]] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -6- base ) Oxygen ) methyl )-8- azabicyclo [3.2.1] Octane -8- tert-butyl formate

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.15 g, 0.33 mmol), (1R,5S)-3-((toluenesulfonyloxy)methyl) -8-Azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (182 mg, 0.66 mmol), cesium carbonate (0.22 g, 0.66 mmol) were dissolved in DMF (8 mL) at 80°C It was stirred overnight and monitored for completion of the reaction. Add water to quench, extract with dichloromethane, wash the organic phase with water, dry and concentrate, column chromatography to obtain tert-butyl 3-(((3-cyano-4-(5-(6-((6-methoxy pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine -6-yl)oxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 110 mg. MS m/z (ESI): 678.4 [M+H] ⁺ .

step 3 :synthesis 6-(((8- azabicyclo [3.2.1] pungent -3- base ) Methoxy )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3 , 6 diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

The tert-butyl 3-(((3-cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]]Heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-8-azabicyclo[3.2.1 ] 3-butyl octane-8-carboxylate (0.11 g, 0.16 mmol) was dissolved in DCM (5 mL), then cooled to 0 °C, and dioxane hydrochloric acid solution (2 mL, 4 mol/L) was added to it , the reaction was carried out at room temperature for 2 hours, and the complete reaction was monitored. The reaction solution was spin-dried, then a small amount of water was added, extracted with dichloromethane, the organic phase was washed with water, dried and concentrated, and subjected to column chromatography to obtain 6-((8-azabicyclo[3.2.1]oct-3-yl)methoxy yl)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptan-3-yl)pyrazine- 2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 40 mg, MS m/z (ESI): 578.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.77(d, J = 2.0 Hz, 1H), 8.65(d, J = 1.2 Hz, 1H), 8.59(s, 1H), 8.27(d, J = 1.1 Hz, 1H), 8.08(d, J = 2.1 Hz, 1H), 7.68(dd, J = 8.5, 2.4 Hz, 1H), 7.59(d, J = 2.0 Hz, 1H), 6.75(d, J = 8.5 Hz, 1H), 4.06(d, J = 7.9 Hz, 2H), 3.79(d, J = 11.4 Hz, 5H), 3.71 – 3.48(m, 7H), 3.44(s, 4H), 2.22(dd, J = 15.8 , 7.9 Hz, 1H), 2.03 – 1.89 (m, 2H), 1.69 (s, 3H), 1.56 (dd, J = 24.8, 11.3 Hz, 3H).

Example 41 : Synthesis of Compound 41

step 1: synthesis 3- cyano group -4-(5-(6- ((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1 , 5-a] Pyridine -6- isopropyl carbamate

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.1 g, 0.22 mmol), triethylamine (0.067 g, 0.66 mmol) were dissolved in DCM (5 mL), The mixture was cooled to 0 °C, and then isopropyl isocyanate (0.057 g, 0.66 mmol) was added to react for 1 hour, quenched by adding water, extracted with dichloromethane, washed with water in the organic phase, dried and concentrated, and subjected to column chromatography to obtain 3-cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridin-6-yl isopropylcarbamate ( compound 41 ) 45 mg. MS m/z (ESI): 540.7 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 9.04(d, J = 1.8 Hz, 1H), 8.71(s, 1H), 8.66(d, J = 1.1 Hz, 1H), 8.31(d, J = 1.2 Hz, 1H), 8.10(d, J = 1.9 Hz, 1H), 7.99(d, J = 7.7 Hz, 1H), 7.75 – 7.65(m, 2H), 6.76(d, J = 8.5 Hz, 1H), 3.81( d, J = 12.0 Hz, 5H), 3.74 – 3.50(m, 7H), 2.55(d, J = 7.0 Hz, 1H), 1.62(d, J = 8.5 Hz, 1H), 1.16(d, J = 6.6 Hz, 6H).

Example 42 : Synthesis of Compound 42

step 1: synthesis 3- cyano group -4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1 , 5-a] Pyridine -6- ethyl carbamate

6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) Pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.1 g, 0.22 mmol), triethylamine (0.067 g, 0.66 mmol) were dissolved in DCM (5 mL), The mixture was cooled to 0 °C, then ethyl isocyanate (0.047 g, 0.66 mmol) was added, and the reaction was carried out for 1 hour, quenched by adding water, extracted with dichloromethane, washed with water in the organic phase, dried and concentrated, and subjected to column chromatography to obtain 3 -Cyano-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine Azin-2-yl)pyrazolo[1,5-a]pyridin-6-ylethylcarbamate ( Compound 42 ) 35 mg. MS m/z (ESI): 526.3 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 9.05(d, J = 1.9 Hz, 1H), 8.72(s, 1H), 8.66(d, J = 1.2 Hz, 1H), 8.31(d, J = 1.2 Hz, 1H) 1H), 8.13 – 8.01(m, 2H), 7.76 – 7.65(m, 2H), 6.77(d, J = 8.5 Hz, 1H), 3.81(d, J = 12.3 Hz, 5H), 3.72 – 3.49(m , 7H), 3.14(dt, J = 12.9, 6.5 Hz, 2H), 2.98(dd, J = 7.1, 5.7 Hz, 1H), 2.55(d, J = 7.4 Hz, 1H), 1.12(t, J = 7.2 Hz, 3H).

Example 47 Synthesis of Compound 47

step 1 :synthesis 4-((4- Methoxybenzyl ) Oxygen )-6-( methylamino ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.4 mmol), iodinated at room temperature Cuprous (40 mg, 0.21 mmol), L-proline (32 mg, 0.28 mmol), potassium carbonate (1.9 g, 14 mmol) were dissolved in anhydrous DMSO (15 mL), under nitrogen protection, methylamine hydrochloride was added salt (940 mg, 14 mmol). The reaction was completed at 100 °C for 10 hours, cooled to room temperature, extracted with EA (50 mL*2) and diluted with water (50 mL), stirred and filtered, separated, extracted, dried, filtered, concentrated, and subjected to column chromatography ( PE:EA=3:1) to obtain 4-((4-methoxybenzyl)oxy)-6-(methylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile (150 mg). MS m/z (ESI): 309.1 [M+H] ⁺ .

step 2 :synthesis 4- hydroxyl -6-( methylamine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

4-((4-Methoxybenzyl)oxy)-6-(methylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile (150 mg, 0.48 mmol) was added at room temperature Dissolve in DCM (3 mL), add trifluoroacetic acid (1 mL) at 0 °C, and react for 0.5 h. The reaction was completed, concentrated and dried at room temperature, and the product was directly used in the next step without further purification. MS m/z (ESI): 189.1 [M+H] ⁺ .

step 3 :synthesis 3- cyano group -6-( methylamine ) Pyrazolo [1,5-a] Pyridine -4- triflate

4-Hydroxy-6-(methylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile (150 mg, 0.8 mmol), DIEA (307 mg, 2.4 mmol) were dissolved in DMF (5 mL) ), N-phenylbis(trifluoromethanesulfonyl)imide (286 mg, 0.8 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 0.5 h. The reaction was complete. After extraction, drying, filtration, concentration, column layering Analysis (PE:EA=3:1) gave 3-cyano-6-(methylamino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (180 mg). MS m/z (ESI): 321.3 [M+H] ⁺ .

step 4 :synthesis 4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptyl -3- base ) Pyridine -3- base )-6-( methylamino ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 3-cyano-6-(methylamino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.15 g, 0.46 mmol), 6-( (6-Methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3-dioxaborolane-2-yl) Pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (0.20 g, 0.46 mmol), Pd2(dba _{)3 (} 46 mg, 0.05 mmol), x-phos (24 mg, 0.05 mmol) was dissolved in Dioxane/H ₂ O=20 mL/4 mL, nitrogen was replaced three times, the reaction was carried out at 100 °C for 6 h, the reaction was complete, cooled, concentrated, extracted with DCM, dried, filtered and concentrated, column chromatography (DCM : MeOH=10:1) to give 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl-3 -yl)pyridin-3-yl)-6-(methylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 47 ) 60 mg. MS m/z (ESI): 467.2 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.28 (s, 1H), 8.13 (d, J = 1.4 Hz, 1H), 8.07 (s, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.79 ( dd, J = 8.8, 2.5 Hz, 1H), 7.67 (d, J = 9.8 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.76 (t, J = 8.1 Hz, 2H), 5.92 ( t, J = 5.4 Hz, 1H), 3.85 (d, J = 3.4 Hz, 4H), 3.76 – 3.62 (m, 5H), 3.50 (s, 4H), 1.03 (t, J = 7.4 Hz, 3H).

Example 48 Synthesis of Compound 48

step 1 :synthesis 6- bromine -4-(6-(6-(((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptyl -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (1.0 g, 2.7 mmol) was dissolved in 1,4-dioxane (15 mL) and water (2 mL), then add 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3 -Dioxaborol-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (1.1 _g , 2.7 mmol), Pd(dppf)2Cl ₂ (0.22 g, 0.27 mmol), KOAc (0.8 g, 8.1 mmol), replaced with nitrogen. Then the reaction was stirred at room temperature for 16 h. After monitoring the completion of the reaction, diluted with water, extracted with ethyl acetate (30 mL*2), the organic phase was washed with water, dried and concentrated, and 0.7 g of 6-bromo-4-(6) was obtained by column chromatography. -(6-(((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl-3-yl)pyridin-3-yl)pyrazole [1,5-a]pyridine-3-carbonitrile ( compound 48 ), 54% yield. MS m/z (ESI): 517.2 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 9.31 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.45 – 8.34 (m, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.8, 2.5 Hz, 1H), 7.64 (t, J = 1.9 Hz, 2H), 6.76 (dd, J = 18.0, 8.6 Hz, 2H), 3.80 (s, 4H), 3.72 (d , J = 11.8 Hz, 2H), 3.66 (d, J = 5.4 Hz, 2H), 3.51 (d, J = 20.6 Hz, 5H).

Example 49 Synthesis of Compound 49

step 1 :synthesis 6-((2- Fluoroethyl ) Amine )-4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Geng -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

Under nitrogen protection at room temperature, 6-bromo-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1] Heptyl-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (600 mg, 1.2 mmol), cuprous iodide (22 mg, 0.12 mmol), L -Proline (14 mg, 0.12 mmol), potassium carbonate (1.6 g, 12 mmol) were dissolved in anhydrous DMSO (15 mL), 2-fluoroethylamine hydrochloride (1.2 g, 12 mmol) was added. 100 °C The reaction was completed for 10 h, cooled to room temperature, diluted with water (30 mL), extracted with EA (50 mL*2), stirred and filtered, separated, dried, filtered, concentrated, and subjected to column chromatography (DCM:MeOH=10 : 1) to obtain 6-((2-fluoroethyl)amino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazepine Bicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 49 ) 50 mg. MS m/z (ESI): 499.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.09 (t, J = 3.2 Hz, 2H), 7.77 (dd, J = 8.8, 2.5 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.77 (t, J = 7.7 Hz, 2H), 6.25 (t, J = 5.8 Hz, 1H), 5.74 (s, 1H), 4.68 (t, J = 4.7 Hz, 1H), 4.56 (t, J = 4.7 Hz, 1H), 3.81 (s, 3H), 3.78 – 3.62 (m, 4H), 3.50 (dd, J = 25.0, 11.4 Hz, 6H).

Example 50 Synthesis of Compound 50

step 1 :synthesis 6-(((2,2- Difluoroethyl ) Amine )-4-(6-(6-((6- Methoxypyridine -3- base ) methyl )- 3,6- diazabicyclo [3.1.1] Geng -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 6-bromo-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl -3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (600 mg, 1.2 mmol), cuprous iodide (22 mg, 0.12 mmol), L-pro Amino acid (14 mg, 0.12 mmol), potassium carbonate (1.6 g, 12 mmol) were dissolved in anhydrous DMSO (15 mL), under nitrogen protection, 2-fluoroethylamine hydrochloride (1.2 g, 12 mmol) was added. 100 The reaction was completed at ℃ for 10 hours, cooled to room temperature, diluted with water (30 mL), extracted with EA (50 mL*2), stirred and filtered, separated, dried, filtered, concentrated, and subjected to column chromatography (DCM:MeOH= 10:1) to give 6-(((2,2-difluoroethyl)amino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3, 6-Diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 50 ) 80 mg. MS m/z (ESI): 517.3 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.43 (s, 1H), 8.37 – 8.32 (m, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.07 (s, 1H), 7.78 (dd, J = 8.8, 2.5 Hz, 1H), 7.68 (dd, J = 8.5, 2.3 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 10.8, 8.8 Hz, 2H), 6.32 (t, J = 6.4 Hz, 1H), 3.81 (s, 3H), 3.76 – 3.47 (m, 10H), 2.53 (s, 1H), 1.58 (d, J = 8.4 Hz, 1H), 1.22 (s, 1H).

Example 51 Synthesis of Compound 51

step 1 :synthesis 6-(((2- Hydroxyethyl ) Amine )-4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Geng -3- base ) Pyridine - 3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 6-bromo-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl -3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (600 mg, 1.2 mmol), cuprous iodide (22 mg, 0.12 mmol), L-pro Amino acid (14 mg, 0.12 mmol), potassium carbonate (500 mg, 3.6 mmol) were dissolved in anhydrous DMSO (15 mL), under nitrogen protection, 2-hydroxyethylamine (220 mg, 3.6 mmol) was added. The reaction was carried out at 100 °C for 10 After hours, the reaction was complete, cooled to room temperature, diluted with water (30 mL), extracted with EA (50 mL*2), stirred and filtered, separated, dried, filtered, concentrated, and subjected to column chromatography (DCM:MeOH=10:1 ) to give 6-(((2-hydroxyethyl)amino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo [3.1.1]Hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 51 ) 40 mg. MS m/z (ESI): 497.3 [ M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H), 8.00 (d, J = 1.8 Hz , 1H), 7.77 (dd, J = 8.8, 2.3 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 1.9 Hz, 1H), 6.77 (t, J = 8.0 Hz , 2H), 5.96 (t, J = 5.6 Hz, 1H), 4.78 (t, J = 5.3 Hz, 1H), 3.81 (s, 3H), 3.61 (ddd, J = 41.1, 32.8, 17.3 Hz, 9H) , 3.14 (q, J = 5.6 Hz, 2H), 1.58 (s, 1H).

Example 52 Synthesis of Compound 52

step 1: synthesis 6-(4- fluorine -1H- Pyrazole -1- base ) methyl nicotinate

At room temperature, methyl 6-chloronicotinate (2.0 g, 11.65 mmol), 4-fluoro-1H-pyrazole (770 mg, 8.96 mmol), potassium carbonate (3.7 g, 34.95 mmol) were dissolved in anhydrous DMF ( 30 mL), under nitrogen protection, reacted at 80 °C overnight, the reaction was complete, cooled to room temperature, added water (250 mL), stirred for 0.5 h, filtered, the filter cake was washed with water for several times, and dried to obtain 6-(4-fluoro) -1H-pyrazol-1-yl) methyl nicotinate 1.9 g, yield 95%. MS m/z (ESI): 222.1 [M+H] ⁺ .

step 2: synthesis (6-(4- fluorine -1H- Pyrazole -1- base ) Pyridine -3- base ) methanol

At room temperature, methyl 6-(4-fluoro-1H-pyrazol-1-yl)nicotinate (1.8 g, 8.0 mmol) was dissolved in anhydrous THF (50 mL), under nitrogen protection, cooled to 0 °C, Lithium aluminum hydride (300 mg, 8.0 mmol) was added, and the reaction was carried out at 0 °C for 15 minutes. The reaction was complete. The reaction was quenched with methanol (1 mL). The reaction was diluted with EA (50 mL) and water (50 mL). After extraction, drying, filtration, Concentration gave 1.44 g of (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanol with a yield of 91%. MS m/z (ESI): 194.1 [M+H] ⁺ .

step 3: synthesis 6-(4- fluorine -1H- Pyrazole -1- base ) Nicotinic aldehyde

(6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanol (1.1 g, 5.6 mmol) was dissolved in dry DCM (40 mL) at room temperature, cooled to 0 °C , Dess-Martin (2.8 g, 6.74 mmol) was added, and the reaction was carried out at room temperature for 0.5 h. The reaction was complete. After extraction, drying, filtration, concentration, and column chromatography, 6-(4-fluoro-1H-pyrazole-1- base) nicotinaldehyde 0.8 g, yield 74%. MS m/z (ESI): 191.1 [M+H] ⁺ .

step 4: synthesis 3-(5- Bromopyridine -2- base )-6-((6-(4- fluorine -1H- Pyrazole -1- base ) Pyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane

6-(4-Fluoro-1H-pyrazol-1-yl)nicotinaldehyde (0.8 g, 4.1 mmol), 3-(5-bromopyridin-2-yl)-3,6-diazo Heterobicyclo[3.1.1]heptane (815 mg, 3.2 mmol), 1 drop of acetic acid, dissolved in DCE (40 mL), cooled to 0 °C, reacted for half an hour, added sodium borohydride (2.0 g, 9.6 mmol) ), reacted at room temperature for 2 h, the reaction was complete, after extraction, drying, filtration, concentration, and column chromatography to obtain 3-(5-bromopyridin-2-yl)-6-((6-(4-fluoro-1H -Pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane 310 mg, 21% yield. MS m/z (ESI): 429.1 [M+H] ⁺ .

step 5: synthesis 6-((6-(4- fluorine -1H- Pyrazole -1- base ) Pyridine -3- base ) methyl )-3-(5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) Pyridine -2- base )-3,6- diazabicyclo [3.1.1] Heptane

At room temperature, 3-(5-bromopyridin-2-yl)-6-(((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3, 6-Diazabicyclo[3.1.1]heptane (306 mg, 0.7 mmol), pinacol diboronate (533 mg, _2.1 mmol), Pd(dppf) _Cl2CH2Cl2 (57 _mg , 0.07 mol), KOAc (206 mg, 2.1 mol), dissolved in Dioxane (10 mL), reacted at 90 °C overnight, the reaction was complete, cooled to room temperature, extracted, dried, filtered, concentrated, and subjected to column chromatography to obtain 6- ((6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane 160 mg, yield 46%. MS m/z (ESI): 477.1 [M+H] ⁺ .

step 6: synthesis 6-( Ethylamino )-4-(6-(6-((6-(4- fluorine -1H- Pyrazole -1- base ) Pyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 3-cyano-6-(ethylamino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (102 mg, 0.3 mmol), 6- ((6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (160 mg, 0.33 mmol), Pd ₂ (dba) ₃ (27 mg, 0.03 mmol), X-phos (28 mg, 0.06 mmol) was dissolved in Dioxane/H ₂ O = 10 mL/1 mL, nitrogen was replaced three times, the reaction was carried out at 90 °C overnight, the reaction was complete, cooled, concentrated, diluted, Extraction, drying, filtration and concentration, column chromatography (DCM:MeOH=10:1) gave 6-(ethylamino)-4-(6-(6-((6-(4-fluoro-1H-pyridine) azol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5 -a]pyridine-3-carbonitrile ( compound 52 ) 51 mg, yield: 33%. MS m/z (ESI): 535.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 8.41 (d, 2H), 8.34 (s, 1H), 7.80-8.00 (m, 4H), 7.77-7.79 (d 1H), 7.04 ( s, 1H), 6.78 (d, 2H), 5.93 (m, 1H), 3.73-3.77 (m, 4H), 3.64 (s, 2H), 3.56-3.59 (m, 2H), 3.06-3.09(m, 2H), 2.56-2.58(m, 1H), 1.61-1.63(d, 1H), 1.21-1.24 (m, 4H).

Example 53 Synthesis of Compound 53

step 1 :synthesis 6-(( cyclopropylmethyl ) Amine )-4-((4- Methoxybenzyl ) Oxygen ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.6 g, 1.7 mmol), iodinated at room temperature Cuprous (32 mg, 0.17 mmol), L-proline (39 mg, 0.34 mmol), potassium phosphate (1.1 g, 5.1 mmol) were dissolved in anhydrous DMSO (10 mL), and cyclopropylmethane was added under nitrogen protection base amine (0.36 g, 5.1 mmol). The reaction was carried out at 120 °C for 5 h. After the reaction was completed, it was cooled to room temperature, and water (10 mL) was added to quench the reaction. After extraction with EA (30 mL*2), the organic phase was dried, filtered, concentrated, and subjected to column chromatography (PE: EA=3:1) to give 6-((cyclopropylmethyl)amino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3- Formonitrile 0.3 g. MS m/z (ESI): 349.1 [M+H] ⁺ .

step 2 :synthesis 6-(( cyclopropylmethyl ) Amine )-4- Hydroxypyrazolo [1,5-a] Pyridine -3- Formonitrile

6-((Cyclopropylmethyl)amino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile at room temperature (0.2 g, 0.57 mmol) was dissolved in DCM (6 mL), then cooled to 0 °C, TFA (2 mL) was added, and the reaction was continued for half an hour. After the reaction was complete, it was directly spin-dried for the next step without further purification. MS m/z (ESI): 228.9 [M+H] ⁺ .

step 3 :synthesis 3- cyano group -6-(( cyclopropylmethyl ) Amine ) Pyrazolo [1,5-a] Pyridine -4- triflate

Combine 6-((cyclopropylmethyl)amino)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (0.15 g, 0.66 mmol), DIEA (0.26 g, 1.96 mmol) It was dissolved in DMF (5 mL), then N-phenylbis(trifluoromethanesulfonyl)imide (0.35 g, 1.0 mmol) was added, and the reaction was stirred at room temperature for 0.5 h. After the reaction was completed, water (10 mL) was added. The reaction was quenched, then extracted with EA (20 mL*2), the organic phase was dried, filtered, concentrated, and subjected to column chromatography (PE:EA=7:1) to obtain 3-cyano-6-((cyclopropylmethyl) )amino)pyrazolo[1,5-a]pyridin-4-yl triflate 0.12 g, MS m/z (ESI): 361.1 [M+H] ⁺ .

step 4 :synthesis 6-(( cyclopropylmethyl ) Amine )-4-(5-(6-(((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Geng -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

3-cyano-6-((cyclopropylmethyl)amino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.12 g, 0.33 mmol), 6- ((6-Methoxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptyl Alkane (0.19 g, 0.33 mmol), Pd(PPh ₃ ) ₄ (38 mg, 0.033 mmol), cuprous iodide (6.2 mg, 0.033 mmol) were dissolved in xylene (10 mL), and the reaction was carried out at 130 °C after nitrogen replacement. 3h, after the reaction was completed, it was cooled, and water (10 mL) was added to quench the reaction, then EA (20 mL*2) was extracted, and the organic phase was dried, filtered, concentrated, and subjected to column chromatography (DCM:MeOH=10:1) to obtain 6-((Cyclopropylmethyl)amino)-4-(5-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]hept-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 53 ) 50 mg, MS m/z (ESI): 508.2 [M +H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.52 (d, J = 1.4 Hz, 1H), 8.40 (s, 1H), 8.28 (d, J = 1.4 Hz, 1H), 8.09 (s, 1H), 7.97 ( d, J = 1.9 Hz, 1H), 7.69 (dd, J = 8.5, 2.3 Hz, 1H), 7.39 (d, J = 1.9 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.09 ( t, J = 5.4 Hz, 1H), 3.84 – 3.75 (m, 5H), 3.61 (dd, J = 41.9, 29.6 Hz, 6H), 3.43 (qd, J = 7.0, 5.1 Hz, 1H), 2.96 – 2.89 (m, 2H), 2.58 – 2.51 (m, 1H), 1.04 (t, J = 7.0 Hz, 1H), 0.52 (dd, J = 8.0, 1.6 Hz, 2H), 0.26 (dd, J = 4.8, 1.3 Hz, 2H).

Example 54 Synthesis of Compound 54

step 1 :synthesis 4-((4- Methoxybenzyl ) Oxygen )-6-(((( tetrahydro -2H- Pyran -4- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.4 g, 1.1 mmol), iodinated at room temperature Cuprous (22 mg, 0.11 mmol), L-proline (26 mg, 0.22 mmol), potassium phosphate (0.49 g, 2.2 mmol) were dissolved in anhydrous DMSO (10 mL), and 4-aminomethane was added under nitrogen protection tetrahydropyran (0.26 g, 2.2 mmol). The reaction was carried out at 120 °C for 5 h. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added to quench the reaction, and then EA (30 mL*2) was extracted. The organic phase was dried, filtered, concentrated, and subjected to column chromatography (PE: EA=3:1) to give 4-((4-methoxybenzyl)oxy)-6-((((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo [1,5-a]pyridine-3-carbonitrile 0.2 g, MS m/z (ESI): 392.3 [M+H] ⁺ .

step 2 :synthesis 4- hydroxyl -6-(((( tetrahydro -2H- Pyran -4- base ) methyl ) Amine ) Amine ] Pyrazolo [1,5-a] Pyridine -3- Formonitrile

4-((4-Methoxybenzyl)oxy)-6-(((((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1 ,5-a]pyridine-3-carbonitrile (0.2 g, 0.51 mmol) was dissolved in DCM (6 mL), then cooled to 0 °C, TFA (2 mL) was added, and the reaction was continued for half an hour. Used dry for the next step without further purification. MS m/z (ESI): 272.9 [M+H] ⁺ .

step 3 :synthesis 3- cyano group -6-((( tetrahydro -2H- Pyran -4- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -4- triflate

At room temperature, 4-hydroxy-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)amino)pyrazolo[1,5-a]pyridine-3-methyl Nitrile (0.1 g, 0.37 mmol), DIEA (0.15 g, 1.1 mmol) was dissolved in DMF (5 mL), then N-phenylbis(trifluoromethanesulfonyl)imide (0.20 g, 0.56 mmol) was added, The reaction was stirred at room temperature for 0.5 h. After the reaction was complete, water (10 mL) was added to quench the reaction, and then EA (20 mL*2) was extracted. The organic phase was dried, filtered, concentrated, and subjected to column chromatography (PE:EA=7: 1) to obtain 3-cyano-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonic acid Ester 0.1 g, MS m/z (ESI): 405.3 [M+H] ⁺ .

step 4 :synthesis 4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptyl -3- base ) Pyridine -3- base )-6-(((-2H- Pyran -4- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

3-cyano-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.1 g, 0.25 mmol), 6-(((6-methoxypyridin-3-yl)methyl)-3-(5-(tributylstannyl)pyridin-2-yl)-3,6- Diazabicyclo[3.1.1]heptane (0.15 g, 0.25 mmol), Pd(PPh ₃ ) ₄ (29 mg, 0.025 mmol), cuprous iodide (4.8 mg, 0.025 mmol) were dissolved in xylene (10 mL), the reaction was carried out at 130 °C for 3 h after nitrogen replacement. After the reaction was complete, it was cooled, water (10 mL) was added to quench the reaction, and then EA (20 mL*2) was extracted. The organic phase was dried, filtered, concentrated, and subjected to column chromatography. (DCM:MeOH=10:1) to give 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl -3-yl)pyridin-3-yl)-6-((((-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 54 ) 30 mg, MS m/z (ESI): 551.2 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.39 (s, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.06 (s, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.79 ( dd, J = 7.6, 3.8 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 6.77 (t, J = 8.0 Hz, 2H), 6.05 ( t, J = 5.7 Hz, 1H), 3.86 (dd, J = 11.3, 2.8 Hz, 2H), 3.81 (d, J = 3.9 Hz, 4H), 3.74 – 3.63 (m, 4H), 3.50 (s, 4H) ), 2.96 (t, J = 6.2 Hz, 2H), 1.90 – 1.79 (m, 1H), 1.70 (d, J = 12.4 Hz, 2H), 1.58 (d, J = 7.9 Hz, 1H), 1.04 (t , J = 7.0 Hz, 2H), 0.83 (ddd, J = 10.9, 7.5, 2.8 Hz, 2H).

Example 55 Synthesis of Compound 55

step 1 :synthesis 4-((4- Methoxybenzyl ) Oxygen )-6-( Pyrrolidine -1- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.6 g, 1.7 mmol), iodinated at room temperature Cuprous (32 mg, 0.17 mmol), L-proline (39 mg, 0.34 mmol), potassium phosphate (1.1 g, 5.1 mmol) were dissolved in anhydrous DMSO (10 mL), and tetrahydropyrrole ( 0.36 g, 5.1 mmol). The reaction was carried out at 120 °C for 5 h. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added to quench the reaction, and then EA (30 mL*2) was extracted. The organic phase was dried, filtered, concentrated, and subjected to column chromatography (PE: EA=3:1) to give 4-((4-methoxybenzyl)oxy)-6-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 0.35 g, MS m/z (ESI): 349.5 [M+H] ⁺ .

step 2 :synthesis 4- hydroxyl -6-( Pyrrolidine -1- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 4-((4-methoxybenzyl)oxy)-6-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.25 g , 0.72 mmol) was dissolved in DCM (6 mL), then cooled to 0 °C, TFA (2 mL) was added, and the reaction was continued for 0.5 h. After the reaction was complete, it was directly spin-dried for the next step without further purification. MS m/z (ESI): 229.2 [M+H] ⁺ .

step 3 :synthesis 3- cyano group 6-( Pyrrolidine -1- base ) Pyrazolo [1,5-a] Pyridine -4- triflate

4-Hydroxy-6-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.2 g, 0.87 mmol), DIEA (0.34 g, 2.62 mmol) was dissolved in DMF (5 mL), then N-phenylbis(trifluoromethanesulfonyl)imide (0.46 g, 1.3 mmol) was added, and the reaction was stirred at room temperature for 0.5 h. After the reaction was completed, water (10 mL) was added to quench the reaction. , then extracted with EA (20 mL*2), the organic phase was dried, filtered, concentrated, and subjected to column chromatography (PE:EA=7:1) to obtain 3-cyano 6-(pyrrolidin-1-yl)pyrazolo [1,5-a]pyridin-4-yl trifluoromethanesulfonate 0.25 g, MS m/z (ESI): 361.5 [M+H] ⁺ .

step 4 :synthesis 4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptyl -3- base ) Pyridine -3- base )-6-( Pyrrolidine -1 - base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

Combine 3-cyano 6-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.2 g, 0.55 mmol), 6-((((6 -Methoxypyridin-3-yl)methyl)-3-(5-(tributylstannyl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (0.32 g , 0.55 mmol), Pd(PPh ₃ ) ₄ (63 mg, 0.055 mmol), cuprous iodide (10 mg, 0.055 mmol) was dissolved in xylene (10 mL), and the reaction was carried out at 130 °C for 3 h after nitrogen replacement, and the reaction was complete After cooling, water (10 mL) was added to quench the reaction, and then EA (20 mL*2) was extracted. The organic phase was dried, filtered, concentrated, and subjected to column chromatography (DCM:MeOH=10:1) to obtain 4-(6 -(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl-3-yl)pyridin-3-yl)-6- (Pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 55 ) 60 mg, MS m/z (ESI): 507.5 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.44 – 8.33 (m, 2H), 8.01 (dd, J = 18.8, 1.9 Hz, 2H), 7.80 (dd, J = 8.8, 2.5 Hz, 1H), 7.64 (dd , J = 8.5, 2.2 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.74 (t, J = 8.4 Hz, 2H), 3.78 (d, J = 2.8 Hz, 3H), 3.74 – 3.37 (m, 9H), 3.28 (s, 4H), 1.95 (t, J = 6.5 Hz, 4H), 1.55 (d, J = 8.3 Hz, 1H).

Example 56 Synthesis of Compound 56

step 1: 4-((4- Methoxybenzyl ) Oxygen )-6-((2,2,2- trifluoroethyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (1.0 g, 2.8 mmol), iodinated at room temperature Cuprous (78 mg, 0.4 mmol), L-proline (64 mg, 0.55 mmol), potassium carbonate (1.1 g, 7.9 mmol) were dissolved in dry DMSO (10 mL), under nitrogen, trifluoroethylamine was added (2.7 g, 28 mmol). The reaction was carried out at 120 °C overnight, the reaction was complete, cooled to room temperature, diluted with EA (50 mL) and water (50 mL), stirred and filtered, extracted, dried, filtered, concentrated, and subjected to column chromatography (PE:EA=3: 1) to obtain 4-((4-methoxybenzyl)oxy)-6-((2,2,2-trifluoroethyl)amino)pyrazolo[1,5-a]pyridine-3 - Formonitrile (180 mg), 18% yield. MS m/z (ESI): 377.1 [M+H] ⁺ .

step 2: 4- hydroxyl -6-((2,2,2- trifluoroethyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

4-((4-Methoxybenzyl)oxy)-6-((2,2,2-trifluoroethyl)amino)pyrazolo[1,5-a]pyridine -3-carbonitrile (150 mg, 0.39 mmol) was dissolved in methanol (10 mL), 10% palladium on carbon (70 mg) was added, hydrogen was replaced three times, the reaction was carried out at 50 °C overnight, the reaction was complete, filtered and concentrated, and the product was directly used in In the next step, no further purification is required. MS m/z (ESI): 257.1 [M+H] ⁺ .

step 3: 3- cyano group -6-((2,2,2- trifluoroethyl ) Amine ) Pyrazolo [1,5-a] Pyridine -4- Triflate

At room temperature, 4-hydroxy-6-((2,2,2-trifluoroethyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile (102 mg, 0.39 mmol), DIEA (0.2 mL, 1.17 mmol) was dissolved in DMF (5 mL), N-phenylbis(trifluoromethanesulfonyl)imide (142 mg, 0.39 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 0.5 h. The reaction was complete. After extraction, drying, filtration, concentration and column chromatography (PE:EA=5:1), 3-cyano-6-((2,2,2-trifluoroethyl)amino)pyrazolo[ 1,5-a]pyridine-4-trifluoromethanesulfonate (130 mg), 85% yield. MS m/z (ESI): 389.1 [M+H] ⁺ .

step 4: 4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyridine -3- base )-6-((2,2,2- trifluoroethyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 3-cyano-6-((2,2,2-trifluoroethyl)amino)pyrazolo[1,5-a]pyridine-4-trifluoromethanesulfonate (130 mg, 0.33 mmol), 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyridin-2-yl)-3,6-diazabis Cyclo[3.1.1]heptane (206 mg, 0.35 mmol), Pd( _PPh3 ) ₄ (38 mg, 0.033 mmol), cuprous iodide (6 mg, 0.033 mmol) were dissolved in xylene (10 mL), Nitrogen was replaced three times, and the reaction was completed at 130 °C for 3 h. The reaction was completed. Cooling, concentration to remove xylene, dilution, extraction, drying, filtration and concentration, column chromatography (DCM:MeOH=10:1) gave 4-(6-(6 -((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(( 2,2,2-Trifluoroethyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 56 ) 22 mg, yield: 11%. MS m/z (ESI): 535.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 8.34 (d, 2H), 8.06 (s, 1H), 7.77 (d, 1H), 7.66 (d, 1H), 7.14 (s, 1H) ), 6.74-6.78 (m, 2H), 6.56-6.59 (m, 1H), 4.05-4.14(m, 2H), 4.57 (d, 2H), 3.49-3.80 (m, 9H), 1.56(d, 2H) ).

Example 57 Synthesis of Compound 57

step 1: 4-((4- Methoxybenzyl ) Oxygen )-6-( propylamine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.4 mmol), iodinated at room temperature Cuprous (40 mg, 0.21 mmol), L-proline (32 mg, 0.28 mmol), potassium carbonate (966 mg, 7.0 mmol) were dissolved in anhydrous DMSO (10 mL), under nitrogen protection, n-propylamine (827 mg, 14 mmol). The reaction was carried out at 120 °C overnight, the reaction was complete, cooled to room temperature, diluted with EA (50 mL) and water (50 mL), stirred and filtered, extracted, dried, filtered, concentrated, and subjected to column chromatography (PE:EA=3: 1) 4-((4-methoxybenzyl)oxy)-6-(propylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile (170 mg) was obtained in yield 36%. MS m/z (ESI): 337.1 [M+H] ⁺ .

step 2: 4- hydroxyl -6-( propylamine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

4-((4-Methoxybenzyl)oxy)-6-(propylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile (170 mg, 0.5 mmol) was dissolved in DCM (1 mL), trifluoroacetic acid (1 mL) was added at 0 °C, and the reaction was carried out for 0.5 h. The reaction was completed, concentrated and dried at room temperature, and the product was directly used in the next step without further purification. MS m/z (ESI): 217.1 [M+H] ⁺ .

step 3: 3- cyano group -6-( propylamine ) Pyrazolo [1,5-a] Pyridine -4- Triflate

4-Hydroxy-6-(propylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile (109 mg, 0.5 mmol), DIEA (193 mg, 1.5 mmol) were dissolved in DMF (5 mL) , N-phenylbis(trifluoromethanesulfonyl)imide (178 mg, 0.55 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 0.5 h. The reaction was complete, after extraction, drying, filtration, concentration, and column chromatography ( PE:EA=3:1) gave 3-cyano-6-(propylamino)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonic acid (170 mg) in 96% yield. MS m/z (ESI): 349.1 [M+H] ⁺ .

step 4: 4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyridine -3- base )-6-( propylamine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 3-cyano-6-(propylamino)pyrazolo[1,5-a]pyridine-4-trifluoromethanesulfonate (170 mg, 0.48 mmol), 6-((6- Methoxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (281 mg, 0.48 mmol), Pd(PPh ₃ ) ₄ (55 mg, 0.048 mmol), cuprous iodide (9 mg, 0.048 mmol) was dissolved in xylene (10 mL), nitrogen was replaced three times, and the reaction was carried out at 130 °C for 3 h. Complete, cooled, concentrated to remove xylene, diluted, extracted, dried, filtered and concentrated, column chromatography (DCM:MeOH=10:1) gave 4-(6-(6-((6-methoxypyridine-3 -yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(propylamino)pyrazolo[1,5-a ]pyridine-3-carbonitrile ( compound 57 ) 35 mg, yield: 14%. MS m/z (ESI): 494.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 8.32 (d, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.77 (d, 1H), 7.66 (d, 1H) ), 7.04(s, 1H), 6.74-6.78 (m, 2H), 5.95 (m, 1H), 3.80 (s, 3H), 3.50-3.74 (m, 9H), 2.97-3.02 (m, 2H), 1.55-1.63 (m, 3H), 0.93-0.98 (m, 3H).

Example 58 Synthesis of Compound 58

step 1: 6-((2-( dimethylamino ) Ethyl )( methyl ) Amine )-4-((4- Methoxybenzyl ) Oxygen ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.4 mmol), iodinated at room temperature Cuprous (26 mg, 0.14 mmol), L-proline (32 mg, 0.28 mmol), potassium phosphate (600 mg, 2.8 mmol) were dissolved in anhydrous DMSO (10 mL), under nitrogen protection, N1, N1, N2-trimethylethane-1,2-diamine (430 mg, 4.2 mmol), reacted at 90 °C overnight, the reaction was complete, cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), Stir and filter, extract, dry, filter, concentrate, column chromatography (DCM:MeOH=20:1) to obtain 6-((2-(dimethylamino)ethyl)(methyl)amino)-4 -((4-Methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (240 mg), 45% yield. MS m/z (ESI): 380.2 [M+H] ⁺ .

step 2: 6-((2-( dimethylamino ) Ethyl )( methyl ) Amine )-4- Hydroxypyrazolo [1,5-a] Pyridine -3- Formonitrile

6-((2-(dimethylamino)ethyl)(methyl)amino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine -3-Carbononitrile (240 mg, 0.63 mmol) was dissolved in DCM (2 mL), trifluoroacetic acid (3 mL) was added at 0 °C, and the reaction was continued for 0.5 h. The reaction was completed, concentrated and dried at room temperature, and the product was directly used in the next step without further purification. MS m/z (ESI): 260.1 [M+H] ⁺ .

step 3: 3- cyano group -6-((2-( dimethylamino ) Ethyl )( methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -4- Triflate

6-((2-(dimethylamino)ethyl)(methyl)amino)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (164 mg, 0.63 mmol) , DIEA (244 mg, 1.89 mmol) was dissolved in DMF (5 mL), N-phenylbis(trifluoromethanesulfonyl)imide (338 mg, 0.94 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 0.5 h. Complete, extracted, dried, filtered, concentrated, and column chromatographed (PE:EA=3:1) to give 3-cyano-6-((2-(dimethylamino)ethyl)(methyl)amine yl)pyrazolo[1,5-a]pyridine-4-trifluoromethanesulfonate (120 mg), 33% yield. MS m/z (ESI): 391.1 [M+H] ⁺ .

step 4: 6-((2-( dimethylamino ) Ethyl )( methyl ) Amine )-4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyrazine -2- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

3-cyano-6-((2-(dimethylamino)ethyl)(methyl)amino)pyrazolo[1,5-a]pyridine-4-trifluoromethanesulfonate (70 mg, 0.18 mmol), 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyrazin-2-yl)-3,6-diazepine Bicyclo[3.1.1]heptane (115 mg, 0.19 mmol), Pd( _PPh3 ) ₄ (20 mg, 0.018 mmol), cuprous iodide (3.4 mg, 0.018 mmol) were dissolved in xylene (10 mL) , nitrogen was replaced three times, the reaction was completed at 130 °C for 3 h, the reaction was complete, cooled, concentrated to remove xylene, diluted, extracted, dried, filtered and concentrated, column chromatography (DCM:MeOH=10:1) to obtain 6-((2- (dimethylamino)ethyl)(methyl)amino)-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabis Cyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 58) 19 mg, yield: 19%. MS m/z (ESI): 539.1 [M+H]+.

¹ H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.68 (d, 1H) ), 7.58 (d, 1H), 7.04(s, 1H), 6.73 (d, 2H), 3.35-3.81 (m, 15 H), 2.96 (s, 3H), 2.56 (s, 2H), 2.29(m , 3H).

Example 59 Synthesis of Compound 59

step 1: 2-((3- cyano group -4-((4- Methoxybenzyl ) Oxygen ) Pyrazolo [1,5-a] Pyridine -6- base ) Amine )-N, N- dimethylacetamide

Under nitrogen at room temperature, 6-bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (400 mg, 1.12 mmol), Cuprous iodide (20 mg, 0.1 mmol), L-proline (25 mg, 0.21 mmol), potassium phosphate (480 mg, 2.2 mmol) were dissolved in dry DMSO (10 mL) and 2-amino- N,N-Dimethylacetamide (344 mg, 3.3 mmol), reacted at 120 °C overnight, the reaction was complete, cooled to room temperature, diluted with EA (50 mL), water (50 mL), stirred and filtered, extracted, Drying, filtration, concentration, and column chromatography (DCM:MeOH=20:1) gave 2-((3-cyano-4-((4-methoxybenzyl)oxy)pyrazolo[1, 5-a]Pyridin-6-yl)amino)-N,N-dimethylacetamide (280 mg), 66% yield. MS m/z (ESI): 378 [M+H] ⁺ .

step 2: 2-((3- cyano group -4- Hydroxypyrazolo [1,5-a] Pyridine -6- base ) Amine )-N,N- dimethylacetamide

At room temperature, 2-((3-cyano-4-((4-methoxybenzyl)oxy) pyrazolo [1,5-a] pyridin -6-yl)amino)-N , N-dimethylacetamide (280 mg, 0.73 mmol) was dissolved in DCM (10 mL), 3 mL of trifluoroacetic acid was added at 0 °C, and the reaction was carried out for 0.5 h. The reaction was completed, concentrated and dried at room temperature, and the product was directly used in the next step without further purification. MS m/z (ESI): 259.1 [M+H] ⁺ .

step 3: 3- cyano group -6-((2-( dimethylamino )-2- oxyethyl ) Amine ) Pyrazolo [1,5-a] Pyridine -4- trifluoromethanesulfonate

At room temperature, 2-((3-cyano-4-hydroxypyrazolo[ 1,5 -a] pyridin -6-yl)amino)-N,N-dimethylacetamide (190 mg , 0.73 mmol), DIEA (285 mg, 2.2 mmol) was dissolved in DMF (5 mL), N-phenylbis(trifluoromethanesulfonyl)imide (395 mg, 1.1 mmol) was added at 0 °C, and the reaction was stirred at room temperature After 0.5 h, the reaction was complete. After extraction, drying, filtration, concentration, and column chromatography (PE:EA=1:1), 3-cyano-6-((2-(dimethylamino)-2-oxygen) was obtained. Ethyl)amino) pyrazolo [1,5-a] pyridin -4-yl trifluoromethanesulfonate (74 mg), 25% yield. MS m/z (ESI): 391.1 [M+H] ⁺ .

step 4: 2-((3- cyano group -4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -6- base ) Amine )-N, N- dimethylacetamide

At room temperature, 3-cyano-6-((2-(dimethylamino)-2-oxoethyl)amino) pyrazolo [1,5-a] pyridin -4-yltrifluoromethane Sulfonate (74 mg, 0.18 mmol), 6-(6-methoxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyridin-2-yl)-3,6- Diazabicyclo[3.1.1]heptane (121 mg, 0.2 mmol), Pd(PPh ₃ ) ₄ (22 mg, 0.018 mmol), cuprous iodide (3.6 mg, 0.018 mmol) were dissolved in xylene ( 10 mL), replaced with nitrogen three times, reacted at 130 ° C for 5 h, the reaction was complete, cooled, concentrated to remove xylene, diluted, extracted, dried, filtered and concentrated, column chromatography (DCM:MeOH=10:1) to obtain 2-( (3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)amino)-N,N-dimethylacetamide ( compound 59 ) 20 mg, yield: 19% . MS m/z (ESI): 538.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.34 (s, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.79 (d, 1H), 7.67 (d, 1H) ), 7.34(s, 1H), 6.75-6.82 (m, 3H), 3.80 (s, 3H), 3.63-3.97 (m, 8H), 3.06 (s, 3H), 2.87(s, 3H), 1.89( s, 2H), 1.23 (s, 3H).

Example 60 Synthesis of Compound 60

step 1: 6-(( Cyclohexylmethyl ) Amine )-4-((4- Methoxybenzyl ) Oxygen ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (400 mg, 1.12 mmol), iodinated at room temperature Cuprous (20 mg, 0.1 mmol), L-proline (25 mg, 0.21 mmol), potassium phosphate (480 mg, 2.2 mmol) were dissolved in anhydrous DMSO (5 mL), under nitrogen protection, cyclohexylmethylamine was added (379 mg, 3.3 mmol), reacted at 120 °C for 3 h, the reaction was complete, cooled to room temperature, diluted with EA (50 mL), water (50 mL), stirred and filtered, extracted, dried, filtered, concentrated, and subjected to column chromatography (PE:EA=5:1) to give 6-((cyclohexylmethyl)amino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine- 3-carbonitrile (150 mg), 36% yield. MS m/z (ESI): 391.2 [M+H] ⁺ .

step 2: 6-(( Cyclohexylmethyl ) Amine )-4- Hydroxypyrazolo [1,5-a] Pyridine -3- Formonitrile

6-((Cyclohexylmethyl)amino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile ( 215 mg, 0.54 mmol) was dissolved in DCM (5 mL), 1 mL of trifluoroacetic acid was added at 0 °C, and the reaction was carried out for 0.5 h. The reaction was completed, concentrated and dried at room temperature, and the product was directly used in the next step without further purification. MS m/z (ESI): 259.1 [M+H] ⁺ .

step 3: 3- cyano group -6-(( Cyclohexylmethyl ) Amine ) Pyrazolo [1,5-a] Pyridine -4- trifluoromethanesulfonate

At room temperature, 6-((cyclohexylmethyl)amino)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (150 mg, 0.54 mmol), DIEA (212 mg, 1.6 mmol) was dissolved in DMF (5 mL), N-phenylbis(trifluoromethanesulfonyl)imide (250 mg, 0.7 mmol) was added at 0 °C, the reaction was stirred at room temperature for 1 h, the reaction was complete, extracted and dried , filtration, concentration, and column chromatography (PE:EA=1:1) to obtain 3-cyano-6-((cyclohexylmethyl)amino)pyrazolo[1,5-a]pyridine-4- trifluoromethanesulfonate (132 mg), 59% yield. MS m/z (ESI): 402.1 [M+H] ⁺ .

step 4: 6-(( Cyclohexylmethyl ) Amine )-4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

3-cyano-6-((cyclohexylmethyl)amino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (132 mg, 0.32 mmol) at room temperature , 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1 ]heptane (187 mg, 0.32 mmol), Pd(PPh ₃ ) ₄ (37 mg, 0.032 mmol), cuprous iodide (9 mg, 0.048 mmol) were dissolved in xylene (10 mL) and replaced with nitrogen three times, The reaction was carried out at 130 °C for 3 h, the reaction was complete, cooled, concentrated to remove xylene, diluted, extracted, dried, filtered and concentrated, and column chromatography (DCM:MeOH=10:1) gave 6-((cyclohexylmethyl)amino group )-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine- 3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( compound 60 ) 10 mg, yield: 5.5%. MS m/z (ESI): 549.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 8.32 (d, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.77 (d, 1H), 7.66 (d, 1H) ), 7.07 (s, 1H), 6.75-6.78 (t, 2H), , 3.81 (s, 3H), 3.63-3.72 (m, 4H), 3.49-3.52 (m, 3H), 2.88-2.91 (t, 2H), 1.58-1.84 (m, 7H), 0.96-1.24 (m, 6H),.

Example 61 Synthesis of Compound 61

step 1: 6-((2-( dimethylamino ) Ethyl )( methyl ) Amine )-4-( methoxymethoxy ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 6-bromo-4-(methoxymethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (1.0 g, 3.5 mmol), N1,N1,N2-tris Methylethane-1,2-diamine (2.16 g, 21.1 mmol), _K3PO4 (3.74 _g , 17.6 mmol), Pd2(dba _{)3 (} 915 mg, 1.04 mmol), Xantphos (500 mg, 1.0 mmol), dissolved in 20 mL of Dioxane, replaced with nitrogen three times, reacted at 100 °C for 3 h, the reaction was complete, cooled, concentrated, diluted, extracted, dried, filtered and concentrated, column chromatography (PE:EA=3:1) yielded 6-((2-(dimethylamino)ethyl)(methyl)amino)-4-(methoxymethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (170 mg), yield: 17%. MS m/z (ESI): 303.1 [M+H] ⁺ .

step 2: 6-((2-( dimethylamino ) Ethyl )( methyl ) Amine )-4- Hydroxypyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 6-((2-(dimethylamino)ethyl)(methyl)amino)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (170 mg , 0.56 mmol) was dissolved in DCM (5 mL), 4M HCl/Dioxane 3 mL was added at 0 °C, and the reaction was carried out for 0.5 h. The reaction was completed, concentrated and drained, and the product was directly used in the next step without further purification. MS m/z (ESI): 259.1 [M+H] ⁺ .

step 3: 3- cyano group -6-((2-( dimethylamino ) Ethyl )( methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -4- Triflate

At room temperature, 6-((2-(dimethylamino)ethyl)(methyl)amino)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (94 mg , 0.36 mmol), DIEA (212 mg, 0.72 mmol) was dissolved in DMF (5 mL), N-phenylbis(trifluoromethanesulfonyl)imide (250 mg, 0.46 mmol) was added at 0 °C, and the reaction was stirred at room temperature 1 h, the reaction was complete, and after extraction, drying, filtration, concentration, and column chromatography (PE:EA=1:1), 3-cyano-6-((2-(dimethylamino)ethyl)( Methyl)amino)pyrazolo[1,5-a]pyridine-4-trifluoromethanesulfonate (107 mg), 75% yield. MS m/z (ESI): 392.1 [M+H] ⁺ .

step 4: 6-((2-( dimethylamino ) Ethyl )( methyl ) Amine )-4-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

3-cyano-6-((2-(dimethylamino)ethyl)(methyl)amino)pyrazolo[1,5-a]pyridine-4-trifluoromethanesulfonate (107 mg, 0.27 mmol), 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyridin-2-yl)-3,6-diazabis Cyclo[3.1.1]heptane (187 mg, 0.32 mmol), Pd( _PPh3 ) ₄ (31 mg, 0.027 mmol), cuprous iodide (8 mg, 0.042 mmol) were dissolved in xylene (10 mL) , replaced by nitrogen three times, reacted at 130 °C for 3 h, the reaction was complete, cooled, concentrated to remove xylene, diluted, extracted, dried, filtered and concentrated, column chromatography (DCM:MeOH=10:1) to obtain 6-((2- (dimethylamino)ethyl)(methyl)amino)-4-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]Heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 61 ) 11 mg, yield: 7.5%. MS m/z (ESI): 537.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.58 (s, 1H) ), 7.04 (s, 1H), 6.73 (d, 2H), 3.35-3.81 (m, 15 H), 2.96 (s, 3H), 2.56 (s, 2H), 2.29 (m, 3H).

Example 62 Synthesis of Compound 62

step 1: 6-( Ethylamino )-4-((4- Methoxybenzyl ) Oxygen ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (1.0 g, 2.8 mmol), iodinated at room temperature Cuprous (53 mg, 0.28 mmol), L-proline (48 mg, 0.42 mmol), potassium carbonate (3.8 g, 28 mmol) were dissolved in anhydrous DMSO (15 mL), under nitrogen protection, ethylamine hydrochloride was added Salt (2.28 g, 28 mmol). The reaction was carried out at 100 °C overnight, the reaction was complete, cooled to room temperature, diluted with EA (100 mL) and water (50 mL), stirred and filtered, extracted, dried, filtered, concentrated, and subjected to column chromatography (PE:EA=3:1 ) to give 6-(ethylamino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (470 mg) in 52 yield %. MS m/z (ESI): 323.1 [M+H] ⁺ .

step 2: 6-( Ethylamino )-4- Hydroxypyrazolo [1,5-a] Pyridine -3- Formonitrile

6-(ethylamino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (2.28 g, 7 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (10 mL) was added at 0 °C, and the reaction was carried out for 0.5 h. The reaction was completed, concentrated and dried at room temperature, and the product was directly used in the next step without further purification. MS m/z (ESI): 203.1 [M+H] ⁺ .

step 3: 3- cyano group -6-( Ethylamino ) Pyrazolo [1,5-a] Pyridine -4- trifluoromethanesulfonate

Dissolve 6-(ethylamino)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (1.43 g, 7 mmol), DIEA (2.7 g, 21 mmol) at room temperature In DMF (10 mL), N-phenylbis(trifluoromethanesulfonyl)imide (2.5 g, 7 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 0.5 h. The reaction was complete. After extraction, drying, filtration, Concentration and column chromatography (PE:EA=3:1) gave 3-cyano-6-(ethylamino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (1.74 g), 76% yield. MS m/z (ESI): 335.1 [M+H] ⁺ .

step 4: 6-( Ethylamino )-4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 6-(ethylamino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.9 g, 2.69 mmol), 6-((6-methoxy pyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3-dioxaborolane-2-yl)pyridin-2-yl )-3,6-diazabicyclo[3.1.1]heptane (1.47 g, 3.5 mmol), Pd2(dba _{)3 (} 246 mg, 0.269 mmol), x-phos (256 mg, 0.053 mmol) Dissolved in Dioxane/H ₂ O=20 mL/4 mL, replaced with nitrogen three times, reacted at 100 °C for 16 h, the reaction was complete, cooled, concentrated, diluted, extracted, dried, filtered and concentrated, column chromatography (DCM:MeOH= 10:1) to give 6-(ethylamino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]Heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 62 ) 1.0 g, purified by ether beating again to obtain 400 mg, yield: 31%. MS m/z (ESI): 481.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 8.32 (d, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.77 (d, 1H), 7.66 (d, 1H) ), 7.04(s, 1H), 6.74-6.78 (m, 2H), 5.95 (m, 1H), 3.80 (s, 3H), 3.50-3.74 (m, 9H), 1.55-1.63(m, 3H), 0.93-0.98 (m, 3H).

Example 63 Synthesis of Compound 63

step 1: 6-((2- hydroxyl -2- methylpropyl ) Amine )-4-((4- Methoxybenzyl ) Oxygen ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.4 mmol), iodinated at room temperature Cuprous (40 mg, 0.21 mmol), L-proline (32 mg, 0.28 mmol), potassium carbonate (966 mg, 7.0 mmol) were dissolved in anhydrous DMSO (10 mL), under nitrogen protection, 1-amino was added -2-Methylpropan-2-ol (623 mg, 7 mmol). The reaction was carried out at 100 °C overnight, the reaction was complete, cooled to room temperature, diluted with EA (50 mL) and water (50 mL), stirred and filtered, extracted, dried, filtered, concentrated, and subjected to column chromatography (PE:EA=3:1 ) to give 6-((2-hydroxy-2-methylpropyl)amino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3- Formonitrile (240 mg), 47% yield. MS m/z (ESI): 367.1 [M+H] ⁺ .

step twenty four- hydroxyl -6-((2- hydroxyl -2- methylpropyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 6-((2-hydroxy-2-methylpropyl)amino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine -3-Carbononitrile (240 mg, 0.65 mmol) was dissolved in DCM (2 mL), trifluoroacetic acid (2 mL) was added at 0°C, and the reaction was continued for 0.5 h. The reaction was completed, concentrated and dried at room temperature, and the product was directly used in the next step without further purification. MS m/z (ESI): 247.1 [M+H] ⁺ .

step 3: 3- cyano group -6-((2- hydroxyl -2- methylpropyl ) Amine ) Pyrazolo [1,5-a] Pyridine -4- Triflate

4-Hydroxy-6-((2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile (161 mg, 0.6 mmol) at room temperature , DIEA (234 mg, 1.8 mmol) was dissolved in DMF (5 mL), N-phenylbis(trifluoromethanesulfonyl)imide (321 mg, 0.9 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 0.5 h. Complete, after extraction, drying, filtration, concentration, column chromatography (PE:EA=3:1) to obtain 3-cyano-6-((2-hydroxy-2-methylpropyl)amino)pyrazole [1,5-a]pyridine-4-trifluoromethanesulfonate (80 mg), 32 % yield. MS m/z (ESI): 379.1 [M+H] ⁺ .

step 4: 6-((2- hydroxyl -2- methylpropyl ) Amine )-4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

3-cyano-6-((2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5-a]pyridine-4-trifluoromethanesulfonate (80 mg, 0.2 mmol ), 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyridin-2-yl)-3,6-diazabicyclo[3.1. 1] Heptane (136 mg, 0.23 mmol), Pd(PPh ₃ ) ₄ (24 mg, 0.02 mmol), cuprous iodide (4 mg, 0.02 mmol) were dissolved in xylene (10 mL) and replaced with nitrogen three times , reacted at 130 °C for 4 h, the reaction was complete, cooled, concentrated to remove xylene, diluted, extracted, dried, filtered and concentrated, and column chromatography (DCM:MeOH=10:1) gave 6-((2-hydroxy-2- Methylpropyl)amino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane -3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 63 ) 13 mg, yield: 11%. MS m/z (ESI): 524.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 8.33 (s, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.75-7.77 (m, 1H), 7.67 (d , 1H), 7.24 (s, 1H), 6.75 (t, 2H), 5.81 (t, 1H), 4.54 (s, 1H), 3.81 (s, 1H), 3.65-3.72 (m, 4H), 3.48- 3.52 (m, 4H), 2.97 (d, 2H), 1.58 (s, 1H), 1.18 (s, 6H).

Example 64 Synthesis of Compound 64

step 1: 4-((4- Methoxybenzyl ) Oxygen )-6-((1- Methylpiperidine -4- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (400 mg, 1.12 mmol), iodinated at room temperature Cuprous (20 mg, 0.1 mmol), L-proline (25 mg, 0.21 mmol), potassium phosphate (480 mg, 2.2 mmol) were dissolved in anhydrous DMSO (5 mL), under nitrogen protection, (1-methyl) Piperidin-4-yl)carboxamide (422 mg, 3.3 mmol), reacted at 120 °C for 3 h, the reaction was complete, cooled to room temperature, diluted with EA (50 mL) and water (50 mL), stirred and filtered, Extraction, drying, filtration, concentration, column chromatography (PE:EA=3:1) gave 4-((4-methoxybenzyl)oxy)-6-((1-methylpiperidine-4) -yl)methyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg), 44% yield. MS m/z (ESI): 406.1 [M+H] ⁺ .

step 2: 4- hydroxyl -6-((1- Methylpiperidine -4- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 4-((4-methoxybenzyl)oxy)-6-((1-methylpiperidin-4-yl)methyl)amino)pyrazolo[1,5- a] Pyridine-3-carbonitrile (200 mg, 0.49 mmol) was dissolved in DCM (2 mL), trifluoroacetic acid (1 mL) was added at 0 °C, and the reaction was continued for 0.5 h. The reaction was completed, concentrated and dried at room temperature, and the product was directly used in the next step without further purification. MS m/z (ESI): 271.1 [M+H] ⁺ .

step 3: 3- cyano group -6-((1- Methylpiperidine -4- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -4- Triflate

At room temperature, 4-hydroxy-6-((1-methylpiperidin-4-yl)methyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile (140 mg, 0.49 mmol), DIEA (190 mg, 1.47 mmol) was dissolved in DMF (5 mL), N-phenylbis(trifluoromethanesulfonyl)imide (262 mg, 0.73 mmol) was added at 0 °C, stirred at room temperature The reaction was completed for 0.5 h. After extraction, drying, filtration, concentration, and column chromatography (PE:EA=1:1), 3-cyano-6-((1-methylpiperidin-4-yl) was obtained. Methyl)amino)pyrazolo[1,5-a]pyridine-4-trifluoromethanesulfonate (90 mg), 44% yield. MS m/z (ESI): 418.1 [M+H] ⁺ .

step 4: 4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptane -3- base ) Pyridine -3- base )-6-((1- Methylpiperidine -4- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

3-cyano-6-((1-methylpiperidin-4-yl)methyl)amino)pyrazolo[1,5-a]pyridine-4-trifluoromethanesulfonic acid at room temperature Ester (90 mg, 0.21 mmol), 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(tributyltinyl)pyridin-2-yl)-3,6-di Azabicyclo[3.1.1]heptane (126 mg, 0.21 mmol), Pd( _PPh3 ) ₄ (24 mg, 0.021 mmol), cuprous iodide (9 mg, 0.048 mmol) were dissolved in xylene (10 mL), replaced with nitrogen three times, reacted at 130 °C for 4 h, the reaction was complete, cooled, concentrated to remove xylene, diluted, extracted, dried, filtered and concentrated, and column chromatography (DCM:MeOH=10:1) gave 4-( 6-(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)- 6-((1-Methylpiperidin-4-yl)methyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 64 ) 6 mg, yield: 5%. MS m/z (ESI): 563.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 8.32 (d, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.77 (d, 1H), 7.66 (d, 1H) ), 7.07 (s, 1H), 6.75-6.78 (t, 2H), , 3.81 (s, 3H), 3.63-3.72 (m, 4H), 3.49-3.52 (m, 3H), 2.67 (s, 3H) , 1.58-1.84 (m, 7H), 0.96-1.24 (m, 6H).

Example 65 Synthesis of Compound 65

step 1: synthesis 4-((4- Methoxybenzyl ) Oxygen )-6-((( tetrahydrofuran -3- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (400 mg, 1.12 mmol), potassium phosphate (475 mg, 2.24 mmol), L-proline (25.8 mg, 0.22 mmol) was dissolved in DMSO (5 mL), (tetrahydrofuran-3-yl)methanamine (0.35 mL, 3.36 mmol), CuI (21.3 mg, 0.11 mmol) was added, Under nitrogen protection, the temperature was raised to 120 °C, refluxed for 5 h, monitored for completion of the reaction, cooled, added with an appropriate amount of water, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated by column chromatography to obtain 4-((4-methoxybenzyl (yl)oxy)-6-(((tetrahydrofuran-3-yl)methyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile 230 mg, 54.3% yield, MS m/ z (ESI): 379.0 [M+H] ⁺ .

step 2: synthesis 4- hydroxyl -6-((( tetrahydrofuran -3- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

4-((4-Methoxybenzyl)oxy)-6-(((tetrahydrofuran-3-yl)methyl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile (230 mg, 0.61 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added to the system under ice bath, stirred at room temperature for 30 min, and the reaction was monitored for completion. The reaction solution was concentrated to obtain the crude product, which was directly put into the next step.

step 3: synthesis 3- cyano group -6-((( tetrahydrofuran -3- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -4- triflate

Dissolve N-phenylbis(trifluoromethanesulfonyl)imide (259 mg, 0.72 mmol) and the crude product obtained in the previous step in DMAc (5 mL), add DIPEA (0.4 mL, 2.42 mmol), and stir at room temperature After 2 h, the complete reaction was monitored. An appropriate amount of water was added, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated by column chromatography to obtain 3-cyano-6-(((tetrahydrofuran-3-yl)methyl)amino)pyrazolo[1,5 -a]pyridin-4-yltrifluoromethanesulfonic acid 110 mg, 46.6% yield, MS m/z (ESI): 390.9 [M+H] ⁺ .

step 4: synthesis 4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptyl -3- base ) Pyridine -3- base )-6-((( tetrahydrofuran -3- base ) methyl ) Amine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

3-cyano-6-(((tetrahydrofuran-3-yl)methyl)amino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (110 mg, 0.28 mmol ), 6-(((6-methoxypyridin-3-yl)methyl)-3-(5-(tributylstannyl)pyridin-2-yl)-3,6-diazabicyclo[3.1 .1] Heptane (166 mg, 0.28 mmol), cuprous iodide (5.39 mg, 0.03 mmol), palladium tetrakistriphenylphosphine (32.66 mg, 0.03 mmol) in xylene (10 mL), N ₂ protection, then heated to 135 °C, refluxed for 4 h, monitored the completion of the reaction, cooled, added an appropriate amount of water, extracted with dichloromethane, the organic phase was dried and concentrated, and separated by column chromatography to obtain 4-(6-(6-((6 -Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl-3-yl)pyridin-3-yl)-6-(((tetrahydrofuran-3- ( Compound 65 ) 20 mg, 13.2% yield. MS m/z (ESI): 537.1 [M+H] ⁺ .

¹ H NMR (300 MHz, DMSO) δ 8.54 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.83 (dd, J = 8.8, 2.5 Hz, 1H), 7.66 (dd, J = 8.5, 2.3 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.6 , 4.9 Hz, 2H), 6.08 (s, 1H), 3.89 – 3.36 (m, 16H), 3.22 – 3.14 (m, 3H), 1.80 (m, 1H), 1.67(m, 2H), 1.22 (s, 2H).

Example 66 Synthesis of Compound 66

step 1 :synthesis 4-(5-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptyl -3- base ) Pyrazine -2- base )-6- morpholinopyrazolo [1,5-a] Pyridine -3- Formonitrile

3-Cyano-6-morpholinopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (220 mg, 0.6 mmol), 6-(((6-methoxy Pyridin-3-yl)methyl)-3-(5-(tributylstannyl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (370 mg, 0.64 mmol ), cuprous iodide (11 mg, 0.06 mmol), tetrakistriphenylphosphine palladium (70 mg, 0.06 mmol) was dissolved in xylene (10 mL), protected by N ₂ , then heated to 135 °C, refluxed for 3 h, Monitor the completion of the reaction, cool, add an appropriate amount of water, extract with ethyl acetate, dry and concentrate the organic phase, and separate by column chromatography to obtain 4-(5-(6-((6-methoxypyridin-3-yl)methyl) )-3,6-diazabicyclo[3.1.1]heptyl-3-yl)pyrazin-2-yl)-6-morpholinopyrazolo[1,5-a]pyridine-3-methyl Nitrile ( compound 66 ) 0.12 g. MS m/z (ESI): 524.5 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.65 (d, J = 1.4 Hz, 1H), 8.54 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 1.4 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 8.5, 2.3 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 3.86 – 3.74 (m, 9H), 3.69 (d, J = 5.1 Hz, 2H), 3.61 (d, J = 12.6 Hz, 2H), 3.53 (s, 2H), 3.24 – 3.16 (m, 4H) ), 2.54 (d, J = 5.9 Hz, 2H).

Example 67 Synthesis of Compound 67

step 1 :synthesis 6-( isobutylamine )-4-((4- Methoxybenzyl ) Oxygen ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.4 mmol), iodinated at room temperature Cuprous (40 mg, 0.21 mmol), L-proline (32 mg, 0.28 mmol), potassium carbonate (580 mg, 4.2 mmol) were dissolved in anhydrous DMSO (10 mL), under nitrogen protection, isobutylamine ( 310 mg, 4.2 mmol). The reaction was completed at 120 °C for 6 hours, cooled to room temperature, extracted with EA (50 mL*2), diluted with water (50 mL), stirred and filtered, separated, extracted, dried, filtered, concentrated, and subjected to column chromatography ( PE:EA=3:1) to obtain 6-(isobutylamino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile ( 200 mg). MS m/z (ESI): 351.1 [M+H] ⁺ .

step 2 :synthesis 4- hydroxyl -6-( isobutylamine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-(isobutylamino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.56 mmol) was added at room temperature ) was dissolved in DCM (3 mL), trifluoroacetic acid (1 mL) was added at 0 °C, and the reaction was carried out for 0.5 h. The reaction was completed, concentrated and dried at room temperature, and the product was directly used in the next step without further purification. MS m/z (ESI): 231.2 [M+H] ⁺ .

step 3 :synthesis 3- cyano group -6-( isobutylamine ) Pyrazolo [1,5-a] Pyridine -4- triflate

4-Hydroxy-6-(isobutylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.87 mmol), DIEA (336 mg, 2.6 mmol) were dissolved in DMF (5 mL), N-phenylbis(trifluoromethanesulfonyl)imide (310 mg, 0.87 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 0.5 h. The reaction was complete. After extraction, drying, filtration, concentration, column Chromatography (PE:EA=3:1) gave 3-cyano-6-(isobutylamino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (180 mg ). MS m/z (ESI): 363.3 [M+H] ⁺ .

step 4 :synthesis 6-( isobutylamine )-4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Geng -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 3-cyano-6-(isobutylamino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.3 g, 0.83 mmol), 6- ((6-Methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3-dioxaborolane-2-yl) )pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (0.35 g, 0.83 mmol), Pd2(dba _{)3 (} 73 mg, 0.08 mmol), X-phos ( 40 mg, 0.08 mmol) was dissolved in Dioxane/H ₂ O=20 mL/4 mL, replaced with nitrogen three times, reacted at 100 °C for 6 h, the reaction was complete, cooled, concentrated, extracted with DCM, dried, filtered and concentrated, column chromatography (DCM : MeOH=10:1) to obtain 6-(isobutylamino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo [3.1.1]Hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 67 ) 80 mg, MS m/z (ESI): 509.4 [ M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.38 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.77 (dd, J = 8.8, 2.5 Hz, 1H), 7.67 (dd, J = 8.5, 2.3 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.76 (t, J = 8.5 Hz, 2H), 5.98 (s, 1H), 3.81 (s, 3H), 3.69 (dd, J = 27.6, 8.8 Hz, 5H), 3.51 (d, J = 12.3 Hz, 4H), 2.92 – 2.81 (m , 2H), 1.93 – 1.83 (m, 1H), 1.58 (d, J = 8.4 Hz, 1H), 0.97 (d, J = 6.6 Hz, 6H).

Example 68 Synthesis of Compound 68

step 1 :synthesis 6-( Butylamine )-4-((4- Methoxybenzyl ) Oxygen ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-Bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.4 mmol), iodinated at room temperature Cuprous (40 mg, 0.21 mmol), L-proline (32 mg, 0.28 mmol), potassium carbonate (580 mg, 4.2 mmol) were dissolved in anhydrous DMSO (10 mL), under nitrogen protection, n-butylamine ( 310 mg, 4.2 mmol). The reaction was completed at 120 °C for 6 hours, cooled to room temperature, extracted with EA (50 mL*2), diluted with water (50 mL), stirred and filtered, separated, extracted, dried, filtered, concentrated, and subjected to column chromatography ( PE:EA=3:1) to obtain 6-(butylamino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile ( 190 mg). MS m/z (ESI): 351.1 [M+H] ⁺ .

step 2 :synthesis 6-( Butylamine )-4- Hydroxypyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 6-(butylamino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (190 mg, 0.5 mmol ) was dissolved in DCM (3 mL), trifluoroacetic acid (1 mL) was added at 0 °C, and the reaction was carried out for 0.5 h. The reaction was completed, concentrated and dried at room temperature, and the product was directly used in the next step without further purification. MS m/z (ESI): 231.2 [M+H] ⁺ .

step 3 :synthesis 6-( Butylamine )-3- Cyanopyrazolo [1,5-a] Pyridine -4- triflate

6-(Butylamino)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.87 mmol), DIEA (336 mg, 2.6 mmol) were dissolved in DMF (5 mL) ), N-phenylbis(trifluoromethanesulfonyl)imide (310 mg, 0.87 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 0.5 h. The reaction was complete. After extraction, drying, filtration, concentration, column layering Analysis (PE:EA=3:1) gave 6-(butylamino)-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (180 mg). MS m/z (ESI): 363.3 [M+H] ⁺ .

step 4 :synthesis 6-( Butylamine )-4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Geng -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

At room temperature, 6-(butylamino)-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.3 g, 0.83 mmol), 6-( (6-Methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3-dioxaborolane-2-yl) Pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (0.35 g, 0.83 mmol), Pd2(dba _{)3 (} 73 mg, 0.08 mmol), X-phos (40 mg, 0.08 mmol) was dissolved in Dioxane/H ₂ O=20 mL/4 mL, nitrogen was replaced three times, the reaction was carried out at 100 °C for 6 h, the reaction was complete, cooled, concentrated, extracted with DCM, dried, filtered and concentrated, column chromatography (DCM: MeOH=10:1) to give 6-(butylamino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[ 3.1.1]Hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 68 ) 90 mg, MS m/z (ESI): 509.4 [M +H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.38 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.77 ( dd, J = 8.8, 2.5 Hz, 1H), 7.67 (d, J = 9.8 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.76 (t, J = 8.1 Hz, 2H), 5.92 ( t, J = 5.4 Hz, 1H), 3.81 (d, J = 3.4 Hz, 4H), 3.76 – 3.62 (m, 5H), 3.50 (s, 4H), 3.03 (dd, J = 12.5, 6.8 Hz, 2H ), 1.58 (d, J = 7.3 Hz, 2H), 1.45 – 1.38 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).

Example 69 Synthesis of Compound 69

step 1: synthesis 6-( isopropylamine )-4-((4- Methoxybenzyl ) Oxygen ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

Compound 6-bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.4 g, 1.12 mmol), CuI (53.3 mg, 0.28 mmol), L-proline (51.8 mg, 0.45 mmol), and _K3PO4 ( _475.5 mg, 2.24 mmol), dissolved in DMSO (10 mL), added isopropylamine (198.6 mg, 3.36 mmol), then switched Under nitrogen protection and sealed, the reaction solution was stirred at 90 °C overnight. After the reaction was complete, washed with 30 mL of saturated brine, concentrated the organic phase, and purified by column chromatography (PE:EA=3:1) to obtain 0.15 g of 6-(iso) Propylamino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile, MS m/z (ESI): 337 [M+H] ⁺ .

step 2: synthesis 4- hydroxyl -6-( isopropylamine ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

6-(Isopropylamino)-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.29 g, 0.86 mmol) was dissolved in DMC /CF ₃ CO ₂ H (3 mL/1 mL), stir at room temperature after the reaction is complete, add water (10 mL) to dilute, add dropwise 4N NaOH aqueous solution to adjust the pH of the solution to 4-5, use EA (2*10 mL) Extraction, combined organic phases, washed with saturated brine (20 mL), concentrated organic phase, purified by ISCO (DCM/MeOH = 0~10%) to obtain 6-(isopropyl)-4-hydroxypyrazolo[1,5 -a]pyridine-3-carbonitrile 0.26 g. MS m/z (ESI): 217 [M+H] ⁺ .

step 3: 3- cyano group -6-( isopropylamine ) Pyrazolo [1,5-a] Pyridine -4- triflate

6-(Isopropylamino)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (185.76 mg, 0.86 mmol) was dissolved in DMA (10 mL) and DIPEA (0.6 mL, 3.44 mmol), PhNTf ₂ (460.53 mg, 1.29 mmol) was slowly added to the reaction solution, and then the reaction was stirred at room temperature for 2 h. After LC-MS monitoring was completed, the reaction was quenched with 10 mL of water, EA (10 mL *3) Extract, combine the organic phases, wash with saturated brine (20 mL), concentrate the organic phase, and obtain 3-cyano-6-(isopropylamino)pyrazolo[1,5-a]pyridine- 4-yl triflate 260 mg. MS m/z (ESI): 349 [M+H] ⁺ .

step 4: synthesis 6-( isopropylamine )-4-(6-((6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptyl -3- base ) Pyridine -3- base ) Pyrazolo [1,5-a] Pyridine -3- Formonitrile

Compound 3-cyano-6-(isopropylamino)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (0.26 g, 0.75 mmol) was prepared under nitrogen protection at 0°C , (1R, 5S)-6-((6-methoxypyridin-3-yl)methyl)-3-(5-tributylstannyl)pyridin-2-yl)-3,6-diazepine Bicyclo[3.1.1]heptane (480.52 mg, 0.82 mmol), Pd( _PPh3 ) ₄ (86.63 mg, 0.075 mmol) and CuI (14.28 mg, 0.075 mmol), dissolved in 1,4-xylene (10 mL) ), the reaction system was stirred evenly, slowly heated to 140 °C, and continued to stir overnight. After the reaction was completed as monitored by LC-MS, the reaction was quenched with 10 mL of saturated NaHCO ₃ aqueous solution, extracted with EA (10 mL*3), and the organic phase was saturated Washed with NaCl solution, dried and concentrated, purified by column chromatography (DCM/MeOH=0~10%) to obtain 6-(isopropylamino)-4-(6-((6-((6-methoxy Pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3- Formonitrile ( compound 69 ) 42 mg. MS m/z (ESI): 495 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO) δ 8.39 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.08 (s, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.77 ( dd, J = 8.8, 2.5 Hz, 1H), 7.69 (dd, J = 8.4, 2.1 Hz, 1H), 7.03 (d, J = 1.9 Hz, 1H), 6.77 (dd, J = 8.5, 5.9 Hz, 2H ), 5.81 (d, J = 8.0 Hz, 1H), 4.36 (t, J = 5.1 Hz, 1H), 3.77 – 3.63 (m, 4H), 3.62 – 3.47 (m, 5H), 1.18 (d, J = 6.3 Hz, 6H).

Example 70 Synthesis of Compound 70

step 1: synthesis 4-((4- Methoxybenzyl ) Oxygen )-6- morpholinopyrazolo [1,5-a] Pyridine -3- Formonitrile

Combine 6-bromo-4-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (1.8 g, 5.04 mmol), potassium phosphate (2.13 g, 10.08 mmol), L-proline (60 mg, 0.50 mmol) was dissolved in DMSO (18 mL), morpholine (1.32 mL, 15.12 mmol), CuI (96 mg, 0.50 mmol) was added, under nitrogen protection, and the temperature was raised to 120 ℃, refluxed for 5 h, monitored the completion of the reaction, cooled, added an appropriate amount of water, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated by column chromatography to obtain 4-((4-methoxybenzyl)oxy)-6 -morpholinopyrazolo[1,5-a]pyridine-3-carbonitrile 270 mg, yield 14.7%. MS m/z (ESI): 365.0 [M+H] ⁺ .

step 2: synthesis 4- hydroxyl -6- morpholinopyrazolo [1,5-a] Pyridine -3- Formonitrile

4-((4-Methoxybenzyl)oxy)-6-morpholinopyrazolo[1,5-a]pyridine-3-carbonitrile (270 mg, 0.74 mmol) was dissolved in dichloromethane (4 mL), under an ice bath, trifluoroacetic acid (1 mL) was added, stirred at room temperature for 30 min, and the completion of the reaction was monitored. The reaction solution was concentrated to obtain the crude product, which was directly put into the next step.

step 3: synthesis 3- cyano group -6- morpholinopyrazolo [1,5-a] Pyridine -4- triflate

Dissolve N-phenylbis(trifluoromethanesulfonyl)imide (316 mg, 0.88 mmol) and the crude product obtained in the previous step in DMAc (5 mL), add DIPEA (0.49 mL, 0.95 mmol), and stir at room temperature After 2 h, the complete reaction was monitored. An appropriate amount of water was added, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated by column chromatography to obtain 3-cyano-6-morpholinopyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonic acid Ester 210 mg, yield 75.7%. MS m/z (ESI): 376.9 [M+H] ⁺ .

step 4: synthesis 4-(6-(6-((6- Methoxypyridine -3- base ) methyl )-3,6- diazabicyclo [3.1.1] Heptyl -3- base ) Pyridine -3- base )-6- morpholinopyrazolo [1, 5-a] Pyridine -3- Formonitrile

3-Cyano-6-morpholinopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (110 mg, 0.29 mmol), 6-(((6-methoxy Pyridin-3-yl)methyl)-3-(5-(tributylstannyl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (188 mg, 0.32 mmol) , cuprous iodide (5.57 mg, 0.03 mmol), tetrakistriphenylphosphine palladium (34 mg, 0.03 mmol) were dissolved in xylene (10 mL), protected by N ₂ , then heated to 135 °C, refluxed for 5 h, Monitor the reaction to complete, cool, add an appropriate amount of water, extract with dichloromethane, dry and concentrate the organic phase, and separate by column chromatography to obtain 4-(6-(6-((6-methoxypyridin-3-yl)methyl) )-3,6-diazabicyclo[3.1.1]heptyl-3-yl)pyridin-3-yl)-6-morpholinopyrazolo[1,5-a]pyridine-3-carbonitrile ( Compound 70 ) 45 mg, 29.5% yield. MS m/z (ESI): 523.1 [M+H] ⁺ .

¹ H NMR (300 MHz, DMSO) δ 8.54 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.83 (dd, J = 8.8, 2.5 Hz, 1H), 7.66 (dd, J = 8.5, 2.3 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.6 , 4.9 Hz, 2H), 3.89 – 3.36 (m, 18H), 3.22 – 3.14 (m, 3H), 1.22 (s, 2H)

Physical and chemical properties test:

(a) Solubility Test

The experimental method is as follows:

1. Sample Preparation

Take 5 μL of the 20 mM compound stock solution prepared in DMSO, add it to 495 μL of phosphate buffer (pH=7.4) (final concentration is 200 μM), mix well, shake it in an incubator at 25°C at 1000 rpm for 1.5 h (n =2). After complete dissolution, the sample solution was filtered. Take 2 μL of each filtrate, add 98 μL of acetonitrile aqueous solution (v/v=1/1) containing internal standard (tolbutamide 200 nM), mix well for 1 min, and inject and analyze by LC-MS/MS.

2. External standard one-point method

×標準溶液濃度 Standard solution preparation: Take 2 μL of 20 mM compound stock solution in DMSO and add to 198 μL of acetonitrile (final concentration of 200 μM), (n=2). After mixing, shake the incubator at 25°C at 1000 rpm for 10 min (n=2) until it is completely dissolved, take 2 μL of each filtrate, add 198 μL of acetonitrile aqueous solution containing internal standard (v/v=1/1), and mix well For 1 min, the samples were injected and analyzed by LC-MS/MS. Calculate the concentration of the sample solution by detecting the peak area of the standard solution of known concentration and the peak area of the sample solution. Solubility (µg/mL)=

×Standard solution concentration

3. Standard curve method

Standard solution preparation: Take 2 μL of 20 mM compound stock solution in DMSO and add to 198 μL of acetonitrile (final concentration of 200 μM), (n=2). After mixing, shake at 1000 rpm in a 25°C shaking incubator for 10 min (n=2) to be completely dissolved, take 4 μL of each filtrate, add 196 μL of acetonitrile aqueous solution containing internal standard (v/v=1/1), namely the concentration was 4000 nM, and then diluted with internal standard acetonitrile aqueous solution (v/v=1/1) successively to obtain standard solutions with concentrations of 2000, 500, 100, 20, 4 and 2 nM, respectively, which were injected and analyzed by LC-MS/MS . The solubility of each compound was obtained by the standard curve method or the external standard one-point method.

Biological activity test case 1 :

(a) In vitro screening experiments -HTRF method to detect compound pairs RET inhibitory activity

]×100% 式中， R0是溶媒空白組的酶標儀板平均比率 R1是測試化合物酶標儀板比率 R2是100%抑制RET酶活性的酶標儀板平均比率 通過將化合物濃度的抑制率值和對數擬合到非線性回歸(劑量反應-可變斜率)中，用GraphPad 6.0軟體計算IC ₅₀。 The experimental method is as follows: 1. Preparation of 1x kinase buffer: 5x enzyme buffer is mixed with distilled water at 1:4, and the final concentration is 5 mM magnesium chloride; 1 mM dithiothreitol. 2. Dilute the test compound (5 mM stock) 5-fold to 1 mM with 100% dimethylsulfoxide and make 10 equal dilutions 1:3 in a 384-well dilution plate. 3. Using the Echo 550 pipetting system, add 0.2 μL of the serially diluted compounds to a 384-well plate, 2 replicate wells for each concentration, with a final concentration of 0.5% (v/v) dimethylsulfoxide. The gradient concentrations of the test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM. 4. Prepare 2x RET (0.1 ng/µl) in 1x Kinase Buffer. 5. Add 5 μL of 2x RET to a 384-well plate, centrifuge at 1000g for 30 s, and incubate at room temperature for 10 min. 6. Prepare a 2x tyrosine kinase-biotinylated substrate (2 μM) and adenosine triphosphate (20 μM) mixture in 1x Kinase Buffer. 7. Add 5 μL of the tyrosine kinase-biotinylated substrate and adenosine triphosphate mix to start the reaction. Centrifuge at 1000g for 30 s, seal the plate, and incubate at room temperature for 30 min. 8. Prepare 2x Sa-XL 665 (Note: One Reagent) (125 μM) and tyrosine kinase-antibody-cryptate mixture in Homogeneous Time-Resolved Fluorescence Detection Buffer. 9. Add 10μL of Sa-XL 665 and tyrosine kinase-antibody-cryptate mixture to each empty space, centrifuge at 1000g for 30s, and incubate at room temperature for 1h. 10. Read the plate at 615 nm and 665 nm on an Envision 2104 microplate reader and calculate the ratio (665/615 nm). 11. The inhibition rate is calculated as follows: Inhibition rate=[1-

]×100% where R0 is the average ratio of the microplate reader plate of the vehicle blank group R1 is the microplate reader plate ratio of the test compound R2 is the average ratio of the microplate reader plate that inhibits RET enzyme activity by 100% by dividing the inhibition rate of the compound concentration Values and logarithms were fitted to a nonlinear regression (dose response - variable slope) and IC50s were calculated using _GraphPad 6.0 software.

(b) In vitro screening experiments - HTRF method Detection compound inhibition VEGFR2 activity test

]×100% 式中， R0是溶媒空白組的酶標儀板平均比率 R1是測試化合物酶標儀板比率 R2是100%抑制RET酶活性的酶標儀板平均比率 12. 通過將化合物濃度的抑制率值和對數擬合到非線性回歸(劑量反應-可變斜率)中，用GraphPad 6.0計算IC ₅₀。 The experimental method is as follows: 1. Preparation of 1x kinase buffer: 5x enzyme buffer is mixed with distilled water at 1:4, and the final concentration is 5mM magnesium chloride; 1mM dithiothreitol; 1mM manganese chloride. 2. Dilute the test compound (5 mM stock) 5-fold to 1 mM with 100% dimethylsulfoxide and make 10 equal dilutions 1:3 in a 384-well dilution plate. 3. Use the Echo 550 pipetting system to add 0.2 μL of the serially diluted compounds to a 384-well cell culture plate (Corning, 3570), with 2 duplicate wells for each concentration, and the final concentration of dimethylsulfoxide is 0.5% (v/ v). The gradient concentrations of the test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM. 4. Prepare 2x VEGFR2 (0.02 ng/μL) in 1x Kinase Buffer. 5. Add 5 μL of 2x VEGFR2 to a 384-well plate, centrifuge at 1000g for 30s, and incubate at room temperature for 10 minutes. 6. Prepare a 2x tyrosine kinase-biotinylated substrate (2 μM) and ATP (8 μM) mix in 1x Kinase Buffer. 7. Add 5 μL of the tyrosine kinase-biotinylated substrate and adenosine triphosphate mix to initiate the reaction. Centrifuge at 1000g for 30s, seal the plate, and incubate at room temperature for 40min. 8. Prepare 2x Sa-XL 665 (125 μM) and tyrosine kinase-antibody-cryptate mixture using homogeneous time-resolved fluorescence detection buffer. 9. Add 10 μL of Sa-XL 665 and tyrosine kinase-antibody-cryptate mixture to each well, centrifuge at 1000g for 30s, and incubate at room temperature for 1h. 10. Envision 2104 microplate reader 615 nm and 665 nm read the plate, calculate the ratio (665/615 nm). 11. The inhibition rate is calculated as follows: Inhibition rate=[1-

]×100% where R0 is the average ratio of the microplate reader plate of the vehicle blank group R1 is the microplate reader plate ratio of the test compound R2 is the average ratio of the microplate reader plate that inhibits RET enzyme activity by 100% 12. By dividing the concentration of the compound Inhibition values and logarithms were fitted to a nonlinear regression (dose response - variable slope) and IC50s were calculated using _GraphPad 6.0.

(c) In vitro screening experiments - CellTiter-Glo Luminescence detection of compound inhibition Ba/F3-KIF5B-RET/ Ba/F3-CCDC6-RET Cell Viability Test

Experimental steps: 1. The mammalian cell expression vector containing human KIF5B-RET/CCDC6-RET cDNA was introduced into Ba/F3 cells using the Neon® transfection system method, and the surviving clones were screened by puromycin for cell growth inhibition function Cell lines with stable high expression of RET were validated by experiments and western blotting. 2. Cells were cultured in RPMI 1640 medium, 10% fetal bovine serum, 1% penicillin-streptomycin, and 2 μg/mL puromycin, and cultured in a 37°C, 5% carbon dioxide cell incubator. 3. Dilute the test compound (5 mM stock) 2.5-fold to 2 mM in 100% dimethylsulfoxide, 10 equal dilutions 1:3 in a 384-well dilution plate. 4. Use the Echo 550 pipetting system to add 0.2 μL of the serially diluted compounds to a 384-well cell culture plate (Corning, 3570), 2 duplicate wells for each concentration, and the final concentration of dimethylsulfoxide is 0.5% (v/ v). The gradient concentrations of the test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM. 5. Add 40 μL of cell suspension containing 800 Ba/F3-KIF5B-RET/Ba/F3-CCDC6-RET cells to each well, and culture in a 5% carbon dioxide cell incubator for 72 hours. 6. Add 20 μL of Cell Titer-Glo reagent per well to the cell culture plate, shake and mix for 2 minutes to lyse the cells, then incubate at room temperature for 30 minutes, and read the fluorescence signal value with an Envision 2104 microplate reader. 7. The data were fitted by XLFit 5.0 according to the 4-parameter formula: Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope)) to calculate the IC ₅₀ value.

(d) In vitro screening experiments -HTRF method to detect compound pairs RET V804M/ RET V804L/ RET G810R/ RET G810S inhibitory activity

]×100% 式中， R0是溶媒空白組的酶標儀板平均比率 R1是測試化合物酶標儀板比率 R2是100%抑制RET酶活性的酶標儀板平均比率 通過將化合物濃度的抑制率值和對數擬合到非線性回歸(劑量反應-可變斜率)中，用GraphPad 6.0軟體計算IC ₅₀。 The experimental method is as follows: 1. Preparation of 1x kinase buffer: 5x enzyme buffer is mixed with distilled water at 1:4, and the final concentration is 5mM magnesium chloride; 1mM dithiothreitol. 2. Dilute the test compound (5 mM stock) 5-fold to 1 mM with 100% dimethylsulfoxide and make 10 equal dilutions 1:3 in a 384-well dilution plate. 3. Using the Echo 550 pipetting system, add 0.2 μL of the serially diluted compounds to a 384-well plate, 2 replicate wells for each concentration, with a final concentration of 0.5% (v/v) dimethylsulfoxide. The gradient concentrations of the test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM. 4. Prepare 2x RET V804M/ RET V804L/ RET G810R/RET G810S (0.1 ng/µl) in 1x Kinase Buffer. 5. Add 5 μL of 2x RET V804M/RET V804L/RET G810R/RET G810S to a 384-well plate, centrifuge at 1000g for 30s, and incubate at room temperature for 10 minutes. 6. Prepare a 2x tyrosine kinase-biotinylated substrate (2 μM) and adenosine triphosphate (20 μM) mixture in 1x Kinase Buffer. 7. Add 5 μL of the tyrosine kinase-biotinylated substrate and adenosine triphosphate mix to start the reaction. Centrifuge at 1000g for 30s, seal the plate, and incubate at room temperature for 40min. 8. Prepare 4x Sa-XL 665 (Note: One Reagent) (125 μM) in Homogeneous Time-Resolved Fluorescence Detection Buffer. 9. Add 5μL Sa-XL 665 and 5μL tyrosine kinase-antibody-cryptate mixture to each empty space, centrifuge at 1000g for 30s, and incubate at room temperature for 1h. 10. Read the plate at 615 nm and 665 nm on an Envision 2104 microplate reader and calculate the ratio (665/615 nm). 11. The inhibition rate is calculated as follows: Inhibition rate=[1-

]×100% where R0 is the average ratio of the microplate reader plate of the vehicle blank group R1 is the microplate reader plate ratio of the test compound R2 is the average ratio of the microplate reader plate that inhibits RET enzyme activity by 100% by dividing the inhibition rate of the compound concentration Values and logarithms were fitted to a nonlinear regression (dose response - variable slope) and IC50s were calculated using _GraphPad 6.0 software.

The activity of the compounds is summarized in Table 1 below

Table 1 compound Wild-type RET kinase (nM) Ba/F3-KIF5B-RET cell activity (nM) VEGFR2 Kinase (nM) RET G810S Kinase (nM) RET G810R Kinase (nM) LOXO-292 0.22 7.08 86.5 11.25 64.76 1 3.1 271.2 / / / 2 >10000 / / / / 3 >10000 / / / / 4 6594 / / / / 5 >10000 / / / / 6 678 / / / / 7 12.74 / 201.5 / / 8 249.6 / 5000 / / 9 >10000 / / / / 10 >10000 / / / / 11 >10000 / / / / 12 >10000 / / / / 13 0.80 223.9 / / / 14 1.6 259.8 / / / 15 1.4 225.1 / / / 16 1.1 203.5 / / / 17 0.32 61.1 / / / 18 0.50 123.2 / / / 19 0.77 182.6 / / / 20 2.63 19.1 / / / twenty one 0.72 191.7 / / / twenty two 1.24 151.3 / / / twenty three 1.35 1125.1 / / / twenty four 2.19 21.3 / / / 25 2.89 27.7 / / / 26 12.73 64.2 / / / 27 15.65 51.7 / / 28 1.3 12.6 / / 29 0.181 4.43 56.0 1.93 23.8 30 3.98 63.4 / / / 31 1.40 5.1 / / / 32 4.14 83.3 / / / 33 5.73 26.0 / / / 34 2.04 13.8 / / / 35 3.08 81.5 / / / 36 2.44 32.1 453.7 / / 37 5.70 800.9 / / 38 3.22 37.3 665.9 / / 39 1.25 15.6 258.7 / / 40 0.86 207.7 112.1 / / 41 6.2 265.6 / / / 42 9.2 / / / / 47 0.04 1.42 33.68 1.23 8.93 48 2.89 104.8 875.4 13.04 63.17 49 0.19 1.52 28.41 0.53 1.85 50 0.13 5.75 59.31 1.35 5.65 51 0.22 / 19.28 / / 52 2.02 141.8 39.02 / / 53 5.54 / / / / 54 2.76 / / / / 55 0.49 6.77 8.48 / / 56 0.20 8.53 102.8 4.73 19.30 57 0.32 1.24 31.30 2.33 10.61 58 10.39 / / / / 59 1.69 11.92 93.76 / / 60 29.60 / / / / 61 1.1 60.4 482.1 / / 62 0.21 1.82 19.99 0.80 6.22 63 0.47 3.39 65.16 14.97 76.85 64 4.83 / / / / 65 6.05 / / / / 66 0.82 6.21 317.9 26.65 173.3 67 0.15 2.19 45.38 11.02 90.90 68 0.37 4.19 59.80 6.18 49.07 69 0.47 4.14 42.24 27.02 42.39 70 0.24 1.97 57.55 10.41 31.40 Note: "/" means no test.

The results show that the compounds designed in this patent all have good RET kinase activity, and some compounds (such as compounds 29, 47, 48, 49, 50, 56, 57, 62, 63, 66, 67, 68, 69, 70 ) also showed good inhibitory activity against the two mutant strains of RET kinase, G810S and G810R; at the same time, it had good selectivity for VEGFR2 kinase. In addition, compound 29 and 52 had half-fold inhibitory activity (IC ₅₀ ) of RET gene fusion CCDC6-RET and KIF5B-RET, RET kinase mutants RET V804M, RET V804L and RET M918T were all less than 5 nM. In addition, the compounds all have good RET kinase and RET-sensitive cytostatic activities.

(e) In vitro screening experiments -CellTiter-Glo Luminescence detection of compound inhibition Ba/F3-KIF5B-RET-G810S/G810R Mutant cell proliferation activity test

Experimental steps: 1. Harvest Ba/F3-KIF5B-RET-G810S/G810R mutant cells in logarithmic growth phase and count the cells using a platelet counter. Cell viability was detected by trypan blue exclusion method to ensure cell viability was above 90%. 2. Adjust cell concentration; add 90 μL of cell suspension to 96-well plates. 3. Incubate the cells in the 96-well plate overnight at 37°C, 5% CO ₂ , and 95% humidity. 4. Prepare a 10-fold drug solution, the highest concentration of Ba/F3 KIF5B-RET-G810S detection is 2000 nM, 9 concentrations, 3.16-fold dilution, add 10 μL of drug solution to each well of a 96-well plate seeded with cells, each drug The concentration was set in three replicate wells. 5. The cells in the medicated 96-well plate were incubated at 37 °C, 5% CO ₂ , and 95% humidity for 72 hours, and then CTG analysis was performed. 6. a) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes; b) Add an equal volume of CTG solution to each well; c) Shake on an orbital shaker for 5 minutes to lyse the cells; d) Place the cell plate in the chamber Warm for 20 minutes to stabilize the luminescence signal; e) read the luminescence value. 7. The data were analyzed using GraphPad Prism 7.0 software, and a dose-response curve was obtained by fitting the data using nonlinear S-curve regression, from which _IC50 values were calculated. Cell viability (%) = (Lum _{drug to be tested-} Lum _{culture medium control} )/(Lum _{cell control} -Lum _{culture medium control} )×100%.

Experimental results:

The compound cell viability results are summarized in Table 2 below:

Table 2 compound Ba/F3-KIF5B-RET-G810S cell activity Ba/F3-KIF5B-RET-G810R cell activity LOXO-292 C D 29 C C 47 B / 48 C D 49 A B 50 B B 62 B C Note: A means IC ₅₀ ≤ 20 nM; B means 20 nM < IC ₅₀ ≤ 100 nM; C means 100 nM < IC ₅₀ ≤ 500 nM; D means 500 nM > IC ₅₀ ; “/” means no test.

As can be seen from Table 2, compared with the existing compound LOXO-292, the compound of the present invention showed better inhibitory activity on RET mutant cells.

(f) In vivo screening experiments - Detection compound inhibition Ba/F3-KIF5B-RET-G810R Cell subcutaneous allograft tumor BALB/c Pharmacodynamic testing in nude mice

Experimental steps: 1. The Ba/F3-KIF5B-RET-G810R cell line was cultured in 1640 medium (Biological Industries) + 10% fetal bovine serum (BI) + 1% double antibody (Penicillin Streptomycin solution, Coring, USA), 37°C for 5 %CO ₂ culture, passage 2-3 times a week. When the cell saturation was 80%~90%, the cells were harvested, counted, and seeded. 2. When the cells in the logarithmic growth phase reach the number required for the experiment, collect the cells, centrifuge at 1000 rpm for 5 min to remove the supernatant, resuspend the cells in medium, count with a cell counter, and dilute the original solution to a viable cell concentration of 1 according to the counting results. *10^7 cells/mL cell suspension, the cell viability rate is 96.6%, P10 generation. 3. Dilute the diluted cell suspension and Matrigel in a ratio of 1:1. After mixing, it was placed on ice, the suspension was drawn with a 1 mL sterile insulin syringe, and 0.2 mL of the cell suspension was inoculated subcutaneously in the right armpit of each mouse. That is, each mouse was inoculated with 1*10^6 Ba/F3-KIF5B-RET-G810R cells. 4. After the inoculation was completed, the tumor growth status was observed daily. When the average tumor volume reached about 91.58 mm ³ , the mice were randomly divided into 7 groups according to the tumor volume, with 6 mice in each group. 1 solvent control group, 6 test drug experimental groups. 5. Mice were orally administered each test compound one to five times a day, Monday through Friday, with a weekend off for two weeks. 6. Detect the health status and death of animals every day. Routine examinations include tumor growth, activity, diet, weight, eyes, hair and other abnormal behaviors of animals, three times a week (Monday, Wednesday and Friday) Tumor volume and body weight were measured. Tumor volume was measured by vernier calipers with the formula TV = 0.5×a×b ² , where a is the long diameter of the tumor and b is the short diameter of the tumor.

Experimental results:

In the Ba/F3-KIF5B-RET-G810R cell subcutaneous allograft tumor BALB/c nude mouse model, compound 49 and compound 62 showed a very significant tumor inhibitory effect at a single dose of less than 50 mg/kg (TGI are all greater than 60%). At the end of the 14-day treatment, using TGI as an indicator, the tumor suppressor effect of compound 49 and compound 62 was significantly better than that of the marketed RET inhibitors BLU-667 and LOXO-292. During the administration period, the general states of the experimental animals in each group were good, such as activity and food intake, and there was no obvious weight loss and adverse reactions. Note: The calculation formula of TGI: TGI (%) = [1-(T ₁₂ -T ₀ )/(V ₁₂ -V ₀ )] × 100 (T ₁₂ -treatment group at the end of administration (the 12th day), the average tumor Volume; T ₀ - the mean tumor volume at the start of the treatment group (day ₀ ); V ₁₂ - the mean tumor volume in the solvent control group at the end of the treatment (the 12 day); Day 0) Mean tumor volume)

(g) In vivo screening experiment - Pharmacodynamics test in NVSG xenograft model of detecting compound inhibition of Ba/F3-KIF5B -RET-G810S 1. Resuscitate Ba/F3 KIF5B-RET-G810S cells and culture in vitro to obtain 1X10E8 cells. 2. 54 6-8 week old male NVSGs were adaptively reared for 1 week and weighed. 3. Dilute the diluted cell suspension and Matrigel in a ratio of 1:1. After mixing, put it on ice, suck the suspension with a 1mL sterile insulin syringe, inoculate 0.1mL of the cell suspension subcutaneously in each mouse, and inoculate 2*10^6 Ba/F3-KIF5B-RET-G810R cells per mouse indivual. 4. After inoculation, observe daily, palpate regularly, measure tumor volume and body weight once a week, when the average tumor volume reaches about 80-120 mm ³ , randomly divide into 6 groups according to tumor volume and body weight, with 6 animals in each group. Dosing was started immediately after grouping. The dosing start date is considered day 0. 5. Mice were orally administered each test compound one to five times a day for a total of 14 days. 6. Check the animal's health and death every working day. Routine checks include the animal's tumor growth, mobility, diet, weight, eyes, hair and other abnormal behaviors. 7. After inoculation and before grouping, when tumors were visible, the tumor volume of experimental animals was measured once a week. After inoculation and grouping, the tumor volume of animals in the experiment was measured once a week. Tumor volume was measured by vernier calipers with the formula TV = π/6×a×b ² , where a is the long diameter of the tumor and b is the short diameter of the tumor.

Experimental results:

In the NVSG xenograft model of Ba/F3 KIF5B-RET-G810S, compound 49 and compound 62 showed a very significant tumor inhibitory effect (TGI greater than 60%) under the condition of a single dose of less than 50 mg/kg. . At the end of the 14-day treatment, using TGI as an indicator, the tumor suppressor effect of compound 49 and compound 62 was significantly better than that of the marketed RET inhibitors BLU-667 and LOXO-292. During the administration period, the general states of the experimental animals in each group were good, such as activity and food intake, and there was no obvious weight loss and adverse reactions. Note: TGI(%)=((mean(C)-mean(C0))- (mean(T)-mean(T0))) / (mean(C)-mean(C0)) * 100%(T– Tumor volume in the administration group; T0—the initial tumor volume in the administration group; C—the tumor volume in the control group; C0—the initial tumor volume in the control group).

)的6位上為胺基的化合物對G810突變的RET具有優異的抑制活性，尤其是6位為烷胺基或氟代烷胺基的化合物。 2、當6位為烷胺基或氟代烷胺基時，對比碳原子個數不同化合物47/57/62/67/68/69，可知烷基為直鏈且碳數為1到3時對G810突變的RET抑制活性較好，尤其是乙基時抑制活性最強。 3、當6位為乙胺基類時，對比未取代和被一個或多個氟原子取代的化合物49/50/56/62的突變型抑制活性，可知乙基被一個氟原子取代的化合物49對G810突變的RET抑制活性更好。 Discussion 1. It can be seen from the above-mentioned biological activity data: Compared with the compound with known activity (LOXO-292), the compound of the present invention is in pyrazolo[1,5-a]pyridine (

The compounds with an amine group at the 6-position of ) have excellent inhibitory activity against G810-mutated RET, especially the compounds with an alkylamino group or a fluoroalkylamine group at the 6-position. 2. When the 6-position is an alkylamine group or a fluoroalkylamine group, compare the compounds with different numbers of carbon atoms 47/57/62/67/68/69, it can be seen that the alkyl group is a straight chain and the carbon number is 1 to 3 The RET inhibitory activity against the G810 mutation was better, especially when the ethyl group had the strongest inhibitory activity. 3. When the 6-position is an ethylamine group, comparing the mutant inhibitory activity of the unsubstituted and substituted compounds 49/50/56/62 with one or more fluorine atoms, it can be seen that the ethyl group is substituted with one fluorine atom. Compound 49 Better RET inhibitory activity against G810 mutation.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above-mentioned teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope limited by the appended patent scope of the present application.

none.

Claims (15)

A compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof;

Wherein, A is selected from the following group: -CN, COOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ or -NHCONR ₂ R ₃ ; B is selected from the following group: R ₇ , -O-(L ₁ ) _m1 -R ₈ , -OCOR ₉ , -NR ₁₀ R ₁₁ , -COOR ₁₂ , -CONR ₁₀ R ₁₁ , -(L ₂ ) _m2 -R ₁₂ , -(L ₂ ) _m2 -NR ₁₀ R ₁₁ ; wherein each L ₁ is independently Selected from the following group: -CR _f R _g -, -CO-, -CO-NH-; each L ₂ is independently selected from the following group: -CR _f R _g , -CO-, -O-CO-; X ₁ and X ₂ are each independently CR or N; wherein, R is selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkyl, H, halogen or cyano; wherein, the substitution refers to being selected from the following One or more groups of the group are substituted: C1-C6 alkyl, halogen, cyano, hydroxyl, amine; Z is selected from substituted or unsubstituted groups of the following group: C1-C6 alkyl, C1-C6 alkoxy base, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 alkylthio; wherein, the substitution means substituted with one or more groups selected from the group consisting of C1-C6 alkyl, halogen, cyano, hydroxyl, amine; R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from substituted or Unsubstituted groups of the following groups: H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C2-C6 alkenyl, C5-C10 aryl or 5-10 membered heteroaryl or R ₂ and R ₃ together with the N atom to which they are attached constitute a substituted or unsubstituted 3-12-membered heterocyclic group; wherein the substitution refers to substitution by one or more groups selected from the group consisting of: C1 -C6 alkyl, halogen, cyano, hydroxyl, amine; R ₇ is a substituted or unsubstituted 5-10 heteroaryl; wherein, the substitution refers to being substituted by one or more groups selected from the following group : C1-C6 alkyl, halogen, cyano, hydroxyl, amine group; R ₈ is selected from substituted or unsubstituted following groups: -C1-C6 alkyl-E, C5-C12 fused bicyclic ring, 5-12 Membered fused heterobicycle, C5-C12 membered spirobicycle or 5-12 membered spiroheterbicycle, E is selected from the group consisting of -CN, -COOR ₁ , -OCOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ or -NHCONR ₂ R ₃ ; wherein the substitution refers to substitution with 1, 2, 3 or 4 groups selected from the group consisting of H, oxo (=O), halogen, cyano, hydroxyl, C1-C6 alkyl , C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 alkyl sulfide base; R ₉ is selected from the group consisting of substituted or unsubstituted: C 1-C6 alkoxy, C1-C6 haloalkoxy, -NR ₁₀ R ₁₁ , -(L ₃ ) _m3 -(3-8 membered cycloheteroalkyl), -(L ₃ ) _m3 -(C5-C10 aryl), -(L ₃ ) _m3 -(5-10-membered heteroaryl), wherein each L ₃ is independently selected from the group of: -CR _f R _g -, -NR _h -; wherein, the substitution Refers to being substituted by one or more groups selected from the following group: C1-C6 alkyl, halogen, cyano, hydroxyl, amino; R ₁₀ and R ₁₁ are independently selected from substituted or unsubstituted groups from the following group: H, C1-C6 alkyl, -(L ₂ ) _m2 -NQ ₁ Q ₂ , C3-C8 cycloalkyl, 3-8-membered cycloheteroalkyl, C6-C10 aryl, 5-10-membered heteroaryl; Alternatively, R ₁₀ and R ₁₁ together with the attached N form a 3-12 membered substituted or unsubstituted heterocycle containing 1-3 N atoms and 0, 1 or 2 O or S atoms; wherein , Q ₁ and Q ₂ are each independently selected from: H, substituted or unsubstituted C1-C6 alkyl, or Q ₁ and Q ₂ and the connected N form a 3-10-membered substituted or unsubstituted heterocycle, so The heterocycle contains 1-3 N atoms and 0, 1 or 2 O or S atoms; wherein, the substitution refers to being substituted by one or more groups selected from the following group: C1-C6 alkyl, cyano base, halogen, hydroxyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl; each R ₁₂ is independently selected from the group consisting of substituted or unsubstituted Group: C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the substitution refers to being selected from the following One or more groups of the group: C1-C6 alkyl, cyano, halogen, hydroxyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl R _f and R _g are each independently selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, OH, NH ₂ , C3-C6 cycloalkyl; R _h is independently selected from the following Group: H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl; n is 0, 1, 2; m ₁ is 1, 2, 3, 4, 5 or 6; m ₂ is 1 , 2, 3, 4, 5 or 6; m ₃ is 0, 1 or 2; with the proviso that, when B is R ₇ , A is selected from the group consisting of: -COOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ , -NHCONR ₂ R ₃ . The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein A is selected from the group consisting of -CN, -COOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ or -NHCONR ₂ R ₃ ; wherein R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered cycloheteroalkane base, C2-C6 alkenyl, C5-C10 aryl or 5-10-membered heteroaryl; R ₄ is selected from the following groups of substituted or unsubstituted: C1-C3 alkyl, C3-C6 cycloalkyl, 3 -6-membered cyclic heteroalkyl, C2-C4 alkenyl, phenyl, pyrazole, pyridine, furan, thiophene, oxazole, isoxazole, triazole; wherein, the substitution refers to C1-C3 alkyl replace. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein B is selected from the group consisting of R ₇ , -O-(L ₁ ) _m1 -R ₈ , -NR ₁₀ R ₁₁ , -CONR ₁₀ R ₁₁ , -(L ₂ ) _{m 2} -R ₁₂ , -(L ₂ ) _{m 2} -NR ₁₀ R ₁₁ ; the limitation is that when B is R ₇ , A is selected from The next group: -COOR ₁ , -CONR ₂ R ₃ , -NHCOR ₄ , -NHCONR ₂ R ₃ ; wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , L ₁ , L ₂ , m ₁ , m ₂ , R ₈ , R ₁₀ , R ₁₁ and R ₁₂ are as defined in claim 1 . The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein -(L ₁ ) _m1 - is selected from the group consisting of -(CH ₂ ) ₂ - , -CO-, -CO-NH-. The compound as claimed in claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein R ₈ is selected from the group consisting of substituted or unsubstituted groups: 5-12-membered condensed A heterobicyclic ring or a 5-12 membered spiroheterobicyclic ring, the heterobicyclic ring contains 1-3 N atoms and 0, ₁ or 2 O or S atoms as ring atoms, and the N atom in the heterobicyclic ring is connected to the L part; Wherein, the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the group consisting of H, oxo (=O), halogen, cyano, hydroxyl, C1-C6 alkyl, C3-C8 Cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 alkylthio. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein R ₁₀ and R ₁₁ are each independently selected from the group consisting of substituted or unsubstituted groups: H , C1-C3 alkyl, -(CH ₂ ) ₂ -NQ ₁ Q ₂ , C3-C6 cycloalkyl, 3-6 membered cycloheteroalkyl, phenyl, pyrazole, pyridine, furan, thiophene, oxazole, Isoxazole, triazole; alternatively, R ₁₀ and R ₁₁ together with the attached N form a 3-8 membered substituted or unsubstituted heterocycle containing 1-3 N atoms and 0, 1 or 2 O or S atoms; wherein, Q ₁ and Q ₂ are each independently selected from: H, C1-C3 alkyl; or Q ₁ and Q ₂ and the connected N form a 3-10-membered substituted or unsubstituted hetero ring, the heterocyclic ring contains 1-3 N atoms and 0, 1 or 2 O or S atoms, and the substitution refers to the substitution of one or more groups selected from the group of C1-C3 alkyl, cyano base, halogen, hydroxyl. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein the compound has the structure represented by formula II

In the formula, R _m and R _n are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C3 alkyl; wherein, the substitution refers to being substituted by 1-2 halogen atoms; X ₁ and X ₂ is each independently CH or N. The compound of claim 7 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein R _m and R _n are each independently selected from: H, methyl, ethyl, n _{- propyl} , _-CH2F , _-CHF2 , _-CH2CH2F , _-CH2CHF2 , _-CHFCH3 , _{-CHFCH2F , -CH2CH2CH2F , or -CH2CHFCH2F} . The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein the compound has the structure represented by formula III

_Rm is selected from: H, methyl, ethyl, n _{- propyl} , _-CH2F , _-CHF2 , _-CH2CH2F , _-CH2CHF2 , _-CHFCH3 , _-CHFCH2F , -CH _{2CH2CH2F or -CH2CHFCH2F . _} The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein the compound has the structure shown in formula IV

In the formula, R _A and R _B are each independently selected from: H, F, methyl. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein the compound is selected from the group consisting of:

. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, wherein the pharmaceutically acceptable salt is acetate, Adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonic acid salt, cyclopentane propionate, diglycolate, lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate Acid salt, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, maleate, mesylate, naphthalenesulfonate, nicotinate, nitrate, oxalic acid Salts, pectates, persulfates, phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates, tartrates , thiocyanate, tosylate, dodecanoate. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof; and a pharmaceutically acceptable carrier or diluent. Use of a compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 in the preparation of a medicament for inhibiting RET kinase activity in a cell or a subject. The use according to claim 14, wherein the medicament is used for the treatment of RET-related diseases and the following disorders: the expression or activity or level of the RET gene, RET kinase, or any of them.