CN115466273A

CN115466273A - Substituted Alkynyl Heterocycles

Info

Publication number: CN115466273A
Application number: CN202210663766.2A
Authority: CN
Inventors: 段小伟; 张凯; 孙永亮; 陈曦; 李海州; 崔先杰; 许新合; 刘希杰; 孙颖慧
Original assignee: Capital Pharmaceutical Holdings Beijing Co ltd
Current assignee: Capital Pharmaceutical Holdings Beijing Co ltd
Priority date: 2021-06-11
Filing date: 2022-06-10
Publication date: 2022-12-13

Abstract

The present application relates to substituted alkynyl heterocyclic compounds of formula II. The present invention relates to substituted alkynyl heterocyclic compounds having biostatic activity, processes for their preparation, pharmaceutical compositions thereof, and to the use of such compounds and their pharmaceutical compositions for the treatment of diseases where biostatic benefits are obtained, such as the treatment of cancer. During the preparation process, the compound of the formula I is obtained through reactions such as iodination, amination, upper protection, coupling, deprotection, ring-closure reaction and the like.

Description

Substituted alkynyl heterocyclic compounds

Technical Field

The present invention relates generally to novel substituted alkynyl heterocyclic compounds having SHP2 inhibitory activity, processes for their preparation, pharmaceutical compositions thereof, and to the use of such compounds and pharmaceutical compositions thereof in the treatment of diseases where SHP2 enzyme inhibition is beneficial, such as in the treatment of cancer.

Background

Cancer is a serious disease which seriously threatens human health and life, particularly, the morbidity and the mortality of cancer in recent years are in a rapid rising trend, and the cancer surpasses cardiovascular diseases and becomes the first killer of human health. The proliferation, apoptosis, metastasis and the like of tumors are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside cells. In these signaling pathways, protein phosphorylation and dephosphorylation are critical, and this reversible process is co-regulated by kinases and phosphatases. Phosphorylation of Protein Tyrosine Kinases (PTKs) and dephosphorylation of Protein Tyrosine Phosphatases (PTPs) are a reversible pair of processes that maintain a dynamic equilibrium between them to maintain normal physiological functions of cells. Whereas abnormal phosphorylation can lead to the development of cancer, inflammation, diabetes and other diseases.

The SHP2 protein is an non-receptor protein tyrosine phosphatase coded by ptpn11 gene, is widely expressed in various tissues, and participates in important physiological and pathological processes such as embryonic development, metabolism, immune response, tumorigenesis and the like.

The SHP2 protein consists of two SH2 domains (N-SH 2 and C-SH 2) connected in series at the N terminal, a PTP catalytic domain and a C terminal tail part with a regulating effect. The SH2 domain is a conformational switch that mediates the interaction of the SHP2 protein with phosphotyrosine-containing activators (e.g., insulin receptor substrate 1-IRS1 and GRB 2-related binding protein 1-GAB 1) and the intramolecular interaction of the SH2 domain with the PTP catalytic domain. In the unstimulated state, the SHP2 domain binds to the PTP domain, blocking the catalytically active site, leaving the SHP2 phosphatase activity in a self-inhibitory state. When the SH2 domain binds to the activator, inhibitory intramolecular interactions are released and the SHP2 phosphatase is in an open conformation, allowing the SHP2 substrate to localize to the catalytically active site and function as a phosphatase. The activity of SHP2 is converted so that various mutations of SHP2 may destroy the self-inhibition state of SHP2, resulting in over-activation of the phosphatase activity of SHP2 protein, and thus cancer. Both experimental and clinical data confirm that SHP2 plays a promoting role in most cancers, and as the first tyrosine phosphatase to be discovered to promote cancer development, it has received great attention in the cancer field, and its phosphatase activity plays an important role in intracellular signaling.

SHP2 is involved in regulating cell signal transduction pathways activated by cytokines, growth factors and hormones, including RAS/ERK, JAK/STAT, PI3K/AKT and NF-kB signal pathways, so as to regulate physiological functions of cell proliferation, differentiation, cell cycle maintenance, migration and the like. Meanwhile, SHP2 also mediates a compensatory activation pathway after kinases such as MEK and the like are inhibited, thereby promoting the occurrence of tumor drug resistance. As a downstream molecule of the PD-1 receptor, SHP2 is also involved in the transduction of T cell inhibitory signals. It has been shown that SHP2 is a downstream molecule of PD-1 signaling that not only inhibits T cell activation but also promotes T cell disability. Thus, targeting SHP2 can restore or enhance T cell-mediated anti-tumor immune function. In addition, SHP2 can inhibit IFN-gamma mediated immune response by inactivating signal transduction and activator of transcription STAT 1.

In recent years, SHP2 activating mutation and high expression are successively found in leukemia, solid tumor, melanoma, glioblastoma, lung cancer, breast cancer and knoop syndrome, and are closely related to the occurrence, development and prognosis of tumor. Currently, SHP2 has been studied as a target molecule for clinical tumors. The action mechanism of the traditional SHP2 inhibitor (such as II-B08 and PHPS 1) is that the traditional SHP2 inhibitor is combined with PTP catalytic domain of SHP2, and prevents tyrosine phosphorylation substrate from entering into catalytic site, thereby inhibiting the phosphatase activity of SHP 2. However, due to the highly conserved, polar and charged environment of the PTP catalytic domains of various phosphatases, the traditional SHP2 inhibitor has great defects in specificity and bioavailability, and the clinical application of the traditional SHP2 inhibitor is limited. Therefore, the development of a SHP2 inhibitor with high specificity, high safety and strong cell membrane permeability is a key for determining whether SHP2 can be a novel tumor intervention target, and an SHP2 protein allosteric inhibitor is a major direction of current research.

Disclosure of Invention

In one aspect, the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof,

wherein,

ring A is

Or alternatively

Wherein carbon is bound to Y, R ₂₁ And R ₂₂ Each independently is H or C _1-6 Alkyl radical, R ₂₀ Is H,

Or alternatively

X is selected from hydrogen and C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl, 3-8 membered heteroalicyclic, C _6-10 Aryl and 5-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl and 3-8 membered heteroalicyclic groups optionally substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ 、C _1-6 Alkyl, or phenyl, said C _6-10 The aryl and 5-to 10-membered heteroaryl groups may be spiro-fused to an unsaturated alicyclic ring, heteroalicyclic ring, or spiro-ring, and may be optionally substituted with one or moreMultiple halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 3-8 membered heterocyclic group, C _6-10 Aryl, -O-C _6-10 Aryl, or 5-10 membered heteroaryl, optionally substituted with one or more halogen, -CF, -C, or spiro rings ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 、C _6-10 Aryl, -O-C _6-10 Aryl, 5-10 membered heteroaryl, or = O,

R ₃₀ and R ₃₁ Each independently selected from H and C _1-6 Alkyl, or

R ₃₀ And R ₃₁ Are joined together to form a bond, or

R ₃₀ And X are linked together to form C _3-8 Cycloalkyl or 3-to 8-membered heteroalicyclic, C _3-8 Cycloalkyl and 3-8 membered heteroalicyclic groups optionally substituted with one or more halogens, -CN, C _3-8 Cycloalkyl, 3-8 membered heteroalicyclic, - (CO) -R ₃₂ 、-(SO ₂ )-R ₃₂ 、-OH、-O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ Or C _1-6 Alkyl is substituted, or

R ₃₁ And X are linked together to form C _3-8 Cycloalkyl or 3-8 membered heteroalicyclic group, C _3-8 Cycloalkyl and 3-8 membered heteroalicyclic groups optionally substituted with one or more halogens, -CN, C _3-8 Cycloalkyl, 3-8 membered heteroalicyclic, - (CO) -R ₃₂ 、-(SO ₂ )-R ₃₂ 、-OH、-O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ Or C _1-6 The substitution of the alkyl group is carried out,

R ₃₂ is selected from C _1-6 Alkyl radical, C _3-8 Cycloalkyl, 3-8 membered heteroalicyclic, said alkyl, cycloalkyl and heteroalicyclic being optionally substituted by halogen,

r is selected from C _1-6 Alkyl and C _3-6 Cycloalkyl radical, said alkyl radicalAnd cycloalkyl optionally substituted by halogen, -CF ₃ 、-OH、-C _1-6 Alkyl, -O-C _1-6 Alkyl, or C _3-6 The cycloalkyl group is substituted by the alkyl group,

R ₃ and R ₄ Each independently selected from hydrogen and C _1-6 Alkyl and C _3-6 A cycloalkyl group, which is a cyclic alkyl group,

y is selected from C _6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heteroalicyclic and 5-15 membered spirocyclic groups, which may optionally be substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Optionally substituted, said heteroalicyclic and spirocyclic groups optionally with C _6-10 Aryl or 5-10 membered heteroaryl fused to heteroalicyclic and spirocyclic groups, the aryl or heteroaryl being optionally fused to one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 And (3) cycloalkyl substitution.

In some embodiments, ring a is

In some embodiments, R ₃₀ And R ₃₁ Joined together to form a bond.

In some embodiments, R ₂₀ Is composed of

In some embodiments, the 5-15 membered spirocyclic group is a 5-15 membered spiroheterocyclic group, which may optionally be substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Substituted spiroheterocyclyl optionally with C _6-10 Aryl or 5-to 10-membered heteroaryl fused with spiroThe heterocyclyl-fused aryl or heteroaryl group may optionally be substituted by one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 And (3) cycloalkyl substitution.

In some embodiments, the 5-10 membered heteroaryl is C _5-10 A heteroaryl group.

In some embodiments, X is selected from a 5-10 membered heteroaryl, which 5-10 membered heteroaryl may be fused with an unsaturated alicyclic, heteroalicyclic, or spiro ring, and may optionally be substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R4、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 3-8 membered heterocyclic group, C _6-10 Aryl, -O-C _6-10 Aryl, or C5-10 heteroaryl, said unsaturated alicyclic, heteroalicyclic, or spirocyclic ring optionally substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 、C _6-10 Aryl, -O-C _6-10 Aryl radical, C _5-10 Heteroaryl, or = O substitution.

In some embodiments, X is selected from 5-10 membered heteroaryl, which 5-10 membered heteroaryl may optionally be substituted with one or more halogens, -CF ₃ 、-OH、-CN、-NH ₂ 、-C _1-6 Alkyl, or 3-8 membered heterocyclyl.

In some embodiments, Y is selected from the following structures:

X ₁ 、X ₂ and X ₃ Each independently selected from the group consisting of a bond, O, CR _a R _b Or NR _c ，X ₄ Is C, CH or N;

R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ and R ₁₂ Each independently of the otherIs selected from H, -OH, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 An alkoxy group; and cannot be simultaneously-OH or-NH ₂ ；

R _a 、R _b And R _c Each independently selected from H, -OH, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 An alkoxy group;

ring A is selected from substituted or unsubstituted C _4-8 Cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted C _5-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclyl or heteroaryl comprising 1-3 heteroatoms selected from the group consisting of: n, O, S or P;

R ₁₃ and R ₁₄ Each independently selected from H, -OH, halogen, cyano, substituted or unsubstituted amino, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 An alkoxy group;

n is any integer of 0 to 3;

by substituted is meant that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogen, -OH, -NO ₂ 、-NH ₂ 、-CN。

In some embodiments, Y is selected from the following structures:

wherein X ₁ 、X ₂ 、X ₃ 、R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And n is as defined above.

In some embodiments, X ₁ And X ₂ One of them is O, X ₃ Is a key.

In some embodiments, X ₁ And X ₂ Is one of CH ₂ And the other is a key.

In some embodiments, Y is selected from C _6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heteroalicyclic, which may optionally be substituted with one or more-OH, -NH ₂ Or C _1-6 Alkyl substitution;

preferably, the 5-10 membered heteroaryl is C _5-10 A heteroaryl group.

In some embodiments, Y is selected from 3-12 membered heteroalicyclic, which may optionally be substituted with one or more-OH, -NH ₂ Or C _1-6 And (3) alkyl substitution.

In some embodiments, R ₃₀ And X are linked together to form C _3-8 Cycloalkyl or 3-to 8-membered heteroalicyclic, C _3-8 Cycloalkyl and 3-8 membered heteroalicyclic groups optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ Or C _1-6 Alkyl is substituted, or

R ₃₁ And X are linked together to form C _3-8 Cycloalkyl or 3-8 membered heteroalicyclic group, C _3-8 Cycloalkyl and 3-8 membered heteroalicyclic groups optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ Or C _1-6 The substitution of the alkyl group is carried out,

in another aspect, the present invention provides a compound represented by formula (I-1) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof,

wherein,

R ₂₀ is H,

Or

X is selected from hydrogen and C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl, 3-8 membered heteroalicyclic, C _6-10 Aryl and 5-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl and C _3-8 The heteroalicyclic group may optionally be substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ 、C _1-6 Alkyl, or phenyl, said C _6-10 The aryl and 5-10 membered heteroaryl groups may be spiro-fused with an unsaturated alicyclic, heteroalicyclic, or ring, and may be optionally substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 3-8 membered heterocyclic group, C _6-10 Aryl, -O-C _6-10 Aryl, or C _5-10 Heteroaryl substituted, said unsaturated alicyclic, heteroalicyclic, or spirocyclic ring optionally substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 、C _6-10 Aryl, -O-C _6-10 Aryl radical, C _5-10 Heteroaryl, or = O substitution,

r is selected from C _1-6 Alkyl and C _3-6 Cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen, -CF ₃ 、-OH、-C _1-6 Alkyl, -O-C _1-6 Alkyl, or C _3-6 The cycloalkyl group is substituted by the alkyl group,

R ₃ and R ₄ Each independently selected from hydrogen and C _1-6 Alkyl and C _3-6 A cycloalkyl group,

y is selected from C _6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heteroalicyclic and 5-15 membered spirocyclic groups, which may optionally be substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Optionally substituted, said heteroalicyclic and spirocyclic groupsGround and C _6-10 Aryl or 5-10 membered heteroaryl fused to heteroalicyclic and spirocyclic groups, the aryl or heteroaryl being optionally fused to one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 The substitution of cycloalkyl is carried out,

in some embodiments, R ₂₀ Is composed of

In some embodiments, the 5-15 membered spirocyclic group is a 5-15 membered spiroheterocyclic group, which may optionally be substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Substituted spiroheterocyclyl optionally with C _6-10 Aryl or 5-10 membered heteroaryl fused, spiro heterocyclyl fused aryl or heteroaryl optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl is substituted.

In some embodiments, X is selected from a 5-10 membered heteroaryl, which 5-10 membered heteroaryl may be fused with an unsaturated alicyclic, heteroalicyclic, or spiro ring, and may optionally be substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 3-8 membered heterocyclic group, C _6-10 Aryl, -O-C _6-10 Aryl, or C _5-10 Heteroaryl substituted, the unsaturated alicyclic, heteroalicyclic, or spiro ring optionally substituted with one or more halogen, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 、C _6-10 Aryl, -O-C _6-10 Aryl radical, C _5-10 Heteroaryl, or = O substitution.

In some embodiments, X is selected from 5-10 membered heteroaryl, which 5-10 membered heteroaryl may optionally be substituted with one or more halogen, -CF ₃ 、-OH、-CN、-NH ₂ 、-C _1-6 Alkyl, or 3-8 membered heterocyclyl.

In some embodiments, Y is selected from the following structures:

X ₁ 、X ₂ and X ₂ Each independently selected from the group consisting of a bond, O, CR _a R _b Or NR _c ；

R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ And R ₁₂ Each independently selected from H, -OH, halogen, substituted or unsubstituted amino, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1-6 An alkoxy group; and cannot be simultaneously-OH or-NH ₂ ；

ring A is selected from substituted or unsubstituted C _4-8 Cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted C _5-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclyl or heteroaryl comprising 1-3 heteroatoms selected from the group consisting of: n, O, S or P;

n is any integer of 0 to 3;

the substituent means a groupOne or more hydrogen atoms of the group are substituted with a substituent selected from the group consisting of: halogen, -OH, -NO ₂ 、-NH ₂ 、-CN。

In some embodiments, X ₁ And X ₂ One of them is O, X ₃ Is a key.

In some embodiments, X ₁ And X ₂ Is one of CH ₂ And the other is a key.

In some embodiments, Y is selected from C _6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heteroalicyclic optionally substituted with one or more-OH, -NH ₂ Or C _1-6 Alkyl substitution;

preferably, the 5-10 membered heteroaryl is C _5-10 A heteroaryl group.

In some embodiments, Y is selected from 3-12 membered heteroalicyclic, which may optionally be substituted with one or more-OH, -NH ₂ Or C _1-6 Alkyl substitution.

In another aspect, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof,

wherein,

x is selected from hydrogen and C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl, C _3-8 Hetero alicyclic group, C _6-10 Aryl and 5-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl and C _3-8 The heteroalicyclic group may optionally be substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ 、C _1-6 Alkyl, or phenyl, said C _6-10 The aryl and 5-10 membered heteroaryl groups can be spiro-fused to an unsaturated alicyclic ring, heteroalicyclic ring, or spiro-ring, and can optionally be fused by one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 3-8 membered heterocyclic group, C _6-10 Aryl, -O-C _6-10 Aryl, or C _5-10 Heteroaryl substituted, said unsaturated alicyclic, heteroalicyclic, or spirocyclic ring optionally substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 、C _6-10 Aryl, -O-C _6-10 Aryl radical, C _5-10 Heteroaryl, or = O substitution,

R ₃ and R ₄ Each independently selected from hydrogen, C _1-6 Alkyl and C _3-6 A cycloalkyl group, which is a cyclic alkyl group,

y is selected from C _6-10 Aryl, 5-10 membered heteroaryl, C _3-12 Heteroalicyclic and 5-15 membered spirocyclic groups, said aryl, heteroaryl, heteroalicyclic and spirocyclic groups optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Optionally substituted, said heteroalicyclic and spirocyclic groups optionally with C _6-10 Aryl or 5-to 10-membered heteroaryl fused to heteroalicyclic and spirocyclic groups, the aryl or heteroaryl being optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 The cycloalkyl group is substituted by the alkyl group,

in some embodiments, Y is selected from C _6-10 Aryl, 5-to 10-membered heteroaryl, C _3-12 Heteroalicyclic and 5-15 membered spirocyclic groups, said aryl, heteroaryl, heteroalicyclic and spirocyclic groups optionally substituted with one or more halogens, -OH, -O-C _1-6 An alkyl group,-NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Substituted, the heteroalicyclic and spirocyclic groups optionally fused with a 5-10 membered heteroaryl, the heteroaryl fused with heteroalicyclic and spirocyclic groups optionally fused with one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 The cycloalkyl group is substituted by the alkyl group,

in some embodiments, the 5-15 membered spirocyclic group is a 5-15 membered spiroheterocyclic group, which may optionally be substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Substituted spiroheterocyclyl optionally with C _6-10 Aryl or 5-to 10-membered heteroaryl fused, spiro heterocyclyl fused aryl or heteroaryl optionally substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl is substituted.

In some embodiments, X is selected from a 5-10 membered heteroaryl group, which 5-10 membered heteroaryl group may be fused to an unsaturated alicyclic, heteroalicyclic, or spirocyclic ring, and may optionally be substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 3-8 membered heterocyclic group, C _6-10 Aryl, -O-C _6-10 Aryl, or C _5-10 Heteroaryl substituted, the unsaturated alicyclic, heteroalicyclic, or spiro ring optionally substituted with one or more halogen, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 、C _6-10 Aryl, -O-C _6-10 Aryl radical, C _5-10 Heteroaryl, or = O substitution.

In some embodiments, Y is selected from the following structures:

n is any integer of 0 to 3;

the substitution refers to one or more hydrogens on the groupThe atoms are substituted with a substituent selected from the group consisting of: halogen, -OH, -NO ₂ 、-NH ₂ 、-CN。

In some embodiments, X ₁ And X ₂ One of them is O, X ₃ Is a bond.

In some embodiments, X ₁ And X ₂ One of them is CH ₂ And the other is a key.

In some embodiments, Y is selected from C _6-1 0 aryl, 5-10 membered heteroaryl and C _3-12 Heteroalicyclic, said aryl, heteroaryl and heteroalicyclic optionally substituted with one or more-OH, -NH ₂ Or C _1-6 Alkyl substitution;

preferably, the 5-10 membered heteroaryl is C _5-10 A heteroaryl group.

In some embodiments, Y is selected from C _3-12 Heteroalicyclic optionally substituted with one or more-OH, -NH ₂ Or C _1-6 And (3) alkyl substitution.

In some embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts, solvates, polymorphs, or tautomers thereof:

in another aspect, the present invention provides a pharmaceutical composition comprising a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, and optionally a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a method of treating a disease associated with SHP2, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, or a pharmaceutical composition thereof.

In another aspect, the present invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, polymorph or tautomer thereof, or a pharmaceutical composition thereof, or any one of the foregoing, in combination with an SHP2 inhibitor or a KRAS inhibitor or an EGFR inhibitor, in the manufacture of a medicament for the treatment of a disease associated with SHP2 and/or KRAS and/or EGFR.

In some embodiments of the invention, the disease associated with SHP2 and/or KRAS and/or EGFR is leukemia, melanoma, glioblastoma, lung cancer, breast cancer or knoop syndrome.

On the other hand, SHP2 acts upstream of KRAS, and the Hana Algul team (Mutant KRAS-driven cancer dependent on PTPN11/SHP2 phohases, nature Medicine 2018) demonstrated that SHP2 small molecule inhibitors have significant efficacy against aggressive KRAS tumors such as Pancreatic Ductal Adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), and protein tyrosine phosphatase SHP2 has become a key drug target for aggressive KRAS tumors, and furthermore, schneeberger, v.e. team (Inhibition of SHP2 suppressed cancers EGFR-induced lung cancer model of lung adoptive cancer. Therefore, the SHP2 small-molecule inhibitor of the present invention can be used alone or in combination with a KRAS inhibitor (AMG 510, etc.) and an EGFR inhibitor (Iressa, tarceva, etc.) in the prior art to effectively inhibit the occurrence and progression of tumors.

On the other hand, similarity in biological activity is often found in functional groups with similar steric or electronic properties. The structures that play the same biological role in a drug molecule are called bioisosteres, which do not affect the primary biological activity of the drug by replacing the original functional group in the drug with another functional group. For example, substitution of a monovalent atom or group such as OH, NH2, F, SH, etc., the carboxyl group may be substituted with a phosphate, tetrazole, etc.

Certain chemical terms

The term "compound" as used herein includes all stereoisomers, geometric isomers, tautomers and isotopes. The compounds of the invention may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

The compounds of the invention also include tautomeric forms. Tautomeric forms result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton.

The invention also includes all isotopic atoms, whether in the intermediate or final compound. Isotopic atoms include those having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The terms "fused" or "fused ring" as used herein, alone or in combination, refer to a cyclic structure in which two or more rings share one or more bonds.

The term "spiro" or "spirocyclic" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

The term "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group consisting of carbon and hydrogen atoms, such as C _1-20 Alkyl, preferably C _1-6 Alkyl groups such as methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl, and the like. The alkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxy, aryl, heteroaryl, amino, halo, sulfonyl, sulfinyl, phosphoryl, and hydroxy.

The term "C _1-6 Alkyl "means a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is connected to the rest of the molecule by a single bond, having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, amino, halo, and hydroxy. Non-limiting examples of unsubstituted alkyl groups include, but are not limited to, groups such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylhexyl, and the like.

The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched chain monovalent hydrocarbon radical having one or more C = C double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The double bond in these groups may be in either the cis or trans conformation and should be understood to encompass both isomers. Examples include, but are not limited to, vinyl (CH)＝CH ₂ ) 1-propenyl (CH) ₂ CH＝CH ₂ ) Isopropenyl (C (CH) ₃ )＝CH ₂ ) Butenyl, 1, 3-butadienyl and the like. When a numerical range is present for alkenyl as defined herein, e.g. "C ₂ -C ₆ Alkenyl "or" C _2-6 The "alkenyl group" means an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkenyl group herein also covers the case where no numerical range is specified.

The term "cycloalkyl" refers to an all-carbon monocyclic saturated hydrocarbon group consisting of carbon and hydrogen atoms, such as C _3-20 Cycloalkyl, preferably C _3-6 Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The cycloalkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxy, aryl, heteroaryl, amino, halo, sulfonyl, sulfinyl, phosphoryl, and hydroxy.

The terms "heterocyclyl", "heterocycloalkyl", "heterocycle" refer to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, the nitrogen, carbon or sulfur of the heterocyclyl group may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule through a single bond via a carbon or heteroatom in the ring. The heterocyclic group containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atoms on the non-aromatic ring are attached to the rest of the molecule. For purposes of this application, a heterocyclyl group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, most preferably 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halo, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms, having 5,6,7,8, 9, 10, 11 or 12 ring atoms, containing 1,2,3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having a completely conjugated pi-electron system. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halo, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.

The term "alicyclic" refers to a monocyclic, fused or spiro carbocyclic ring of 3 to 12 ring atoms, having 3,4, 5,6,7,8, 9, 10, 11 or 12 ring atoms, such rings may be saturated or unsaturated (e.g. having one or more double bonds), but not having a fully conjugated pi-electron system.

The term "alicyclic" refers to a group remaining after 1 hydrogen atom has been removed from an "alicyclic" molecule. Heteroalicyclic groups may be unsubstituted or have hydrogen atoms optionally substituted with substituents including, but not limited to, alkyl, alkoxy, = O, aryl, aralkyl, -COOH, -CN, amino, halogen, and hydroxy.

The term "heteroalicyclic" refers to a monocyclic, fused or spiro ring of 3 to 12 ring atoms having 3,4, 5,6,7,8, 9, 10, 11 or 12 ring atoms wherein 1 or 2 ring atoms are selected from N, O, S (O) _n (wherein n is 0,1 or 2) and the remaining ring atoms are C. Such rings may be saturated or unsaturated (e.g. having one or more double bonds), but do not have a fully conjugated pi-electron system. Examples of 3-membered saturated heteroalicyclic include, but are not limited to

Examples of 4-membered saturated heteroalicyclic include, but are not limited to

Examples of 5-membered saturated heteroalicyclic include, but are not limited to

Examples of 6-membered saturated heteroalicyclic include, but are not limited to

Examples of 7-membered saturated heteroalicyclic include, but are not limited to

Examples of 5-membered unsaturated heteroalicyclic include, but are not limited to

Examples of 6-membered unsaturated heteroalicyclic include, but are not limited to

The term "heteroalicyclic" refers to a group that remains after 1 hydrogen atom has been removed from the "heteroalicyclic" molecule. Heteroalicyclic groups may be unsubstituted or have hydrogen atoms optionally substituted with substituents including, but not limited to, alkyl, alkoxy, = O, aryl, aralkyl, -COOH, -CN, amino, halogen, and hydroxy.

The compounds of the invention or their salts can be administered alone as the active substance, preferably in the form of their pharmaceutical compositions.

"pharmaceutical composition" refers to a formulation of one or more compounds of the invention or salts thereof with a carrier generally accepted in the art for the delivery of biologically active compounds to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the invention to an organism.

The term "pharmaceutically acceptable carrier" refers to those carriers which do not have a significant irritating effect on the organism and which do not impair the biological activity and performance of the active compound. "pharmaceutically acceptable carrier" means an inert substance useful for administering an active ingredient in conjunction with the active ingredient, including, but not limited to, any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is approved by the U.S. food and drug administration for use in humans or animals (e.g., livestock). Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

Administration of a compound of the invention or a pharmaceutically acceptable salt thereof, in pure form or in a suitable pharmaceutical composition, may be carried out by any acceptable mode of administration providing agents of similar use. The pharmaceutical compositions of the invention may be prepared by combining a compound of the invention with a suitable pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral.

The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.

In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.

Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid excipients, optionally the resulting mixture is milled, if desired with further suitable auxiliaries, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like. Such as microcrystalline cellulose, glucose solutions, gum arabic syrups, gelatin solutions, sucrose and starch pastes; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silicon dioxide; croscarmellose sodium, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, cross-linked polyvinylpyrrolidone, and the like. The dragee cores may optionally be coated, in particular with an enteric coating, according to methods well known in normal pharmaceutical practice.

The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Suitable excipients, such as fillers, buffers or surfactants can be used.

Yet another aspect of the invention relates to the use of compounds of formulae I to VI, or pharmaceutically acceptable salts, solvates, polymorphs, metabolites and the like thereof, in the treatment of a disease benefiting from SHP2 inhibition. The disease benefiting from SHP2 inhibition is selected from cancer.

The substituted alkynyl heterocyclic compound provided by the invention has very good SHP2 inhibitory activity and is expected to become a high-efficiency SHP2 inhibitor drug.

Detailed Description

The following specific examples are included to provide those skilled in the art with a clear understanding of the invention and are included to provide a further understanding of the invention. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. Those skilled in the art will understand that: there are other synthetic routes to the compounds of the present invention, and the following non-limiting examples are provided.

All operations involving easily oxidizable or hydrolyzable raw materials were carried out under nitrogen protection. Unless otherwise stated, the starting materials used in the present invention were all commercially available and used without further purification.

The column chromatography adopts silica gel (200-300 mesh) produced by Qingdao chemical industry Co. The thin layer chromatography was carried out using a precast slab (silica gel 60 PF) manufactured by Merck, inc ₂₅₄ 0.25 mm). Chiral compound separation and determination of enantiomeric excess (ee) using Agilent LC 1200 series (column: CHIRALPAK AD-H,

mm, 5 μm, 30 ℃). Nuclear magnetic resonance chromatography (NMR) was measured using a Varian VNMRS-400 nuclear magnetic resonance instrument; liquid qualityThe combination (LC/MS) used a FINNIGAN Thermo LCQ Advantage MAX, agilent LC 1200 series (column: waters Symmetry C18,

mm, 5 μm, 35 ℃), using ESI (+) ion mode.

Experimental part

Intermediate 1:(3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5]Decane-4-amine dihydrochloride

(3S,4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine dihydrochloride was synthesized following the procedure of intermediate 14 in patent WO 2017216706.

Intermediate 2:((3S, 4S) -8- (3-iodo-5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) oxy) Yl) ethoxy) methyl) -1H-pyrazolo [4,3-b]Pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decane-4-Yl) carbamic acid tert-butyl ester

The starting intermediate (6-chloro-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-5-yl) methanol was synthesized according to the same method as in preparation 179 at page 237 in patent WO 2019167000.

Step 1: 6-chloro-3-iodo-5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-e

The intermediate (6-chloro-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-5-yl) methanol (2.28 g), triisopropylsilicon chloride (1.49 g) and imidazole (693 mg) were added to methylene chloride (40 mL), stirred at room temperature overnight, the reaction solution was washed with water, the organic phase was dried over anhydrous sodium sulfate and then the solvent was removed by rotary evaporation under reduced pressure, and 6-chloro-3-iodo-5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine (2.75 g) was obtained by silica gel column chromatography (petroleum ether: ethyl acetate, 5: 1). MS m/z [ LC-MS ]:597.14[ M ] +1].

And 2, step: (3S, 4S) -8- (3-iodo-5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

6-chloro-3-iodo-5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine (2.70 g) was added to n-butanol (30 mL), followed by addition of intermediate 1 (1.32 g) and diisopropylethylamine (5 mL), heating to 120 ℃ and stirring for 2 hours, cooling to room temperature, rotary evaporation of the organic solvent, and silica gel column chromatography (dichloromethane: methanol, 10: 1) to give (3S, 4S) -8- (3-iodo-5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (2.82 g). MS m/z [ LC-MS ]:731.3[ M ] +1].

And step 3: ((3S, 4S) -8- (3-iodo-5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-aminaspiro [4.5] decan-4-yl) carbamic acid tert-butyl ester

(3S, 4S) -8- (3-iodo-5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (2.80 g) was added to methylene chloride (30 mL), diisopropylethylamine (2 mL) was added thereto, di-tert-butyl dicarbonate (1.25 g) was added dropwise with cooling in an ice water bath, and after completion of the addition, it was warmed to room temperature and stirred for 4 hours, the organic solvent was evaporated off by rotary evaporation, and ((3S, 4S) -8- (3-iodo-5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4.05 g) carbamic acid tert-butyl ester was obtained by column chromatography on silica gel. MS m/z [ LC-MS ]:831.35[ M ] +1].

Intermediate 3: (S) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4' -piperidine ] -5-amine trihydrochloride

(S) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidine ] -5-amine trihydrochloride was synthesized according to the method for intermediate AP in patent WO 2020081848.

Intermediate 4: (R) -3H-spiro [ furo [2,3-b ] pyridine-2, 4' -piperidine ] -3-amine dihydrochloride

(R) -3H-spiro [ furo [2,3-b ] pyridine-2,4' -piperidine ] -3-amine dihydrochloride was synthesized according to the method of intermediate S in patent WO 2020201991.

Intermediate 5:(S) -3-methyl-5, 7-dihydrospiro [ cyclopenta [ c ] S]Pyridine-6, 4' -piperidines]-7-Aminotrihydrochloride Salt (salt)

(S) -3-methyl-5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4' -piperidine ] -7-amine trihydrochloride was synthesized by the method of intermediate A5 in patent WO 2020094018.

Intermediate 6:((3S, 4S) -8- (5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) - 1H-pyrazolo [4,3-b ]]Pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decan-4-yl) carbamic acid tert-butyl ester Esters of salicylic acid

The starting intermediate (6-chloro-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-5-yl) methanol was synthesized according to the same method as in preparation 179 on page 237 of patent WO 2019167000.

Step 1: 6-chloro-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine-5-carbaldehyde

Adding the intermediate (6-chloro-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-5-yl) methanol (2.20 g) into dichloromethane (40 mL), adding dess-martin reagent (2.54 g) in portions under cooling in an ice water bath, keeping 0 ℃ for stirring for 2 hours after the addition, washing the reaction solution with saturated sodium sulfite solution, saturated sodium bicarbonate solution and water in sequence, drying the organic phase with anhydrous sodium sulfate, removing the solvent by rotary evaporation under reduced pressure, and separating by silica gel column chromatography (petroleum ether: ethyl acetate, 4: 1) to obtain 6-chloro-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine-5-carbaldehyde (1.98 g). MS m/z [ LC-MS ]:438.98[ 2 ] M +1].

And 2, step: 6-chloro-5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine

6-chloro-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine-5-carbaldehyde (1.96 g) was added to dichloromethane (40 mL), and diethylaminosulfur trifluoride (1.44 g) was added dropwise with cooling in an ice-water bath, and after the dropwise addition, stirring was carried out at 0 ℃ for 1 hour, followed by stirring at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution, washed with water, the organic phase was washed with water, dried over anhydrous sodium sulfate and rotary evaporated under reduced pressure to remove the solvent, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 5: 1) to give 6-chloro-5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine (1.65 g). MS m/z [ LC-MS ]:460.99[ 2 ] M +1].

And step 3: (3S, 4S) -8- (5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

6-chloro-5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine (0.92 g) was added to n-butanol (10 mL), and intermediate 1 (0.56 g) and diisopropylethylamine (2.2 mL) were added, heated to 120 ℃ and stirred for 2 hours, cooled to room temperature, the organic solvent was removed by rotary evaporation, and separated by silica gel column chromatography (dichloromethane: methanol, 10: 1) to give (3S, 4S) -8- (5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (1.10 g). MS m/z [ LC-MS ]:595.15[ M ] +1].

And 4, step 4: ((3S, 4S) -8- (5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamic acid tert-butyl ester

(3S, 4S) -8- (5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (1.10 g) was added to methylene chloride (10 mL), diisopropylethylamine (1 mL) was added, di-tert-butyl dicarbonate (807 mg) was added dropwise with cooling in an ice water bath, after completion of the addition, the mixture was allowed to warm to room temperature and stirred for 4 hours, the organic solvent was removed by rotary evaporation, and silica gel column chromatography (petroleum ether: ethyl acetate, 8: 1) was used to obtain tert-butyl ((3S, 4S) -8- (5- (difluoromethyl) -3-iodo 1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate (1.25 g). MS m/z [ LC-MS ]:695.21[ M ] +1].

Intermediate 7:(S) - (1' - (5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H- Pyrazolo [4,3-b]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-yl) carbamic acid Tert-butyl ester

Referring to the procedure in intermediate 6, intermediate 3 was used instead of intermediate 1 to synthesize (S) - (1 '- (5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4' -piperidin ] -5-yl) carbamic acid tert-butyl ester. MS m/z [ LC-MS ]:728.21[ M ] +1].

Intermediate 8:(S) - (1' - (3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4, 3-b)] Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-yl) carbamic acid tert-butyl ester

Referring to the procedure in intermediate 6, tert-butyl (S) - (1 '- (3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine, can be synthesized by substituting 6-chloro-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine for 6-chloro-5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4' -piperidin ] -5-yl) carbamate with intermediate 3 for intermediate 1. MS m/z [ LC-MS ]:678.21[ M +1].

Intermediate 9:((3S, 4S) -8- (3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4, 3-b]pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decan-4-yl) carbamic acid tert-butyl ester

Referring to the procedure in intermediate 6, tert-butyl ((3S, 4S) -8- (3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate can be synthesized by substituting 6-chloro-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine for 6-chloro-5- (difluoromethyl) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-b ] pyrazine. MS m/z [ LC-MS ]:645.21[ M ] +1].

Example 1:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- ((3-chloro-5-fluoropyridin-4-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanols

Step 1: ((3S, 4S) -8- (3- ((3-chloro-5-fluoropyridin-4-yl) ethynyl) -5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamic acid tert-butyl ester

Intermediate 2 (150 mg), 3-chloro-4-ethynyl-5-fluoropyridine (60 mg), cuprous iodide (12 mg), triethylamine (100 mg), bis (triphenylphosphine) palladium dichloride (21 mg), and tetrahydrofuran (10 mL) were added to a closed tube, replaced with nitrogen, and heated to 80 ℃ and stirred overnight. Cooled to room temperature, poured into water, extracted with methylene chloride, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 5: 1) to give tert-butyl ((3S, 4S) -8- (3- ((3-chloro-5-fluoropyridin-4-yl) ethynyl) -5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate (83 mg). MS m/z [ LC-MS ]:858.43[ M ] +1].

Step 2: ((3S, 4S) -8- (3- ((3-chloro-5-fluoropyridin-4-yl) ethynyl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamic acid tert-butyl ester

Tert-butyl ((3S, 4S) -8- (3- ((3-chloro-5-fluoropyridin-4-yl) ethynyl) -5- (((triisopropylsilyl) oxy) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate (80 mg), tetrabutylammonium fluoride (100 mg) were successively added to tetrahydrofuran (5 mL) and stirred at room temperature overnight. Poured into water, extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude tert-butyl ((3S, 4S) -8- (3- ((3-chloro-5-fluoropyridin-4-yl) ethynyl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate (50 mg) which was used directly in the next reaction. MS m/z [ LC-MS ]:572.22[ M +1].

And step 3: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- ((3-chloro-5-fluoropyridin-4-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

(3S, 4S) -8- (3- ((3-chloro-5-fluoropyridin-4-yl) ethynyl) -5- (hydroxymethyl) -1H-pyrazolo [3, 4-b)]Pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Dec-4-yl) carbamic acid tert-butyl ester (50 mg) was added to a solution of 4M hydrogen chloride in dioxane (2 mL) and stirred at room temperature for 1 hour, dried, 10% aqueous sodium carbonate (10 mL) was added, extraction was performed with dichloromethane, the extracts were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and chromatographed on thin layer silica gel (dichloromethane: methanol, 10: 1) to give (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5.5)]Decan-8-yl) -3- ((3-chloro-5-fluoropyridin-4-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol (30 mg). MS m/z [ LC-MS]：472.17[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.58(s，1H)，8.54(s，1H)，4.79(s，2H)，4.20-4.27(m，1H)，3.86(d，J＝8.8Hz，1H)，3.72(d，J＝8.8Hz，1H)，3.61-3.70(m，2H)，3.10-3.24(m，2H)，3.04(d，J＝4.8Hz，1H)，1.88-2.01(m，2H)，1.70-1.80(m，2H)，1.22(d，J＝6.8Hz，3H)。

Example 2:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) -3- (pyrimidin-5-ylethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanols

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：421.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝9.11(s，1H)，9.02(s，2H)，4.81(s，2H)，4.20-4.26(m，1H)，3.85(d，J＝8.8Hz，1H)，3.71(d，J＝8.8Hz，1H)，3.53-3.62(m，2H)，3.15-3.22(m，1H)，3.06-3.14(m，1H)，3.03(d，J＝4.4Hz，1H)，1.88-2.02(m，2H)，1.70-1.80(m，2H)，1.21(d，J＝6.8Hz，3H)。

Example 3:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (pyridin-4-ylethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：420.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.56(d，J＝6.0Hz，2H)，7.61(d，J＝6.0Hz，2H)，4.81(s，2H)，4.20-4.27(m，1H)，3.85(d，J＝8.8Hz，1H)，3.72(d，J＝8.8Hz，1H)，3.51-3.60(m，2H)，3.04-3.22(m，2H)，3.03(d，J＝4.8Hz，1H)，1.86-2.01(m，2H)，1.70-1.80(m，2H)，1.21(d，J＝6.4Hz，3H)。

Example 4:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (pyrrolidin-3-ylethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：412.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝4.77(s，2H)，4.20-4.27(m，1H)，3.87(d，J＝8.8Hz，1H)，3.73(d，J＝8.8Hz，1H)，3.58-3.71(m，2H)，3.44-3.50(m，2H)，3.06-3.40(m，6H)，2.32-2.40(m，1H)，2.14-2.22(m，1H)，1.89-2.01(m，2H)，1.69-1.82(m，2H)，1.23(d，J＝6.4Hz，3H)。

Example 5:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) -3- (imidazo [1,2-b ]]Pyridazin-3-ylethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：460.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.61(dd，J＝4.4Hz，1.2Hz，1H)，8.13(s，1H)，8.11(dd，J＝9.2Hz，1.2Hz，1H)，7.37(dd，J＝9.2Hz，4.4Hz，1H)，4.79(s，2H)，4.20-4.28(m，1H)，3.86(d，J＝8.4Hz，1H)，3.72(d，J＝8.4Hz，1H)，3.61-3.70(m，2H)，3.10-3.22(m，2H)，3.04(d，J＝5.2Hz，1H)，1.87-2.03(m，2H)，1.70-1.80(m，2H)，1.22(d，J＝6.8Hz，3H)。

Example 6:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (pyridin-2-ylethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：420.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.58(d，J＝4.4Hz，1H)，7.90(td，J＝7.6Hz，1.6Hz，1H)，7.76(d，J＝7.6Hz，1H)，7.44-7.47(m，1H)，4.79(s，2H)，4.21-4.27(m，1H)，3.86(d，J＝8.8Hz，1H)，3.72(d，J＝8.8Hz，1H)，3.60-3.70(m，2H)，3.10-3.25(m，2H)，3.05(d，J＝5.2Hz，1H)，1.88-2.02(m，2H)，1.70-1.81(m，2H)，1.22(d，J＝6.8Hz，3H)。

Example 7:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- ((2-aminopyridin-3-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：435.23[M+1]。 ¹ H NMR(400MHz，DMSO-d ₆ )：δ＝8.01(dd，J＝4.8Hz，1.6Hz，1H)，7.66(dd，J＝7.6Hz，1.6Hz，1H)，6.60(dd，J＝7.6Hz，4.8Hz，1H)，6.25(s，2H)，5.54(t，J＝6.0Hz，1H)，4.59(d，J＝5.6Hz，2H)，4.08-4.15(m，1H)，3.74(d，J＝8.8Hz，1H)，3.55-3.71(m，3H)，3.02-3.16(m，3H)，1.79-1.92(m，2H)，1.56-1.70(m，2H)，1.13(d，J＝6.0Hz，3H)。

Example 8:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- ((3-chloro-2- (cyclopropylamino) pyridin-4-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：509.22[M+1]。 ¹ H NMR(400MHz，DMSO-d ₆ )：δ＝8.08(d，J＝4.8Hz，1H)，6.84(d，J＝4.8Hz，1H)，6.83(s，1H)，5.58(t，J＝6.0Hz，1H)，4.60(d，J＝6.0Hz，2H)，4.14-4.20(m，1H)，3.63-3.82(m，4H)，2.98-3.12(m，3H)，1.82-1.92(m，2H)，1.70-1.77(m，1H)，1.57-1.64(m，1H)，1.40-1.45(m，1H)，1.17(d，J＝6.4Hz，3H)，0.66-0.70(m，2H)，0.52-0.56(m，2H)。

Example 9:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- ((3, 5-dichloropyridin-4-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanols

With reference to the procedure of example 1, appropriate starting materials and intermediates were usedSynthesizing to obtain the target compound. MS m/z [ LC-MS]：488.14[M+1]。 ¹ H NMR(400MHz，DMSO-d ₆ )：δ＝8.79(s，2H)，5.53(t，J＝4.8Hz，1H)，4.60(d，J＝4.8Hz，2H)，4.06-4.15(m，1H)，3.62-3.78(m，3H)，3.57(d，J＝8.8Hz，1H)，3.05-3.20(m，3H)，1.78-1.92(m，2H)，1.54-1.71(m，2H)，1.13(d，J＝6.4Hz，3H)。

Example 10:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) -3- ((4-Azopyridin-3-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：454.18[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.84(s，1H)，8.48(d，J＝5.2Hz，1H)，7.62(d，J＝5.2Hz，1H)，4.79(s，2H)，4.20-4.28(m，1H)，3.86(d，J＝8.8Hz，1H)，3.61-3.74(m，3H)，3.07-3.24(m，3H)，1.88-2.02(m，2H)，1.70-1.82(m，2H)，1.23(d，J＝6.4Hz，3H)。

Example 11:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) -3- (pyridin-3-ylethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：420.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.56(dd，J＝5.2Hz，1.6Hz，1H)，8.06-8.09(m，1H)，8.00(d，J＝2.0Hz，1H)，7.48-7.51(m，1H)，4.80(s，2H)，4.21-4.27(m，1H)，3.86(d，J＝8.8Hz，1H)，3.72(d，J＝8.8Hz，1H)，3.61-3.72(m，2H)，3.09-3.26(m，2H)，3.05(d，J＝4.8Hz，1H)，1.89-2.03(m，2H)，1.70-1.81(m，2H)，1.22(d，J＝6.8Hz，3H)。

Example 12:4- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) - 5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) pyridinecarbonitriles

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：445.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.93(s，1H)，8.20(dd，J＝8.0Hz，2.0Hz，1H)，7.93(d，J＝8.0Hz，1H)，4.80(s，2H)，4.27-4.33(m，1H)，3.96(d，J＝9.2Hz，1H)，3.74-3.86(m，3H)，3.44(d，J＝4.0Hz，1H)，3.04-3.18(m，2H)，1.89-2.09(m，3H)，1.72-1.80(m，1H)，1.31(d，J＝6.8Hz，3H)。

Example 13:5- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) - 5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) nicotinonitrile

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：445.21[M+1]。 ¹ H NMR(400MHz，DMSO-d ₆ )：δ＝9.04-9.09(m，2H)，8.64(s，1H)，5.55(t，J＝4.8Hz，1H)，4.60(d，J＝4.8Hz，2H)，4.06-4.15(m，1H)，3.74(d，J＝8.8Hz，1H)，3.58-3.72(m，2H)，3.56(d，J＝8.8Hz，1H)，3.04-3.18(m，3H)，1.76-1.93(m，2H)，1.54-1.70(m，2H)，1.12(d，J＝6.4Hz，3H)。

Example 14:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- ((2- (trifluoromethyl) pyridin-3-yl) ethynyl) -1HPyrazolo [3,4-b]Pyrazin-5-yl) methanols

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：488.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.67(d，J＝4.8Hz，1H)，8.30(d，J＝8.0Hz，1H)，7.71(dd，J＝8.0Hz，4.8Hz，1H)，4.80(s，2H)，4.26-4.33(m，1H)，3.96(d，J＝8.8Hz，1H)，3.74-3.86(m，3H)，4.35(d，J＝4.0Hz，1H)，3.03-3.17(m，2H)，1.98-2.07(m，2H)，1.88-1.95(m，1H)，1.73-1.80(m，1H)，1.32(d，J＝6.4Hz，3H)。

Example 15:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- ((5-Aminopyridin-3-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：435.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝＝8.05(s，1H)，7.97(s，1H)，7.39(s，1H)，4.80(s，2H)，4.27-4.33(m，1H)，3.97(d，J＝9.2Hz，1H)，3.85(d，J＝9.2Hz，1H)，3.72-3.83(m，2H)，3.48(d，J＝4.0Hz，1H)，3.02-3.17(m，2H)，1.97-2.08(m，2H)，1.88-1.96(m，1H)，1.74-1.80(m，1H)，1.32(d，J＝6.0Hz，3H)。

Example 16:5- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) - 5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) pyridinecarbonitriles

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：445.21[M+1]。 ¹ H NMR(400MHz，DMSO-d ₆ )：δ＝8.96(d，J＝1.6Hz，1H)，8.29(dd，J＝8.4Hz，2.0Hz，1H)，8.12(d，J＝8.4Hz，1H)，5.51-5.60(br，1H)，4.60(s，2H)，4.07-4.15(m，1H)，3.74(d，J＝8.8Hz，1H)，3.59-3.72(m，2H)，3.56(d，J＝8.8Hz，1H)，3.04-3.18(m，3H)，1.77-1.93(m，2H)，1.55-1.70(m，2H)，1.12(d，J＝6.8Hz，3H)。

Example 17:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) -3- ((3-Chloropyridin-2-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：454.18[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.52(d，J＝4.8Hz，1H)，8.00(d，J＝8.4Hz，1H)，7.45(dd，J＝8.4Hz，4.8Hz，1H)，4.79(s，2H)，4.26-4.33(m，1H)，3.97(d，J＝9.2Hz，1H)，3.85(d，J＝9.2Hz，1H)，3.73-3.84(m，2H)，3.47(d，J＝4.4Hz，1H)，3.03-3.17(m，2H)，1.97-2.07(m，2H)，1.88-1.96(m，1H)，1.73-1.80(m，1H)，1.30(d，J＝6.4Hz，3H)。

Example 18:(6- ((3S = 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decane-8-yl) -3- ((2- (hydroxymethyl) pyridin-3-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The compound can be synthesized by the method described in reference example 1 using appropriate starting materials and intermediatesA target compound. MS m/z [ LC-MS]：450.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.57(d，J＝4.8Hz，1H)，8.05(d，J＝7.6Hz，1H)，7.41(dd，J＝7.6Hz，4.8Hz，1H)，5.00(s，2H)，4.80(s，2H)，4.27-4.33(m，1H)，3.96(d，J＝8.8Hz，1H)，3.73-3.87(m，3H)，3.44(d，J＝4.4Hz，1H)，3.04-3.18(m，2H)，1.96-2.07(m，2H)，1.89-1.96(m，1H)，1.72-1.80(m，1H)，1.31(d，J＝6.4Hz，3H)。

Example 19:(3- ((2-amino-3-chloropyridin-4-yl) ethynyl) -6- ((3S, 4S) -4-amino-3-methyl- 2-oxa-8-azaspiro [4.5]]Decan-8-yl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：469.19[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.90(d，J＝5.2Hz，1H)，6.89(d，J＝5.2Hz，1H)，4.80(s，2H)，4.26-4.53(m，1H)，3.96(d，J＝9.2Hz，1H)，3.74-3.87(m，3H)，3.44(d，J＝4.0Hz，1H)，3.04-3.18(m，2H)，1.88-2.06(m，3H)，1.72-1.79(m，1H)，1.31(d，J＝6.8Hz，3H)。

Example 20:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- ((3-chloro-2-morpholinylpyridin-4-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanols

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：539.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.20(d，J＝5.2Hz，1H)，7.26(d，J＝5.2Hz，1H)，4.80(s，2H)，4.26-4.32(m，1H)，3.95(d，J＝8.8Hz，1H)，3.73-3.86(m，7H)，3.41(d，J＝4.4Hz，1H)，3.34-3.36(m，4H)，3.04-3.20(m，2H)，1.88-2.06(m，3H)，1.72-1.79(m，1H)，1.31(d，J＝7.2Hz，3H)。

Example 21:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- ((2, 4-Dimethylthiazol-5-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：454.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝4.78(s，2H)，4.26-4.32(m，1H)，3.95(d，J＝9.2Hz，1H)，3.72-3.86(m，3H)，3.43(d，J＝4.4Hz，1H)，3.03-3.18(m，2H)，2.67(s，3H)，2.53(s，3H)，1.88-2.06(m，3H)，1.72-1.79(m，1H)，1.31(d，J＝6.8Hz，3H)。

Example 22: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- ((1-methyl-1H-pyrazol-5-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：423.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.52(d，J＝1.6Hz，1H)，6.63(d，J＝1.6Hz，1H)，4.79(s，2H)，4.27-4.32(m，1H)，4.04(s，3H)，3.97(d，J＝8.8Hz，1H)，3.72-3.86(m，3H)，3.48(d，J＝4.4Hz，1H)，3.02-3.16(m，2H)，1.97-2.08(m，2H)，1.88-1.95(m，1H)，1.73-1.80(m，1H)，1.32(d，J＝6.4Hz，3H)。

Example 23: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- ((1-methyl-1H-pyrazol-3-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：423.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.65(d，J＝1.6Hz，1H)，6.56(d，J＝1.6Hz，1H)，4.78(s，2H)，4.27-4.33(m，1H)，3.96(d，J＝9.2Hz，1H)，3.93(s，3H)，3.72-3.87(m，3H)，3.46(d，J＝4.4Hz，1H)，3.02-3.16(m，2H)，1.88-2.06(m，3H)，1.72-1.78(m，1H)，1.31(d，J＝6.4Hz，3H)。

Example 24: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (pyrimidin-2-ylethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：421.21[M+1]。 ¹ H NMR(400MHz，DMSO-d ₆ )：δ＝8.86(d，J＝4.4Hz，2H)，7.54(t，J＝4.4Hz，1H)，5.62-5.84(m，1H)，4.59(s，2H)，4.15(m，1H)，3.64-3.81(m，3H)，3.60(d，J＝8.8Hz，1H)，3.28(s，1H)，2.98-3.12(m，2H)，1.82-1.94(m，2H)，1.56-1.74(m，2H)，1.16(d，J＝6.4Hz，3H)。

Example 25: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- ((2-amino-5-chloro-3-fluoropyridin-4-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

Reference exampleThe method in 1, adopting proper starting materials and intermediates, can synthesize the target compound. MS m/z [ LC-MS]：487.18[M+1]。 ¹ H NMR(400MHz，DMSO-d ₆ )：δ＝7.96(s，1H)，6.70(s，2H)，5.60(t，J＝5.6Hz，1H)，4.60(d，J＝5.6Hz，2H)，4.14-4.20(m，1H)，3.68-3.84(m，3H)，3.63(d，J＝8.8Hz，1H)，3.32(d，J＝4.4Hz，1H)，2.98-3.11(m，2H)，1.82-1.92(m，2H)，1.69-1.76(m，1H)，1.57-1.64(m，1H)，1.17(d，J＝6.4Hz，3H)。

Example 26: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- ((3, 5-dimethylisoxazol-4-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：438.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝4.79(s，2H)，4.26-4.32(m，1H)，3.95(d，J＝9.2Hz，1H)，3.71-3.86(m，3H)，3.42(d，J＝4.0Hz，1H)，3.02-3.17(m，2H)，2.56(s，3H)，2.37(s，3H)，1.86-2.05(m，3H)，1.72-1.79(m，1H)，1.31(d，J＝6.8Hz，3H)。

Example 27: (3- ((2-amino-3, 5-dichloropyridin-4-yl) ethynyl) -6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：503.15[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.01(s，1H)，4.79(s，2H)，4.27-4.34(m，1H)，3.97(d，J＝9.2Hz，1H)，3.72-3.90(m，3H)，3.46(d，J＝4.4Hz，1H)，3.04-3.18(m，2H)，1.90-2.08(m，3H)，1.73-1.79(m，1H)，1.32(d，J＝6.4Hz，3H)。

Example 28: (3- ((2-amino-3, 5-difluoropyridin-4-yl) ethynyl) -6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：471.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.83(s，1H)，4.79(s，2H)，4.26-4.33(m，1H)，3.96(d，J＝9.2Hz，1H)，3.73-3.86(m，3H)，3.43(d，J＝4.4Hz，1H)，3.04-3.17(m，2H)，1.96-2.06(m，2H)，1.88-1.94(m，1H)，1.72-1.79(m，1H)，1.31(d，J＝6.8Hz，3H)。

Example 29: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- ((4- (trifluoromethyl) pyridin-3-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：488.20[M+1]。 ¹ H NMR(400MH，CD ₃ OD)：δ＝9.07(s，1H)，8.78(d，J＝4.8Hz，1H)，7.78(d，J＝4.8Hz，1H)，4.79(s，2H)，4.21-4.27(m，1H)，3.87(d，J＝9.2Hz，1H)，3.63-3.75(m，3H)，3.08-3.24(m，3H)，1.90-2.02(m，2H)，1.70-1.82(m，2H)，1.23(d，J＝6.4Hz，3H)。

Example 30: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- ((4-methylthiazol-5-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：440.19[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.93(s，1H)，4.79(s，2H)，4.27-4.33(m，1H)，3.96(d，J＝9.2Hz，1H)，3.72-3.84(m，3H)，3.46(d，J＝3.6Hz，1H)，3.02-3.16(m，2H)，2.61(s，3H)，1.88-2.07(m，3H)，1.72-1.80(m，1H)，1.31(d，J＝6.4Hz，3H)。

Example 31: (3- ((2-amino-3-chloro-5-fluoropyridin-4-yl) ethynyl) -6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS ]:487.18[ M ] +1].

Example 32: (S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4 '-piperidine ] -1' -yl) -3- ((2-chloro-4, 6-difluorophenyl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：522.16[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.55(d，J＝4.8Hz，1H)，7.99(d，J＝7.6Hz，1H)，7.40(dd，J＝7.6Hz，4.8Hz，1H)，7.28-7.31(m，1H)，7.16(td，J＝9.2Hz，2.4Hz，1H)，4.81(s，2H)，4.57(s，2H)，3.88-3.96(m，1H)，3.78-3.86(m，1H)，3.20-3.35(m，3H)，1.98-2.12(m，2H)，1.76-1.82(m，1H)，1.67-1.74(m，1H)。

Example 33: (R) - (6- (3-amino-3H-spiro [ benzofuran-2, 4 '-piperidine ] -1' -yl) -3- ((2-chloro-4, 6-difluorophenyl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS ]:523.15[ 2 ] M +1].

Example 34: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- ((1-methyl-1H-pyrazol-5-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：423.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.77(s，1H)，7.36(s，1H)，4.77(s，2H)，4.23-4.31(m，1H)，3.92(d，J＝9.2Hz，1H)，3.66-3.85(m，6H)，3.32-3.35(m，1H)，3.01-3.16(m，2H)，1.93-2.04(m，2H)，1.81-1.89(m，1H)，1.71-1.78(m，1H)，1.28(d，J＝6.4Hz，3H)。

Example 35: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- ((2-isopropyl-4-methylthiazol-5-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：482.23[M+1]。 ¹ H NMR(400MHz，CDCl ₃ )：δ＝4.73(s，2H)，4.09-4.30(m，1H)，3.83-4.06(m，1H)，3.29-3.78(m，4H)，3.15-3.29(m，1H)，2.77-3.12(m，2H)，2.50(s，3H)，1.54-2.12(m，4H)，1.29-1.38(m，9H)。

Example 36: (S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4 '-piperidine ] -1' -yl) -3- ((2- (trifluoromethyl) pyridin-3-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：521.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.66(d，J＝4.0Hz，1H)，8.34-8.44(m，1H)，8.27-8.32(m，1H)，7.84-7.93(m，1H)，7.67-7.73(m，1H)，7.26-7.35(m，1H)，4.82(s，2H)，4.17-4.32(m，1H)，3.70-3.88(m，2H)，3.39-3.50(m，1H)，3.18-3.32(m，2H)，2.96-3.06(m，1H)，1.96-2.12(m，2H)，1.64-1.73(m，1H)，1.52-1.62(m，1H)。

Example 37: (6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- ((3-chloro-2- (3, 3-difluoroazetidin-1-yl) pyridin-4-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：545.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.11(d，J＝4.8Hz，1H)，7.11(d，J＝4.8Hz，1H)，4.79(s，2H)，4.57(t，J＝12.4Hz，4H)，4.264.33(m，1H)，3.96(d，J＝9.2Hz，1H)，3.74-3.87(m，3H)，3.44(d，J＝4.4Hz，1H)，3.04-3.17(m，2H)，1.89-2.06(m，3H)，1.72-1.79(m，1H)，1.31(d，J＝6.8Hz，3H)。

Example 38: (S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4 '-piperidine ] -1' -yl) -3- ((4-chloro-2-fluorophenyl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：504.17[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.48(d，J＝4.8Hz，1H)，7.92(d，J＝7.2Hz，1H)，7.66(t，J＝8.0Hz，1H)，7.34-7.37(m，2H)，7.29(dd，J＝8.0Hz，2.0Hz，1H)，4.81(s，2H)，4.40(s，1H)，3.76-3.91(m，2H)，3.23-3.30(m，3H)，3.12(d，J＝17.2Hz，1H)，1.99-2.08(m，2H)，1.66-1.73(m，2H)。

Example 39: (S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4 '-piperidine ] -1' -yl) -3- ((3-chloro-5-fluoropyridin-4-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：505.17[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.58(s，1H)，8.55(s，1H)，8.50(d，J＝5.6Hz，1H)，7.94(d，J＝7.6Hz，1H)，7.37(dd，J＝7.6Hz，5.6Hz，1H)，4.82(s，2H)，4.44(s，1H)，3.79-3.95(m，2H)，3.24-3.34(m，3H)，3.15(d，J＝17.6Hz，1H)，1.99-2.10(m，2H)，1.66-1.76(m，2H)。

Example 40: (S) -5- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4 '-piperidine ] -1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) ethynyl) -2-cyanopyridine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：478.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.92(d，J＝1.6Hz，1H)，8.49(d，J＝4.4Hz，1H)，8.19(dd，J＝8.0Hz，2.0Hz，1H)，7.90-7.95(m，2H)，7.36(dd，J＝7.6Hz，5.2Hz，1H)，4.82(s，2H)，4.43(s，1H)，3.77-3.92(m，2H)，3.23-3.34(m，3H)，3.14(d，J＝17.2Hz，1H)，1.98-2.10(m，2H)，1.67-1.75(m，2H)。

Example 41: (S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4 '-piperidine ] -1' -yl) -3- ((2-isopropyl-4-methylthiazol-5-yl) ethynyl) -1H-pyrazolo [3,4-b ] pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：515.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.50(d，J＝4.8Hz，1H)，7.94(d，J＝7.6Hz，1H)，7.37(dd，J＝7.6Hz，4.8Hz，1H)，4.81(s，2H)，4.46(s，1H)，3.77-3.92(m，2H)，3.23-3.34(m，4H)，3.15(d，J＝16.8Hz，1H)，2.55(s，3H)，1.99-2.09(m，2H)，1.67-1.76(m，2H)，1.39(d，J＝6.4Hz，6H)。

Example 42:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- ((4- (trifluoromethyl) pyridin-3-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanols

With reference to the method of example 1,the target compound can be synthesized by adopting proper starting materials and intermediates. MS m/z [ LC-MS]：521.20[M+1]。 ¹ H NMR(400MHz，DMSO-d ₆ )：δ＝9.09(s，1H)，8.87(d，J＝4.8Hz，1H)，8.45-8.52(m，1H)，7.99(d，J＝8.0Hz，1H)，7.89(d，J＝4.8Hz，1H)，7.28-8.31(m，1H)，5.52(t，J＝5.2Hz，1H)，4.63(d，J＝5.2Hz，2H)，4.45(s，1H)，3.78-3.94(m，2H)，3.01-3.52(m，4H)，1.52-1.66(m，3H)，1.39-1.46(m，1H)。

Example 43:(S) - (3- ((2-amino-3-chloropyridin-4-yl) ethynyl) -6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：502.19[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.49(d，J＝5.2Hz，1H)，7.94(d，J＝8.0Hz，1H)，7.88(d，J＝5.2Hz，1H)，7.36(dd，J＝8.0Hz，5.2Hz，1H)，6.88(d，J＝5.2Hz，1H)，4.82(s，2H)，4.46(s，1H)，3.76-3.92(m，2H)，3.21-3.34(m，3H)，3.14(d，J＝17.2Hz，1H)，1.88-2.11(m，2H)，1.64-1.77(m，2H)。

Example 44:(6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- ((5, 6,7, 8-Tetrahydroimidazo [1, 2-a))]Pyridin-3-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanols

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：463.26[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.75(s，1H)，4.18-4.34(m，3H)，3.95(d，J＝8.8Hz，1H)，3.62-3.86(m，3H)，3.36-3.50(m，2H)，2.97-3.14(m，3H)，2.69-2.80(m，2H)，1.96-2.07(m，2H)，1.86-1.94(m，1H)，1.71-1.80(m，1H)，1.53-1.63(m，2H)，1.28-1.40(m，5H)。

Example 45:(S) - (3- ((2-amino-3-chloropyridin-4-yl) ethynyl) -6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：521.14[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.36(d，J＝5.2Hz，1H)，8.34(d，J＝5.2Hz，1H)，7.85(d，J＝7.6Hz，1H)，7.67(d，J＝5.2Hz，1H)，7.28(dd，J＝7.6Hz，5.2Hz，1H)，4.82(s，2H)，4.14(s，1H)，3.76-3.86(m，2H)，3.29-3.33(m，3H)，2.95(d，J＝16.8Hz，1H)，1.96-2.12(m，2H)，1.64-1.72(m，1H)，1.48-1.56(m，1H)。

Example 46:(S) -4- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -3-chloro-5-fluorobenzonitrile

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：529.17[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.44(d，J＝5.2Hz，1H)，7.92(d，J＝7.2Hz，1H)，7.81(t，J＝1.6Hz，1H)，7.67(dd，J＝8.8Hz，1.6Hz，1H)，7.33(dd，J＝7.6Hz，5.2Hz，1H)，4.80(s，2H)，4.36(s，1H)，3.77-3.90(m，2H)，3.21-3.28(m，3H)，3.08(d，J＝16.4Hz，1H)，1.98-2.09(m，2H)，1.62-1.72(m，2H)。

Example 47:(S) -5- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -4-methyl-2-cyanopyridine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：492.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.67(s，1H)，8.52(d，J＝5.2Hz，1H)，8.02(d，J＝7.2Hz，1H)，7.74(s，1H)，7.38(dd，J＝7.6Hz，5.2Hz，1H)，4.82(s，2H)，4.58(s，1H)，3.86-3.96(m，1H)，3.76-3.84(m，1H)，3.17-3.34(m，4H)，2.59(s，3H)，1.98-2.16(m，2H)，1.79-1.86(m，1H)，1.64-1.72(m，1H)。

Example 48:4- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) - 1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -3-chloro-5-fluorobenzonitrile

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：466.16[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.40(s，1H)，7.83(t，J＝1.6Hz，1H)，7.68(dd，J＝8.0Hz，1.6Hz，1H)，4.24-4.38(m，2H)，3.95(d，J＝8.8Hz，1H)，3.81(d，J＝8.8Hz，1H)，3.32-3.41(m，2H)，3.24-3.31(m，2H)，1.78-1.90(m，2H)，1.68-1.75(m，1H)，1.22-1.34(m，4H)。

Example 49:(S) -1' - (3- ((2-chloro-4, 6-difluorophenyl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazine- 6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ]]6,4 'pyridine'-piperidine]-5-amine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：492.15[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.44(d，J＝4.8Hz，1H)，8.37(s，1H)，7.89(d，J＝7.2Hz，1H)，7.31(dd，J＝7.6Hz，5.2Hz，1H)，7.18-7.24(m，1H)，7.04-7.09(m，1H)，4.42-4.51(m，2H)，4.27(s，1H)，3.32-3.43(m，2H)，3.27(d，J＝17.2Hz，1H)，3.09(d，J＝17.2Hz，1H)，1.82-1.93(m，2H)，1.58-1.72(m，2H)。

Example 50:methanol (S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ])]Pyridine-6, 4' -piperidines]- 1' -yl) -3- ((2, 4-difluorophenyl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：488.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.54(d，J＝5.2Hz，1H)，7.71(d，J＝7.6Hz，1H)，7.68-7.74(m，1H)，7.40(dd，J＝7.6Hz，5.2Hz，1H)，7.03-7.13(m，2H)，4.82(s，2H)，4.59(s，1H)，3.86-3.94(m，1H)，3.76-3.84(m，1H)，3.19-3.33(m，4H)，1.97-2.13(m，2H)，1.78-1.85(m，1H)，1.66-1.74(m，1H)。

Example 51:(S) -5- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -3-fluoro-2-cyanopyridine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：496.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.77(s，1H)，8.53(d，J＝3.2Hz，1H)，8.14(d，J＝8.8Hz，1H)，7.98(d，J＝7.6Hz，1H)，7.39(dd，J＝7.6Hz，5.2Hz，1H)，4.83(s，2H)，4.53(s，1H)，3.86-3.94(m，1H)，3.77-3.85(m，1H)，3.17-3.36(m，4H)，1.97-2.12(m，2H)，1.75-1.82(m，1H)，1.66-1.74(m，1H)。

Example 52:(S) -4- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -3-chloro-5-fluorobenzonitrile

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：499.16[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.41(d，J＝5.2Hz，1H)，8.37(s，1H)，7.88(d，J＝7.6Hz，1H)，7.74(s，1H)，7.58(d，J＝8.4Hz，1H)，7.29(dd，J＝7.6Hz，5.2Hz，1H)，4.38-4.51(m，2H)，4.23(s，1H)，3.31-3.41(m，2H)，3.26(d，J＝16.4Hz，1H)，3.04(d，J＝16.4Hz，1H)，1.82-1.94(m，2H)，1.56-1.70(m，2H)。

Example 53:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- ((6-Chloropyridin-3-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：487.18[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.61(s，1H)，8.37(d，J＝4.8Hz，1H)，8.02(dd，J＝8.8Hz，1.6Hz，1H)，7.86(d，J＝8.0Hz，1H)，7.51(d，J＝8.8Hz，1H)，7.29(dd，J＝8.8Hz，5.6Hz，1H)，4.81(s，2H)，4.18(s，1H)，3.74-3.84(m，2H)，3.14-3.28(m，3H)，2.97(d，J＝16.8Hz，1H)，1.97-2.10(m，2H)，1.64-1.72(m，1H)，1.50-1.58(m，1H)。

Example 54:(S) -5- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -3-methyl-2-cyanopyridine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：492.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.55(d，J＝1.2Hz，1H)，8.39(d，J＝5.2Hz，1H)，7.91(s，1H)，7.88(d，J＝7.6Hz，1H)，7.29(dd，J＝7.6Hz，5.2Hz，1H)，4.79(s，2H)，4.23(s，1H)，3.71-3.83(m，2H)，3.15-3.26(m，3H)，3.98(d，J＝16.8Hz，1H)，2.47(s，3H)，1.97-2.08(m，2H)，1.53-1.69(m，2H)。

Example 55:(S) -5- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -3-methoxy-2-cyanopyridine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：508.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.48-8.65(br，1H)，8.43(s，1H)，8.00(d，J＝7.2Hz，1H)，7.91(s，1H)，7.38-7.45(m，1H)，4.84(s，2H)，4.59(s，1H)，4.04(s，3H)，3.88-3.96(m，1H)，3.78-3.85(m，1H)，3.21-3.36(m，4H)，1.96-2.14(m，2H)，1.78-1.86(m，1H)，1.66-1.74(m，1H)。

Example 56:(S) -5- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -3-trifluoromethyl-2-cyanopyridine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：546.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝9.13(s，1H)，8.61(s，1H)，8.45(d，J＝5.2Hz，1H)，7.93(d，J＝7.6Hz，1H)，7.34(dd，J＝7.6Hz，5.2Hz，1H)，4.83(s，2H)，4.35(s，1H)，3.77-3.90(m，2H)，3.22-3.29(m，3H)，3.08(d，J＝16.8Hz，1H)，1.98-2.10(m，2H)，1.62-1.73(m，2H)。

Example 57:(S) -5- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -3-chloro-2-cyanopyridine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：512.17[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.72(s，1H)，8.46(d，J＝5.2Hz，1H)，8.25(s，1H)，7.94(d，J＝8.0Hz，1H)，7.34(dd，J＝7.6Hz，5.2Hz，1H)，4.81(s，2H)，4.38(s，1H)，3.76-3.90(m，2H)，3.21-3.29(m，3H)，3.09(d，J＝16.8Hz，1H)，1.98-2.12(m，2H)，1.64-1.72(m，2H)。

Example 58:(S)-5- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -2-cyanopyridine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：448.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.92(d，J＝2.0Hz，1H)，8.49(d，J＝5.2Hz，1H)，8.41(s，1H)，8.18(dd，J＝8.8Hz，2.0Hz，1H)，7.88-7.92(m，2H)，7.34(dd，J＝7.6Hz，5.2Hz，1H)，4.41-4.56(m，2H)，4.36(s，1H)，3.26-3.47(m，3H)，3.15(d，J＝16.8Hz，1H)，1.83-1.94(m，2H)，1.65-1.73(m，2H)。

Example 59:(S) -5- ((6- (7-amino-3-methyl-5, 7-dihydrospiro [ cyclopenta [ c)]Pyridine-6, 4- Piperidine derivatives]-1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) 2-cyanopyridine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：492.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.90(s，1H)，8.54(s，1H)，8.17(dd，J＝8.0Hz，1.6Hz，1H)，7.88(d，J＝8.0Hz，1H)，7.31(s，1H)，4.81(s，2H)，1.48(s，1H)，3.81-3.90(m，1H)，3.70-3.79(m，1H)，3.08-3.28(m，4H)，2.56(s，3H)，1.90-2.13(m，2H)，1.76-1.84(m，1H)，1.58-1.66(m，1H)。

Example 60:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- ((2-cyclopropyl-4-methylthiazol-5-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：513.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.46(d，J＝4.8Hz，1H)，7.91(d，J＝8.0Hz，1H)，7.34(dd，J＝8.0Hz，4.8Hz，1H)，4.80(s，2H)，4.36(s，1H)，3.76-3.90(m，2H)，3.20-3.34(m，3H)，3.08(d，J＝16.8Hz，1H)，2.49(s，3H)，2.28-2.36(m，1H)，1.98-2.08(m，2H)，1.62-1.72(m，2H)，1.16-1.22(m，2H)，1.02-1.08(m，2H)。

Example 61:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- ((6-chloro-2-methylpyridin-3-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：501.19[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.41(d，J＝5.2Hz，1H)，7.96(d，J＝8.0Hz，1H)，7.88(d，J＝7.6Hz，1H)，7.29-7.35(m，2H)，4.81(s，2H)，4.24(s，1H)，3.76-3.87(m，2H)，3.19-3.28(m，3H)，3.02(d，J＝16.4Hz，1H)，2.75(s，3H)，1.98-2.10(m，2H)，1.64-1.72(m，1H)，1.55-1.62(m，1H)。

Example 62:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- ((2-cyclopropyl-4-trifluoromethylthiazol-5-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：567.19[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.44(d，J＝5.2Hz，1H)，7.93(d，J＝7.6Hz，1H)，7.32(dd，J＝7.6Hz，5.2Hz，1H)，4.79(s，2H)，4.35(s，1H)，3.73-3.88(m，2H)，3.18-3.28(m，3H)，3.06(d，J＝16.4Hz，1H)，2.37-2.43(m，1H)，1.97-2.09(m，2H)，1.62-1.71(m，2H)，1.19-1.26(m，2H)，1.12-1.16(m，2H)。

Example 63:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- ((2, 6-dichloropyridin-3-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：521.14[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.43(d，J＝5.6Hz，1H)，8.07(d，J＝8.4Hz，1H)，7.92(d，J＝7.2Hz，1H)，7.47(d，J＝8.4Hz，1H)，7.32(dd，J＝7.2Hz，5.6Hz，1H)，4.81(s，2H)，4.34(s，1H)，3.74-3.88(m，2H)，3.16-3.28(m，3H)，3.06(d，J＝16.8Hz，1H)，1.98-2.10(m，2H)，1.60-1.73(m，2H)。

Example 64:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- ((2, 4-dimethyloxazol-5-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：471.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.31(d，J＝5.2Hz，1H)，7.81(d，J＝7.6Hz，1H)，7.24(dd，J＝7.6Hz，5.2Hz，1H)，4.78(s，2H)，4.04(s，1H)，3.70-3.78(m，2H)，3.13-3.24(m，3H)，2.88(d，J＝16.8Hz，1H)，2.44(s，3H)，2.24(s，3H)，1.93-2.09(m，2H)，1.61-1.68(m，1H)，1.40-1.48(m，1H)。

Example 65:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- ((6-methylpyridin-3-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：467.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.66(d，J＝2.0Hz，1H)，8.42(d，J＝5.2Hz，1H)，7.94(dd，J＝8.4Hz，2.0Hz，1H)，7.89(d，J＝7.2Hz，1H)，7.36(d，J＝8.4Hz，1H)，7.32(dd，J＝7.2Hz，5.2Hz，1H)，4.81(s，2H)，4.29(s，1H)，3.75-3.87(m，2H)，3.21-3.28(m，3H)，3.04(d，J＝16.8Hz，1H)，2.57(s，3H)，1.99-2.09(m，2H)，1.58-1.72(m，2H)。

Example 66:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- ((6- (difluoromethyl) pyridin-3-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：503.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.87(s，1H)，8.43(d，J＝5.2Hz，1H)，8.19(dd，J＝8.0Hz，1.6Hz，1H)，7.90(d，J＝7.6Hz，1H)，7.74(d，J＝8.4Hz，1H)，7.32(dd，J＝7.6Hz，5.2Hz，1H)，6.75(t，J＝55.2Hz，1H)，4.82(s，2H)，4.30(s，1H)，3.75-3.88(m，2H)，3.21-3.28(m，3H)，3.05(d，J＝16.8Hz，1H)，1.99-2.09(m，2H)，1.59-1.72(m，2H)。

Example 67:(3S, 4S) -8- (3- ((2-chloro-4, 6-difluorophenyl) ethynyl) -5- (difluoromethyl) -1H-pir-inyl Azolo [3,4-b ]]Pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decan-4-amines

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：509.15[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.27(d，J＝8.4Hz，1H)，7.14(td，J＝8.8Hz，2.4Hz，1H)，6.98(t，J＝54.0Hz，1H)，4.21-4.28(m，1H)，3.88(d，J＝8.4Hz，1H)，3.62-3.76(m，3H)，3.11-3.28(m，3H)，1.91-2.04(m，2H)，1.70-1.86(m，2H)，1.25(d，J＝6.4Hz，3H)。

Example 68:(S) -1' - (3- ((6-chloropyridin-3-yl) ethynyl) -5- (difluoromethyl) -1H-pyrazolo [3, 4-b]pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amines

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：507.16[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.65(d，J＝2.4Hz，1H)，8.48(d，J＝5.2Hz，1H)，8.06(dd，J＝8.4Hz，2.4Hz，1H)，7.93(d，J＝7.2Hz，1H)，7.53(d，J＝8.8Hz，1H)，7.35(dd，J＝7.6Hz，5.2Hz，1H)，7.05(t，J＝54.0Hz，1H)，4.40(s，1H)，3.71-3.84(m，2H)，3.31-3.40(m，2H)，3.25(d，J＝16.8Hz，1H)，3.12(d，J＝16.8Hz，1H)，2.00-2.12(m，2H)，1.66-1.74(m，2H)。

Example 69:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- (cyclopropylethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：416.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.47(d，J＝5.2Hz，1H)，7.92(d，J＝7.6Hz，1H)，7.35(dd，J＝7.6Hz，5.2Hz，1H)，4.78(s，2H)，4.40(s，1H)，3.72-3.86(m，2H)，3.19-3.28(m，3H)，3.11(d，J＝16.8Hz，1H)，1.98-2.08(m，2H)，1.64-1.72(m，2H)，1.54-1.61(m，1H)，0.93-0.98(m，2H)，0.83-0.87(m，2H)。

Example 70:(S) -4- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -2-methylbut-3-yn-2-ol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：434.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.35(d，J＝5.2Hz，1H)，7.84(d，J＝7.6Hz，1H)，7.27(dd，J＝7.6Hz，5.2Hz，1H)，4.79(s，2H)，4.12(s，1H)，3.72-3.80(m，2H)，3.16-3.26(m，3H)，3.93(d，J＝16.4Hz，1H)，1.96-2.10(m，2H)，1.63-1.70(m，1H)，1.60(s，6H)，1.46-1.53(m，1H)。

Example 71:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- ((4-chloro-2-methylthiazol-5-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazine-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：507.15[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.49(d，J＝5.2Hz，1H)，7.95(d，J＝8.0Hz，1H)，7.36(dd，J＝8.0Hz，5.2Hz，1H)，4.80(s，2H)，4.45(s，1H)，3.76-3.92(m，2H)，3.20-3.32(m，3H)，3.14(d，J＝16.8Hz，1H)，2.69(s，3H)，1.97-2.10(m，2H)，1.64-1.76(m，2H)。

Example 72:(S) -1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclohexyl-1-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：474.26[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.45(d，J＝5.2Hz，1H)，7.92(d，J＝7.2Hz，1H)，7.33(dd，J＝7.2Hz，5.2Hz，1H)，4.79(s，2H)，4.36(s，1H)，3.73-3.86(m，2H)，3.18-3.28(m，3H)，3.07(d，J＝16.8Hz，1H)，1.97-2.09(m，4H)，1.50-1.81(m，10H)。

Example 73:(S) -1' - (3- (cyclopropylethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-6-yl) -5, 7-dihydro Spiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

According to the method of the reference example 1, the compound can be synthesized by using appropriate starting materials and intermediatesTo the target compound. MS m/z [ LC-MS]：386.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.43(d，J＝5.2Hz，1H)，8.29(s，1H)，7.89(d，J＝7.2Hz，1H)，7.32(dd，J＝7.2Hz，5.2Hz，1H)，4.36-4.49(m，2H)，4.26(s，1H)，3.30-3.39(m，2H)，3.27(d，J＝16.8Hz，1H)，3.07(d，J＝16.8Hz，1H)，1.82-1.92(m，2H)，1.53-1.69(m，3H)，0.91-0.96(m，2H)，0.83-0.86(m，2H)。

Example 74:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- (3, 3-dimethylbut-1-yn-1-yl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanols

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：432.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.37(d，J＝5.2Hz，1H)，7.83(d，J＝7.6Hz，1H)，7.25(dd，J＝7.6Hz，5.2Hz，1H)，4.77(s，2H)，4.16(s，1H)，3.67-3.77(m，2H)，3.14-3.24(m，3H)，2.96(d，J＝16.8Hz，1H)，1.93-2.06(m，2H)，1.63-1.70(m，1H)，1.50-1.58(m，1H)，1.35(s，9H)。

Example 75:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- ((2- (difluoromethyl) -4-methylthiazol-5-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol I

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：523.18[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.39(d，J＝5.2Hz，1H)，7.87(d，J＝8.0Hz，1H)，7.30(dd，J＝8.0Hz，5.2Hz，1H)，6.98(t，J＝54.4Hz，1H)，4.80(s，2H)，4.21(s，1H)，3.74-3.86(m，2H)，3.18-3.28(m，3H)，2.99(d，J＝16.8Hz，1H)，2.61(s，3H)，1.98-2.09(m，2H)，1.64-1.71(m，1H)，1.52-1.60(m，1H)。

Example 76:(S) -4- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -2-cyanopyridine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：478.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.72(d，J＝5.2Hz，1H)，8.46(d，J＝2.0Hz，1H)，8.07(s，1H)，7.93(d，J＝7.6Hz，1H)，7.80-7.84(m，1H)，7.33-7.36(m，1H)，4.82(s，2H)，4.39(s，1H)，3.75-3.90(m，2H)，3.20-3.30(m，3H)，3.10(d，J＝16.8Hz，1H)，1.98-2.12(m，2H)，1.64-1.73(m，2H)。

Example 77:(S) -5- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -6-methyl-2-cyanopyridine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：492.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.41(d，J＝5.2Hz，1H)，8.05(d，J＝8.4Hz，1H)，7.89(d，J＝7.6Hz，1H)，7.68(d，J＝8.4Hz，1H)，7.31(dd，J＝7.6Hz，5.2Hz，1H)，4.81(s，2H)，4.26(s，1H)，3.76-3.87(m，2H)，3.20-3.29(m，3H)，3.02(d，J＝16.8Hz，1H)，2.77(s，3H)，1.98-2.09(m，2H)，1.56-1.72(m，2H)。

Example 78:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Base (C)]-1' -yl) -3- ((2, 4-dimethylthiazol-5-yl) ethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanols

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：487.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.45(d，J＝5.2Hz，1H)，7.91(d，J＝7.6Hz，1H)，7.33(dd，J＝7.6Hz，5.2Hz，1H)，4.81(s，2H)，4.33(s，1H)，3.76-3.89(m，2H)，3.19-3.28(m，3H)，3.07(d，J＝16.8Hz，1H)，2.67(s，3H)，2.53(s，3H)，1.99-2.08(m，2H)，1.61-1.72(m，2H)。

Example 79:5- ((6- ((3S, 4S) 4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) - 1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -2-cyanopyridine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：415.20[M+1]。 ¹ H NMR(400MHz，DMSO-d ₆ )：δ＝8.94(d，J＝5.2Hz，1H)，8.50(s，1H)，8.27(dd，J＝8.0Hz，2.4Hz，1H)，8.09(d，J＝8.0Hz，1H)，4.14-4.20(m，1H)，3.87(d，J＝9.2Hz，1H)，3.64(d，J＝9.2Hz，1H)，3.12-3.32(m，4H)，3.08-3.10(m，1H)，1.64-1.78(m，2H)，1.53-1.62(m，2H)，1.17(d，J＝6.4Hz，3H)。

Example 80:(3S, 4S) -8- (3- ((2-chloro-4, 6-difluorophenyl) ethynyl) -1H-pyrazolo [3,4-b]Pyridine (II) Oxazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decan-4-amines

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：459.15[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.37(s，1H)，77.26-7.29(m，1H)，7.14(td，J＝8.8Hz，2.4Hz，1H)，4.24-4.39(m，3H)，3.96(d，J＝8.8Hz，1H)，3.82(d，J＝8.8Hz，1H)，3.20-3.38(m，3H)，1.81-1.90(m，3H)，1.67-1.74(m，1H)，1.28(d，J＝6.8Hz，3H)。

Example 81:(S) -5- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) -2-cyanopyridine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：498.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.95(d，J＝2.4Hz，1H)，8.33(d，J＝5.2Hz，1H)，8.24(dd，J＝8.0Hz，1H)，7.92(d，J＝8.0Hz，1H)，7.83(d，J＝8.0Hz，1H)，7.26(dd，J＝8.0Hz，5.2Hz，1H)，7.06(t，J＝54.0Hz，1H)，4.07(s，1H)，3.68-3.76(m，2H)，3.25-3.36(m，2H)，3.21(d，J＝16.8Hz，1H)，2.91(d，J＝16.8Hz，1H)，1.98-2.14(m，2H)，1.65-1.72(m，1H)，1.44-1.50(m，1H)。

Example 82:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- (cyclopropylethynyl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：416.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.47(d，J＝4.8Hz，1H)，7.92(d，J＝7.6Hz，1H)，7.35(dd，J＝7.6Hz，4.8Hz，1H)，4.78(s，2H)，4.40(s，1H)，3.72-3.86(m，2H)，3.20-3.26(m，3H)，3.11(d，J＝16.8Hz，1H)，1.98-2.08(m，2H)，1.64-1.72(m，2H)，1.54-1.61(m，1H)，0.93-0.98(m，2H)，0.83-0.87(m，2H)。

Example 83:(S) -4- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -2-methylbut-3-yn-2-ol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：434.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.35(d，J＝4.4Hz，1H)，7.84(d，J＝7.6Hz，1H)，7.27(dd，J＝7.6Hz，5.2Hz，1H)，4.79(s，2H)，4.12(s，1H)，3.72-3.80(m，2H)，3.16-3.26(m，3H)，2.93(d，J＝16.4Hz，1H)，1.96-2.09(m，，2H)，1.63-1.70(m，1H)，1.60(s，6H)，1.46-1.53(m，1H)。

Example 84:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- ((2- (difluoromethyl) -4-methylthiazol-5-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：523.18[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.39(d，J＝4.8Hz，1H)，7.87(d，J＝8.0Hz，1H)，7.30(dd，J＝8.0Hz，4.8Hz，1H)，6.98(t，J＝54.8Hz，1H)，4.80(s，2H)，4.21(s，1H)，3.75-3.85(m，2H)，3.18-3.28(m，3H)，2.99(d，J＝16.8Hz，1H)，2.61(s，3H)，1.98-2.09(m，2H)，1.66-1.69(m，1H)，1.54-1.58(m，1H)。

Example 85:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- ((4-chloro-2-methylthiazol-5-yl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanols

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：507.15[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.49(d，J＝5.2Hz，1H)，7.95(d，J＝8.0Hz，1H)，7.36(dd，J＝8.0Hz，5.2Hz，1H)，4.80(s，2H)，4.45(s，1H)，3.77-3.89(m，2H)，3.21-3.28(m，3H)，3.14(d，J＝17.2Hz，1H)，2.69(s，3H)，1.98-2.10(m，2H)，1.64-1.76(m，2H)。

Example 86:(S) -1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclohexan-1-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：474.26[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.45(d，J＝4.8Hz，1H)，7.92(d，J＝7.2Hz，1H)，7.33(dd，J＝7.2Hz，4.8Hz，1H)，4.79(s，2H)，4.36(s，1H)，3.75-3.84(m，2H)，3.18-3.26(m，3H)，3.07(d，J＝16.8Hz，1H)，1.98-2.09(m，4H)，1.50-1.80(m，10H)。

Example 87:(S) -1' - (3- (cyclopropylethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-6-yl) -5, 7-dihydro Spiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：386.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.43(d，J＝4.8Hz，1H)，8.29(s，1H)，7.89(d，J＝7.2Hz，1H)，7.32(dd，J＝7.2Hz，5.2Hz，1H)，4.36-4.50(m，2H)，4.26(s，1H)，3.31-3.39(m，2H)，3.27(d，J＝16.8Hz，1H)，3.07(d，J＝16.8Hz，1H)，1.82-1.92(m，2H)，1.52-1.69(m，3H)，0.91-0.96(m，2H)，0.82-0.86(m，2H)。

Example 88:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- (3, 3-dimethylbut-1-yn-1-yl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：432.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.37(d，J＝4.8Hz，1H)，7.83(d，J＝7.6Hz，1H)，7.25(dd，J＝7.6Hz，5.2Hz，1H)，4.77(s，2H)，4.16(s，1H)，3.68-3.78(m，2H)，3.14-3.24(m，3H)，2.96(d，J＝16.8Hz，1H)，1.92-2.05(m，2H)，1.62-1.70(m，1H)，1.51-1.58(m，1H)，1.35(s，9H)。

Example 89:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- (3-methoxy-3-methylbut-1-yn-1-yl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanols

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：448.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.33(d，J＝4.8Hz，1H)，7.82(d，J＝7.6Hz，1H)，7.26(dd，J＝7.6Hz，4.8Hz，1H)，4.78(s，2H)，4.07(s，1H)，3.72-3.80(m，2H)，3.46(s，3H)，3.14-3.25(m，3H)，2.90(d，J＝16.8Hz，1H)，1.95-2.10(m，2H)，1.62-1.69(m，1H)，1.57(s，6H)，1.42-1.50(m，1H)。

Example 90:(S) -4- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]-1′- Yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -2-methylbut-3-yn-2-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：454.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.37(d，J＝4.8Hz，1H)，7.86(d，J＝7.6Hz，1H)，7.29(dd，J＝7.6Hz，5.2Hz，1H)，7.02(t，J＝54.4Hz，1H)，4.17(s，1H)，3.67-3.76(m，2H)，3.19-3.33(m，3H)，2.97(d，J＝16.8Hz，1H)，1.98-2.11(m，2H)，1.64-1.72(m，1H)，1.62(s，6H)，1.50-1.57(m，1H)。

Example 91:(S) -1' - (3- (3-morpholinylprop-1-yn-1-yl) -1H-pyrazolo [3, 4-b)]Pyrazin-6-yl) - 5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

Reference example 1The target compound can be synthesized by adopting proper starting materials and intermediates. MS m/z [ LC-MS]：445.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.52(d，J＝4.8Hz，1H)，8.36(s，1H)，7.97(d，J＝7.6Hz，1H)，7.38(dd，J＝7.6Hz，4.8Hz，1H)，4.48-4.56(m，2H)，4.38-4.46(m，1H)，3.72-3.75(m，4H)，3.66(s，2H)，3.30-3.43(m，3H)，3.21(d，J＝16.8Hz，1H)，2.71-2.73(m，4H)，1.82-1.95(m，2H)，1.72-1.80(m，1H)，1.63-1.71(m，1H)。

Example 92:(S) -1' - (5- (difluoromethyl) -3- (3- (dimethylamino) prop-1-yn-1-yl) -1H-pyrazole And [3,4-b ]]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：453.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.53(d，J＝5.2Hz，1H)，7.98(d，J＝7.6Hz，1H)，7.38(dd，J＝7.6Hz，5.2Hz，1H)，7.01(t，J＝54.0Hz，1H)，4.56(s，1H)，4.19(s，2H)，3.77-3.85(m，1H)，3.68-3.76(m，1H)，3.17-3.39(m，4H)，2.86(s，6H)，1.98-2.13(m，2H)，1.77-1.84(m，1H)，1.66-1.73(m，1H)。

Example 93:(S) -1' - (5- (difluoromethyl) -3- (3-morpholinylprop-1-yn-1-yl) -1H-pyrazolo [3,4- b) Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidine) -5-amines

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：495.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.51(d，J＝4.8Hz，1H)，7.94(d，J＝7.2Hz，1H)，7.37(dd，J＝7.2Hz，4.8Hz，1H)，7.00(t，J＝54.0Hz，1H)，4.47(s，1H)，3.69-3.83(m，6H)，3.67(s，2H)，3.23-3.38(m，3H)，3.16(d，J＝17.2Hz，1H)，2.71-2.73(m，4H)，1.99-2.10(m，2H)，1.66-1.78(m，2H)。

Example 94:(S) -3- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]-1′- Yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -1, 1-diphenylprop-2-yn-1-ol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：528.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.43(d，J＝4.8Hz，1H)，7.89(d，J＝8.0Hz，1H)，7.84(s，1H)，7.19-7.42(m，11H)，4.34-4.47(m，2H)，4.23(s，1H)，3.23-3.33(m，3H)，3.05(d，J＝17.6Hz，1H)，1.93-2.04(m，2H)，1.78-1.90(m，2H)。

Example 95:(S) -1' - (3- ((3, 3-difluorocyclobutyl) ethynyl) -5- (difluoromethyl) -1H-pyrazolo [3, 4-b]pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：486.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.36(d，J＝4.4Hz，1H)，7.81(d，J＝7.2Hz，1H)，7.23(dd，J＝7.6Hz，5.2Hz，1H)，6.92(t，J＝54.4Hz，1H)，4.16(s，1H)，3.66-3.78(m，2H)，3.16-3.28(m，3H)，2.77-3.04(m，6H)，1.94-2.06(m，2H)，1.62-1.70(m，1H)，1.50-1.58(m，1H)。

Example 96:(S) -1' - (3- (cyclopentylethynyl) -5- (difluoromethyl) -1H-pyrazolo [3, 4-b)]Pyrazine- 6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amines

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：464.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.46(d，J＝4.8Hz，1H)，7.91(d，J＝7.6Hz，1H)，7.34(dd，J＝7.6Hz，5.2Hz，1H)，7.01(t，J＝54.4Hz，1H)，4.38(s，1H)，3.68-3.81(m，2H)，3.20-3.36(m，3H)，3.10(d，J＝16.8Hz，1H)，2.94-3.02(m，1H)，1.99-2.12(m，4H)，1.75-1.88(m，4H)，1.59-1.72(m，4H)。

Example 97:(S) -1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclobutan-1-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：496.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.42(d，J＝4.8Hz，1H)，7.88(d，J＝7.6Hz，1H)，7.32(dd，J＝7.6Hz，4.8Hz，1H)，7.02(t，J＝54.0Hz，1H)，4.26(s，1H)，3.68-3.79(m，2H)，3.21-3.37(m，3H)，3.03(d，J＝16.8Hz，1H)，2.54-2.62(m，2H)，2.30-2.39(m，2H)，1.86-2.10(m，4H)，1.66-1.72(m，1H)，1.56-1.63(m，1H)。

Example 98:(S) -1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclopropyl-1-carbonitrile

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：461.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.47(d，J＝5.2Hz，1H)，7.91(d，J＝7.6Hz，1H)，7.35(dd，J＝7.6Hz，5.2Hz，1H)，7.02(t，J＝54.0Hz，1H)，4.39(s，1H)，3.70-3.82(m，2H)，3.22-3.38(m，3H)，3.11(d，J＝17.2Hz，1H)，1.99-2.09(m，2H)，1.76-1.80(m，2H)，1.64-1.74(m，4H)。

Example 99:(S) -1' - (3- (3- (dimethylamino) prop-1-yn-1-yl) -1H-pyrazolo [3, 4-b)]Pyrazine- 6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：403.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.84(dd，J＝5.2Hz，1.6Hz，1H)，8.44(s，1H)，8.12(dd，J＝7.6Hz，1.6Hz，1H)，7.51(dd，J＝7.6Hz，5.2Hz，1H)，4.52-4.60(m，2H)，4.42(s，2H)，4.10(s，3H)，3.41-3.49(m，2H)，3.06(s，6H)，1.97-2.04(m，2H)，1.63-1.70(m，2H)。

Example 100:(S) -1' - (3- (cyclobutylethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-6-yl) -5, 7-bis Hydrogen spiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates。MS m/z[LC-MS]：400.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.43-8.90(m，1H)，8.35(s，1H)，8.02(d，J＝7.6Hz，1H)，7.42-7.53(m，1H)，4.50-4.58(m，2H)，4.39-4.46(m，1H)，3.24-3.45(m，5H)，2.23-2.43(m，4H)，1.74-2.09(m，5H)，1.64-1.72(m，1H)。

Example 101:(S) -1' - (3- (3-methoxyprop-1-yn-1-yl) -1H-pyrazolo [3, 4-b)]Pyrazine-6- Radical) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amines

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：390.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.43(d，J＝5.2Hz，1H)，8.36(s，1H)，7.87(d，J＝8.0Hz，1H)，7.32(dd，J＝8.0Hz，5.2Hz，1H)，4.39-4.52(m，4H)，4.24(s，1H)，3.46(s，3H)，3.35-3.42(m，2H)，3.27(d，J＝16.8Hz，1H)，3.08(d，J＝16.8Hz，1H)，1.82-1.83(m，2H)，1.55-1.70(m，2H)。

Example 102:(R) -4- (6- ((S) -5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperazines Pyridine (I)]-1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) but-3-yn-2-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：390.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.24-8.88(m，2H)，7.99(d，J＝8.0Hz，1H)，7.34-7.52(m，1H)，4.75(q，J＝6.8Hz，1H)，4.51-4.58(m，2H)，4.39-4.47(m，1H)，3.18-3.47(m，4H)，1.75-1.96(m，3H)，1.64-1.71(m，1H)，1.53(d，J＝6.8Hz，3H)。

Example 103:(S) -4- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -2, 2-dimethylbut-3-yn-1-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：418.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.45-8.52(m，1H)，8.32(s，1H)，7.94(d，J＝7.6Hz，1H)，7.32-7.38(m，1H)，4.36-4.53(m，3H)，3.52(s，2H)，3.24-3.41(m，3H)，3.15(d，J＝17.2Hz，1H)，1.82-1.94(m，2H)，1.62-1.74(m，2H)，1.31(s，6H)。

Example 104:(S) -1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclobutan-1-ol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：416.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.32(d，J＝4.8Hz，1H)，8.19(s，1H)，7.71(d，J＝7.6Hz，1H)，7.18(dd，J＝7.6Hz，4.8Hz，1H)，4.30-4.38(m，1H)，4.21-4.28(m，1H)，4.00(s，1H)，3.23-3.34(m，2H)，3.17(d，J＝16.4Hz，1H)，2.88(d，J＝16.4Hz，1H)，2.48-2.56(m，2H)，2.26-2.35(m，2H)，1.51-2.00(m，6H)。

Example 105:(S) -1' - (3- (3-ethylpent-1-yn-1-yl) -1H-pyrazolo [3, 4-b)]Pyrazine-6-yl) -substituted acids 5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amines

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：416.26[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.54-8.65(m，1H)，8.36(s，1H)，8.00(d，J＝7.6Hz，1H)，7.40-7.46(m，1H)，4.52-4.59(m，2H)，4.40-4.48(m，1H)，3.23-3.48(m，4H)，2.48-2.56(m，1H)，1.54-2.06(m，8H)，1.10(t，J＝7.2Hz，6H)。

Example 106:(S) -1' - (3- (cyclobutylethynyl) -5- (difluoromethyl) -1H-pyrazolo [3, 4-b)]Pyrazine- 6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：450.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.42(d，J＝4.8Hz，1H)，7.88(d，J＝7.6Hz，1H)，7.32(dd，J＝7.6Hz，4.8Hz，1H)，7.01(t，J＝54.0Hz，1H)，4.28(s，1H)，3.68-3.79(m，2H)，3.35-3.44(m，1H)，3.26-3.33(m，2H)，3.23(d，J＝16.8Hz，1H)，3.04(d，J＝16.8Hz，1H)，2.26-2.46(m，4H)，1.94-2.10(m，4H)，1.57-1.72(m，2H)。

Example 107:(S) - (1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclopropyl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：466.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.43(d，J＝4.4Hz，1H)，7.89(d，J＝7.6Hz，1H)，7.33(dd，J＝8.0Hz，4.2Hz，1H)，7.02(t，J＝54.0Hz，1H)，4.31(s，1H)，3.66-3.78(m，2H)，3.60(s，2H)，3.27-3.32(m，2H)，3.23(d，J＝16.8Hz，1H)，3.05(d，J＝16.8Hz，1H)，2.00-2.09(m，2H)，1.59-1.72(m，2H)，1.10-1.13(m，2H)，0.95-0.98(m，2H)。

Example 108:(S) - (1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclopropyl) methanol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：416.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.52(dd，J＝5.2Hz，1.2Hz，1H)，8.35(s，1H)，7.93(d，J＝7.6Hz，1H)，7.38(dd，J＝7.6Hz，5.2Hz，1H)，4.40-4.57(m，3H)，3.58(s，2H)，3.28-3.47(m，3H)，3.21(d，J＝16.8Hz，1H)，1.82-1.93(m，2H)，1.64-1.76(m，2H)，1.07-1.09(m，2H)，0.93-0.96(m，2H)。

Example 109:(S) -4- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -2, 2-dimethylbut-3-yn-1-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：468.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.41(d，J＝4.8Hz，1H)，7.87(d，J＝8.0Hz，1H)，7.31(dd，J＝8.0Hz，4.8Hz，1H)，7.03(t，J＝54.0Hz，1H)，4.24(s，1H)，3.67-3.78(m，2H)，3.55(s，2H)，3.20-3.32(m，3H)，3.02(d，J＝16.4Hz，1H)，1.99-2.10(m，2H)，1.65-1.72(m，1H)，1.56-1.62(m，1H)，1.34(s，6H)。

Example 110:(S) -5- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -2-methylpent-4-yn-2-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：418.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.46-8.54(m，1H)，8.33(s，1H)，7.97(d，J＝7.2Hz，1H)，7.32-7.38(m，1H)，4.35-4.55(m，3H)，3.12-3.42(m，4H)，2.67(s，2H)，1.82-1.96(m，2H)，1.72-1.79(m，1H)，1.62-1.70(m，1H)，1.37(s，6H)。

Example 111:(S) -5- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -2-methylpent-4-yn-2-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：468.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.42(d，J＝4.8Hz，1H)，7.89(d，J＝7.6Hz，1H)，7.32(dd，J＝7.6Hz，4.8Hz，1H)，7.01(t，J＝54.0Hz，1H)，4.28(s，1H)，3.67-3.78(m，2H)，3.26-3.32(m，2H)，3.23(d，J＝16.8Hz，1H)，3.03(d，J＝16.8Hz，1H)，2.71(s，2H)，1.99-2.10(m，2H)，1.65-1.72(m，1H)，1.57-1.64(m，1H)，1.39(s，6H)。

Example 112:(S) -1' - (5- (difluoromethyl) carbonyl)Yl) -3- (oxetan-3-ylethynyl) -1H-pyrazolo [3,4- b]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：452.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.54(dd，J＝5.2Hz，1.2Hz，1H)，7.96(d，J＝7.6Hz，1H)，7.39(dd，J＝7.6Hz，5.2Hz，1H)，7.01(t，J＝54.4Hz，1H)，4.91-4.97(m，2H)，4.81-4.87(m，2H)，4.55(s，1H)，4.23-4.28(m，1H)，3.66-3.82(m，2H)，3.18-3.38(m，4H)，1.98-2.12(m，2H)，1.72-1.80(m，1H)，1.60-1.68(m，1H)。

Example 113:(S) -1' - (3- ((6-aminopyridin-3-yl) ethynyl) -5- (difluoromethyl) -1H-pyrazolo [3，4-b]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amine e

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：488.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.48(d，J＝4.8Hz，1H)，8.21(d，J＝1.6Hz，1H)，7.93(d，J＝7.6Hz，1H)，7.67(dd，J＝8.8Hz，2.0Hz，1H)，7.35(dd，J＝7.6Hz，4.8Hz，1H)，7.04(t，J＝54.4Hz，1H)，6.59(d，J＝8.8Hz，1H)，4.41(s，1H)，3.71-3.84(m，2H)，3.23-3.38(m，3H)，3.12(d，J＝16.8Hz，1H)，1.99-2.11(m，2H)，1.67-1.73(m，2H)。

Example 114:(S) -1' - (3- (cyclopropylethynyl) -5- (difluoromethyl) -1H-pyrazolo [3, 4-b)]Pyrazine- 6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：436.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.41(d，J＝4.8Hz，1H)，7.88(d，J＝8.0Hz，1H)，7.31(dd，J＝8.0Hz，4.8Hz，1H)，7.01(t，J＝54.0Hz，1H)，4.26(s，1H)，3.68-3.78(m，2H)，3.25-3.34(m，2H)，3.22(d，J＝16.8Hz，1H)，3.02(d，J＝16.8Hz，1H)，1.99-2.09(m，2H)，1.64-1.71(m，1H)，1.56-1.63(m，2H)，0.92-0.99(m，2H)，0.86-0.91(m，2H)。

Example 115:(S) -1' - (5- (difluoromethyl) -3- ((3-methyloxycyclobutan-3-yl) ethynyl) -1H-pir-inyl) Azolo [3,4-b ]]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：466.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.50(d，J＝4.8Hz，1H)，7.94(d，J＝7.6Hz，1H)，7.37(dd，J＝7.6Hz，4.8Hz，1H)，7.02(t，J＝54.0Hz，1H)，4.97(d，J＝5.6Hz，2H)，4.54(d，J＝5.6Hz，2H)，4.44(s，1H)，3.69-3.82(m，2H)，3.29-3.38(m，2H)，3.25(d，J＝16.8Hz，1H)，3.16(d，J＝16.8Hz，1H)，1.99-2.10(m，2H)，1.77(s，3H)，1.66-1.75(m，2H)。

Example 116:(S) -3- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) oxetan-3-ols

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：468.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.55(d，J＝4.8Hz，1H)，8.00(d，J＝7.6Hz，1H)，7.40(dd，J＝7.6Hz，4.8Hz，1H)，7.02(t，J＝54.0Hz，1H)，4.97(d，J＝6.4Hz，2H)，4.74(d，J＝6.4Hz，2H)，4.59(s，1H)，3.68-3.85(m，2H)，3.28-3.40(m，3H)，3.22(d，J＝16.8Hz，1H)，1.99-2.14(m，2H)，1.79-1.85(m，1H)，1.66-1.73(m，1H)。

Example 117:(S) -1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (hydroxymethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclopropan-1-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：432.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.52(d，J＝5.2Hz，1H)，7.96(d，J＝7.6Hz，1H)，7.38(dd，J＝7.6Hz，5.2Hz，1H)，4.79(s，2H)，4.53(s，1H)，3.82-3.90(m，1H)，3.74-3.80(m，1H)，3.16-3.30(m，4H)，1.97-2.10(m，2H)，1.74-1.82(m，1H)，1.65-1.72(m，1H)，1.08-1.14(m，4H)。

Example 118:(S) -3- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) oxetan-3-ols

By following the procedure of example 1, the appropriate starting materials and intermediates were usedSo as to synthesize the target compound. MS m/z [ LC-MS]：418.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.50(d，J＝4.4Hz，1H)，8.35(s，1H)，7.95(d，J＝8.0Hz，1H)，7.36(dd，J＝7.6Hz，4.4Hz，1H)，4.95(d，J＝6.4Hz，2H)，4.73(d，J＝6.4Hz，2H)，4.36-4.54(m，3H)，3.28-3.41(m，3H)，3.18(d，J＝16.8Hz，1H)，1.82-1.95(m，2H)，1.62-1.76(m，2H)。

Example 119:(S) -1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclopropan-1-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：402.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.54(d，J＝4.4Hz，1H)，8.36(s，1H)，7.97(d，J＝7.2Hz，1H)，7.39(dd，J＝7.2Hz，4.4Hz，1H)，4.50-4.57(m，2H)，4.28-4.46(m，1H)，3.21-3.47(m，4H)，1.74-1.96(m，3H)，1.63-1.72(m，1H)，1.06-1.15(m，4H)。

Example 120:(S) -1' - (3, 3-dimethylbut-1-yn-1-yl) -1H-pyrazolo [3, 4-b)]Pyrazine-6- Radical) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：402.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.51(d，J＝4.4Hz，1H)，8.34(s，1H)，7.94(d，J＝8.0Hz，1H)，7.37(dd，J＝7.6Hz，5.2Hz，1H)，4.39-4.56(m，3H)，3.28-3.43(m，3H)，3.18(d，J＝16.8Hz，1H)，1.82-1.93(m，2H)，1.64-1.73(m，2H)，1.37(s，9H)。

Example 121:(S) -1' - (3- ((1- (trifluoromethyl) cyclopropyl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyridine (II) Oxazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：454.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.49(d，J＝4.8Hz，1H)，8.38(s，1H)，7.91(d，J＝7.6Hz，1H)，7.36(dd，J＝7.6Hz，4.8Hz，1H)，4.40-4.55(m，2H)，4.37(s，1H)，3.27-3.44(m，3H)，3.16(d，J＝16.8Hz，1H)，1.82-1.92(m，2H)，1.63-1.70(m，2H)，1.39-1.48(m，4H)。

Example 122:(S) -1' - (5- (difluoromethyl) -3- ((1- (trifluoromethyl) cyclopropyl) ethynyl) -1H-pyrazole And [3,4-b ]]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：504.19[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.50(d，J＝4.8Hz，1H)，7.97(d，J＝7.6Hz，1H)，7.37(dd，J＝7.6Hz，4.8Hz，1H)，7.02(t，J＝54.0Hz，1H)，4.47(s，1H)，3.69-3.84(m，2H)，3.25-3.38(m，3H)，3.15(d，J＝17.2Hz，1H)，2.00-2.12(m，2H)，1.66-1.76(m，2H)，1.42-1.50(m，4H)。

Example 123:(S) -1' - (5- (difluoromethyl) -3- ((1-methylcyclopropyl) ethynyl) -1H-pyrazolo [3, 4-b]pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amines

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：450.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.52(d，J＝4.8Hz，1H)，7.95(d，J＝7.2Hz，1H)，7.38(dd，J＝7.2Hz，4.8Hz，1H)，7.01(t，J＝54.0Hz，1H)，4.49(s，1H)，3.68-3.83(m，2H)，3.24-3.38(m，3H)，3.17(d，J＝16.8Hz，1H)，1.98-2.10(m，2H)，1.66-1.78(m，2H)，1.41(s，3H)，1.09-1.11(m，2H)，0.77-0.80(m，2H)。

Example 124:(S) -1' - (3- ((1-methylcyclopropyl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazine-6- Base) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：400.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.46(d，J＝4.8Hz，1H)，8.33(s，1H)，7.89(d，J＝7.2Hz，1H)，7.34(dd，J＝7.2Hz，4.8Hz，1H)，4.39-4.53(m，2H)，4.31(s，1H)，3.25-3.42(m，3H)，3.12(d，J＝16.8Hz，1H)，1.82-1.91(m，2H)，1.59-1.70(m，2H)，1.39(s，3H)，1.06-1.08(m，2H)，0.75-0.78(m，2H)。

Example 125:(S) -1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclopropane-1-carbonitrile

Reference fruitThe procedure of example 1, using appropriate starting materials and intermediates, gave the title compound. MS m/z [ LC-MS]：411.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.53(d，J＝4.8Hz，1H)，8.39(s，1H)，7.95(d，J＝8.0Hz，1H)，7.38(dd，J＝8.0Hz，4.8Hz，1H)，4.40-4.57(m，3H)，3.20-3.48(m，4H)，1.81-1.95(m，2H)，1.62-1.72(m，2H)，0.83-0.91(m，4H)。

Example 126:(S) -N- (1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperazines Pyridine (II)]-1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) cyclopropyl) methanesulfonamide

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：479.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.47-8.53(m，1H)，8.37(s，1H)，7.92(d，J＝7.6Hz，1H)，7.36(dd，J＝7.6Hz，4.8Hz，1H)，4.38-4.56(m，3H)，3.27-3.44(m，3H)，3.24(s，3H)，3.17(d，J＝16.8Hz，1H)，1.82-1.92(m，2H)，1.64-1.72(m，2H)，1.42-1.45(m，2H)，1.33-1.35(m，2H)。

Example 127:(S) -4- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -2-methylbut-3-yn-2-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：404.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.47(d，J＝4.8Hz，1H)，8.33(s，1H)，7.92(d，J＝7.6Hz，1H)，7.34(dd，J＝7.6Hz，4.8Hz，1H)，4.36-4.52(m，3H)，3.27-3.29(m，3H)，3.14(d，J＝16.8Hz，1H)，1.83-1.93(m，2H)，1.56-1.72(m，8H)。

Example 128:(S) -N- (4- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]) or a salt thereof]Pyridine-6, 4' -piperazines Pyridine (II)]-1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -2-methylbut-3-yn-2-yl) methanesulfonamide

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：481.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.43(d，J＝4.8Hz，1H)，8.34(s，1H)，7.88(d，J＝7.6Hz，1H)，7.32(dd，J＝7.6Hz，4.8Hz，1H)，4.37-4.50(m，2H)，4.27(s，1H)，3.30-3.40(m，2H)，3.21-3.26(m，4H)，3.08(d，J＝17.2Hz，1H)，1.82-1.92(m，2H)，1.56-1.74(m，8H)。

Example 129:(S) -1' - (3- (cyclopentylethynyl) -1H-pyrazolo [3, 4-b)]Pyrazin-6-yl) -5, 7-bis Hydrogen spiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amines

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：414.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.47(d，J＝4.8Hz，1H)，8.33(s，1H)，7.92(d，J＝7.6Hz，1H)，7.35(dd，J＝7.6Hz，4.8Hz，1H)，4.38-4.53(m，2H)，4.37(s，1H)，3.27-3.42(m，3H)，3.14(d，J＝16.8Hz，1H)，2.91-2.98(m，1H)，1.99-2.10(m，2H)，1.72-1.92(m，6H)，1.62-1.70(m，4H)。

Example 130:(S) -4- (6- ((S) -5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperazines Pyridine (I)]-1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) but-3-yn-2-ol

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：390.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.49(d，J＝4.8Hz，1H)，8.31(s，1H)，7.96(d，J＝7.2Hz，1H)，7.35(dd，J＝7.6Hz，4.8Hz，1H)，4.76(q，J＝6.8Hz，1H)，4.46-4.53(m，2H)，4.35-4.42(m，1H)，3.29-3.40(m，3H)，3.19(d，J＝17.2Hz，1H)，1.82-1.95(m，2H)，1.70-1.77(m，1H)，1.62-1.68(m，1H)，1.53(d，J＝6.8Hz，3H)。

Example 131:(S) -N- (1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]))]Pyridine-6, 4' -piperazines Pyridine (II)]-1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclopropyl) methanesulfonamide

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：529.19[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.45(d，J＝5.2Hz，1H)，7.90(d，J＝8.0Hz，1H)，7.34(dd，J＝8.0Hz，5.2Hz，1H)，7.01(t，J＝54.0Hz，1H)，4.35(s，1H)，3.67-3.79(m，2H)，3.27-3.35(m，5H)，3.23(d，J＝16.8Hz，1H)，3.08(d，J＝16.8Hz，1H)，2.00-2.09(m，2H)，1.62-1.72(m，2H)，1.42-1.47(m，2H)，1.36-1.40(m，2H)-

Example 132:(S) -1- ((6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) ethynyl) cyclopropan-1-ol

The title compound can be synthesized by the method described in example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：452.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.53(d，J＝5.2Hz，1H)，7.96(d，J＝7.2Hz，1H)，7.39(dd，J＝7.2Hz，5.2Hz，1H)，7.01(t，J＝54.0Hz，1H)，4.53(s，1H)，3.76-3.84(m，1H)，3.68-3.75(m，1H)，3.30-3.38(m，2H)，3.26(d，J＝17.2Hz，1H)，3.19(d，J＝17.2Hz，1H)，1.98-2.10(m，2H)，1.74-1.81(m，1H)，1.66-1.73(m，1H)，1.10-1.17(m，4H)。

Example 133:(S) -1' - (3- ((3-methyloxetan-3-yl) ethynyl) -1H-pyrazolo [3,4-b] Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amines

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：416.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.55(d，J＝4.8Hz，1H)，8.38(s，1H)，7.96(d，J＝7.2Hz，1H)，7.39(dd，J＝7.2Hz，4.8Hz，1H)，4.95(d，J＝5.6Hz，2H)，4.50-4.58(m，4H)，4.40-4.48(m，1H)，3.23-3.48(m，4H)，1.64-1.94(m，7H)。

Example 134:(S) -1' - (3- ((3, 3-difluorocyclobutyl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyrazine-6- Base) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：436.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.46(d，J＝4.8Hz，1H)，8.34(s，1H)，7.92(d，J＝7.2Hz，1H)，7.34(dd，J＝7.2Hz，4.8Hz，1H)，4.384.52(m，2H)，4.34(s，1H)，3.22-3.42(m，4H)，3.12(d，J＝16.8Hz，1H)，2.96-3.06(m，2H)，2.75-2.88(m，2H)，1.82-1.92(m，2H)，1.61-1.72(m，2H)。

Example 135:(S) -1' - (5- (difluoromethyl) -3- (3, 3-dimethylbut-1-yn-1-yl) -1H-pyrazolo [3，4-b]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：452.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.52(d，J＝4.8Hz，1H)，7.97(d，J＝7.6Hz，1H)，7.38(dd，J＝7.6Hz，4.8Hz，1H)，7.02(t，J＝54.0Hz，1H)，4.49(s，1H)，3.68-3.84(m，2H)，3.25-3.37(m，3H)，3.17(d，J＝16.8Hz，1H)，1.99-2.12(m，2H)，1.66-1.78(m，2H)，1.39(s，9H)。

Example 136:(S) -1' - (5- (difluoromethyl) -3- (3-methylbut-3-en-1-yn-1-yl) -1H-pyrazolo [3，4-b]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amines

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：436.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.50(d，J＝4.8Hz，1H)，7.97(d，J＝7.2Hz，1H)，7.37(dd，J＝7.6Hz，5.2Hz，1H)，7.02(t，J＝54.0Hz，1H)，5.55(s，1H)，5.46(s，1H)，4.47(s，1H)，3.69-3.84(m，2H)，3.25-3.38(m，3H)，3.15(d，J＝16.8Hz，1H)，1.98-2.12(m，5H)，1.66-1.78(m，2H)。

Example 137:(S) -1' - (3- (3-methylbut-3-en-1-yn-1-yl) -1H-pyrazolo [3, 4-b)]Pyrazine-6- Base) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：386.21[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.51(d，J＝4.8Hz，1H)，8.37(s，1H)，7.94(d，J＝7.6Hz，1H)，7.37(dd，J＝7.6Hz，4.8Hz，1H)，5.51(s，1H)，5.43(s，1H)，4.38-4.58(m，3H)，3.17-3.30(m，4H)，2.03(s，3H)，1.82-1.94(m，2H)，1.63-1.72(m，2H)。

Example 138:(S) -1' - (3- (3-amino-3-methylbut-1-yn-1-yl) -5- (difluoromethyl) -1H-pyrazole And [3,4-b ]]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amine

The title compound can be synthesized by following the procedure of example 1 using appropriate starting materials and intermediates. MS m/z [ LC-MS]：453.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.55(d，J＝4.8Hz，1H)，7.99(d，J＝7.2Hz，1H)，7.40(dd，J＝7.6Hz，4.8Hz，1H)，7.03(t，J＝54.0Hz，1H)，4.57(s，1H)，3.76-3.83(m，1H)，3.67-3.74(m，1H)，3.27-3.40(m，3H)，3.22(d，J＝17.6Hz，1H)，1.99-2.14(m，2H)，1.76-1.84(m，7H)，1.66-1.74(m，1H)。

Example 139:(S) -1' - (3- (2-methylpropan-1-en-1-yl) -1H-pyrazolo [3, 4-b)]Pyrazin-6-yl) - 5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amines

Step 1: (S) - (1 '- (3- (2-methylpropan-1-en-1-yl) -1- ((2- (trimethylsilyl) methoxy) methyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4' -piperidine ] -5-yl) carbamic acid tert-butyl ester

Intermediate 5 (136 mg), 4, 5-tetramethyl-2- (2-methylpropan-1-en-1-yl) -1,3, 2-dioxaborolane (44 mg), sodium carbonate (64 mg), tetrakis (triphenylphosphine) palladium (12 mg), and a dioxane/water 10: 1 mixed solvent (10 mL) were added to a single-neck flask, replaced with nitrogen, heated to 80 ℃ and stirred overnight. Cooled to room temperature, poured into water, extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol, 20: 1) to give tert-butyl (S) - (1 '- (3- (2-methylprop-1-en-1-yl) -1- ((2- (trimethylsilyl) methoxy) methyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4' -piperidin ] -5-yl) carbamate (90 mg). MS m/z [ LC-MS ]:606.36[ M ] +1].

Step 2: (S) -1'- (3- (2-methylpropan-1-en-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4' -piperidine ] -5-amine

Mixing (S) - (1' - (3- (2-methylpropane-1-en-1-yl) -1- ((2- (trimethylsilyl) methoxyl) methyl) -1H-pyrazolo [3, 4-b)]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-yl) carbamic acid tert-butyl ester (90 mg) was added to a dioxane solution (3 mL) of 4M hydrogen chloride, stirred at room temperature for 1 hour, concentrated under reduced pressure, added with 10% aqueous sodium carbonate solution (10 mL), extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (dichloromethane: methanol, 10: 1) to give (S) -1' - (3- (2-methylprop-1-en-1-yl) -1H-pyrazolo [3,4-b ]]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine (32 mg). MS m/z [ LC-MS]：376.22[M+1]。 ¹ HNMR(400MHz，CD ₃ OD)：δ＝8.53(d，J＝5.2Hz，1H)，8.29(s，1H)，7.95(d，J＝7.6Hz，1H)，7.38(dd，J＝7.6Hz，5.2Hz，1H)，6.42(s，1H)，4.37-4.54(m，3H)，3.18-3.39(m，4H)，2.09(s，3H)，1.09(s，3H)，1.81-1.91(m，2H)，1.64-1.75(m，2H)。

Example 140:(S) -1' - (3, 6-dihydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b)]Pyrazin-6-yl) - 5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：404.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.46(d，J＝4.8Hz，1H)，8.32(s，1H)，7.90(d，J＝7.2Hz，1H)，7.34(dd，J＝7.6Hz，4.8Hz，1H)，7.16-7.19(m，1H)，4.34-4.52(m，4H)，4.32(s，1H)，3.94(t，J＝5.2Hz，2H)，3.31-3.40(m，2H)，3.28(t，J＝16.8Hz，1H)，3.12(d，J＝16.8Hz，1H)，2.64-2.69(m，2H)，1.84-1.91(m，2H)，1.60-1.70(m，2H)。

Example 141:(S) -1' - (3- ((tetrahydro-4H-pyran-4-ylidene) methyl) -1H-pyrazolo [3, 4-b)]Pyrazine- 6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：418.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.38(d，J＝5.2Hz，1H)，8.28(s，1H)，7.86(d，J＝7.6Hz，1H)，7.29(dd，J＝7.6Hz，5.2Hz，1H)，6.44(s，1H)，4.36-4.47(m，2H)，4.15(s，1H)，3.79(t，J＝5.6Hz，2H)，3.72(t，J＝5.6Hz，2H)，3.31-3.38(m，2H)，3.25(d，J＝16.8Hz，1H)，3.00(d，J＝16.8Hz，1H)，2.90(t，J＝5.2Hz，2H)，2.46(t，J＝5.2Hz，2H)，1.82-1.93(m，2H)，1.61-1.67(m，1H)，1.49-1.56(m，1H)。

Example 142:(S) -1' - (3- (cyclobutylidenemethyl) -1H-pyrazolo [3, 4-b)]Pyrazin-6-yl) -5, 7-bis Hydrogen spiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amines

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：388.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.45(d，J＝4.8Hz，1H)，8.28(s，1H)，7.89(d，J＝7.2Hz，1H)，7.33(dd，J＝7.2Hz，4.8Hz，1H)，6.32-6.35(m，1H)，4.37-4.50(m，2H)，4.29(s，1H)，3.31-3.37(m，2H)，3.27(d，J＝16.8Hz，1H)，3.08-3.18(m，3H)，2.88-2.95(m，2H)，2.04-2.12(m，2H)，1.83-1.91(m，2H)，1.57-1.68(m，2H)。

Example 143:(3S, 4S) -8- (9- (cyclobutylidenemethyl) -7H-imidazo [1, 2-c)]Pyrazolo [4,3-e]Pyrimidine as one kind of food Pyridin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decan-4-amines

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：394.24[M+1]。 ¹ H NMR(400MHz，CDCl ₃ )：δ＝7.28-7.48(m，2H)，6.74(s，1H)，4.12-4.26(m，1H)，3.54-3.80(m，3H)，2.77-3.32(m，8H)，1.72-2.33(m，6H)，1.30-1.38(m，3H)。

Example 144:(S) -1' - (5- (difluoromethyl) -3- (3, 6-dihydro-2H-pyran-4-yl) -1H-pyrazolo [3, 4-b]pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopentadieneAnd [ b ]]Pyridine-6, 4' -piperidines]-5-amines

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：454.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.43(d，J＝4.8Hz，1H)，7.89(d，J＝7.2Hz，1H)，7.31-7.37(m，2H)，7.01(t，J＝54.0Hz，1H)，4.38-4.40(m，2H)，4.30(s，1H)，3.96(t，J＝5.2Hz，2H)，3.65-3.76(m，2H)，3.21-3.34(m，3H)，3.05(d，J＝16.4Hz，1H)，2.68-2.74(m，2H)，2.00-2.10(m，2H)，1.58-1.72(m，2H)。

Example 145:(S) -1' - (8- ((tetrahydro-4H-pyran-4-ylidene) methyl) imidazo [1, 2-c)]Pyrimidine-5- Radical) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amines

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：417.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.41(d，J＝4.8Hz，1H)，7.89(d，J＝7.6Hz，1H)，7.73(d，J＝1.2Hz，1H)，7.63(s，1H)，7.58(d，J＝1.2Hz，1H)，7.32(dd，J＝7.6Hz，4.8Hz，1H)，6.46(s，1H)，4.27(s，1H)，3.77-3.86(m，4H)，3.66(t，J＝5.6Hz，2H)，3.22-3.31(m，3H)，3.04(d，J＝16.8Hz，1H)，2.49-2.53(m，4H)，2.04-2.12(m，2H)，1.68-1.75(m，1H)，1.59-1.65(m，1H)。

Example 146:(3S, 4S) -8- (9- (3, 6-dihydro-2H-pyran-4-yl) -7H-imidazo [1, 2-c)]Pyrazolo ring [4，3-e]Pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decan-4-amines

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：410.23[M+1]。 ¹ H NMR(400MHz，CDCl ₃ )：δ＝8.09(s，1H)，7.47(s，1H)，7.43(s，1H)，4.49(s，2H)，4.17-4.28(m，1H)，3.85-4.06(m，3H)，3.57-3.78(m，3H)，2.88-3.33(m，3H)，2.68-2.84(m，2H)，2.08-2.24(m，1H)，1.77-2.04(m，3H)，1.28-1.34(m，3H)。

Example 147:(S) -1' - (8- (3, 6-dihydro-2H-pyran-4-yl) imidazo [1, 2-c)]Pyrimidin-5-yl) -5 (I) with (II), 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amines

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：403.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.46(d，J＝4.8Hz，1H)，7.91(d，J＝8.0Hz，1H)，7.73(s，2H)，7.60(s，1H)，7.34(dd，J＝8.0Hz，4.8Hz，1H)，6.83-6.86(m，1H)，4.46(s，1H)，4.34-4.37(m，2H)，3.96(t，J＝5.2Hz，2H)，3.76-3.87(m，2H)，3.26-3.35(m，3H)，3.10(d，J＝16.8Hz，1H)，2.59-2.65(m，2H)，2.00-2.13(m，2H)，1.65-1.75(m，2H)。

Example 148:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- (3, 6-dihydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b]Pyrazin-5-yl) methanol

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ L ]C-MS]：434.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.54(d，J＝4.8Hz，1H)，7.97(d，J＝7.2Hz，1H)，7.37-7.42(m，2H)，4.79(s，2H)，4.55(s，1H)，4.37-4.39(m，2H)，3.95(t，J＝5.6Hz，2H)，3.79-3.86(m，1H)，3.69-3.79(m，1H)，3.18-3.27(m，4H)，2.67-2.73(m，2H)，1.97-2.01(m，2H)，1.75-1.82(m，1H)，1.66-1.72(m，1H)。

Example 149:(3- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5- Methyl-6- ((tetrahydro-4H-pyran-4-ylidene) methyl) pyrazin-2-yl) methanol

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：389.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝6.35(s，1H)，4.62(s，2H)，4.23-4.29(m，1H)，3.90(d，J＝8.8Hz，1H)，3.76-3.80(m，3H)，3.66(t，J＝5.2Hz，2H)，3.47-3.59(m，2H)，3.32(d，J＝4.4Hz，1H)，2.90-3.04(m，2H)，2.67(t，J＝5.2Hz，2H)，2.43(t，J＝5.2Hz，2H)，2.40(s，3H)，1.88-1.98(m，2H)，1.78-1.86(m，1H)，1.66-1.72(m，1H)，1.28(d，J＝6.8Hz，3H)。

Example 150:(S) - (3- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -5-methyl-6- ((tetrahydro-4H-pyran-4-ylidene) methyl) pyrazin-2-yl) methanol

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：422.26[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.36(d，J＝4.8Hz，1H)，7.85(d，J＝7.2Hz，1H)，7.28(dd，J＝7.2Hz，4.8Hz，1H)，6.36(s，1H)，4.64(s，2H)，4.14(s，1H)，3.78(t，J＝5.2Hz，2H)，3.66(t，J＝5.2Hz，2H)，3.51-3.60(m，2H)，3.06-3.21(m，3H)，2.93(d，J＝16.8Hz，1H)，2.67(t，J＝5.2Hz，2H)，2.43(t，J＝5.2Hz，2H)，2.41(s，3H)，1.92-2.02(m，2H)，1.58-1.65(m，1H)，1.44-1.52(m，1H)。

Example 151:(S) -1' - (3- (4, 4-difluorocyclohex-1-en-1-yl) -1H-pyrazolo [3, 4-b)]Pyrazine-6- Base) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：438.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.38(d，J＝4.8Hz，1H)，8.28(s，1H)，7.84(d，J＝7.6Hz，1H)，7.29(dd，J＝8.0Hz，5.2Hz，1H)，7.05-7.09(m，1H)，4.36-4.45(m，2H)，4.12(s，1H)，3.22-3.34(m，3H)，2.99(d，J＝16.8Hz，1H)，2.83-2.87(m，2H)，2.70-2.81(m，2H)，2.11-2.22(m，2H)，1.80-1.92(m，2H)，1.60-1.67(m，1H)，1.46-1.53(m，1H)。

Example 152:(S) - (3- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 6- (3, 6-dihydro-2H-pyran-4-yl) -5-methylpyrazin-2-yl) -methanol

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：408.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.35(d，J＝4.8Hz，1H)，7.85(d，J＝7.2Hz，1H)，7.27(dd，J＝7.6Hz，5.2Hz，1H)，5.91-5.94(m，1H)，4.64(s，2H)，4.28-4.30(m，2H)，4.13(s，1H)，3.91(t，J＝5.6Hz，2H)，3.54-3.62(m，2H)，3.18(d，J＝16.8Hz，1H)，3.07-3.15(m，2H)，2.92(d，J＝16.8Hz，1H)，2.51-2.57(m，2H)，2.49(s，3H)，1.91-2.02(m，2H)，1.58-1.64(m，1H)，1.44-1.51(m，1H)。

Example 153:6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5- Methyl-3- ((tetrahydro-4H-pyran-4-ylidene) methyl) -1, 5-dihydro-4H-pyrazolo [3,4-d]Pyrimidin-4-ones

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：415.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝6.56-6.59(m，1H)，4.22-4.28(m，1H)，3.88(d，J＝8.4Hz，1H)，3.75-3.79(m，3H)，3.70(t，J＝5.6Hz，2H)，3.36-3.53(m，5H)，3.21-3.27(m，1H)，2.93-3.08(m，2H)，2.43(t，J＝5.6Hz，2H)，1.90-2.05(m，4H)，1.78-1.86(m，1H)，1.68-1.78(m，1H)，1.26(d，J＝6.8Hz，3H)。

Example 154:6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (3, 6-dihydro-2H-pyran-4-yl) -5-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d)]Pyrimidin-4-ones

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：401.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.46-7.51(m，1H)，4.32-4.35(m，2H)，3.86-3.92(m，3H)，3.81(d，J＝8.8Hz，1H)，3.62-3.70(m，1H)，3.45-3.59(m，5H)，2.88-2.99(m，2H)，2.66(d，J＝7.6Hz，1H)，2.58-2.64(m，2H)，1.84-2.04(m，3H)，1.58-1.66(m，1H)，1.33(d，J＝6.0Hz，3H)。

Example 155: (S) -1'- (9- (3, 6-dihydro-2H-pyran-4-yl) -7H-imidazo [1,2-c ] pyrazolo [4,3-e ] pyrimidin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4' -piperidine ] -5-amine

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：443.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.33(d，J＝4.8Hz，1H)，7.79(d，J＝7.6Hz，1H)，7.73(s，1H)，7.58(d，J＝1.2Hz，1H)，7.39(d，J＝1.2Hz，1H)，7.22(dd，J＝7.6Hz，4.8Hz，1H)，4.43-4.47(m，2H)，4.11(s，1H)，3.96(t，J＝5.6Hz，2H)，3.75-3.84(m，2H)，3.18-3.31(m，3H)，2.92(d，J＝16.8Hz，1H)，2.68-2.75(m，2H)，1.98-2.16(m，2H)，1.68-1.75(m，1H)，1.48-1.56(m，1H)。

Example 156:(3- ((S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -6- (3, 6-dihydro-2H-pyran-4-yl) -5-methylpyrazin-2-yl) methanol

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：375.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝5.91-5.94(m，1H)，4.62(s，2H)，4.23-4.30(m，3H)，3.88-3.93(m，3H)，3.79(d，J＝9.2Hz，1H)，3.48-3.60(m，2H)，3.30-3.31(m，1H)，2.90-3.05(m，2H)，2.51-2.57(m，2H)，2.49(s，3H)，1.87-1.97(m，2H)，1.79-1.86(m，1H)，1.65-1.72(m，1H)，1.27(d，J＝6.8Hz，3H)。

Example 157:(S) -1' - (3- (4, 4-difluorocyclohex-1-en-1-yl) -5- (difluoromethyl) -1H-pyrazolo [3，4-b]Pyrazin-6-yl) -5, 7-dihydroSpiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：488.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.42(d，J＝4.8Hz，1H)，7.88(d，J＝7.6Hz，1H)，7.32(dd，J＝7.6Hz，4.8Hz，1H)，7.25-7.30(m，1H)，7.01(t，J＝54.0Hz，1H)，4.26(s，1H)，3.64-3.76(m，2H)，3.20-3.36(m，3H)，3.03(d，J＝16.8Hz，1H)，2.76-2.94(m，4H)，2.15-2.25(m，2H)，2.00-2.10(m，2H)，1.65-1.72(m，1H)，1.56-1.63(m，1H)。

Example 158:(S) -1' - (5- (difluoromethyl) -3- ((tetrahydro-4H-pyran-4-ylidene) methyl) -1H-pyrazole And [3,4-b ]]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：468.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.42(d，J＝4.8Hz，1H)，7.89(d，J＝7.6Hz，1H)，7.32(dd，J＝7.6Hz，4.8Hz，1H)，7.01(t，J＝54.0Hz，1H)，6.55(s，1H)，4.27(s，1H)，3.81(t，J＝5.6Hz，2H)，3.76(t，J＝5.6Hz，2H)，3.61-3.73(m，2H)，3.20-3.32(m，3H)，3.02(d，J＝16.8Hz，1H)，2.97(t，J＝5.2Hz，2H)，2.49(t，J＝5.2Hz，2H)，2.00-2.10(m，2H)，1.64-1.72(m，1H)，1.56-1.63(m，1H)。

Example 159:(S) - (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- ((tetrahydro-4H-pyran-4-ylidene) methyl) -1H-pyrazolo [3, 4-b)]Pyrazin-5-yl) methanol

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：448.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.52(d，J＝4.8Hz，1H)，7.94(d，J＝7.6Hz，1H)，7.38(dd，J＝7.6Hz，4.8Hz，1H)，4.57(s，1H)，4.71(s，2H)，4.50(s，1H)，3.78-3.85(m，3H)，3.70-3.76(m，3H)，3.15-3.30(m，4H)，2.93-3.00(m，2H)，2.49(t，J＝5.2Hz，2H)，1.97-2.09(m，2H)，1.65-1.78(m，2H)。

Example 160:(3S, 4S) -8- (9- (4, 4-Difluorocyclohex-1-en-1-yl) -7H-imidazo [1, 2-c)]Pyrazoles And [4,3-e ]]Pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decan-4-amines

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：444.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.71(d，J＝1.6Hz，1H)，7.47-7.59(m，1H)，7.45(d，J＝1.6Hz，1H)，4.26-4.31(m，1H)，3.94(d，J＝8.8Hz，1H)，3.70-3.83(m，3H)，3.11-3.33(m，3H)，2.79-2.95(m，4H)，2.16-2.27(m，2H)，1.98-2.10(m，2H)，1.87-1.94(m，1H)，1.76-1.83(m，1H)，1.28(d，J＝6.4Hz，3H)。

Example 161:(S) -1' - (9- (2, 6-tetramethyl-3, 6-dihydro-2H-pyran-4-yl) -7H-imidazo [1，2-c]Pyrazolo [4,3-e ]]Pyrimidin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：499.29[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.36(d，J＝4.0Hz，1H)，7.88(s，1H)，7.83(d，J＝7.6Hz，1H)，7.64(d，J＝1.6Hz，1H)，7.44(d，J＝1.2Hz，1H)，7.26(dd，J＝7.6Hz，4.8Hz，1H)，4.16(s，1H)，3.75-3.84(m，2H)，3.19-3.32(m，4H)，2.95(d，J＝16.8Hz，1H)，2.60(s，2H)，1.99-2.16(m，2H)，1.65-1.75(m，1H)，1.48-1.61(m，1H)，1.40(3，6H)，1.32(3，6H)。

Example 162:(S) -1' - (9- (4, 4-difluorocyclohex-1-en-1-yl) -7H-imidazo [1, 2-c)]Pyrazolo of the formula [4，3-e]Pyrimidin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amines

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：477.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.39(d，J＝4.4Hz，1H)，7.87(d，J＝8.0Hz，1H)，7.68(d，J＝0.8Hz，1H)，7.49(s，1H)，7.41(d，J＝0.8Hz，1H)，7.30(dd，J＝7.6Hz，4.4Hz，1H)，4.22(s，2H)，3.75-3.85(m，2H)，3.18-3.31(m，2H)，2.99(d，J＝16.4Hz，1H)，2.75-2.92(m，4H)，2.01-2.23(m，4H)，1.67-1.74(m，1H)，1.55-1.62(m，1H)。

Example 163 is as follows:6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (4, 4-Difluorocyclohex-1-en-1-yl) -5-methyl-1, 5-dihydro-4H-pyrazolo [3,4-d]Pyrimidin-4-ones

With reference to the procedure in example 139, using the appropriate starterThe target compound can be synthesized from the raw materials and the intermediate. MS m/z [ LC-MS]：435.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.23(s，1H)，4.18-4.25(m，1H)，3.82(d，J＝8.8Hz，1H)，3.68(d，J＝9.2Hz，1H)，3.50(s，3H)，3.37-3.44(m，2H)，2.93-3.12(m，3H)，2.64-2.83(m，4H)，2.08-2.19(m，2H)，1.82-1.98(m，2H)，1.64-1.76(m，2H)，1.20(d，J＝6.0Hz，3H)。

Example 164:6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5- Methyl-3- (1, 2,3, 6-tetrahydropyridin-4-yl) -1, 5-dihydro-4H-pyrazolo [3,4-d]Pyrimidin-4-ones

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：400.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.58(s，1H)，4.27-4.31(m，1H)，3.87-3.97(m，3H)，3.81(d，J＝9.2Hz，1H)，3.40-3.60(m，6H)，2.86-3.01(m，4H)，1.94-2.06(m，2H)，1.83-1.94(m，2H)，1.70-1.78(m，2H)，1.32(d，J＝6.0Hz，3H)。

Example 165:(S) -1' - (3- (1, 2,3, 6-tetrahydropyridin-4-yl) -1H-pyrazolo [3, 4-b)]Pyrazine-6- Base) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：403.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.54(d，J＝5.2Hz，1H)，8.36(s，1H)，7.96(d，J＝7.6Hz，1H)，7.39(dd，J＝7.6Hz，5.2Hz，1H)，7.24(s，1H)，4.53(d，J＝14.4Hz，1H)，4.51(s，1H)，4.41(d，J＝14.0Hz，1H)，3.93(d，J＝2.4Hz，2H)，3.49(t，J＝6.0Hz，2H)，3.24-3.40(m，4H)，2.93-3.00(m，2H)，1.72-1.97(m，3H)，1.62-1.69(m，1H)。

Example 166:(S) -3- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -4, 4-dimethylcyclohex-2-en-1-one

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：494.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.40(d，J＝4.8Hz，1H)，7.87(d，J＝7.6Hz，1H)，7.38-7.50(m，1H)，7.31(dd，J＝7.6Hz，4.8Hz，1H)，7.00(t，J＝54.0Hz，1H)，4.24(s，1H)，3.62-3.76(m，2H)，3.20-3.32(m，3H)，2.97-3.04(m，1H)，2.68-2.74(m，2H)，1.98-2.10(m，4H)，1.52-1.69(m，2H)，1.33(s，6H)。

Example 167:(S) -1' - (3- (1-cyclopropyl-1, 2,3, 6-tetrahydropyridin-4-yl) -5- (difluoromethyl) -1H- Pyrazolo [3,4-b]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amines

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：493.26[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.54(d，J＝4.8Hz，1H)，7.98(d，J＝8.0Hz，1H)，7.37-7.41(m，2H)，7.02(t，J＝54.4Hz，1H)，4.58(s，1H)，4.16(s，2H)，3.60-3.82(m，4H)，3.31-3.37(m，2H)，3.19-3.30(m，2H)，3.04-3.14(m，2H)，2.90-2.99(m，1H)，1.98-2.13(m，2H)，1.78-1.85(m，1H)，1.66-1.73(m，1H)，0.98-1.05(m，4H)。

Example 168:(S) -1- (4- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]) or a salt thereof]Pyridine-6, 4' -piperazines Pyridine (II)]-1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -3, 6-dihydropyridin-1 (2H) -yl) acetic acid 1-ketones

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：495.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.55(d，J＝4.0Hz，1H)，7.97(d，J＝7.6Hz，1H)，7.40(dd，J＝7.6Hz，4.8Hz，1H)，7.34-7.38(m，1H)，7.01(t，J＝54.4Hz，1H)，4.58(s，1H)，4.29-4.36(m，2H)，3.65-3.88(m，4H)，3.20-3.40(m，4H)，2.81-2.88(m，1H)，2.72-2.79(m，1H)，2.19(s，1.5H)，2.16(s，1.5H)，1.98-2.11(m，2H)，1.77-1.84(m，1H)，1.66-1.74(m，1H)。

Example 169:(S) -1' - (9- ((tetrahydro-4H-pyran-4-ylidenyl) methyl) -7H-imidazo [1, 2-c)]Pyridine (II) Azolo [4,3-e ] s]Pyridin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：457.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.33(d，J＝5.2Hz，1H)，7.83(d，J＝8.0Hz，1H)，7.69(d，J＝1.2Hz，1H)，7.42(d，J＝1.2Hz，1H)，7.26(dd，J＝7.6Hz，5.2Hz，1H)，6.72(s，1H)，4.08(s，1H)，3.77-3.85(m，4H)，3.70(t，J＝5.6Hz，2H)，3.20-3.32(m，3H)，2.91(d，J＝16.4Hz，1H)，2.80-2.87(m，2H)，2.51(t，J＝5.2Hz，2H)，2.02-2.17(m，2H)，1.71(d，J＝13.2Hz，1H)，1.50(d，J＝13.2Hz，1H)。

Example 170:(S) - (4- (5- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]) or a salt thereof]Pyridine-6, 4' -piperidines]- 1' -yl) -7H-imidazo [1,2-c]Pyrazolo [4,3-e]Pyridin-9-yl) -3, 6-dihydropyridin-1 (2H) -yl) (cyclopropyl) Ketone

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：510.27[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.34(d，J＝4.8Hz，1H)，7.80(d，J＝7.2Hz，1H)，7.67-7.72(m，1H)，7.61-7.64(m，1H)，7.42(d，J＝1.6Hz，1H)，7.24(dd，J＝7.6Hz，5.2Hz，1H)，4.57(s，1H)，4.36(s，1H)，4.12(s，1H)，3.98(t，J＝5.6Hz，1H)，3.78-3.86(m，3H)，3.19-3.32(m，3H)，2.85-2.95(m，2H)，2.73-2.79(m，1H)，1.88-2.14(m，3H)，1.68-1.76(m，1H)，1.50-1.57(m，1H)，0.91-0.97(m，2H)，0.79-0.88(m，2H)。

Example 171:(S) -1- (4- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]) or a salt thereof]Pyridine-6, 4' -piperazines Pyridine (I)]-1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2, 2-trifluoroethyl-1- Ketones

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：499.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.37(d，J＝5.2Hz，1H)，8.32(s，1H)，7.83(d，J＝7.6Hz，1H)，7.28(dd，J＝7.6Hz，5.2Hz，1H)，7.15-7.22(m，1H)，4.35-4.46(m，4H)，4.10(s，1H)，3.87-3.94(m，2H)，3.23-3.38(m，3H)，2.98(d，J＝16.8Hz，1H)，2.76-2.85(m，2H)，1.81-1.94(m，2H)，1.62-1.68(m，1H)，1.45-1.52(m，1H)。

Example 172:(S) -1' - (9- (1- (cyclopropylsulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -7H-imidazole And [1,2-c ]]Pyrazolo [4,3-e]Pyridin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amines

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：546.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.34(d，J＝5.2Hz，1H)，7.80(d，J＝8.0Hz，1H)，7.72(s，1H)，7.63(d，J＝1.6Hz，1H)，7.42(d，J＝1.6Hz，1H)，7.24(dd，J＝7.6Hz，5.2Hz，1H)，4.16-4.19(m，2H)，4.12(s，1H)，3.79-3.86(m，2H)，3.59-3.62(m，2H)，3.19-3.33(m，3H)，2.93(d，J＝16.8Hz，1H)，2.82-2.90(m，2H)，2.44-2.51(m，1H)，2.01-2.15(m，2H)，1.69-1.76(m，1H)，1.50-1.57(m，1H)，1.13-1.17(m，2H)，0.99-1.04(m，2H)。

Example 173:(S) -1' - (9- ((2-oxaspiro [ 3.5)]Nonan-7-ylidene) methyl) -7H-imidazo [1,2- c]Pyrazolo [4,3-e]Pyridin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amines

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：497.28[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.41(d，J＝4.8Hz，1H)，7.69(d，J＝7.2Hz，1H)，7.46(s，1H)，7.38(s，1H)，7.15(dd，J＝7.2Hz，5.2Hz，1H)，6.72(s，1H)，4.42-4.46(m，4H)，4.13(s，1H)，3.74-3.82(m，2H)，3.11-3.27(m，3H)，2.92(d，J＝16.8Hz，1H)，2.70-2.78(m，2H)，2.31-2.34(m，2H)，2.00-2.11(m，2H)，1.85-1.93(m，4H)，1.69(d，J＝12.8Hz，1H)，1.54(d，J＝12.8Hz，1H)。

Example 174:(S) -1' - (9- (3, 4-dihydro-2H-pyran-5-yl) -7H-imidazo [1, 2-c)]The presence of a pyrazolo [4 ] group, 3-e]pyridin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：443.23[M+1]. ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.58(s，1H)，8.41(d，J＝5.2Hz，1H)，7.87(d，J＝8.0Hz，1H)，7.55(d，J＝1.6Hz，1H)，7.37(d，J＝1.6Hz，1H)，7.27(dd，J＝8.0Hz，5.2Hz，1H)，4.28(s，1H)，4.11(t，J＝5.2Hz，2H)，3.76-3.83(m，2H)，3.21-3.28(m，3H)，3.04(d，J＝16.8Hz，1H)，2.57(t，J＝6.0Hz，2H)，2.02-2.12(m，4H)，1.64-1.72(m，2H)。

Example 175:(S) -1' - (5- (difluoromethyl) -3- (4, 5-dihydrofuran-2-yl) -1H-pyrazolo [3, 4-b)] Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amines

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：440.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.54(d，J＝4.0Hz，1H)，7.97(d，J＝7.2Hz，1H)，7.39(dd，J＝7.6Hz，5.2Hz，1H)，7.02(t，J＝54.4Hz，1H)，4.50(s，1H)，3.60-3.83(m，5H)，3.09-3.24(m，2H)，1.87-2.14(m，2H)，1.60-1.80(m，4H)，1.53-1.59(m，2H)。

Example 176:(S) -1' - (5- (difluoromethyl) -3- (2, 6-tetramethyl-3, 6-dihydro-2H-pyran-4- Yl) -1H-pyrazolo [3,4-b]Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：510.28[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.41(d，J＝5.2Hz，1H)，7.88(d，J＝7.2Hz，1H)，7.30-7.33(m，2H)，7.02(t，J＝54.4Hz，1H)，4.25(s，1H)，3.68-3.74(m，2H)，3.21-3.32(m，3H)，3.02(d，J＝16.8Hz，1H)，2.59(s，2H)，2.01-2.10(m，2H)，1.68(d，J＝13.6Hz，1H)，1.59(d，J＝13.6Hz，1H)，1.38(s，6H)，1.32(s，6H)。

Example 177:(S) - (4- (66- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]))]Pyridine-6, 4' -piperidines]- 1' -yl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -3, 6-dihydropyridin-1 (2H) -yl) (cyclopropyl) methanone

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：471.26[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.36(d，J＝4.8Hz，1H)，8.30(s，1H)，7.82(d，J＝8.0Hz，1H)，7.27(dd，J＝7.6Hz，4.8Hz，1H)，7.16-7.22(m，1H)，4.51(s，1H)，4.37-4.46(m，2H)，4.27(s，1H)，4.08(s，1H)，3.99(t，J＝6.0Hz，1H)，3.82(t，J＝5.2Hz，1H)，3.22-3.36(m，3H)，2.96(d，J＝16.4Hz，1H)，2.78-2.85(m，1H)，2.67-2.73(m，1H)，1.80-2.10(m，3H)，1.64(d，J＝12.4Hz，1H)，1.47(d，J＝12.4Hz，1H)，0.82-0.94(m，4H)。

Example 178:1- (4- (5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decane-8- Radical) -7H-imidazo [1,2-c]Pyrazolo [4,3-e]Pyridin-9-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：451.26[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝7.63-7.70(m，2H)，7.44-7.45(m，1H)，4.28-4.38(m，3H)，3.98(d，J＝9.2Hz，1H)，3.76-3.88(m，5H)，3.52(d，J＝4.4Hz，1H)，3.09-3.22(m，2H)，2.80-2.86(m，1H)，2.71-2.76(m，1H)，2.19(s，1.5H)，2.18(s，1.5H)，2.02-2.14(m，2H)，1.96(d，J＝12.8Hz，1H)，1.81(d，J＝12.8Hz，1H)，1.33(d，J＝6.4Hz，3H)。

Example 179:(S) -4- (5- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -7H-imidazo [1,2-c]Pyrazolo [4,3-e ]]Pyridin-9-yl) -3, 6-dihydropyridine-1 (2H) -carbonitrile

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS ]:467.24[ M ] +1].

Example 180:(S) -6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- (3, 4-dihydro-2H-pyran-5-yl) -5-methyl-1, 5-dihydro-4H-pyrazolo [3,4-d]Pyrimidine 4-ones

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：434.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.39-8.42(m，2H)，7.88(d，J＝7.6Hz，1H)，7.31(dd，J＝7.6Hz，4.8Hz，1H)，4.26(s，1H)，4.05(t，J＝4.8Hz，2H)，3.45-3.62(m，5H)，3.10-3.23(m，3H)，3.01(d，J＝16.8，1H)，2.48(t，J＝6.0Hz，2H)，1.94-2.06(m，4H)，1.53-1.69(m，2H)。

Example 181:(S) -6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Base) -3- (3, 6-dihydro-2H-pyran-4-yl) -5-methyl-1, 5-dihydro-4H-pyrazolo [3,4-d]Pyrimidin-4-ones

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：434.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.38(d，J＝5.2Hz，1H)，7.86(d，J＝7.6Hz，1H)，7.49(s，1H)，7.30(dd，J＝7.6Hz，5.2Hz，1H)，4.336-4.37(m，2H)，4.19(s，1H)，3.90(t，J＝5.2Hz，2H)，3.49-3.58(m，5H)，3.09-3.22(m，3H)，2.96(d，J＝16.4Hz，1H)，2.59-2.64(m，2H)，1.95-2.06(m，2H)，1.66(d，J＝12.8Hz，1H)，1.53(d，J＝12.8Hz，1H)。

Example 182:(S) -6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- (4, 4-difluorocyclohex-1-en-1-yl) -5-methyl-1, 5-dihydro-4H-pyrazolo [3,4-d]Pyrimidin-4-ones

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：468.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.34(d，J＝5.2Hz，1H)，7.83(d，J＝7.6Hz，1H)，7.21-7.28(m，2H)，4.09(s，1H)，3.48-3.55(m，5H)，3.06-3.20(m，3H)，2.87-2.98(m，2H)，2.68-2.83(m，2H)，2.50-2.57(m，1H)，1.92-2.18(m，4H)，1.64(d，J＝13.6Hz，1H)，1.45(d，J＝13.6Hz，1H)。

Example 183:(S) -6- ((5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- (4-fluorocyclohexa-1, 3-dien-1-yl) -5-methyl-1, 5-dihydro-4H-pyrazolo [3,4-d]Pyrimidin-4-ones

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：448.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.46(d，J＝5.6Hz，1H)，7.91(d，J＝7.2Hz，1H)，7.58-7.68(m，1H)，7.34(dd，J＝7.2Hz，5.2Hz，1H)，5.63-5.68(m，1H)，4.36(s，1H)，3.46-3.62(m，5H)，3.04-3.24(m，6H)，2.94-3.00(m，1H)，2.52-2.58(m，1H)，1.96-2.04(m，2H)，1.60-1.69(m，2H)。

Example 184:(S) -N- (1' - (3- (1- (cyclopropylcarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -5-methyl-) 4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d]Pyrimidin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6,4- Piperidine derivatives]-5-yl) cyclopropylcarboxamide

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：569.30[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.58(d，J＝9.6Hz，1H)，8.38(d，J＝4.8Hz，1H)，7.71(d，J＝7.6Hz，1H)，7.42-7.50(m，1H)，7.29(dd，J＝7.6Hz，4.8Hz，1H)，5.35(d，J＝9.6Hz，1H)，4.49(s，1H)，4.25(s，1H)，3.95(t，J＝5.6Hz，1H)，3.78(t，J＝5.6Hz，1H)，3.40-3.55(m，5H)，3.11-3.21(m，3H)，2.97(d，J＝16.8Hz，1H)，2.74-2.80(m，1H)，2.62-2.68(m，1H)，1.86-2.09(m，3H)，1.70-1.78(m，1H)，1.58-1.68(m，2H)，0.76-0.94(m，8H)。

Example 185:(5S) -1' - (9- (3-methyl-3, 6-dihydro-2H-pyran-4-yl) -7H-imidazo [1, 2-c)] Pyrazolo [4,3-e ]]Pyridin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amines

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：457.25[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.42(d，J＝4.8Hz，1H)，7.91(d，J＝8.0Hz，1H)，7.69(s，1H)，7.37-7.41(m，2H)，7.32(dd，J＝7.6Hz，4.8Hz，1H)，4.47(dd，J＝17.6Hz，3.2Hz，1H)，4.30-4.37(m，2H)，3.75-3.88(m，4H)，3.23-3.35(m，3H)，3.02-3.13(m，2H)，2.04-2.17(m，2H)，1.63-1.72(m，2H)，1.20(d，J＝7.2Hz，3H)。

Example 186:(S) -6- (5-amino-5)，7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- 3- (1- (cyclopropylcarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -5-methyl-1, 5-dihydro-4H-pyrazolo [3,4-d] Pyrimidin-4-ones

The title compound was synthesized according to the procedure described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：501.27[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.38(d，J＝5.2Hz，1H)，7.86(d，J＝7.6Hz，1H)，7.44-7.50(m，1H)，7.30(dd，J＝7.6Hz，5.2Hz，1H)，4.49(s，1H)，4.25(s，1H)，4.19(s，1H)，3.96(t，J＝5.6Hz，1H)，3.78(t，J＝5.6Hz，1H)，3.50-3.58(m，5H)，3.09-3.22(m，3H)，2.96(d，J＝16.8Hz，1H)，2.74-2.81(m，1H)，2.62-2.68(m，1H)，1.94-2.08(m，3H)，1.66(d，J＝12.4Hz，1H)，1.53(d，J＝12.4Hz，1H)，0.80-0.92(m，4H)。

Example 187:(S) -6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1′- Yl) -3- (1- (cyclopropylsulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -5-methyl-1, 5-dihydro-4H-pyrazolo [3,4- d]Pyrimidin-4-ones

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：537.24[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.36(d，J＝5.2Hz，1H)，7.85(d，J＝7.2Hz，1H)，7.48(s，1H)，7.27-7.30(m，1H)，4.14(s，1H)，4.06(s，2H)，3.46-3.58(m，7H)，3.08-3.21(m，3H)，2.94(d，J＝16.4Hz，1H)，2.74-2.80(m，2H)，2.51-2.57(m，1H)，1.94-2.08(m，2H)，1.66(d，J＝12.4Hz，1H)，1.46-1.54(m，1H)，1.07-1.11(m，2H)，0.99-1.05(m，2H)。

Example 188:(S) -1' - (9- (2-oxaspiro [3.5 ]) spiro [ 2-oxa ] spiro [3.5 ]]Non-6-en-7-yl) -7H-imidazo [1,2-c]Pyrazoles And [4,3-e ]]Pyridin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：483.26[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.43(d，J＝4.0Hz，1H)，7.91(d，J＝7.6Hz，1H)，7.69(d，J＝1.6Hz，1H)，7.48(s，1H)，7.41(d，J＝1.6Hz，1H)，7.32(dd，J＝7.6Hz，5.2Hz，1H)，4.53(d，J＝6.0Hz，2H)，4.49(d，J＝6.0Hz，2H)，4.34(s，1H)，3.75-3.86(m，2H)，3.23-3.35(m，3H)，3.05(d，J＝16.8Hz，1H)，2.65-2.73(m，4H)，2.06-2.14(m，4H)，1.64-1.72(m，2H)。

Example 189:(S) -1' - (5- (difluoromethyl) -3- (4, 5-dihydrofuran-3-yl) -1H-pyrazolo [3, 4-b)] Pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：440.20[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.40(dd，J＝5.2Hz，1.2Hz，1H)，7.88(d，J＝7.2Hz，1H)，7.65(t，J＝2.0Hz，1H)，7.30(dd，J＝7.2Hz，5.2Hz，1H)，7.00(t，J＝54.0Hz，1H)，4.51(t，J＝9.2Hz，2H)，4.24(s，1H)，3.61-3.74(m，2H)，3.20-3.30(m，3H)，3.10(td，J＝9.6Hz，2.0Hz，2H)，3.00(d，J＝16.8Hz，1H)，2.00-2.10(m，2H)，1.64-1.71(m，1H)，1.54-1.61(m，1H)。

Example 190:(S) -1' - (9- (4, 5-dihydrofuran-3-yl) -7H-imidazo [1, 2-c)]Pyrazolo [4,3-e] Pyridin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：429.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.44-8.48(m，2H)，7.93(d，J＝7.6Hz，1H)，7.69(d，J＝1.6Hz，1H)，7.45(d，J＝1.6Hz，1H)，7.35(dd，J＝7.6Hz，5.2Hz，1H)，4.56(t，J＝9.6Hz，2H)，4.41(s，1H)，3.80-3.92(m，2H)，3.26-3.37(m，3H)，3.10-3.15(m，3H)，2.05-2.16(m，2H)，1.68-1.77(m，2H)。

Example 191:(S) -1' - (5- (difluoromethyl) -3- (3, 4-dihydro-2H-pyran-5-yl) -1H-pyrazolo [3, 4-b]pyrazin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b]Pyridine-6, 4' -piperidines]-5-amine

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：454.22[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.33(d，J＝4.4Hz，1H)，8.14(s，1H)，7.83(d，J＝7.6Hz，1H)，7.26(dd，J＝7.6Hz，5.2Hz，1H)，6.99(t，J＝54.4Hz，1H)，4.11(t，J＝5.2Hz，2H)，4.07(s，1H)，3.62-3.70(m，2H)，3.18-3.30(m，3H)，2.90(d，J＝16.4Hz，1H)，2.56(t，J＝6.4Hz，2H)，1.97-2.12(m，4H)，1.64-1.70(m，1H)，1.43-1.49(m，1H)。

Example 192:(S) -4- (6- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]- 1' -yl) -5- (difluoromethyl) -1H-pyrazolo [3,4-b]Pyrazin-3-yl) -3, (dihydropyridine-1 (2H) -carbonitrile

The title compound was synthesized by the method described in example 139 using the appropriate starting materials and intermediates. MS m/z [ LC-MS]：478.23[M+1]。 ¹ H NMR(400MHz，CD ₃ OD)：δ＝8.45(d，J＝5.2Hz，1H)，7.90(d，J＝7.6Hz，1H)，7.32-7.35(m，2H)，7.00(td，J＝54.4Hz，6.4Hz，1H)，4.34(s，1H)，4.06-4.10(m，2H)，3.65-3.84(m，2H)，3.53(t，J＝6.0Hz，2H)，3.22-3.36(m，3H)，3.07(d，J＝16.4Hz，1H)，2.84-2.90(m，2H)，2.00-2.10(m，2H)，1.61-1.72(m，2H)。

In vitro enzymatic Activity of Compounds on SHP2Determination of the inhibitory Effect

The enzymatic activity detection of SHP2 in the patent is carried out by adopting a rapid fluorescence method, diFMUP is used as a substitute substrate for reaction, and a high-flux screening platform is optimized and established. The detection of the inhibitory activity of compounds on SHP2 was performed on this platform. The specific method comprises the following steps: SHP2 was preincubated at a final concentration of 1nM with a mixture of 2.5. Mu.M of the peptide fragment of diphosphorylated IRS1 (SEQ ID: H2N-LN (pY) IDLDLV (dPEG 8) LST (pY) ASINFQK-amide) for 30 min at 23 ℃. Compounds were diluted 5-fold in 100% DMSO gradient starting at 0.2mM (7 concentrations in total), and 2. Mu.L of each compound was added to 48. Mu.L of reaction buffer (60mM HEPES, pH 7.2, 75mM NaCl,75mM KCl,1mM EDTA,0.05% Tween 20,5mM DTT) for dilution and mixing. mu.L of the diluted compound was added to a black 384 well plate (OptiPlate-384, cat. 6007270, purchased from Perkinelmer), followed by 10. Mu.L of the pre-incubated SHP2 and IRS1 peptide fragment mixture, centrifuged and mixed, and incubated at 23 ℃ for 30 min. mu.L of the surrogate substrate DiFMUP (final concentration 50. Mu.M, cat # D6567, purchased from Invitrogen) was added to the reaction and incubated for 60 min at 23 ℃. The reaction was then stopped by adding 5. Mu.L of 160. Mu. MbpV (Phen) solution (SC-22137, purchased from Santa). Immediately after the reaction is terminated, fluorescence signals are detected and measured by using a microplate reader (Perkin-Elmer) at excitation and emission wavelengths of 340nm and 450nm respectively, and the data are calculated by using GraphPad Prism software to obtain the IC of the compound ₅₀ The value is obtained. The detection shows that the specific compounds in the embodiment of the invention have SHP2 in-vitro enzymology inhibitory activity and IC ₅₀ Values lie in the interval 0.1nM to 1uM, and the activity of an exemplary partial compound is shown in Table 1:

TABLE 1 SHP2 enzyme inhibitory Activity of some Compounds

The SHP2 protease inhibition activity of the compounds is within 20nM, and specific data of part of the compounds are shown in Table 1, which shows that the compounds provided by the invention have good SHP2 protease inhibition activity.

Determination of the inhibitory Effect of Compounds on the proliferation of SHP 2-Positive cells

Human non-small cell lung cancer cell line NCI-H358 cells were cultured using RPMI-1640 medium (cat # C11875500BT, purchased from Biological Industries) plus 10% fetal bovine serum (FBS, cat # 04-001-1ACS, purchased from Biological Industries, BI) and 1% penicillin/streptomycin diabody (P/S, cat # 15070-063, purchased from Gibco) at 37 ℃ and 5% CO2. The day before compound detection, NCI-H358 cells were plated in a 196-well plate (cat. No. 3917, purchased from Corning) at a concentration of 2000 cells/195. Mu.L/well. After 24 hours, compounds were diluted 3-fold in 100% dmso from 10mM (10 concentrations in total), and then 2 μ L of each compound was added to 48 μ L of serum-free and double-antibody-free medium. mu.L of each diluted compound was added to the plated Cell suspension, the compound and cells were co-incubated in a Cell incubator for 72 hours (3 days), after the medium was aspirated, 25. Mu.L of Cell-Titer Glo (G7570, purchased from Promega) reagent was added and re-incubated for 5-10 minutes. Fluorescence values were then read on Envision and the data were calculated using GraphPad Prism software to obtain the IC of the compound for inhibition of cell proliferation ₅₀ The value is obtained. Human acute myeloblastic leukemia cell line Kasumi-1 cells were cultured using RPMI-1640 medium (cat # C11875500BT, purchased from Biological Industries) plus 20% fetal bovine serum (FBS, cat # 04-001-1ACS, purchased from Biological Industries, BI) and 1% penicillin/streptomycin diabody (P/S, cat # 15070-063, purchased from Gibco) at 37 ℃ with 5 CO2. The day before compound detection, kasumi-1 cells were plated in a 196-well plate (cat # 3599, purchased from Corning) at a concentration of 3000 cells/195. Mu.L/well. After 24 hours, compounds were diluted in 100% DMSO starting at 10mM in a 3-fold gradient (10 concentrations in total), and then 2. Mu.L of each compound was added to 48. Mu.L of the serum-free and double-antibody medium. mu.L of each diluted compound was added to the plated Cell suspension, the compound and cells were incubated together for 72 hours (3 days) in a Cell incubator, and 35. Mu.L of Cell-Titer Blue (G8082, purchased from Promega) was addedThe agents were incubated for 4 hours again. Fluorescence values were then read on Flexstation III (560 nm excitation, 590nm detection) and the data were calculated using GraphPad Prism software to obtain the IC for inhibition of cell proliferation by this compound ₅₀ The value is obtained. The results of some compound assays are shown in Table 2.

TABLE 2 proliferation inhibitory Activity of some Compounds on cells (NCI-H358)

The proliferation inhibition activity of the compounds in the embodiment of the invention on SHP2 positive expression cells is within 1 mu M, and the test data of the table 2 shows the specific data of part of the compounds, which shows that the compounds provided by the invention have good inhibition activity on the proliferation of SHP2 positive expression cells.

Determination of pharmacokinetic data of Compounds in SD rats

Male SD rats are from Beijing Wintolidhua laboratory animal technology, inc., the rats are divided into groups of 3 rats, and suspension (5 mg/kg, suspension is 0.5% methyl cellulose) of a sample to be tested is orally administrated by gavage respectively. Animals were fasted overnight prior to the experiment, with the fasting time ranging from 10 hours prior to dosing to 4 hours post-dosing. Blood was collected at 0.25, 0.5, 1,2, 4,6, 8, and 24 hours post-dose, respectively. After isoflurane anesthesia by using a small animal anesthesia machine, 0.3mL of whole blood is collected through an eyeground venous plexus, the whole blood is placed in a heparin anticoagulation tube, a sample is centrifuged for 5min at 4 ℃ and 4000rpm, and blood plasma is transferred to a centrifuge tube and stored at-80 ℃ until analysis. Samples from plasma were extracted using protein precipitation and the extracts were analyzed by LC/MS. The results of the partial compound detection are shown in Table 3.

TABLE 3 pharmacokinetic data for some of the compounds

Table 3 shows the pharmacokinetic data of some compounds of the invention in SD rats. The compounds provided by the invention are shown to have very good in vivo metabolism levels.

Determination of compound inhibition of hERG

A patch clamp Amplifier system (multiclad 700B Amplifier) (AXON), olympus (Olympus IX 51/71/73) microscope, MP285 micromanipulator was used.

HEK293 cell line, which stably transfected hERG, was purchased from Invitrogen. Cells were grown in medium containing 85% DMEM,10% fetal bovine serum, 0.1mM non-essential amino acids, 25mM HEPES buffer, 100U/mL penicillin-streptomycin, 5. Mu.g/mL blasticidin, 400. Mu.g/mL G418 geneticin.

Three passages per week, cells were digested with TrypLE Express, maintaining about 40% -80% confluence. Before detection, 5X 10 culture dishes with each diameter of 6 cm are used ⁵ The cells were seeded at a density of one cell and induced with doxycycline at 1. Mu.g/mL for 48 hours.

The test concentration of the compound in solution was 10,1,0.1. Mu.M, each diluted 1000-fold, and the final concentration of DMSO was in the range of 0.1%.

The manipulator is adjusted to move the electrode tip towards the cell surface, forming a high block. Compensating liquid boundary potential and fast capacitance, and breaking cell membrane to form whole cell record mode. The membrane potential was set to-60 mV to ensure that the hERG channel was not opened. Using C on amplifier _slow To eliminate the peak of the capacity current. The holding voltage was set at-90 mV for 500ms. The leakage current test was performed at-80 mV for 500ms. Depolarizing +30mV for 4.8 seconds activates hERG channel, and then returning the voltage to-50 mV for 5.2 seconds, and observing the tail current.

Peak current suppression = [1- (tail current peak value) _Inhibitors -peak tail current _{Positive control} ) /(Peak Tail Current) _{Blank space} -peak tail current _{Positive control} )]×100％。

TABLE 4 hERG inhibitory Activity of reference substances and of some of the compounds of the invention

Table 4 lists the hERG inhibition rate data of the reference substance and some compounds of the present invention at different concentrations, which shows that the compounds of the present invention have lower hERG inhibition activity and lower cardiotoxicity.

Industrial applicability

The compounds of the invention can inhibit the activity of SHP2 protease to provide anti-tumor effects.

Introduction by introduction

All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof,

wherein,

ring A is

Or alternatively

Or

X is selected from hydrogen and C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl, 3-8 membered heteroalicyclic, C _6-10 Aryl and 5-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl and 3-8 membered heteroalicyclic groups optionally substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ 、C _1-6 Alkyl, or phenyl, said C _6-10 The aryl and 5-10 membered heteroaryl groups may be spiro-fused with an unsaturated alicyclic, heteroalicyclic, or ring, and may be optionally substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 3-8 membered heterocyclic group, C _6-10 Aryl, -O-C _6-10 Aryl, or 5-10 membered heteroaryl, said unsaturated alicyclic, heteroalicyclic, or spirocyclic ring optionally substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 、C _6-10 Aryl, -O-C _6-10 Aryl, 5-10 membered heteroaryl, or = O,

R ₃₀ and R ₃₁ Each independently selected from H and C _1-6 Alkyl, or

R ₃₀ And R ₃₁ Are joined together to form a bond, or

R ₃₀ And X are linked together to form C _3-8 Cycloalkyl or 3-to 8-membered heteroalicyclic, C _3-8 Cycloalkyl and 3-to 8-membered heteroalicyclic groups optionally substituted by one or more halogen, -CN, C _3-8 Cycloalkyl, 3-to 8-membered heteroalicyclic, - (CO) -R ₃₂ 、-(SO ₂ )-R ₃₂ 、-OH、-O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ Or C _1-6 Alkyl is substituted, or

R ₃₁ And X are linked together to form C _3-8 Cycloalkyl or 3-to 8-membered heteroalicyclic, C _3-8 Cycloalkyl and 3-to 8-membered heteroalicyclic groups optionally substituted by one or more halogen, -CN, C _3-8 Cycloalkyl, 3-8 membered heteroalicyclic, - (CO) -R ₃₂ 、-(SO ₂ )-R ₃₂ 、-OH、-O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ Or C _1-6 The substitution of alkyl groups is carried out,

y is selected from C _6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heteroalicyclic and 5-15 membered spirocyclic, the aryl, heteroaryl, heteroalicyclic and spirocyclic optionally substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Substituted, the heteroalicyclic and spirocyclic groups may optionally be substituted with C _6-10 Aryl or 5-10 membered heteroaryl fused to heteroalicyclic and spirocyclic groups, the aryl or heteroaryl being optionally fused to one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl is substituted.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein

R ₃₀ And X are linked together to form C _3-8 Cycloalkyl or 3-to 8-membered heteroalicyclic, C _3-8 Cycloalkyl and 3-8 membered heteroalicyclic groups optionally substituted with one or more halogen, -OH, or,-O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ Or C _1-6 Alkyl is substituted, or

R ₃₁ And X are linked together to form C _3-8 Cycloalkyl or 3-to 8-membered heteroalicyclic, C _3-8 Cycloalkyl and 3-8 membered heteroalicyclic groups optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ Or C _1-6 And (3) alkyl substitution.

3. The compound according to claim 1, having a structure represented by formula (I-1), or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof

Wherein,

R ₂₀ is H,

Or alternatively

X is selected from hydrogen and C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl, 3-8 membered heteroalicyclic, C _6-10 Aryl and 5-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl and C _3-8 The heteroalicyclic group may optionally be substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ 、C _1-6 Alkyl, or phenyl, said C _6-10 The aryl and 5-10 membered heteroaryl groups can be spiro-fused to an unsaturated alicyclic ring, heteroalicyclic ring, or spiro-ring, and can optionally be fused by one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 3-8 membered heterocyclic group, C _6-10 Aryl, -O-C _6-10 Aryl, or C _5-10 Heteroaryl substituted, said unsaturated alicyclic, heteroalicyclic, or spirocyclic ring optionally substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 、C _6-10 Aryl, -O-C _6-10 Aryl radical, C _5-10 Heteroaryl, or = O substitution,

r is selected from C _1-6 Alkyl and C _3-6 Cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen, -CF ₃ 、-OH、-C _1-6 Alkyl, -O-C _1-6 Alkyl, or C _3-6 The substitution of cycloalkyl is carried out,

R ₃ and R ₄ Each independently selected from hydrogen, C _1-6 Alkyl and C _3-6 A cycloalkyl group,

y is selected from C _6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heteroalicyclic and 5-15 membered spirocyclic groups, which may optionally be substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Optionally substituted, said heteroalicyclic and spirocyclic groups optionally with C _6-10 Aryl or 5-to 10-membered heteroaryl fused to heteroalicyclic and spirocyclic groups, the aryl or heteroaryl being optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl is substituted.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, having a structure according to formula (I)

Wherein,

x is selected from hydrogen and C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl radical, C _3-8 Hetero-alicyclic group, C _6-10 Aryl and 5-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _3-8 Cycloalkyl and C _3-8 The heteroalicyclic group may optionally be substituted with one or more halogen, -OH, -O-C _1-6 Alkyl, -CF ₃ 、-NH ₂ 、C _1-6 Alkyl, or phenyl, said C _6-10 The aryl and 5-10 membered heteroaryl groups may be spiro-fused with an unsaturated alicyclic, heteroalicyclic, or ring, and may be optionally substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 3-8 membered heterocyclic group, C _6-10 Aryl, -O-C _6-10 Aryl, or C _5-10 Heteroaryl substituted, said unsaturated alicyclic, heteroalicyclic, or spirocyclic ring optionally substituted with one or more halogens, -CF ₃ 、-OH、-CN、R、-OR、-NR ₃ R ₄ 、-O-C(O)NR ₃ R ₄ 、-NH-(CO)-C _1-6 Alkyl, -S-CH ₂ -(CO)NH ₂ 、C _6-10 Aryl, -O-C _6-10 Aryl radical, C _5-10 Heteroaryl, or = O substitution,

y is selected from C _6-10 Aryl, 5-10 membered heteroaryl, C _3-12 Heteroalicyclic and 5-15 membered spirocyclic groups, said aryl, heteroaryl, heteroalicyclic and spirocyclic groups optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Optionally substituted, said heteroalicyclic and spirocyclic groups optionally with C _6-10 Aryl or 5-to 10-membered heteroaryl fused to heteroalicyclic and spirocyclic groups, the aryl or heteroaryl being optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl is substituted.

5. The compound of claim 4, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein

Y is selected from C _6-10 Aryl, 5-10 membered heteroaryl, C _3-12 Heteroalicyclic and 5-15 membered spirocyclic groups, said aryl, heteroaryl, heteroalicyclic and spirocyclic groups optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Substituted, the heteroalicyclic and spirocyclic groups optionally fused with a 5-10 membered heteroaryl group, the heteroaryl group fused with the heteroalicyclic and spirocyclic groups optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl is substituted.

6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein

The 5-15 membered spirocyclic group is a 5-15 membered spiroheterocyclic group optionally substituted with one or more halogens, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 Cycloalkyl optionally substituted by halogen, -OH, -O-C _1-6 Alkyl, or-NH ₂ Substituted spiroheterocyclyl optionally with C _6-10 Aryl or 5-to 10-membered heteroaryl fused, spiro heterocyclyl fused aryl orThe heteroaryl group may optionally be substituted by one or more halogen, -OH, -O-C _1-6 Alkyl, -NH ₂ 、C _1-6 Alkyl, or C _3-6 The cycloalkyl group is substituted by the alkyl group,

the 5-to 10-membered heteroaryl group is C _5-10 A heteroaryl group.

7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein X is selected from 5-10 membered heteroaryl, which 5-10 membered heteroaryl may optionally be substituted with one or more halogen, -CF ₃ 、-OH、-CN、-NH ₂ 、-C _1-6 Alkyl, or 3-8 membered heterocyclyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein said Y is selected from the following structures:

wherein,

ring A is selected from substituted or unsubstituted C _4-8 Cycloalkyl, substituted orUnsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted C _5-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heterocyclyl or heteroaryl comprising 1-3 heteroatoms selected from the group consisting of: n, O, S or P;

n is any integer of 0 to 3;

by substituted is meant that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: halogen, -OH, -NO ₂ 、-NH ₂ 、-CN。

9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein X ₁ And X ₂ One of them is O, X ₃ Is a bond.

10. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein X ₁ And X ₂ One of them is CH ₂ And the other is a key.

11. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein Y is selected from C _6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heteroalicyclic optionally substituted with one or more-OH, -NH ₂ Or C _1-6 Alkyl substitution;

preferably, the 5-10 membered heteroaryl is C _5-10 A heteroaryl group.

12. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein Y is selected from 3-12 membered heteroalicyclic, which may optionally beBy one or more of-OH, -NH ₂ Or C _1-6 Alkyl substitution.

13. The following compounds, or pharmaceutically acceptable salts, solvates, polymorphs, or tautomers thereof:

14. a pharmaceutical composition comprising a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, and optionally a pharmaceutically acceptable adjuvant.

15. Use of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, pharmaceutical composition of claim 14, or a compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, or pharmaceutical composition of claim 14, in combination with an SHP2 inhibitor, or a KRAS inhibitor, or an EGFR inhibitor, in the manufacture of a medicament for the treatment of a disease associated with SHP2 and/or KRAS and/or EGFR.

16. The use of claim 15, wherein the disease associated with SHP2 and/or KRAS and/or EGFR is leukemia, melanoma, glioblastoma, lung cancer, breast cancer or knoop syndrome.