Heterocyclic compound with biological activity

Abstract

The invention relates to a heterocyclic compound with biological activity as shown in a formula (I), a preparation method and a pharmaceutical composition thereof, and further relates to application of the compound and the pharmaceutical composition thereof, such as cancer treatment. In the preparation process, the compound shown in the formula I is obtained through substitution, coupling, deprotection and other reactions. # imgabs0 #

Description

Biologically active heterocyclic compounds

[0001] Cross-references

[0002] This application claims priority to Chinese Patent Application No. 202210888300.2 filed on July 26, 2022, Chinese Patent Application No. 202211098407.3 filed on September 8, 2022, Chinese Patent Application No. 202211264067.7 filed on October 14, 2022, and Chinese Patent Application No. 202211365522.2 filed on November 2, 2022, the entire disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention generally relates to novel substituted pyridyl heterocyclic compounds having SHP2 inhibitory activity, methods for their preparation, and pharmaceutical compositions thereof, and also relates to the use of such compounds and pharmaceutical compositions thereof in treating diseases that benefit from SHP2 enzyme inhibition, such as cancer. Background Art

[0004] Cancer is a serious disease that poses a serious threat to human health and life. In recent years, the incidence and mortality of cancer have been rapidly increasing, surpassing cardiovascular disease as the leading cause of death. Tumor proliferation, apoptosis, and metastasis are closely linked to abnormalities in a series of intracellular and extracellular signaling pathways. Protein phosphorylation and dephosphorylation are crucial in these signaling pathways, a reversible process regulated by kinases and phosphatases. Phosphorylation by protein tyrosine kinases (PTKs) and dephosphorylation by protein tyrosine phosphatases (PTPs) are examples of such reversible processes, maintaining a dynamic equilibrium between them to maintain normal cellular function. Abnormal phosphorylation can lead to cancer, inflammation, diabetes, and other diseases.

[0005] SHP2 protein is a non-receptor protein tyrosine phosphatase encoded by the ptpn11 gene. It is widely expressed in various tissues and participates in important physiological and pathological processes such as embryonic development, metabolism, immune response and tumorigenesis.

[0006] The SHP2 protein consists of two tandem SH2 domains at the N-terminus (N-SH2 and C-SH2), a PTP catalytic domain, and a regulatory C-terminal tail. The SH2 domain acts as a conformational switch, mediating 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 unstimulated state, the SHP2 domain binds to the PTP domain, blocking the catalytic active site and rendering SHP2 phosphatase activity autoinhibited. Upon activator binding, the inhibitory intramolecular interaction is released, and the SHP2 phosphatase enters an open conformation, allowing SHP2 substrates to localize to the catalytic active site and perform phosphatase function. This activity-switching property of SHP2 makes it possible for various SHP2 mutations to disrupt the autoinhibitory state, leading to overactivation of SHP2 protein phosphatase activity and, in turn, cancer. 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.

[0007] SHP2 is involved in regulating cell signaling pathways activated by cytokines, growth factors, and hormones, including the RAS / ERK, JAK / STAT, PI3K / AKT, and NF-κB signaling pathways, thereby regulating physiological functions such as cell proliferation, differentiation, cell cycle maintenance, and migration. Furthermore, SHP2 mediates compensatory activation pathways following inhibition of kinases such as MEK, thereby promoting the development of tumor drug resistance. As a downstream molecule of the PD-1 receptor, SHP2 is also involved in the transmission of inhibitory signals in T cells. Studies have shown that SHP2, a downstream molecule of PD-1 signaling, not only inhibits T cell activation but also promotes T cell anergy. Therefore, targeting SHP2 may restore or enhance T cell-mediated anti-tumor immunity. Furthermore, SHP2 can inhibit IFN-γ-mediated immune responses by inactivating the signal transducer and activator of transcription 1.

[0008] In recent years, activating mutations and elevated expression of SHP2 have been discovered in leukemia, solid tumors, melanoma, malignant glioma, lung cancer, breast cancer, and Numan syndrome, and are closely associated with tumor development, progression, and prognosis. Currently, SHP2 has been investigated as a target molecule for clinical tumorigenesis. Traditional SHP2 inhibitors (e.g., II-B08 and PHPS1) all bind to the PTP catalytic domain of SHP2, preventing tyrosine-phosphorylated substrates from entering the catalytic site, thereby inhibiting SHP2 phosphatase activity. However, due to the highly conserved, polar, and charged environments of the PTP catalytic domains of various phosphatases, traditional SHP2 inhibitors have significant limitations in specificity and bioavailability, limiting their clinical application. Therefore, the development of SHP2 inhibitors with high specificity, safety, and strong cell membrane permeability is crucial for determining whether SHP2 can become a novel target for tumor intervention. Allosteric inhibitors of the SHP2 protein have become a major research focus. In summary, the development of SHP2 allosteric inhibitors is rapidly gaining momentum, and competition is intensifying both domestically and internationally. This class of drugs is poised to become a powerful new weapon in cancer treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG1 shows the tumor inhibition effect of the compounds of the present invention.

[0010] FIG2 shows the effects of the compounds of the present invention on the body weight of mice.

[0011] Summary of the Invention

[0012] In one aspect, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,

[0013] in,

[0014] Ring A is or

[0015] Wherein the * carbon is connected to Y, X3 and X4 are each independently N or CR 10 ,

[0016] R3, R 20 、R 21 and R 22 Each is independently H, halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl,

[0017] The alkyl, cycloalkyl and heterocycloalkyl groups may be optionally substituted with one or more halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution,

[0018] Ring B is a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring, or

[0019] Ring B is a bicyclic or tricyclic ring system comprising a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring connected to N, and a 3-8 membered alicyclic ring or a 3-8 membered heteroalicyclic ring fused to the aromatic ring or heteroaromatic ring, wherein the alicyclic ring and the heteroalicyclic ring may be optionally oxidized.

[0020] X1 and X2 are each independently N or CR7,

[0021] R7 and R 10 Each is independently H, halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, said alkyl, cycloalkyl and heterocycloalkyl may be optionally substituted with one or more halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution,

[0022] R2 is H or C 1-6 alkyl,

[0023] R1 is halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, -O-(6-10 membered aryl), -NR-(6-10 membered aryl), 5-12 membered heteroaryl, -O-(5-12 membered heteroaryl), -NR-(5-12 membered heteroaryl), -P(O)RR, -(SO)-R, -(CO)-R, -COOH, -(CO)-O-R, or -(CO)-NR-R, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R,

[0024] R4 are each independently selected from halogen, -CN, -NH2, -OH, -NO2, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P(O)R8R9, -(SO2)-R6, -(CO)-R6, -COOH, -(CO)-O-R6, or -(CO)-NR-R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be optionally substituted with one or more halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 substituted by cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P(O)R8R9, -(SO2)-R6, -(CO)-R6, -COOH, -(CO)-O-R6 or -(CO)-NR-R6,

[0025] R5 and R6 are each independently selected from C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl and cycloalkyl being optionally substituted with one or more halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 1-6 Alkyl or -NH-C 1-6 Alkyl substitution,

[0026] R8 and R9 are each independently selected from C 1-6 Alkyl and C 3-8 Cycloalkyl,

[0027] R is each independently selected from H and C 1-6 alkyl,

[0028] Y is selected from C 6-10 aryl, 5-12 membered heteroaryl, 3-12 membered heteroalicyclic and 5-15 membered spirocyclic, wherein the aryl, heteroaryl, heteroalicyclic and spirocyclic groups may be optionally substituted with one or more halogen, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, C 1-6 Alkyl, or C 3-8 Cycloalkyl substituted, said alkyl or cycloalkyl may be optionally substituted with halogen, -OH, -OC 1-6 Alkyl, -NH2, or -NH-C 1-6 Alkyl substituted, the heteroalicyclic group and spirocyclic group can be optionally with C 6-10The aryl or 5-10 membered heteroaryl fused, the aryl or heteroaryl fused with heteroalicyclic and spirocyclic groups may be optionally substituted with one or more halogen, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, C 1-6 Alkyl, or C 3-8 Cycloalkyl substitution,

[0029] n is 0, 1, 2 or 3,

[0030] Provided that the following compounds are not included

[0031] In some embodiments, R1 is halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, -O-(6-10 membered aryl), -NR-(6-10 membered aryl), 5-12 membered heteroaryl, -O-(5-12 membered heteroaryl), -NR-(5-12 membered heteroaryl), -P(O)RR, -(SO)-R, -COOH, -(CO)-O-R, or -(CO)-NR-R, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R,

[0032] R4 are each independently selected from halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P(O)R8R9, -(SO2)-R6, -COOH, -(CO)-O-R6, or -(CO)-NR-R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be optionally substituted with one or more halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P(O)R8R9, -(SO2)-R6, -COOH, -(CO)-O-R6 or -(CO)-NR-R6,

[0033] R5 and R6 are each independently selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, said alkyl and cycloalkyl groups may be optionally substituted with one or more halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl or -NH-C 1-6 Alkyl substitution,

[0034] R, R8 and R9 are as defined above.

[0035] In some embodiments, Ring A is where R 20 and R 22 As defined above.

[0036] In some embodiments, X1 and X2 are each independently CR7, and R7 are each independently H, halogen, -CN, -NH2, -OH, or C 1-6 Alkyl, preferably H or C 1-6 Alkyl, more preferably, X1 and X2 are CH.

[0037] In some embodiments, X3 and X4 are each independently CR 10 , R 10 are each independently H, halogen, -CN, -NH2, -OH, or C 1-6 Alkyl, preferably H or C 1-6 Alkyl, more preferably, X3 and X4 are CH.

[0038] In some embodiments, R2 is H.

[0039] In some embodiments, R3 is halogen, preferably Cl.

[0040] In some embodiments, R5 and R6 are each independently selected from C 1-6 Alkyl and C 3-8 Cycloalkyl.

[0041] In some embodiments, n is 0, 1, or 2, preferably 0 or 1.

[0042] In some embodiments,

[0043] Y is a 5-15 membered spirocycloalkyl or a 5-15 membered heterospirocycloalkyl, which may be optionally substituted with one or more halogens, C 1-6 Alkyl, -OH or -NH2 substituted.

[0044] In some preferred embodiments, Y is a 5-15 membered oxazaspirocycloalkyl group, which may be optionally substituted with one or more halogens, C1-6 Alkyl, -OH or -NH2 substituted.

[0045] In some more preferred embodiments, Y is The group may be optionally substituted with one or more halogen, C 1-6 Alkyl, -OH, or -NH2 substituted.

[0046] In some embodiments, ring B is a pyridine ring or a pyrimidine ring, or

[0047] Ring B is a bicyclic or tricyclic ring system including a pyridine ring or a pyrimidine ring connected to N, and a 5-6 membered alicyclic ring or a 5-6 membered heteroalicyclic ring fused to the pyridine ring or the pyrimidine ring, wherein the alicyclic ring and the heteroalicyclic ring may be optionally oxidized.

[0048] In some embodiments, ring B is a pyridine ring or a pyrimidine ring, preferably a pyrimidine ring.

[0049] In some embodiments, the present invention provides the following compounds or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, metabolites or prodrugs thereof:

[0050] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, and optionally comprising a pharmaceutically acceptable excipient.

[0051] In another aspect, the present invention provides a method for treating a disease associated with SHP2, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition thereof.

[0052] On the other hand, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition thereof, or use of any one of the foregoing in combination with a SHP2 inhibitor or a KRAS inhibitor or an EGFR inhibitor in the preparation of a medicament for treating diseases associated with SHP2 and / or KRAS and / or EGFR.

[0053] In some embodiments of the present invention, the disease associated with SHP2 and / or KRAS and / or EGFR is leukemia, melanoma, malignant glioma, lung cancer, breast cancer or Noonan syndrome.

[0054] On the other hand, SHP2 acts upstream of KRAS. The Hana Algul team (Mutant KRAS-driven cancers depend on PTPN11 / SHP2 phosphatase, Nature Medicine 2018) confirmed that SHP2 small molecule inhibitors have significant therapeutic effects on aggressive KRAS tumors such as pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Protein tyrosine phosphatase SHP2 has become a key drug target for aggressive KRAS tumors. In addition, Schneeberger, VE's team (Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma. Onco target 2015) confirmed that in EGFR-mutated non-small cell lung cancer, SHP2 can promote RAS-RAF-MEK-ERK signaling. Therefore, the SHP2 small molecule inhibitor of the present invention, used alone or in combination with KRAS inhibitors (AMG510, etc.) or EGFR inhibitors (Iressa, Tarceva, etc.) in the prior art, can effectively inhibit the occurrence and progression of tumors.

[0055] On the other hand, similarities in biological activity are often found between functional groups with similar steric or electronic properties. Structures that share the same biological role within a drug molecule are called bioisosteres. Isosteres are structures that replace the original functional group in the drug with another one without affecting the primary biological activity of the drug. Examples include the replacement of monovalent atoms or groups such as OH, NH2, F, and SH, and the replacement of carboxyl groups with phosphates or tetrazoles.

[0056] Detailed Description of the Invention

[0057] Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description of the invention. The features and advantages of the present invention may be better understood by reference to the following summary of the invention.

[0058] It should be understood that the scope of protection of various aspects of the present invention is determined by the claims, and methods and structures within the scope of these claims and their equivalents are all within the scope of the claims.

[0059] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

[0060] It should be understood that the foregoing brief description and the following detailed description are exemplary and explanatory, rather than limiting, of any subject matter of the present invention. Unless otherwise specifically stated, the use of the singular also includes the plural. Unless otherwise specified, the use of "or" and "alternatively" means "and / or." In addition, the use of the term "include," as well as other forms such as "comprises," "includes," and "comprising" are not limiting.

[0061] Some chemical terms

[0062] 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.

[0063] The compounds of the present invention also include tautomeric forms, which result from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0064] The present invention also includes all isotopes of atoms, whether in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0065]

[0046] The term "fused" or "fused ring," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

[0066]

[00146] The term "spiro" or "spirocycle," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

[0067] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0068] 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 1-6 Alkyl groups such as methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl, etc. The alkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl and hydroxyl.

[0069] The term "C 1-6 "Alkyl" refers to a straight or branched chain 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 to 6 carbon atoms. The alkyl group can be unsubstituted or substituted with 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, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylhexyl, and the like.

[0070] The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched monovalent hydrocarbon group having one or more C=C double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The double bonds in these groups can be in cis or trans configurations and should be understood to include both isomers. Examples include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl and 1,3-butadienyl, etc. When a numerical range appears for an alkenyl group as defined herein, for example, "C2-C6 alkenyl" or "C2-6 alkenyl" refers to an alkenyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and the alkenyl group herein also encompasses situations where no numerical range is specified.

[0071] The term "cycloalkyl" refers to an all-carbon monocyclic, fused-ring, or spirocyclic saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, preferably 3, 4, 5, 6, 7, or 8 ring atoms, more preferably 3, 4, 5, or 6 ring atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The cycloalkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl, and hydroxyl.

[0072] The term "heterocycloalkyl" refers to a monocyclic, fused-ring or spirocyclic saturated hydrocarbon group consisting of carbon atoms, hydrogen atoms, and at least one heteroatom, having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, preferably 3, 4, 5, 6, 7 or 8 ring atoms, more preferably 3, 4, 5 or 6 ring atoms, wherein one or more ring atoms are selected from N, O, S(O) n(wherein n is 0, 1 or 2) heteroatom, and the remaining ring atoms are C. The heterocycloalkyl 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.

[0073] The term "aryl" refers to an all-carbon monocyclic or fused ring having a completely conjugated π electron system 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 groups. Non-limiting examples of unsubstituted aryl include but are not limited to phenyl, naphthyl, and anthracenyl.

[0074] 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, of which 1, 2, 3 or 4 ring atoms are selected from N, O, S, and the remaining ring atoms are C, and having a completely conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl and triazinyl.

[0075] The term "alicyclic" refers to a monocyclic, fused or spirocyclic carbocyclic ring having 3-12 ring atoms, having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, such rings may be saturated or unsaturated (e.g., having one or more double bonds), but not having a completely conjugated π-electron system.

[0076] The term "alicyclic" refers to the residue remaining after removing one hydrogen atom from an "alicyclic" molecule. A heteroalicyclic group may be unsubstituted or the hydrogen atoms thereof may be optionally substituted with substituents including, but not limited to, alkyl, alkoxy, =0, aryl, aralkyl, -COOH, -CN, amino, halogen, and hydroxyl.

[0077] 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

[0078] The term "heteroalicyclic group" refers to the group remaining after removing one hydrogen atom from the "heteroalicyclic" molecule. The heteroalicyclic group may be unsubstituted or the hydrogen atoms thereof may be optionally substituted with substituents, including but not limited to alkyl, alkoxy, Aryl, aralkyl, -COOH, -CN, amino, halogen and hydroxy.

[0079] The term "spirocyclic group" refers to the group remaining after removing one hydrogen atom from a polycyclic compound in which two monocyclic rings share one carbon atom; it can be divided into carbocyclic spirocyclic groups and heterocyclic spirocyclic groups according to the types of atoms contained. When the carbon atoms constituting the carbocyclic spirocyclic group are replaced by other heteroatoms such as O, N and S, a heterocyclic spirocyclic group is formed.

[0080] The term "spirocycloalkyl" refers to a saturated carbocyclic ring that forms two rings, wherein both rings share one carbon atom as part of the ring.

[0081] The term "heterospirocycloalkyl" refers to a spirocycloalkyl group as described above containing at least one heteroatom selected from O, N and S.

[0082] The term "oxazaspirocycloalkyl" refers to the above-described heterospirocycloalkyl group containing at least one O and at least one N.

[0083] The compound of the present invention or its salt can be administered alone as an active substance, or preferably in the form of a pharmaceutical composition.

[0084] "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 (e.g., humans). The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention to an organism.

[0085] The term "pharmaceutically acceptable carrier" refers to carriers that have no significant irritating effect on organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carrier" refers to an inert substance that is administered together with the active ingredient and facilitates 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 such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0086] 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 compositions 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 compositions of the present invention can be formulated into solid, semisolid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0087] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred route of administration is oral administration.

[0088] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0089] 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 invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0090] Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents. Examples include microcrystalline cellulose, glucose solution, acacia mucilage, 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-gelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, and the like. The dragee core can optionally be coated according to methods known in conventional pharmaceutical practice, particularly with an enteric coating.

[0091] 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.

[0092] 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 the treatment of diseases that benefit from SHP2 inhibition, wherein the disease that benefits from SHP2 inhibition is selected from cancer.

[0093] 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

[0094] The following specific examples are provided for the purpose of enabling 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 illustrative and representative 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 the following are non-limiting examples.

[0095] All operations involving raw materials that are easily oxidized or hydrolyzed were carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention were purchased directly from the market and used directly without further purification.

[0096] Column chromatography used silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd. Thin layer chromatography used prefabricated plates (silica gel 60PF) produced by E. Merck 254Chiral compound separation and enantiomeric excess (ee) determination were performed using an Agilent LC 1200 series (column: CHIRALPAK AD-H, mm, 5 μm, 30°C). NMR data ( 1 HNMR was performed using a Varian instrument at 400 MHz. The solvents used for NMR data included CDCl3, CD3OD, D2O, and DMSO-d6, with tetramethylsilane (0.00 ppm) as the reference or residual solvent as the reference (CDCl3: 7.26 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm). When peak shape diversity is indicated, the following abbreviations are used to represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double of doublets), and dt (double of triplets). Coupling constants, if given, are in Hertz (Hz). Liquid chromatography-mass spectrometry (LC / MS) was performed using a FINNIGAN Thermo LCQ Advantage MAX and an Agilent LC 1200 series (columns: Waters Symmetry C18, mm, 5 μm, 35 °C), using ESI (+) ion mode.

[0097] Abbreviations:

[0098] Experimental part

[0099] Intermediate 1: (R)-N-(3S,4S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0100] Step 1: (R)-2-methyl-N-(3S,4S)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-yl)propane-2-sulfenamide trifluoroacetate

[0101] To a solution of tert-butyl (3S,4S)-tert-butyl 4-((R)-1,1-dimethylethylsulfonamido)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (3.74 g) in dichloromethane (50 mL) was added trifluoroacetic acid (10 mL) dropwise at room temperature, followed by stirring at room temperature for 5 hours. The mixture was concentrated under reduced pressure to afford the crude product, which was used in the next step without purification (3.88 g).

[0102] Step 2: (R)-N-(3S,4S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0103] The product from the previous step (3.88 g) and 3-chloro-4-(5-chloropyrazin-2-yl)thio)pyridin-2-amine (2.73 g) (synthesized according to patent WO2016 / 203406) were dissolved in DMF (100 mL), DIEA (10 mL) was added thereto and heated to 100°C and stirred for 12 hours. The mixture was cooled to room temperature, poured into cold water (300 mL) and extracted with ethyl acetate (100 mL*2). The extract was washed with saturated brine (200 mL*2) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol, 20:1) to obtain the title compound (4.0 g).

[0104] 1 H NMR(400MHz, CDCl3),8.23(s,1H),8.28(s,1H),7.69(d,J=5.6Hz,1H),6.00 (d,J=5.6Hz,1H),4.88(s,2H),4.12-4.28(m,3H),3.59(d,J=9.2Hz,1H),3. 67(d,J=9.2Hz,1H),3.49-3.53(m,1H),3.41-3.44(m,1H),3.13-3.24(m,2H ),1.94-2.08(m,2H),1.58-1.76(m,2H),1.24(s,9H),1.21(d,J=6.8Hz,3H).

[0105] Intermediate 2: (R)-N-((S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[b]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfenamide

[0106] Referring to the synthesis method of intermediate 1, intermediate 2 was obtained using tert-butyl (S)-1-(((R)-tert-butylsulfoxide)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate as the starting material.

[0107] Intermediate 3: (R)-N-((S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0108] Referring to the synthesis method of intermediate 1, intermediate 3 was obtained using tert-butyl (S)-1-(((R)-tert-butylsulfoxide)amino)-5-fluoro-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate as the starting material.

[0109] Intermediate 4: (R)-N-((3S,4S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)-3-(hydroxymethyl)-6-methylpyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-methyl)-2-methylpropane-2-sulfenamide

[0110] Referring to the synthesis method of intermediate 1, intermediate 4 was obtained by using (6-((2-amino-3-chloropyridin-4-yl)sulfanyl)-3-chloro-5-methylpyrazin-2-yl)methanol as the second step raw material.

[0111] Example 1: (3S,4S)-8-(5-((3-chloro-2-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0112] Step 1: (R)-N-((3S,4S)-8-(5-((3-chloro-2-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0113] Under nitrogen protection, the intermediate 1(R)-N-(3S,4S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfinamide (51 mg), 3-(2-chloropyrimidin-4-yl)-1-methylindole (24 mg) (synthesized according to patent WO2013 / 14448), RuPhos-Pd-G3 (8 mg) and cesium carbonate (100 mg) were dissolved in dioxane (10 mL), the reaction flask was replaced with nitrogen three times and heated to 100 ° C and stirred for 12 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography (developing solvent: dichloromethane:methanol=20:1 (v:v)) to give the title compound (20 mg).

[0114] Step 2: (3S,4S)-8-(5-((3-chloro-2-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0115] To a solution of (R)-N-(3S,4S)-8-(5-((3-chloro-2-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide (20 mg) in THF (10 mL) was added dropwise 6N dioxane hydrochloride (1 mL), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the title compound (15 mg).

[0116] 1H NMR(400MHz, DMSO),8.69(s,1H),8.57(s,1H),8.55(d,J=7.6Hz,1H),8.39(s,1H),8.32(d,J=6.8Hz,1H),8.18-8.2 6(brs,3H),8.17(d,J=5.6Hz,1H),8.57(d,J=8.0Hz,1H),8.52(d,J=6.4Hz,1H),7.32(t,J=7.6Hz,1H),7.27(t,J=7 .6Hz,1H),6.64(d,J=5.6Hz,1H),4.17-4.36(m,3H),3.91(s,3H),3.47(d,J=4.4Hz,1H),3.44(d,J=4.4Hz,1H),3.3 5-3.39(m,1H),3.12-3.22(m,2H),1.77-1.88(m,2H),1.67-1.74(m,1H),1.57-1.64(m,1H),1.22(d,J=6.4Hz,3H).

[0117] Example 2: (3S,4S)-8-(5-(3-chloro-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0118] Referring to the method in Example 1, 4-chloro-6,7-dimethoxy-2-methylquinazoline (synthesized according to patent WO2018 / 172250) was used as the starting material to obtain the target compound.

[0119] 1 H NMR(400MHz,CD3OD),8.46(s,1H),8.37(s,1H),8.21(d,J=5.2Hz,1H),7.93( s,1H),7.19(s,1H),6.86(d,J=5.2Hz,1H),4.40-4.46(m,1H),4.28-4.38(m, 2H),4.07(s,3H),4.04(s,3H),4.02(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.47(d,J=4.0Hz,1 H),3.20-3.33(m,2H),2.62(s,3H),1.85-1.96(m,3H),1.72-1.79(m,1H),1.33(d,J=6.4Hz,3H).

[0120] Example 3: (3S,4S)-8-(5-((2-(6,7-bis(2-methoxyethoxy)quinazolin-4-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0121] Referring to the method in Example 1, the target compound was obtained using 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (synthesized according to patent WO2009 / 7984) as the starting material.

[0122] 1 HNMR(400MHz,CD3OD),8.66(s,1H),8.43(s,1H),8.37(d,J=1.2Hz,1H),8.16(d, J=5.6Hz,1H),7.97(s,1H),7.28(s,1H),6.79(d,J=5.6Hz,1H),4.39-4.46(m,3H) ,4.29-4.37(m,4H),4.00(d,J=9.2Hz,1H),3.86-3.91(m,5H),3.45-3.47(m,7H) ,3.18-3.33(m,2H),1.82-1.93(m,3H),1.70-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0123] Example 4: (3S,4S)-8-(5-((3-chloro-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0124] Referring to the method in Example 1, 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (synthesized according to patent WO2014 / 11900) was used as the starting material to obtain the target compound.

[0125] 1H NMR(400MHz,DMSO),9.40(s,1H),8.56(s,1H),8.39(s,1H),8.13-8.26(brs,4H),7.87(d,J=2.0H z,1H),7.76(d,J=8.4Hz,1H),7.65(dd,J=8.4Hz,1.6Hz,1H),7.01(s,1H),6.61(d,J=5.6Hz,1H),4 .16-4.34(m,3H),3.95(s,6H),3.47(d,J=4.4Hz,1H),3.44(d,J=4.4Hz,1H),3.35-3.41(m,1H),3 .12-3.22(m,2H),1.75-1.86(m,2H),1.66-1.74(m,1H),1.56-1.64(m,1H),1.22(d,J=6.4Hz,3H).

[0126] Example 5: 2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one hydrochloride

[0127] Referring to the method in Example 1, 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (synthesized according to patent WO2011 / 157397) was used as the starting material to obtain the target compound.

[0128] 1 H NMR(400MHz,CD3OD),8.43(s,1H),8.36(s,1H),8.22(s,1H),8.14(s,1H),6 .69(s,1H),4.62-4.72(m,1H),4.26-4.48(m,3H),4.08-4.12(m,2H),4.01(d J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.70-3.74(m,1H),3.63-3.67(m,2H),3.46(s, 3H), 3.18-3.32 (m, 2H), 2.66-2.78 (m, 2H), 1.69-1.97 (m, 6H), 1.32 (d, J = 6.0Hz, 3H).

[0129] Example 6: (6-((2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride

[0130] Referring to the method in Example 1, the target compound was obtained using (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxaline-5-yl)dimethylphosphine oxide (synthesized according to patent WO2022 / 12622) as the starting material.

[0131] 1 H NMR(400MHz, CD3OD),9.24(dd,J=9.6Hz,4.0Hz,1H),8.91-8.92(m,2H),8.54(s,1H),8.44(d,J=1.2Hz ,1H),8.36(d,J=1.2Hz,1H),8.34(d,J=9.6Hz,1H),8.10(d,J=6.0Hz,1H),6.73(d,J=6.0Hz,1H),4.39- 4.46(m,1H),4.24-4.37(m,2H),4.01(d,J=8.8Hz,1H),3.89(d,J=8.8Hz,1H),3.46(d,J=3.6Hz,1H),3 .08-3.28(m,2H),2.18(d,J=14.4Hz,6H),1.82-1.92(m,3H),1.70-1.77(m,1H),1.32(d,J=6.0Hz,3H).

[0132] Example 7: N 2 -(4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-5-chloro-N 4 -(2-(Isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine hydrochloride

[0133] Referring to the method in Example 1, the target compound was obtained using 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (synthesized according to patent WO2011 / 140338) as a starting material.

[0134] 1H NMR(400MHz,CD3OD),8.62(d,J=8.0Hz,1H),8.40-8.46(m,2H),8.35(s,1H),8.05-8.12(brs, 1H),8.00(d,J=7.6Hz,1H),7.87(t,J=7.6Hz,1H),7.54(t,J=7.6Hz,1H),6.68-6.75(brs,1H) ,4.26-4.46(m,3H),4.00(d,J=8.8Hz,1H),3.88(d,J=8.8Hz,1H),3.37-3.49(m,2H),3.18-3. 30(m,2H),1.82-1.96(m,3H),1.70-1.78(m,1H),1.32(d,J=6.0Hz,3H),1.26(d,J=6.4Hz,6H).

[0135] Example 8: (3S,4S)-8-(5-(3-chloro-2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0136] Referring to the method in Example 1, 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridine (synthesized according to patent WO2014 / 60375) was used as the starting material to obtain the target compound.

[0137] 1 H NMR(400MHz, CD3OD),8.45(s,1H),8.34-8.40(m,2H),8.09(s,1H),7.72(d,J=5.2Hz,1H),7.38-7.41(m,1H),7.00(dd,J=10.8Hz,2.4Hz,1H),6.87(td,J =8.0Hz,2.4Hz,1H),6.72(s,1H),4.25-4.48(m,3H),4.02(d,J=8.8Hz,1H),3.89(d,J=8.8Hz,1H),3.85(s ,3H),3.44-3.51(m,1H),3.19-3.35(m,2H),1.84-1.97(m,3H),1.71-1.79(m,1H),1.33(d,J=5.6Hz,3H).

[0138] Example 9: (3S,4S)-8-(5-(3-chloro-2-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0139] Referring to the method in Example 1, the target compound was obtained using 3-(2-chloropyrimidin-4-yl)-1-cyclopropyl-1H-indole (synthesized according to patent CN109761960) as the starting material.

[0140] 1 H NMR(400MHz,CD3OD),8.73-8.76(m,1H),8.58(s,1H),8.42(s,1H),8.36(s,1H),8.27(d,J=6.8Hz,1H),8.12(d,J =5.6Hz,1H),7.74-7.76(m,1H),7.71(d,J=6.8Hz,1H),7.37-7.43(m,2H),6.64(d,J=5.6Hz,1H),4.38-4.45(m,1H ),4.27-4.36(m,2H),4.00(d,J=8.8Hz,1H),3.90(d,J=8.8Hz,1H),3.60-3.66(m,1H),3.45(d,J=4.0Hz,1H),3.18 -3.30(m,2H),1.80-1.96(m,3H),1.70-1.78(m,1H),1.32(d,J=6.4Hz,3H),1.24-1.28(m,2H),1.11-1.16(m,2H).

[0141] Example 10: (3S,4S)-8-(5-(3-chloro-2-(6,7-dimethoxyquinazolin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0142] Referring to the method in Example 1, the target compound was obtained using 4-chloro-6,7-dimethoxyquinazoline (synthesized according to patent CN114105890) as the starting material.

[0143] 1HNMR(400MHz,DMSO),8.82(s,1H),8.56(s,1H),8.41(s,1H),8.26(d,J=5.2Hz,1H),8.14-8 .24(m,4H),7.38(s,1H),6.78(d,J=5.6Hz,1H),4.27-4.35(m,1H),4.16-4.26(m,2H),3.99( s,3H),3.98(s,3H),3.47(d,J=4.8Hz,1H),3.44(d,J=4.8Hz,1H),3.36-3.39(m,1H),3.12-3 .22(m,2H),1.76-1.87(m,2H),1.67-1.74(m,1H),1.57-1.64(m,1H),1.22(d,J=6.8Hz,3H).

[0144] Example 11: (2-((2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide hydrochloride

[0145] Referring to the method in Example 1, the target compound was obtained using (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (synthesized according to patent CN111138492) as the starting material.

[0146] 1 H NMR(400MHz, DMSO),11.59(s,1H),9.72-10.02(brs,1H),8.57(s,1H),8.47(dd,J=8.4Hz,4.0Hz,1H),8.37(d,J=1.2Hz,1H),8.22(s,1H),8.11-8.19(m, 4H),7.53(dd,J=10.0Hz,7.2Hz,1H),7.43(t,J=8.0Hz,1H),7.11(t,J=8.0Hz,1H),6.55(d,J=5.6Hz,1H),4.16-4.35(m,3H),3.48(d,J =4.4Hz,1H),3.44(d,J=4.8Hz,1H),3.36-3.40(m,1H),3.12-3.22(m,2H),1.68-1.86(m,9H),1.56-1.64(m,1H),1.22(d,J=6.8Hz,3H).

[0147] Example 12: (3S,4S)-8-(5-(3-chloro-2-((4-morpholinopyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0148] Referring to the method in Example 1, 4-(2-chloropyrimidin-4-yl)morpholine (synthesized according to patent WO2020 / 6497) was used as the starting material to obtain the target compound.

[0149] 1 H NMR(400MHz, CD3OD),8.41(d,J=1.2Hz,1H),8.33(d,J=1.2Hz,1H),8.07(d,J=5.6Hz,1H),7.99( d,J=7.6Hz,1H),6.79(d,J=7.6Hz,1H),6.57(d,J=5.6Hz,1H),4.38-4.44(m,1H),4.28-4.35(m, 2H),4.05-4.11(m,2H),4.00(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.72-3.82(m,6H),3.46(d ,J=4.0Hz,1H),3.18-3.32(m,2H),1.83-1.92(m,3H),1.70-1.77(m,1H),1.32(d,J=6.0Hz,3H).

[0150] Example 13: 2-(6-(2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-6-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)propan-2-ol hydrochloride

[0151] Following the method in Example 1, the title compound was obtained using 2-(6-(2-chloro-6-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)propan-2-ol (synthesized by reference to patent CN111718348). MS m / z [LC-MS]: 699.29 [M+1].

[0152] 1H NMR(400MHz,CD3OD),8.87(s,1H),8.41(s,1H),8.33(s,1H),8.08-8.14(m,2H),7.89(d,J= 7.6Hz,1H),7.64(d,J=7.6Hz,1H),6.58-6.60(m,2H),4.27-4.45(m,3H),4.00(d,J=9.2Hz, 1H),3.89(d,J=9.2Hz,1H),3.47(d,J=3.6Hz,1H),3.15-3.26(m,2H),1.98-2.07(m,1H),1. 82-1.94(m,3H),1.70-1.77(m,1H),1.56(s,6H),1.32(d,J=6.4Hz,3H),0.82-0.97(m,4H).

[0153] Example 14: (3S,4S)-8-(5-((3-chloro-2-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0154] The target compound was obtained by following the method in Example 1 using 2-chloro-4-(pyridin-3-yl)pyrimidine (synthesized according to patent WO2021 / 74138) as the starting material. MS m / z [LC-MS]: 562.19 [M+1].

[0155] 1 H NMR (400MHz, CD3OD), 9.69 (s, 1H), 9.36 (d, J=7.6Hz, 1H), 9.05 (d, J= 5.6Hz,1H),8.99(d,J=5.6Hz,1H),8.46(s,1H),8.39(s,1H),8.24-8.29(m,1H) ,8.19(d,J=6.4Hz,1H),8.09(d,J=5.6Hz,1H),6.88(d,J=6.4Hz,1H),4.28-4.4 9(m,3H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=3.2Hz,1H),3 .20-3.35(m,2H),1.84-1.95(m,3H),1.71-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0156] Example 15: N 2-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-N 4 -(2,3-dimethyl-2H-indazol-6-yl)-N 4 -Methylpyrimidine-2,4-diamine hydrochloride

[0157] Following the method in Example 1, the target compound was obtained using N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (synthesized according to patent WO2021 / 162647). MS m / z [LC-MS]: 658.26 [M+1].

[0158] 1 HNMR(400MHz, CD3OD),8.41(s,1H),8.34(s,1H),8.06(d,J=6.0Hz,1H),7.94(d,J=9.2Hz,1H),7.87(d,J= 7.2Hz,1H),7.61(s,1H),7.06(d,J=9.2Hz,1H),6.58(d,J=5.6Hz,1H),6.22-6.32(m,1H),4.38-4.44(m,1 H),4.28-4.36(m,2H),4.16(s,3H),4.00(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.70(s,3H),3.45(d,J= 4.0Hz,1H),3.18-3.36(m,2H),2.72(s,3H),1.81-1.96(m,3H),1.70-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0159] Example 16: (R)-2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one hydrochloride

[0160] The target compound was obtained by following the method of Example 1 using (R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (synthesized according to patent WO2011 / 79114) as the starting material. MS m / z [LC-MS]: 665.30 [M+1].

[0161] 1 HNMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.10(d,J=5.6Hz,1H),7.68(s,1H),6.59(d,J=5.6 Hz,1H),4.60-4.70(m,1H),4.51(dd,J=6.8Hz,3.6Hz,1H),4.38-4.45(m,1H),4.28-4.36(m,2H),4.0 0(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.47(d,J=4.0Hz,1H),3.33(s,3H),3.18-3.32(m,2H),2.1 7-2.25(m,1H),1.83-2.09(m,10H),1.65-1.78(m,3H),1.32(d,J=6.4Hz,3H),0.88(t,J=7.2Hz,3H).

[0162] Example 17: (3S,4S)-8-(5-((3-chloro-2-((6,7-dimethoxyquinolin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0163] The target compound was obtained by following the method of Example 1 using 4-chloro-6,7-dimethoxyquinoline (synthesized according to patent WO2005 / 121125) as the starting material. MS m / z [LC-MS]: 594.22 [M+1].

[0164] 1 H NMR(400MHz,CD3OD),8.43(s,1H),8.36-8.38(m,2H),8.18(d,J=5.6Hz,1H),7.89 (s,1H),7.40(d,J=7.2Hz,1H),7.34(s,1H),6.74(d,J=5.2Hz,1H),4.27-4.46(m,3 H),4.08(s,6H),4.01(d,J=9.2Hz,1H),3.90(d,J=9.2Hz,1H),3.46(d,J=3.6Hz,1H ),3.18-3.34(m,2H),1.84-1.96(m,3H),1.71-1.78(m,1H),1.32(d,J=6.0Hz,3H).

[0165] Example 18: 4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-methyl)amino)-7-methoxyquinoline-6-carboxamide hydrochloride

[0166] Referring to the method in Example 1, 4-chloro-7-methoxyquinoline-6-carboxamide (synthesized according to patent WO2019 / 92625) was used as the starting material to obtain the target compound.

[0167] 1 H NMR(400MHz,CD3OD),9.10(s,1H),8.50(d,J=7.2Hz,1H),8.43(s,1H),8.36(s,1H), 8.17-8.23(m,1H),7.47(s,1H),7.46(d,J=7.2Hz,1H),6.76-6.80(m,1H),4.27-4.4 7(m,3H),4.16(s,3H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.44-3.49(m,1 H), 3.18-3.24 (m, 2H), 1.83-1.96 (m, 3H), 1.70-1.79 (m, 1H), 1.32 (d, J = 6.0Hz, 3H).

[0168] Example 19: (3S,4S)-8-(5-((3-chloro-2-((4-(1-(ethylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0169] Referring to the method in Example 1, the target compound was obtained using 3-(2-chloropyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indole (synthesized according to patent CN114380806) as the starting material.

[0170] 1H NMR(400MHz,CD3OD),8.61(d,J=7.2Hz,1H),8.45-8.46(m,2H),8.38(s,1H),8.33(s,1H)8.06(d,J=5.6Hz,1 H),7.91(d,J=7.6Hz,1H),7.61(d,J=6.0Hz,1H),7.35-7.44(m,2H),6.60(d,J=6.0Hz,1H),4.34-4.43(m,1H ),4.23-4.33(m,2H),3.99(d,J=9.6Hz,1H),3.86(d,J=8.8Hz,1H),3.56(q,J=7.2Hz,2H),3.44(d,J=4.0Hz, 1H), 3.14-3.28 (m, 2H), 1.79-1.92 (m, 3H), 1.69-1.77 (m, 1H), 1.32 (d, J = 6.8Hz, 3H), 1.20 (t, J = 7.2Hz, 3H).

[0171] Example 20: 2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-9-(5-(dimethylphosphoryl)quinoxalin-6-yl)-7-methyl-7,9-dihydro-8H-purin-8-one hydrochloride

[0172] Referring to the method in Example 1, the target compound was obtained using 2-chloro-9-(5-(dimethylphosphoryl)quinoxalin-6-yl)-7-methyl-7,9-dihydro-8H-purin-8-one as the starting material.

[0173] 1H NMR(400MHz, CD3OD),9.12(d,J=1.6Hz,1H),9.07(d,J=2.0Hz,1H),8.55(d,J=8.8Hz,1H),8.42(s,1H),8.33-8. 34(m,2H),8.11(d,J=6.4Hz,1H),8.03(dd,J=8.8Hz,3.2Hz,1H),6.68(d,J=6.0Hz,1H),4.38-4.46(m,1H),4.27 -4.37(m,2H),4.00(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.57(s,3H),3.45(d,J=4.4Hz,1H),3.18-3.32(m,2 H), 2.11 (d, J = 14.8Hz, 3H), 2.04 (d, J = 14.8Hz, 3H), 1.81-1.92 (m, 3H), 1.69-1.77 (m, 1H), 1.32 (d, J = 6.4Hz, 3H).

[0174] Example 21: (3S,4S)-8-(5-((3-chloro-2-)((5-chloro-4-(1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0175] Referring to the method in Example 1, the target compound was obtained using 1-(2,5-dichloropyrimidin-4-yl)-1H-pyrrolo[3,2-b]pyridine as the starting material.

[0176] 1H NMR(400MHz, CD3OD),9.22(d,J=8.4Hz,1H),8.77(s,1H),8.71(d,J=3.6Hz,1H),8.69(d,J=6.0Hz,1H), 8.40(s,1H),8.33(s,1H),8.14(d,J=4.8Hz,1H),7.81(dd,J=8.4Hz,6.0Hz,1H),7.12(d,J=4.0Hz,1H),6 .59(d,J=5.6Hz,1H),4.34-4.45(m,1H),4.26-4.36(m,2H),4.00(d,J=8.8Hz,1H),3.89(d,J=9.2Hz,1H) ,3.45(d,J=4.4Hz,1H),3.17-3.28(m,2H),1.80-1.94(m,3H),1.70-1.77(m,1H),1.32(d,J=6.4Hz,3H).

[0177] Example 22: (R)-2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropterin-6(5H)-one hydrochloride

[0178] Referring to the method in Example 1, the target compound was obtained using (7R)-2-chloro-7-ethyl-7,8-dihydro-5-methyl-8-(1-methylethyl)-6(5H)-pteridinone (synthesized according to patent WO2007 / 90844) as the starting material.

[0179] 1HNMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.09(d,J=5.6Hz,1H),7.69(s ,1H),7.58(d,J=5.6Hz,1H),4.72-4.80(m,1H),4.54(dd,J=6.4Hz,2.8Hz,1H), 4.38-4.45(m,1H),4.27-4.36(m,2H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz, 1H),3.47(d,J=3.6Hz,1H),3.33(s,3H),3.18-3.30(m,2H),2.04-2.14(m,1H), 1.82-1.98(m,4H),1.70-1.78(m,1H),1.47-1.51(m,6H),1.32(d,J=6.4Hz,3H),0.87(t,J=7.2Hz,3H).

[0180] Example 23: (3S,4S)-8-(5-((3-chloro-2-((5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0181] Referring to the method in Example 1, 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (synthesized according to patent WO2013 / 37896) was used as the starting material to obtain the target compound.

[0182] 1 HNMR(400MHz,CD3OD),8.66(s,1H),8.43(s,1H),8.38(s,1H),8.06(d,J=6.8Hz,1H),7.62(dd,J =8.4Hz, 6.8Hz, 1H), 7.02 (dd, J = 7.2Hz, 2.4Hz, 1H), 6.89 (td, J = 8.4Hz, 2.4Hz, 1H), 6.73 (d, J = 6. 8Hz,1H),4.39-4.46(m,1H),4.26-4.38(m,2H),4.00(d,J=9.2Hz,1H),3.87-3.97(m,4H),3.45( d,J=4.4Hz,1H),3.19-3.35(m,2H),1.82-1.92(m,3H),1.70-1.77(m,1H),1.32(d,J=6.4Hz,3H).

[0183] Example 24: (3S,4S)-8-(5-((3-chloro-2-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0184] Referring to the method in Example 1, the target compound was obtained using 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole (synthesized according to patent WO2013 / 14448) as the starting material.

[0185] 1 H NMR(400MHz,CD3OD),8.58-8.60(m,2H),8.40(s,1H),8.34(s,1H),8.03(s,1H),7.47-7 .50(m,2H),7.33(t,J=7.6Hz,1H),7.28(t,J=7.6Hz,1H),6.44(d,J=6.4Hz,1H),4.37-4 .44(m,1H),4.26-4.36(m,2H),3.99(d,J=9.2Hz,1H),3.86-3.88(m,4H),3.44(d,J=4.0 Hz, 1H), 3.16-3.30 (m, 2H), 1.82-1.92 (m, 3H), 1.68-1.76 (m, 1H), 1.31 (d, J = 6.8Hz, 3H).

[0186] Example 25: (3S,4S)-8-(5-((3-chloro-2-((4-(1-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0187] Referring to the method in Example 1, the target compound was obtained using 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-1H-indole (synthesized according to patent CN111574503) as the starting material.

[0188] 1HNMR(400MHz,CD3OD),8.88(s,1H),8.44(s,1H),8.42(d,J=8.0Hz,1H),8.37(s,1H),8.03-8.05( m,2H),7.54(d,J=8.4Hz,1H),7.36(t,J=7.6Hz,1H),7.29(t,J=7.6Hz,1H),6.81(d,J=6.4Hz,1H), 4.40-4.47(m,1H),4.27-4.38(m,2H),4.01(d,J=9.2Hz,1H),3.95(s,3H),3.89(d,J=9.2Hz,1H), 3.46(d,J=4.4Hz,1H),3.18-3.35(m,2H),1.83-1.95(m,3H),1.70-1.78(m,1H),1.32(d,J=6.4Hz, 3H).

[0189] Example 26: 1-(2-((4-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-4-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one hydrochloride

[0190] Referring to the method in Example 1, the target compound was obtained using 1-(2-chloropyrimidin-4-yl)-3-methyl-1,3-2H-benzo[D]imidazol-2-one (synthesized according to patent CN107540661) as the starting material.

[0191] 1 H NMR(400MHz,DMSO-d6),9.86-10.22(brs,1H),8.57(s,1H),8.52(d,J=6.0Hz,1H),8.37(s,1H), 8.19-8.22(m,2H),7.97-8.10(brs,3H),7.88(d,J=5.6Hz,1H),7.17-7.22(m,2H),7.02-7.06(m ,1H),6.60(d,J=4.8Hz,1H),4.16-4.34(m,3H),3.90(d,J=9.2Hz,1H),3.68(d,J=9.2Hz,1H),3. 29-3.35(m,4H),3.13-3.23(m,2H),3.68-3.84(m,3H),1.56-1.64(m,1H),1.21(d,J=6.4Hz,3H).

[0192] Example 27: (3S,4S)-8-(5-((2-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0193] Referring to the method in Example 1, the target compound was obtained using 3-(2-chloro-pyrimidin-4-yl)-1H-indole (synthesized according to patent CN109761960) as the starting material.

[0194] 1 HNMR(400MHz,CD3OD),8.70(d,J=7.6Hz,1H),8.55(s,1H),8.42(s,1H),8.35(s,1H),8.26(d, J=6.8Hz,1H),8.11(s,1H),7.70(d,J=6.4Hz,1H),7.49(d,J=8.0Hz,1H),7.28-7.35(m,2H),6. 62(s,1H),4.40-4.43(m,1H),4.28-4.36(m,2H),4.01(d,J=8.8Hz,1H),3.89(d,J=8.8Hz,1H) ,3.47(s,1H),3.17-3.32(m,2H),1.82-1.95(m,3H),1.71-1.78(m,1H),1.32(d,J=6.0Hz,3H).

[0195] Example 28: (3S,4S)-8-(5-((3-chloro-2-((2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0196] Step 1: (R)-N-((3S,4S)-8-(5-((3-chloro-2-((2-chloropyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0197] Under nitrogen, the intermediate 1(R)-N-(3S,4S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide (510 mg), 4-bromo-2-chloropyrimidine (200 mg), RuPhos-Pd-G3 (80 mg), and cesium carbonate (900 mg) were dissolved in dioxane (100 mL). The reaction flask was purged with nitrogen three times and heated to 90°C with stirring for 3 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (301 mg).

[0198] Step 2: (R)-N-((3S,4S)-8-(5-((3-chloro-2-((2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-alkyl)-2-methylpropane-2-sulfenamide

[0199] (R)-N-((3S,4S)-8-(5-((3-chloro-2-((2-chloropyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-alkyl)-2-methylpropane-2-sulfenamide (30 mg) and (3S,4R)-3-fluoro-4-methoxypiperidine hydrochloride (90 mg) were dissolved in n-butanol (1 mL). DIEA (0.5 mL) was added, and the mixture was heated to 100° C. and stirred for 12 hours. The mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was purified by thin layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (20 mg).

[0200] Step 3: (3S,4S)-8-(5-((3-chloro-2-((2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0201] To a solution of (R)-N-((3S,4S)-8-(5-((3-chloro-2-((2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-alkyl)-2-methylpropane-2-sulfenamide (20 mg) in THF (5 mL) was added dropwise 6N dioxane hydrochloride (1 mL), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the title compound (15 mg).

[0202] 1 HNMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.10(d,J=5.6Hz,1H),7.91(d,J=7.2Hz,1H) ,6.88-7.01(brs,1H),6.68(d,J=5.2Hz,1H),4.89-5.05(m,1H),4.37-4.48(m,2H),4.16-4.36 (m,3H),4.00(d,J=8.8Hz,1H),3.89(d,J=8.8Hz,1H),3.52-3.68(m,2H),3.46(d,J=4.4Hz,1H) ,3.44(s,3H),3.18-3.39(m,3H),1.80-1.98(m,5H),1.70-1.77(m,1H),1.32(d,J=6.0Hz,3H).

[0203] Example 29: (3S,4S)-8-(5-((3-chloro-2-)((4-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0204] Referring to the method in Example 28, the target compound was obtained using 2,4-dichloro-1,3,5-triazine as the starting material.

[0205] 1HNMR(400MHz,CD3OD),8.55(d,J=4.0Hz,1H),8.41(s,1H),8.34(s,1H),8.09(d,J=5 .6Hz,1H),6.65(d,J=5.2Hz,1H),4.68-5.07(m,4H),4.38-4.44(m,1H),4.27-4.36(m ,2H),4.00(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.60-3.70(m,2H),3.43-3.48(m, 4H), 3.17-3.28 (m, 2H), 1.82-2.05 (m, 5H), 1.70-1.77 (m, 1H), 1.32 (d, J = 6.8Hz, 3H).

[0206] Example 30: (2-((2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-5-bromopyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide hydrochloride

[0207] Referring to the method in Example 1, the target compound was obtained using (2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (synthesized according to patent WO2012 / 151561) as a starting material.

[0208] 1 H NMR(400MHz,CD3OD),8.37-8.43(m,3H),8.34(s,1H),8.05(d,J=5.6Hz,1H),7.7 0-7.77(m,2H),7.44-7.50(m,1H),6.65(d,J=6.0Hz,1H),4.38-4.45(m,1H),4.28 -4.36(m,2H),4.00(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.45(d,J=3.6Hz,1H) ,3.18-3.32(m,2H),1.83-1.94(m,9H),1.70-1.78(m,1H),1.32(d,J=6.0Hz,3H).

[0209] Example 31: (S)-1'-(5-((3-chloro-2-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine hydrochloride

[0210] Referring to the method in Example 1, the target compound was obtained using 3-(2-chloropyrimidin-4-yl)-1-methylindole and intermediate 3 as starting materials.

[0211] 1 H NMR(400MHz,CD3OD),8.68-8.70(m,1H),8.51(s,1H),8.44(s,1H),8.36(s,1H),8.24(d,J=6.4Hz,1H),8.0 9(d,J=3.6Hz,1H),7.62(d,J=6.8Hz,1H),7.49-7.55(m,2H),7.35-7.37(m,2H),7.14(dd,J=8.4Hz,2.0Hz, 1H),7.08(td,J=8.4Hz,2.4Hz,1H),6.62(d,J=4.0Hz,1H),4.44-4.52(m,1H),4.42(s,1H),4.29-4.38(m,1 H),3.94(s,3H),3.33-3.49(m,2H),3.22(s,2H),1.88-1.99(m,1H),1.75-1.87(m,2H),1.61-1.68(m,1H).

[0212] Example 32: (3S,4S)-8-(5-((3-chloro-2-((5-methyl-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0213] Referring to the method in Example 1, the target compound was obtained using 3-(2-chloro-5-methylpyrimidin-4-yl)-1-methyl-1H-indole (synthesized according to patent WO2013 / 14448) as the starting material.

[0214] 1H NMR(400MHz, DMSO-d6),10.26-10.55(brs,1H),8.62(d,J=7.6Hz,1H),8.57(s,1H),8.41(s,1H),8.38(s,1H),8. 28(s,1H),8.16(d,J=5.2Hz,1H),8.03-8.13(brs,3H),7.56(d,J=8.4Hz,1H),7.31(t,J=7.6Hz,1H),7.22(t,J=7. 6Hz,1H),6.61(d,J=5.6Hz,1H),4.17-4.34(m,3H),3.93(s,3H),3.91(d,J=9.2Hz,1H),3.68(d,J=9.2Hz,1H),3. 38(d,J=4.8Hz,1H),3.12-3.24(m,2H),2.47(s,3H),1.68-1.86(m,3H),1.56-1.64(m,1H),1.21(d,J=6.0Hz,3H).

[0215] Example 33: (3S,4S)-8-(5-((3-chloro-2-((5-fluoro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0216] Referring to the method in Example 1, 3-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-indole (synthesized according to patent WO2015 / 188777) was used as the starting material to obtain the target compound.

[0217] 1H NMR(400MHz, DMSO-d6),9.72(s,1H),8.58(s,1H),8.40(d,J=4.0Hz,1H),8.38(s,1H),8.36(d,J=8.0Hz,1H),8 .17-8.26(m,4H),8.14(d,J=5.6Hz,1H),7.51(d,J=8.0Hz,1H),7.25(t,J=7.2Hz,1H),7.16(t,J=7.6Hz,1H),6 .57(d,J=5.2Hz,1H),4.17-4.26(m,3H),3.93(d,J=9.2Hz,1H),3.89(s,3H),3.67(d,J=9.2Hz,1H),3.37(d,J= 4.0Hz,1H),3.12-3.23(m,2H),1.76-1.88(m,2H),1.67-1.74(m,1H),1.58-1.65(m,1H),1.22(d,J=6.4Hz,3H).

[0218] Example 34: N 2 -(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-5-chloro-N 4 -(((R)-tetrahydrofuran-2-yl)methyl)pyrimidine-2,4-diamine hydrochloride

[0219] Referring to the method in Example 1, the target compound was obtained using (R)-2,5-dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-4-amine (synthesized according to patent WO2015 / 21149) as the starting material.

[0220] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.33(s,1H),8.15(s,1H),8.08(d,J=5.6Hz,1H),6.61(d ,J=5.6Hz,1H),4.38-4.45(m,1H),4.28-4.36(m,2H),4.18-4.24(m,1H),4.00(d,J=9.2Hz,1 H),3.86-3.93(m,2H),3.74-3.83(m,2H),3.65-3.70(m,1H),3.49(d,J=4.0Hz,1H),3.18-3 .34(m,2H),2.04-2.12(m,1H),1.82-2.02(m,5H),1.67-1.77(m,2H),1.32(d,J=6.4Hz,3H).

[0221] Example 35: (2-((4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-1,3,5-triazin-2-yl)amino)phenyl)dimethylphosphine oxide hydrochloride

[0222] Referring to the method in Example 29, the target compound was obtained using 2,4-dichloro-1,3,5-triazine as the starting material.

[0223] 1 H NMR(400MHz,CD3OD),8.63(s,1H),8.22-8.47(m,3H),8.06-8.14(m,1H),7. 64-7.74(m,2H),7.39-7.46(m,1H),6.75(d,J=6.0Hz,1H),4.27-4.46(m,3H ),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=3.6Hz,1H),3.19 -3.33(m,2H),1.84-1.90(m,9H),1.70-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0224] Example 36: (3S,4S)-8-(5-((3-chloro-2-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0225] Referring to the method in Example 1, the target compound was obtained using 3-(2,5-dichloropyrimidin-4-yl)-1H indole (synthesized according to patent WO2013 / 14448) as the starting material.

[0226] 1 H NMR(400MHz,CD3OD),8.73(s,1H),8.66-8.68(m,1H),8.64(s,1H),8.45(s,1H),8.39(s,1H ),8.04(d,J=6.4Hz,1H),7.52-7.54(m,1H),7.28-7.33(m,2H),6.79(d,J=6.4Hz,1H),4.40 -4.48(m,1H),4.28-4.38(m,2H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=4 .4Hz,1H),3.19-3.34(m,2H),1.84-1.94(m,3H),1.71-1.78(m,1H),1.32(d,J=6.0Hz,3H).

[0227] Example 37: (S)-1'-(5-((3-chloro-2-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-amine hydrochloride

[0228] Referring to the method in Example 1, the target compound was obtained using 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole and intermediate 2 as starting materials.

[0229] 1H NMR(400MHz, CD3OD),8.81(d,J=5.6Hz,1H),8.75-8.78(m,1H),8.53-8.55(m,2H),8.47(s,1H),8.39(s, 1H),8.27(d,J=6.8Hz,1H),8.14(d,J=5.6Hz,1H),7.89(dd,J=7.6Hz,5.6Hz,1H),7.67(d,J=7.2Hz,1H),7 .55-7.58(m,1H),7.38-7.41(m,2H),6.67(d,J=5.6Hz,1H),4.78(s,1H),4.53-4.61(m,1H),4.41-4.49(m ,1H),3.98(s,3H),3.63(d,J=17.6Hz,1H),3.52(d,J=17.6Hz,1H),3.33-3.47(m,2H),1.79-2.01(m,4H).

[0230] Example 38: (3S,4S)-8-(5-((3-chloro-2-((4-methylpyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0231] Referring to the method in Example 1, the target compound was obtained using 2-chloro-4-methylpyrimidine as the starting material.

[0232] 1 H NMR(400MHz,CD3OD),8.60(d,J=5.6Hz,1H),8.43(s,1H),8.37(s,1H),8.13(d, J=6.4Hz,1H),7.29(d,J=6.0Hz,1H),6.75(d,J=6.0Hz,1H),4.28-4.46(m,3H),4 .00(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.45(d,J=4.0Hz,1H),3.19-3.36(m ,2H),2.65(s,3H),1.82-1.92(m,3H),1.71-1.78(m,1H),1.32(d,J=6.0Hz,3H).

[0233] Example 39: 2-((2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-5-chloropyrimidin-4-yl)amino)-N-methylbenzamide hydrochloride

[0234] Referring to the method in Example 1, the target compound was obtained using 2-((2,5-dichloropyrimidin-4-yl)amino)-N-methylbenzamide (synthesized according to patent WO2008 / 147831) as the starting material.

[0235] 1 H NMR(400MHz,CD3OD),8.78(d,J=8.0Hz,1H),8.42(s,1H),8.35(s,1H),8.33(s,1H),8.08(d,J=5 .6Hz,1H),7.78(dd,J=8.0Hz,1.6Hz,1H),7.63-7.68(m,1H),7.35(t,J=7.2Hz,1H),6.66(d,J=6 .0Hz,1H),4.27-4.46(m,3H),4.00(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=4.0Hz,1H ),3.18-3.36(m,2H),2.92(s,3H),1.82-1.96(m,3H),1.70-1.77(m,1H),1.32(d,J=6.4Hz,3H).

[0236] Example 40: (3S,4S)-8-(5-((3-chloro-2-((2-(pyridin-3-yl)pyrimidin-4-yl)amino)pyridin-4-alkyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0237] Referring to the method in Example 1, the target compound was obtained using 4-chloro-2-(pyridin-3-yl)pyrimidine as the starting material.

[0238] 1HNMR(400MHz,CD3OD),9.72(s,1H),9.51(d,J=7.6Hz,1H),9.00(d,J=6.0Hz,1H),8.81(d,J=6.0Hz,1H), 8.45(s,1H),8.38(s,1H),8.26(dd,J=7.6Hz,6.0Hz,1H),8.22(d,J=6.0Hz,1H),7.88(d,J=5.6Hz,1H),6 .76(d,J=5.2Hz,1H),4.40-4.48(m,1H),4.28-4.39(m,2H),4.02(d,J=9.2Hz,1H),3.90(d,J=9.2Hz,1H) ,3.48(d,J=4.0Hz,1H),3.20-3.34(m,2H),1.86-1.96(m,3H),1.72-1.79(m,1H),1.33(d,J=6.8Hz,3H).

[0239] Example 41: (3S,4S)-8-(5-((3-chloro-2-)((4-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0240] Referring to the method in Example 1, the target compound was obtained using 2-chloro-4-(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidine as the starting material.

[0241] 1 H NMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.06(d,J=5.2Hz,1H),7.99(t,J=7.2Hz,1H ),6.89(dd,J=7.2Hz,2.4Hz,1H),6.57(d,J=5.2Hz,1H),4.74-5.11(m,4H),4.38-4.45(m,1H ),4.28-4.36(m,2H),4.00(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.61-.75(m,2H),3.44-3 .49(m,4H),3.18-3.34(m,2H),1.82-2.04(m,5H),1.71-1.78(m,1H),1.32(d,J=6.0Hz,3H).

[0242] Example 42: (1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-4-(chloromethyl)piperidin-4-yl)methanol hydrochloride

[0243] By referring to the method of Example 28, the target compound was obtained using (4-(chloromethyl)piperidin-4-yl)methanol hydrochloride as the starting material.

[0244] 1 H NMR(400MHz, CD3OD),8.42(s,1H),8.34(s,1H),8.12(d,J=5.2Hz,1H),7.91(d,J=7.2Hz,1H),6.90(d J=7.2Hz,1H),6.71(d,J=5.6Hz,1H),4.38-4.46(m,1H),4.27-4.36(m,2H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.70-3.78(m ,4H),3.69(s,2H),3.57(s,2H),3.47(d,J=4.4Hz,1H),3.18-3.32(m,2H),1.84-1.93(m,3H),1.67-1.78(m,5H),1.33(d,J=6.0Hz,3H).

[0245] Example 43: (3S,4S)-8-(5-((3-chloro-2-)((6-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0246] By referring to the method in Example 28, the target compound was obtained using 2,6-dichloropyrimidine and (3S,4R)-3-fluoro-4-methoxypiperidine hydrochloride as starting materials.

[0247] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.06(d,J=6.0Hz,1H),7.89(t,J=8.0Hz,1 H),6.87(d,J=8.0Hz,1H),6.83(d,J=8.8Hz,1H),6.57(d,J=5.2Hz,1H),4.99-5.15(m,1H) ,4.24-4.46(m,4H),3.98-4.07(m,2H),3.89(d,J=9.2Hz,1H),3.60-3.74(m,2H),3.40-3. 49(m,5H),3.18-3.32(m,2H),1.84-2.06(m,5H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0248] Example 44: (3S,4S)-8-(5-((3-chloro-2-((2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)pyridine-4-methyl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0249] Referring to the method in Example 28, the target compound was obtained using 4,4-difluoropiperidine as the starting material.

[0250] 1 H NMR(400MHz,CD3OD),8.43(s,1H),8.35(s,1H),8.12(d,J=5.6Hz,1H),7.96(d,J=7.2 Hz,1H),6.96(d,J=7.2Hz,1H),6.71(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.27-4.37( m,2H),4.01(d,J=9.2Hz,1H),3.80-3.94(m,5H),3.47(d,J=4.0Hz,1H),3.18-3.33(m ,2H),2.08-2.20(m,4H),1.84-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0251] Example 45: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-methyl)piperidin-3-ol hydrochloride

[0252] Referring to the method in Example 28, the target compound was obtained using 3-hydroxypiperidine as the starting material.

[0253] 1 H NMR(400MHz,CD3OD),8.43(s,1H),8.35(s,1H),8.13(d,J=5.6Hz,1H),7.90(d,J =7.2Hz,1H),6.92(d,J=7.2Hz,1H),6.73(d,J=5.6Hz,1H),4.28-4.4.6(m,3H),4. 01(d,J=9.6Hz,1H),3.81-3.90(m,3H),3.56-3.76(m,3H),3.47(d,J=4.0Hz,1H) ,3.19-3.33(m,2H),1.85-2.00(m,5H),1.55-1.78(m,3H),1.33(d,J=6.4Hz,3H).

[0254] Example 46: (R)-3-((2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-5-chloropyrimidin-4-yl)oxy)propane-1,2-diol hydrochloride

[0255] Referring to the method in Example 1, the target compound was obtained using (R)-3-(2,5-dichloropyrimidin-4-yl)oxy)propane-1,2-diol as the starting material.

[0256] 1 H NMR(400MHz,CD3OD),8.52(s,1H),8.45(s,1H),8.37(s,1H),8.14(d,J=6.4Hz,1H),6.81 (d,J=6.4Hz,1H),4.65-4.73(m,2H),4.40-4.48(m,1H),4.29-4.39(m,2H),4.04-4.10(m ,1H),4.02(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.69(d,J=5.2Hz,2H),3.47(d,J=4.4 Hz, 1H), 3.19-3.37 (m, 2H), 1.84-1.94 (m, 3H), 1.71-1.78 (m, 1H), 1.33 (d, J = 6.4Hz, 3H).

[0257] Example 47: (2-((6-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-amino)pyridin-2-yl)amino)phenyl)dimethylphosphine oxide hydrochloride

[0258] Referring to the method in Example 1, the target compound was obtained using 2,6-dichloropyrimidine as the starting material.

[0259] 1 H NMR(400MHz, CDCl3),9.95(s,1H),8.43(dd,J=8.4Hz,4.8Hz,1H),8.26(s,1H),8.22(s,1H),7.90(d ,J=5.6Hz,1H),7.81(d,J=8.0Hz,1H),7.64(s,1H),7.45-7.52(m,2H),7.19-7.25(m,1H),6.93-6.9 8(m,1H),6.47(d,J=8.4Hz,1H),6.18(d,J=5.2Hz,1H),4.04-4.28(m,3H),3.98(d,J=9.2Hz,1H),3. 74(d,J=9.2Hz,1H),3.18-3.36(m,3H),1.98-2.10(m,1H),1.73-1.94(m,9H),1.39(d,J=6.4Hz,3H).

[0260] Example 48: (S)-3-((2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-ylamino)-5-chloropyrimidin-4-yl)oxy)propane-1,2-diol hydrochloride

[0261] Referring to the method in Example 1, the target compound was obtained using (S)-3-(2,5-dichloropyrimidin-4-yl)oxy)propane-1,2-diol as the starting material.

[0262] 1H NMR(400MHz,CD3OD),8.52(s,1H),8.44(s,1H),8.38(s,1H),8.14(d,J=6.8Hz,1H),6.81 (d,J=6.8Hz,1H),4.64-4.73(m,2H),4.40-4.47(m,1H),4.28-4.39(m,2H),4.04-4.09(m ,1H),4.02(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.69(d,J=5.6Hz,2H),3.46(d,J=4.0 Hz, 1H), 3.19-3.37 (m, 2H), 1.84-1.94 (m, 3H), 1.71-1.78 (m, 1H), 1.33 (d, J = 6.0Hz, 3H).

[0263] Example 49: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-4-methylpiperidin-4-ol hydrochloride

[0264] Referring to the method in Example 28, the target compound was obtained using 4-methylpiperidin-4-ol as the starting material.

[0265] 1 H NMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.10(d,J=5.6Hz,1H),7.87(d,J=7 .6Hz,1H),6.89(d,J=6.4Hz,1H),6.67(d,J=5.6Hz,1H),4.38-4.45(m,1H),4.28-4 .37(m,2H),3.96-4.14(m,3H),3.59(d,J=9.2Hz,1H),3.44-3.56(m,3H),3.18-3.3 6(m,2H),1.82-1.93(m,3H),1.62-1.77(m,5H),1.32(d,J=6.4Hz,3H),1.27(s,3H).

[0266] Example 50: (3S,4S)-8-(5-((3-chloro-2-((2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0267] Referring to the method in Example 28, the target compound was obtained using 4-methoxypiperidine as the starting material.

[0268] 1 H NMR(400MHz,CD3OD),8.43(s,1H),8.34(s,1H),8.10-8.13(m,1H),7.88-7.91(m,1H) ,6.90(d,J=7.2Hz,1H),6.69-6.72(m,1H),4.38-4.46(m,1H),4.28-4.36(m,2H),4.01 (d,J=9.2Hz,1H),3.85-3.93(m,3H),3.55-3.67(m,3H),3.47(d,J=4.0Hz,1H),3.38(s ,3H),3.18-3.32(m,2H),1.84-2.01(m,5H),1.65-1.78(m,3H),1.33(d,J=6.4Hz,3H).

[0269] Example 51: (3S,4S)-8-(5-((2-((R)-3-aminopiperidin-1-yl)pyrimidin-4-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0270] By referring to the method in Example 28, the target compound was obtained using tert-butyl (R)-piperidin-3-ylcarbamate as the starting material.

[0271] m / z[LC-MS]:583.29[M+1].

[0272] 1 H NMR(400MHz, CD3OD),8.43(s,1H),8.35(s,1H),8.13(d,J=5.2Hz,1H),7.99(d,J=6.8Hz,1H),7.09(d,J=6.8Hz,1H),6.70(d,J=5.2Hz,1H),4.28-4.46 (m,4H),4.01(d,J=9.2Hz,1H),3.86-3.96(m,2H),3.46-3.72(m,4H),3.18 -3.34(m,2H),2.14-2.24(m,1H),1.66-1.97(m,7H),1.33(d,J=6.4Hz,3H).

[0273] Example 52: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamide hydrochloride

[0274] Referring to the method in Example 28, the target compound was obtained using piperidine-4-carboxamide as the starting material.

[0275] m / z[LC-MS]:611.22[M+1].

[0276] 1 H NMR (400MHz, CD3OD), 8.42 (s, 1H), 8.34 (s, 1H), 8.11 (d, J = 5.2Hz, 1H), 7.89-7. 92(m,1H),6.91(d,J=6.4Hz,1H),6.69-6.71(m,1H),4.27-4.46(m,5H),4.01(d, J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=4.0Hz,1H),3.17-3.32(m,4H), 2.58-2.68(m,1H),1.82-1.98(m,5H),1.68-1.80(m,3H),1.33(d,J=6.4Hz,3H).

[0277] Example 53: (3S,4S)-8-(5-((3-chloro-2-((5-chloro-4-(((3S,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxo)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl 2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0278] Referring to the method in Example 1, the target compound was obtained using (3S, 3aR, 6R, 6aR)-6-methoxyhexahydrofuran[3,2-b]furan-3-ol as the starting material.

[0279] m / z[LC-MS]:677.13[M+1].

[0280] 1H NMR(400MHz,CD3OD),8.54(s,1H),8.45(s,1H),8.38(s,1H),8.13(d,J=6.4Hz,1H),6.83(d,J=6.4Hz,1H ),5.60(d,J=3.6Hz,1H),4.84-4.86(m,1H),4.73(d,J=5.2Hz,1H),4.28-4.48(m,3H),4.25(dd,J=11.2Hz ,4.0Hz,1H),4.18(d,J=11.2Hz,1H),3.96-4.06(m,3H),3.89(d,J=8.8Hz,1H),3.74(dd,J=8.8Hz,6.0Hz ,1H),3.46-3.48(m,4H),3.20-3.34(m,2H),1.84-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.0Hz,3H).

[0281] Example 54: (3S,4S)-8-(5-((3-chloro-2-((5-chloro-4-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxo)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0282] Referring to the method in Example 1, the target compound was obtained using (3R, 3R, 6R, 6aR)-6-methoxyhexahydrofuran[3,2-b]furan-3-ol as the starting material.

[0283] m / z[LC-MS]:677.09[M+1].

[0284] 1H NMR(400MHz,CD3OD),8.48(s,1H),8.44(s,1H),8.37(s,1H),8.11(d,J=5.2Hz,1H),6.77(d,J=5 .2Hz,1H),5.67(q,J=4.8Hz,1H),5.01(t,J=4.8Hz,1H),4.61(t,J=4.8Hz,1H),4.28-4.48(m,3H ),4.16(dd,J=10.8Hz,3.6Hz,1H),4.08-4.12(m,1H),3.88-4.03(m,4H),3.57-3.61(m,1H),3.4 3-3.49(m,4H),3.18-3.35(m,2H),1.82-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.0Hz,3H).

[0285] Example 55: 1-((2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-4-yl)amino)-2-methylpropan-2-ol hydrochloride

[0286] Referring to the method in Example 1, the target compound was obtained using 1-((2-chloropyrimidin-4-yl)amino)-2-methylpropan-2-ol as the starting material.

[0287] m / z[LC-MS]:572.24[M+1].

[0288] Example 56: (3S,4S)-8-(5-((3-chloro-2-((2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0289] Referring to the method in Example 28, the target compound was obtained using 1-methylpiperazine as the starting material.

[0290] m / z[LC-MS]:583.19[M+1].

[0291] 1H NMR(400MHz,CD3OD),8.43(s,1H),8.35(s,1H),8.13(d,J=4.8Hz,1H),8.05(d,J=6 .8Hz,1H),7.06(d,J=6.4Hz,1H),6.71(d,J=4.0Hz,1H),4.53-4.65(m,2H),4.38-4 .46(m,1H),4.28-4.37(m,2H),3.53-3.73(m,4H),3.47(d,J=3.2Hz,1H),3.18-3.3 4(m,4H),2.97(s,3H),1.84-1.95(m,3H),1.71-1.78(m,1H),1.33(d,J=6.0Hz,3H).

[0292] Example 57: (3S,4S)-8-(5-((3-chloro-2-((2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0293] By referring to the method of Example 28, the target compound was obtained using 1-methylsulfonylpiperazine as the starting material.

[0294] m / z[LC-MS]:647.13[M+1].

[0295] 1 H NMR(400MHz,CD3OD),8.44(s,1H),8.35(s,1H),8.14(d,J=5.2Hz,1H),7.98(d,J=7.2Hz, 1H),6.96(d,J=7.2Hz,1H),6.74(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.28-4.37(m,2H), 4.01(d,J=9.6Hz,1H),3.82-3.90(m,5H),3.47(d,J=4.0Hz,1H),3.36-3.39(m,4H),3.19 -3.33(m,2H),2.89(s,3H),1.85-1.94(m,3H),1.71-1.79(m,1H),1.33(d,J=6.4Hz,3H).

[0296] Example 58: (3S,4S)-8-(5-((2-((2-(2,7-diazaspiro[3.5]non-7-yl)pyrimidin-4-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0297] Referring to the method in Example 28, the target compound was obtained using tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate as the starting material.

[0298] m / z[LC-MS]:609.19[M+1].

[0299] 1 H NMR(400MHz, CD3OD),8.43(s,1H),8.35(s,1H),8.11(d,J=4.8Hz,1H),7.92(d,J=7.2Hz,1H),6.92(d,J=7.2Hz, 1H),6.69(d,J=4.8Hz,1H),4.38-4.46(m,1H),4.27-4.37(m,2H),4.01(d,J=5.2Hz,1H),3.95(s,4H),3.89(d,J =9.2Hz,1H),3.70-3.78(m,4H),3.47(d,J=4.0Hz,1H),3.19-3.36(m,2H),1. 98-2.04(m,4H),1.86-1.94(m,3H),1.70-1.79(m,1H),1.33(d,J=6.4Hz,3H).

[0300] Example 59: N 4 -(4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-N 2 -(((R)-tetrahydrofuran-2-yl)methyl)pyrimidine-2,4-diamine hydrochloride

[0301] By referring to the method of Example 28, the target compound was obtained using (R)-(tetrahydrofuran-2-yl)methanamine as the starting material.

[0302] m / z[LC-MS]:584.22[M+1].

[0303] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.12(d,J=5.2Hz,1H),7.91(d,J=7.6Hz, 1H),6.76-7.00(brs,1H),6.71(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.28-4.37(m,2H),4 .00-4.10(m,2H),3.72-3.91(m,3H),3.49-3.56(m,1H),3.46(d,J=4.4Hz,1H),3.18-3.4 0(m,3H),1.84-2.06(m,6H),1.70-1.78(m,1H),1.54-1.66(m,1H),1.33(d,J=6.4Hz,3H).

[0304] Example 60: (2-((2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide hydrochloride

[0305] Referring to the method in Example 1, (2-((2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (synthesized according to patent WO2020 / 147702) was used as the starting material to obtain the target compound.

[0306] m / z[LC-MS]:652.17[M+1].

[0307] 1 H NMR(400MHz, CD3OD),8.03-8.48(m,5H),7.72-7.81(m,2H),7.50(t,J=7.6Hz,1H),6.60-6.68(m,2H),4.38-4.45(m,1H),4.28-4.37(m,2H),4.0 1(d,J=9.2Hz,1H),3.09(d,J=9.2Hz,1H),3.49(d,J=4.0Hz,1H),3.19-3 .34(m,2H),1.84-1.93(m,9H),1.71-1.77(m,1H),1.33(d,J=6.4Hz,3H).

[0308] Example 61: (3S,4R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-3-fluoropiperidin-4-ol hydrochloride

[0309] By referring to the method in Example 28, the target compound was obtained using (3S,4R)-3-fluoropiperidin-4-ol as the starting material.

[0310] m / z[LC-MS]:602.20[M+1].

[0311] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.12(d,J=5.2Hz,1H),7.92(d, J=7.2Hz,1H),6.94(d,J=7.2Hz,1H),6.70(d,J=5.2Hz,1H),4.70-4.86(m,1H),4 .16-4.46(m,5H),3.87-4.02(m,3H),3.55-3.67(m,1H),3.46(d,J=4.0Hz,1H), 3.19-3.40(m,3H),1.83-1.96(m,5H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0312] Example 62: (3S,4S)-8-(5-((3-chloro-2-((2-(4-(methylsulfonyl)piperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0313] By referring to the method of Example 28, the target compound was obtained using 4-(methylsulfonyl)piperidine as the starting material.

[0314] m / z[LC-MS]:646.19[M+1].

[0315] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.12(d,J=5.2Hz,1H),7.93(d, J=7.2Hz,1H),6.94(d,J=7.2Hz,1H),6.70(d,J=5.6Hz,1H),4.28-4.55(m,5H), 4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.43-3.52(m,2H),3.19-3.33(m, 4H), 2.96 (s, 3H), 2.22-2.32 (m, 2H), 1.70-1.92 (m, 6H), 1.33 (d, J = 6.4Hz, 3H).

[0316] Example 63: 2-(1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)piperidin-4-yl)propanol hydrochloride

[0317] Referring to the method in Example 28, the target compound was obtained using 2-(piperidin-4-yl)propan-2-ol as the starting material.

[0318] m / z[LC-MS]:626.25[M+1].

[0319] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.11(d,J=5.6Hz,1H),7.88(d,J=7.2Hz, 1H),6.88(d,J=5.6Hz,1H),6.68(d,J=5.2Hz,1H),4.79-4.97(m,1H),4.28-4.50(m,4H), 4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=4.0Hz,1H),3.18-3.32(m,2H),3 .00-3.12(m,2H),1.83-1.96(m,5H),1.61-1.78(m,2H),1.30-1.44(m,5H),1.16(s,6H).

[0320] Example 64: (3S,4S)-8-(5-((3-chloro-2-((5-chloro-4-(((S)-tetrahydrofuran-2-yl)methoxy)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0321] Referring to the method in Example 1, the target compound was obtained using (S)-(tetrahydrofuran-2-yl)methanol as the starting material.

[0322] m / z[LC-MS]:619.15[M+1].

[0323] 1 H NMR(400MHz,CD3OD),8.49(s,1H),8.41(s,1H),8.34(s,1H),8.08-8.22(br s,1H),6.74-6.86(brs,1H),4.68-4.74(m,1H),4.50-4.54(m,1H),4.26-4. 48(m,4H),4.01(d,J=8.4Hz,1H),3.79-3.73(m,3H),3.42-3.48(m,1H),3.1 6-3.32(m,2H),1.83-2.20(m,7H),1.70-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0324] Example 65: (3S,4S)-8-(5-((3-chloro-2-((5-chloro-4-(((R-tetrahydrofuran-2-yl)methoxy)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0325] Referring to the method in Example 1, the target compound was obtained using (R)-(tetrahydrofuran-2-yl)methanol as the starting material.

[0326] m / z[LC-MS]:619.18[M+1].

[0327] 1H NMR(400MHz,CD3OD),8.50(s,1H),8.44(s,1H),8.37(s,1H),8.13(d,J=6.0Hz,1H),6.80(d,J=6.0 Hz,1H),4.70(dd,J=11.6Hz,3.6Hz,1H),4.55(dd,J=11.6Hz,5.6Hz,1H),4.40-4.48(m,1H),4.27- 4.39(m,3H),4.01(d,J=9.2Hz,1H),3.87-3.93(m,2H),3.78-3.84(m,1H),3.48(d,J=3.6Hz,1H),3 .19-3.36(m,2H),2.10-2.20(m,1H),1.82-2.08(m,6H),1.71-1.78(m,1H),1.33(d,J=6.0Hz,3H).

[0328] Example 66: (3S,4S)-8-(5-((3-chloro-2-((4-(1-methyl-1H-indazol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0329] Referring to the method in Example 1, 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indazole (synthesized according to patent WO2016 / 94821) was used as a raw material to obtain the target compound.

[0330] m / z[LC-MS]:615.20[M+1].

[0331] 1 H NMR(400MHz,CD3OD),8.80-8.88(m,1H),8.65(d,J=4.8Hz,1H),8.45(s,1H),8.38(s,1H),8.14- 8.23(m,1H),8.09(d,J=6.4Hz,1H),7.70(d,J=8.8Hz,1H),7.56(t,J=7.6Hz,1H),7.43(t,J=7.6H z,1H),6.75(d,J=5.2Hz,1H),4.22-4.48(m,6H),4.02(d,J=9.6Hz,1H),3.90(d,J=9.6Hz,1H),3 .50(d,J=3.6Hz,1H),3.20-3.34(m,2H),1.86-1.95(m,3H),1.71-1.79(m,1H),1.33(d,J=6.4Hz, 3H).

[0332] Example 67: (R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)piperidin-3-ol hydrochloride

[0333] Referring to the method in Example 28, the target compound was obtained using (R)-piperidin-3-ol as a starting material.

[0334] m / z[LC-MS]:584.17[M+1].

[0335] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.12(d,J=5.2Hz,1H),7.89(d,J=7.2 Hz,1H),6.92(d,J=7.2Hz,1H),6.70(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.28-4.37( m,2H),4.01(d,J=9.6Hz,1H),3.81-3.90(m,3H),3.54-3.75(m,3H),3.47(d,J=4.0Hz ,1H),3.18-3.32(m,2H),1.84-2.01(m,5H),1.54-1.78(m,3H),1.33(d,J=6.4Hz,3H).

[0336] Example 68: (S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)piperidin-3-ol hydrochloride

[0337] Referring to the method in Example 28, the target compound was obtained using (S)-piperidin-3-ol as a starting material.

[0338] m / z[LC-MS]:584.18[M+1].

[0339] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.07-8.16(brs,1H),7.88(d ,J=6.8Hz,1H),6.88-6.96(brs,1H),6.65-6.73(brs,1H),4.26-4.46(m,3H), 4.01(d,J=9.2Hz,1H),3.80-3.92(m,3H),3.54-3.75(m,3H),3.47(s,1H),3. 18-3.32(m,2H),1.82-2.02(m,5H),1.54-1.78(m,3H),1.32(d,J=6.0Hz,3H).

[0340] Example 69: (3S,4S)-8-(5-((3-chloro-2-((2-(((R)-tetrahydrofuran-2-yl)methoxy)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0341] Referring to the method in Example 28, the target compound was obtained using (R)-(tetrahydrofuran-2-yl)methanol as a starting material.

[0342] m / z[LC-MS]:585.19[M+1].

[0343] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.21(d,J=7.2Hz,1H),8.12(d,J=5.2Hz, 1H),7.34(d,J=6.4Hz,1H),6.69(d,J=5.6Hz,1H),4.52(dd,J=11.2Hz,3.6Hz,1H),4.38- 4.47(m,2H),4.25-4.36(m,3H),4.01(d,J=9.2Hz,1H),3.78-3.91(m,3H),3.46(d,J=3.6 Hz, 1H), 3.18-3.29 (m, 2H), 1.82-2.13 (m, 6H), 1.69-1.78 (m, 2H), 1.33 (d, J = 6.4Hz, 3H).

[0344] Example 70: (3S,4S)-8-(5-((3-chloro-2-((2-(((S)-tetrahydrofuran-2-yl)methoxy)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0345] Referring to the method in Example 28, the target compound was obtained using (S)-(tetrahydrofuran-2-yl)methanol as a starting material.

[0346] m / z[LC-MS]:585.17[M+1].

[0347] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.21(d,J=7.2Hz,1H),8.14(d,J=4.8Hz, 1H),7.29(d,J=7.2Hz,1H),6.72(d,J=4.8Hz,1H),4.54(dd,J=11.2Hz,3.2Hz,1H),4.38- 4.48(m,2H),4.25-4.37(m,3H),4.01(d,J=9.2Hz,1H),3.77-3.90(m,3H),3.46(d,J=4.0 Hz, 1H), 3.16-3.32 (m, 2H), 1.82-2.13 (m, 6H), 1.68-1.78 (m, 2H), 1.32 (d, J = 6.4Hz, 3H).

[0348] Example 71: (3S,4S)-8-(5-((2-((2-(2,8-diazaspiro[4.5]decane-8-yl)pyrimidin-4-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.4]dec-4-amine hydrochloride

[0349] Referring to the method in Example 28, the target compound was obtained using tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate as a raw material.

[0350] m / z[LC-MS]:623.22[M+1].

[0351] 1H NMR(400MHz,CD3OD),8.43(s,1H),8.34(s,1H),8.11(d,J=4.8Hz,1H),7.92(d,J=7.2 Hz,1H),6.86-6.97(brs,1H),6.69(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.28-4.37(m ,2H),4.01(d,J=9.6Hz,1H),3.80-3.90(m,3H),3.68-3.78(m,2H),3.42-3.47(m,3H) ,3.18-3.33(m,4H),2.05(t,J=7.2Hz,2H),1.71-1.94(m,8H),1.33(d,J=6.4Hz,3H).

[0352] Example 72: (3S,4S)-8-(5-((2-((2-((S)-3-aminopiperidin-1-yl)pyrimidin-4-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decane-4-amine hydrochloride

[0353] Referring to the method in Example 28, the target compound was obtained using (S)-piperidin-3-ylcarbamic acid tert-butyl ester as a starting material.

[0354] m / z[LC-MS]:583.21[M+1].

[0355] 1 H NMR(400MHz,CD3OD),8.43(s,1H),8.35(s,1H),8.14(d,J=5.2Hz,1H),8.00(d ,J=7.2Hz,1H),7.04-7.13(brs,1H),6.70(d,J=5.2Hz,1H),4.39-4.46(m,1H), 4.28-4.37(m,3H),4.01(d,J=9.6Hz,1H),3.87-3.96(m,2H),3.66-3.74(m,1H ),3.45-3.59(m,3H),3.19-3.34(m,2H),2.14-2.24(m,1H),1.72-1.99(m,7H), 1.33 (d, J = 6.4 Hz, 3H).

[0356] Example 73: (3S,4S)-8-(5-((3-chloro-2-((2-(4-(dimethylamino)piperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decane-4-amine hydrochloride

[0357] Referring to the method in Example 28, the target compound was obtained using N,N-dimethylpiperidin-4-amine as a raw material.

[0358] m / z[LC-MS]:611.26[M+1].

[0359] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.11(d,J=4.8Hz,1H),7.95(d,J=7.6Hz, 1H),6.91-7.01(brs,1H),6.68(d,J=5.2Hz,1H),4.52-4.64(m,2H),4.27-4.45(m,3H),4. 01(d,J=9.6Hz,1H),3.89(d,J=9.6Hz,1H),3.56-3.65(m,1H),3.46(d,J=4.4Hz,1H),3.1 5-3.32(m,4H),2.89(s,6H),2.20-2.28(m,2H),1.70-1.93(m,6H),1.33(d,J=6.4Hz,3H).

[0360] Example 74: 4-(4-((4-)((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidine-2-methyl)thiomorpholine-1,1-dioxide hydrochloride

[0361] Referring to the method in Example 28, the target compound was obtained using thiomorpholine 1,1-dioxide as a raw material.

[0362] m / z[LC-MS]:618.18[M+1].

[0363] 1H NMR(400MHz,CD3OD),8.41(s,1H),8.35(s,1H),8.11(d,J=5.6Hz,1H),8.03(d,J= 7.2Hz,1H),7.06(d,J=6.4Hz,1H),6.66(d,J=5.6Hz,1H),4.38-4.45(m,1H),4.18 -4.36(m,6H),4.01(d,J=8.8Hz,1H),3.89(d,J=8.8Hz,1H),3.46(d,J=3.6Hz,1H) ,3.18-3.35(m,6H),1.83-1.93(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0364] Example 75: (S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)pyrrolidin-3-ol hydrochloride

[0365] Referring to the method in Example 28, the target compound was obtained using (S)-3-pyrrolidinol as a starting material.

[0366] m / z[LC-MS]:570.17[M+1].

[0367] 1 H NMR(400MHz, CD3OD),8.41(s,1H),8.34(s,1H),8.11(d,J=5.6Hz,1H),7.89(d,J=6.8Hz,1H),6.92(d,J=6.4Hz,1H),6.68(d,J=5.2Hz,1H), 4.73-4.98(m,2H),4.38-4.45(m,1H),4.27-4.36(m,2H),4.01(d,J=9.6Hz,1H),3.89(d,J=9.6Hz,1H),3.58-3.82(m,3H), 3.46(d,J=4.0Hz,1H),3.18-3.32(m,2H),1.98-2.28(m,2H),1.84-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0368] Example 76: (3S,4S)-8-(5-((3-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-ylpyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0369] Referring to the method in Example 28, the target compound was obtained using 1-methyl-4-(piperidin-4-yl)piperazine as a starting material.

[0370] m / z[LC-MS]:666.29[M+1].

[0371] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.11(d,J=5.2Hz,1H),7.94(d,J=7.6Hz,1H),6.90 -7.01(brs,1H),6.68(d,J=5.2Hz,1H),4.52-4.62(m,2H),4.38-4.45(m,1H),4.28-4.37(m,2H),4. 01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.50-3.85(m,9H),3.46(d,J=4.4Hz,1H),3.16-3.38(m ,4H),3.00(s,3H),2.30-2.39(m,2H),1.82-1.98(m,5H),1.70-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0372] Example 77: (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-((3-chloro-2-((2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)-5-methylpyrazin-2-yl)methanol hydrochloride

[0373] By referring to the method in Example 28, the target compound was obtained using (3S,4R)-3-fluoro-4-methoxypiperidine hydrochloride and intermediate 4 as raw materials.

[0374] m / z[LC-MS]:660.25[M+1].

[0375] Example 78: 1-(4-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)piperazin-1-yl)ethan-1-one hydrochloride

[0376] Referring to the method in Example 28, the target compound was obtained using 1-acetylpiperazine as a starting material.

[0377] m / z[LC-MS]:611.22[M+1].

[0378] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.12(d,J=4.8Hz,1H),7.95(d,J=7.2Hz ,1H),6.92-7.01(brs,1H),6.70(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.28-4.37(m,2H), 4.01(d,J=9.6Hz,1H),3.81-3.90(m,3H),3.68-3.80(m,6H),3.47(d,J=4.0Hz,1H),3.18 -3.32(m,2H),2.15(s,3H),1.84-1.95(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0379] Example 79: (3S,4S)-8-(5-((3-chloro-2-((2-(4-(2-methoxyethyl)piperazin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0380] Referring to the method in Example 28, the target compound was obtained using 1-(2-methoxyethyl)piperazine as a starting material.

[0381] m / z[LC-MS]:628.18[M+1].

[0382] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.12(d,J=4.4Hz,1H),8.04(d,J=6.8 Hz,1H),7.02-7.11(brs,1H),6.69(d,J=4.4Hz,1H),4.38-4.69(m,3H),4.28-4.37(m ,2H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.54-3.86(m,6H),3.40-3.50(m, 6H), 3.14-3.36 (m, 4H), 1.82-1.96 (m, 3H), 1.70-1.78 (m, 1H), 1.33 (d, J = 6.0Hz, 3H).

[0383] Example 80: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)piperidine-4-carbonitrile hydrochloride

[0384] Referring to the method in Example 28, the target compound was obtained using 4-cyanopiperidine as a raw material.

[0385] m / z[LC-MS]:593.19[M+1].

[0386] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.12(d,J=4.8Hz,1H),7.93(d,J=7.2 Hz,1H),6.87-6.99(brs,1H),6.70(d,J=5.6Hz,1H),4.28-4.46(m,3H),3.95-4.05(m ,2H),3.89(d,J=9.2Hz,1H),3.59-3.68(m,2H),3.47(d,J=4.4Hz,1H),3.11-3.33(m, 4H), 2.02-2.13 (m, 2H), 1.83-1.99 (m, 5H), 1.70-1.79 (m, 1H), 1.33 (d, J = 6.4Hz, 3H).

[0387] Example 81: (3R,3aR,6R,6aR)-6-((4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)oxa)hexahydrofuro[3,2-b]furan-3-ol hydrochloride

[0388] Referring to the method in Example 28, the target compound was obtained using 1,4:3,6-dianhydromannitol as a raw material.

[0389] m / z[LC-MS]:629.21[M+1].

[0390] 1 H NMR(400MHz,CD3OD),8.34(s,1H),8.23(d,J=6.8Hz,1H),8.13(d,J=3.6Hz,1H),7.31(d,J=6.8H z,1H),6.70(d,J=3.6Hz,1H),5.44-5.50(m,1H),4.88-4.91(m,1H),4.38-4.46(m,2H),4.24-4.3 7(m,3H),4.06-4.12(m,2H),4.01(d,J=9.6Hz,1H),3.84-3.90(m,2H),3.51(t,J=7.2Hz,1H),3. 45-3.50(m,1H),3.18-3.36(m,2H),1.83-1.95(m,3H),1.71-1.78(m,1H),1.33(d,J=6.0Hz,3H).

[0391] Example 82: 2-(4-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)piperazin-1-yl)ethan-1-ol hydrochloride

[0392] Referring to the method in Example 28, the target compound was obtained using 2-(piperazin-1-yl)ethan-1-ol as a starting material.

[0393] m / z[LC-MS]:613.24[M+1].

[0394] 1H NMR(400MHz,CD3OD),8.43(s,1H),8.35(s,1H),8.13(d,J=5.2Hz,1H),8.04(d,J=6.8Hz,1H ),7.06(d,J=5.2Hz,1H),6.71(d,J=6.8Hz,1H),4.48-4.64(m,2H),4.28-4.46(m,3H),4.02 (d,J=9.6Hz,1H),3.93-3.95(m,2H),3.89(d,J=9.6Hz,1H),3.52-3.86(m,4H),3.47(d,J=4 .0Hz,1H),3.19-3.38(m,6H),1.84-1.94(m,3H),1.71-1.79(m,1H),1.33(d,J=6.4Hz,3H).

[0395] Example 83: (2-((4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)amino)phenyl)dimethylphosphine oxide hydrochloride

[0396] Referring to the method in Example 28, the target compound was obtained using (2-aminophenyl)dimethylphosphine oxide as a starting material.

[0397] MS m / z[LC-MS]:652.20[M+1].

[0398] Example 84: Isopropyl 2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate hydrochloride

[0399] Referring to the method in Example 1, 2-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid isopropyl ester (synthesized according to patent WO2019 / 222093) was used as a raw material to obtain the target compound.

[0400] MS m / z[LC-MS]:700.24[M+1].

[0401] Example 85: 2-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)-9-(2-(dimethylphosphoryl)phenyl)-7-methyl-7,9-dihydro-8H-purin-8-one hydrochloride

[0402] The target compound was obtained by following the method of Example 1 using (2-aminophenyl)dimethylphosphine oxide as a starting material. MS m / z [LC-MS]: 707.19 [M+1].

[0403] Example 86: (3S,4S)-8-(5-((3-chloro-2-((4-(1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0404] Referring to the method in Example 1, 3-(2-chloropyrimidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H indole (synthesized according to patent WO2019 / 218987) was used as a raw material to obtain the target compound.

[0405] MS m / z[LC-MS]:682.15[M+1].

[0406] Example 87: (3S,4S)-8-(5-((3-chloro-2-((2-((S)-3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine hydrochloride

[0407] Referring to the method in Example 28, the target compound was obtained using (S)-N,N-dimethylpyrrolidin-3-amine as a starting material.

[0408] MS m / z[LC-MS]:597.22[M+1].

[0409] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.12(d,J=5.2Hz,1H),7.98(d,J=7.6Hz,1H),6.98-7.09(brs,1H),6 .68(d,J=4.8Hz,1H),4.38-4.46(m,1H),4.28-4.37(m,2H),4.08-4.18(m,2H),4.01(d,J=9.6Hz,1H),3.82-3.96(m, 3H),3.62-3.71(m,1H),3.47(d,J=4.0Hz,1H),3.17-3.33(m,2H),2.98(s,6H),2.56-2.7 2(m,1H),2.34-2.54(m,1H),1.84-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0410] Example 88: (3S,4S)-8-(5-((3-chloro-2-((2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0411] Referring to the method in Example 28, the target compound was obtained using 3-methyl-3,9-diazaspiro[5.5]undecane as a raw material.

[0412] MS m / z[LC-MS]:651.25[M+1].

[0413] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.10(d,J=5.6Hz,1H),7.90(d,J=7.6Hz,1H),6.88-6.9 6(brs,1H),6.66(d,J=5.6Hz,1H),4.38-4.45(m,1H),4.28-4.36(m,2H),4.01(d,J=9.2Hz,1H),3.89(d, J=9.2Hz,1H),3.70-3.80(m,4H),3.46(d,J=4.0Hz,1H),3.36-3.43(m,2H),3.11-3.28(m,4H),2.88(s, 3H), 1.99-2.06 (m, 2H), 1.81-1.93 (m, 5H), 1.66-1.78 (m, 3H), 1.59-1.62 (m, 2H), 1.33 (d, J = 6.0Hz, 3H).

[0414] Example 89: ((S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)pyrrolidin-2-yl)methanol hydrochloride

[0415] Referring to the method in Example 28, the target compound was obtained using (S)-pyrrolidin-2-ylmethanol undecane as a raw material.

[0416] MS m / z[LC-MS]:584.20[M+1].

[0417] 1 H NMR(400MHz, CD3OD),8.41(s,1H),8.35(s,1H),8.11(d,J=5.2Hz,1H),7.92(d,J=7.2Hz,1H),6.85- 6.94(brs,1H),6.70(d,J=5.6Hz,1H),4.38-4.46(m,1H),4.28-4.36(m,2H),4.13-4.27(m,1H),4.01 (d,J=5.2Hz,1H),3.89(d,J=9.2Hz,1H),3.73-3.78(m,1H),3.50-3.70(m,3H),3.46(d,J=4.0Hz,1H) ,3.18-3.32(m,2H),1.97-2.27(m,4H),1.83-1.94(m,3H),1.70-1.78(m,1H),1.33(d,J=7.2Hz,3H).

[0418] Example 90: 8-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-3-one hydrochloride

[0419] Referring to the method in Example 28, the target compound was obtained using 2,8-diazaspiro[4.5]decan-3-one as a raw material.

[0420] MS m / z[LC-MS]:637.23[M+1].

[0421] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.11(d,J=5.6Hz,1H),7.90(d,J=7 .2Hz,1H),6.86-6.94(brs,1H),6.69(d,J=5.2Hz,1H),4.38-4.45(m,1H),4.28-4.3 6(m,2H),4.01(d,J=8.8Hz,1H),3.79-3.90(m,3H),3.62-3.72(m,2H),3.46(d,J=4. 4Hz, 1H), 3.18-3.34 (m, 4H), 2.33 (s, 2H), 1.71-1.94 (m, 8H), 1.33 (d, J = 6.4Hz, 3H).

[0422] Example 91: (R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)pyrrolidin-3-ol hydrochloride

[0423] Referring to the method in Example 28, the target compound was obtained using (R)-pyrrolidin-3-ol as a starting material.

[0424] MS m / z[LC-MS]:570.18[M+1].

[0425] 1H NMR(400MHz, CD3OD),8.42(s,1H),8.35(s,1H),8.12(d,J=5.2Hz,1H),7.91(d,J=7.6Hz,1H),6.92(d, J=6.4Hz,1H),6.71(d,J=5.6Hz,1H),4.57-4.64(m,0.5H),4.47-4.53(m,0.5H),4.38-4.46(m,1H),4. 28-4.37(m,2H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.57-3.82(m,4H),3.47(d,J=4.0Hz,1H ),3.18-3.30(m,2H),1.98-2.28(m,2H),1.84-1.95(m,3H),1.72-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0426] Example 92: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-N-methylpiperidine-4-carboxamide hydrochloride

[0427] Referring to the method in Example 28, the target compound was obtained using N-methylpiperidine-4-carboxamide as a starting material.

[0428] MS m / z[LC-MS]:625.20[M+1].

[0429] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.12(d,J=5.2Hz,1H),7.91 (d,J=7.6Hz,1H),6.92(d,J=6.4Hz,1H),6.71(d,J=5.6Hz,1H),4.57-4.64( m,0.5H),4.47-4.53(m,0.5H),4.38-4.46(m,1H),4.28-4.37(m,2H),4.01( d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.57-3.82(m,4H),3.47(d,J=4.0Hz, 1H), 3.18-3.30 (m, 2H), 1.98-2.28 (m, 2H), 1.84-1.95 (m, 3H), 1.72-1.78 (m, 1H), 1.33 (d, J = 6.4Hz, 3H).

[0430] Example 93: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)azetidine-3-carboxamide hydrochloride

[0431] Referring to the method in Example 28, the target compound was obtained using azetidine-3-carboxamide as a starting material.

[0432] MS m / z[LC-MS]:583.17[M+1].

[0433] 1 H NMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.09(d,J=5.6Hz,1H),7.88-7.9 2(m,1H),6.94-7.01(brs,1H),6.66(d,J=5.6Hz,1H),4.28-4.47(m,7H),4.01(d ,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.59-3.74(m,1H),3.46(d,J=4.0Hz,1H), 3.18-3.32(m,2H),1.81-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0434] Example 94: Methyl 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)azetidine-3-carboxylate hydrochloride

[0435] Referring to the method in Example 28, the target compound was obtained using methyl azetidine-3-carboxylate as a starting material.

[0436] MS m / z[LC-MS]:598.18[M+1].

[0437] 1H NMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.09(d,J=5.6Hz,1H),7.88-7.92( m,1H),6.94-7.01(brs,1H),6.66(d,J=5.6Hz,1H),4.28-4.47(m,7H),4.01(d,J=9. 2Hz,1H),3.89(d,J=9.2Hz,1H),3.77(s,3H),3.59-3.74(m,1H),3.46(d,J=4.0Hz,1 H),3.18-3.32(m,2H),1.81-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0438] Example 95: (3S,4S)-8-(5-((3-chloro-2-((2-((R)-3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0439] Referring to the method in Example 28, the target compound was obtained using (R)-N,N-dimethylpyrrolidin-3-amine as a starting material.

[0440] MS m / z[LC-MS]:597.28[M+1].

[0441] 1 H NMR(400MHz, CD3OD),8.43(s,1H),8.34(s,1H),8.13(d,J=5.6Hz,1H),7.99(d,J=7.6Hz,1H),6.98-7.08(brs,1H),6.71(d,J=5.6Hz,1H),4.38-4.46 (m,1H),4.28-4.37(m,2H),4.08-4.17(m,2H),4.01(d,J=9.6Hz,1H),3.83-3.96(m,3H),3.63-3.71(m,1H),3.47(d,J=4.4Hz,1H), 3.18-3.34(m,2H),2.98(s,6H),2.56-2.70(m,1H),2.33-2.54(m,1H),1.84-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0442] Example 96: ((S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)pyrrolidin-2-yl)methanol hydrochloride

[0443] Referring to the method in Example 28, the target compound was obtained using (S)-pyrrolidin-2-ylmethanol as a starting material.

[0444] MS m / z[LC-MS]:584.23[M+1].

[0445] 1 H NMR(400MHz,CD3OD),8.43(s,1H),8.35(s,1H),8.14(d,J=4.0Hz,1H),7.96(d,J=7.2Hz,1H),6 .91(d,J=6.8Hz,1H),6.70-6.80(brs,1H),4.38-4.46(m,1H),4.25-4.37(m,3H),4.01(d,J=9.2 Hz,1H),3.89(d,J=9.2Hz,1H),3.72-3.78(m,1H),3.57-3.68(m,3H),3.47(d,J=4.0Hz,1H),3.1 8-3.34(m,2H),1.96-2.28(m,4H),1.84-1.95(m,3H),1.71-1.78(m,1H),1.33(d,J=6.0Hz,3H).

[0446] Example 97: (3S,4S)-8-(5-((2-((2-(2-amino-7-azaspiro[3.5]non-7-yl)pyrimidin-4-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0447] Referring to the method in Example 28, the target compound was obtained using tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate as a starting material.

[0448] MS m / z[LC-MS]:623.22[M+1].

[0449] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.10(d,J=5.2Hz,1H),7.89(d,J=7.2Hz,1 H),6.84-6.96(brs,1H),6.67(d,J=5.2Hz,1H),4.28-4.46(m,3H),4.01(d,J=9.6Hz,1H), 3.80-3.90(m,2H),3.69-3.76(m,2H),3.40-3.70(m,2H),3.46(d,J=4.0Hz,1H),3.18-3.3 2(m,2H),2.36-2.41(m,2H),1.98-2.05(m,2H),1.72-1.95(m,8H),1.33(d,J=6.4Hz,3H).

[0450] Example 98: (3R,4S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-3-fluoropiperidin-4-ol hydrochloride

[0451] Referring to the method in Example 28, the target compound was obtained using (3R,4S)-3-fluoropiperidin-4-ol as a starting material.

[0452] MS m / z[LC-MS]:602.16[M+1].

[0453] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.11(d,J=5.2Hz,1H),7.91(d, J=7.2Hz,1H),6.90-6.98(brs,1H),6.69(d,J=5.2Hz,1H),4.71-4.82(m,1H),4 .28-4.46(m,4H),3.88-4.04(m,4H),3.54-3.66(m,2H),3.46(d,J=4.0Hz,1H), 3.18-3.40(m,2H),1.84-1.94(m,5H),1.70-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0454] Example 99: (3S,4S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-3-fluoropiperidin-4-ol hydrochloride

[0455] Referring to the method in Example 28, the target compound was obtained using (3S,4S)-3-fluoropiperidin-4-ol as a starting material.

[0456] MS m / z[LC-MS]:602.17[M+1].

[0457] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.41(s,1H),8.34(s,1H),8.11(d,J=5.6Hz,1H),7.9 1(d,J=8.0Hz,1H),6.88-7.00(brs,1H),6.68(d,J=5.2Hz,1H),4.28-4.60(m,4H),3.94- 4.06(m,4H),3.89(d,J=9.2Hz,1H),3.70-3.87(m,2H),3.46(d,J=3.6Hz,1H),3.18-3.33 (m,2H),1.99-2.10(m,1H),1.83-1.95(m,3H),1.65-1.78(m,2H),1.33(d,J=6.0Hz,3H).

[0458] Example 100: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-N,N-dimethylpiperidine-4-carboxamide hydrochloride

[0459] Referring to the method in Example 28, the target compound was obtained using N,N-dimethylpiperidine-4-carboxamide hydrochloride as a raw material.

[0460] MS m / z[LC-MS]:640.20[M+1].

[0461] 1H NMR (400MHz, CD3OD), 8.42 (s, 1H), 8.34 (s, 1H), 8.11 (d, J = 5.2Hz, 1H), 7.90 (d, J = 7. 2Hz,1H),6.88-6.96(brs,1H),6.68(d,J=5.2Hz,1H),4.27-4.46(m,5H),4.01(d,J=9 .2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=4.0Hz,1H),3.18-3.32(m,4H),3.07-3. 17(m,4H),2.93(s,3H),1.83-1.95(m,5H),1.66-1.79(m,3H),1.33(d,J=6.0Hz,3H).

[0462] Example 101: N 4 -(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-N 2 -(((S)-Tetrahydrofuran-2-yl)methyl)pyrimidine-2,4-diamine hydrochloride

[0463] Referring to the method in Example 28, the target compound was obtained using (S)-(tetrahydrofuran-2-yl)methylamine as a starting material.

[0464] MS m / z[LC-MS]:584.21[M+1].

[0465] 1 H NMR(400MHz, CD3OD),8.42(s,1H),8.34(s,1H),8.12(d,J=5.2Hz,1H),7.91(d,J=7.2Hz,1H),6.76- 7.01(brs,1H),6.71(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.28-4.37(m,2H),4.02-4.10(m,1H),4.0 1(d,J=9.2Hz,1H),3.80-3.90(m,2H),3.72-3.77(m,1H),3.49-3.57(m,1H),3.46(d,J=4.4Hz,1H), 3.18-3.40(m,3H),1.83-2.07(m,6H),1.71-1.78(m,1H),1.53-1.66(m,1H),1.32(d,J=6.0Hz,3H).

[0466] Example 102: ((R)-4-(4-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl(morpholin-2-yl)methanol hydrochloride

[0467] Referring to the method in Example 28, the target compound was obtained using (R)-morpholin-2-ylmethanol as a starting material.

[0468] MS m / z[LC-MS]:600.17[M+1].

[0469] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.11(d,J=5.2Hz,1H),7.93(d,J=7.6Hz,1H),6 .89-7.01(brs,1H),6.69(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.23-4.37(m,3H),4.08-4.19(m ,1H),3.99-4.06(m,2H),3.89(d,J=9.2Hz,1H),3.56-3.70(m,4H),3.46(d,J=4.0Hz,1H),3.18 -3.33(m,3H),3.02-3.14(m,1H),1.82-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0470] Example 103: ((S)-4-(4-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl(morpholin-2-yl)methanol hydrochloride

[0471] Referring to the method in Example 28, the target compound was obtained using (S)-morpholin-2-ylmethanol as a starting material.

[0472] MS m / z[LC-MS]:600.17[M+1].

[0473] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.11(d,J=4.0Hz,1H),7.94(d,J=7.2Hz,1H),6 .90-7.00(brs,1H),6.69(d,J=4.0Hz,1H),4.38-4.46(m,1H),4.22-4.37(m,3H),4.09-4.20(m ,1H),3.98-4.06(m,2H),3.89(d,J=9.2Hz,1H),3.56-3.71(m,4H),3.47(d,J=3.2Hz,1H),3.17 -3.33(m,3H),3.02-3.14(m,1H),1.83-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0474] Example 104: 2-((4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-ylamino)pyrimidin-2-yl)amino)-N-methylbenzamide hydrochloride

[0475] Referring to the method in Example 28, the target compound was obtained using 2-amino-N-methylbenzamide as a starting material.

[0476] MS m / z[LC-MS]:633.19[M+1].

[0477] 1 H NMR(400MHz, CD3OD),9.07(d,J=8.0Hz,1H),8.45(s,1H),8.35-8.37(m,2H),8.20(d,J=4. 0Hz,1H),7.97(t,J=7.6Hz,1H),7.06-7.64(m,3H),6.77-6.85(m,1H),4.39-4.48(m,1H), 4.28-4.38(m,2H),4.03(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.49(d,J=3.2Hz,1H),3. 19-3.34(m,2H),2.54(s,3H),1.86-1.95(m,3H),1.72-1.80(m,1H),1.33(d,J=6.8Hz,3H).

[0478] Example 105: (R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)piperidine-3-carboxamide hydrochloride

[0479] Referring to the method in Example 28, the target compound was obtained using (R)-piperidine-3-carboxamide as a starting material.

[0480] MS m / z[LC-MS]:611.23[M+1].

[0481] 1 H NMR(400MHz,CD3OD),8.43(s,1H),8.35(s,1H),8.12(d,J=4.4Hz,1H),7.93(d,J=7.2Hz, 1H),6.91(d,J=5.6Hz,1H),6.73(d,J=4.0Hz,1H),4.38-4.46(m,1H),4.12-4.37(m,3H),3 .98-4.07(m,2H),3.89(d,J=9.2Hz,1H),3.38-3.54(m,3H),3.18-3.35(m,2H),2.56-2.6 5(m,1H),2.02-2.12(m,1H),1.80-1.97(m,5H),1.59-1.78(m,2H),1.33(d,J=6.4Hz,3H).

[0482] Example 106: 1-(4-((4-((5-(((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl]-4-(trifluoromethyl)piperidin-4-ol hydrochloride

[0483] Referring to the method in Example 28, the target compound was obtained using (R)-piperidine-3-carboxamide as a starting material.

[0484] MS m / z[LC-MS]:652.22[M+1].

[0485] 1H NMR(400MHz,CD3OD),8.43(s,1H),8.34(s,1H),8.12(d,J=5.2Hz,1H),7.93 (d,J=6.8Hz,1H),6.89-6.98(brs,1H),6.71(d,J=5.2Hz,1H),4.24-4.46(m ,5H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.37-3.49(m,3H),3.19 -3.32(m,2H),1.82-1.96(m,7H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0486] Example 107: (3S,4S)-8-(5-((2-((2-(2-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxaspiro[4.5]dec-4-amine hydrochloride

[0487] Referring to the method in Example 28, the target compound was obtained using (R)-piperidine-3-carboxamide as a starting material.

[0488] MS m / z[LC-MS]:610.24[M+1].

[0489] 1 H NMR(400MHz, CD3Cl),8.25(s,1H),8.24(s,1H),8.16(d,J=5.6Hz,1H),7.91(d,J=5.2Hz,1H),7.63(s,1H),7.56(d,J=6.0Hz,1H),6.23(d,J=5.6 Hz, 1H), 4.49 (s, 4H), 4.08-4.10 (m, 3H), 3.99 (d, J = 9.2Hz, 1H), 3.68-3. 76(m,5H),3.18-3.34(m,3H),1.74-2.10(m,8H),1.39(d,J=6.4Hz,3H).

[0490] Example 108: (3S,4S)-8-(5-((2-((2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)pyrimidin-4-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0491] Referring to the method in Example 28, the target compound was obtained using 2-oxa-6-azaspiro[3.3]heptane as a starting material.

[0492] MS m / z[LC-MS]:582.22[M+1].

[0493] 1 H NMR(400MHz,CD3Cl),8.27(s,1H),8.23(s,1H),8.16(d,J=5.6Hz,1H),7.92(d,J=5.6Hz ,1H),7.70(s,1H),7.67(d,J=5.6Hz,1H),6.26(d,J=5.6Hz,1H),4.85(s,4H),4.21-4.28 (m,5H),4.02-4.18(m,2H),3.95(d,J=9.2Hz,1H),3.74(d,J=9.2Hz,1H),3.24-3.42(m, 2H), 3.18 (d, J = 3.6Hz, 1H), 1.96-2.05 (m, 1H), 1.74-1.92 (m, 3H), 1.35 (d, J = 6.4Hz, 3H).

[0494] Example 109: (3S,4S)-8-(5-(3-chloro-2-((2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuran[3,2-b]furan-3-yl)oxo)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine hydrochloride

[0495] By referring to the method in Example 28, the target compound was obtained using (3R, 3aR, 6R, 6aR)-6-methoxyhexahydrofuran[3,2-b]furan-3-ol as a raw material.

[0496] MS m / z[LC-MS]:643.20[M+1].

[0497] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.23(d,J=6.8Hz,1H),8.14(d,J=5.6Hz,1H),7.22 -7.30(brs,1H),6.73(d,J=5.6Hz,1H),5.45-5.52(m,1H),4.82-4.90(m,1H),4.58(t,J=4.8Hz,1H) ,4.38-4.46(m,1H),4.28-4.37(m,2H),3.88-4.13(m,6H),3.54(t,J=8.0Hz,1H),3.46(d,J=4.0Hz ,1H),3.45(s,3H),3.18-3.33(m,2H),1.82-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.0Hz,3H).

[0498] Example 110: (R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl]-3-methylpyrrolidin-3-ol hydrochloride

[0499] Referring to the method in Example 28, the target compound was obtained using (R)-3-methylpyrrolidin-3-ol as a starting material.

[0500] MS m / z[LC-MS]:584.19[M+1].

[0501] 1 H NMR(400MHz, CD3OD),8.42(s,1H),8.35(s,1H),8.12(d,J=5.2Hz,1H),7.90(d,J=7.2Hz,1H),6.92(d, J=6.8Hz,1H),6.71(d,J=5.6Hz,1H),4.38-4.46(m,1H),4.28-4.37(m,2H),4.01(d,J=9.2Hz,1H),3.89 (d,J=9.2Hz,1H),3.62-3.85(m,3H),3.40-3.48(m,2H),3.18-3.32(m,2H),2.08-2.16(m,1H),1.96-2. 06(m,1H),1.84-1.95(m,3H),1.71-1.78(m,1H),1.48(s,1.5H),1.44(s,1.5H),1.33(d,J=6.0Hz,3H).

[0502] Example 111: (3R, 4R)-1-(4-((4-((5-((3S, 4S)-4-amino-3-methyl-2-oxa-8-azaspiro

[0503] [4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl-3-fluoropiperidin-4-ol hydrochloride

[0504] Referring to the method in Example 28, the target compound was obtained using (3R,4R)-3-fluoropyridin-4-ol as a starting material.

[0505] MS m / z[LC-MS]:602.22[M+1].

[0506] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.12(d,J=4.8Hz,1H),7.92(d,J=7.2Hz,1 H),6.90-6.98(brs,1H),6.70(d,J=5.6Hz,1H),4.38-4.59(m,2H),4.28-4.37(m,2H),3.9 4-4.04(m,4H),3.89(d,J=9.2Hz,1H),3.71-3.86(m,2H),3.47(d,J=4.0Hz,1H),3.18-3.3 3(m,2H),1.99-2.10(m,1H),1.83-1.96(m,3H),1.65-1.78(m,2H),1.33(d,J=6.0Hz,3H).

[0507] Example 112: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl]-4-(hydroxymethyl)piperidin-4-ol hydrochloride

[0508] Referring to the method in Example 28, the target compound was obtained using 4-(hydroxymethyl)piperidin-4-ol as a starting material.

[0509] MS m / z[LC-MS]:614.24[M+1].

[0510] 1H NMR(400MHz, CD3OD),8.43(s,1H),8.34(s,1H),8.12(d,J=4.8Hz,1H),7.90(d,J=7.2Hz,1H),6.88(d,J=5.2H z,1H),6.71(d,J=4.8Hz,1H),4.38-4.46(m,1H),4.28-4.36(m,2H),4.05-4.27(m,2H),4.01(d,J=9.2Hz,1H), 3.89(d,J=9.2Hz,1H),3.42-3.54(m,3H),3.39(s,2H),3.18-3.34(m,2H),1.83-1.96(m,3H),1.59-1.78(m,5H),1.33(d,J=6.0Hz,3H).

[0511] Example 113: (S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl]-3-methylpyrrolidin-3-ol hydrochloride

[0512] Referring to the method in Example 28, the target compound was obtained using (S)-3-methylpyrrolidin-3-ol as a starting material.

[0513] MS m / z[LC-MS]:584.20[M+1].

[0514] 1 H NMR(400MHz, CD3OD),8.43(s,1H),8.35(s,1H),8.12(d,J=5.2Hz,1H),7.90(d,J=7.2Hz,1H),6.92(d, J=5.2Hz,1H),6.71(d,J=5.6Hz,1H),4.38-4.46(m,1H),4.28-4.37(m,2H),4.01(d,J=9.2Hz,1H),3.89 (d,J=9.2Hz,1H),3.61-3.86(m,3H),3.39-3.49(m,2H),3.18-3.34(m,2H),2.08-2.16(m,1H),1.97-2. 06(m,1H),1.83-1.96(m,3H),1.71-1.78(m,1H),1.48(s,1.5H),1.44(s,1.5H),1.33(d,J=6.4Hz,3H).

[0515] Example 114: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl-3,3-difluoropiperidin-4-ol hydrochloride

[0516] Referring to the method in Example 28, the target compound was obtained using 3,3-difluoropyridin-4-ol as a raw material.

[0517] MS m / z[LC-MS]:620.21[M+1].

[0518] 1 H NMR (400MHz, CD3OD), 8.42 (s, 1H), 8.34 (s, 1H), 8.12 (d, J = 5.2Hz, 1H), 7.96 (d, J = 7. 2Hz,1H),6.95-7.05(brs,1H),6.71(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.28-4.37 (m,2H),3.99-4.23(m,4H),3.76-3.90(m,3H),3.47(d,J=4.0Hz,1H),3.18-3.32(m, 2H),1.98-2.08(m,1H),1.84-1.95(m,4H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0519] Example 115: (3R,4S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl-4-fluoropyrrolidin-3-ol hydrochloride

[0520] Referring to the method in Example 28, the target compound was obtained using (3R,4S)-4-fluoropyrrolidin-3-ol as a starting material.

[0521] MS m / z[LC-MS]:588.21[M+1].

[0522] 1H NMR (400MHz, CD3OD), 8.42 (s, 1H), 8.35 (s, 1H), 8.11 (d, J = 5.6Hz, 1H),7.92(d,J=7.2Hz,1H),6.90-7.00(brs,1H),6.69(d,J=4.8Hz,1H),4.28-4.52(m,4H),3.68-4.04(m ,6H),3.38-3.49(m,2H),3.18-3.32(m,2H),1.82-1.96(m,3H),1.71-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0523] Example 116: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl-3-methylazepin-3-ol hydrochloride

[0524] Referring to the method in Example 28, the target compound was obtained using 3-methylazetidin-3-ol as a starting material.

[0525] MS m / z[LC-MS]:570.18[M+1].

[0526] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.10(d,J=5.6Hz,1H),7.90(d,J=7.6Hz, 1H),6.95(d,J=6.4Hz,1H),6.68(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.28-4.37(m,2H),4 .08-4.15(m,4H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=3.6Hz,1H),3.1 8-3.32(m,2H),1.82-1.95(m,3H),1.71-1.78(m,1H),1.54(s,3H),1.32(d,J=6.4Hz,3H).

[0527] Example 117: (3S,4S)-8-(6-amino-5-((3-chloro-2-((2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0528] By referring to the method in Example 28, the title compound was obtained using (R)-N-((3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]-2-methylpropane-2-sulfenamide as a raw material.

[0529] MS m / z[LC-MS]:631.22[M+1].

[0530] 1 H NMR(400MHz, CD3Cl),8.17(d,J=5.6Hz,1H),7.92(d,J=5.6Hz,1H),7.63-7.67(m,2H),7.61(d,J=5.6Hz,1H),6.25( d,J=5.6Hz,1H),4.89(s,2H),4.71-4.88(m,1H),4.49-4.57(m,1H),4.19-4.28(m,2H),3.95-4.10(m,2H),3.92(d, J=9.2Hz,1H),3.72(d,J=9.2Hz,1H),3.41-3.68(m,6H),3.12-3.34(m,3H),1.90-2.04(m,2H),1.68-1.88(m,4H),1.34(d,J=6.4Hz,3H).

[0531] Example 118: (3S,4S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl-4-fluoropyrrolidin-3-ol hydrochloride

[0532] Referring to the method in Example 28, the target compound was obtained using (3S,4S)-4-fluoropyrrolidin-3-ol as a starting material.

[0533] MS m / z[LC-MS]:588.18[M+1].

[0534] 1H NMR(400MHz, CD3OD),8.41(s,1H),8.35(s,1H),8.12(d,J=5.2Hz,1H),7.93(d,J=7.2Hz,1H),6.97(d,J=7.2Hz,1H),6.70(d,J=5.2Hz,1H),4.96-5 .24(m,2H),4.38-4.58(m,2H),4.28-4.37(m,2H),4.01(d,J=9.2Hz,1H), 3.70-3.97(m,4H),3.46(d,J=4.4Hz,1H),3.18-3.32(m,2H),1.82-1.91H NMR (400MHz, CDCl3), 6 (m, 3H), 1.71-1.78 (m, 1H), 1.33 (d, J = 6.4Hz, 3H).

[0535] Example 119: 4-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl-1-imino- -Thiomorpholine-1-oxide hydrochloride

[0536] Referring to the method in Example 28, 1-imine- -Thiomorpholine-1-oxide hydrochloride was used as the raw material to obtain the target compound.

[0537] MS m / z[LC-MS]:617.19[M+1].

[0538] 1 H NMR(400MHz,CD3OD),8.43(s,1H),8.35(s,1H),8.13-8.15(m,2H),7.14(d,J= 6.8Hz,1H),6.70(d,J=6.0Hz,1H),4.78-4.86(m,2H),4.39-4.46(m,1H),4.28- 4.37(m,2H),3.94-4.14(m,7H),3.89(d,J=9.2Hz,1H),3.46(d,J=4.4Hz,1H),3 .19-3.32(m,2H),1.84-1.94(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0539] Example 120: (3S,4S)-8-(5-((2-((2-(1-oxa-8-azaspiro[4.5]dec-8-yl)pyrimidin-4-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

[0540] Referring to the method in Example 28, the target compound was obtained using 1-oxa-8-azaspiro[4.5]decane as a raw material.

[0541] MS m / z[LC-MS]:624.26[M+1].

[0542] 1 H NMR (400MHz, CD3OD), 8.42 (s, 1H), 8.34 (s, 1H), 8.11 (d, J = 5.2Hz, 1H),7.89(d,J=6.8Hz,1H),6.86-6.93(m,1H),6.69(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.28-4.37(m,2H),3.94-4.09(m,3H),3.85-3 .90(m,3H),3.52-3.60(m,2H),3.47(d,J=3.6Hz,1H),3.19-3.32(m,2H),1.84-2.02(m,5H),1.68-1.82(m,7H),1.33(d,J=6.0Hz,3H).

[0543] Example 121: 1-(1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-ylpiperidin-4-yl)ethan-1-one hydrochloride

[0544] Referring to the method in Example 28, the target compound was obtained using 1-(piperidin-4-yl)ethan-1-one as a starting material.

[0545] MS m / z[LC-MS]:610.25[M+1].

[0546] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.10(d,J=5.6Hz,1H),7.87-7.90(m,1H),6.86- 6.94(m,1H),6.67(d,J=5.6Hz,1H),4.24-4.46(m,5H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1 H),3.46(d,J=4.0Hz,1H),3.18-3.32(m,3H),3.02-3.13(m,1H),2.78-2.86(m,1H),2.20(s,2H) ,1.98-2.10(m,3H),1.79-1.96(m,3H),1.70-1.78(m,1H),1.58-1.68(m,1H),1.28-1.43(m,4H).

[0547] Example 122: (3S,4S)-8-(5-((2-((2-(2-(1-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-4-yl)amino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0548] Referring to the method in Example 28, the target compound was obtained using 1-oxa-7-azaspiro[3.5]nonane as a raw material.

[0549] MS m / z[LC-MS]:610.26[M+1].

[0550] 1 H NMR(400MHz, CD3Cl),8.27(s,1H),8.23(s,1H),8.17(d,J=5.6Hz,1H),7.92(d,J=5.6Hz,1H),7.63(s ,1H),7.56(d,J=5.6Hz,1H),6.24(d,J=5.6Hz,1H),4.57(t,J=8.0Hz,2H),4.20-4.28(m,1H),4.02-4 .18(m,2H),3.95(d,J=9.2Hz,1H),3.81-3.84(m,4H),3.74(d,J=9.2Hz,1H),3.24-3.42(m,2H),3.18 (d,J=4.0Hz,1H),2.43(t,J=8.0Hz,2H),1.93-2.06(m,4H),1.74-1.91(m,4H),1.35(d,J=6.4Hz,3H).

[0551] Example 123: (3S,4S)-8-(5-((3-chloro-2-((2-(4-(oxa-3-yl)piperazin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0552] Referring to the method in Example 28, the target compound was obtained using 1-(3-oxetanyl)piperazine as the starting material.

[0553] 1 H NMR(400MHz,CD3Cl),8.27(s,1H),8.23(s,1H),8.19(d,J=5.6Hz,1H),7.92(d,J=5.2Hz,1H), 7.65(s,1H),7.61(d,J=5.6Hz,1H),6.25(d,J=5.2Hz,1H),4.64-4.73(m,4H),4.18-4.25(m,1 H),3.97-4.12(m,2H),3.81-3.92(m,5H),3.72(d,J=8.8Hz,1H),3.30-3.56(m,3H),3.10(d,J =4.4Hz,1H),2.37-2.40(m,4H),1.91-2.00(m,1H),1.71-1.88(m,3H),1.30(d,J=6.8Hz,3H).

[0554] MS m / z[LC-MS]:625.28[M+1].

[0555] Example 124: N 4 -(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-N 2 -(3-Methyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine hydrochloride

[0556] Referring to the method in Example 28, the target compound was obtained using 3-methyl-1H-pyrazol-5-amine as a starting material.

[0557] MS m / z[LC-MS]:580.17[M+1].

[0558] Example 125: (3S,4S)-8-(5-((3-chloro-2-((2-((R)-3-methoxypyrrolidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0559] Referring to the method in Example 28, the target compound was obtained using (R)-3-methoxypyrrolidine as the starting material.

[0560] MS m / z[LC-MS]:584.20[M+1].

[0561] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.10(d,J=5.6Hz,1H),7.89(d,J=6.8Hz,1H),6.90 -6.96(m,1H),6.67(d,J=5.6Hz,1H),4.38-4.45(m,1H),4.28-4.37(m,2H),4.06-4.26(m,1H),4.0 1(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.50-3.86(m,4H),3.49(d,J=3.6Hz,1H),3.36(s,3H),3 .18-3.32(m,2H),1.98-2.37(m,2H),1.82-1.96(m,3H),1.70-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0562] Example 126: 7-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-7-azaspiro[3.5]nonan-2-ol hydrochloride

[0563] Referring to the method in Example 28, the target compound was obtained using 2-methyl-7-azaspiro[3.5]nonan-2-ol as a starting material.

[0564] MS m / z[LC-MS]:638.29[M+1].

[0565] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.10(d,J=5.6Hz,1H),7.87(d,J=7.6Hz,1H), 6.84-6.91(m,1H),6.68(d,J=5.6Hz,1H),4.38-4.46(m,1H),4.28-4.36(m,2H),4.01(d,J=9. 2Hz,1H),3.89(d,J=9.2Hz,1H),3.59-3.69(m,4H),3.46(d,J=4.0Hz,1H),3.18-3.32(m,2H), 1.95-2.03(m,4H),1.83-1.92(m,3H),1.66-1.81(m,5H),1.36(s,3H),1.33(d,J=6.4Hz,3H).

[0566] Example 127: 2-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl]-6-methyl-2-azaspiro[3.3]heptan-6-ol hydrochloride

[0567] Referring to the method in Example 28, the target compound was obtained using 6-methyl-2-azaspiro[3.3]heptane-6-ol as a starting material.

[0568] MS m / z[LC-MS]:610.22[M+1].

[0569] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.09(d,J=5.6Hz,1H),7.87(d,J=7.6Hz,1H), 6.91-6.97(m,1H),6.66(d,J=5.6Hz,1H),4.38-4.45(m,1H),4.29-4.36(m,2H),4.18-4.28(m ,4H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=4.0Hz,1H),3.18-3.32(m,2H), 2.30-2.38(m,4H),1.82-1.96(m,3H),1.71-1.78(m,1H),1.32(d,J=6.4Hz,3H),1.29(s,3H).

[0570] Example 128: (3S,4S)-8-(5-((3-chloro-2-((2-((S)-3-methoxypyrrolidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0571] Referring to the method in Example 28, the target compound was obtained using (S)-3-methoxypyrrolidine as a starting material.

[0572] MS m / z[LC-MS]:584.25[M+1].

[0573] 1 H NMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.10(d,J=5.2Hz,1H),7.89(d,J=7.2Hz,1H),6.90 -6.97(m,1H),6.67(d,J=5.2Hz,1H),4.38-4.45(m,1H),4.27-4.36(m,2H),4.06-4.26(m,1H),4.0 1(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.50-3.86(m,4H),3.46(d,J=4.0Hz,1H),3.36(s,3H),3 .18-3.32(m,2H),1.98-2.36(m,2H),1.82-1.96(m,3H),1.70-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0574] Example 129: (3S,4R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl-4-fluoropyrrolidin-3-ol hydrochloride

[0575] Referring to the method in Example 28, the target compound was obtained using (3S,4R)-4-fluoropyrrolidin-3-ol as a starting material.

[0576] MS m / z[LC-MS]:588.18[M+1].

[0577] 1H NMR(400MHz, CD3OD),8.43(s,1H),8.35(s,1H),8.13(d,J=5.6Hz,1H),7.94(d,J=7.2Hz,1H),6.92-6.99(m,1H),6.72(d,J=5.6Hz,1H),5.06-5.29 (m,1H),4.26-4.60(m,4H),3.68-4.04(m,5H),3.38-3.50(m,2H),3.17-3 .33(m,2H),1.84-1.95(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0578] Example 130: (3S,4S)-8-(5-((3-chloro-2-((2-((3R,4S)-3-fluoro-4-methoxypyrrolidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0579] Referring to the method in Example 28, the target compound was obtained using (3R,4S)-3-fluoro-4-methoxypyrrolidine as a starting material.

[0580] MS m / z[LC-MS]:602.19[M+1].

[0581] 1 HNMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.11(d,J=5.6Hz,1H),7.93(d,J =6.8Hz,1H),6.93-7.01(m,1H),6.68(d,J=5.6Hz,1H),5.21-5.52(m,1H),4.38-4 .45(m,1H),4.08-4.37(m,3H),3.66-4.06(m,5H),3.50(s,3H),3.41-3.49(m,2H) ,3.18-3.33(m,2H),1.83-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.0Hz,3H).

[0582] Example 131: (3S,4S)-8-(5-((3-chloro-2-((2-((3R,4R)-3-fluoro-4-methoxypyrrolidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0583] Referring to the method in Example 28, the target compound was obtained using (3R,4R)-3-fluoro-4-methoxypyrrolidine as a starting material.

[0584] MS m / z[LC-MS]:602.19[M+1].

[0585] 1 H NMR(400MHz,CD3OD),8.41(s,1H),8.35(s,1H),8.11(d,J=5.6Hz,1H),7.92(d ,J=7.2Hz,1H),6.93-7.02(m,1H),6.68(d,J=5.6Hz,1H),5.14-5.43(m,1H),4 .38-4.46(m,1H),4.09-4.36(m,3H),3.68-4.04(m,6H),3.41-3.49(m,4H),3. 18-3.32(m,2H),1.82-1.96(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0586] Example 132: (3R,4R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl-4-fluoropyrrolidin-3-ol hydrochloride

[0587] Referring to the method in Example 28, the target compound was obtained using (3R,4R)-4-fluoropyrrolidin-3-ol as a starting material.

[0588] MS m / z[LC-MS]:588.15[M+1].

[0589] 1HNMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.11(d,J=5.6Hz,1H),7.93(d,J=7 .2Hz,1H),6.93-7.01(m,1H),6.69(d,J=5.6Hz,1H),4.96-5.25(m,1H),4.38-4.58(m ,2H),4.28-4.36(m,2H),4.01(d,J=8.8Hz,1H),3.56-3.98(m,5H),3.46(d,J=4.4Hz, 1H), 3.18-3.32 (m, 2H), 1.83-1.95 (m, 3H), 1.71-1.78 (m, 1H), 1.33 (d, J = 6.4Hz, 3H).

[0590] Example 133: (3S,4S)-8-(5-((3-chloro-2-((2-(((S)-tetrahydro-2H-pyran-2-yl)methoxy)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0591] Referring to the method in Example 28, the target compound was obtained using (S)-(tetrahydro-2H-pyran-2-yl)methanol as a starting material.

[0592] MS m / z[LC-MS]:599.20[M+1].

[0593] 1 H NMR(400MHz, CD3OD),8.44(s,1H),8.33(s,1H),8.22(d,J=7.2Hz,1H),8.12-8.18(m,1H),7. 23-7.34(m,1H),6.73-6.79(m,1H),4.27-4.52(m,5H),4.02(d,J=9.2Hz,1H),3.92-3.98(m, 1H),3.89(d,J=9.2Hz,1H),3.70-3.78(m,1H),3.42-3.52(m,2H),3.19-3.34(m,2H),1.84-1 .96(m,4H),1.72-1.79(m,1H),1.52-1.66(m,4H),1.35-1.45(m,1H),1.33(d,J=6.4Hz,3H).

[0594] Example 134: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-4-(hydroxymethyl)piperidine-4-carbonitrile hydrochloride

[0595] Referring to the method in Example 28, the target compound was obtained using 4-(hydroxymethyl)piperidine-4-carbonitrile as a raw material.

[0596] MS m / z[LC-MS]:623.20[M+1].

[0597] 1 HNMR(400MHz,CD3OD),8.41(s,1H),8.35(s,1H),8.11(d,J=5.6Hz,1H), 7.92(d,J=7.2Hz,1H),6.89-6.99(m,1H),6.68(d,J=5.6Hz,1H),4.27-4.50(m,5H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3. 62(s,2H),3.46(d,J=4.0Hz,1H),3.18-3.41(m,4H),2.04-2.12(m,2H),1.82-1.95(m,3H),1.66-1.78(m,3H),1.32(d,J=6.4Hz,3H).

[0598] Example 135: ((3S,4R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl-3-fluoropiperidin-4-yl)methanol hydrochloride

[0599] Referring to the method in Example 28, the target compound was obtained using ((3S,4R)-3-fluoropiperidin-4-yl)methanol as a raw material.

[0600] MS m / z[LC-MS]:616.23[M+1].

[0601] 1H NMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.10(d,J=5.2Hz,1H),7.89(d,J=7.6Hz,1H), 6.88-6.98(m,1H),6.68(d,J=5.2Hz,1H),4.94-5.06(m,1H),4.59-4.82(m,2H),4.28-4.56(m, 4H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.57-3.62(m,1H),3.46-3.51(m,2H),3.11 -3.32(m,3H),1.82-2.09(m,4H),1.66-1.78(m,2H),1.50-1.62(m,1H),1.33(d,J=6.0Hz,3H).

[0602] Example 136: (3aR,5r,6aS)-2-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-ol hydrochloride

[0603] Referring to the method in Example 28, the target compound was obtained using (3aR, 5r, 6aS)-octahydrocyclopenta[c]pyrrol-5-ol as a starting material.

[0604] MS m / z[LC-MS]:610.25[M+1].

[0605] 1 H NMR(400MHz, CD3OD),8.42(s,1H),8.35(s,1H),8.12(d,J=5.2Hz,1H),7.89(d,J=6.8Hz,1H),6. 91(d,J=6.8Hz,1H),6.71(d,J=5.2Hz,1H),4.28-4.46(m,4H),4.01(d,J=9.2Hz,1H),3.89(d,J= 9.2Hz,1H),3.53-3.84(m,4H),3.47(d,J=4.0Hz,1H),3.18-3.33(m,2H),2.76-3.01(m,2H),2.1 5-2.22(m,2H),1.84-1.96(m,3H),1.71-1.79(m,1H),1.52-1.66(m,2H),1.33(d,J=6.4Hz,3H).

[0606] Example 137: (1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-4-fluoropiperidin-4-yl)methanol hydrochloride

[0607] Referring to the method in Example 28, the target compound was obtained using (4-fluoropiperidin-4-yl)methanol as a starting material.

[0608] MS m / z[LC-MS]:616.25[M+1].

[0609] 1 HNMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.11(d,J=5.6Hz,1H),7.90(d, J=7.2Hz,1H),6.86-6.96(m,1H),6.68(d,J=5.6Hz,1H),4.38-4.45(m,1H),4.18- 4.37(m,4H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.57(d,J=20.0Hz,2H) ,3.38-3.48(m,3H),3.18-3.30(m,2H),1.70-2.04(m,8H),1.32(d,J=6.0Hz,3H).

[0610] Example 138: (1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl-4-methylpiperidin-4-yl)methanol hydrochloride

[0611] Referring to the method in Example 28, the target compound was obtained using (4-methylpiperidin-4-yl)methanol as a starting material.

[0612] MS m / z[LC-MS]:612.23[M+1].

[0613] 1H NMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.10(d,J=5.6Hz,1H),7.87(d,J=7.6Hz,1 H),6.85-6.92(m,1H),6.67(d,J=5.6Hz,1H),4.37-4.45(m,1H),4.28-4.36(m,2H),3.87- 4.02(m,4H),3.49-3.56(m,2H),3.46(d,J=3.6Hz,1H),3.35(s,2H),3.18-3.32(m,2H),1. 82-1.96(m,3H),1.60-1.78(m,3H),1.40-1.48(m,2H),1.33(d,J=6.0Hz,3H),1.05(s,3H).

[0614] Example 139: ((R)-4-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)morpholin-3-yl)methanol hydrochloride

[0615] Referring to the method in Example 28, the target compound was obtained using (R)-morpholin-3-ylmethanol as a starting material.

[0616] MS m / z[LC-MS]:600.24[M+1].

[0617] 1 H NMR (400MHz, CD3OD), 8.42 (s, 1H), 8.34 (s, 1H), 8.10 (d, J = 4.8Hz, 1H), 7.93 (d, J = 7.2Hz, 1H), 6.96-7. 06(m,1H),6.66(d,J=4.8Hz,1H),4.24-4.46(m,4H),4.05-4.20(m,1H),3.93-4.04(m,4H),3.89(d,J= 9.2Hz,1H),3.80-3.84(m,1H),3.69(dd,J=12.0Hz,3.6Hz,1H),3.55-3.63(m,1H),3.46(d,J=3.6Hz,1 H),3.34-3.44(m,1H),3.17-3.28(m,2H),1.82-1.94(m,3H),1.70-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0618] Example 140: ((S)-4-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)morpholin-3-yl)methanol hydrochloride

[0619] Referring to the method in Example 28, the target compound was obtained using (S)-morpholin-3-ylmethanol as a starting material.

[0620] MS m / z[LC-MS]:600.23[M+1].

[0621] 1 H NMR(400MHz, CD3OD),8.41(s,1H),8.34(s,1H),8.10(d,J=5.6Hz,1H),7.93(d,J=7.2Hz,1H),6.95-7.06( m,1H),6.66(d,J=5.6Hz,1H),4.23-4.46(m,4H),4.04-4.18(m,1H),3.93-4.03(m,4H),3.89(d,J=9.2Hz, 1H),3.82(dd,J=11.6Hz,6.0Hz,1H),3.69(dd,J=12.0Hz,3.2Hz,1H),3.55-3.63(m,1H),3.46(d,J=4.0Hz ,1H),3.34-3.44(m,1H),3.16-3.30(m,2H),1.82-1.94(m,3H),1.70-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0622] Example 141: (R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-ol hydrochloride

[0623] Referring to the method in Example 28, the target compound was obtained using (R)-3,3-difluoropiperidin-4-ol as a starting material.

[0624] MS m / z[LC-MS]:620.18[M+1].

[0625] 1H NMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.10(d,J=5.2Hz,1H),7.95(d ,J=7.2Hz,1H),6.96-7.07(m,1H),6.67(d,J=5.2Hz,1H),4.38-4.45(m,1H),4. 27-4.37(m,2H),3.96-4.22(m,4H),3.75-3.92(m,3H),3.45(d,J=3.6Hz,1H),3 .17-3.32(m,2H),1.81-2.08(m,5H),1.70-1.77(m,1H),1.32(d,J=6.4Hz,3H).

[0626] Example 142: (S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-ol hydrochloride

[0627] Referring to the method in Example 28, the target compound was obtained using (S)-3,3-difluoropiperidin-4-ol as a raw material.

[0628] MS m / z[LC-MS]:620.18[M+1].

[0629] Example 143: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-4-(aminomethyl)piperidin-4-ol hydrochloride

[0630] Referring to the method in Example 28, the target compound was obtained using 4-(aminomethyl)piperidin-4-ol as a starting material.

[0631] MS m / z[LC-MS]:613.23[M+1].

[0632] 1HNMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.11(d,J=5.2Hz,1H),7.92( d,J=6.8Hz,1H),6.88-6.97(m,1H),6.68(d,J=5.2Hz,1H),4.38-4.46(m,1H),4 .13-4.37(m,4H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.44-3.59(m, 3H), 3.18-3.30 (m, 2H), 2.95 (s, 2H), 1.68-1.95 (m, 8H), 1.33 (d, J = 6.0Hz, 3H).

[0633] Example 144: ((R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-ylpiperidin-2-yl)methanol hydrochloride

[0634] Referring to the method in Example 28, the target compound was obtained using (R)-piperidin-2-ylmethanol as a starting material.

[0635] MS m / z[LC-MS]:598.21[M+1].

[0636] 1 H NMR(400MHz,CD3OD),8.41(s,1H),8.35(s,1H),8.09(d,J=5.6Hz,1H),7.87(d,J=7.2Hz ,1H),6.92-6.99(m,1H),6.65(d,J=5.6Hz,1H),4.48-4.60(m,1H),4.38-4.46(m,1H),4. 24-4.37(m,3H),3.94-4.02(m,2H),3.89(d,J=9.2Hz,1H),3.68(dd,J=11.2Hz,5.6Hz,1 H), 3.46 (d, J = 4.0Hz, 1H), 3.11-3.37 (m, 3H), 1.51-1.96 (m, 10H), 1.32 (d, J = 6.4Hz, 3H).

[0637] Example 145: (3S,4S)-8-(5-((3-chloro-2-((2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0638] Referring to the method in Example 28, the target compound was obtained using 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine as a raw material.

[0639] MS m / z[LC-MS]:675.19[M+1].

[0640] 1 H NMR(400MHz, CD3OD),8.42(s,1H),8.36(s,1H),8.08-8.12(m,2H),7.08-7.15(m,1H),6.66(d,J=5.2Hz,1H),5.19(s,2H),4.26-4.46(m,7H),4.0 1(d,J=9.2Hz,1H),3.90(d,J=9.2Hz,1H),3.46(d,J=4.0Hz,1H),3.18-3 .32(m,2H),1.82-1.96(m,3H),1.70-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0641] Example 146: ((S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)piperidin-2-yl)methanol hydrochloride

[0642] Referring to the method in Example 28, the target compound was obtained using (S)-piperidin-2-ylmethanol as a starting material.

[0643] MS m / z[LC-MS]:598.22[M+1].

[0644] 1H NMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.09(d,J=5.6Hz,1H),7.87(d,J=7.6Hz ,1H),6.92-7.00(m,1H),6.65(d,J=5.6Hz,1H),4.50-4.60(m,1H),4.38-4.45(m,1H),4. 26-4.37(m,3H),3.94-4.02(m,2H),3.89(d,J=9.2Hz,1H),3.68(dd,J=11.6Hz,5.2Hz,1 H), 3.46 (d, J = 4.0Hz, 1H), 3.11-3.30 (m, 3H), 1.51-1.96 (m, 10H), 1.32 (d, J = 6.4Hz, 3H).

[0645] Example 147: (3S,4S)-8-(5-((3-chloro-2-((2-(((R)-tetrahydro-2H-pyran-2-yl)methoxy)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0646] Referring to the method in Example 28, the target compound was obtained using (R)-(tetrahydro-2H-pyran-2-yl)methanol as a starting material.

[0647] MS m / z[LC-MS]:599.22[M+1].

[0648] 1 H NMR(400MHz, CD3OD),8.43(s,1H),8.34(s,1H),8.21(d,J=7.2Hz,1H),8.10-8.18(m,1H),7. 22-7.34(m,1H),6.71-6.78(m,1H),4.26-4.52(m,5H),4.02(d,J=9.2Hz,1H),3.92-3.98(m, 1H),3.89(d,J=9.2Hz,1H),3.70-3.78(m,1H),3.43-3.52(m,2H),3.18-3.34(m,2H),1.84-1 .97(m,4H),1.71-1.79(m,1H),1.52-1.67(m,4H),1.34-1.45(m,1H),1.33(d,J=6.4Hz,3H).

[0649] Example 148: (1S,3S)-3-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)amino)cyclopentan-1-ol hydrochloride

[0650] Referring to the method in Example 28, the target compound was obtained using (1S,3S)-3-aminocyclopentane-1-ol as a raw material.

[0651] MS m / z[LC-MS]:584.21[M+1].

[0652] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.12(d,J=4.8Hz,1H),7.84-7.91(m ,1H),6.74-6.93(m,1H),6.69(d,J=4.8Hz,1H),4.28-4.46(m,5H),4.01(d,J=9.2Hz, 1H),3.89(d,J=9.2Hz,1H),3.46(d,J=3.6Hz,1H),3.18-3.32(m,2H),2.14-2.30(m, 1H), 1.96-2.09 (m, 2H), 1.70-1.95 (m, 5H), 1.50-1.68 (m, 2H), 1.32 (d, J = 6.4Hz, 3H).

[0653] Example 149: (1R,3R)-3-((4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)amino)cyclopentan-1-ol hydrochloride

[0654] Referring to the method in Example 28, the target compound was obtained using (1R,3R)-3-aminocyclopentane-1-ol as a raw material.

[0655] MS m / z[LC-MS]:584.21[M+1].

[0656] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.10-8.18(m,1H),7.84-7.94 (m,1H),6.62-7.03(m,2H),4.28-4.46(m,5H),4.01(d,J=9.2Hz,1H),3.89(d, J=9.2Hz,1H),3.46(d,J=3.6Hz,1H),3.18-3.34(m,2H),2.14-2.32(m,1H),1. 97-2.11(m,2H),1.70-1.94(m,5H),1.50-1.68(m,2H),1.32(d,J=6.4Hz,3H).

[0657] Example 150: 1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-4-(methoxymethyl)piperidin-4-ol hydrochloride

[0658] Referring to the method in Example 28, the target compound was obtained using 4-(methoxymethyl)piperidin-4-ol as a starting material.

[0659] MS m / z[LC-MS]:628.25[M+1].

[0660] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.10(d,J=5.2Hz,1H),7.88(d,J=6.8Hz ,1H),6.85-6.93(m,1H),6.68(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.28-4.37(m,2H),4 .04-4.24(m,2H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.41-3.53(m,3H),3.37 (s,3H),3.18-3.32(m,4H),1.83-1.96(m,3H),1.64-1.79(m,5H),1.32(d,J=6.0Hz,3H).

[0661] Example 151: (1R,3S)-3-((4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)amino)cyclopentan-1-ol hydrochloride

[0662] Referring to the method in Example 28, the target compound was obtained using (1R,3S)-3-aminocyclopentane-1-ol as a raw material.

[0663] MS m / z[LC-MS]:584.21[M+1].

[0664] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.11(d,J=5.2Hz,1H),7.88(d,J=7.2 Hz,1H),6.74-6.86(m,1H),6.69(d,J=5.2Hz,1H),4.38-4.46(m,1H),4.23-4.37(m,4 H),4.00(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=4.0Hz,1H),3.18-3.36(m ,2H),1.97-2.22(m,2H),1.71-1.96(m,7H),1.58-1.67(m,1H),1.32(d,J=6.4Hz,3H).

[0665] Example 152: (3S,4S)-8-(5-((3-chloro-2-((2-(((R)-quinin-3-yl)oxy)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0666] Referring to the method in Example 28, the target compound was obtained using (R)-quinuclidine-3-ol as a raw material.

[0667] MS m / z[LC-MS]:610.20[M+1].

[0668] 1H NMR(400MHz,CD3OD),8.40(s,1H),8.34(s,1H),8.29(d,J=5.6Hz,1H),8.03(d,J =5.6Hz,1H),7.63(d,J=5.6Hz,1H),6.47(d,J=5.6Hz,1H),5.29-5.34(m,1H),4. 27-4.46(m,4H),4.00(d,J=9.2Hz,1H),3.82-3.91(m,2H),3.45(d,J=3.6Hz,1H) ,3.14-3.44(m,6H),2.54-2.60(m,1H),1.66-2.07(m,8H),1.32(d,J=6.0Hz,3H).

[0669] Example 153: (1S,3R)-3-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)amino)cyclopentan-1-ol hydrochloride

[0670] Referring to the method in Example 28, the target compound was obtained using (R)-quinuclidine-3-ol as a raw material.

[0671] MS m / z[LC-MS]:584.22[M+1].

[0672] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.10(d,J=5.2Hz,1H),7.87(d,J =7.2Hz,1H),6.74-6.86(m,1H),6.67(d,J=5.2Hz,1H),4.21-4.46(m,5H),4.00( d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.46(d,J=3.6Hz,1H),3.17-3.32(m,2H) ,1.98-2.21(m,2H),1.69-1.96(m,7H),1.58-1.67(m,1H),1.32(d,J=6.4Hz,3H).

[0673] Example 154: (3S,4S)-8-(5-((3-chloro-2-((2-((3S,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0674] Referring to the method in Example 28, the target compound was obtained using (3S,4S)-3-fluoro-4-methoxypiperidine as a raw material.

[0675] MS m / z[LC-MS]:616.23[M+1].

[0676] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.10(d,J=5.2Hz,1H),7.90(d,J=7.6Hz,1H),6.8 9-6.99(m,1H),6.67(d,J=5.2Hz,1H),4.60-4.76(m,1H),4.38-4.46(m,1H),4.28-4.36(m,2H),4. 06-4.16(m,1H),4.01(d,J=9.2Hz,1H),3.79-3.92(m,3H),3.58-3.68(m,2H),3.44-3.48(m,4H),3 .18-3.32(m,2H),1.97-2.08(m,1H),1.79-1.96(m,4H),1.71-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0677] Example 155: (3S,4S)-8-(5-((3-chloro-2-((2-((3S,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0678] Referring to the method in Example 28, the target compound was obtained using (3R, 4R)-3-fluoro-4-methoxypiperidine as a starting material.

[0679] MS m / z[LC-MS]:616.23[M+1].

[0680] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.10(d,J=5.2Hz,1H),7.90(d,J=7.6Hz,1H),6.8 9-6.99(m,1H),6.67(d,J=5.2Hz,1H),4.60-4.76(m,1H),4.38-4.46(m,1H),4.28-4.36(m,2H),4. 06-4.16(m,1H),4.01(d,J=9.2Hz,1H),3.79-3.92(m,3H),3.58-3.68(m,2H),3.44-3.48(m,4H),3 .18-3.32(m,2H),1.97-2.08(m,1H),1.79-1.96(m,4H),1.71-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0681] Example 156: (3S,4S)-8-(5-((3-chloro-2-((2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0682] Referring to the method in Example 28, the target compound was obtained using (3R,4S)-3-fluoro-4-methoxypiperidine as a raw material.

[0683] MS m / z[LC-MS]:616.23[M+1].

[0684] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.11(d,J=5.2Hz,1H),7.91(d,J=7.6Hz,1H), 6.88-7.02(m,1H),6.68(d,J=5.2Hz,1H),4.90-5.06(m,1H),4.38-4.49(m,2H),4.28-4.36(m, 2H),4.16-4.27(m,1H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.52-3.69(m,2H),3.42 -3.48(m,4H),3.17-3.39(m,3H),1.81-1.98(m,5H),1.71-1.78(m,1H),1.32(d,J=6.4Hz,3H).

[0685] Example 157: (3S,4S)-8-(5-((3-chloro-2-((2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0686] By referring to the method of Example 28, the target compound was obtained using (tetrahydro-1H-pyrrolidinone-7a(5H)yl)methanol as a raw material.

[0687] MS m / z[LC-MS]:624.25[M+1].

[0688] Example 158: (S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)piperidine-3-carboxamide hydrochloride

[0689] Referring to the method in Example 28, the target compound was obtained using (S)-piperidine-3-carboxamide as a starting material.

[0690] MS m / z[LC-MS]:611.22[M+1].

[0691] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.10(d,J=5.6Hz,1H),7.90(d,J=7.2Hz ,1H),6.85-6.96(m,1H),6.68(d,J=5.6Hz,1H),4.38-4.46(m,1H),4.13-4.36(m,3H),3. 96-4.08(m,2H),3.89(d,J=8.8Hz,1H),3.37-3.53(m,3H),3.17-3.31(m,2H),2.54-2.64 (m,1H),2.01-2.12(m,1H),1.80-1.96(m,5H),1.58-1.78(m,2H),1.32(d,J=6.4Hz,3H).

[0692] Example 159: N 4 -(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-N 2-(Tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine hydrochloride

[0693] Referring to the method in Example 28, the target compound was obtained using tetrahydro-2H-pyran-4-amine as a starting material.

[0694] MS m / z[LC-MS]:584.22[M+1].

[0695] 1 H NMR(400MHz,CD3OD),8.44(s,1H),8.34(s,1H),8.09-8.24(m,1H),7.84-8.00(m,1H),6.66-6.86(m,2H),4.39-4.47(m,1H),4.28-4.38(m,2 H),3.82-4.03(m,5H),3.38-3.54(m,3H),3.19-3.34(m,2H),1.83-1.9 9(m,5H),1.71-1.79(m,1H),1.52-1.70(m,2H),1.33(d,J=6.0Hz,3H).

[0696] Example 160: (3S,4S)-8-(5-((3-chloro-2-((2-((3S)4S)-3-fluoro-4-methoxypyrrolidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0697] Referring to the method in Example 28, the target compound was obtained using (3S,4S)-3-fluoro-4-methoxypyrrolidine as a starting material.

[0698] MS m / z[LC-MS]:602.22[M+1].

[0699] 1H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.11(d,J=5.2Hz,1H),7.93(d,J=7 .2Hz,1H),6.94-7.01(m,1H),6.68(d,J=5.2Hz,1H),5.14-5.44(m,1H),4.38-4.46 (m,1H),4.28-4.37(m,2H),4.10-4.37(m,1H),3.61-4.025(m,6H),3.42-3.48(m,4 H), 3.18-3.33 (m, 2H), 1.82-1.96 (m, 3H), 1.71-1.78 (m, 1H), 1.32 (d, J = 6.4Hz, 3H).

[0700] Example 161: (1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)-4-methoxypiperidin-4-yl)methanol hydrochloride

[0701] Referring to the method in Example 28, the target compound was obtained using (4-methoxypiperidin-4-yl)methanol as a starting material.

[0702] MS m / z[LC-MS]:628.25[M+1].

[0703] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.10(d,J=5.6Hz,1H),7.88(d,J=7.2Hz,1H), 6.86-6.92(m,1H),6.68(d,J=5.6Hz,1H),4.38-4.46(m,1H),4.27-4.37(m,2H),4.04-4.23(m ,2H),4.01(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.52(s,2H),3.46(d,J=4.0Hz,1H),3.18- 3.43(m,7H),1.82-1.98(m,5H),1.71-1.78(m,1H),1.55-1.63(m,2H),1.32(d,J=6.4Hz,3H).

[0704] Example 162: ((R)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)azepin-2-yl)methanol hydrochloride

[0705] By referring to the method of Example 28, the target compound was obtained using (R)-azetidin-2-ylmethanol as a starting material.

[0706] MS m / z[LC-MS]:570.21[M+1].

[0707] 1 H NMR(400MHz, CD3OD),8.43(s,1H),8.35(s,1H),8.12(d,J=5.2Hz,1H),7.98(d,J=7.6Hz,1H),6.91(d,J=6.8H z,1H),6.73-6.79(m,1H),4.68-4.76(m,1H),4.38-4.46(m,1H),4.28-4.37(m,2H),4.10-4.23(m,2H),4.01( d,J=9.2Hz,1H),3.92-3.98(m,1H),3.89(d,J=9.2Hz,1H),3.72-3.81(m,1H),3.46(d,J=4.4Hz,1H),3.18-3. 33(m,2H),2.45-2.56(m,1H),2.24-2.38(m,1H),1.84-1.94(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0708] Example 163: ((S)-1-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)pyrimidin-2-yl)azepine-2-yl)methanol hydrochloride

[0709] By referring to the method in Example 28, the target compound was obtained using (S)-azetidin-2-ylmethanol as a starting material.

[0710] MS m / z[LC-MS]:570.21[M+1].

[0711] 1H NMR(400MHz, CD3OD),8.42(s,1H),8.34(s,1H),8.11(d,J=5.6Hz,1H),7.95(d,J=7.2Hz,1H),6.85-6.95(m,1 H),6.72(d,J=5.6Hz,1H),4.64-4.74(m,1H),4.38-4.46(m,1H),4.28-4.37(m,2H),4.07-4.20(m,2H),4.01( d,J=9.2Hz,1H),3.92-3.98(m,1H),3.89(d,J=9.2Hz,1H),3.69-3.80(m,1H),3.46(d,J=4.0Hz,1H),3.18-3. 33(m,2H),2.45-2.55(m,1H),2.25-2.39(m,1H),1.83-1.94(m,3H),1.71-1.78(m,1H),1.32(d,J=6.0Hz,3H).

[0712] Example 164: (3S,4S)-8-(5-((3-chloro-2-((2-((3S,4R)-3-fluoro-4-methoxypyrrolidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0713] Referring to the method in Example 28, the target compound was obtained using (3S,4R)-3-fluoro-4-methoxypyrrolidine as a starting material.

[0714] MS m / z[LC-MS]:602.23[M+1].

[0715] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.35(s,1H),8.10(d,J=5.2Hz,1H),7.93(d,J =7.2Hz,1H),6.92-7.00(m,1H),6.69(d,J=5.2Hz,1H),5.22-5.50(m,1H),4.38-4 .46(m,1H),4.09-4.37(m,3H),3.68-4.07(m,5H),3.50(s,3H),3.41-3.49(m,2H) ,3.18-3.32(m,2H),1.82-1.96(m,3H),1.72-1.77(m,1H),1.33(d,J=6.4Hz,3H).

[0716] Example 165: (3S,4S)-8-(5-((3-chloro-2-((2-((R)-3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0717] Referring to the method in Example 28, the target compound was obtained using (R)-3,3-difluoro-4-methoxypiperidine as a raw material.

[0718] MS m / z[LC-MS]:634.21[M+1].

[0719] 1 H NMR(400MHz,CD3OD),8.42(s,1H),8.34(s,1H),8.11(d,J=5.6Hz,1H),7.95(d,J=7.6Hz,1H) ,6.94-7.04(m,1H),6.69(d,J=5.6Hz,1H),4.38-4.46(m,1H),4.18-4.36(m,3H),4.01(d,J= 9.2Hz,1H),3.85-3.97(m,3H),3.65-3.78(m,2H),3.53(s,3H),3.46(d,J=3.6Hz,1H),3.18- 3.32(m,2H),1.97-2.03(m,2H),1.83-1.92(m,3H),1.71-1.78(m,1H),1.33(d,J=6.4Hz,3H).

[0720] Example 166: (3S,4S)-8-(5-((3-chloro-2-((2-((S)-3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[0721] Referring to the method in Example 28, the target compound was obtained using (S)-3,3-difluoro-4-methoxypiperidine as a raw material.

[0722] MS m / z[LC-MS]:634.21[M+1].

[0723] 1H NMR(400MHz,CD3OD),8.41(s,1H),8.34(s,1H),8.11(d,J=5.6Hz,1H),7.94(d,J=7.6Hz,1H) ,6.93-7.06(m,1H),6.68(d,J=5.6Hz,1H),4.38-4.45(m,1H),4.18-4.36(m,3H),4.01(d,J= 9.2Hz,1H),3.84-3.98(m,3H),3.64-3.78(m,2H),3.53(s,3H),3.46(d,J=4.0Hz,1H),3.18- 3.32(m,2H),1.96-2.04(m,2H),1.82-1.94(m,3H),1.71-1.77(m,1H),1.32(d,J=6.0Hz,3H).

[0724] Biological testing

[0725] Compounds against SHP2 WT Determination of in vitro enzyme activity inhibition

[0726] SHP2 in this patent WT The enzyme activity was detected by rapid fluorescence method, DiFMUP was used as an alternative substrate for reaction and a high-throughput screening platform was established. WT The inhibitory activity of SHP2 was detected on this platform. The specific method is as follows: SHP2 was added to a final concentration of 1 nM. WTThe mixture was preincubated with a 2.5 μM diphosphorylated IRS1 peptide (sequence: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide) at 23°C for 30 minutes. The compound was serially diluted five-fold starting at 0.2 mM in 100% DMSO (7 concentrations total). At each concentration, 2 μL of compound was added to 48 μL of reaction buffer (60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% Tween 20, 5 mM DTT) and mixed thoroughly. 5 μL of the diluted compound was then added to a black 384-well plate (OptiPlate-384, Cat. No. 6007270, purchased from PerkinElmer). Then, 10 μL of the preincubated SHP2 and IRS1 peptide mixture was added, centrifuged to mix, and incubated at 23°C for 30 minutes. 5 μL of the surrogate substrate DiFMUP (final concentration 50 μM, product number D6567, purchased from Invitrogen) was added to the reaction and incubated at 23°C for 60 minutes. The reaction was then terminated by adding 5 μL of a 160 μM bpV (Phen) solution (SC-22137, purchased from Santa Clara). Immediately after the reaction was terminated, the fluorescence signal was measured using a microplate reader (Perkin-Elmer) at excitation and emission wavelengths of 340 nm and 450 nm, respectively. The data were used to calculate the IC value of the compound using GraphPad Prism software. 50 value.

[0727] In vitro enzymatic activity assay of compounds against SHP2E76K

[0728] SHP2 in this patent E76K The enzyme activity was detected by rapid fluorescence method, DiFMUP was used as an alternative substrate for reaction and a high-throughput screening platform was established. E76K The detection of enzyme inhibitory activity is performed on this platform. The specific method is as follows: the compound is diluted 5-fold with 100% DMSO starting from 1mM (a total of 7 concentrations), and 2μL of the compound at each concentration 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 5μL of the diluted compound and add it to a black 384-well plate (OptiPlate-384, product number 6007270, purchased from PerkinElmer), and add 5μL SHP2 to each well. E76K, final concentration 0.2nM, centrifuge to mix, and incubate at 23°C for 30 minutes. Add 5μL of alternative substrate DiFMUP (final concentration 50μM, product number D6567, purchased from Invitrogen) to the reaction and incubate at 23°C for 60 minutes. The reaction was then terminated by adding 5μL of 160μM bpV (Phen) solution (SC-22137, purchased from Santa). Immediately after the reaction was terminated, the fluorescence signal was detected using a microplate reader (Perkin-Elmer) at excitation and emission wavelengths of 340nm and 450nm, respectively. The data were calculated using GraphPad Prism software to obtain the IC value of the compound. 50 The activity of some compounds is shown in Table 1:

[0729] Table 1. Inhibitory activity of some compounds on SHP2 enzyme

[0730] NT: Not tested

[0731] The compounds in the examples of the present invention have an inhibitory activity against SHP2 protease of less than 20 nM, indicating that the compounds of the present invention have good inhibitory activity against SHP2 protease.

[0732] Determination of the inhibitory effect of compounds on SHP2 positive cell proliferation

[0733] Human non-small cell lung cancer cell line NCI-H358 cells were cultured in RPMI-1640 medium (Cat. No. C11875500BT, purchased from Biological Industries) supplemented with 10% fetal bovine serum (FBS, Cat. No. 04-001-1ACS, purchased from Biological Industries, BI) and 1% penicillin / streptomycin (P / S, Cat. No. 15070-063, purchased from Gibco) at 37°C and 5% CO2. The day before compound testing, NCI-H358 cells were plated at a density of 2000 cells / 195 μL / well in a 196-well plate (Cat. No. 3917, purchased from Corning). After 24 hours, compounds were serially diluted three-fold starting at 10 mM in 100% DMSO (a total of 10 concentrations). At each concentration, 2 μL of compound was diluted in 48 μL of serum- and P / S-free culture medium. 5 μL of each diluted compound concentration was added to the plated cell suspension. The compound and cells were incubated in a cell culture incubator for 72 hours (3 days). After the culture medium was aspirated, 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. 50Value. Kasumi-1 cells, a human acute myeloblastic leukemia cell line, were cultured using RPMI-1640 medium (Cat. No. C11875500BT, purchased from Biological Industries) supplemented with 20% 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) at 37°C and 5% CO2. The day before compound detection, Kasumi-1 cells were plated in 196-well plates (Cat. No. 3599, purchased from Corning) at a concentration of 3,000 cells / 195 μL / well. After 24 hours, the compound was diluted 3-fold starting from 10 mM with 100% DMSO (a total of 10 concentrations), and then 2 μL of compound was added to 48 μL of culture medium without serum and dual antibody for dilution at each concentration. 5 μL of each diluted compound concentration was added to the plated cell suspension. The compound and cells were incubated in a cell culture incubator for 72 hours (3 days). 35 μL Cell-Titer Blue (G8082, purchased from Promega) was added and incubated for another 4 hours. Fluorescence values ​​were then read on a Flexstation III (560 nm excitation, 590 nm detection). The data were used to calculate the IC50 of the compound for inhibition of cell proliferation using GraphPad Prism software. 50 The detection results of some compounds are shown in Table 2.

[0734] Table 2. Inhibitory activity of some compounds on cell (NCI-H358) proliferation

[0735] The compounds in the examples of the present invention have an inhibitory activity on the proliferation of SHP2-positive cells within 500 nM, which indicates that the compounds provided by the present invention have a good inhibitory activity on the proliferation of SHP2-positive cells.

[0736] Pharmacokinetic data of compounds

[0737] Male Sprague-Dawley rats were obtained from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Rats were divided into groups of three and orally gavaged with a suspension of the test sample (5 mg / kg, in 20% EtOH, 40% PEG 400, and 40% H2O). Animals were fasted overnight and from 10 hours before dosing until 4 hours after dosing. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Under isoflurane anesthesia, 0.3 mL of whole blood was collected from the retinal venous plexus in a heparinized tube. The sample was centrifuged at 4000 rpm for 5 minutes at 4°C. Plasma was transferred to a centrifuge tube and stored at -80°C until analysis. Plasma samples were extracted using protein precipitation, and the extracts were analyzed by LC / MS. The results are shown in Table 3.

[0738] Table 3. Pharmacokinetic data of some compounds

[0739] In vivo pharmacodynamics of the compound on a subcutaneous xenograft tumor mouse model of human non-small cell lung cancer NCI-H358 cells

[0740] Experimental animals: Female NOD / SCID mice, 6-8 weeks old, weighing 18-22 g.

[0741] Experimental methods and steps:

[0742] 1. Cell Culture

[0743] Human non-small cell lung cancer (NCl-H358) cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37°C in a 5% CO2 incubator. Twice weekly, cells were routinely digested and passaged using trypsin-EDTA. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and plated.

[0744] 2. Tumor Cell Inoculation (Tumor Inoculation)

[0745] NCI-H358 cells (5×10 6 cells / 0.1 ml, containing 30% matrigel) were subcutaneously inoculated on the left and right sides of the back of each mouse, and the average tumor volume reached about 150 mm 3 The group dosing started at 14:00.

[0746] 3. Preparation of test substance:

[0747] The compound was prepared into 1 mg / ml and 3 mg / mL solutions in a solvent of 20% EtOH+40% PEG400+40% H2O.

[0748] 4. Tumor Measurement and Experimental Indicators

[0749] Tumor diameter was measured with a vernier caliper 2-3 times a week. Tumor volume was calculated using the formula: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.

[0750] The tumor inhibition effect of the compound was evaluated using TGl (%) or relative tumor growth rate T / C (%). Tumor growth inhibition rate TGI (%), TGI (%) = [1-(average tumor volume of a treatment group at the end of drug administration - average tumor volume of the treatment group at the start of drug administration) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the start of treatment)] × 100%. Relative tumor growth rate T / C (%) = T RTV / C RTV ×100%(T RTV : Average RTV value of treatment group; C RTV : the average RTV of the negative control group). The relative tumor volume (RTV) was calculated based on the results of tumor measurement. The calculation formula is RTV = V / Vo, where V0 is the tumor volume measured at the time of group administration (i.e., day 0), V1 is the tumor volume at a certain measurement, and T RTV with C RTV Get data for the same day.

[0751] 5. Statistical Analysis

[0752] Statistical analysis was performed using SPSS software based on RTV data at the end of the trial. The treatment group demonstrated the greatest therapeutic effect on day 16 after dosing, so statistical analysis was performed based on this data to assess intergroup differences. Comparisons between the two groups were analyzed using a T-test, with a p < 0.05 considered significant.

[0753] 6. Experimental results and conclusions

[0754] The experimental results of Example 115 and Example 164 at 10 mg / kg and 30 mg / kg doses are shown in the following table

[0755] Note: a. Mean ± SEM, n = 5; b. Tumor growth inhibition was evaluated by T / C and TGI calculation; cp values ​​were obtained by analyzing relative tumor volume (RTV) using t-test;

[0756] Conclusion: In this experiment, compared with the control group, the compounds in the examples of the present invention have significant tumor inhibition effects, and the tumor-bearing mice show good tolerance to the compounds.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, in, Ring A is or Wherein the * carbon is connected to Y, X3 and X4 are each independently N or CR 10 , R3, R 20 、R 21 and R 22 Each is independently H, halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, The alkyl, cycloalkyl and heterocycloalkyl groups may be optionally substituted with one or more halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution, Ring B is a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring, or Ring B is a bicyclic or tricyclic ring system comprising a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring connected to N, and a 3-8 membered alicyclic ring or a 3-8 membered heteroalicyclic ring fused to the aromatic ring or heteroaromatic ring, wherein the alicyclic ring and the heteroalicyclic ring may be optionally oxidized. X1 and X2 are each independently N or CR7, R7 and R 10 Each is independently H, halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, said alkyl, cycloalkyl and heterocycloalkyl may be optionally substituted with one or more halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution, R2 is H or C 1-6 alkyl, R1 is halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, -O-(6-10 membered aryl), -NR-(6-10 membered aryl), 5-12 membered heteroaryl, -O-(5-12 membered heteroaryl), -NR-(5-12 membered heteroaryl), -P(O)RR, -(SO)-R, -(CO)-R, -COOH, -(CO)-O-R, or -(CO)-NR-R, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R, R4 are each independently selected from halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P(O)R8R9, -(SO2)-R6, -(CO)-R6, -COOH, -(CO)-O-R6, or -(CO)-NR-R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be optionally substituted with one or more halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 substituted by cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P(O)R8R9, -(SO2)-R6, -(CO)-R6, -COOH, -(CO)-O-R6 or -(CO)-NR-R6, R5 and R6 are each independently selected from C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, the alkyl and cycloalkyl groups may be optionally substituted with one or more halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 1-6 Alkyl or -NH-C 1-6 Alkyl substitution, R8 and R9 are each independently selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, R is each independently selected from H and C 1-6 alkyl, Y is selected from C 6-10 Aryl, 5-12 membered heteroaryl, 3-12 membered heteroalicyclic and 5-15 membered spirocyclic, wherein the aryl, heteroaryl, heteroalicyclic and spirocyclic groups may be optionally substituted with one or more halogen, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, C 1-6 Alkyl, or C 3-8 Cycloalkyl substituted, said alkyl or cycloalkyl may be optionally substituted with halogen, -OH, -OC 1-6 Alkyl, -NH2, or -NH-C 1-6 Alkyl substituted, the heteroalicyclic group and spirocyclic group can be optionally with C 6-10 The aryl or 5-10 membered heteroaryl fused, the aryl or heteroaryl fused with heteroalicyclic and spirocyclic groups may be optionally substituted with one or more halogen, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, C 1-6 Alkyl, or C 3-8 Cycloalkyl substitution, n is 0, 1, 2 or 3, Provided that the following compounds are not included 2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein R1 is halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, -O-(6-10 membered aryl), -NR-(6-10 membered aryl), 5-12 membered heteroaryl, -O-(5-12 membered heteroaryl), -NR-(5-12 membered heteroaryl), -P(O)RR, -(SO)-R, -COOH, -(CO)-O-R, or -(CO)-NR-R, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R, R4 are each independently selected from halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P(O)R8R9, -(SO2)-R6, -COOH, -(CO)-O-R6, or -(CO)-NR-R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be optionally substituted with one or more halogen, -CN, -NH2, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -NR-R5, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P(O)R8R9, -(SO2)-R6, -COOH, -(CO)-O-R6 or -(CO)-NR-R6, R5 and R6 are each independently selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, said alkyl and cycloalkyl groups may be optionally substituted with one or more halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl or -NH-C 1-6 Alkyl substitution, R, R8 and R9 are as defined in claim 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein Y is a 5-15 membered spirocycloalkyl or a 5-15 membered heterospirocycloalkyl, wherein the spirocycloalkyl or heterospirocycloalkyl is optionally substituted with one or more halogens, C 1-6 Alkyl, -OH or -NH2 substituted.

4. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein: Ring B is a pyridine ring or a pyrimidine ring, or Ring B is a bicyclic or tricyclic ring system including a pyridine ring or a pyrimidine ring connected to N, and a 5-6 membered alicyclic ring or a 5-6 membered heteroalicyclic ring fused to the pyridine ring or the pyrimidine ring, wherein the alicyclic ring and the heteroalicyclic ring may be optionally oxidized.

5. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein: R 21 and R 22 Each independently is H or C 1-6 Alkyl, R 20 For H, or trifluoromethyl, R3 is halogen or C 1-6 alkyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein: X1, X2, X3 and X4 are CH, R2 is H, and R3 is halogen.

7. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein Y is a 5-15 membered oxazaspirocycloalkyl group, which may be optionally substituted with one or more halogens, C 1-6 Alkyl, -OH or -NH2 substituted.

8. The compound according to claim 1 or 6, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein: Y is The group may be optionally substituted with one or more halogen, C 1-6 Alkyl, -OH, or -NH2 substituted.

9. The following compound or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof:

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, and optionally comprising a pharmaceutically acceptable excipient.

11. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 10, or any one of them in combination with a SHP2 inhibitor, a KRAS inhibitor or an EGFR inhibitor, in the preparation of a medicament for treating diseases associated with SHP2 and / or KRAS and / or EGFR.

12. The use according to claim 11, wherein the disease associated with SHP2 and / or KRAS and / or EGFR is leukemia, melanoma, malignant glioma, lung cancer, breast cancer or Noonan syndrome

Images