Substituted alkynyl heterocyclic compounds

Abstract

This application relates to substituted alkynyl heterocyclic compounds of Formula I. The present invention relates to substituted alkynyl heterocyclic compounds having SHP2 inhibitory activity, methods for their preparation, pharmaceutical compositions thereof, and also to the use of such compounds and pharmaceutical compositions in treating diseases benefiting from SHP2 enzyme inhibition, 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] The present invention generally relates to novel substituted alkynyl heterocyclic compounds having SHP2 inhibitory activity, methods for preparing the same, pharmaceutical compositions thereof, and also relates to the use of such compounds and pharmaceutical compositions thereof for treating diseases that benefit from SHP2 enzyme inhibition, such as treating cancer. Background Art

[0002] Cancer is a serious disease that threatens human health and life. In particular, the incidence and mortality of cancer have been rising rapidly in recent years, surpassing cardiovascular disease to become the number one killer of human health. Tumor proliferation, apoptosis, metastasis, etc. are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside the cell. In these signal transduction pathways, protein phosphorylation and dephosphorylation are crucial. 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, and they maintain a dynamic balance to maintain the normal physiological function of cells. On the contrary, abnormal phosphorylation can lead to cancer, inflammation, diabetes and other diseases.

[0003] SHP2 protein is a non-receptor protein tyrosine phosphatase encoded by the ptpnll 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 C-terminal tail with a regulatory function. The SH2 domain is a conformational switch that mediates the interaction of the SHP2 protein with phosphotyrosine-containing activators (such as insulin receptor substrate 1-IRS1 and GRB2-associated binding protein 1-GAB1) and the intramolecular interaction between the SH2 domain and the PTP catalytic domain. In the absence of stimulation, the SHP2 domain binds to the PTP domain, blocking the catalytic active site and placing the SHP2 phosphatase activity in an autoinhibitory state. When the SH2 domain binds to the activator, the inhibitory intramolecular interaction is released, and the SHP2 phosphatase is in an open conformation, allowing the SHP2 substrate to locate to the catalytic active site and perform the phosphatase function. This activity conversion characteristic of SHP2 makes it possible for various mutations in SHP2 to destroy the SHP2 autoinhibitory state, leading to overactivation of the SHP2 protein phosphatase activity, and then inducing carcinogenesis. Both experimental and clinical data have confirmed that SHP2 plays a promoting role in most cancers. As the first tyrosine phosphatase discovered to promote cancer development, it has received great attention in the field of cancer. Its phosphatase activity plays an important role in intracellular signal regulation.

[0005] SHP2 is involved in regulating cell signal transduction pathways activated by cytokines, growth factors and hormones, including RAS / ERK, JAK / STAT, PI3K / AKT and NF-κB signaling pathways, thereby regulating physiological functions such as cell proliferation, differentiation, cell cycle maintenance and migration. At the same time, SHP2 also mediates compensatory activation pathways after kinases such as MEK are inhibited, thereby promoting the occurrence of tumor resistance. As a downstream molecule of the PD-1 receptor, SHP2 is also involved in the conduction of T cell inhibitory signals. Studies have shown that SHP2 is a downstream molecule of PD-1 signaling, which not only inhibits T cell activation but also promotes T cell dysfunction. Therefore, targeting SHP2 can restore or enhance T cell-mediated anti-tumor immune function. In addition, SHP2 can inhibit IFN-γ-mediated immune responses by inactivating the signal transducer and transcription activator STAT1.

[0006] In recent years, SHP2 activation mutations and high expression have been found in leukemia, solid tumors, melanoma, malignant glioma, lung cancer, breast cancer and Nunan syndrome, and are closely related to the occurrence, development and prognosis of tumors. At present, SHP2 has been studied as a target molecule for clinical tumors. The mechanism of action of traditional SHP2 inhibitors (such as II-B08 and PHPS1) is to bind to the PTP catalytic domain of SHP2, prevent tyrosine phosphorylated substrates from entering the catalytic site, and thus inhibit 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 great defects in specificity and bioavailability, which limits their clinical application. Therefore, the development of SHP2 inhibitors with high specificity, high safety and strong cell membrane permeability is the key to determining whether SHP2 can become a new tumor intervention target, and SHP2 protein allosteric inhibitors have become the main direction of current research.

[0007] Currently, no SHP2 inhibitors have been approved for marketing. There are three compounds in the clinical research stage. Among them, JAB-3068 of Jacobios has made the fastest progress and has been approved for Phase II clinical trials. TNO155 of Novartis and RMC-4630 of Newray Pharmaceuticals are both in Phase I clinical research. Summary of the invention

[0008] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,

[0009]

[0010] in,

[0011] A is selected from the following dicyclic or tricyclic heterocyclic rings;

[0012]

[0013] R1 is selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with halogen, -OH, or -OC 1-6 Alkyl substitution;

[0014] R2 is selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0015] X is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-8 Cycloalkyl, C 3-8 Heteroalicyclic, C 6-10 Aryl and C 5-10 Heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-8 Cycloalkyl and C 3-8 The heteroalicyclic group may be optionally substituted with one or more halogen, -OH, -OC 1-6 Alkyl, -CF3, -NH2, C 1-6 Alkyl or phenyl substituted, the C 6-10 Aryl and C 5-10 The heteroaryl group may be fused to an unsaturated alicyclic, heteroalicyclic, or spirocyclic ring and may be optionally substituted by one or more halogen, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3R4, -NH-(CO)-C 1-6 Alkyl, -S-CH2-(CO)NH2, C 6-10 Aryl, -OC 6-10 Aryl, or C 5-10 Heteroaryl substitution, the unsaturated alicyclic, heteroalicyclic, or spirocyclic ring may be optionally substituted by one or more halogen or =O;

[0016] R is selected from C 1-6 Alkyl and C 3-6 Cycloalkyl, the alkyl and cycloalkyl groups may be optionally substituted with halogen, -CF3, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, or C 3-6 Cycloalkyl substitution;

[0017] R3 and R4 are each independently selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0018] Y is selected from C 6-10 Aryl, C 5-10 Heteroaryl and C 3-12 The aryl, heteroaryl and heteroalicyclic groups may be optionally substituted with one or more halogen, -OH, -OC 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 The alkyl or cycloalkyl group may be optionally substituted with halogen, -OH, -OC 1-6 Alkyl, or -NH2 substituted;

[0019] Z is selected from a single bond, -S- and -C≡C-.

[0020] According to some embodiments of the present invention, the compound of formula (I) of the present invention has the following formula II to X:

[0021]

[0022] in,

[0023] R1 is selected from hydrogen, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with halogen, -OH, or -OC 1-6 Alkyl substitution;

[0024] R2 is selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0025] X is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-8 Cycloalkyl, C 3-8 Heteroalicyclic, C 6-10 Aryl and C 5-10 Heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-8 Cycloalkyl and C 3-8 The heteroalicyclic group may be optionally substituted with one or more halogen, -OH, -OC 1-6 Alkyl, -CF3, -NH2, C 1-6 Alkyl or phenyl substituted, the C 6-10 Aryl and C 5-10 The heteroaryl group may be fused to an unsaturated alicyclic, heteroalicyclic, or spirocyclic ring and may be optionally substituted by one or more halogen, -CF3, -OH, -CN, R, -OR, -NR3R4, -OC(O)NR3RR4, -NH-(CO)-C 1-6Alkyl, -S-CH2-(CO)NH2, C 6-10 Aryl, -OC 6-10 Aryl, or C 5-10 Heteroaryl substitution, the unsaturated alicyclic, heteroalicyclic, or spirocyclic ring may be optionally substituted by one or more halogen or =O;

[0026] R is selected from C 1-6 Alkyl and C 3-6 Cycloalkyl, the alkyl and cycloalkyl may be optionally substituted with halogen, -CF3, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, or C 3-6 Cycloalkyl substitution;

[0027] R3 and R4 are each independently selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0028] Y is selected from C 6-10 Aryl, C 5-10 Heteroaryl and C 3-12 The aryl, heteroaryl and heteroalicyclic groups may be optionally substituted with one or more halogen, -OH, -OC 1-6 Alkyl, -NH2, C 1-6 Alkyl, or C 3-6 The alkyl or cycloalkyl group may be optionally substituted with halogen, -OH, -OC 1-6 Alkyl, or -NH2 substituted.

[0029] In some embodiments, R1 is selected from hydrogen, halogen and C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with halogen, -OH, or -OC 1-6 Alkyl substituted, R2 is selected from hydrogen and C 1-6 alkyl.;

[0030] In some embodiments, X is selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, the C 1-6 Alkyl and C 3-8 The cycloalkyl group may be optionally substituted with one or more halogen, -OH, -OC 1-6 Alkyl, -NH2, or C 1-6 Alkyl substituted, the C 6-10 Aryl and C 5-10 The heteroaryl group may be optionally substituted with one or more halogen, -CF3, -OH, -CN, -OC 1-6Alkyl, -NR3R4, -OC(O)NR3R4, -NH-(CO)-C 1-6 Alkyl, -S-CH2-CONH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, or C 5-10 Heteroaryl substitution,

[0031] R3 and R4 are each independently selected from hydrogen and C 1-6 alkyl;

[0032] In some embodiments, Y is selected from C 6-10 Aryl, C 5-10 Heteroaryl and C 3-12 The aryl, heteroaryl and heteroalicyclic groups may be optionally substituted with one or more -OH, -NH2, or C 1-6 Alkyl substitution;

[0033] In some embodiments, Y is selected from C 3-12 Heteroalicyclic groups, which may be optionally substituted with one or more -OH, -NH2, or C 1-6 Alkyl substitution;

[0034] In some embodiments, Y is selected from C 3-12 Heteroalicyclic group, the heteroalicyclic group may be optionally substituted by one or more -NH2 or C 1-6 Alkyl substitution;

[0035] According to some embodiments of the present invention, the present invention provides the following compounds:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof. In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0043] In another aspect, the present invention provides a method for treating a disease associated with SHP2, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0044] In another aspect, the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease associated with SHP2.

[0045] In some embodiments of the present invention, the disease associated with SHP2 is leukemia, melanoma, malignant glioma, lung cancer, breast cancer or Noonan syndrome.

[0046] Some chemical terms

[0047] The "compounds" of the present invention include all stereoisomers, geometric isomers, tautomers and isotopes. The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0048] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0049] The present invention also includes all isotopes of atoms, whether in the intermediates or the final compounds. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0050] In the above definition of compounds of formula IV, the terms used herein have the following meanings:

[0051] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0052] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, such as C 1-20 Alkyl, preferably C 1-6Alkyl, such as methyl, ethyl, propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (such as 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.

[0053] The term "C 1-6 "Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond and has 1-6 carbon atoms. The alkyl group can be unsubstituted or substituted by one or more substituents selected from alkyl, alkoxy, amino, halogen and hydroxy. Non-limiting examples of unsubstituted alkyl groups include, but are not limited to, groups such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylhexyl, etc.

[0054] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, such as C 3-20 Cycloalkyl, preferably C 3-6 Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The cycloalkyl 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.

[0055] The term "aryl" refers to a fully conjugated π electron system of all-carbon monocyclic or fused rings having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. Aryl 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 heteroalicyclic. Non-limiting examples of unsubstituted aryl include but are not limited to phenyl, naphthyl and anthracenyl.

[0056] The term "heteroaryl" refers to a monocyclic or fused ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein 1, 2, 3 or 4 ring atoms are selected from N, O, S, and the remaining ring atoms are C, and have a completely conjugated π-electron system. Heteroaryl 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 heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazinyl.

[0057] The term "heteroalicyclic" refers to a monocyclic, fused or spirocyclic ring having 3-12 ring atoms, having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein 1 or 2 ring atoms are selected from N, O, S(O) n (where n is 0, 1 or 2) with the remaining ring atoms being C. Such rings may be saturated or unsaturated (e.g., have one or more double bonds), but do not have a completely conjugated π-electron system. Examples of 3-membered saturated heteroalicyclic rings include, but are not limited to Examples of 4-membered saturated heteroalicyclic rings include, but are not limited to Examples of 5-membered saturated heteroalicyclic rings include, but are not limited to Examples of 6-membered saturated heteroalicyclic rings include, but are not limited to Examples of 7-membered saturated heteroalicyclic rings include, but are not limited to Examples of 5-membered unsaturated heteroalicyclic rings include, but are not limited to Examples of 6-membered unsaturated heteroalicyclic rings include, but are not limited to

[0058] The term "heteroalicyclic group" refers to the group remaining after removing one hydrogen atom from a "heteroalicyclic" molecule. The heteroalicyclic group may be unsubstituted or the hydrogen atoms therein may be optionally substituted with substituents, including but not limited to alkyl, alkoxy, =O, aryl, aralkyl, -COOH, -CN, amino, halogen and hydroxyl.

[0059] The present invention also provides a method for preparing the compound of the above formula, comprising the following synthesis scheme:

[0060] Synthesis Scheme 1:

[0061]

[0062] Compound 1-6 can be synthesized using Synthesis Scheme 1. 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine is reacted with an appropriate protecting agent to obtain intermediate 1-1. Intermediate 1-1 is reacted with sodium hydroxide solution to obtain intermediate 1-2. Intermediate 1-2 is reacted with iodomethane and a base to obtain intermediate 1-3. Intermediate 1-3 is reacted with a compound containing NH or borate to obtain intermediate 1-4. Intermediate 1-4 is deprotected to obtain intermediate 1-5. Intermediate 1-5 is reacted with N-iodosuccinimide to obtain compound 1-6.

[0063] Synthesis Scheme 2:

[0064]

[0065] Compound 2-5 can be synthesized using Synthesis Scheme 2. 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine reacts with N-iodosuccinimide to obtain iodinated intermediate 2-1. Intermediate 2-1 reacts with aqueous ammonia to obtain intermediate 2-2. Intermediate 2-2 reacts with an appropriate protective agent to obtain intermediate 2-3. Intermediate 2-3 is ring-closed with chloroacetaldehyde to obtain intermediate 2-4. Intermediate 2-4 reacts with a compound containing NH or borate to obtain compound 2-5.

[0066] Synthesis Scheme 3:

[0067]

[0068] Compound 3-3 can be synthesized by Synthesis Scheme 3. 6-Chloro-1H-pyrazolo[3,4-b]pyrazine reacts with N-iodosuccinimide to obtain iodinated intermediate 3-1. Intermediate 3-1 reacts with a suitable protecting agent to obtain intermediate 3-2. Intermediate 3-2 reacts with a compound containing NH or borate to obtain compound 3-3.

[0069] Synthesis Scheme 4:

[0070]

[0071] The final compound 4-1 can be synthesized by Synthesis Scheme 4. R1 represents terminal acetylene, boric acid or boric acid ester, thiol, R2 represents iodine or bromine, and the two raw materials react in the presence of a palladium catalyst and a base to obtain the product 4-1. If the group on 4-1 has a protecting group, the protecting group is removed by a corresponding method.

[0072] The above synthesis scheme only lists the preparation methods of some compounds in the present invention. According to the known technology in the art, technicians can also synthesize the compounds in the present invention by using similar methods based on the above synthesis scheme.

[0073] The compound of the present invention or a salt thereof can be administered alone as an active substance, or preferably in the form of a pharmaceutical composition thereof.

[0074] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I, II, III, IV or V or a pharmaceutically acceptable salt, solvate, polymorph, metabolite thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.

[0075] "Pharmaceutical composition" refers to a preparation of one or more compounds of the present invention or their salts with carriers generally accepted in the art for delivering biologically active compounds to organisms (eg, humans). The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention to an organism.

[0076] The term "pharmaceutically acceptable carrier" refers to those carriers that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" refers to an inert substance that is administered together with the active ingredient and is conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or animals (e.g., livestock). Non-limiting examples of the carrier include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0077] The administration of the compounds of the present invention or their pharmaceutically acceptable salts in pure form or in the form of suitable pharmaceutical compositions can be carried out by any acceptable mode of administration of medicaments of similar use. The pharmaceutical composition of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0078] Typical routes of administration of the compounds of the invention or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral administration.

[0079] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making sugar-coated pills methods, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0080] In a preferred embodiment, the pharmaceutical composition is in 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, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0081] Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by the following method: the active compound is mixed with a solid excipient, the mixture is optionally ground, other suitable adjuvants are added if necessary, and then the mixture is processed into particles to obtain the core of a tablet or a sugar-coated agent. Suitable adjuvants include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc. Such as microcrystalline cellulose, glucose solution, acacia gum, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol or dicalcium phosphate; silicon dioxide; cross-linked sodium carboxymethylcellulose, pre-cross-linked starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, etc. The core of the sugar-coated agent can be optionally coated according to methods known in common pharmaceutical practice, especially using enteric coatings.

[0082] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Appropriate excipients such as fillers, buffers or surfactants can be used.

[0083] Another aspect of the present invention relates to the use of compounds of Formula I to Formula VI or pharmaceutically acceptable salts, solvates, polymorphs, metabolites, etc., in drugs for treating diseases that benefit from SHP2 inhibition. The diseases that benefit from SHP2 inhibition are selected from cancer.

[0084] The substituted alkynyl heterocyclic compounds provided by the present invention have very good SHP2 inhibitory activity and are expected to become highly effective SHP2 inhibitor drugs. DETAILED DESCRIPTION

[0085] The following specific examples are intended to enable those skilled in the art to more clearly understand and implement the present invention. They should not be considered as limiting the scope of the present invention, but are merely exemplary and typical representations of the present invention. It will be appreciated by those skilled in the art that there are other synthetic pathways for forming the compounds of the present invention, and non-limiting examples are provided below.

[0086] All operations involving raw materials that are easily oxidized or hydrolyzed are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are directly purchased from the market and used directly without further purification.

[0087] Column chromatography used silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd. Thin layer chromatography used prefabricated plates (silica gel 60PF 254 Chiral compound separation and enantiomeric excess (ee) determination were performed using an Agilent LC 1200 series (column: CHIRALPAK AD-H, 4.6x250 mm, 5 μm, 30°C). Nuclear magnetic resonance chromatography (NMR) was measured using a Varian VNMRS-400 nuclear magnetic resonance instrument; liquid chromatography-mass spectrometry (LC / MS) was performed using a FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry C18, 4.6x50 mm, 5 μm, 35°C), using ESI (+) ion mode.

[0088] Experimental Section

[0089] Intermediate 1: (3S,4S)-3-Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine dihydrochloride

[0090]

[0091] (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.

[0092] Intermediate 2: 6-Chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-4(5H)- ketone

[0093]

[0094] Step 1: 4,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

[0095] 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (2.7 g), 3,4-dihydro-2H-pyran (2.4 g), p-toluenesulfonic acid (0.25 g) were added to tetrahydrofuran (25 mL), refluxed for 8 hours, cooled to room temperature, concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 10: 1) to obtain 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.0 g). MS m / z [LC-MS]: 273.03 [M+1].

[0096] Step 2: 6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

[0097] 4,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.0 g) and 20% sodium hydroxide solution (4 mL) were added to acetonitrile (40 mL), stirred at room temperature overnight, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 6: 1) to obtain 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (2.4 g). MS m / z[LC-MS]: 255.07[M+1]. 1 HNMR (400MHz, DMSO-d6): δ = 13.300 (1H, brs), 8.113 (1H, s), 5.693 (1H, m), 3.908 (1H, m) , 3.645(1H,m), 2.286(1H,m), 1.967(1H,m), 1.820(1H,m), 1.708(1H,m), 1.523(2H,m).

[0098] Step 3: 6-Chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

[0099] 6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (2.4 g) and potassium carbonate (3.8 g) were added to N,N-dimethylformamide (40 mL), and then iodomethane (1.0 mL) was added dropwise and stirred at room temperature for 4 hours. The reaction solution was poured into 200 mL of water and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 8: 1) to obtain 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (1.8 g). MS m / z[LC-MS]: 269.08[M+1].1 HNMR (400MHz, DMSO-d6): δ = 8.150 (1H, s), 5.710 (1H, m), 3.911 (1H, m), 3.659 (1H, m), 3.567 (3H, s), 2.310 (1H, m), 1.974 (1H, m), 1.822 (1H, m), 1.708 (1H, m), 1.530 (2H, m).

[0100] Intermediate 3: 9-iodo-5-chloro-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine

[0101]

[0102] Step 1: 3-iodo-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine

[0103] 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (4.0 g) and N-iodosuccinimide (5.72 g) were added to acetonitrile (25 mL), heated to 100°C for microwave reaction for 25 minutes, cooled to room temperature, concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 8: 1) to obtain 3-iodo-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (5.4 g). MS m / z [LC-MS]: 314.87 [M+1].

[0104] Step 2: 3-iodo-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0105] 3-iodo-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (1.2 g) and concentrated aqueous ammonia (25%-28%, 2 mL) were added to acetonitrile (20 mL), stirred at room temperature overnight, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 3:1) to obtain 3-iodo-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.1 g). MS m / z [LC-MS]: 295.92 [M+1].

[0106] Step 3: 3-iodo-6-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0107] 3-iodo-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.1 g) and potassium carbonate (1.3 g) were added to N,N-dimethylformamide (20 mL), and then 4-methoxybenzyl chloride (0.5 mL) was added dropwise and stirred at room temperature for 2 hours. The reaction solution was poured into 150 mL of water and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 4:1) to obtain 3-iodo-6-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.90 g). MS m / z[LC-MS]: 415.98[M+1].

[0108] Step 4: 9-iodo-5-chloro-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine

[0109] 3-iodo-6-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (700 mg) and chloroacetaldehyde (2 mL) were added to acetonitrile (20 mL), heated to 100°C and sealed for reaction for 5 hours, poured into water, adjusted the pH value to 9-10 with saturated sodium carbonate aqueous solution, extracted with dichloromethane, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 8: 1) to obtain 9-iodo-5-chloro-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine (460 mg). MS m / z[LC-MS]: 439.98[M+1]. 1 HNMR (400MHz, DMSO-d6): δ=8.097 (1H, d, J=1.6Hz), 7.629 (1H, d, J=1.6Hz), 7.261 (2H, d, J=8.4Hz), 6.898 (2H, d, J=8.4Hz), 5.381 (2H, s), 3.72 (3H, s).

[0110] Intermediate 4: 6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyrazine

[0111]

[0112] 6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyrazine was synthesized according to the method of the same intermediate in Example 29 on page 83 of patent WO2018057884.

[0113] Intermediate 5: 1-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4- Tert-butyl methylpiperidin-4-ylcarbamate

[0114]

[0115] Step 1: tert-Butyl 4-methyl-1-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate

[0116] Intermediate 2 (538 mg), tert-butyl 4-methylpiperidin-4-ylcarbamate (514 mg), and diisopropylethylamine (1 mL) were added to tetrahydrofuran (20 mL), heated to 120° C. and stirred for 2 hours, and the solvent was removed by rotary evaporation under reduced pressure. The product was separated by silica gel column chromatography (petroleum ether: ethyl acetate, 5: 1) to obtain tert-butyl 4-methyl-1-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate (800 mg). MS m / z [LC-MS]: 447.27 [M+1].

[0117] Step 2: tert-Butyl 4-methyl-1-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate

[0118] 4-Methyl-1-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamic acid tert-butyl ester (445 mg) was added to methanol (10 mL), and then 1M hydrochloric acid solution (2 mL) was added, and stirred at room temperature overnight, and the pH value was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution, and the organic solvent was removed by rotary evaporation, and then extracted with ethyl acetate. The extract was dried and concentrated, and then separated by silica gel column chromatography (petroleum ether: ethyl acetate, 4: 1) to obtain 4-methyl-1-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamic acid tert-butyl ester (305 mg). MS m / z [LC-MS]: 363.22 [M+1].

[0119] Step 3: tert-Butyl 1-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-ylcarbamate

[0120] 4-Methyl-1-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamic acid tert-butyl ester (300 mg) and N-iodosuccinimide (177 mg) were added to acetonitrile (5 mL), heated to 100° C. for microwave reaction for 25 minutes, cooled to room temperature, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 4:1) to obtain 1-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-ylcarbamic acid tert-butyl ester (320 mg). MS m / z[LC-MS]: 489.11[M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 13.545 (1H, s), 6.583 (1H, s), 3.317 (3H, s), 3.168 ( 2H, m), 2.994 (2H, m), 2.102 (1H, m), 1.529 (2H, m), 1.356 (9H, s), 1.230 (3H, s).

[0121] Intermediate 6: ((3S,4S)-8-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine- tert-Butyl 6-(6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0122]

[0123] Step 1: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0124] Referring to the method of step 1 in intermediate 5, intermediate 1 was used to replace tert-butyl 4-methylpiperidin-4-ylcarbamate to obtain 6-((3S, 4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one. MS m / z[LC-MS]: 403.25[M+1].

[0125] Step 2: tert-Butyl ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0126] 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (400 mg) and triethylamine (500 mg) were added to dichloromethane (10 mL), and di-tert-butyl dicarbonate (260 mg) was added dropwise under ice-water cooling. After the addition was complete, the mixture was heated to room temperature and stirred. The mixture was stirred for 4 hours, washed with water and saturated brine in sequence, and the organic phase was dried and concentrated, and then separated by silica gel column chromatography (petroleum ether: ethyl acetate, 4: 1) to obtain tert-butyl ((3S, 4S)-3-methyl-8-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (420 mg). MSm / z[LC-MS]: 503.3[M+1].

[0127] Step 3: tert-Butyl ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0128] Referring to the method of step 2 in intermediate 5, 4-methyl-1-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamic acid tert-butyl ester was used instead of 4-methyl-1-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate. =Tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamic acid tert-butyl ester to obtain ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamic acid tert-butyl ester. MS m / z[LC-MS]: 419.24[M+1].

[0129] Step 4: tert-Butyl ((3S,4S)-8-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0130] Referring to the method of step 3 in intermediate 5, tert-butyl ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate was used to replace tert-butyl 4-methyl-1-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate to obtain tert-butyl ((3S,4S)-8-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate. MS m / z[LC-MS]: 545.14[M+1]. 1 HNMR (400MHz, DMSO-d6): δ = 13.562 (1H, s), 6.988 (1H, s), 4.134 (1H, m), 3.848 (1H, m), 3.638 (1H, d, J = 8.4Hz), 3.487 (1H, d, J = 8.4Hz), 3.328 (3H, s), 3.184 (1H, m), 3.092 (2H, m), 1.62-1.76 (3H, m), 1.50-1.60 (1H, m), 1.37 (9H, s), 0.994 (3H, d, J = 6.0Hz).

[0131] Intermediate 7: ((3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3- e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

[0132]

[0133] Step 1: (3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0134] Referring to the method of step 1 in intermediate 5, intermediate 3 was used to replace intermediate 2, and intermediate 1 was used to replace tert-butyl 4-methylpiperidin-4-ylcarbamate to obtain (3S, 4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine. MS m / z[LC-MS]: 574.14[M+1].

[0135] Step 2: tert-Butyl ((3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0136] Referring to the procedure of step 2 of intermediate 6, substituting (3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine for 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-thiazolyl-2-ol -5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one to give ((3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamic acid tert-butyl ester. MS m / z[LC-MS]: 674.2[M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.707 (1H, d, J=1.2Hz), 7.437 (1H, d, J=1.2Hz), 7.251 (2H, d, J=8.4Hz), 6.850 (2H, d, J=8.4Hz), 5.391 (2H, s), 4 .163(1H,m), 3.913(1H,m), 3.673(3H,s), 3.35-3.55(6H,m), 1.72-1.90(3H,m), 1.60-1.72(1H,m), 1.352(9H,s), 1.007(3H,d,J=6.4Hz).

[0137] Intermediate 8: ((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine- tert-Butyl 6-(6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0138]

[0139] Step 1: (3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0140] Referring to the method of step 1 in intermediate 5, intermediate 4 was used to replace intermediate 2, and intermediate 1 was used to replace tert-butyl 4-methylpiperidin-4-ylcarbamate to obtain (3S, 4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine. MS m / z[LC-MS]: 499.13[M+1].

[0141] Step 2: tert-Butyl ((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0142] Referring to the procedure of step 2 of intermediate 6, substituting (3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine for 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine -5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one to give ((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamic acid tert-butyl ester. MS m / z [LC-MS]: 599.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.410 (1H, s), 6.988 (1H, s), 5.71 (1H, m), 4.14 (1H, m), 3.84-3.92 (2H, m), 3.65 (2H, m), 3.472 (1H, d, J = 8.4 Hz), 3.18 (1H, m), 3.09 (2H, m), 2.31 (1H, m), 1.98 (1H, m), 1.62-1.83 (5H, m), 1.49-1.60 (3H, m), 1.38 (9H, s), 1.004 (3H, d, J = 6.0Hz).

[0143] Intermediate 9: ((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine- tert-Butyl 6-(6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0144]

[0145] Step 1: 8-Bromo-7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine

[0146] 5-Bromo-6-chloro-2-(methylthio)pyrimidin-4-amine (1.0 g) and 40% chloroacetaldehyde aqueous solution (1.2 mL) were dissolved in dioxane (6 mL), refluxed for 14 hours under nitrogen protection, cooled to room temperature and filtered to obtain 8-bromo-7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine (900 mg). MS m / z [LC-MS]: 277.92 [M+1].

[0147] Step 2: 8-Bromo-7-chloro-5-(methylsulfinyl)imidazo[1,2-c]pyrimidine

[0148] 8-Bromo-7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine (557 mg) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (85%, 487 mg) was added. The mixture was stirred at room temperature for 6 hours. The reaction solution was washed with saturated sodium bicarbonate aqueous solution, water, and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The mixture was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 5: 1) to obtain 8-bromo-7-chloro-5-(methylsulfinyl)imidazo[1,2-c]pyrimidine (420 mg). MS m / z[LC-MS]: 293.91[M+1].

[0149] Step 3: (3S,4S)-8-(8-bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0150] Referring to the method of step 1 in intermediate 5, 8-bromo-7-chloro-5-(methylsulfinyl)imidazo[1,2-c]pyrimidine was used to replace intermediate 2, and intermediate 1 was used to replace tert-butyl 4-methylpiperidin-4-ylcarbamate to obtain (3S,4S)-8-(8-bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine. MS m / z[LC-MS]: 400.06[M+1].

[0151] Step 4: tert-Butyl ((3S,4S)-8-(8-bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate

[0152] Referring to the method of step 2 in intermediate 6, (3S,4S)-8-(8-bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine was used to replace 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one to obtain tert-butyl ((3S,4S)-8-(8-bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate. MS m / z[LC-MS]: 500.11[M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.79 (1H, d, J=1.6Hz), 7.62 (1H, d, J=1.6Hz),

[0153] Intermediate 10: 2-Ethynyl-1,1-difluorocyclopropane

[0154]

[0155] 2-Ethynyl-1,1-difluorocyclopropane was synthesized according to the method of intermediate 3.1.35d in patent WO2015066413.

[0156] Intermediate 11: 1-Ethynyl-1-methylcyclopropane

[0157]

[0158] 1-Ethynyl-1-methylcyclopropane was synthesized according to the method of Example 4 in patent WO2011059784.

[0159] Intermediate 12: (2-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl (Alkynyl)trimethylsilane

[0160]

[0161] Step 1: (2-(3-bromo-2-chlorophenyl)ethynyl)trimethylsilane

[0162] 1-Bromo-2-chloro-3-iodobenzene (560 mg), ethynyltrimethylsilane (196 mg), cuprous iodide (34 mg), bis(triphenylphosphine)palladium dichloride (121 mg) and triethylamine (533 mg) were added to tetrahydrofuran (10 mL), and the air in the reaction system was replaced with high-purity nitrogen three times. The reaction mixture was refluxed for 12 hours, cooled to room temperature, concentrated under reduced pressure and separated by silica gel column chromatography (with n-hexane as eluent) to obtain (2-(3-bromo-2-chlorophenyl)ethynyl)trimethylsilane (424 mg). 1 HNMR (400MHz, CDCl3): δ=7.55 (1H, m), 7.43 (1H, m), 7.03 (1H, m), 0.25 (9H, m).

[0163] Step 2: (2-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethynyl)trimethylsilane

[0164] (2-(3-bromo-2-chlorophenyl)ethynyl)trimethylsilane (232 mg), pinacol diboron (244 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride (56 mg) and anhydrous potassium acetate (157 mg) were added to dioxane (2 mL), and the air in the reaction system was replaced with high-purity nitrogen three times, heated to 90° C. for 12 hours, and the reaction mixture was directly used for the next coupling reaction without treatment. MS m / z [LC-MS]: 335.14 [M+1].

[0165] Intermediate 13: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-spiro[benzofuran- 2,1′-cyclopropane]-3-one

[0166]

[0167] The raw material 5-bromo-3H-spiro[benzofuran-2,1′-cyclopropane]-3-one was synthesized according to the reference Chemical and Pharmaceutical Bulletin; vol. 32; nb. 9; (1984); p. 3532-3550.

[0168] 5-Bromo-3H-spiro[benzofuran-2,1′-cyclopropane]-3-one was reacted according to the method of step 2 of intermediate 12 to obtain the corresponding boronate ester, and the reaction mixture was directly used for the next coupling reaction without treatment. MS m / z [LC-MS]: 287.15 [M+1].

[0169] Intermediate 14: 2-(3-Chloro-[1,1′-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane alkyl

[0170]

[0171] The raw material 4-bromo-3-chloro-1,1′-biphenyl was synthesized according to the document Journal of the Chemical Society; (1964); p. 3786-3790.

[0172] 4-Bromo-3-chloro-1,1′-biphenyl was reacted according to the method of step 2 of intermediate 12 to obtain the corresponding borate ester, and the reaction mixture was directly used for the next coupling reaction without treatment. MS m / z [LC-MS]: 315.13 [M+1].

[0173] Intermediate 15: ((3S,4S)-8-(3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)oxy)methyl) 1H-pyrazolo[4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl) tert-Butyl)carbamate

[0174]

[0175] The starting intermediate (6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine-5-yl)methanol was synthesized according to the same method as Preparation 179 on page 237 of patent WO2019167000.

[0176] Step 1: 6-Chloro-3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine

[0177] The intermediate (6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine-5-yl)methanol (2.28 g), triisopropylsilyl chloride (1.49 g) and imidazole (693 mg) were added to dichloromethane (40 mL) and stirred at room temperature overnight. The reaction solution was washed with water, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The mixture was separated 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].

[0178] 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]decan-4-amine

[0179] 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), and intermediate 1 (1.32 g) and diisopropylethylamine (5 mL) were added. The mixture was heated to 120° C. and stirred for 2 hours. The mixture was cooled to room temperature and the organic solvent was removed by rotary evaporation. The mixture was separated by silica gel column chromatography (dichloromethane: methanol, 10:1) to give (3S,4S)-8-(3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (2.82 g). MS m / z [LC-MS]: 731.3 [M+1].

[0180] Step 3: tert-Butyl ((3S,4S)-8-(3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0181] (3S,4S)-8-(3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (2.80 g) was added to dichloromethane (30 mL), and diisopropylethylamine (2 mL) was added, and di-tert-butyl dicarbonate (1.25 g) was added dropwise under ice-water cooling, and then the mixture was added dropwise. After the addition was completed, the temperature was raised to room temperature and stirred for 4 hours. The organic solvent was removed by rotary evaporation and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 8: 1) to give tert-butyl ((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-yl)carbamate (3.05 g). MS m / z[LC-MS]: 831.35[M+1].

[0182] Intermediate 16: tert-butyl ((3S,4S)-8-(5-(fluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0183]

[0184] Step 1: tert-Butyl ((3S,4S)-8-(5-(hydroxymethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0185] Intermediate 15 (1.66 g) and tetrabutylammonium fluoride (670 mg) were added to tetrahydrofuran (20 mL), stirred at room temperature for 2 hours, and the organic solvent was removed by rotary evaporation. The residue was partitioned between water and ethyl acetate, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was separated by silica gel column chromatography (petroleum ether: ethyl acetate, 5: 1) to obtain tert-butyl ((3S, 4S)-8-(5-(hydroxymethyl)-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)carbamate (1.25 g). MS m / z [LC-MS]: 675.22 [M+1].

[0186] Step 2: tert-Butyl ((3S,4S)-8-(5-(fluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0187] Tert-butyl ((3S,4S)-8-(5-(hydroxymethyl)-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)carbamate (1.25 g) was added to dichloromethane (15 mL), and diethylaminosulfur trifluoride (358 mg) was added dropwise under ice-water cooling until the addition was complete. The temperature was then raised to room temperature and stirred for 1 hour, the organic solvent was removed by rotary evaporation, and the mixture was separated by silica gel column chromatography (petroleum ether: ethyl acetate, 8: 1) to give tert-butyl ((3S, 4S)-8-(5-(fluoromethyl)-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)carbamate (1.06 g). MS m / z [LC-MS]: 677.22 [M+1].

[0188] Embodiment 1: 6-(4-amino-4-methylpiperidin-1-yl)-3-(2-(2-chlorophenyl)ethynyl)-5-methyl-1H- Pyrazolo[3.4-d]pyrimidin-4(5H)-one

[0189]

[0190] Step 1: tert-Butyl 1-(3-(2-((2-chlorophenyl)ethynyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate

[0191] Intermediate 5 (150 mg), 1-chloro-2-ethynylbenzene (50 mg), cuprous iodide (12 mg), triethylamine (100 mg), bis(triphenylphosphine)palladium dichloride (21 mg) and tetrahydrofuran (10 mL) were added to a sealed tube, replaced with nitrogen, heated to 80°C and stirred overnight. The mixture was cooled to room temperature, poured into water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 6: 1) to obtain tert-butyl 1-(3-((2-(2-chlorophenyl)ethynyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate (75 mg). MS m / z [LC-MS]: 498.0 [M+1].

[0192] Step 2: 6-(4-amino-4-methylpiperidin-1-yl)-3-(2-(2-chlorophenyl)ethynyl)-5-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

[0193] Tert-butyl 1-(3-(2-((2-chlorophenyl)ethynyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate (70 mg) was added to a 4M solution of hydrogen chloride in dioxane (3 mL), stirred at room temperature for 1 hour, spin-dried, added with 10% aqueous sodium carbonate solution (10 mL), extracted with dichloromethane, and the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by thin layer silica gel chromatography (dichloromethane: methanol, 10: 1) to give 6-(4-amino-4-methylpiperidin-1-yl)-3-(2-(2-chlorophenyl)ethynyl)-5-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (35 mg). MS m / z[LC-MS]: 397.16[M+1]. 1HNMR (400MHz, DMSO-d6): δ=7.70-8.40 (3H, brs), 7.66 (1H, dd, J=8.0Hz, 1.6Hz), 7.59 (1H, d, J=8.0Hz), 7.46 (1H, td, J=8.0H z, 1.6Hz), 7.41 (1H, t, J = 8.0Hz), 3.36-3.46 (5H, m), 3.08-3.16 (2H, m), 1.83-1.91 (2H, m), 1.72-1.80 (2H, m), 1.34 (3H, s).

[0194] Embodiment 2: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2,4-Difluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0195]

[0196] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 455.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.2-13.9 (1H, brs), 7.69 (1H, td, J=8.4Hz, 6.4Hz), 7.45 (1 H, td, J=9.6Hz, 2.8Hz), 7.19 (1H, td, J=8.4Hz, 2.8Hz), 6.71-6.84 (2H, brs), 4.13-4.1 7 (1H, m), 3.79 (1H, d, J = 8.8Hz), 3.59 (1H, d, J = 8.8Hz), 3.34-3.48 (6H, m), 2.85-2.96 ( 2H, m), 1.82-1.91 (2H, m), 1.66-1.73 (1H, m), 1.56-1.62 (1H, m), 1.17 (3H, d, J=6.4Hz).

[0197] Embodiment 3: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-Chlorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0198]

[0199] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 453.18 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.66 (1H, dd, J=7.6Hz, 2.0Hz), 7.59 (1H, dd, J=8.0Hz, 1.6Hz), 7.4 6(1H, td, J=7.6Hz, 1.6Hz), 7.41(1H, td, J=7.6Hz, 1.6Hz), 6.71-6.84(3H, brs), 4.01-4.08( 1H, m), 3.64 (1H, d, J = 8.8Hz), 3.47 (1H, d, J = 8.8Hz), 3.39 (3H, s), 3.22-3.34 (2H, m), 2.90-3 .07(3H,m), 1.79-1.87(1H,m), 1.69-1.78(1H,m), 1.50-1.63(2H,m), 1.06(3H,d,J=6.0Hz).

[0200] Embodiment 4: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((3-Chlorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0201]

[0202] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 453.18 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.60 (1H, t, J=2.0Hz), 7.45-7.54 (3H, m), 4.01-4.06 (1H, m), 3.63 (1H, d, J=8.4Hz), 3.46 (1H, d, J=8.4Hz) , 3.39 (3H, s), 3.26-3.34 (2H, m), 2.89-3.07 (3H, m), 1.80-1.86 (1H, m), 1.69-1.77 (1H, m), 1.51-1.61 (2H, m), 1.06 (3H, d, J = 6.4Hz).

[0203] Embodiment 5: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-Methoxyphenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0204]

[0205] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 449.23 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=12.80-13.80 (1H, brs), 7.46 (1H, dd, J=7.6Hz, 1.6Hz), 7.41 (1H, td, J=7.6Hz, 1.6Hz), 7.09 (1H, d, J=8.4Hz), 6.98 (1H, t, J=7.6Hz), 4.01-4.08 (1H, m), 3.84 ( 3H, s), 3.64 (1H, d, J = 8.8Hz), 3.47 (1H, d, J = 8.8Hz), 3.38 (3H, s), 3.26-3.34 (2H, m), 2.88-3 .05(3H,m), 1.79-1.88(1H,m), 1.69-1.76(1H,m), 1.50-1.62(2H,m), 1.07(3H,d,J=6.0Hz).

[0206] Embodiment 6: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-(phenylethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0207]

[0208] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 419.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 7.54-7.57 (2H, m), 7.42-7.47 (3H, m), 4.03-4.09 (1H, m), 3.66 (1H, d, J = 8.4Hz), 3.49 (1H, d, J = 8.4Hz), 3 .39(3H,s), 3.26-3.35(2H,m), 2.90-3.04(3H,m), 1.82-1.88(1H,m), 1.72-1.78(1H,m), 1.52-1.64(2H,m), 1.08(3H,d,J=6.8Hz).

[0209] Embodiment 7: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-Fluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0210]

[0211] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 437.21 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.62 (1H, td, J=7.6Hz, 1.6Hz), 7.47-7.53 (1H, m), 7. 35 (1H, t, J = 8.8Hz), 7.28 (1H, t, J = 8.0Hz), 4.01-4.07 (1H, m), 3.63 (1H, d, J = 8.4 Hz), 3.46 (1H, d, J = 8.4Hz), 3.39 (3H, s), 3.25-3.34 (2H, m), 2.88-3.07 (3H, m), 1.80-1.87 (1H, m), 1.68-1.76 (1H, m), 1.50-1.62 (2H, m), 1.06 (3H, d, J=6.0Hz).

[0212] Embodiment 8: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((3-Aminophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0213]

[0214] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 434.23 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.3-13.8 (1H, brs), 7.05 (1H, t, J=8.0Hz), 6.73 (1 H, s), 6.65 (1H, d, J = 7.6Hz), 6.61 (1H, d, J = 7.6Hz), 5.30 (2H, s), 4.08-4.16 (1H , m), 3.75 (1H, d, J = 8.8Hz), 3.54 (1H, d, J = 8.8Hz), 3.39 (3H, s), 3.26-3.37 (3H, m), 2.88-2.98 (2H, m), 1.80-1.90 (2H, m), 1.56-1.70 (2H, m), 1.14 (3H, 5.6Hz).

[0215] Embodiment 9: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-(pyridin-3-ylethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0216]

[0217] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 420.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.71 (1H, s), 8.74 (1H, s), 8.62 (1H, d, J=4.8Hz), 7.9 6-8.04 (3H, m), 7.49 (1H, dd, J = 8.0hz, 4.8Hz), 4.16-4.22 (1H, m), 3.83 (1H, d, J = 9 .2Hz), 3.64 (1H, d, J=9.2Hz), 3.40-3.50 (3H, m), 3.39 (3H, s), 2.84-2.94 (2H, m) , 1.82-1.92(2H,m), 1.70-1.76(1H,m), 1.58-1.64(1H,m), 1.20(3H,d,J=6.0Hz).

[0218] Embodiment 10: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-(pyridin-4-ylethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0219]

[0220] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 420.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.65 (2H, d, J=5.6Hz), 7.51 (2H, d, J=5.6Hz), 4.10-4.16 (1H, m), 3.77 (1H, d, J=8.8Hz), 3.56 (1H, d, J=8.8Hz ), 3.40 (3H, s), 3.22-3.32 (3H, m), 2.87-2.99 (2H, m), 1.80-1.90 (2H, m), 1.65-1.70 (1H, m), 1.55-1.61 (1H, m), 1.15 (3H, d, J = 6.4Hz).

[0221] Embodiment 11: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((3,5-Dimethoxyphenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0222]

[0223] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 479.24 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 13.48-13.80 (1H, brs), 6.68 (2H, s), 6.58 (1H, s), 4.08-4.16 (1H, m), 3.76 (6H, s), 3.74 (1H, d, J = 8.8Hz), 3.56 (1H, d, J = 8.8Hz), 3.35-3.43 (5H, m), 3.16-3.22 (1H, m), 2.86-2.99 (2H, m), 1.78-1 .88(2H,m), 1.64-1.69(1H,m), 1.54-1.61(1H,m), 1.14(3H,d,J=6.4Hz).

[0224] Embodiment 12: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0225]

[0226] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 401.23 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 13.36-13.48 (1H, brs), 5.52 (1H, s), 4.08-4.14 (1H, m), 3.73 (1H, d, J = 8.8Hz), 3.55 (1H, d, J = 8.8Hz), 3.37 (3H , s), 3.11-3.21 (2H, m), 2.84-2.96 (3H, m), 1.77-1.86 (2H, m), 1.63-1.67 (1H, m), 1.54-1.58 (1H, m), 1.45 (6H, s), 1.13 (3H, d, J = 6.4Hz).

[0227] Embodiment 13: 4-((6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)- 5-Methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)benzonitrile

[0228]

[0229] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 444.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.91 (2H, d, J=8.0Hz), 7.73 (2H, d, J=8.0Hz), 4.06-4.13 (1H, m), 3.72 (1H, d, J=8.8Hz), 3.53 (1H, d, J=8.8Hz), 3.40 (3 H, s), 3.34-3.38 (2H, m), 3.09-3.13 (1H, m), 2.89-3.01 (2H, m), 1.77-1. 88 (2H, m), 1.62-1.66 (1H, m), 1.54-1.58 (1H, m), 1.12 (3H, d, J=6.8Hz).

[0230] Embodiment 14: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((4-Chlorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0231]

[0232] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 453.18 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.57 (2H, d, J=8.0Hz), 7.51 (2H, d, J=8.0Hz), 4.08-4.14 (1H, m), 3.74 (1H, d, J=8.8Hz), 3.54 (1H, d, J=8.8Hz), 3.39 (3 H, s), 3.34-3.38 (2H, m), 3.15-3.18 (1H, m), 2.87-2.99 (2H, m), 1.79-1. 89 (2H, m), 1.63-1.67 (1H, m), 1.55-1.59 (1H, m), 1.14 (3H, d, J=6.0Hz).

[0233] Embodiment 15: (3S,4S)-8-(3-((2-chlorophenyl)ethynyl)- 1 H-pyrazolo[4,3-b]pyrazin-6-yl)-3- Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0234]

[0235] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 423.17 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=8.30 (1H, s), 7.68 (1H, dd, J=7.2Hz, 2.0Hz), 7.43 (1H , d, J=8.0Hz), 7.23-7.32(2H,m), 4.17-4.22(1H,m), 3.96-4.06(2H,m), 3.82(1H , d, J=8.4Hz), 3.70 (1H, d, J=8.4Hz), 3.52-3.59 (1H, m), 3.42-3.49 (1H, m), 3.0 1(1H,d,J=4.0Hz), 1.88-2.03(2H,m), 1.67-1.79(2H,m), 1.24(3H,d,J=6.8Hz).

[0236] Embodiment 16: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (3-Amino-3-methylbut-1-yn-1-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0237]

[0238] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 400.25 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.33-13.46 (1H, brs), 4.08-4.14 (1H, m), 3.73 (1H, d, J=8.8Hz), 3.55 (1H, d, J=8.8Hz), 3.37 (3H, s), 3 .11-3.21(2H,m), 2.85-2.96(3H,m), 1.76-1.86(2H,m), 1.63-1.67(1H,m), 1.54-1.59(1H,m), 1.43(6H,s), 1.14(3H,d,J=6.4Hz).

[0239] Embodiment 17: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-((thiophen-2-yl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0240]

[0241] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 425.18 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.71 (1H, dd, J=5.2Hz, 0.8Hz), 7.45 (1H, dd, J=3.6Hz, 0.8 Hz), 7.14 (1H, dd, J = 5.2Hz, 3.6Hz), 4.07-4.13 (1H, m), 3.72 (1H, d, J = 8.8Hz), 3.53 (1 H, d, J = 8.8Hz), 3.39 (3H, s), 3.32-3.38 (2H, m), 3.11 (1H, d, J = 5.2Hz), 2.88-2.99 (2H , m), 1.77-1.88 (2H, m), 1.61-1.66 (1H, m), 1.53-1.58 (1H, m), 1.12 (3H, d, J=6.8Hz).

[0242] Embodiment 18: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-Aminophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0243]

[0244] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 434.23 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.21 (1H, d, J=8.0Hz), 7.09 (1H, t, J=8.0Hz), 6.71 (1H, d, J=8.4H z), 6.51 (1H, t, J = 7.2Hz), 6.01 (2H, s), 4.41-4.46 (1H, m), 4.12-4.20 (1H, m), 3.82 (1H, d, J =8.4Hz), 3.58 (1H, d, J = 8.4Hz), 3.45-3.49 (1H, m), 3.42 (3H, s), 3.13-3.15 (1H, m), 2.85-2 .95(2H,m), 1.84-1.98(2H,m), 1.66-1.72(2H,m), 1.58-1.63(2H,m), 1.19(3H,d,J=6.4Hz).

[0245] Embodiment 19: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (Cyclopropylethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0246]

[0247] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 383.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.20-13.58 (1H, brs), 4.02-4.08 (1H, m), 3.90- 4.00 (1H, m), 3.65 (1H, d, J = 8.4Hz), 3.47 (1H, d, J = 8.4Hz), 3.35 (3H, s), 3.24 -3.30(1H,m), 3.11-3.15(1H,m), 2.86-2.99(3H,m), 1.70-1.85(2H,m), 1.5 0-1.62 (2H, m), 1.08 (3H, d, J=6.4Hz), 0.91-0.94 (2H, m), 0.75-0.83 (2H, m).

[0248] Embodiment 20: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((3-Amino-4-fluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0249]

[0250] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 452.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.07 (1H, d, J=8.0Hz), 6.94-6.99 (1H, m), 6.87-6.91 (1H, m), 4.26-4.32 (1H, m), 3.93 (1H, d, J=8.0Hz), 3.82 ( 1H, d, J = 8.4Hz), 3.47-3.58 (5H, m), 3.39-3.42 (1H, m), 2.96-3.08 (2H, m), 1.86-2.02 (3H, m), 1.71-1.75 (1H, m), 1.30 (3H, d, J = 7.2Hz).

[0251] Embodiment 21: 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3- ((2-Cyanophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0252]

[0253] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 444.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 7.75 (1H, d, J = 8.0Hz), 7.63-7.68 (1H, m), 7.51-7.58 (1H, m), 7.45 (1H, m), 4.14-4.20 (1H, m), 3.81 (1H, d, J=8.8Hz), 3.68 (1H, d, J=8.8Hz), 3.53 (3H, s), 3.30-3.43 (2H, m), 2.94-3.16 (3H, m), 1.52-1.86 (4H, m), 0.86 (3H, d, J=6.4Hz).

[0254] Embodiment 22: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-((2-(trifluoromethyl)phenyl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0255]

[0256] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 487.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.82(1H,d,J=7.6Hz), 7.68(1H,d,J=8.4Hz), 7.52(1H,m), 7.44(1H,m), 4.13-4.19(1H,m), 3.79(1H,d , J=8.8Hz), 3.67 (1H, d, J=8.8Hz), 3.53 (3H, s), 3.31-3.41 (2H, m), 2.98-3.16 (3H, m), 1.46-1.90 (4H, m), 0.95 (3H, d, J=6.8Hz).

[0257] Embodiment 23: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2,6-Difluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0258]

[0259] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 455.2 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.51-7.59 (1H, m), 7.22-7.27 (2H, m), 4.04-4.1 1 (1H, m), 3.69 (1H, d, J = 8.4Hz), 3.51 (1H, d, J = 8.8Hz), 3.38 (3H, s), 3.32- 3.6(1H,m), 3.11-3.15(1H,m), 3.05-3.08(1H,m), 2.88-3.01(2H,m), 1.73 -1.86 (2H, m), 1.60-1.66 (1H, m), 1.52-1.58 (1H, m), 1.10 (3H, d, J = 6.4Hz).

[0260] Embodiment 24: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-(prop-1-yn-1-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0261]

[0262] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 357.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.12-13.58 (1H, brs), 4.02-4.08 (1H, m), 3.65 (1H, d, J=8.4Hz), 3.47 (1H, d, J=8.4Hz), 3.35 (3H, s), 3 .24-3.30(1H,m), 3.11-3.15(1H,m), 2.86-2.99(3H,m), 2.05(3H,s), 1.70-1.85(2H,m), 1.50-1.62(2H,m), 1.07(3H,d,J=6.4Hz).

[0263] Embodiment 25: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (Imidazolo[1,2-b]pyridazin-3-ylethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0264]

[0265] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 460.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.66-1.84 (1H, brs), 8.67 (1H, dd, J=4.8Hz, 2.4Hz), 8.24 (1H, dd, J=8 .8Hz, 1.6Hz), 8.19 (1H, s), 7.37 (1H, dd, J=8.8Hz, 4.8Hz), 4.40-4.43 (1H, m), 4.16-4.20 (1H, m), 3 .83 (1H, d, J = 8.8Hz), 3.62 (1H, d, J = 8.8Hz), 3.43-3.50 (1H, m), 3.39 (3H, s), 3.34-3.36 (1H, m), 2 .85-2.94(2H,m), 1.85-1.94(2H,m), 1.70-1.73(1H,m), 1.58-1.62(1H,m), 1.19(3H,d,J=6.4Hz).

[0266] Embodiment 26: (3S,4S)-8-(9-((2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3- e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0267]

[0268] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 446.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.71(1H,m), 7.68(1H,t,J=8.0Hz), 7.50-7.55(2H,m), 7.37(1H,t,J=8.0Hz), 7.31(1H,t,J=8.0Hz), 4.11-4.16(1H,m ), 3.76 (1H, d, J = 8.0Hz), 3.58-3.64 (2H, m), 3.14-3.32 (4H, m), 1.89-1. 99 (2H, m), 1.72-1.77 (1H, m), 1.62-1.68 (1H, m), 1.14 (3H, d, J=6.8Hz).

[0269] Embodiment 27: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-ethyl Alkynyl-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0270]

[0271] Step 1: tert-Butyl ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-3-((trimethylsilyl)ethynyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0272] Referring to the method of step 1 in Example 1, intermediate 6 was used instead of intermediate 5, and trimethylsilyl acetylene was used instead of 1-chloro-2-ethynylbenzene to obtain the target compound. MS m / z [LC-MS]: 515.28 [M+1].

[0273] Step 2: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-ethynyl-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0274] Dissolve tert-butyl ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-3-((trimethylsilyl)ethynyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (40 mg) in dichloromethane (1 mL), add 1M tetrabutylammonium fluoride tetrahydrofuran solution (0.5 mL), and stir at room temperature for 0.5 hours. Then add 4M hydrogen chloride dioxane solution (3 mL), stir at room temperature for 1 hour, spin dry, add 10% sodium carbonate aqueous solution (10 mL), extract with dichloromethane, dry the extract with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate by thin layer silica gel chromatography to obtain the target compound (15 mg). MS m / z[LC-MS]: 343.19[M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 13.29-13.74 (1H, brs), 4.35 (1H, s), 4.05-4.12 (1H, m), 3.70 (1H, d, J = 8.8Hz), 3.52 (1H, d, J = 8.8Hz), 3.36 (3H, s) ), 3.22-3.35(2H,m), 3.08-3.12(1H,m), 2.86-2.98(2H,m), 1.74-1.88(2H,m), 1.60-1.64(1H,m), 1.52-1.56(1H,m), 1.11(3H,d,J=6.0Hz).

[0275] Embodiment 28: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-(3,3,3-trifluoroprop-1-yn-1-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0276]

[0277] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 452.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 4.06-4.12 (1H, m), 3.71 (1H, d, J = 8.8Hz), 3.52 (1H, d, J = 8.8Hz), 3.38 (3H, s), 3.24-3.36 (2H, m ), 3.10-3.14(1H,m), 2.89-3.01(2H,m), 1.76-1.86(2H,m), 1.61-1.65(1H,m), 1.53-1.57(1H,m), 1.11(3H,d,J=6.4Hz).

[0278] Embodiment 29: (3S,4S)-8-(8-((3-aminophenyl)ethynyl)-7-chloroimidazo[1,2-c]pyrimidine-5-yl)- 2-oxa-8-azaspiro[4.5]decan-4-amine

[0279]

[0280] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 437.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.75 (1H, d, J=1.6Hz), 7.59 (1H, d, J=1.6Hz), 7.10 (1H, t, J=8.0H z), 6.98 (1H, t, J = 1.6Hz), 6.95 (1H, d, J = 7.6Hz), 6.73 (1H, dd, J = 8.0Hz, 1.6Hz), 4.56 (1H, s) , 4.23-4.29 (1H, m), 3.84-3.93 (3H, m), 3.79 (1H, d, J = 9.2Hz), 3.35-3.39 (1H, m), 3.23 (1H, d , J=4.8Hz), 1.94-2.05 (2H, m), 1.83-1.87 (1H, m), 1.74-1.78 (1H, m), 1.26 (3H, d, J=6.4Hz).

[0281] Embodiment 30: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-aminopyridin-3-yl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0282]

[0283] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 435.23 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.97 (1H, d, J=5.2Hz), 7.60 (1H, dd, J=7.6Hz, 2.0Hz), 6.73 (2H, s), 6.55 (1H, dd, J=7.6Hz, 5.2Hz), 4.09-4.16 (1H, m), 3.77 (1H, d, J=8. 8Hz), 3.55 (1H, d, J = 8.8Hz), 3.41 (3H, s), 3.22-3.39 (2H, m), 2.86-2.97 (3H, m), 1.82-1.92(2H,m), 1.65-1.68(1H,m), 1.56-1.61(1H,m), 1.15(3H,d,J=6.8Hz).

[0284] Embodiment 31: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((1-Hydroxycyclopropyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0285]

[0286] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 399.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.38-13.54(1H, brs), 6.35(1H, s), 4.05-4.11(1H, m), 3.68 (1H, d, J = 9.2Hz), 3.51 (1H, d, J = 8.4Hz), 3.35 (3H, s), 3.17-3.32 (2H, m ), 3.02-3.08(1H, m), 2.84-2.98(2H, m), 1.72-1.84(2H, m), 1.59-1.64(1H, m), 1.51-1.56 (1H, m), 1.09 (3H, d, J=6.0Hz), 0.97-0.99 (2H, m), 0.85-0.93 (2H, m).

[0287] Embodiment 32: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-((1-methyl-1H-imidazol-4-yl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0288]

[0289] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 423.23 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 13.54 (1H, s), 7.69 (1H, s), 7.58 (1H, s), 4.15-4.20 (1H, m), 3.82 (1H, d, J = 8.8Hz), 3.66 (3H, s), 3.63 (1H, d, J=8.8Hz), 3.36-3.47 (5H, m), 2.82-2.93 (3H, m), 1.82-1.92 (2H, m), 1.70-1.74 (1H, m), 1.57-1.60 (1H, m), 1.19 (3H, d, J=6.8Hz).

[0290] Embodiment 33: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-(pyridin-2-ylethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0291]

[0292] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 420.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=12.92-13.88 (1H, brs), 8.61 (1H, d, J=5.2Hz), 7.86 (1H, td , J=8.0Hz, 1.6Hz), 7.62 (1H, d, J=7.6Hz), 7.43 (1H, dd, J=7.6Hz, 5.2Hz), 4.04-4.10 ( 1H, m), 3.68 (1H, d, J = 8.8Hz), 3.51 (1H, d, J = 8.8Hz), 3.36-3.42 (5H, m), 2.89-3.06 (3 H, m), 1.72-1.84 (2H, m), 1.60-1.64 (1H, m), 1.52-1.56 (1H, m), 1.09 (3H, d, J=6.4Hz).

[0293] Embodiment 34: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0294]

[0295] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 423.23 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.22-1.82 (1H, brs), 7.85 (1H, s), 7.70 (1H, s), 4.04-4.10 (1H, m), 3.85 (3H, s), 3.68 (1H, d, J=8.8Hz), 3.51 (1H, d, J = 8.8Hz), 3.32-3.42 (5H, m), 2.88-3.04 (3H, m), 1.72-1.86 (2H, m), 1.60-1.64 (1H, m), 1.52-1.56 (1H, m), 1.09 (3H, d, J = 6.4Hz).

[0296] Embodiment 35: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 3-((1-methyl-1H-pyrazol-3-yl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0297]

[0298] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 423.23 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.22-1.82 (1H, brs), 7.78 (1H, d, J=2.4Hz), 6.52 (1H, d, J=2.4Hz), 4.04-4.10 (1H, m), 3.85 (3H, s), 3.68 (1H, d, J=8.8 Hz), 3.51 (1H, d, J = 8.8Hz), 3.32-3.42 (5H, m), 2.88-3.04 (3H, m), 1.72-1 .86(2H,m), 1.60-1.64(1H,m), 1.52-1.56(1H,m), 1.09(3H,d,J=6.4Hz).

[0299] Embodiment 36: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (2-Chloro-3-ethynylphenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0300]

[0301] Step 1: tert-Butyl ((3S,4S)-8-(3-(2-chloro-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

[0302] Intermediate 6 (160 mg), reaction solution containing intermediate 12 (0.8 mL), tetrakis(triphenylphosphine)palladium (18 mg), potassium phosphate (185 mg) were added to a mixed solvent of dioxane and water (10:1, 5 mL), the air in the reaction system was replaced with nitrogen three times, heated to 80°C and stirred overnight. The mixture was cooled to room temperature, poured into water, extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 3:1) to obtain tert-butyl ((3S, 4S)-8-(3-(2-chloro-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (80 mg). MS m / z[LC-MS]: 625.27[M+1].

[0303] Step 2: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(2-chloro-3-ethynylphenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0304] Tert-butyl ((3S,4S)-8-(3-(2-chloro-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (80 mg) was added to a 4M solution of hydrogen chloride in dioxane (3 mL), stirred at room temperature for 1 hour, dried by rotation, and a 10% aqueous sodium carbonate solution was added. (10 mL), extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by thin layer silica gel chromatography (dichloromethane: methanol, 10: 1) to give 6-((3S, 4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro-3-ethynylphenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (38 mg). MS m / z [LC-MS]: 453.18 [M+1]. 1H NMR (400MHz, CD3OD): δ = 7.70 (1H, d, J = 8.0Hz), 7.49 (1H, d, J = 7.6Hz), 7.34-7.40 (1H, m), 4.25-4.32 (1H, m), 3.94 (1H, d, J = 10.4Hz), 3.83 (1H, d, J = 10.4Hz), 3.71-3.73 (1H, m), 3.46-3.68 (6H, m), 2.94-3.09 (2H, m), 1.87- 2.05 (2H, m), 1.70-1.77 (1H, m), 1.56-1.62 (1H, m), 1.29 (3H, d, J=7.6Hz).

[0305] Embodiment 37: 6-(4-amino-4-methylpiperidin-1-yl)-3-((2-fluoro-3,5-dimethoxyphenyl)acetylene 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0306]

[0307] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 441.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.21-13.90 (1H, brs), 8.22 (2H, s), 6.81 (1H, dd, J=7.2Hz, 2.8Hz), 6.60 (1H, dd, J=4.4Hz, 2.8Hz), 3 .84(3H,s), 3.76(3H,s), 3.38-3.46(2H,m), 3.37(3H,s), 3.07-3.14(2H,m), 1.86-1.95(2H,m), 1.73-1.82(2H,m), 1.35(3H,s).

[0308] Embodiment 38: 6-(4-amino-4-methylpiperidin-1-yl)-3-((2,5-difluorophenyl)ethynyl)-5-methyl- 1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0309]

[0310] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 399.18 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.63-13.90 (1H, brs), 8.13 (2H, s), 7.47-7.51 (1H, m), 7.34-7.44 (2H, m), 3.41-3.44(2H,m), 3.37(3H,s), 3.08-3.14(2H,m), 1.85-1.92(2H,m), 1.73-1.79(2H,m), 1.35(3H,s).

[0311] Embodiment 39: (S)-1-(4-(9-(2,3-dichlorophenyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine pyridin-5-yl)-1H-pyrazol-1-yl)propan-2-amine

[0312]

[0313] The target compound can be synthesized by referring to the method in Example 36 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 427.10 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.78-8.92 (1H, brs), 8.28-8.42 (1H, brs), 8.24 (1H, s), 7.77 (1H, dd, J=8.0Hz, 1.6H z), 7.69 (1H, dd, J = 7.6Hz, 1.6Hz), 7.48-7.51 (2H, m), 4.22-4.54 (2H, m), 3.50-3.85 (1H, m), 1.02-1.32 (3H, m).

[0314] Embodiment 40: 3-((1H-pyrazol-4-yl)ethynyl)-6-(4-amino-4-methylpiperidin-1-yl)-5-methyl- 1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0315]

[0316] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 353.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.19-13.86 (1H, brs), 8.23 ​​(2H, s), 7.94 (2H, s), 3.37-3.44 ( 2H, m), 3.35 (3H, s), 3.05-3.13 (2H, m), 1.86-1.94 (2H, m), 1.72-7.8 (2H, m), 1.34 (3H, s).

[0317] Embodiment 41: 6-(4-amino-4-methylpiperidin-1-yl)-5-methyl-3-(pyrimidin-5-ylethynyl)-1,5-di Hydrogen-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0318]

[0319] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 365.18 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 13.61-13.94 (1H, brs), 9.22 (1H, s), 8.99 (2H, s), 7.78-8.22 (2H, brs), 3. 39-3.46 (2H, m), 3.38 (3H, s), 3.08-3.15 (2H, m), 1.83-1.91 (2H, m), 1.72-1.79 (2H, m), 1.34 (3H, s).

[0320] Embodiment 42: 6-(4-amino-4-methylpiperidin-1-yl)-3-((3,5-bis(trifluoromethyl)phenyl)ethynyl)- 5-Methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0321]

[0322] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 499.17 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.17-8.21(3H,m), 3.37(3H,s), 3.12-3.28(4H,m), 1.54-1.61(2H,m), 1.46-1.52(2H,m), 1.10(3H,s).

[0323] Embodiment 43: 6-(4-amino-4-methylpiperidin-1-yl)-5-methyl-3-((3-(trifluoromethyl)phenyl)acetylene 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0324]

[0325] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 431.18 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.58-13.86 (1H, brs), 8.08-8.18 (2H, brs), 7.85-7.87 (2H, m), 7.81 (1H, d, J=7.6Hz), 7.69 ( 1H, t, J = 7.6Hz), 3.40-3.46 (2H, m), 3.38 (3H, s), 3.08-3.14 (2H, m), 1.86-1.93 (2H, m), 1.73-1.80 (2H, m), 1.35 (3H, s).

[0326] Embodiment 44: 6-(4-amino-4-methylpiperidin-1-yl)-5-methyl-3-(thiophen-3-ylethynyl)-1,5-di Hydrogen-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0327]

[0328] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 369.14 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=8.21 (2H, s), 7.95 (1H, d, J=1.6Hz), 7.69 (1H, dd, J=4.8Hz, 2.8Hz), 7.27 (1H, d, J=4 .8Hz), 3.65-3.73(2H, m), 3.39(3H, s), 3.01-3.06(2H, m), 1.89-1.97(2H, m), 1.76-1.84(2H, m), 1.38(3H, s).

[0329] Embodiment 45: 6-(4-amino-4-methylpiperidin-1-yl)-3-((3-fluorophenyl)ethynyl)-5-methyl-1,5- Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0330]

[0331] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 381.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=12.74-13.90 (1H, brs), 7.70-8.90 (2H, brs), 7.46-7.51 (1H, m), 7.36-7.40 (2H, m), 7.28- 7.33 (1H, m), 3.38-3.46 (2H, m), 3.37 (3H, s), 3.07-3.14 (2H, m), 1.91-1.98 (2H, m), 1.75-1.80 (2H, m), 1.35 (3H, s).

[0332] Embodiment 46: 6-(4-amino-4-methylpiperidin-1-yl)-3-((2,3-difluorophenyl)ethynyl)-5-methyl- 1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0333]

[0334] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 399.18 [M+1]. 1H NMR (400MHz, CD3OD): δ=7.43-7.47(1H,m), 7.30-7.37(1H,m), 7.17-7.23(1H,m), 3.5 1-3.59 (5H, m), 3.21-3.29 (2H, m), 1.99-2.06 (2H, m), 1.88-1.94 (2H, m), 1.48 (3H, s).

[0335] Embodiment 47: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2,3-Difluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0336]

[0337] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 455.20 [M+1]. 1 H NMR (400MHz, CD3OD): δ=7.43-7.47(1H,m), 7.30-7.37(1H,m), 7.17-7.22(1H,m), 4.22-4.28(1H,m), 3.89(1H,d,J=8.8Hz), 3.76(1H,d,J =8.8Hz), 3.46-3.54(5H,m), 3.24-3.29(1H,m), 3.97-3.12(2H,m), 1.91-2.02(2H,m), 1.80-1.86(1H,m), 1.68-1.74(1H,m), 1.40(3H,s).

[0338] Embodiment 48: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-Fluorophenyl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0339]

[0340] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 423.20 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.19-13.37 (1H, brs), 7.61 (1H, td, J=7.2Hz, 1.6Hz ), 7.46-7.52 (1H, m), 7.34 (1H, t, J = 8.4Hz), 7.27 (1H, td, J = 8.4Hz, 0.8Hz), 3.96 -4.19 (3H, m), 3.77 (1H, d, J = 8.8Hz), 3.54 (1H, d, J = 8.8Hz), 3.13-3.25 (m, 3H), 1.64-1.75 (2H, m), 1.53-1.62 (1H, m), 1.43-1.50 (1H, m), 1.14 (3H, d, J=6.0Hz).

[0341] Embodiment 49: (3S,4S)-8-(9-((2,3-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0342]

[0343] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 464.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 7.70 (1H, m), 7.48-7.59 (3H, m), 7.28-7.33 (1H, m), 4.13-4.21 (1H, m), 3.81 (1H, d, J=8.4Hz), 3.60-3.72(3H,m), 3.13-3.25(3H,m), 1.90-2.01(2H,m), 1.62-1.80(2H,m), 1.17(3H,d,J=5.6Hz).

[0344] Embodiment 50: (3S,4S)-8-(9-((3-chloro-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0345]

[0346] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 480.17 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.62-7.72 (3H, m), 7.52 (1H, d, J=1.6Hz), 7.33 (1H, t, J=7.6Hz), 4.14-4.20 (1H, m), 3.82 (1H, d, J=8 .8Hz), 3.62-3.72(3H,m), 3.12-3.24(3H,m), 1.91-1.99(2H,m), 1.74-1.81(1H,m), 1.64-1.71(1H,m), 1.17(3H,d,J=6.0Hz).

[0347] Embodiment 51: (3S,4S)-8-(9-((2-fluoro-3,5-dimethoxyphenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0348]

[0349] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 506.23 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.69 (1H, s), 7.50 (1H, s), 6.84 (1H, dd, J=6.8Hz, 2.8Hz), 6.70-6.69 (1H, m), 4.14-4.19 (1H, m), 3.85 (3H, s), 3 .77-3.81(4H,m), 3.60-3.69(3H,m), 3.12-3.22(4H,m), 1.89-1.99(2H,m), 1.63-1.68(1H,m), 1.64-1.68(1H,m), 1.16(3H,d,J=6.8Hz).

[0350] Embodiment 52: (3S,4S)-8-(9-((2-fluoro-5-(trifluoromethyl)phenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0351]

[0352] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 514.20 [M+1]. 1H NMR (400MHz, DMSO-d6]: δ = 8.04-8.07 (1H, m), 7.89-7.94 (1H, m), 7.70 (1H, s), 7.64 (1H, t, J = 8.8Hz), 7.52 (1H, s), 4.15-4.21 (1H, m), 3.8 1(1H,d,J=8.0Hz), 3.61-3.70(3H,m), 3.13-3.23(3H,m), 1.90-2.01(2H,m), 1.73-1.80(1H,m), 1.62-1.70(1H,m), 1.17(3H,d,J=6.4Hz).

[0353] Embodiment 53: (3S,4S)-3-methyl-8-(9-((3-(trifluoromethyl)phenyl)ethynyl)-7H-imidazo[1, 2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0354]

[0355] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 496.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.90-7.93 (2H, m), 7.83 (1H, d, J=7.6Hz), 7.69-7.74 (2H, m), 7.53 (1H, s), 4.15-4.21 (1H, m), 3.83 (1H, d, J=9.2Hz) , 3.63-3.71 (3H, m), 3.34 (1H, d, J = 5.2Hz), 3.10-3.19 (2H, m), 1.92-2. 01 (2H, m), 1.75-1.79 (1H, m), 1.65-1.70 (1H, m), 1.18 (3H, d, J=6.4Hz).

[0356] Embodiment 54: (3S,4S)-8-(9-((2,5-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0357]

[0358] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 464.20 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 7.70 (1H, m), 7.48-7.59 (2H, m), 7.35-7.44 (2H, m), 4.13-4.21 (1H, m), 3.82 (1H, d, J=8.4Hz), 3.61-3.72(3H,m), 3.13-3.25(3H,m), 1.91-2.01(2H,m), 1.62-1.81(2H,m), 1.17(3H,d,J=5.6Hz). .

[0359] Embodiment 55: (3S,4S)-8-(9-((2-fluoro-3-(trifluoromethyl)phenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0360]

[0361] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 514.20 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.11 (1H, t, J=6.8Hz), 7.72-7.77 (2H, m), 7.52 (1H, d, J=1.2Hz), 7.42 (1H, t, J=8.0Hz), 4.27-4.32 (1H, m), 3.96 (1 H, d, J=8.8Hz), 3.79-3.89 (3H, m), 3.41 (1H, d, J=4.0Hz), 3.17-3.28 (2H, m), 1.95-2.09 (3H, m), 1.78-1.82 (1H, m), 1.30 (3H, d, J=6.8Hz).

[0362] Embodiment 56: 3-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)- 7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)-2-chlorophenyl dimethylcarbamate

[0363]

[0364] The target compound can be synthesized by referring to the method in Example 36 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 525.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.85 (1H, s), 7.64 (1H, d, J=1.6Hz), 7.60 (1H, dd, J=7.2Hz, 1.6Hz), 7.45 (1H, t, J=7.6Hz), 7.36-7.39 (2H, m), 4.15-4.21 (1H, m) , 3.84 (1H, d, J = 9.2Hz), 3.60-3.72 (3H, m), 3.06-3.20 (6H, m), 2.91 (3H, s), 1. 90-1.99 (2H, m), 1.74-1.81 (1H, m), 1.64-1.70 (1H, m), 1.19 (3H, d, J=6.4Hz).

[0365] Embodiment 57: 3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)- 7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)ethynyl)-2-fluorobenzonitrile

[0366]

[0367] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 471.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 7.99-8.06 (2H, m), 7.72 (1H, s), 7.48-7.52 (2H, m), 4.09-4.15 (1H, m), 3.46 (1H, d, J=8.4Hz), 3.55-3.66(3H,m), 3.12-3.25(3H,m), 1.87-1.99(2H,m), 1.62-1.74(2H,m), 1.13(3H,d,J=6.4Hz).

[0368] Embodiment 58: (3S,4S)-8-(9-(Cyclopropylethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine pyridin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0369]

[0370] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 392.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 13.56-13.84 (1H, brs), 7.65 (1H, d, J = 0.8Hz), 7.45 (1H, d, J = 0.8Hz), 4.05-4.13 (1H, m), 3.94-4.02 (1H, m), 3.71 (1H, d, J) =8.4Hz), 3.46-3.60 (3H, m), 3.02-3.23 (3H, m), 1.80-1.99 (3H, m), 1.64- 1.74(1H,m), 1.10(3H,d,J=6.4Hz), 0.90-0.94(2H,m), 0.75-0.82(2H,m).

[0371] Embodiment 59: N-(3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8- yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)ethynyl)-2-fluorophenyl)acetamide

[0372]

[0373] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 503.23 [M+1]. 1 H NMR (400MHz, CD3OD): δ=7.98 (1H, t, J=7.6Hz), 7.75 (1H, d, J=1.6Hz), 7.59 (1H, t, J =7.2Hz), 7.50 (1H, d, J = 1.6Hz), 7.19 (1H, t, J = 8.0Hz), 4.26-4.32 (1H, m), 3.95 (1H , d, J=9.2Hz), 3.77-3.85 (3H, m), 3.33-3.36 (1H, m), 3.14-3.24 (2H, m), 2.18 (3H, s ), 1.99-2.10 (2H, m), 1.89-1.95 (1H, m), 1.76-1.83 (1H, m), 1.29 (3H, d, J = 6.4Hz).

[0374] Embodiment 60: (3S,4S)-8-(9-((3-amino-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazole 2-oxa-8-azaspiro[4.5]decan-4-amine

[0375]

[0376] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 461.22 [M+1]. 1H NMR (400MHz, CD3OD): δ=7.73 (1H, d, J=2.0Hz), 7.49 (1H, d, J=2.0Hz), 7.03-7.07 ( 1H, m), 6.93 (1H, t, J = 7.6Hz), 6.88 (1H, td, J = 8.0Hz, 2.0Hz), 4.26-4.32 (1H, m), 3 .95 (1H, d, J = 9.2Hz), 3.76-3.85 (3H, m), 3.35 (1H, d, J = 4.4Hz), 3.17-3.25 (2H, m) , 1.99-2.10 (2H, m), 1.88-1.96 (1H, m), 1.76-1.83 (1H, m), 1.29 (3H, d, J = 6.4Hz).

[0377] Example 61: 5-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)- 7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)-3H-spiro[benzofuran-2,1′-cyclopropane]-3-one

[0378]

[0379] The target compound can be synthesized by referring to the method in Example 36 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 486.23 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.93 (1H, s), 7.87 (1H, d, J=8.8Hz), 7.73 (1H, s), 7.49 (1H, s), 7.38 (1H, d, J = 8.4Hz), 4.25-4.32 (1H, m), 3.98 (1H, d, J = 9.2Hz), 3.76 -3.88(3H,m), 3.44(1H,d,J=4.4Hz), 3.11-3.29(2H,m), 2.04-2.11(2H,m), 1. 93-1.98 (1H, m), 1.74-1.84 (3H, m), 1.55-1.58 (2H, m), 1.31 (3H, d, J=6.4Hz).

[0380] Embodiment 62: (3S,4S)-8-(9-((2,3-dichlorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0381]

[0382] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 496.14 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.61-7.74 (3H, m), 7.51 (1H, d, J=1.6Hz), 7.31 (1H, t, J=7.6Hz), 4.11-4.20 (1H, m), 3.78 (1H, d, J=8 .4Hz), 3.61-3.74(3H,m), 3.10-3.24(3H,m), 1.89-1.99(2H,m), 1.73-1.85(1H,m), 1.64-1.72(1H,m), 1.16(3H,d,J=6.4Hz).

[0383] Embodiment 63: (3S,4S)-8-(9-((2-fluoro-3-methoxyphenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolidone oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0384]

[0385] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 476.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 7.70 (1H, m), 7.50 (1H, m), 7.16-7.32 (3H, m), 4.10-4.22 (1H, m), 3.87 (3H, s), 3.78 (1H, d, J = 8.4 Hz), 3.57-3.69 (3H, m), 3.12-3.26 (3H, m), 1.87-2.01 (2H, m), 1.71-1.79 (1H, m), 1.62-1.69 (1H, m), 1.15 (3H, d, J = 5.6Hz).

[0386] Embodiment 64: (3S,4S)-8-(9-(3-chloro-[1,1′-biphenyl]-4-yl)-7H-imidazo[1,2-c]pyrazole 2-oxa-8-azaspiro[4.5]decan-4-amine

[0387]

[0388] The target compound can be synthesized by referring to the method in Example 36 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 514.21 [M+1]. 1H NMR (400MHz, CD3OD): δ=7.84 (1H, s), 7.70-7.72 (5H, m), 7.49 (2H, t, J=7.6H z), 7.38-7.42 (1H, m), 7.35 (1H, d, J = 1.6Hz), 4.26-4.32 (1H, m), 3.97 (1H, d, J=8.8Hz), 3.78-3.87 (3H, m), 3.39 (1H, d, J=3.6Hz), 3.17-3.27 (2H, m), 1.9 9-2.12 (2H, m), 1.91-1.98 (1H, m), 1.78-1.84 (1H, m), 1.30 (3H, d, J=6.8Hz).

[0389] Embodiment 65: 2-((3-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8- 2-(2-(4-(2-(4-(2-(4-(2-chlorophenyl)thio)acetamide)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)-2-chlorophenyl)thio)acetamide

[0390]

[0391] The target compound can be synthesized by referring to the method in Example 36 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 527.18 [M+1]. 1 H NMR (400MHz, CD3OD): δ = 7.71-7.77 (1H, m), 7.53 (1H, d, J = 6.8Hz), 7.36-7.46 (3H, m), 4.29-4.35 (1H, m), 4.01 (1H, d, J = 10.0Hz), 3.81-3.91 (3H, m), 3.76 (2H, s), 3.52-3.54 (1H, m), 3.17-3.24 (2H, m), 2.03-2.22 (2H, m), 1.95-2.04 (1H, m), 1.80-1.86 (1H, m), 1.33 (3H, d, J=6.4Hz).

[0392] Embodiment 66: 3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)- 7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)ethynyl)-2-fluorophenol

[0393]

[0394] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 462.21 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=10.14-10.29 (1H, brs), 7.68 (1H, d, J=1.2Hz), 7.50 (1H, d, J=1.2Hz), 7.01-7.08 (3H, m), 4.16-4.23 (1H, m), 3.84 (1H, d, J= 9.2Hz), 3.63-3.73 (3H, m), 3.40 (1H, d, J=4.4Hz), 3.08-3.19 (2H, m), 1.89 -2.01(2H,m), 1.76-1.82(1H,m), 1.64-1.72(1H,m), 1.19(3H,d,J=6.8Hz).

[0395] Embodiment 67: (3S,4S)-8-(9-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)acetylene yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane- 4-Amine

[0396]

[0397] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 508.19 [M+1]. 1 H NMR (400MHz, CD3OD): δ=7.74 (1H, d, J=1.6Hz), 7.55 (1H, d, J=8.0Hz), 7.51 (1H, d , J=1.6Hz), 7.26 (1H, d, J=8.0Hz), 7.20 (1H, t, J=8.0Hz), 4.26-4.32 (1H, m), 3.9 5(1H,d,J=8.8Hz), 3.77-3.88(3H,m), 3.39(1H,d,J=4.4Hz), 3.16-3.25(2H,m), 2.01-2.02(2H,m), 1.89-1.96(1H,m), 1.76-1.83(1H,m), 1.29(3H,d,J=6.4Hz).

[0398] Embodiment 68: (3S,4S)-8-(9-((2-fluoro-3-methylphenyl)ethynyl)-7H-imidazo[1,2-c]pyrazole 2-oxa-8-azaspiro[4.5]decan-4-amine

[0399]

[0400] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 460.23 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.80 (1H, m), 7.62-7.70 (2H, m), 7.52 (1H, d, J=1.6Hz), 7.41-7.20 (1H, m), 4.13-4.20 (1H, m), 3.81 (1H, d, J=8. 8Hz), 3.60-3.72(3H,m), 3.27-3.29(1H,m), 3.12-3.21(2H,m), 2.35(3H,s), 1.89-1.97(2H,m), 1.61-1.79(2H,m), 1.18(3H,d,J=6.4Hz).

[0401] Embodiment 69: (3S,4S)-8-(9-((2-fluoro-3-isopropylphenyl)ethynyl)-7H-imidazo[1,2-c]pyridine oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0402]

[0403] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 504.25 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.70 (1H, d, J=1.4Hz), 7.51 (1H, d, J=1.4Hz), 7.18-7.32 (3H, m), 4.55 (1H, m), 4.10-4.21 (1H, m), 3.77 (1H, d, J=8.4Hz ), 3.57-3.68(3H, m), 3.10-3.25(3H, m), 1.87-2.02(2H, m), 1.70-1.79( 1H, m), 1.60-1.70 (1H, m), 1.32 (6H, d, J = 6.8Hz), 1.16 (3H, d, J = 5.6Hz).

[0404] Embodiment 70: (3S,4S)-8-(9-((3-(difluoromethoxy)-2-fluorophenyl)ethynyl)-7H-imidazo[1, 2-e]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0405]

[0406] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 512.20 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.76 (1H, d, J=1.6Hz), 7.51 (1H, d, J=1.6Hz), 7.38 (1H, t, J=56.0Hz), 7.21-7.35 (3H, m), 4.12-4.22 (1H, m), 3.7 9(1H,d,J=8.4Hz), 3.58-3.68(3H,m), 3.12-3.26(3H,m), 1.88-2.01(2H,m), 1.70-1.80(1H,m), 1.61-1.70(1H,m), 1.18(3H,d,J=5.6Hz).

[0407] Embodiment 71: (3S,4S)-8-(9-((3-(difluoromethyl)-2-fluorophenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0408]

[0409] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 496.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.84-7.88 (1H, m), 7.70-7.74 (2H, m), 7.51 (1H, d, J=1.6Hz), 7.41-7.18 (1H, m), 7.28 (1H, t, J=54.0Hz), 4.13-4.19 (1H , m), 3.80 (1H, d, J = 8.8Hz), 3.60-3.71 (3H, m), 3.27-3.28 (1H, m), 3.12-3 .21(2H,m), 1.90-1.99(2H,m), 1.61-1.78(2H,m), 1.17(3H,d,J=6.8Hz).

[0410] Embodiment 72: (3S,4S)-3-methyl-8-(9-((2,3,4-trifluorophenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0411]

[0412] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 482.19 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.70 (1H, d, J=1.2Hz), 7.52-7.59 (1H, m), 7.51 (1H, d, J=1.2Hz), 7.40-7.47 (1H, m), 4.13-4.19 (1H, m), 3.80 (1H, d, J=8 .8Hz), 3.60-3.71 (3H, m), 3.28-3.29 (1H, m), 3.12-3.21 (2H, m), 1.90-1 .99(2H,m), 1.72-1.79(1H,m), 1.64-1.70(1H,m), 1.16(3H,d,J=6.8Hz).

[0413] Embodiment 73: (3S,4S)-8-(9-((3-chloro-2,5-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolidone oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0414]

[0415] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 498.16 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.85-8.11 (1H, brs), 7.77-7.83 (1H, m), 7.74 (0.5H, d , J=1.6Hz), 7.70 (0.5H, d, J=1.6Hz), 7.59-7.63 (1H, m), 7.52 (0.5H, d, J=1.6Hz), 7.49 (0.5H, d, J=1.6Hz), 4.18-4.28 (1H, m), 3.66-3.88 (4H, m), 3.43 (1H, d, J=4.4 Hz), 3.11-3.21 (2H, m), 1.91-2.02 (2H, m), 1.66-1.86 (2H, m), 1.14-1.28 (3H, m).

[0416] Embodiment 74: (3S,4S)-8-(9-((2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)ethynyl)-7H-imidazole 2-oxa-8-azaspiro[4.5]decan-4-amine

[0417]

[0418] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 544.21 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.73 (1H, d, J=1.6Hz), 7.50 (1H, d, J=1.6Hz), 7.20-7.34 (3H, m), 4.46 (2H, m), 4.10-4.22 (1H, m), 3.78 (1H , d, J=8.4Hz), 3.57-3.68 (3H, m), 3.12-3.25 (3H, m), 1.87-2.01 (2H, m), 1.70-1.79 (1H, m), 1.62-1.70 (1H, m), 1.17 (3H, d, J=5.6Hz).

[0419] Embodiment 75: (3S,4S)-8-(9-(3,3-dimethylbut-1-yn-1-yl)-7H-imidazo[1,2-c]pyrazolo ... [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0420]

[0421] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 408.25 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.65 (1H, d, J=1.2Hz), 7.45 (1H, d, J=1.2Hz), 4.04-4.16 (1H, m), 3.70 (1H, d, J=8.6Hz), 3.4 0-3.60 (3H, m), 3.00-3.24 (3H, m), 1.81-1.99 (3H, m), 1.64-1.75 (1H, d, J = 6.8Hz), 1.27 (9H, s), 1.08 (3H, d, J = 6.4Hz).

[0422] Embodiment 76: (3S,4S)-8-(9-(3-chloro-3-methylbut-1-yn-1-yl)-7H-imidazo[1,2-c]pyrazole 2-oxa-8-azaspiro[4.5]decan-4-amine

[0423]

[0424] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 428.20 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.46-13.81 (1H, brs), 7.68 (1H, d, J=1.2Hz), 7.50 (1H, d, J=1.2Hz), 4.02-4.17 (1H, m), 3.7 1(1H,m), 3.42-3.61(3H,m), 2.99-3.25(3H,m), 1.80-2.00(9H,m), 1.64-1.79(1H,d,J=6.8Hz), 1.10(3H,d,J=6.8Hz).

[0425] Embodiment 77: (3S,4S)-3-methyl-8-(9-(3-methylbut-1-yn-1-yl)-7H-imidazo[1,2-c]pyrrolidone Oxalo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0426]

[0427] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 394.24 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.65 (1H, d, J=1.2Hz), 7.45 (1H, d, J=1.2Hz), 4.04-4.16 (1H, m), 3.70 (1H, d, J=8.6Hz), 3.4 0-3.60 (3H, m), 2.98-3.24 (4H, m), 1.81-1.99 (3H, m), 1.64-1.75 (1H, m), 1.28 (6H, d, J = 6.8Hz), 1.07 (3H, d, J = 6.4Hz).

[0428] Embodiment 78: (3S,4S)-3-methyl-8-(9-((1-methylcyclopropyl)ethynyl)-7H-imidazo[1,2-c] Pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0429]

[0430] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 406.24 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.58-13.84 (1H, brs), 7.63 (1H, d, J=0.8Hz), 7.43 (1H, d, J=0.8Hz), 4.05-4.14 (1H, m), 3.72 (1H, d, J=8.6Hz), 3.46- 3.60(3H,m), 3.02-3.23(3H,m), 1.80-1.99(3H,m), 1.64-1.74(1H,m), 1 .26(3H,s), 1.10(3H,d,J=6.4Hz), 0.92-0.95(2H,m), 0.72-0.80(2H,m).

[0431] Embodiment 79: (3S,4S)-8-(9-((2,2-difluorocyclopropyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0432]

[0433] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 428.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.68 (1H, d, J=1.2Hz), 7.48 (1H, d, J=1.2Hz), 4.05-4.17 (2H, m), 3.71 (1H, d, J=8.6Hz) , 3.46-3.60(3H,m), 3.02-3.23(3H,m), 1.80-1.99(3H,m), 1.64-1.78(2H,m), 1.52(1H,m), 1.12(3H,d,J=6.4Hz).

[0434] Embodiment 80: (3S,4S)-8-(9-((3-(cyclopropylmethoxy)-2-fluorophenyl)ethynyl)-7H-imidazo [1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0435]

[0436] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 516.25 [M+1]. 1H NMR (400MHz, CD3OD): δ=7.75 (1H, d, J=1.6Hz), 7.49 (1H, d, J=1.6Hz), 7.32- 7.36(1H,m),7.07-7.16(2H,m),4.23-4.28(1H,m),3.89-3.92(3H,m),3.71 -3.79(3H,m), 3.16-3.26(3H,m), 1.97-2.05(2H,m), 1.75-1.88(2H,m), 1.2 4(3H,d,J=6.4Hz), 0.84-0.91(1H,m), 0.61-0.65(2H,m), 0.35-0.39(2H,m).

[0437] Embodiment 81: (3S,4S)-8-(9-((3-ethoxy-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolidone oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0438]

[0439] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 490.24 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.71 (1H, d, J=1.6Hz), 7.48 (1H, d, J=1.6Hz), 7.24-7 .29(1H,m),7.16-7.21(2H,m),4.13(2H,q,J=6.8Hz),4.04-4.11(1H,m),3.68(1 H, d, J = 8.4Hz), 3.50-3.61 (3H, m), 3.17-3.26 (2H, m), 2.98 (1H, d, J = 5.2Hz), 1.8 1-1.96(2H,m), 1.57-1.72(2H,m), 1.34(3H,t,J=6.8Hz), 1.08(3H,d,J=6.8Hz).

[0440] Embodiment 82: (3S,4S)-3-methyl-8-(9-(3-methylbut-3-en-1-yn-1-yl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0441]

[0442] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 392.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.69 (1H, d, J=1.6Hz), 7.48 (1H, d, J=1.6Hz), 5.46-5.48 (2H, m), 4.05-4.11 (1H, m), 3.69 (1H, d, J=8.4Hz), 3 .51-3.60 (3H, m), 3.12-3.26 (2H, m), 3.04 (1H, d, J = 4.0Hz), 1.98 (3H, s), 1.82-1.95 (2H, m), 1.59-1.70 (m, 2H), 1.09 (3H, d, J = 6.4Hz).

[0443] Embodiment 83: (3S,4S)-8-(9-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetylene yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane- 4-Amine

[0444]

[0445] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 508.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.67-7.73 (2H, m), 7.45-7.53 (3H, m), 4.09-4.16 (1H, m), 3.75 (1H, d, J=8.8H z), 3.51-3.66 (3H, m), 3.11-3.25 (3H, m), 1.87-1.98 (2H, m), 1.61-1.76 (2H, m), 1.13 (3H, d, J=6.4Hz).

[0446] Embodiment 84: (3S,4S)-8-(9-((2,4-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0447]

[0448] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 464.20 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.74 (1H, td, J=8.4Hz, 6.4Hz), 7.70 (1H, d, J=1.6Hz), 7 .49 (1H, d, J = 1.6Hz), 7.46 (1H, td, J = 9.6Hz, 2.4Hz), 7.21 (1H, td, J = 8.4Hz, 2.0Hz ), 4.09-4.16 (1H, m), 3.75 (1H, d, J = 8.8Hz), 3.50-3.61 (3H, m), 3.13-3.24 (3H, m) , 1.87-1.99 (2H, m), 1.71-1.75 (1H, m), 1.63-1.67 (1H, m), 1.13 (3H, d, J=6.0Hz).

[0449] Embodiment 85: (3S,4S)-8-(9-((3-chloro-2,4-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolidone oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0450]

[0451] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 498.16 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 7.71-7.77 (2H, m), 7.51 (1H, d, J = 1.6Hz), 7.44 (1H, td, J = 8.8Hz, 1.6Hz), 4.10-4.16 (1H, m), 3.76 (1H, d , J=8.8Hz), 3.56-3.66(3H,m), 3.13-3.24(3H,m), 1.88-1.97(2H,m), 1.71-1.75(1H,m), 1.62-1.68(1H,m), 1.14(3H,d,J=6.0Hz).

[0452] Embodiment 86: (3S,4S)-8-(9-((2-fluoro-3-(fluoromethoxy)phenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0453]

[0454] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 494.21 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.71 (1H, d, J=1.6Hz), 7.50 (1H, d, J=1.6Hz), 7.38-7.46 (2H, m), 7.28 (1H, t, J=8.0Hz), 5.92 (2H, d, J=53.6Hz), 4.09-4.15 (1H, m), 3.75 (1H, d, J = 8.8Hz), 3.55-3.67 (3H, m), 3.14-3.26 (3H, m), 1.87 -1.98(2H,m), 1.70-1.76(1H,m), 1.60-1.67(1H,m), 1.13(3H,d,J=6.4Hz).

[0455] Embodiment 87: (3S,4S)-8-(9-((4-phenoxyphenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4, 3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0456]

[0457] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 520.25 [M+1]. 1 H NMR (400MHz, CD3OD): δ=7.66 (1H, d, J=1.6Hz), 7.57 (1H, d, J=1.6Hz), 7.30-7.4 1 (4H, m), 7.10 (1H, t, J = 7.2Hz), 6.93 (2H, d, J = 8.0Hz), 6.78 (2H, .d, J = 8.4Hz), 4 .21-4.29(1H,m), 3.89(1H,d,J=8.8Hz), 3.63-3.82(3H,m), 3.10-3.26(3H,m), 1.96-2.07 (2H, m), 1.82-1.88 (1H, m), 1.73-1.79 (1H, m), 1.25 (3H, d, J=6.0Hz).

[0458] Embodiment 88: (3S,4S)-8-(9-((2,4,5-trifluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0459]

[0460] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 482.19 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 7.83-7.90 (1H, m), 7.73-7.80 (1H, m), 7.70 (1H, d, J = 1.6Hz), 7.51 (1H, d, J = 1.6Hz), 4.14-4.20 (1H, m), 3.80 ( 1H, d, J = 9.2Hz), 3.61-3.69 (3H, m), 3.11-3.24 (3H, m), 1.90-1.98 (2H, m), 1.74-1.78 (1H, m), 1.64-1.68 (1H, m), 1.16 (3H, d, J = 6.8Hz).

[0461] Embodiment 89: (3S,4S)-8-(9-((2-fluoro-3-(fluoromethyl)phenyl)ethynyl)-7H-imidazo[1,2-c] Pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0462]

[0463] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 478.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.68-7.74(2H, m), 7.60-7.66(1H, m), 7.52(1H, d, J= 1.6Hz), 7.35 (1H, t, J=7.6Hz), 5.53 (2H, d, J=47.6Hz), 4.17-4.23 (1H, m), 3.84 (1H, d, J = 8.8Hz), 3.63-3.74 (3H, m), 3.41 (1H, d, J = 4.8Hz), 3.09-3.19 (2H, m), 1.91-1.99 (2H, m), 1.77-1.81 (1H, m), 1.66-1.70 (1H, m), 1.19 (3H, d, J=6.8Hz).

[0464] Embodiment 90: (3S,4S)-3-methyl-8-(9-(thien-2-ylethynyl)-7H-imidazo[1,2-c]pyrazolo ... [4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0465]

[0466] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 434.18 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.70-7.73 (2H, m), 7.48-7.50 (2H, m), 7.15 (1H, t, J=4.0Hz), 4.08-4.15 (1H, m), 3.73 (1H, d, J=8. 0Hz), 3.50-3.64(3H,m), 3.10-3.24(3H,m), 1.85-1.99(2H,m), 1.69-1.74(1H,m), 1.61-1.67(1H,m), 1.12(3H,d,J=6.4Hz).

[0467] Embodiment 91: (3S,4S)-8-(9-((2,3,5-trifluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0468]

[0469] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 482.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.68-7.76 (2H, m), 7.52 (1H, d, J=1.6Hz), 7.43-7.48 (1H, m), 4.12-4.18 (1H, m), 3.78 (1H, d, J=8. 8Hz), 3.59-3.68(3H,m), 3.13-3.28(3H,m), 1.88-1.99(2H,m), 1.72-1.78(1H,m), 1.62-1.69(1H,m), 1.15(3H,d,J=6.4Hz).

[0470] Embodiment 92: 4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)- 7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)-2-methylbut-3-yn-2-ol

[0471]

[0472] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 410.23 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.72-13.94 (1H, brs), 7.65 (1H, d, J=1.6Hz), 7. 49 (1H, d, J = 1.6Hz), 5.57 (1H, s), 4.12-4.18 (1H, m), 3.79 (1H, d, J = 9.2Hz), 3 .55-3.64(3H,m), 3.26(1H,d,J=3.6Hz), 3.08-3.16(2H,m), 1.90-1.98(2H,m ), 1.71-1.78 (1H, m), 1.61-1.68 (1H, m), 1.49 (6H, s), 1.16 (3H, d, J = 6.4Hz).

[0473] Embodiment 93: (3S,4S)-8-(9-(3,3-dimethylbut-1-yn-1-yl)-7H-imidazo[1,2-c]pyrrolo ... [3,2-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0474]

[0475] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 407.26 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=11.92 (1H, d, J=2.4Hz), 7.55 (1H, d, J=1.6Hz), 7.47 (1H, d, J = 1.6Hz), 7.25 (1H, d, J = 2.4Hz), 4.14-4.20 (1H, m), 3.80 (1H, d, J = 8.8H z), 3.62 (1H, d, J = 8.8Hz), 3.45-3.54 (2H, m), 3.27-3.29 (1H, m), 2.96-3.04 (2H , m), 1.89-1.99 (2H, m), 1.64-1.80 (2H, m), 1.28 (9H, s), 1.17 (3H, d, J=6.8Hz).

[0476] Embodiment 94: (3S,4S)-8-(9-((2,3,4,5-tetrafluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazole 2-oxa-8-azaspiro[4.5]decan-4-amine

[0477]

[0478] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 500.18 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.71-7.79 (2H, m), 7.52 (1H, d, J=1.6Hz), 4.26-4.32 (1H, m), 3.95 (1H, d, J=9.2Hz), 3.76-3.88 (3H, m), 3.40 (1H, d, J = 4.0Hz), 3.15-3.25 (2H, m), 2.01-2.11 (2H, m), 1.90-1.94 (1H, m), 1.78-1.82 (1H, m), 1.29 (3H, d, J = 6.8Hz).

[0479] Embodiment 95: (3S,4S)-8-(9-((2-fluoro-3-(methoxymethyl)phenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0480]

[0481] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 490.24 [M+1]. 1 H NMR (400MHz, CD3OD): δ=7.74-7.79 (2H, m), 7.48-7.52 (2H, m), 7.23 (1H, t, J=8.0Hz), 4.55 (2H, s), 4.27-4.33 (1H, m), 3.97 (1H, d, J=9.2Hz), 3.78-3 .87 (3H, m), 3.42 (1H, d, J = 4.0Hz), 3.41 (3H, s), 3.16-3.25 (2H, m), 1.99- 2.12(2H,m), 1.92-1.97(1H,m), 1.78-1.83(1H,m), 1.30(3H,d,J=6.8Hz).

[0482] Embodiment 96: (3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8- yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)ethynyl)-2-fluorophenyl)methanol

[0483]

[0484] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 476.22 [M+1]. 1H NMR (400MHz, CD3OD): δ = 7.72-7.76 (2H, m), 7.50-7.56 (2H, m), 7.23 (1H, t, J = 8.0Hz), 4.70 (2H, s), 4.28-4.34 (1H, m), 3.98 (1H, d, J =9.6Hz), 3.80-3.91 (3H, m), 3.50 (1H, d, J = 4.0Hz), 3.11-3.27 (2H, m), 1.95-2.14 (3H, m), 1.78-1.84 (1H, m), 1.32 (3H, d, J = 6.4Hz).

[0485] Embodiment 97: (3S,4S)-8-(9-((2,6-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0486]

[0487] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 494.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.71 (1H, d, J=1.6Hz), 7.53-7.61 (1H, m), 7.49 (1H, d, J=1.6Hz), 7.24-7.30 (2H, m), 4.08-4.13 (1H, m), 3.73 (1H, d, J = 8.4Hz), 3.53-3.64 (3H, m), 3.11-3.25 (3H, m), 1.85-1.97 (2H, m), 1.60-1.75 (2H, m), 1.11 (3H, d, J = 6.4Hz).

[0488] Embodiment 98: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (3,3-Dimethylbut-1-yn-1-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0489]

[0490] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 399.25 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.14-13.55 (1H, brs), 4.04-4.10 (1H, m), 3.68 (1H, d, J=8.8Hz), 3.50 (1H, d, J=8.8Hz), 3.35 (3H, s), 3 .23-3.34(2H,m), 3.04-3.08(1H,m), 2.83-2.97(2H,m), 1.71-1.84(2H,m), 1.50-1.64(2H,m), 1.26(9H,s), 1.09(3H,d,J=6.0Hz).

[0491] Embodiment 99: (3S,4S)-8-(9-((2,4-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolo ... [3,2-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0492]

[0493] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 463.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 12.23 (1H, s), 7.58-7.65 (2H, m), 7.56 (1H, s), 7.48 (1H , s), 7.36-7.42 (1H, m), 7.12-7.18 (1H, m), 4.15-4.22 (1H, m), 3.82 (1H, d, J = 8.4H z), 3.64 (1H, d, J = 8.4Hz), 3.50-3.60 (2H, m), 3.35-3.38 (1H, m), 2.99-3.07 (2H, m ), 1.88-2.01 (2H, m), 1.76-1.82 (1H, m), 1.64-1.72 (1H, m), 1.18 (3H, d, J = 6.8Hz).

[0494] Embodiment 100: (3S,4S)-8-(9-((2-fluoro-3-isobutyloxyphenyl)ethynyl)-7H-imidazo[1,2-c] Pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decan-4-amine

[0495]

[0496] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 518.27 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.69 (1H, d, J=1.6Hz), 7.51 (1H, d, J=1.6Hz), 7.24-7.29 (1H, m), 7.15-7.20 (2H, m), 4.15-4.21 (1H, m), 3.82-3.83 (3H, m) ), 3.62-3.70 (3H, m), 3.33 (1H, d, J = 4.8Hz), 3.10-3.20 (2H, m), 1.92-2.0 8 (3H, m), 1.64-1.80 (2H, m), 1.18 (3H, d, J = 6.4Hz), 0.97 (6H, d, J = 7.2Hz).

[0497] Embodiment 101: (3S,4S)-8-(9-((3,4-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0498]

[0499] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 464.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.68-7.74 (2H, m), 7.46-7.58 (3H, m), 4.10-4.16 (1H, m), 3.76 (1H, d, J=9.2Hz), 3.57- 3.67(3H,m), 3.13-3.22(3H,m), 1.87-1.98(2H,m), 1.71-1.75(1H,m), 1.62-1.68(1H,m), 1.13(3H,d,J=6.4Hz).

[0500] Embodiment 102: (3S,4S)-8-(9-((3-(dimethylamino)-2-fluorophenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0501]

[0502] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 489.25 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.69 (1H, d, J=1.2Hz), 7.50 (1H, d, J=1.2Hz), 7.02-7.14 (3H, m), 4.11-4.17 (1H, m), 3.77 (1H, d, J=8.4Hz) , 3.57-3.66 (3H, m), 3.13-3.24 (3H, m), 2.80 (6H, s), 1.88-1.99 (2H, m), 1.71-1.77 (1H, m), 1.62-1.68 (1H, m), 1.14 (3H, d, J = 6.4Hz).

[0503] Embodiment 103: (3S,4S)-8-(9-((2,3-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolo ... [3,2-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0504]

[0505] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 463.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=12.31 (1H, s), 7.58-7.62 (2H, m), 7.48 (1H, d, J=1.2Hz ), 7.37-7.46 (2H, m), 7.21-7.27 (1H, m), 4.12-4.18 (1H, m), 3.78 (1H, d, J = 8.4Hz) , 3.59 (1H, d, J = 8.4Hz), 3.47-3.56 (2H, m), 3.22-3.25 (1H, m), 3.01-3.10 (2H, m) , 1.89-1.99(2H,m), 1.73-1.77(1H,m), 1.64-1.69(1H,m), 1.15(3H,d,J=6.8Hz).

[0506] Embodiment 104: (3S,4S)-8-(9-((2,6-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolo ... [3,2-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0507]

[0508] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 463.21 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=12.31 (1H, s), 7.58-7.62 (2H, m), 7.43-7.50 (2H , m), 7.18-7.24 (2H, m), 4.11-4.17 (1H, m), 3.76 (1H, d, J=8.8Hz), 3.58 (1H, d, J=8.4Hz), 3.46-3.55 (2H, m), 3.19-3.22 (1H, m), 3.01-3.10 (2H, m), 1.89 -1.99(2H,m), 1.72-1.76(1H,m), 1.64-1.68(1H,m), 1.14(3H,d,J=6.4Hz).

[0509] Embodiment 105: (3S,4S)-8-(9-((4-chloro-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0510]

[0511] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 480.17 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.67-7.72 (2H, m), 7.65 (1H, dd, J=9.2Hz, 2.0Hz), 7 .51 (1H, d, J = 1.6Hz), 7.40 (1H, dd, J = 8.4Hz, 2.0Hz), 4.12-4.18 (1H, m), 3.79 (1 H, d, J = 8.8Hz), 3.59-3.70 (3H, m), 3.25 (1H, d, J = 4.8Hz), 3.11-3.21 (2H, m), 1 .89-1.98(2H,m), 1.72-1.78(1H,m), 1.63-1.68(1H,m), 1.15(3H,d,J=6.4Hz).

[0512] Embodiment 106: (3S,4S)-3-methyl-8-(9-((1-(trifluoromethyl)cyclopropyl)ethynyl)-7H-imidazo [1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0513]

[0514] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 460.21 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.66 (1H, d, J=1.2Hz), 7.50 (1H, d, J=1.2Hz), 4.14-4.20 (1H, m), 3.82 (1H, d, J=8.8Hz), 3.59-3.70 (3H, m), 3.35 (1H, d, J) =4.0Hz), 3.07-3.16 (2H, m), 1.90-1.99 (2H, m), 1.74-1.78 (1H, m), 1.64- 1.68 (1H, m), 1.48-1.52 (2H, m), 1.38-1.43 (2H, m), 1.18 (3H, d, J=6.0Hz).

[0515] Embodiment 107: (3S,4S)-3-methyl-8-(9-((2,3,6-trifluorophenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0516]

[0517] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 482.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.71 (1H, d, J=1.6Hz), 7.62-7.69 (1H, m), 7.51 (1H, d, J=1.6Hz), 7.29-7.35 (1H, m), 4.13-4.19 (1H, m), 3.80 (1H, d, J=9. 2Hz), 3.60-3.71 (3H, m), 3.33 (1H, d, J = 4.0Hz), 3.11-3.21 (2H, m), 1.89- 1.97 (2H, m), 1.74-1.78 (1H, m), 1.64-1.68 (1H, m), 1.16 (3H, d, J=6.4Hz).

[0518] Embodiment 108: (3S,4S)-8-(9-((3,5-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0519]

[0520] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 464.20 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.72 (1H, d, J=1.4Hz), 7.51 (1H, d, J=1.4Hz), 7.33-7.44 (3H, m), 4.06-4.12 (1H, m), 3.70 (1H, d, J=8. 4Hz), 3.51-3.62 (3H, m), 3.13-3.24 (2H, m), 3.03 (1H, d, J = 4.8Hz), 1.82-1.96 (2H, m), 1.60-1.72 (2H, m), 1.09 (3H, d, J = 6.4Hz).

[0521] Embodiment 109: (3S,4S)-8-(9-((2-chloro-3,6-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolidone oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0522]

[0523] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 498.16 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.70 (1H, d, J=1.6Hz), 7.59-7.64 (1H, m), 7.51 (1H, d, J=1.6Hz), 7.44-7.50 (1H, m), 4.16-4.21 (1H, m), 3.82 (1H, d, J=9. 2Hz), 3.64-3.71 (3H, m), 3.37 (1H, d, J = 4.4Hz), 3.11-3.20 (2H, m), 1.89- 1.99 (2H, m), 1.76-1.80 (1H, m), 1.66-1.69 (1H, m), 1.18 (3H, d, J=6.4Hz).

[0524] Embodiment 110: (3S,4S)-3-Methyl-8-(9-((pentafluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazole 2-(4,3-e)pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0525]

[0526] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 518.17 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.72 (1H, d, J=1.6Hz), 7.51 (1H, d, J=1.6Hz), 4.104.16 (1H, m), 3.76 (1H, d, J=9.2Hz), 3. 55-3.67 (3H, m), 3.12-3.25 (3H, m), 1.88-1.99 (2H, m), 1.71-1.75 (1H, m), 1.62-1.67 (1H, m), 1.13 (3H, d, J=6.0Hz).

[0527] Embodiment 111: (3S,4S)-3-methyl-8-(9-((2,4,6-trifluorophenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0528]

[0529] Referring to the method in Example 1, the target compound can be synthesized using appropriate starting materials and intermediates - MS m / z [LC-MS]: 482.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.70 (1H, d, J=1.6Hz), 7.51 (1H, d, J=1.6Hz), 7.41-7.45 (2H, m), 4.16-4.20 (1H, m), 3.81 (1H, d, J=9.2Hz), 3. 62-3.71(3H,m), 3.33-3.35(1H,m), 3.10-3.20(2H,m), 1.90-1.99(2H,m), 1.75-1.79(1H,m), 1.64-1.69(1H,m), 1.17(3H,d,J=6.4Hz).

[0530] Embodiment 112: (3S,4S)-3-methyl-8-(9-((2,3,4,5-tetrafluorophenyl)ethynyl)-7H-imidazo[1, 2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0531]

[0532] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 500.18 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=8.03-8.12(1H,m), 7.72(1H,d,J=1.6Hz), 7.52(1H,d,J=1.6Hz), 4.12-4.19(1H,m), 3.78(1H,d,J=8 .4Hz), 3.59-3.70(3H,m), 3.12-3.26(3H,m), 1.88-1.99(2H,m), 1.72-1.78(1H,m), 1.62-1.68(1H,m), 1.15(3H,d,J=6.8Hz).

[0533] Embodiment 113: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-Fluoro-3-methoxyphenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[0534]

[0535] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 467.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.26 (JH, td, J=8.0Hz, 1.6Hz), 7.19 (1H, t, J=8.0H z), 7.10-7.14 (1H, m), 4.07-4.12 (1H, m), 3.85 (3H, s), 3.72 (1H, d, J = 8.8Hz), 3.53 (1H, d, J = 8.8Hz), 3.38 (3H, s), 3.22-3.36 (3H, m), 2.87-2.99 (2H, m), 1. 76-1.87 (2H, m), 1.62-1.66 (1H, m), 1.54-1.58 (1H, m), 1.11 (3H, d, J=6.8Hz).

[0536] Embodiment 114: (3S,4S)-8-(9-((3-methoxypyridin-4-yl)ethynyl)-7H-imidazo[1,2-c]pyrrolidone oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0537]

[0538] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 459.23 [M+1]. 1H NMR (400MHz, CD3OD): δ=8.78 (1H, s), 8.43 (1H, d, J=6.0Hz), 7.75 (1H, d, J=1 .6Hz), 7.52 (1H, d, J = 1.6Hz), 7.16 (1H, d, J = 6.0Hz), 4.27-4.33 (1H, m), 4.02 (3H, s), 3.98 (1H, d, J = 9.6Hz), 3.80-3.89 (3H, m), 3.50 (1H, d, J = 3.6Hz), 3.1 5-3.24 (2H, m), 1.94-2.11 (3H, m), 1.78-1.83 (1H, m), 1.32 (3H, d, J=6.4Hz).

[0539] Embodiment 115: (3S,4S)-8-(9-((3-fluoropyridin-4-yl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0540]

[0541] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 447.21 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ = 8.33 (1H, d, J = 5.2Hz), 7.72 (1H, d, J = 1.6Hz), 7.52-7.54 (2H, m), 7.40-7.41 (1H, m), 4.13-4.19 (1H, m), 3.80 ( 1H, d, J = 8.8Hz), 3.60-3.71 (3H, m), 3.14-3.27 (3H, m), 1.90-1.99 (2H, m), 1.73-1.78 (1H, m), 1.64-1.68 (1H, m), 1.16 (3H, d, J = 6.4Hz).

[0542] Embodiment 116: (3S,4S)-3-methyl-8-(9-(spiro[chromane-2,1′-cyclobutane]-6-yl)-7H-imidazo [1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0543]

[0544] The target compound can be synthesized by referring to the method in Example 36 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 500.28 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=13.51-13.77 (1H, brs), 8.52 (1H, d, J=8.8Hz), 8.35 (1H, d, J=1.6Hz), 7.67 ( 1H, d, J=1.6Hz), 7.51 (1H, d, J=1.2Hz), 6.83 (1H, d, J=8.4Hz), 4.13-4.19 (1H, m), 3.81 (1H, d, J=8.8Hz ), 3.56-3.66 (3H, m), 3.28 (1H, d, J = 5.2Hz), 3.07-3.16 (2H, m), 2.82 (2H, t, J = 6.8Hz), 2.13-2.21 (2H, m), 2.03-2.10 (2H, m), 191-2.01 (4H, m), 1.72-1.83 (2H, m), 1.62-1.71 (2H, m), 1.17 (3H, d, J=6.0Hz).

[0545] Embodiment 117: (3S,4S)-3-methyl-8-(9-(spiro[chromane-2,1′-cyclobutane]-7-yl)-7H-imidazo [1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0546]

[0547] The target compound can be synthesized by referring to the method in Example 36 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 500.28 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.58-13.82 (1H, brs), 8.20-8.25 (1H, m), 8.13 (1H, d, J=7.6Hz), 7. 69 (1H, d, J = 1.4Hz), 7.55 (1H, d, J = 1.4Hz), 7.14 (1H, d, J = 7.6Hz), 4.16-4.22 (1H, m), 3.83 (1H, d , J=9.6Hz), 3.59-3.70 (3H, m), 3.06-3.18 (3H, m), 2.77 (2H, t, J=6.4Hz), 2.14-2.23 (2H, m), 2.0 2-2.10 (2H, m), 1.90-1.98 (4H, m), 1.76-1.83 (2H, m), 1.64-1.70 (2H, m), 1.18 (3H, d, J=6.0Hz).

[0548] Embodiment 118: (3S,4S)-8-(9-((5-chloro-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0549]

[0550] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 480.17 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.70-7.75 (2H, m), 7.56-7.60 (1H, m), 7.50 (1H, d, J=1.6Hz), 7.43 (1H, t, J=9.2Hz), 4.08-4.14 (1H, m), 3.73 ( 1H, d, J = 8.0Hz), 3.54-3.64 (3H, m), 3.10-3.26 (3H, m), 1.85-1.97 (2H, m), 1.69-1.74 (1H, m), 1.62-1.66 (1H, m), 1.11 (3H, d, J = 6.4Hz).

[0551] Embodiment 119: (3S,4S)-8-(9-(Benzofuran-7-ylethynyl)-7H-imidazo[1,2-c]pyrazolo ... [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0552]

[0553] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 468.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.76 (1H, d, J=6.8Hz), 7.68 (1H, d, J=1.6Hz), 7.56 (1H, d, J=7.2Hz), 7.51 (1H, d, J=1.6Hz), 7.31-7.36 (2H, m), 7.06 (1H, d, J=6.8Hz), 4.18-4.2 5 (1H, m), 3.90 (1H, d, J = 8.4Hz), 3.63-3.76 (3H, m), 3.41-3.46 (1H, m), 3.07-3.17 (2H , m), 1.92-2.08 (2H, m), 1.77-1.82 (1H, m), 1.68-1.72 (1H, m), 1.23 (3H, d, J=6.0Hz).

[0554] Embodiment 120: (3S,4S)-8-(9-((1H-indol-7-yl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0555]

[0556] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 467.23 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.98 (1H, d, J=8.0Hz), 7.87 (1H, d, J=6.4Hz), 7.68 (1H, d, J=1.6H z), 7.65 (1H, d, J = 6.8Hz), 7.55 (1H, d, J = 5.6Hz), 7.52 (1H, d, J = 1.6Hz), 7.48 (1H, t, J = 8.0H z), 4.18-4.25 (1H, m), 3.89 (1H, d, J = 8.4Hz), 3.63-3.76 (3H, m), 3.42-3.45 (1H, m), 3.08-3 .17(2H,m), 1.93-2.06(2H,m), 1.78-1.82(1H,m), 1.69-1.72(1H,m), 1.22(3H,d,J=6.4Hz).

[0557] Embodiment 121: (3S,4S)-8-(9-((2-fluoro-4-methylphenyl)ethynyl)-7H-imidazo[1,2-c]pyrazole 2-oxa-8-azaspiro[4.5]decan-4-amine

[0558]

[0559] Referring to the method in Example 1, the target compound can be synthesized using appropriate starting materials and intermediates. MS m / z [LC-MS]: 460.23 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.69 (1H, d, J=1.2Hz), 7.54 (1H, t, J=8.0Hz), 7.49 (1H, d, J=1.2Hz), 7.20(1H, d, J=10.8Hz), 7.11(1H, d, J=7.6Hz), 4.12-4.18(1H, m), 3.78(1H , d, J = 8.8Hz), 3.59-3.69 (3H, m), 3.24 (1H, d, J = 4.8Hz), 3.12-3.20 (2H, m), 2.36 (3H , s), 1.90-1.97 (2H, m), 1.72-1.76 (1H, m), 1.64-1.68 (1H, m), 1.15 (3H, d, J = 6.8Hz).

[0560] Embodiment 122: (3S,4S)-8-(9-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)ethynyl)-7H-imidazo [1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0561]

[0562] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 518.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=8.08 (1H, d, J=4.8Hz), 7.71 (1H, d, J=1.6Hz), 7.50 (1H, d, J=1. 6Hz), 6.84 (1H, d, J = 4.8Hz), 4.08-4.13 (1H, m), 3.73 (1H, d, J = 8.4Hz), 3.53-3.64 (3H, m), 3.13-3.25(2H,m), 3.10(1H,d,J=4.8Hz), 2.71-2.77(1H,m), 1.85-1.97(2H,m), 1.69-1.7 3(1H,m), 1.62-1.66(1H,m), 1.11(3H,d,J=6.4Hz), 0.65-0.70(2H,m), 0.52-0.56(2H,m).

[0563] Embodiment 123: (3S,4S)-8-(9-((4-chloro-2,6-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolidone oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0564]

[0565] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 498.16 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.70(1H,d,J=1.6Hz), 7.58(2H,d,J=7.2Hz), 7.50(1H,d,J=1.6Hz), 4.12-4.18(1H,m), 3.77(1H,d,J =8.0Hz), 3.58-3.69(3H,m), 3.12-3.25(3H,m), 1.87-1.97(2H,m), 1.72-1.78(1H,m), 1.62-1.67(1H,m), 1.14(3H,d,J=6.8Hz).

[0566] Embodiment 124: (3S,4S)-8-(9-((6-chloro-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0567]

[0568] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 480.17 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.71 (1H, d, J=1.6Hz), 7.48-7.55 (3H, m), 7.37-7.42 (1H, m), 4.08-4.14 (1H, m), 3.73 (1H, d, J=8. 0Hz), 3.54-3.64(3H,m), 3.10-3.24(3H,m), 1.85-1.97(2H,m), 1.69-1.75(1H,m), 1.61-1.67(1H,m), 1.11(3H,d,J=6.4Hz).

[0569] Embodiment 125: (3S,4S)-8-(9-(spiro[chromane-2,1′-cyclobutane]-8-yl)-7H-imidazo[1,2-c]pyrrolidone oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0570]

[0571] The target compound can be synthesized by referring to the method in Example 36 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 500.28 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.20-13.48 (1H, brs), 8.10-8.30 (1H, m), 7.64 (1H, d, J=1.6Hz ), 7.36 (1H, d, J = 1.6Hz), 7.13 (1H, d, J = 7.6Hz), 6.83-6.98 (1H, m), 4.12-4.18 (1H, m), 3.78 (1H, d, J = 9.2Hz), 3.50-3.62 (3H, m), 3.23 (1H, d, J = 4.4Hz), 3.07-3.17 (2H, m), 2.81 (2H, t, J=6.0Hz), 1.86-2.01 (7H, m), 1.73-1.77 (1H, m), 1.52-1.68 (4H, m), 1.15 (3H, d, J=6.4Hz).

[0572] Embodiment 126: (3S,4S)-8-(9-((2,2-difluorocyclopropyl)ethynyl)-7H-imidazo[1,2-c]pyrazole 2-oxa-8-azaspiro[4.5]decan-4-amine

[0573]

[0574] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 506.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=8.19 (1H, d, J=5.2Hz), 7.70 (1H, d, J=1.2Hz), 7.52 (1H, d, J=1.2Hz), 7.14 (1H, d, J=5.2Hz), 4.12-4.19 (1H, m), 3.80 (1H , d, J=8.8Hz), 3.60-3.70 (3H, m), 3.12-3.28 (3H, m), 2.94 (6H, s), 1.90-1 .99(2H,m), 1.73-1.77(1H,m), 1.65-1.68(1H,m), 1.16(3H,d,J=6.8Hz).

[0575] Embodiment 127: (3S,4S)-8-(9-((3,5-dichloro-2,6-difluorophenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0576]

[0577] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 532.13 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=.

[0578] Embodiment 128: (3S,4S)-3-methyl-8-(9-((1-phenylcyclopropyl)ethynyl)-7H-imidazo[1,2-c] Pyrazolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0579]

[0580] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 468.25 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=13.64-13.90 (brs, 1H), 7.68 (d, J=1.6Hz, 1H), 7.54 (d, J=8 .4Hz, 2H), 7.50 (d, J=1.6Hz, 1H), 7.33 (t, J=8.0Hz, 2H), 7.21 (t, J=7.2Hz, 1H), 4.08-4 .14(m, 1H), 3.73(d, J=8.8Hz, 1H), 3.50-3.63(m, 3H), 3.08-3.23(m, 3H), 1.84-1.99(m , 2H), 1.60-1.76 (m, 2H), 1.56-1.59 (m, 2H), 1.44-1.47 (m, 2H), 1.12 (d, J=6.4Hz, 3H).

[0581] Embodiment 129: (3S,4S)-8-(9-((3,5-dichlorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[1,2-c] [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0582]

[0583] Referring to the method in Example 1, the target compound can be synthesized using appropriate starting materials and intermediates. MS m / z [LC-MS]: 496.14 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.75 (t, J=2.0Hz, 1H), 7.70 (d, J=1.6Hz, 1H), 7.66 (d, J=2.0Hz, 2H), 7.55 (d, J=1.6Hz, 1H), 4.14-4.21 (m, 1H), 3.82 (d, J=9 .6Hz, 1H), 3.58-3.74(m, 4H), 3.34-3.40(m, 1H), 3.08-3.21(m, 1H), 1.86- 1.99 (m, 2H), 1.74-1.83 (m, 1H), 1.62-1.71 (m, 1H), 1.18 (d, J=6.0Hz, 3H).

[0584] Embodiment 130: (3S,4S)-8-(9-((3-chloro-2,6-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolidone oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0585]

[0586] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 498.16 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.75-7.81(m, 1H), 7.70(d, J=1.6Hz, 1H), 7.52(d , J=1.6Hz, 1H), 7.36 (td, J=8.8Hz, 1.6Hz, 1H), 4.16-4.22 (m, 1H), 3.83 (d, J =9.2Hz, 1H), 3.62-3.76 (m, 4H), 3.36-3.41 (m, 1H), 3.12-3.20 (m, 1H), 1.86 -2.01 (m, 2H), 1.74-1.82 (m, 1H), 1.62-1.71 (m, 1H), 1.18 (d, J=6.8Hz, 3H).

[0587] Embodiment 131: (6-(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3- ((5-chloro-2-fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0588]

[0589] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 471.17 [M+1]. 1 H NMR (400MHz, CD3OD): δ=7.69 (dd, J=6.0Hz, 2.8Hz, 1H), 7.43-7.47 (m, 1H), 7.23 (t, J=9.2Hz, 1H), 4.79 (s, 2H), 4.25-4.32 (m, 1H), 3.96 (d, J=9.2H z, 1H), 3.68-3.86 (m, 3H), 3.46-3.48 (m, 1H), 3.01-3.16 (m, 2H), 1.96-2 .07 (m, 2H), 1.88-1.95 (m, 1H), 1.72-1.79 (m, 1H), 1.31 (d, J=6.4Hz, 3H).

[0590] Embodiment 132: (3S,4S)-8-(9-((5-chloro-2,4-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolidone oxazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0591]

[0592] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 498.16 [M+1]. 1 H NMR (400MHz, CD3OD): δ=8.07 (t, J=7.6Hz, 1H), 7.73 (d, J=1.6Hz, 1H), 7.50 (d, J=1.6Hz, 1H), 7.27 (t, J=9.2Hz, 1H), 4.24-4.30 (m, 1H), 3.9 2 (d, J=8.8Hz, 1H), 3.74-3.84 (m, 3H), 3.14-3.32 (m, 3H), 1.99-2.10 (m, 2H), 1.86-1.93 (m, 1H), 1-76-1.82 (m, 1H), 1.27 (d, J=6.4Hz, 3H).

[0593] Embodiment 133: (3S,4S)-8-(9-((2-fluoro-4-(trifluoromethyl)phenyl)ethynyl)-7H-imidazo[1,2- c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0594]

[0595] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 514.20 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.86-7.92 (m.2H), 7.71 (d, J=1.6Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.52 (d, J=1.6Hz, 1H), 4.10-4.17 (m, 1H), 3.8 7 (d, J=8.4Hz, 1H), 3.57-3.70 (m, 3H), 3.12-3.24 (m, 3H), 1.87-1.98 (m, 2H), 1.70-1.79 (m, 1H), 1.62-1.69 (m, 1H), 1.14 (d, J=6.8Hz, 3H).

[0596] Embodiment 134: (3S,4S)-3-Methyl-8-(9-(3-phenylprop-1-yn-1-yl)-7H-imidazo[1,2-c]pyrrolidone Oxalo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

[0597]

[0598] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 442.24 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.77 (d, J=1.6Hz, 1H), 7.58 (d, J=1.6Hz, 1H), 7.21-7.36 (m, 5H), 4.13-4.22 (m, 1H), 4.80 (d, J=6.4H z, 1H), 3.58-3.72 (m, 3H), 3.06-3.35 (m, 5H), 1.85-2.01 (m, 2H), 1.73-1.82 (m, 1H), 1.62-1.71 (m, 1H), 1.16 (d, J=6.8Hz, 3H).

[0599] Embodiment 135: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2,3-Difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0600]

[0601] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 455.20 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.46-7.60 (m, 2H), 7.24-7.34 (m, 1H), 5.58 (t, J=4.8Hz, 1H), 4.59 (d, J=4.8Hz, 2H), 4.0 7-4.16 (m, 1H), 3.49-3.78 (m, 4H), 2.99-3.36 (m, 3H), 1.77-2.01 (m, 2H), 1.54-1.72 (m, 2H), 1.13 (d, J=6.8Hz, 3H).

[0602] Embodiment 136: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((6-Chloro-2-fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0603]

[0604] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 471.17 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.48-7.56 (m, 2H), 7.37-7.42 (m, 1H), 5.56 (t, J=5.2Hz, 1H), 4.59 (d, J=5.2Hz, 2H), 4.11-4.18 (m, 1H), 3.5 9-3.80 (m, 4H), 3.24-3.26 (m, 1H), 3.01-3.14 (m, 2H), 1.80-1.93 (m, 2H), 1.66-1.75 (m, 1H), 1.55-1.65 (m, 1H), 1.15 (d, J=6.4Hz, 3H).

[0605] Embodiment 137: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((4-chloro-2-fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0606]

[0607] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 471.17 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.59-7.80 (m, 2H), 7.35-7.48 (m, 1H), 5.50-5.62 (brs, 1H), 4.50-4.64 (m, 2H), 4.04 -4.16 (m, 1H), 3.50-3.78 (m, 4H), 2.98-3.18 (m, 3H), 1.75-2.03 (m, 2H), 1.50-1.72 (m, 2H), 1.06-1.15 (m, 3H).

[0608] Embodiment 138: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2,3,6-Trifluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0609]

[0610] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 473.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.61-7.70 (m, 1H), 7.29-7.35 (m, 1H), 5.57 (t, J=5.6Hz, 1H), 4.58 (d, J=4.2Hz, 2H), 4.054.11 (m, 1H), 3.57-3 .72 (m, 3H), 3.53 (d, J=12.8Hz, 1H), 3.37-3.44 (m, 1H), 3.01-3.21 (m, 2H), 1.72-1.90 (m, 2H), 1.51-1.68 (m, 2H), 1.09 (d, J=6.0Hz, 3H).

[0611] Embodiment 139: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (3,3-Dimethylbut-1-yn-1-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0612]

[0613] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 399.25 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=4.85-4.93 (m, 1H), 4.56 (d, J=5.6Hz, 2H), 4.11-4.20 (m, 1H), 3.57-3.83 (m, 4H), 3. 36-3.44 (m, 1H), 3.16-3.22 (m, 2H), 1.78-1.92 (m, 2H), 1.52-1.66 (m, 2H), 1.32 (s, 9H), 1.15 (d, J=6.4Hz, 3H).

[0614] Embodiment 140: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((3,5-Difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0615]

[0616] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 455.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.36-7.44 (m, 3H), 5.56 (t, J=6.0Hz, 1H), 4.59 (d, J=4.2Hz, 2H), 4.06-4.16 (m, 1H), 3.75 (d, J=8.8H z, 1H), 3.50-3.72 (m, 3H), 3.02-3.18 (m, 3H), 1.77-1.92 (m, 2H), 1.64-1.72 (m, 1H), 1.55-1.62 (m, 1H), 1.13 (d, J=6.0Hz, 3H).

[0617] Example 141: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((4-chloro-2,6-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0618]

[0619] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 488.15 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.57-7.61 (m, 2H), 5.62 (t, J=5.6Hz, 1H), 4.58 (d, J=5.6Hz, 2H), 4.13-4.20 (m, 1H), 3.68-3.84 (m, 2H), 3.64 (d, J=9.2H z, 1H), 3.34-3.38 (m, 1H), 3.28-3.30 (m, 1H), 2.97-3.11 (m, 2H), 1.83-1 .92 (m, 2H), 1.70-1.78 (m, 1H), 1.57-1.65 (m, 1H), 1.18 (d, J=6.8Hz, 3H).

[0620] Embodiment 142: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2,3,5,6-Tetrafluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0621]

[0622] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 491.18 [M+1]. 1 H NMR (400MHz, CD3OD): δ=7.51-7.60 (m, 1H), 4.78 (s, 2H), 4.23-4.29 (m, 1H), 3.90 (d, J=9.2Hz, 1H), 3.68-3.8 0 (m, 3H), 3.06-3.26 (m, 3H), 1.92-2.04 (m, 2H), 1.80-1.88 (m, 1H), 1.70-1.77 (m, 1H), 1.26 (d, J=7.2Hz, 3H).

[0623] Embodiment 143: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-Fluoro-3-methoxyphenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0624]

[0625] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 467.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.26-7.30 (m, 1H), 7.18-7.22 (m, 2H), 5.59 (t, J= 5.6Hz, 1H), 4.58 (d, J=5.6Hz, 2H), 4.12-4.18 (m, 1H), 3.86 (s, 3H), 3.64-3. 81 (m, 3H), 3.60 (d, J = 8.8Hz, 1H), 3.23-3.27 (m, 1H), 2.99-3.11 (m, 2H), 1.8 2-1.92 (m, 2H), 1.66-1.74 (m, 1H), 1.57-1.63 (m, 1H), 1.16 (d, J=6.0Hz, 3H).

[0626] Embodiment 144: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2,6-Difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0627]

[0628] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 455.20 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.53-7.61 (m, 1H), 7.25-7.30 (m, 2H), 5.61 (t, J=5.6Hz, 1H), 4.58 (d, J=5.6Hz, 2H), 4.12-4.18 (m, 1H), 3.65-3.82 (m, 3H ), 3.60 (d, J = 8.8Hz, 1H), 3.27 (d, J = 4.4Hz, 1H), 3.01-3.14 (m, 2H), 1.84- 1.94 (m, 2H), 1.68-1.74 (m, 1H), 1.58-1.64 (m, 1H), 1.17 (d, J=6.0Hz, 3H).

[0629] Embodiment 145: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2,4-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0630]

[0631] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 455.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.73-7.79 (m, 1H), 7.47 (td, J=9.6Hz, 2.4Hz, 1H), 7.18-7.2 2 (m, 1H), 5.58 (t, J=5.6Hz, 1H), 4.58 (d, J=5.6Hz, 2H), 4.10-4.16 (m, 1H), 3.77 (d, J=8. 8Hz, 1H), 3.62-3.75 (m, 2H), 3.58 (d, J=8.8Hz, 1H), 3.20 (d, J=4.8Hz, 1H), 3.01-3.14( m, 2H), 1.80-1.92 (m, 2H), 1.64-1.72 (m, 1H), 1.55-1.63 (m, 1H), 1.14 (d, J=6.4Hz, 3H).

[0632] Embodiment 146: (3S,4S)-8-(3-((5-chloro-2-fluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[2-(4-(5-chloro-2-fluorophenyl)ethynyl ...5-(fluoromethyl)-1H-pyrazolo[2-(4-(5-chloro-2-fluorophenyl)ethynyl)-1H- [3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0633]

[0634] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 473.17 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.81 (dd, J=6.4Hz, 2.8Hz, 1H), 7.57-7.61 (m, 1H), 7.44 (t, J=8.8Hz, 1H), 5.54 (d, J=48.0Hz, 2H), 4.12-4.18 (m, 1H), 3.80 (d, J= 8.8Hz, 1H), 3.48-3.62 (m, 3H), 3.26 (d, J=4.4Hz, 1H), 3.02-3.14 (m, 2H), 1.8 4-1.96 (m, 2H), 1.68-1.74 (m, 1H), 1.58-1.65 (m, 1H), 1.16 (d, J=6.0Hz, 3H).

[0635] Embodiment 147: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2,4,5-Trifluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0636]

[0637] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 473.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.89-7.96 (m, 1H), 7.74-7.81 (m, 1H), 5.58 (t, J=6.0Hz, 1H), 4.58 (d, J=5.6Hz, 2H), 4.10-4.16 (m, 1H), 3.62-3.79 (m, 3H ), 3.58 (d, J = 8.8Hz, 1H), 3.21 (d, J = 4.8Hz, 1H), 3.01-3.12 (m, 2H), 1.80- 1.92 (m, 2H), 1.65-1.72 (m, 1H), 1.56-1.63 (m, 1H), 1.14 (d, J=6.8Hz, 3H).

[0638] Embodiment 148: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-Chloro-3,6-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0639]

[0640] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 489.16 [M+1]. 1H NMR (400MHz, DMSO-d6): δ = 7.59-7.65 (m, 1H), 7.45-7.50 (m, 1H), 5.60 (t, J = 6.0Hz, 1H), 4.59 (d, J = 6.0Hz, 2H), 4.15-4.21 (m, 1H), 3.70-3.85 (m, 3H) ), 3.66 (d, J=8.8Hz, 1H), 3.39 (d, J=4.8Hz, 1H), 2.98-3.10 (m, 2H), 1.84- 1.92 (m, 2H), 1.72-1.78 (m, 1H), 1.57-1.64 (m, 1H), 1.18 (d, J=6.8Hz, 3H).

[0641] Embodiment 149: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- ((2-Fluoro-4-methylphenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0642]

[0643] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 451.23 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.55 (t, J=7.6Hz, 1H), 7.21 (d, J=7.2Hz, 1H), 7.10 (d, J= 7.2Hz, 1H), 5.60 (t, J=5.6Hz, 1H), 4.58 (d, J=5.6Hz, 2H), 4.10-4.16 (m, 1H), 3.64-3 .81(m, 3H), 3.61(d, J=8.4Hz, 1H), 3.26-3.30(m, 1H), 2.98-3.01(m, 2H), 2.35(s, 3 H), 1.82-1.92 (m, 2H), 1.68-1.75 (m, 1H), 1.57-1.62 (m, 1H), 1.16 (d, J=6.4Hz, 3H).

[0644] Embodiment 150: (3S,4S)-8-(3-((4-chloro-2,6-dimethoxyphenyl)ethynyl)-5-(methoxymethyl 1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0645]

[0646] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 527.22 [M+1]. 1H NMR (400MHz, CD3OD): δ=6.72 (s, 2H), 4.62 (s, 2H), 4.19-4.25 (m, 1H), 3.88 (s, 6H), 3.84 (d, J=8.4Hz, 1H), 3.64-3.72 (m, 3H), 3.49 (s, 3H), 3.09-3.27 (m, 2H), 3.02 (d, J=5.2Hz, 1H), 1.87-2.04 (m, 2H), 1.68-1.79 (m, 2H), 1.20 (d, J=6.0Hz, 3H).

[0647] Embodiment 151: (3S,4S)-8-(3-((4-chloro-2,6-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazole 2-(3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0648]

[0649] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 491.16 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.57-7.61 (m, 2H), 5.54 (d, J=47.6Hz, 2H), 4.07-4.13 (m, 1H), 3.72 (d, J=8.4Hz, 1H), 3.4 5-3.58 (m, 3H), 3.04-3.08 (m, 3H), 1.78-1.94 (m, 2H), 1.64-1.72 (m, 1H), 1.55-1.63 (m, 1H), 1.11 (d, J=6.4Hz, 3H).

[0650] Embodiment 152: (3S,4S)-8-(3-((4-chloro-2-fluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[2-(4-chloro-2-fluorophenyl)ethynyl)- [3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0651]

[0652] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 473.17 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.73 (t, J=8.0Hz, 1H), 7.65 (dd, J=9.6Hz, 2.0Hz, 1H), 7.38 (dd, J=8.0Hz, 2.0Hz, 1H), 5.54 (d, J=48.0Hz, 2H), 4.08-4.14 ( m, 1H), 3.73 (d, J=8.4Hz, 1H), 3.46-3.58 (m, 3H), 3.04-3.18 (m, 3H), 1.79- 1.93 (m, 2H), 1.64-1.73 (m, 1H), 1.55-1.63 (m, 1H), 1.12 (d, J=6.4Hz, 3H).

[0653] Embodiment 153: (3S,4S)-8-(3-((2-fluoro-3-methoxyphenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazole 2-(3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0654]

[0655] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 469.22 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.24-7.32 (m, 1H), 7.17-7.23 (m, 2H), 5.54 (d, J=48.0Hz, 2H), 4.09-4.15 (m, 1H), 3.86 (s, 3H), 3.74 (d, J =8.8Hz, 1H), 3.46-3.60 (m, 3H), 3.02-3.19 (m, 3H), 1.76-1.94 (m, 2H), 1.65-1.73 (m, 1H), 1.55-1.64 (m, 1H), 1.12 (d, J = 6.4Hz, 3H).

[0656] Embodiment 154: (3S,4S)-8-(3-((2-chloro-3,6-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazole 2-(3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0657]

[0658] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 491.16 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.59-7.65 (m, 1H), 7.45-7.51 (m, 1H), 5.55 (d, J=47.6Hz, 2H), 4.13-4.19 (m, 1H), 3.81 (d, J=9.2Hz , 1H), 3.50-3.65 (m, 3H), 2.98-3.14 (m, 3H), 1.84-1.95 (m, 2H), 1.70-1.77 (m, 1H), 1.58-1.66 (m, 1H), 1.17 (d, J=6.4Hz, 3H).

[0659] Embodiment 155: (3S,4S)-8-(3-((3,5-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[3, 4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0660]

[0661] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 457.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.38-7.44 (m, 3H), 5.54 (d, J=47.6Hz, 2H), 4.08-4.15 (m, 1H), 3.74 (d, J=9.2Hz, 1H), 3.4 6-3.60 (m, 3H), 3.02-3.20 (m, 3H), 1.79-1.93 (m, 2H), 1.66-1.74 (m, 1H), 1.55-1.64 (m, 1H), 1.13 (d, J=6.4Hz, 3H).

[0662] Embodiment 156: (3S,4S)-8-(3-((2-chloro-6-fluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[2-yl]- [3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0663]

[0664] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 473.17 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.48-7.56 (m, 2H), 7.38-7.43 (m, 1H), 5.54 (d, J=47.6Hz, 2H), 4.11-4.18 (m, 1H), 3.79 (d, J=8.8Hz , 1H), 3.49-3.63 (m, 3H), 3.02-3.15 (m, 3H), 1.83-1.95 (m, 2H), 1.69-1.76 (m, 1H), 1.57-1.65 (m, 1H), 1.16 (d, J=6.4Hz, 3H).

[0665] Embodiment 157: (3S,4S)-8-(3-((2,4-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[3, 4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0666]

[0667] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 457.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.75-7.81 (m, 1H), 7.44-7.50 (m, 1H), 7.18-7.22 (m, 1H), 5.54 (d, J=48.0Hz, 2H), 4.06-4.12 (m, 1H) ), 3.70 (d, J=8.4Hz, 1H), 3.44-3.56 (m, 3H), 3.02-3.20 (m, 3H), 1.76-1.92 (m, 2H), 1.54-1.70 (m, 2H), 1.10 (d, J=6.0Hz, 3H).

[0668] Embodiment 158: (3S,4S)-8-(5-(Fluoromethyl)-3-((2,4,5-trifluorophenyl)ethynyl)-1H-pyrazolo[2,4,5-trifluorophenyl]ethynyl)-1H-pyrazolo[2,4,5-trifluorophenyl]ethynyl [3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0669]

[0670] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 475.19 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.92-7.98 (m, 1H), 7.74-7.80 (m, 1H), 5.54 (d, J=47.6Hz, 2H), 4.10-4.16 (m, 1H), 3.76 (d, J=8.8Hz, 1H), 3.48 -3.60 (m, 3H), 3.02-3.16 (m, 2H), 3.18 (d, J=5.2Hz, 1H), 1.80-1.94 (m, 2H), 1.65-1.73 (m, 1H), 1.56-1.64 (m, 1H), 1.14 (d, J=6.4Hz, 3H).

[0671] Embodiment 159: (3S,4S)-8-(5-(Fluoromethyl)-3-((2,3,6-trifluorophenyl)ethynyl)-1H-pyrazolo[3-( ...(2,3,6-trifluorophenyl)ethynyl)-8-(((((2,3,6-trifluorophenyl)ethynyl)-1H-pyrazolo[3-(((((2,3,6-trifluorophenyl)ethynyl)-8-((((( [3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0672]

[0673] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 475.19 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.62-7.71 (m, 1H), 7.29-7.35 (m, 1H), 5.54 (d, J=48.0Hz, 2H), 4.08-4.15 (m, 1H), 3.74 (d, J=8.8Hz , 1H), 3.48-3.60 (m, 3H), 3.04-3.18 (m, 3H), 1.79-1.94 (m, 2H), 1.66-1.73 (m, 1H), 1.56-1.64 (m, 1H), 1.13 (d, J=6.8Hz, 3H).

[0674] Embodiment 160: (3S,4S)-8-(3-((2-fluoro-4-methylphenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[2-(4-((2-fluoro-4-methylphenyl)ethynyl ... [3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0675]

[0676] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 453.22 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=7.56 (t, J=7.6Hz, 1H), 7.21 (d, J=7.2Hz, 1H), 7.10 (d, J=7.6Hz, 1H), 5.54 (d, J=48.0Hz, 2H), 4.09-4.15 (m, 1H), 3.75 (d, J=9.2Hz, 1H), 3.46-3.60 (m, 3H), 3.02-3.19 (m, 3H), 2.35 (s, 3H), 1.81-1 .85 (m, 2H), 1.66-1.72 (m, 1H), 1.57-1.64 (m, 1H), 1.13 (d, J=6.4Hz, 3H).

[0677] Example 161: (3S,4S)-8-(3-((2,6-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[3, 4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0678]

[0679] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 457.20 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.54-7.63 (m, 1H), 7.25-7.32 (m, 2H), 5.55 (d, J=47.6Hz, 2H), 4.13-4.19 (m, 1H), 3.81 (d, J=8.8Hz, 1H), 3.5 0-3.64 (m, 3H), 3.26-3.32 (m, 1H), 3.02-3.12 (m, 2H), 1.85-1.98 (m, 2H), 1.69-1.76 (m, 1H), 1.59-1.66 (m, 1H), 1.18 (d, J=6.0Hz, 3H).

[0680] Embodiment 162: (3S,4S)-8-(5-(Fluoromethyl)-3-((2,3,5,6-tetrafluorophenyl)ethynyl)-1H-pyrazole 2-oxa-8-azaspiro[4.5]decan-4-amine

[0681]

[0682] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 493.18 [M+1]. 1H NMR (400MHz, DMSO-d6): δ=8.03-8.12 (m, 1H), 5.54 (d, J=47.6Hz, 2H), 4.09-4.15 (m, 1H), 3.76 (d, J=8.8Hz, 1H), 3.4 7-3.60 (m, 3H), 3.04-3.21 (m, 3H), 1.80-1..94 (m, 2H), 1.66-1.73 (m, 1H), 1.56-1.64 (m, 1H), 1.13 (d, J=6.4Hz, 3H).

[0683] Embodiment 163: (3S,4S)-8-(3-((2-chloro-4,6-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazole 2-oxa-8-azaspiro[4.5]decan-4-amine

[0684]

[0685] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 491.16 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.54-7.63 (m, 2H), 5.54 (d, J=47.6Hz, 2H), 4.08-4.14 (m, 1H), 3.73 (d, J=8.4Hz, 1H), 3.4 6-3.58 (m, 3H), 3.03-3.18 (m, 3H), 1.78-1.92 (m, 2H), 1.65-1.72 (m, 1H), 1.55-1.63 (m, 1H), 1.12 (d, J=6.8Hz, 3H).

[0686] Embodiment 164: (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3- (2(2-chloro-4,6-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[0687]

[0688] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 489.16 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.53-7.62 (m, 2H), 5.52 (t, J=5.4Hz, 1H), 4.58 (d, J=5.4Hz, 2H), 4.06-4.12 (m, 1H), 3.57- 3.72 (m, 3H), 3.53 (d, J=8.4Hz, 1H), 3.04-3.19 (m, 3H), 1.75-1.90 (m, 2H), 1.53-1.68 (m, 2H), 1.10 (d, J=6.4Hz, 3H).

[0689] Embodiment 165: (3S,4S)-8-(3-((2,3-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[3, 4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

[0690]

[0691] The target compound can be synthesized by referring to the method in Example 1 using appropriate starting materials and intermediates. MS m / z [LC-MS]: 457.48 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ=7.48-7.60(m, 2H), 7.27-7.32(m, 1H), 5.54(d, J=48.0Hz, 2H), 4.06-4.13(m, 1H), 3.72(d , J=9.2Hz, 1H), 3.45-3.56 (m, 3H), 3.04-3.20 (m, 3H), 1.76-1.94 (m, 2H), 1.54-1.71 (m, 2H), 1.11 (d, J=6.4Hz, 3H).

[0692] Determination of the inhibitory effect of compounds on SHP2 enzymatic activity in vitro

[0693] In this patent, the enzymatic activity detection of SHP2 is carried out by rapid fluorescence method, DiFMUP is used as an alternative substrate for reaction and a high-throughput screening platform is optimized and established. The detection of the inhibitory activity of the compound on SHP2 is operated on this platform. The specific method is as follows: a mixture of SHP2 with a final concentration of 1nM and a diphosphorylated IRS1 peptide (sequence: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide) is pre-incubated at 23°C for 30 minutes. The compound is diluted 5 times with 100% DMSO starting from 0.2mM (7 concentrations in total), and 2μL of the compound is added to 48μL of reaction buffer (60mM HEPES, pH 7.2, 75mM NaCl, 75mM KCl, 1mM EDTA, 0.05% Tween 20, 5mM DTT) for dilution and mixing. Take 5 μL of the diluted compound and add it to a black 384-well plate (OptiPlate-384, product number 6007270, purchased from PerkinElmer), then add 10 μL of the pre-incubated SHP2 and IRS1 peptide mixture, centrifuge to mix, and incubate at 23°C for 30 minutes. Add 5 μL of the alternative substrate DiFMUP (final concentration 50 μM, product number D6567, purchased from Invitrogen) to the reaction and incubate at 23°C for 60 minutes. The reaction was then terminated by adding 5 μL of 160 μM bpV (Phen) solution (SC-22137, purchased from Santa). Immediately after the reaction was terminated, a microplate reader (Perkin-Elmer) was used to detect the fluorescence signal at excitation and emission wavelengths of 340 nm and 450 nm, respectively. The data was calculated using GraphPad Prism software to obtain the IC value of the compound. 50 value.

[0694] Determination of the inhibitory effect of compounds on the proliferation of SHP2 positive cells

[0695] Human non-small cell lung cancer cell line NCI-H358 cells were cultured using RPMI-1640 medium (Cat. No. C11875500BT, purchased from Biological Industries) plus 10% fetal bovine serum (FBS, Cat. No. 04-001-1ACS, purchased from Biological Industries, BI) and 1% penicillin / streptomycin dual antibody (P / S, Cat. No. 15070-063, purchased from Gibco), and the culture conditions were 37°C, 5% CO2. One day before the compound detection, NCI-H358 cells were plated in a 196-well plate (Cat. No. 3917, purchased from Corning) at a concentration of 2000 cells / 195 μL / well. After 24 hours, the compound was diluted 3 times from 10 mM with 100% DMSO (a total of 10 concentrations), and then 2 μL of the compound was taken at each concentration and added to 48 μL of medium without serum and dual antibody for dilution. 5 μL of each diluted compound concentration was added to the cell suspension, and the compound and cells were incubated in a cell culture incubator for 72 hours (3 days). After the culture medium was removed, 25 μL of Cell-Titer Glo (G7570, purchased from Promega) reagent was added and incubated again for 5-10 minutes. The fluorescence value was then read on Envision, and the data were calculated using GraphPad Prism software to obtain the IC value of the compound's inhibition of cell proliferation. 50 value.

[0696] Kasumi-1 cells, a human acute myeloblastic leukemia cell line, were cultured using RPMI-1640 medium (Cat. No. C11875500BT, purchased from Biological Industries) plus 20% fetal bovine serum (FBS, Cat. No. 04-001-1ACS, purchased from Biological Industries, BI) and 1% penicillin / streptomycin double antibody (P / S, Cat. No. 15070-063, purchased from Gibco) at 37°C and 5% CO2. One day before the compound test, Kasumi-1 cells were plated in a 196-well plate (Cat. No. 3599, purchased from Corning) at a concentration of 3000 cells / 195 μL / well. After 24 hours, the compound was diluted 3-fold with 100% DMSO starting from 10 mM (a total of 10 concentrations), and then 2 μL of the compound was taken at each concentration and diluted in 48 μL of medium without serum and double antibody. 5 μL of each diluted compound concentration was added to the cell suspension, and the compound and cells were incubated in a cell culture incubator for 72 hours (3 days), and 35 μL of Cell-Titer Blue (G8082, purchased from Promega) reagent was added and incubated again for 4 hours. After that, the fluorescence value was read on Flexstation III (560 nm excitation, 590 nm detection), and the data were calculated using GraphPad Prism software to obtain the IC value of the compound's inhibition of cell proliferation. 50 value.

[0697] Table 1 Inhibitory activity of the compounds in the examples on SHP2 enzyme and cell proliferation

[0698]

[0699] The test data in Table 1 show that the compounds provided by the present invention have good SHP2 kinase inhibitory activity and also have good inhibitory activity on the proliferation of SHP2 positive expression cells.

Claims

1. The compound shown below:

2. A pharmaceutical composition comprising the compound according to claim 1, and optionally comprising a pharmaceutically acceptable excipient.

3. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating diseases associated with SHP2.

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

Images