Substituted alkynyl heterocyclic compounds

Abstract

This application relates to substituted alkynyl heterocyclic compounds of Formula II. The present invention relates to substituted alkynyl heterocyclic compounds with bioinhibitory activity, methods for their preparation, pharmaceutical compositions thereof, and also to the use of such compounds and pharmaceutical compositions for treating diseases that benefit from bioinhibition, such as cancer. In the preparation process, compounds of Formula I are obtained through reactions such as iodination, amination, protection, coupling, deprotection, and ring-closing reactions.

Description

Technical Field

[0001] This invention generally relates to novel substituted alkyne heterocyclic compounds having SHP2 inhibitory activity, methods for their preparation, pharmaceutical compositions thereof, and uses of such compounds and pharmaceutical compositions thereof for treating diseases that benefit from SHP2 enzyme inhibition, such as cancer. Background Technology

[0002] Cancer is a serious disease that severely threatens human health and life. In recent years, its incidence and mortality rates have been rising rapidly, surpassing cardiovascular disease to become the leading cause of death worldwide. Tumor proliferation, apoptosis, and metastasis are closely related to abnormalities in certain stages of a series of intracellular and extracellular signaling pathways. Among these pathways, protein phosphorylation and dephosphorylation are crucial, and this reversible process is jointly regulated by kinases and phosphatases. Phosphorylation of protein tyrosine kinase (PTK) and dephosphorylation of protein tyrosine phosphatase (PTP) are such a pair of reversible processes, maintaining a dynamic balance to sustain normal cellular physiological functions. Conversely, abnormal phosphorylation can lead to cancer, inflammation, diabetes, and other diseases.

[0003] SHP2 protein is a non-receptor protein tyrosine phosphatase encoded by the ptpn11 gene. It is widely expressed in various tissues and participates in important physiological and pathological processes such as embryonic development, metabolism, immune response, and tumorigenesis.

[0004] The SHP2 protein consists of two tandem SH2 domains (N-SH2 and C-SH2) at the N-terminus, a PTP catalytic domain, and a regulatory C-terminal tail. The SH2 domain acts as a conformational switch, mediating interactions between the SHP2 protein and phosphotyrosine-containing activators (such as insulin receptor substrate 1-IRS1 and GRB2-associated binding protein 1-GAB1), as well as intramolecular interactions between the SH2 domain and the PTP catalytic domain. In the unstimulated state, the SHP2 domain binds to the PTP domain, blocking the catalytic active site and maintaining SHP2 phosphatase activity in an autoinhibited state. When the SH2 domain binds to an activator, the inhibitory intramolecular interaction is released, and the SHP2 phosphatase enters an open conformation, allowing the SHP2 substrate to localize to the catalytic active site and perform its phosphatase function. This activity-switching characteristic of SHP2 means that various mutations in SHP2 can disrupt its autoinhibitory state, leading to overactivation of SHP2 protein phosphatase activity and potentially inducing carcinogenesis. Both experimental and clinical data have confirmed that SHP2 plays a promoting role in most cancers. As the first discovered tyrosine phosphatase to promote cancer development, it has received great attention in the field of cancer, and its phosphatase activity plays an important role in intracellular signal regulation.

[0005] SHP2 participates in regulating cell signaling pathways activated by cytokines, growth factors, and hormones, including the RAS / ERK, JAK / STAT, PI3K / AKT, and NF-κB signaling pathways, thereby regulating physiological functions such as cell proliferation, differentiation, cell cycle maintenance, and migration. Simultaneously, SHP2 mediates compensatory activation pathways following the inhibition of kinases such as MEK, thus promoting tumor drug resistance. As a downstream molecule of the PD-1 receptor, SHP2 also participates in the transduction of inhibitory signals in T cells. Previous studies have shown that SHP2 is a downstream molecule of PD-1 signaling, inhibiting not only T cell activation but also promoting T cell dysfunction. Therefore, targeting SHP2 can restore or enhance T cell-mediated anti-tumor immune function. Furthermore, SHP2 can inhibit IFN-γ-mediated immune responses by inactivating signal transduction and transcription activator STAT1.

[0006] In recent years, SHP2 activating mutations and high expression have been successively discovered in leukemia, solid tumors, melanoma, malignant glioma, lung cancer, breast cancer, and Norman Syndrome, and are closely related to the occurrence, development, and prognosis of tumors. Currently, SHP2 has been studied as a target molecule for clinical oncology. The mechanism of action of traditional SHP2 inhibitors (such as II-B08 and PHPS1) is to bind to the PTP catalytic domain of SHP2, preventing tyrosine phosphorylated substrates from entering the catalytic site, thereby inhibiting the phosphatase activity of SHP2. However, due to the highly conserved, polar, and charged environment of the PTP catalytic domains of various phosphatases, traditional SHP2 inhibitors have significant deficiencies in terms of specificity and bioavailability, limiting their clinical application. Therefore, developing SHP2 inhibitors with high specificity, high safety, and strong cell membrane permeability is crucial to determining whether SHP2 can become a novel tumor intervention target, and SHP2 protein allosteric inhibitors have become the main research direction. Summary of the Invention

[0007] 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.

[0008]

[0009] in,

[0010] Ring A is or In which carbon is bonded to Y, and R 21 and R 22 Each independently is either H or C. 1-6 Alkyl, R 20 For H, or

[0011] X is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 2-6 alkenyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group may optionally be replaced by one or more halogens, -OH, -OC. 1-6 Alkyl, -CF3, -NH2, C 1-6 Alkyl or phenyl substitution, wherein the C 6-10 Aryl and 5-10 membered heteroaryl groups can fused with unsaturated alicyclic, heterocyclic, or spirocyclic rings, and can optionally be reacted with one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, -NH-(CO)-C 1-6 Alkyl, -S-CH2-(CO)NH2, 3-8 membered heterocyclic groups, C 6-10 Aryl, -OC 6-10 The unsaturated alicyclic, heterocyclic, or spirocyclic ring may optionally be replaced by one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, or -NH-(CO)-C. 1-6 Alkyl group, -S-CH2-(CO)NH2, C 6-10 Aryl, -OC 6-10 Aryl, 5-10 heteroaryl, or =O substitution,

[0012] R 30 and R 31 Each is independently selected from H and C. 1-6 Alkyl, or

[0013] R 30 and R 31 Connect together to form a bond, or

[0014] R 30 Connected with X to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic cycloalcohols, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group may optionally be replaced by one or more halogens, -CN, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, -(CO)-R 32 -(SO2)-R 32 -OH, -OC 1-6 Alkyl, -CF3, -NH2, or C 1-6Alkyl substitution, or

[0015] R 31 Connected with X to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic cycloalcohols, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group may optionally be replaced by one or more halogens, -CN, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, -(CO)-R 32 -(SO2)-R 32 -OH, -OC 1-6 Alkyl, -CF3, -NH2, or C 1-6 Alkyl substitution,

[0016] R 32 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic cycloalkyl, wherein the alkyl, cycloalkyl and heterocyclic cycloalkyl groups may optionally be substituted with halogens.

[0017] R is selected from C 1-6 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl group and the cycloalkyl group may optionally be converted by halogen, -CF3, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, or C 3-6 Cycloalkyl substitution,

[0018] R3 and R4 are each independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl,

[0019] Y is selected from C 6-10 Aryl, 5-10-membered heteroaryl, 3-12-membered heterocyclic, and 5-15-membered spirocyclic, wherein the aryl, heteroaryl, heterocyclic, and spirocyclic groups may optionally be reacted with one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution, wherein the alkyl or cycloalkyl group may optionally be replaced by a halogen, -OH, or -OC. 1-6 Alkyl or -NH2 substituted, the heterocyclic and spirocyclic groups may optionally be C 6-10 Aryl or 5-10-membered heteroaryl groups are fused together. The aryl or heteroaryl groups fused with heterocyclic and spirocyclic groups may optionally be reacted with one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution.

[0020] In some implementations, ring A is

[0021] In some implementations, R 30 and R 31 They connect together to form a bond.

[0022] In some implementations, R 20 for

[0023] In some embodiments, the 5-15 spirocyclic group is a 5-15 spiroheterocyclic group, which may optionally be converted by one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution, wherein the alkyl or cycloalkyl group may optionally be replaced by a halogen, -OH, or -OC. 1-6 Alkyl or -NH2 substitution, wherein the spiroheterocyclic group may optionally be C 6-10 The aryl or 5-10-membered heteroaryl groups are fused together, and the aryl or heteroaryl groups fused with the spiroheterocyclic group may optionally be reacted with one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution.

[0024] In some embodiments, the 5-10 member heteroaryl group is C 5-10 Mixed aromatic compounds.

[0025] In some embodiments, X is selected from 5-10-membered heteroaryl groups, which may be fused with unsaturated alicyclic, heterocyclic, or spirocyclic rings, and may optionally be reacted with one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, or -NH-(CO)-C 1-6 Alkyl, -S-CH2-(CO)NH2, 3-8 membered heterocyclic groups, C 6-10 Aryl, -OC 6-10 The unsaturated alicyclic, heterocyclic, or spirocyclic ring may optionally be replaced by one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, or -NH-(CO)-C 1-6 Alkyl group, -S-CH2-(CO)NH2, C 6-10 Aryl, -OC 6-10 Aryl, C 5-10 heteroaryl or =O substitution.

[0026] In some embodiments, X is selected from 5-10 heteroaryl groups, which may optionally be converted by one or more halogens, -CF3, -OH, -CN, -NH2, -C 1-6 Alkyl groups or 3-8 membered heterocyclic groups are used for substitution.

[0027] In some implementations, the Y is selected from the following structures:

[0028]

[0029] X1, X2, and X3 are each independently selected from bonds, O, and CR. a R b or NR c X4 is C, CH, or N;

[0030] R5, R6, R7, R8, R9, R 10 R 11 and R 12 Each is independently selected from H, -OH, halogen, substituted or unsubstituted amino group, substituted or unsubstituted C group. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl group; and cannot be both -OH or -NH2 simultaneously;

[0031] R a R b and R c Each is independently selected from H, -OH, halogen, substituted or unsubstituted amino group, substituted or unsubstituted C group. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy;

[0032] Ring A is selected from substituted or unsubstituted C. 4-8 Cyclic hydrocarbon group, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1-3 heteroatoms selected from the group consisting of N, O, S or P;

[0033] R 13 and R 14 Each is independently selected from H, -OH, halogen, cyano, substituted or unsubstituted amino, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy;

[0034] n is any integer from 0 to 3;

[0035] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -CN.

[0036] In some implementations, Y is selected from the following structures:

[0037] Among them, X1, X2, X3, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 And n is as defined above.

[0038] In some implementations, one of X1 and X2 is 0, and X3 is a bond.

[0039] In some implementations, one of X1 and X2 is CH2, and the other is a bond.

[0040] In some implementations, Y is selected from C. 6-10 Aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclic cycloyl groups, wherein the aryl, heteroaryl, and heterocyclic cycloyl groups may optionally be converted by one or more -OH, -NH2, or C groups. 1-6 Alkyl substitution;

[0041] Preferably, the 5-10 member heteroaryl group is C 5-10 Mixed aromatic compounds.

[0042] In some embodiments, Y is selected from 3-12 membered heterocyclic groups, which may optionally be surrounded by one or more -OH, -NH2, or C groups. 1-6 Alkyl substitution.

[0043] In some implementations, R 30 Connected with X to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic cycloalcohols, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group may optionally be replaced by one or more halogens, -OH, -OC. 1-6 Alkyl, -CF3, -NH2, or C 1-6 Alkyl substitution, or

[0044] R 31 Connected with X to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic cycloalcohols, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group may optionally be replaced by one or more halogens, -OH, -OC. 1-6 Alkyl, -CF3, -NH2, or C 1-6 Alkyl substitution,

[0045] 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.

[0046]

[0047] in,

[0048] R 20 For H, or

[0049] X is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl and C 3-8 The heterocyclic group may optionally be replaced by one or more halogens, -OH, -OC. 1-6 Alkyl, -CF3, -NH2, C 1-6 Alkyl or phenyl substitution, wherein the C 6-10 Aryl and 5-10 membered heteroaryl groups can fused with unsaturated alicyclic, heterocyclic, or spirocyclic rings, and can optionally be reacted with one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, -NH-(CO)-C 1-6 Alkyl, -S-CH2-(CO)NH2, 3-8 membered heterocyclic groups, C 6-10 Aryl, -OC 6-10 aryl, or C 5-10 The unsaturated alicyclic, heterocyclic, or spirocyclic ring may optionally be substituted with one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, or -NH-(CO)-C. 1-6 Alkyl group, -S-CH2-(CO)NH2, C 6-10 Aryl, -OC 6-10 Aryl, C 5-10 heteroaryl, or =O substitution,

[0050] R is selected from C 1-6 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl group and the cycloalkyl group may optionally be converted by halogen, -CF3, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, or C 3-6 Cycloalkyl substitution,

[0051] R3 and R4 are each independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl,

[0052] Y is selected from C 6-10 Aryl, 5-10-membered heteroaryl, 3-12-membered heterocyclic, and 5-15-membered spirocyclic, wherein the aryl, heteroaryl, heterocyclic, and spirocyclic groups may optionally be reacted with one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution, wherein the alkyl or cycloalkyl group may optionally be replaced by a halogen, -OH, or -OC. 1-6 Alkyl or -NH2 substituted, the heterocyclic and spirocyclic groups may optionally be C 6-10 Aryl or 5-10-membered heteroaryl groups are fused together. The aryl or heteroaryl groups fused with heterocyclic and spirocyclic groups may optionally be reacted with one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution,

[0053] In some implementations, R 20 for

[0054] In some embodiments, the 5-15 spirocyclic group is a 5-15 spiroheterocyclic group, which may optionally be converted by one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution, wherein the alkyl or cycloalkyl group may optionally be replaced by a halogen, -OH, or -OC. 1-6 Alkyl or -NH2 substitution, wherein the spiroheterocyclic group may optionally be C 6-10 The aryl or 5-10-membered heteroaryl groups are fused together, and the aryl or heteroaryl groups fused with the spiroheterocyclic group may optionally be reacted with one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution.

[0055] In some embodiments, the 5-10 member heteroaryl group is C 5-10 Mixed aromatic compounds.

[0056] In some embodiments, X is selected from 5-10-membered heteroaryl groups, which may be fused with unsaturated alicyclic, heterocyclic, or spirocyclic rings, and may optionally be reacted with one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, or -NH-(CO)-C 1-6 Alkyl, -S-CH2-(CO)NH2, 3-8 membered heterocyclic groups, C 6-10 Aryl, -OC 6-10 aryl, or C 5-10 The unsaturated alicyclic, heterocyclic, or spirocyclic ring may optionally be substituted with one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, or -NH-(CO)-C. 1-6 Alkyl group, -S-CH2-(CO)NH2, C 6-10 Aryl, -OC 6-10 Aryl, C 5-10 heteroaryl or =O substitution.

[0057] In some embodiments, X is selected from 5-10 heteroaryl groups, which may optionally be converted by one or more halogens, -CF3, -OH, -CN, -NH2, -C 1-6 Alkyl groups or 3-8 membered heterocyclic groups are used for substitution.

[0058] In some implementations, the Y is selected from the following structures:

[0059]

[0060] X1, X2, and X3 are each independently selected from bonds, O, and CR. a R b or NR c ;

[0061] R5, R6, R7, R8, R9, R 10 R 11 and R 12 Each is independently selected from H, -OH, halogen, substituted or unsubstituted amino group, substituted or unsubstituted C group. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl group; and cannot be both -OH or -NH2 simultaneously;

[0062] R a R b and R c Each is independently selected from H, -OH, halogen, substituted or unsubstituted amino group, substituted or unsubstituted C group. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy;

[0063] Ring A is selected from substituted or unsubstituted C. 4-8 Cyclic hydrocarbon group, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1-3 heteroatoms selected from the group consisting of N, O, S or P;

[0064] R 13 and R 14 Each is independently selected from H, -OH, halogen, cyano, substituted or unsubstituted amino, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy;

[0065] n is any integer from 0 to 3;

[0066] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -CN.

[0067] In some implementations, one of X1 and X2 is 0, and X3 is a bond.

[0068] In some implementations, one of X1 and X2 is CH2, and the other is a bond.

[0069] In some implementations, Y is selected from C. 6-10 Aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclic cycloyl groups, wherein the aryl, heteroaryl, and heterocyclic cycloyl groups may optionally be converted by one or more -OH, -NH2, or C groups. 1-6 Alkyl substitution;

[0070] Preferably, the 5-10 member heteroaryl group is C 5-10 Mixed aromatic compounds.

[0071] In some embodiments, Y is selected from 3-12 membered heterocyclic groups, which may optionally be surrounded by one or more -OH, -NH2, or C groups. 1-6 Alkyl substitution.

[0072] 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.

[0073]

[0074] in,

[0075] X is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 3-8cycloalkyl, C 3-8 heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl and C 3-8 The heterocyclic group may optionally be replaced by one or more halogens, -OH, -OC. 1-6 Alkyl, -CF3, -NH2, C 1-6 Alkyl or phenyl substitution, wherein the C 6-10 Aryl and 5-10 membered heteroaryl groups can fused with unsaturated alicyclic, heterocyclic, or spirocyclic rings, and can optionally be reacted with one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, -NH-(CO)-C 1-6 Alkyl, -S-CH2-(CO)NH2, 3-8 membered heterocyclic groups, C 6-10 Aryl, -OC 6-10 aryl, or C 5-10 The unsaturated alicyclic, heterocyclic, or spirocyclic ring may optionally be substituted with one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, or -NH-(CO)-C. 1-6 Alkyl group, -S-CH2-(CO)NH2, C 6-10 Aryl, -OC 6-10 Aryl, C 5-10 heteroaryl, or =O substitution,

[0076] R is selected from C 1-6 Alkyl and C 3-6 Cycloalkyl groups, wherein the alkyl group and the cycloalkyl group may optionally be converted by halogen, -CF3, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, or C 3-6 Cycloalkyl substitution,

[0077] R3 and R4 are each independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl,

[0078] Y is selected from C 6-10 Aryl, 5-10 heteroaryl, C 3-12 The aryl, heteroaryl, heterocyclic, and spirocyclic groups may optionally be converted by one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution, wherein the alkyl or cycloalkyl group may optionally be replaced by a halogen, -OH, or -OC.1-6 Alkyl or -NH2 substituted, the heterocyclic and spirocyclic groups may optionally be C 6-10 Aryl or 5-10-membered heteroaryl groups are fused together. The aryl or heteroaryl groups fused with heterocyclic and spirocyclic groups may optionally be reacted with one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution,

[0079] In some implementations, Y is selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-12 The aryl, heteroaryl, heterocyclic, and spirocyclic groups may optionally be converted by one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution, wherein the alkyl or cycloalkyl group may optionally be replaced by a halogen, -OH, or -OC. 1-6 Alkyl groups or -NH2 substitutions are used, and the heterocyclic and spirocyclic groups may optionally be fused with 5-10-membered heteroaryl groups. The heteroaryl groups fused with the heterocyclic and spirocyclic groups may optionally be replaced with one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution,

[0080] In some embodiments, the 5-15 spirocyclic group is a 5-15 spiroheterocyclic group, which may optionally be converted by one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution, wherein the alkyl or cycloalkyl group may optionally be replaced by a halogen, -OH, or -OC. 1-6 Alkyl or -NH2 substitution, wherein the spiroheterocyclic group may optionally be C 6-10 The aryl or 5-10-membered heteroaryl groups are fused together, and the aryl or heteroaryl groups fused with the spiroheterocyclic group may optionally be reacted with one or more halogens, -OH, or -OC. 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 Cycloalkyl substitution.

[0081] In some embodiments, the 5-10 member heteroaryl group is C 5-10 Mixed aromatic compounds.

[0082] In some embodiments, X is selected from 5-10-membered heteroaryl groups, which may be fused with unsaturated alicyclic, heterocyclic, or spirocyclic rings, and may optionally be reacted with one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, or -NH-(CO)-C 1-6 Alkyl, -S-CH2-(CO)NH2, 3-8 membered heterocyclic groups, C 6-10 Aryl, -OC 6-10 aryl, or C 5-10 The unsaturated alicyclic, heterocyclic, or spirocyclic ring may optionally be substituted with one or more halogens, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, or -NH-(CO)-C. 1-6 Alkyl group, -S-CH2-(CO)NH2, C 6-10 Aryl, -OC 6-10 Aryl, C 5-10 heteroaryl or =O substitution.

[0083] In some embodiments, X is selected from 5-10 heteroaryl groups, which may optionally be converted by one or more halogens, -CF3, -OH, -CN, -NH2, -C 1-6 Alkyl groups or 3-8 membered heterocyclic groups are used for substitution.

[0084] In some implementations, the Y is selected from the following structures:

[0085]

[0086] X1, X2, and X3 are each independently selected from bonds, O, and CR. a R b or NR c ;

[0087] R5, R6, R7, R8, R9, R 10 R 11 and R 12 Each is independently selected from H, -OH, halogen, substituted or unsubstituted amino group, substituted or unsubstituted C group. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl group; and cannot be both -OH or -NH2 simultaneously;

[0088] R a R b and R c Each is independently selected from H, -OH, halogen, substituted or unsubstituted amino group, substituted or unsubstituted C group. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy;

[0089] Ring A is selected from substituted or unsubstituted C. 4-8 Cyclic hydrocarbon group, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1-3 heteroatoms selected from the group consisting of N, O, S or P;

[0090] R 13 and R 14 Each is independently selected from H, -OH, halogen, cyano, substituted or unsubstituted amino, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy;

[0091] n is any integer from 0 to 3;

[0092] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -CN.

[0093] In some implementations, one of X1 and X2 is 0, and X3 is a bond.

[0094] In some implementations, one of X1 and X2 is CH2, and the other is a bond.

[0095] In some implementations, Y is selected from C. 6-1 0-aryl, 5-10-membered heteroaryl and C 3-12 The heterocyclic group, wherein the aryl, heteroaryl, and heterocyclic groups may optionally be converted to one or more -OH, -NH2, or C groups. 1-6 Alkyl substitution;

[0096] Preferably, the 5-10 member heteroaryl group is C 5-10 Mixed aromatic compounds.

[0097] In some implementations, Y is selected from C. 3-12 The heterocyclic group may optionally be converted to one or more -OH, -NH2, or C groups. 1-6 Alkyl substitution.

[0098] In some embodiments, the present invention provides the following compounds or their pharmaceutically acceptable salts, solvates, polymorphs, or tautomers:

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107] On the other hand, 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 comprising a pharmaceutically acceptable excipient.

[0108] On the other hand, the present invention provides a method for treating diseases related to SHP2, comprising administering to a mammal, preferably a human, a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer of the present invention or a pharmaceutical composition thereof.

[0109] On the other hand, the present invention provides the use of the compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, or a pharmaceutical composition thereof, or any of the above in combination with an SHP2 inhibitor or a KRAS inhibitor or an EGFR inhibitor in the preparation of a medicament for treating diseases related to SHP2 and / or KRAS and / or EGFR.

[0110] In some embodiments of the present invention, the diseases associated with SHP2 and / or KRAS and / or EGFR are leukemia, melanoma, malignant glioma, lung cancer, breast cancer, or Nursing syndrome.

[0111] On the other hand, SHP2 plays an upstream role in KRAS. Hana Algul's team (Mutant KRAS-driven cancers depend on PTPN11 / SHP2 phosphatase, Nature Medicine 2018) demonstrated that small molecule inhibitors of SHP2 have significant efficacy against aggressive KRAS tumors such as pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Protein tyrosine phosphatase SHP2 has become a key drug target for aggressive KRAS tumors. In addition, Schneeberger, VE's team (Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma. Onco target 2015) demonstrated that SHP2 can promote RAS-RAF-MEK-ERK signaling in EGFR-mutant NSCLC. Therefore, the SHP2 small molecule inhibitor of the present invention, used alone or in combination with existing KRAS inhibitors (AMG510, etc.) and EGFR inhibitors (Iressa, Tarceva, etc.), can effectively inhibit the occurrence and progression of tumors.

[0112] On the other hand, similarities in biological activity are frequently found in functional groups with similar spatial or electronic properties. Structures in drug molecules that perform the same biological function are called bioisosteres. Bioisosteres replace the original functional groups in a drug with another functional group without affecting the drug's main biological activity. Examples include the substitution of monovalent atoms or groups such as OH, NH2, F, and SH; and the replacement of carboxyl groups with phosphate esters or tetrazolium, etc.

[0113] Some chemical terms

[0114] The term "compound" as used in this invention includes all stereoisomers, geometric isomers, tautomers, and isotopes. The compounds of this invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of this 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 racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0115] The compounds of this invention also include tautomer forms. Tautomer forms arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0116] This invention also includes atoms of all isotopes, whether in intermediates or final compounds. Isotopic atoms include those having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0117] The term “dense” or “dense ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more bonds.

[0118] The term “spiral” or “spiral ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more atoms.

[0119] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0120] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, such as C... 1-20 Alkyl group, 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, etc. The alkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl, and hydroxyl groups.

[0121] Term "C" 1-6 "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, connected to the rest of the molecule by single bonds, and having 1-6 carbon atoms. The alkyl group may be unsubstituted or substituted with one or more substituents selected from alkyl, alkoxy, amino, halogen, and hydroxyl groups. Non-limiting examples of unsubstituted alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylhexyl, etc.

[0122] The term "alkenyl" as used alone or in combination herein refers to a monovalent hydrocarbon group of optional substituted straight or optional substituted branched form, having one or more C=C double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The double bonds in these groups may be in cis or trans conformations and should be understood to include both isomers. Examples include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl, and 1,3-butadienyl. When alkenyl as defined herein appears in numerical ranges, for example, "C2-C6 alkenyl" or "C 2-6"Alkenyl" refers to an alkenyl group that can be composed of 2, 3, 4, 5, or 6 carbon atoms. In this article, alkenyl also includes cases where no numerical range is specified.

[0123] The term "cycloalkyl" refers to a saturated hydrocarbon group consisting of a monocyclic carbon ring composed of carbon and hydrogen atoms, such as C. 3-20 Cycloalkyl, preferably C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The cycloalkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl, and hydroxyl groups.

[0124] The terms "heterocyclic group," "heterocyclic alkyl group," and "heterocycle" refer to a stable 3-18 member monovalent non-aromatic ring comprising 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may contain fused rings, spirocyclic, or bridged ring systems. The nitrogen, carbon, or sulfur on the heterocyclic group may be selectively oxidized, and the nitrogen atom may be selectively quaternized. The heterocyclic group may be partially or completely saturated. A heterocyclic group can be connected to the rest of the molecule via a single bond through a carbon atom or heteroatom on the ring. Heterocyclic groups containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atoms connected to the rest of the molecule are atoms from non-aromatic rings. For the purposes of this application, the heterocyclic group is preferably a stable 4-11 valent monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; more preferably, it is a stable 4-8 valent monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclic groups include azirheptanyl, azirheptanyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolyl, dioxopentyl, 1,1-dioxo-thiomorpholinyl, imidazoalkyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinoneyl, pyranyl, pyrazolyl, pyrrolidinyl, quinazinyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

[0125] The term "aryl" refers to a fully carbon monocyclic or fused ring having a fully conjugated π-electron system, having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. The aryl group can be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, sulfonyl, sulfinyl, phosphoryl, and heterocyclic groups. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthraceneyl.

[0126] The term "heteroaryl" refers to a monocyclic or fused ring with 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, of which 1, 2, 3, or 4 are selected from N, O, and S, and the remaining ring atoms are C, and possessing a fully conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heterocyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, and triazineyl.

[0127] The term "alicyclic" refers to a monocyclic, fused, or spirocyclic carbon ring with 3 to 12 ring atoms. Such rings can be saturated or unsaturated (e.g., with one or more double bonds), but do not have a fully conjugated π-electron system.

[0128] The term "alicyclic group" refers to the group remaining after removing one hydrogen atom from an alicyclic molecule. Alicyclic groups can be unsubstituted or have their hydrogen atoms optionally substituted with substituents, including but not limited to alkyl, alkoxy, =O, aryl, aralkyl, -COOH, -CN, amino, halogen, and hydroxyl groups.

[0129] The term "heterocyclic ring" refers to a monocyclic, fused, or spirocyclic ring having 3 to 12 ring atoms, of which 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms are selected from N, O, and S(O). n The ring consists of heteroatoms (where n is 0, 1, or 2), with the remaining ring atoms being carbon. Such a ring can be saturated or unsaturated (e.g., having one or more double bonds), but does not possess a fully conjugated π-electron system. Examples of ternary saturated heterocyclic rings include, but are not limited to, those shown below. Examples of 4-membered saturated heterocyclic rings include, but are not limited to, Examples of 5-membered saturated heterocyclic rings include, but are not limited to, those that are not part of the above. Examples of 6-membered saturated heterocyclic rings include, but are not limited to, those that are not part of the above. Examples of 7-membered saturated heterocyclic rings include, but are not limited to, Examples of 5-membered unsaturated heterocyclic rings include, but are not limited to, Examples of 6-membered unsaturated heterocyclic rings include, but are not limited to, those with 6-membered ...

[0130] The term "heterocyclic group" refers to the group remaining after removing one hydrogen atom from a "heterocyclic" molecule. Heterocyclic groups can be unsubstituted or have their hydrogen atoms optionally substituted by substituents, including but not limited to alkyl, alkoxy, =O, aryl, aralkyl, -COOH, -CN, amino, halogen, and hydroxyl groups.

[0131] The compounds or their salts of the present invention can be administered as active substances alone, preferably in the form of pharmaceutical compositions.

[0132] "Pharmaceutical composition" refers to a formulation of one or more compounds of the present invention or salts thereof with a carrier commonly accepted in the art for delivering a bioactive compound to an organism (e.g., a human). The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of the present invention to an organism.

[0133] The term "pharmaceutically acceptable carrier" refers to carriers that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carrier" refers to an inert substance that is administered co-administered with the active ingredient and facilitates the administration of the active ingredient, including, but not limited to, any flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers 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 starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0134] Administration of the compounds of the present invention, either in pure form or in the form of a suitable pharmaceutical composition, or of a pharmaceutically acceptable salt thereof, may be carried out by any acceptable mode of administration providing a pharmaceutical agent of similar use. The pharmaceutical compositions of the present invention may be prepared by combining the compounds of the present invention with a suitable pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutical compositions of the present invention may be formulated into solid, semi-solid, liquid, or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols, etc.

[0135] 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, and intravenous administration. The preferred route of administration is oral.

[0136] The pharmaceutical compositions of the present invention can be manufactured using methods known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0137] In a preferred embodiment, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0138] Solid oral pharmaceutical compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain a tablet or sugar-coated core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents. Examples include microcrystalline cellulose, glucose solution, gum arabic, gelatin solution, sucrose, and starch paste; talc, starch, magnesium stearate, calcium stearate, or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silica; croscarmellose sodium, precrossyl cellulose, precrossyl starch, sodium starch glycolate, alginate, corn starch, potato starch, methylcellulose, agar, carboxymethyl cellulose, croscarmellose, etc. The sugar-coated core can be optionally coated using methods known in general pharmaceutical practice, particularly enteric coating.

[0139] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions, or lyophilized products. Appropriate excipients, such as fillers, buffers, or surfactants, can be used.

[0140] Another aspect of this invention relates to the use of compounds of general formulas I to VI, or pharmaceutically acceptable salts, solvates, polymorphs, metabolites, etc., thereof, in medicaments for treating diseases that benefit from SHP2 inhibition. The diseases benefiting from SHP2 inhibition are selected from cancer.

[0141] The substituted alkynyl heterocyclic compounds provided by this invention have very good SHP2 inhibitory activity and are expected to become highly effective SHP2 inhibitor drugs. Detailed Implementation

[0142] The specific embodiments described below are intended to enable those skilled in the art to better understand and implement the present invention. They should not be considered as limiting the scope of the invention, but merely as exemplary illustrations and typical representatives. Those skilled in the art should understand that there are other synthetic routes for forming the compounds of the present invention; the examples provided below are non-limiting.

[0143] All operations involving easily oxidized or hydrolyzed raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and used directly without further purification.

[0144] Column chromatography used silica gel (200-300 mesh) manufactured by Qingdao Chemical Co., Ltd. Thin-layer chromatography used pre-prepared plates (60PF silica gel) manufactured by E. Merck. 254 Chiral compound separation and enantiomeric excess (ee) determination were performed using an Agilent LC 1200 series column (CHIRALPAK AD-H). (mm, 5 μm, 30℃). Nuclear magnetic resonance chromatography (NMR) was performed using a Varian VNMRS-400 NMR spectrometer; liquid chromatography-mass spectrometry (LC / MS) was performed using a FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry C18). (millimeter, 5 micrometer, 35℃), using ESI(+) ion mode.

[0145] Experimental Section

[0146] Intermediate 1: (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine dihydrochloride

[0147]

[0148] (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine dihydrochloride was synthesized according to the method of intermediate 14 in patent WO2017216706.

[0149] Intermediate 2: ((3S,4S)-8-(3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl) yl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4- tert-butyl carbamate

[0150]

[0151] 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 described in Preparation 179 on page 237 of patent WO2019167000.

[0152] Step 1: 6-Chloro-3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine

[0153] Intermediate (6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazin-5-yl)methanol (2.28 g), triisopropylsilane chloride (1.49 g), and imidazole (693 mg) were added to dichloromethane (40 mL) and stirred overnight at room temperature. The reaction solution was washed with water, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. Separation was performed by silica gel column chromatography (petroleum ether:ethyl acetate, 5:1) to obtain 6-chloro-3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine (2.75 g). MS m / z [LC-MS]: 597.14 [M+1].

[0154] Step 2: (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]decane-4-amine

[0155] 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 intermediate 1 (1.32 g) and diisopropylethylamine (5 mL). The mixture was heated to 120 °C and stirred for 2 hours. After cooling to room temperature, the organic solvent was removed by rotary evaporation. The mixture was then separated by silica gel column chromatography (dichloromethane:methanol, 10:1) to obtain (3S,4S)-8-(3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (2.82 g). MS m / z [LC-MS]: 731.3 [M+1].

[0156] 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-aminospiro[4,5]decane-4-yl)tert-butyl carbamate

[0157] Add (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]decane-4-amine (2.80 g) to dichloromethane (30 mL), then add diisopropylethylamine (2 mL), and add di-tert-butyl dicarbonate (1.25 g) dropwise under ice-water bath cooling. After addition, the mixture was heated to room temperature and stirred for 4 hours. The organic solvent was removed by rotary evaporation, and the product was separated by silica gel column chromatography (petroleum ether: ethyl acetate, 8:1) to obtain ((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]decane-4-yl) tert-butyl carbamate (3.05 g). MS m / z [LC-MS]: 831.35 [M+1].

[0158] Intermediate 3: (S)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine trihydrochloride

[0159]

[0160] (S)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine trihydrochloride was synthesized according to the method of intermediate AP in patent WO2020081848.

[0161] Intermediate 4: (R)-3H-spiro[furano[2,3-b]pyridine-2,4′-piperidine]-3-amine dihydrochloride

[0162]

[0163] (R)-3H-spiro[furano[2,3-b]pyridine-2,4′-piperidine]-3-amine dihydrochloride was synthesized according to the method of intermediate S in patent WO2020201991.

[0164] Intermediate 5: (S)-3-methyl-5,7-dihydrospiro[cyclopentadieno[c]pyridine-6,4′-piperidine]-7-amine trihydrochloride

[0165]

[0166] (S)-3-methyl-5,7-dihydrospiro[cyclopentadieno[c]pyridine-6,4′-piperidine]-7-amine trihydrochloride was synthesized by the method of intermediate A5 in patent WO2020094018.

[0167] 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]decane-4-yl) tert-butyl carbamate

[0168]

[0169] 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 described in Preparation 179 on page 237 of patent WO2019167000.

[0170] Step 1: 6-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine-5-carboxaldehyde

[0171] Intermediate (6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazin-5-yl)methanol (2.20 g) was added to dichloromethane (40 mL). The solution was cooled in an ice-water bath, and Dys-Martin reagent (2.54 g) was added in portions. After the addition was complete, the mixture was stirred at 0 °C for 2 hours. The reaction solution was washed successively with saturated sodium sulfite solution, saturated sodium bicarbonate solution, and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. Separation was performed 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]pyrazin-5-carboxaldehyde (1.98 g). MS m / z [LC-MS]: 438.98 [M+1].

[0172] Step 2: 6-Chloro-5-(difluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine

[0173] 1.96 g of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine-5-carboxaldehyde was added to 40 mL of dichloromethane. Diethylaminosulfur trifluoride (1.44 g) was added dropwise under ice-water bath cooling. After the addition was complete, the mixture was stirred at 0°C for 1 hour, then at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution, washed with water, and the organic phase was washed with water. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure. Separation was performed by silica gel column chromatography (petroleum ether:ethyl acetate, 5:1) to obtain 1.65 g of 6-chloro-5-(difluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine. MS m / z [LC-MS]: 460.99 [M+1].

[0174] 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]decane-4-amine

[0175] 0.92 g of 6-chloro-5-(difluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine was added to n-butanol (10 mL), followed by intermediate 1 (0.56 g) and diisopropylethylamine (2.2 mL). The mixture was heated to 120 °C and stirred for 2 hours. After cooling to room temperature, the organic solvent was removed by rotary evaporation. The mixture was then separated by silica gel column chromatography (dichloromethane:methanol, 10:1) to obtain (3S,4S)-8-(5-(difluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (1.10 g). MSm / z [LC-MS]: 595.15 [M+1].

[0176] 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]decane-4-yl) tert-butyl carbamate

[0177] Add (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]decane-4-amine (1.10 g) to dichloromethane (10 mL), then add diisopropylethylamine (1 mL), and add di-tert-butyl dicarbonate (807 mg) dropwise under ice-water bath cooling. After addition, the mixture was heated to room temperature and stirred for 4 hours. The organic solvent was removed by rotary evaporation, and the product was separated by silica gel column chromatography (petroleum ether: ethyl acetate, 8:1) to obtain ((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]decane-4-yl) tert-butyl carbamate (1.25 g). MS m / z [LC-MS]: 695.21 [M+1].

[0178] Intermediate 7: (S)-(1′-(5-(difluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Pyrazolo[4,3-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidine]-5-yl)carbamic acid tert-butyl ester

[0179]

[0180] Following the method described in Intermediate 6, and replacing Intermediate 1 with Intermediate 3, (S)-(1′-(5-(difluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-5-yl) tert-butyl carbamate can be synthesized. MS m / z [LC-MS]: 728.21 [M+1].

[0181] Intermediate 8: (S)-(1′-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b] pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidine]-5-yl) tert-butyl carbamate

[0182]

[0183] Following the method described in Intermediate 6, 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine was used instead of 6-chloro-5-(difluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine, and Intermediate 3 was used instead of Intermediate 1 to synthesize (S)-(1′-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine-6-yl)-5,7-dihydrospiro[cyclopentadien[b]pyridin-6,4′-piperidin]-5-yl)carbamate tert-butyl. MS m / z [LC-MS]: 678.21 [M+1].

[0184] 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]decane-4-yl)tert-butyl carbamate

[0185]

[0186] Following the method described in Intermediate 6, 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine was substituted for 6-chloro-5-(difluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine to synthesize ((3S,4S)-8-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate tert-butyl carbamate. MS m / z [LC-MS]: 645.21 [M+1].

[0187] Example 1: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((3-chloro-5-fluoropyridin-4-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0188]

[0189] 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]decane-4-yl)tert-butyl carbamate

[0190] 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 sealed tube, purged with nitrogen, and heated to 80 °C with stirring overnight. Cool to room temperature, pour into water, extract with dichloromethane, wash the extract with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate by silica gel column chromatography (petroleum ether: ethyl acetate, 5:1) to give ((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]decane-4-yl)carbamate tert-butyl (83 mg). MS m / z [LC-MS]: 858.43 [M+1].

[0191] 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]decane-4-yl)tert-butyl carbamate

[0192] ((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]decane-4-yl) tert-butyl carbamate (80 mg) and tetrabutylammonium fluoride (100 mg) were added sequentially to tetrahydrofuran (5 mL) and stirred overnight at room temperature. Pour into water, extract with dichloromethane, wash the extract with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude ((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]decane-4-yl)carbamate (50 mg), which was used directly in the next step of the reaction. MS m / z [LC-MS]: 572.22 [M+1].

[0193] Step 3: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((3-chloro-5-fluoropyridin-4-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0194] Add 50 mg of ((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]decane-4-yl)carbamate to a 4M solution of dioxane (2 mL), stir at room temperature for 1 hour, evaporate to dryness, and add 10 mL of 10% sodium carbonate aqueous solution. Extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then separated by thin-layer silica gel chromatography (dichloromethane:methanol, 10:1) to yield (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-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]. 1H NMR (400MHz, CD3OD): 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, 1 H), 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).

[0195] 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)methanol

[0196]

[0197] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 421.21 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0198] Example 3: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (pyridin-4-ylethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0199]

[0200] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 420.22 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0201] Example 4: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (pyrrolidine-3-ylethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0202]

[0203] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 412.25 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0204] Example 5: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (imidazo[1,2-b]pyrazin-3-ylethynyl)-1H-pyrazo[3,4-b]pyrazin-5-yl)methanol

[0205]

[0206] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 460.22 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0207] Example 6: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (pyridin-2-ylethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0208]

[0209] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 420.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 3.0 5 (d, J=5.2Hz, 1H), 1.88-2.02 (m, 2H), 1.70-1.81 (m, 2H), 1.22 (d, J=6.8Hz, 3H).

[0210] Example 7: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-aminopyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0211]

[0212] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 435.23 [M+1]. 1H NMR (400MHz, DMSO-d6): 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), 4.5 9(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).

[0213] Example 8: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((3-chloro-2-(cyclopropylamino)pyridin-4-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0214]

[0215] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 509.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.08 (d, J=4.8Hz, 1H), 6.84 (d, J=4.8Hz, 1H), 6.83 (s, 1 H), 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).

[0216] Example 9: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((3,5-dichloropyridin-4-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0217]

[0218] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 488.14 [M+1]. 1H NMR (400MHz, DMSO-d6): 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).

[0219] Example 10: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((4-N-pyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0220]

[0221] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 454.18 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 3.8 6 (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).

[0222] 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

[0223]

[0224] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 420.22 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0225] 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)pyridinenitrile

[0226]

[0227] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 445.21 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0228] 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

[0229]

[0230] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 445.21 [M+1]. 1H NMR (400MHz, DMSO-d6): 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).

[0231] Example 14: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-(trifluoromethyl)pyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0232]

[0233] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 488.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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=8.8H z, 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).

[0234] Example 15: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((5-aminopyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0235]

[0236] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 435.23 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0237] 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)pyridinenitrile

[0238]

[0239] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 445.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): 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).

[0240] 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

[0241]

[0242] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 454.18 [M+1]. 1H NMR (400MHz, CD3OD): 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), 3.8 5(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).

[0243] 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

[0244]

[0245] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 450.23 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.57 (d, J=4.8Hz, 1H), 8.05 (d, J=7.6Hz, 1H), 7.41 (d d, 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).

[0246] Example 19: (3-((2-amino-3-chloropyridin-4-yl)ethynyl)-6-((3S,4S)-4-amino-3-methyl- 2-Oxa-8-azaspiro[4.5]decane-8-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0247]

[0248] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 469.19 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0249] Example 20: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((3-chloro-2-morpholinylpyridin-4-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0250]

[0251] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 539.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0252] Example 21: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2,4-dimethylthiazo-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0253]

[0254] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 454.20 [M+1]. 1H NMR (400MHz, CD3OD): 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=4.4H z, 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).

[0255] Example 22: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((1-methyl-1H-pyrazol-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0256]

[0257] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 423.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0258] Example 23: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0259]

[0260] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 423.23 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0261] Example 24: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(pyrimidin-2-ylethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0262]

[0263] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 421.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): 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).

[0264] Example 25: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2-amino-5-chloro-3-fluoropyridin-4-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0265]

[0266] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 487.18 [M+1]. 1H NMR (400MHz, DMSO-d6): 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), 3.6 3 (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).

[0267] Example 26: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((3,5-dimethylisoxazol-4-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0268]

[0269] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 438.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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=4.0H z, 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).

[0270] Example 27: (3-((2-amino-3,5-dichloropyridin-4-yl)ethynyl)-6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0271]

[0272] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 503.15 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0273] Example 28: (3-((2-amino-3,5-difluoropyridin-4-yl)ethynyl)-6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0274]

[0275] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 471.21 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0276] Example 29: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((4-(trifluoromethyl)pyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0277]

[0278] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 488.20 [M+1]. 1H NMR (400MH, CD3OD): 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), 3.8 7 (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).

[0279] Example 30: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((4-methylthiazolyl-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0280]

[0281] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 440.19 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0282] 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]decane-8-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0283]

[0284] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 487.18 [M+1].

[0285] Example 32: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-3-((2-chloro-4,6-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0286]

[0287] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 522.16 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 3.2 0-3.35 (m, 3H), 1.98-2.12 (m, 2H), 1.76-1.82 (m, 1H), 1.67-1.74 (m, 1H).

[0288] Example 33: (R)-(6-(3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-3-((2-chloro-4,6-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0289]

[0290] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 523.15 [M+1].

[0291] Example 34: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((1-methyl-1H-pyrazol-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0292]

[0293] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 423.23 [M+1]. 1H NMR (400MHz, CD3OD): 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, 6 H), 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).

[0294] Example 35: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2-isopropyl-4-methylthiazolyl-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0295]

[0296] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 482.23 [M+1]. 1 H NMR (400MHz, CDCl3): 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).

[0297] Example 36: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-3-((2-(trifluoromethyl)pyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0298]

[0299] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 521.20 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0300] Example 37: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((3-chloro-2-(3,3-difluoroazacyclobutane-1-yl)pyridin-4-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0301]

[0302] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 545.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0303] Example 38: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-3-((4-chloro-2-fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0304]

[0305] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 504.17 [M+1]. 1 H NMR (400MHz, CD3OD): 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, 2.0 Hz, 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).

[0306] Example 39: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-3-((3-chloro-5-fluoropyridin-4-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0307]

[0308] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 505.17 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0309] Example 40: (S)-5-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)-2-cyanopyridine

[0310]

[0311] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 478.21 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0312] Example 41: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-3-((2-isopropyl-4-methylthiazolyl-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0313]

[0314] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 515.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0315] Example 42: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-((4-(trifluoromethyl)pyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0316]

[0317] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 521.20 [M+1]. 1H NMR (400MHz, DMSO-d6): 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).

[0318] Example 43: (S)-(3-((2-amino-3-chloropyridin-4-yl)ethynyl)-6-(5-amino-5,7-dihydrospiro) [cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0319]

[0320] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 502.19 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0321] Example 44: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((5,6,7,8-tetrahydroimidazol[1,2-a]pyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0322]

[0323] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 463.26 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0324] Example 45: (S)-(3-((2-amino-3-chloropyridin-4-yl)ethynyl)-6-(5-amino-5,7-dihydrospiro) [cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0325]

[0326] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 521.14 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0327] Example 46: (S)-4-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-3-chloro-5-fluorobenzonitrile

[0328]

[0329] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 529.17 [M+1]. 1H NMR (400MHz, CD3OD): 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=7.6H z, 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).

[0330] Example 47: (S)-5-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-4-methyl-2-cyanopyridine

[0331]

[0332] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 492.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0333] 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

[0334]

[0335] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 466.16 [M+1]. 1H NMR (400MHz, CD3OD): 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=8.8H z, 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).

[0336] Example 49: (S)-1′-(3-((2-chloro-4,6-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazine- 6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0337]

[0338] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 492.15 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0339] Example 50: Methanol (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-3-((2,4-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0340]

[0341] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 488.20 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0342] Example 51: (S)-5-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-3-fluoro-2-cyanopyridine

[0343]

[0344] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 496.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0345] Example 52: (S)-4-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-3-chloro-5-fluorobenzonitrile

[0346]

[0347] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 499.16 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0348] Example 53: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- (6-chloropyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0349]

[0350] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 487.18 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0351] Example 54: (S)-5-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-3-methyl-2-cyanopyridine

[0352]

[0353] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 492.23 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0354] Example 55: (S)-5-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-3-methoxy-2-cyanopyridine

[0355]

[0356] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 508.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0357] Example 56: (S)-5-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-3-trifluoromethyl-2-cyanopyridine

[0358]

[0359] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 546.20 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0360] Example 57: (S)-5-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-3-chloro-2-cyanopyridine

[0361]

[0362] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 512.17 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0363] Example 58: (S)-5-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-2-cyanopyridine

[0364]

[0365] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 448.20 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0366] Example 59: (S)-5-((6-(7-amino-3-methyl-5,7-dihydrospiro[cyclopentadieno[c]pyridine-6,4′- [piperidine]-1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)2-cyanopyridine

[0367]

[0368] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 492.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0369] Example 60: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-((2-cyclopropyl-4-methylthiazolyl-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0370]

[0371] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 513.22 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0372] Example 61: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-((6-chloro-2-methylpyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0373]

[0374] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 501.19 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0375] Example 62: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-((2-cyclopropyl-4-trifluoromethylthiazolyl-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0376]

[0377] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 567.19 [M+1]. 1H NMR (400MHz, CD3OD): 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, 2 H), 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).

[0378] Example 63: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-((2,6-dichloropyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0379]

[0380] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 521.14 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0381] Example 64: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-((2,4-dimethyloxazol-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0382]

[0383] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 471.23 [M+1]. 1H NMR (400MHz, CD3OD): 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), 3.70-3.7 8 (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).

[0384] Example 65: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- (6-methylpyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0385]

[0386] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 467.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0387] Example 66: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-((6-(difluoromethyl)pyridin-3-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0388]

[0389] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 503.21 [M+1]. 1H NMR (400MHz, CD3OD): 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, 5.2 Hz, 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).

[0390] Example 67: (3S,4S)-8-(3-((2-chloro-4,6-difluorophenyl)ethynyl)-5-(difluoromethyl)-1H-pyridine Azo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine

[0391]

[0392] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 509.15 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0393] Example 68: (S)-1′-(3-((6-chloropyridin-3-yl)ethynyl)-5-(difluoromethyl)-1H-pyrazolo[3, [4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0394]

[0395] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 507.16 [M+1]. 1H NMR (400MHz, CD3OD): 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, 5.2 Hz, 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).

[0396] Example 69: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-(cyclopropylethynyl)-1H-pyrazolo[3,4-b]pyrazine-5-yl)methanol

[0397]

[0398] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 416.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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, 2 H), 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).

[0399] Example 70: (S)-4-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2-methylbut-3-yn-2-ol

[0400]

[0401] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 434.23 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0402] Example 71: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-((4-chloro-2-methylthiazolyl-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0403]

[0404] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 507.15 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0405] Example 72: (S)-1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)cyclohexyl-1-ol

[0406]

[0407] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 474.26 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0408] Example 73: (S)-1′-(3-(cyclopropylethynyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7-dihydro Spiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0409]

[0410] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 386.21 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 1.8 2-1.92 (m, 2H), 1.53-1.69 (m, 3H), 0.91-0.96 (m, 2H), 0.83-0.86 (m, 2H).

[0411] Example 74: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-(3,3-dimethylbut-1-yn-1-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0412]

[0413] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 432.25 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0414] Example 75: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-((2-(difluoromethyl)-4-methylthiazolyl-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanolI

[0415]

[0416] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 523.18 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 4.2 1(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).

[0417] Example 76: (S)-4-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-2-cyanopyridine

[0418]

[0419] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 478.21 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0420] Example 77: (S)-5-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-6-methyl-2-cyanopyridine

[0421]

[0422] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 492.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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, 1 H), 4.81 (s, 2H), 4.26 (s, 1H), 3.76-3.87 (m, 2H), 3.20-3.29 (m, 3H), 3.0 2(d, J=16.8Hz, 1H), 2.77(s, 3H), 1.98-2.09(m, 2H), 1.56-1.72(m, 2H).

[0423] Example 78: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- [1'-yl]-3-((2,4-dimethylthiazolyl-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0424]

[0425] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 487.20 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0426] 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

[0427]

[0428] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 415.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): 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).

[0429] Example 80: (3S,4S)-8-(3-((2-chloro-4,6-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazolyl (azine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0430]

[0431] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 459.15 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0432] Example 81: (S)-5-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)-2-cyanopyridine

[0433]

[0434] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 498.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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=16.8H z, 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).

[0435] Example 82: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-(cyclopropylethynyl)-1H-pyrazolo[3,4-b]pyrazine-5-yl)methanol

[0436]

[0437] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 416.22 [M+1]. 1H NMR (400MHz, CD3OD): 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, 2 H), 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).

[0438] Example 83: (S)-4-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2-methylbut-3-yn-2-ol

[0439]

[0440] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 434.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 3.7 2-3.80 (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).

[0441] Example 84: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-((2-(difluoromethyl)-4-methylthiazo-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0442]

[0443] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 523.18 [M+1]. 1H NMR (400MHz, CD3OD): 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), 4.2 1(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).

[0444] Example 85: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-((4-chloro-2-methylthiazolyl-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0445]

[0446] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 507.15 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0447] Example 86: (S)-1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)cyclohexyl-1-ol

[0448]

[0449] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 474.26 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0450] Example 87: (S)-1′-(3-(cyclopropylethynyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7-dihydro Spiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0451]

[0452] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 386.21 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 1.8 2-1.92 (m, 2H), 1.52-1.69 (m, 3H), 0.91-0.96 (m, 2H), 0.82-0.86 (m, 2H).

[0453] Example 88: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-(3,3-dimethylbut-1-yn-1-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0454]

[0455] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 432.25 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0456] Example 89: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-(3-methoxy-3-methylbut-1-yn-1-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0457]

[0458] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 448.25 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 3.72-3.8 0 (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).

[0459] Example 90: (S)-4-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2-methylbut-3-yn-2-ol

[0460]

[0461] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 454.22 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0462] Example 91: (S)-1′-(3-(3-morpholinylprop-1-yn-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 5,7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0463]

[0464] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 445.25 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.52 (d, J=4.8Hz, 1H), 8.36 (s, 1H), 7.97 (d, J=7.6H z, 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).

[0465] Example 92: (S)-1′-(5-(difluoromethyl)-3-(3-(dimethylamino)prop-1-yn-1-yl)-1H-pyrazole [3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0466]

[0467] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 453.23 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0468] Example 93: (S)-1′-(5-(difluoromethyl)-3-(3-morpholinylprop-1-yn-1-yl)-1H-pyrazolo[3,4-] b)Pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine)-5-amine

[0469]

[0470] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 495.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0471] Example 94: (S)-3-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,1-diphenylprop-2-yn-1-ol

[0472]

[0473] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 528.25 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0474] Example 95: (S)-1′-(3-((3,3-difluorocyclobutyl)ethynyl)-5-(difluoromethyl)-1H-pyrazolo[3, [4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0475]

[0476] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 486.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0477] Example 96: (S)-1′-(3-(cyclopentylethynyl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine- 6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0478]

[0479] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 464.24 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0480] Example 97: (S)-1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)cyclobut-1-ol

[0481]

[0482] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 496.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 3.68-3.7 9(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).

[0483] Example 98: (S)-1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)cyclopropyl-1-onitrile

[0484]

[0485] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 461.20 [M+1]. 1H NMR (400MHz, CD3OD): 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), 4.3 9 (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).

[0486] Example 99: (S)-1′-(3-(3-(dimethylamino)prop-1-yn-1-yl)-1H-pyrazolo[3,4-b]pyrazine- 6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0487]

[0488] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 403.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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, 5.2H z, 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).

[0489] Example 100: (S)-1′-(3-(cyclobutylethynyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7-di Hydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0490]

[0491] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 400.22 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0492] Example 101: (S)-1′-(3-(3-methoxypropyl-1-yn-1-yl)-1H-pyrazolo[3,4-b]pyrazine-6- 5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0493]

[0494] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 390.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0495] Example 102: (R)-4-(6-((S)-5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine) [Pyridine]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)but-3-yn-2-ol

[0496]

[0497] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 390.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0498] Example 103: (S)-4-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2,2-dimethylbut-3-yn-1-ol

[0499]

[0500] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 418.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0501] Example 104: (S)-1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)cyclobut-1-ol

[0502]

[0503] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 416.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0504] Example 105: (S)-1′-(3-(3-ethylpent-1-yn-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 5,7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0505]

[0506] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 416.26 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.54-8.65 (m, 1H), 8.36 (s, 1H), 8.00 (d, J=7.6Hz, 1H), 7.40-7.46 (m, 1H), 4.52-4.5 9 (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).

[0507] Example 106: (S)-1′-(3-(cyclobutylethynyl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine- 6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0508]

[0509] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 450.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0510] Example 107: (S)-(1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)cyclopropyl)methanol

[0511]

[0512] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 466.22 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0513] Example 108: (S)-(1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)ethynyl)cyclopropyl)methanol

[0514]

[0515] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 416.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0516] Example 109: (S)-4-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2,2-dimethylbut-3-yn-1-ol

[0517]

[0518] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 468.23 [M+1]. 1H NMR (400MHz, CD3OD): 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), 3.6 7-3.78(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).

[0519] Example 110: (S)-5-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2-methylpent-4-yn-2-ol

[0520]

[0521] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 418.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0522] Example 111: (S)-5-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2-methylpent-4-yn-2-ol

[0523]

[0524] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 468.23 [M+1]. 1H NMR (400MHz, CD3OD): δ=8.42 (d, J=4.8Hz, 1H), 7.89 (d, J=7.6Hz, 1H), 7.32 (d d, J=7.6Hz, 4.8Hz, 1H), 7.01 (t, J=54.0Hz, 1H), 4.28 (s, 1H), 3.67-3.78 (m, 2 H), 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).

[0525] Example 112: (S)-1′-(5-(difluoromethyl)-3-(oxetane-3-ylethynyl)-1H-pyrazolo[3,4-] b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0526]

[0527] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 452.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0528] Example 113: (S)-1′-(3-((6-aminopyridin-3-yl)ethynyl)-5-(difluoromethyl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0529]

[0530] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 488.21 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0531] Example 114: (S)-1′-(3-(cyclopropylethynyl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine- 6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0532]

[0533] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 436.21 [M+1]. 1 H NMR (400MHz, CD3OD): 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, 2 H), 1.64-1.71 (m, 1H), 1.56-1.63 (m, 2H), 0.92-0.99 (m, 2H), 0.86-0.91 (m, 2H).

[0534] Example 115: (S)-1′-(5-(difluoromethyl)-3-((3-methyloxetane-3-yl)ethynyl)-1H-pyridine Azo[3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0535]

[0536] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 466.22 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0537] Example 116: (S)-3-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)oxetanebut-3-ol

[0538]

[0539] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 468.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 4.7 4(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).

[0540] Example 117: (S)-1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)cycloprop-1-ol

[0541]

[0542] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 432.21 [M+1]. 1H NMR (400MHz, CD3OD): 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), 3.8 2-3.90 (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).

[0543] Example 118: (S)-3-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)oxetanebut-3-ol

[0544]

[0545] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 418.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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=6.4H z, 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).

[0546] Example 119: (S)-1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)cycloprop-1-ol

[0547]

[0548] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 402.20 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0549] Example 120: (S)-1′-(3-(3,3-dimethylbut-1-yn-1-yl)-1H-pyrazolo[3,4-b]pyrazine-6- 5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0550]

[0551] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 402.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0552] Example 121: (S)-1′-(3-((1-(trifluoromethyl)cyclopropyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazol (azinyl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0553]

[0554] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 454.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 4.40-4.5 5 (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).

[0555] Example 122: (S)-1′-(5-(difluoromethyl)-3-((1-(trifluoromethyl)cyclopropyl)ethynyl)-1H-pyrazole [3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0556]

[0557] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 504.19 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 4.4 7 (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).

[0558] Example 123: (S)-1′-(5-(difluoromethyl)-3-((1-methylcyclopropyl)ethynyl)-1H-pyrazolo[3, [4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0559]

[0560] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 450.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0561] Example 124: (S)-1′-(3-((1-methylcyclopropyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazine-6- 5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0562]

[0563] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 400.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0564] Example 125: (S)-1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)cyclopropane-1-nitrile

[0565]

[0566] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 411.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0567] Example 126: (S)-N-(1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine) [Pyridine]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)cyclopropyl)methanesulfonamide

[0568]

[0569] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 479.20 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0570] Example 127: (S)-4-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2-methylbut-3-yn-2-ol

[0571]

[0572] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 404.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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, 4.8H z, 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).

[0573] Example 128: (S)-N-(4-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine) [Pyridine]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2-methylbut-3-yn-2-yl)methanesulfonamide

[0574]

[0575] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 481.21 [M+1]. 1H NMR (400MHz, CD3OD): 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), 4.37-4.5 0 (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).

[0576] Example 129: (S)-1′-(3-(cyclopentylethynyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7-di Hydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0577]

[0578] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 414.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0579] Example 130: (S)-4-(6-((S)-5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine) [Pyridine]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)but-3-yn-2-ol

[0580]

[0581] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 390.20 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0582] Example 131: (S)-N-(1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine) [Pyridine]-1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)cyclopropyl)methanesulfonamide

[0583]

[0584] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 529.19 [M+1]. 1 H NMR (400MHz, CD3OD): 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)-

[0585] Example 132: (S)-1-((6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethynyl)cycloprop-1-ol

[0586]

[0587] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 452.20 [M+1]. 1H NMR (400MHz, CD3OD): 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, 1 H), 1.98-2.10(m, 2H), 1.74-1.81(m, 1H), 1.66-1.73(m, 1H), 1.10-1.17(m, 4H).

[0588] Example 133: (S)-1′-(3-((3-methyloxetane-3-yl)ethynyl)-1H-pyrazolo[3,4-b] Pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0589]

[0590] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 416.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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, 4.8H z, 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).

[0591] Example 134: (S)-1′-(3-((3,3-difluorocyclobutyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazine-6- 5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0592]

[0593] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 436.21 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0594] 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[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0595]

[0596] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 452.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0597] Example 136: (S)-1′-(5-(difluoromethyl)-3-(3-methylbut-3-en-1-yn-1-yl)-1H-pyrazol [3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0598]

[0599] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 436.21 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0600] Example 137: (S)-1′-(3-(3-methylbut-3-en-1-yn-1-yl)-1H-pyrazolo[3,4-b]pyrazine-6- 5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0601]

[0602] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 386.21 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0603] Example 138: (S)-1′-(3-(3-amino-3-methylbut-1-yn-1-yl)-5-(difluoromethyl)-1H-pyrazole [3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0604]

[0605] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 1. MS m / z [LC-MS]: 453.23 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0606] Example 139: (S)-1′-(3-(2-methylprop-1-en-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 5,7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0607]

[0608] Step 1: (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[cyclopentadieno[b]pyridin-6,4′-piperidin]-5-yl)tert-butyl carbamate

[0609] Intermediate 5 (136 mg), 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborane (44 mg), sodium carbonate (64 mg), tetra(triphenylphosphine)palladium (12 mg), and dioxane / water 10:1 mixed solvent (10 mL) were added to a single-necked flask, purged with nitrogen, heated to 80 °C, and stirred overnight. Cool to room temperature, pour into water, extract with dichloromethane, wash the extract with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane:methanol, 20:1) to give (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[cyclopentadieno[b]pyridin-6,4′-piperidin]-5-yl) tert-butyl carbamate (90 mg). MS m / z [LC-MS]: 606.36 [M+1].

[0610] Step 2: (S)-1′-(3-(2-methylprop-1-en-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidine]-5-amine

[0611] (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[cyclopentadieno[b]pyridin-6,4′-piperidin]-5-yl) tert-butyl carbamate (90 mg) was added to a 4M solution of dioxane in hydrogen chloride (3 mL), stirred at room temperature for 1 hour, concentrated under reduced pressure, and then 10% hydrogen chloride was added. Sodium carbonate aqueous solution (10 mL) was 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[cyclopentadien[b]pyridin-6,4′-piperidine]-5-amine (32 mg). MS m / z [LC-MS]: 376.22 [M+1]. 1 HNMR (400MHz, CD3OD): 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).

[0612] Example 140: (S)-1′-(3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazole[3,4-b]pyrazine-6-yl)- 5,7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0613]

[0614] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 404.22 [M+1]. 1H NMR (400MHz, CD3OD): 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), 4.3 2 (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).

[0615] Example 141: (S)-1′-(3-((tetrahydro-4H-pyran-4-ylidene)methyl)-1H-pyrazolo[3,4-b]pyrazine- 6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0616]

[0617] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 418.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0618] Example 142: (S)-1′-(3-(cyclobutyrylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7-di Hydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0619]

[0620] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 388.22 [M+1]. 1H NMR (400MHz, CD3OD): δ=8.45 (d, J=4.8Hz, 1H), 8.28 (s, 1H), 7.89 (d, J=7.2H z, 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).

[0621] Example 143: (3S,4S)-8-(9-(cyclobutyrylmethyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimimethanil (Pyridine-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0622]

[0623] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 394.24 [M+1]. 1 H NMR (400MHz, CDCl3): 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).

[0624] 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[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0625]

[0626] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 454.22 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0627] Example 145: (S)-1′-(8-((tetrahydro-4H-pyran-4-ylidene)methyl)imidazo[1,2-c]pyrimidine-5- 5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0628]

[0629] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 417.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0630] Example 146: (3S,4S)-8-(9-(3,6-dihydro-2H-pyran-4-yl)-7H-imidazo[1,2-c]pyrazolo [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0631]

[0632] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 410.23 [M+1]. 1H NMR (400MHz, CDCl3): 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).

[0633] Example 147: (S)-1′-(8-(3,6-dihydro-2H-pyran-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-5, 7-Dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0634]

[0635] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 403.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0636] Example 148: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyrazine-5-yl)methanol

[0637]

[0638] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 434.23 [M+1]. 1H NMR (400MHz, CD3OD): 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), 2.6 7-2.73(m, 2H), 1.97-2.01(m, 2H), 1.75-1.82(m, 1H), 1.66-1.72(m, 1H).

[0639] Example 149: (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5- Methyl-6-((tetrahydro-4H-pyran-4-ylidene)methyl)pyrazin-2-yl)methanol

[0640]

[0641] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 389.25 [M+1]. 1 H NMR (400MHz, CD3OD): 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, 3 H), 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).

[0642] Example 150: (S)-(3-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 5-methyl-6-((tetrahydro-4H-pyran-4-yl)methyl)pyrazin-2-yl)methanol

[0643]

[0644] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 422.26 [M+1]. 1H NMR (400MHz, CD3OD): 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, 2 H), 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).

[0645] Example 151: (S)-1′-(3-(4,4-difluorocyclohex-1-en-1-yl)-1H-pyrazolo[3,4-b]pyrazine-6- 5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0646]

[0647] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 438.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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, 1 H), 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).

[0648] Example 152: (S)-(3-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 6-(3,6-dihydro-2H-pyran-4-yl)-5-methylpyrazine-2-yl)methanol

[0649]

[0650] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 408.24 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0651] Example 153: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5- Methyl-3-((tetrahydro-4H-pyran-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0652]

[0653] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 415.25 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0654] Example 154: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (3,6-dihydro-2H-pyran-4-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0655]

[0656] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 401.23 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0657] 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[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0658]

[0659] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 443.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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=1 6.8Hz, 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).

[0660] Example 156: (3-((S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6- (3,6-dihydro-2H-pyran-4-yl)-5-methylpyrazine-2-yl)methanol

[0661]

[0662] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 375.24 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0663] Example 157: (S)-1′-(3-(4,4-difluorocyclohex-1-en-1-yl)-5-(difluoromethyl)-1H-pyrazol [3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0664]

[0665] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 488.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0666] Example 158: (S)-1′-(5-(difluoromethyl)-3-((tetrahydro-4H-pyran-4-ylidene)methyl)-1H-pyrazole [3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0667]

[0668] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 468.23 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0669] Example 159: (S)-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-((tetrahydro-4H-pyran-4-ylidene)methyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0670]

[0671] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 448.25 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0672] Example 160: (3S,4S)-8-(9-(4,4-difluorocyclohex-1-en-1-yl)-7H-imidazo[1,2-c]pyrazole [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine

[0673]

[0674] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 444.23 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0675] Example 161: (S)-1′-(9-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-7H-imidazo[] [1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0676]

[0677] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 499.29 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0678] Example 162: (S)-1′-(9-(4,4-difluorocyclohex-1-en-1-yl)-7H-imidazo[1,2-c]pyrazolo [4,3-e]pyrimidin-5-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0679]

[0680] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 477.23 [M+1]. 1H NMR (400MHz, CD3OD): 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, 1 H), 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).

[0681] Example 163: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (4,4-Difluorocyclohex-1-en-1-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0682]

[0683] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 435.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0684] Example 164: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5- Methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0685]

[0686] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 400.25 [M+1]. 1H NMR (400MHz, CD3OD): δ=7.58 (s, 1H), 4.27-4.31 (m, 1H), 3.87-3.97 (m, 3H), 3.81 (d, J=9.2Hz, 1H), 3.40-3.6 0 (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).

[0687] Example 165: (S)-1′-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazine-6- 5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0688]

[0689] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 403.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 4.5 1 (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).

[0690] Example 166: (S)-3-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-4,4-dimethylcyclohex-2-en-1-one

[0691]

[0692] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 494.25 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0693] 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[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0694]

[0695] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 493.26 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0696] Example 168: (S)-1-(4-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine) [Pyridinium]-1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3,6-dihydropyridin-1(2H)-yl)ethyl 1-keto

[0697]

[0698] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 495.24 [M+1]. 1H NMR (400MHz, CD3OD): δ=8.55 (d, J=4.0Hz, 1H), 7.97 (d, J=7.6Hz, 1H), 7.40 (dd, J=7.6 Hz, 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).

[0699] Example 169: (S)-1′-(9-((tetrahydro-4H-pyran-4-ylyl)methyl)-7H-imidazo[1,2-c]pyran Azo[4,3-e]pyridin-5-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidine]-5-amine

[0700]

[0701] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 457.25 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0702] Example 170: (S)-(4-(5-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyridin-9-yl)-3,6-dihydropyridin-1(2H)-yl)(cyclopropyl) Methyl ketone

[0703]

[0704] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 510.27 [M+1].1 H NMR (400MHz, CD3OD): δ=8.34 (d, J=4.8Hz, 1H), 7.80 (d, J=7.2Hz, 1H), 7.67-7.72 (m, 1H), 7.61-7.6 4 (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, 1 H), 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, 1 H), 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).

[0705] Example 171: (S)-1-(4-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine) [Pyridinium]-1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3,6-dihydropyridin-1(2H)-yl)-2,2,2-trifluoroethyl-1-one

[0706]

[0707] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 499.22 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.37 (d, J=5.2Hz, 1H), 8.32 (s, 1H), 7.83 (d, J=7.6H z, 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).

[0708] Example 172: (S)-1′-(9-(1-(cyclopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7H-imidazolium [1,2-c]pyrazolo[4,3-e]pyridin-5-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidine]-5-amine

[0709]

[0710] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 546.24 [M+1]. 1H NMR (400MHz, CD3OD): 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, 1 H), 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).

[0711] Example 173: (S)-1′-(9-((2-oxaspiro[3.5]nonane-7-yl subunit)methyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyridin-5-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidine]-5-amine

[0712]

[0713] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 497.28 [M+1]. 1 H NMR (400MHz, CD3OD): 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, 2 H), 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).

[0714] Example 174: (S)-1′-(9-(3,4-dihydro-2H-pyran-5-yl)-7H-imidazo[1,2-c]pyrazolo[4, [3-e]pyridin-5-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidine]-5-amine

[0715]

[0716] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 443.23 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.58 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.87 (d, J=8.0Hz, 1 H), 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).

[0717] Example 175: (S)-1′-(5-(difluoromethyl)-3-(4,5-dihydrofuran-2-yl)-1H-pyrazolo[3,4-b] Pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0718]

[0719] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 440.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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=54.4 Hz, 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).

[0720] Example 176: (S)-1′-(5-(difluoromethyl)-3-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4- 6-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0721]

[0722] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 510.28 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0723] Example 177: (S)-(4-(66-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3,6-dihydropyridine-1(2H)-yl)(cyclopropyl) methyl ketone

[0724]

[0725] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 471.26 [M+1]. 1 H NMR (400MHz, CD3OD): 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), 2.6 7-2.73 (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).

[0726] Example 178: 1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8- )-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyridine-9-yl)-3,6-dihydropyridine-1(2H)-yl)ethyl-1-one

[0727]

[0728] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 451.26 [M+1]. 1H NMR (400MHz, CD3OD): 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, 2 H), 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).

[0729] Example 179: (S)-4-(5-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyridin-9-yl)-3,6-dihydropyridine-1(2H)-formonitrile

[0730]

[0731] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 467.24 [M+1].

[0732] Example 180: (S)-6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-(3,4-dihydro-2H-pyran-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0733]

[0734] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 434.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0735] Example 181: (S)-6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0736]

[0737] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 434.23 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.38 (d, J=5.2Hz, 1H), 7.86 (d, J=7.6Hz, 1H), 7.49 (s, 1 H), 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).

[0738] Example 182: (S)-6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-(4,4-difluorocyclohex-1-en-1-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0739]

[0740] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 468.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0741] Example 183: (S)-6.-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-(4-fluorocyclohexyl-1,3-dien-1-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0742]

[0743] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 448.23 [M+1]. 1H NMR (400MHz, CD3OD): 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).

[0744] Example 184: (S)-N-(1′-(3-(1-(cyclopropylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methyl- 4-O-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′- [piperidine]-5-yl)cyclopropylformamide

[0745]

[0746] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 569.30 [M+1]. 1 H NMR (400MHz, CD3OD): 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=5.6H z, 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).

[0747] 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[cyclopentadieno[b]pyridin-6,4′-piperidine]-5-amine

[0748]

[0749] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 457.25 [M+1]. 1H NMR (400MHz, CD3OD): 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=17.6H z, 3.2Hz, 1H), 4.30-4.37(m, 2H), 3.75-3.88(m, 4H), 3.23-3.35(m, 3H), 3.0 2-3.13 (m, 2H), 2.04-2.17 (m, 2H), 1.63-1.72 (m, 2H), 1.20 (d, J=7.2Hz, 3H).

[0750] Example 186: (S)-6-(5-amino-5- 7 -Dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- 3-(1-(cyclopropylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d] Pyrimidin-4-one

[0751]

[0752] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 501.27 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0753] Example 187: (S)-6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-1′- )-3-(1-(cyclopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one

[0754]

[0755] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 537.24 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0756] Example 188: (S)-1′-(9-(2-oxaspiro[3.5]non-6-en-7-yl)-7H-imidazo[1,2-c]pyrazole [4,3-e]pyridin-5-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidine]-5-amine

[0757]

[0758] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 483.26 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.43 (d, J=4.0Hz, 1H), 7.91 (d, J=7.6Hz, 1H), 7.69 (d, J=1.6 Hz, 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, 3 H), 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).

[0759] Example 189: (S)-1′-(5-(difluoromethyl)-3-(4,5-dihydrofuran-3-yl)-1H-pyrazolo[3,4-b] Pyrazin-6-yl)-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0760]

[0761] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 440.20 [M+1]. 1 H NMR (400MHz, CD3OD): 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=9.2H z, 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).

[0762] 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[cyclopentadieno[b]pyridin-6,4′-piperidine]-5-amine

[0763]

[0764] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 429.22 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0765] 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[cyclopentadieno[b]pyridine-6,4′-piperidine]-5-amine

[0766]

[0767] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 454.22 [M+1]. 1H NMR (400MHz, CD3OD): δ=8.33 (d, J=4.4Hz, 1H), 8.14 (s, 1H), 7.83 (d, J=7.6Hz, 1 H), 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).

[0768] Example 192: (S)-4-(6-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridine-6,4′-piperidine]- 1′-yl)-5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3,(dihydropyridine-1(2H)-formonitrile

[0769]

[0770] The target compound can be synthesized using suitable starting materials and intermediates, following the method described in Example 139. MS m / z [LC-MS]: 478.23 [M+1]. 1 H NMR (400MHz, CD3OD): 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).

[0771] Determination of the in vitro enzymatic activity inhibitory effect of the compound on SHP2

[0772] In this patent, the enzymatic activity of SHP2 is detected using a rapid fluorescence method. DiFMUP is used as an alternative substrate, and a high-throughput screening platform has been optimized and established. The inhibitory activity of the compound against SHP2 is detected on this platform. The specific method is as follows: A mixture of 1 nM SHP2 and 2.5 μM of diphosphorylated IRS 1 peptide (sequence: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide) is pre-incubated at 23°C for 30 minutes. The compound is serially diluted 5-fold with 100% DMSO starting from 0.2 mM (total of 7 concentrations). 2 μL of each concentration is added to 48 μL of reaction buffer (60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% Tween 20, 5 mM DTT) for dilution and mixing. Add 5 μL of the diluted compound to a black 384-well plate (OptiPlate-384, catalog number 6007270, purchased from PerkinElmer), then add 10 μL of pre-incubated SHP2 and IRS1 peptide mixture, centrifuge to mix, and incubate at 23°C for 30 min. Add 5 μL of the substrate substitute DiFMUP (final concentration 50 μM, catalog number D6567, purchased from Invitrogen) to the reaction and incubate at 23°C for 60 min. Then terminate the reaction by adding 5 μL of 160 μM bpV (Phen) solution (SC-22137, purchased from Santa). Immediately after the reaction is terminated, the fluorescence signal is detected using a microplate reader (PerkinElmer) at excitation and emission wavelengths of 340 nm and 450 nm, respectively. The IC50 of the compound is calculated using GraphPad Prism software. 50 Value. Testing revealed that all the specific compounds in the embodiments of this invention possess SHP2 in vitro enzymatic inhibitory activity, IC50. 50 The values ​​are in the range of 0.1 nM to 1 μM. Table 1 lists the activities of some compounds:

[0773] Table 1. Inhibitory activity of some compounds against SHP2 enzyme

[0774]

[0775] The compounds of this invention all exhibit SHP2 protease inhibitory activity within 20 nM. Table 1 shows the specific data for some of the compounds, indicating that the compounds provided by this invention all have good SHP2 protease inhibitory activity.

[0776] Determination of the inhibitory effect of the compound on the proliferation of SHP2 positive cells

[0777] Human non-small cell lung cancer cell line NCI-H358 cells were cultured in RPMI-1640 medium (catalog number C11875500BT, purchased from Biological Industries) with 10% fetal bovine serum (FBS, catalog number 04-001-1ACS, purchased from Biological Industries, BI) and 1% penicillin / streptomycin antibiotics (P / S, catalog number 15070-063, purchased from Gibco) at 37°C and 5% CO2. The day before compound detection, NCI-H358 cells were seeded at a concentration of 2000 cells / 195 μL / well in 196-well plates (catalog number 3917, purchased from Corning). 24 hours later, the compound was serially diluted 3-fold starting at 10 mM with 100% DMSO (totaling 10 concentrations). 2 μL of each concentration was then added to 48 μL of serum- and antibiotic-free medium for further dilution. Five μL of each diluted compound was added to the prepared cell suspension. The compound and cells were incubated together in a cell culture incubator for 72 hours (3 days). After aspirating the culture medium, 25 μL of Cell-Titer Glo (G7570, purchased from Promega) reagent was added, and the cells were incubated again for 5-10 minutes. Fluorescence values ​​were then read on Envision, and the IC50 of the compound's inhibitory effect on cell proliferation was calculated using GraphPad Prism software. 50Values. The human acute myeloid leukemia cell line Kasumi-1 was cultured in RPMI-1640 medium (C11875500BT, purchased from Biological Industries) with 20% fetal bovine serum (FBS, 04-001-1ACS, purchased from Biological Industries, BI) and 1% penicillin / streptomycin antibiotics (P / S, 15070-063, purchased from Gibco) at 37°C and 5% CO2. The day before compound detection, Kasumi-1 cells were seeded at a concentration of 3000 cells / 195 μL / well in 196-well plates (Catalog No. 3599, purchased from Corning). 24 hours later, the compound was serially diluted 3-fold with 100% DMSO, starting at 10 mM (totaling 10 concentrations). Then, 2 μL of each concentration was added to 48 μL of serum- and antibiotic-free medium for further dilution. Five μL of each diluted compound was added to the prepared cell suspension, and the compound and cells were incubated together in a cell culture incubator for 72 hours (3 days). Then, 35 μL of Cell-Titer Blue (G8082, purchased from Promega) was added, and the cells were incubated again for 4 hours. Fluorescence values ​​were then read on a Flexstation III (excitation at 560 nm, detection at 590 nm). The IC50 of the compound on cell proliferation was calculated using GraphPad Prism software. 50 Values. Results for some compounds are shown in Table 2.

[0778] Table 2. Inhibitory activity of some compounds on cell (NCI-H358) proliferation

[0779]

[0780]

[0781] The compounds in the embodiments of the present invention all exhibited inhibitory activity against the proliferation of SHP2-positive cells within 1 μM. The experimental data in Table 2 show the specific data of some compounds, indicating that the compounds provided by the present invention have good inhibitory activity against the proliferation of SHP2-positive cells.

[0782] Determination of pharmacokinetic data of the compound in SD rats

[0783] Male SD rats were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. Rats were divided into groups of three and orally administered a suspension of the test sample (5 mg / kg, suspension of 0.5% methylcellulose) via gavage. Animals were fasted overnight before the experiment, from 10 hours before administration to 4 hours after administration. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with isoflurane using a small animal anesthesia machine, 0.3 mL of whole blood was collected through the fundus venous plexus and placed in heparin anticoagulant tubes. The samples were centrifuged at 4000 rpm for 5 min at 4℃, and the plasma was transferred to centrifuge tubes and stored at -80℃ until analysis. Protein precipitation was used to extract the plasma samples, and the extract was analyzed by LC / MS. Results for some compounds are shown in Table 3.

[0784] Table 3. Pharmacokinetic data of some compounds

[0785]

[0786] Table 3 lists the pharmacokinetic data of some compounds of the present invention in SD rats. This indicates that the compounds provided by the present invention have very good in vivo metabolic levels.

[0787] Determination of the inhibitory effect of the compound on hERG

[0788] The system used was a patch-clamp amplifier system (Multiclamp 700B Amplifier) ​​(AXON), an Olympus (Olympus IX51 / 71 / 73) microscope, and an MP285 micromanipulator.

[0789] The HEK293 cell line stably transfected with hERG was purchased from Invitrogen. Cells were grown in a medium containing 85% DMEM, 10% fetal bovine serum, 0.1 mM non-essential amino acids, 25 mM HEPES buffer, 100 U / mL penicillin-streptomycin, 5 μg / mL blastomycin, and 400 μg / mL G418 genimycin.

[0790] Subculture three times a week, digesting cells with TrypLE Express to maintain approximately 40%-80% confluence. Before detection, fill each 6 cm diameter culture dish with 5 × 10⁶ cells / day. 5 Cells were seeded at a density of 100 cells per cell and induced with 1 μg / mL doxycycline for 48 hours.

[0791] The compound was tested in solutions at concentrations of 10, 1, and 0.1 μM, and after being diluted 1000 times, the final concentration of DMSO was in the range of 0.1%.

[0792] Adjust the manipulator to move the electrode tip toward the cell surface, creating a high-level blockade. Compensate for the liquid boundary potential and fast capacitance, and rupture the cell membrane to establish a whole-cell recording mode. Set the membrane potential to -60mV to ensure the hERG channel is not open. Use the C on the amplifier. slow To eliminate the peak capacitance current, set the holding voltage to -90mV for 500ms. Perform a leakage current test at -80mV for 500ms. Depolarize to +30mV for 4.8 seconds to activate the hERG channel, then restore the voltage to -50mV for 5.2 seconds and observe the tail current.

[0793] Peak current suppression = [1 - (peak tail current)] 抑制剂 - Peak tail current 阳性对照 ) / (peak tail current) 空白 - Peak tail current 阳性对照 )]×100%.

[0794] Table 4. Inhibitory activity of reference materials and some compounds of the present invention against hERG

[0795]

[0796] Table 4 lists the inhibition rate data of hERG of the reference material and some compounds of the present invention at different concentrations, indicating that the compounds of the present invention have low inhibitory activity against hERG and low cardiotoxicity.

[0797] Industrial applicability

[0798] The compounds of this invention can inhibit SHP2 protease activity to provide antitumor effects.

[0799] Citing Join

[0800] All publications and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication or patent application is specifically and individually cited.

Claims

1. The following compounds or their pharmaceutically acceptable salts:

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 2 in the preparation of a medicament for treating diseases associated with SHP2 and / or KRAS and / or EGFR.

4. The use according to claim 3, wherein the disease associated with SHP2 and / or KRAS and / or EGFR is leukemia, melanoma, malignant glioma, lung cancer, breast cancer, or Nursing syndrome.

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