CN115340559A

CN115340559A - Preparation and application of SHP2 phosphatase heterocyclic inhibitor

Info

Publication number: CN115340559A
Application number: CN202110517521.4A
Authority: CN
Inventors: 梁永宏; 许志勇; 严文广; 曾兆森; 熊方均
Original assignee: Yaoya Technology Shanghai Co ltd
Current assignee: Yaoya Technology Shanghai Co ltd
Priority date: 2021-05-12
Filing date: 2021-05-12
Publication date: 2022-11-15

Abstract

The invention discloses an SHP2 phosphatase inhibitor and application thereof. Particularly, the compound shown in the general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as a protein tyrosine phosphatase SHP-2 inhibitor in medicines for treating leukemia, neuroblastoma, melanoma, acute bone leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large-cell lymphoma and glioblastoma are disclosed, wherein each substituent in the general formula (I) k is defined as the specification.

Description

Preparation and application of SHP2 phosphatase heterocyclic inhibitor

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a novel SHP2 phosphatase inhibitor, and a preparation method and application thereof.

Background

The present invention relates generally to novel compounds, methods for their preparation, and their use as SHP2 phosphatase inhibitors (e.g., for the treatment of cancer).

SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, containing two N-terminal Src homology 2 (SH 2) domains, a Protein Tyrosine Phosphatase (PTP) domain and a poorly sequenced C-terminus. X-ray crystallography studies have shown that SHP2 inhibits its own phosphatase activity by blocking access to the catalytic site on the PTP domain using the N-terminal SH2 domain. It has been demonstrated that the binding of a tyrosyl diphosphate protein or peptide (e.g., IRS-1) to the SH2 domain of SHP2 disrupts the N-terminal SH2-PTP domain interaction. This binding allows the substrate to enter the catalytic site and activate the phosphatase.

SHP2 is recruited by RTKs to induce cellular signaling and is involved in multiple intracellular oncogenic signaling cascades, such as Jak/STAT, PI3K/AKT, RAS/Raf/MAPK, PD-1/PD-L1, and the mTOR pathway. Wherein the GTP binding mode, which conducts extracellular signals to the nuclear key gtpase RAS, regulated (dephosphorylation of tyrosine in adaptor/scaffold proteins) by SHP2 to the activated state, exerts carcinogenic effects; on the other hand, SHP2 activation of RAS signals in acquired resistance promotes compensatory activation of signaling pathways (e.g., negative feedback regulation of MEK activates RTK, activating SHP2 and thus downstream pathways), in which case, inhibition of SHP2 may eliminate reactivation of the RAS/Raf/ERK pathway and represent a potential therapeutic strategy as a new strategy to address the problem of RTK resistance.

Moreover, germline or somatic mutations in PTPN11 leading to the overactivation of SHP2 have been identified in a variety of pathophysiological states: noonan syndrome, hematological malignancies including juvenile myelomonocytic leukemia, myelodysplastic syndrome, B-cell acute lymphocytic leukemia and acute myelogenous leukemia, and low frequency solid tumors. Thus, SHP2 is one of the most recently attractive targets for the development of new therapies for the treatment of various diseases.

The published patent applications of related researches on SHP2 targets have; currently, there are clinically established SHP2 phosphatase inhibitors: norwa TNO155 and JAB-3068 to JACOBIO, both in phase I clinical stage. There is no product of the target on the market. Therefore, it is of great importance to develop inhibitors that inhibit the target more efficiently.

Disclosure of Invention

In order to solve the above problems, the present invention provides a compound having the general formula (I) and the general formula (II) or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, polymorph or isomer thereof,

wherein:

each L ₁ Independently at each occurrence selected from the group consisting of a bond, O, CH ₂ 、NH、CO、-S(O) _m -, or S;

each L ₂ Independently at each occurrence selected from the group consisting of a bond, O, CH ₂ 、NH、CONH ₂ 、CO、-S(O) _m -, or S;

each Ar ₁ Independently at each occurrence is selected from

Each Ar ₁ Optionally at each occurrence independently by 1 or 2R ₁₉ Substituted or unsubstituted;

each Ar ₂ Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence comprising 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₂ Optionally at each occurrence independently by 1,2, 3, 4,5 or 6R ₁₉ Substituted or unsubstituted;

each Ar ₃ Independently at each occurrence selected from H, phenyl,Naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence comprising 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₃ Optionally at each occurrence independently by 1,2, 3, 4,5 or 6R ₁₉ Substituted or unsubstituted;

each R ₁₉ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₁₀ 、-C _1-6 Alkylene- (OR) ₁₀ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₁₀ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₁₀ R ₁₁ -C1-6 alkylene-NR ₁₀ R ₁₁ 、-C(＝O)R ₁₀ 、-C(＝O)OR ₁₀ 、-OC(＝O)R ₁₀ 、-C(＝O)NR ₁₀ R ₁₁ 、-NR ₁₀ C(＝O)R ₁₁ 、-S(O) ₂ NR ₁₀ R ₁₁ or-C _3-6 A carbocyclic group; each R ₁₉ Independently optionally substituted by 1,2, 3, 4,5 or 6 substituents selected from deuterium, halogen, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₁₀ 、-NR ₁₀ R ₁₁ 、-CN、-C(＝O)R ₁₀ 、-C(＝O)OR ₁₀ 、-OC(＝O)R ₁₀ 、-C(＝O)NR ₁₀ R ₁₁ 、-NR ₁₀ C(＝O)R ₁₁ or-S (O) ₂ NR ₆ R ₁₁ Substituted or unsubstituted;

each R ₁₀ And R ₁₁ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-6 Alkyl radical, each R ₁₀ And R ₁₁ Independently optionally substituted by 1,2, 3, 4,5 or 6R ₁₉ Substituted or unsubstituted; or R ₁₀ And R ₁₁ Together with the N atom to which they are both attached form a 3-10 membered heterocyclic ring, which 3-10 membered heterocyclic ring may further comprise 1,2, 3 or 4 substituents selected from N, O, S, S (= O) or S (= O) ₂ And said 3-to 10-memberedThe heterocycle is independently optionally substituted with 1,2, 3, 4,5, or 6R ₂₀ Substituted or unsubstituted;

each R ₂₀ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OC _1-6 、-C _1-6 Alkylene- (OC) _1-6 ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SC _1-6 、-S-C _1-6 Alkylene- (halogen) _1-3 or-C _3-6 A carbocyclic group;

each X ₈ Independently at each occurrence is selected from CR ₄ R ₅ 、SiR ₄ R ₅ 、NH、O；

Each X ₉ Independently at each occurrence is selected from CR ₆ NH, wherein X ₇ And X ₈ One must be carbon;

each R ₁ Independently at each occurrence, selected from H, deuterium, -C _1-6 An alkyl group;

each R ₂ Independently at each occurrence, selected from H, deuterium, OH, CH ₂ NH ₂ ；

Each R ₃ 、R ₇ 、R ₈ Independently at each occurrence is selected from H, deuterium;

each R ₄ Independently at each occurrence, selected from H, deuterium, OH, C _0-3 NR ₁₂ R ₁₃ ；

Each R ₅ Independently at each occurrence, selected from H, deuterium, OH, C _1-6 Alkyl radical, C _1-6 Alkyl substituted by 1,2, 3, 4,5 or 6 deuterium, OH, methyl, OCH ₃ 5-10 membered heteroaryl;

each R ₆ Independently at each occurrence, selected from H, deuterium, NH ₂ ；

R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ Two of them can be connected in the following way:

R ₁ and R ₂ May adopt CH ₂ NHCH ₂ Are connected to form a thick double ring,

R ₁ and R ₆ Alkylene groups may be employed to link to form bridged bicyclic rings,

R ₂ and R ₃ Can adopt a quilt NH ₂ Substituted alkylene groups are linked to form a spiro ring,

R ₄ and R ₅ Can be connected to form C _3-12 Cycloalkyl of, C _3-12 Heterocycloalkyl of (A), C _3-12 Bicycloalkyl of, C _3-12 Hetero bicycloalkyl of (b), wherein C _3-12 Heterocycloalkyl of (A), C _3-12 Independently at each occurrence, contains 1,2, 3, or 4 heteroatoms selected from N, O, or S, each C _3-12 Cycloalkyl of (C) _3-12 Heterocycloalkyl of (C) _3-12 Bicycloalkyl of, C _3-12 Independently at each occurrence, optionally deuterium, halogen, OH, CH ₃ 、OCH ₃ 、NH ₂ The substitution forms a spiro ring,

R ₁ and R ₇ Can be connected to form bridged bicyclic rings through alkylene, O and NH,

R ₂ and R ₆ May be linked through an alkylene group to form a bridged bicyclic ring,

R ₂ and R ₇ May be linked through alkylene, O, to form bridged bicyclic rings,

R ₄ and R ₆ Can be prepared through NHCH ₂ Is NH is ₂ Substituted C _3-12 The cycloalkyl groups of the two are connected to form a thick bicyclic ring,

each a, b, c, d is independently selected at each occurrence from 0, 1;

in some embodiments, the compound of (I) described above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof

In the step (1), the first step,

selected from the following structures:

in some embodiments, the compound of (I) described above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein Ar ₂ Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence comprising 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₃ Optionally at each occurrence independently by 1,2, 3, 4,5 or 6R ₁₉ Substituted or unsubstituted;

each Ar ₃ Independently at each occurrence selected from H, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence containing 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₂ Optionally at each occurrence independently by 1,2, 3, 4,5 or 6R ₁₉ Substituted or unsubstituted;

each R ₁₀ And R ₁₁ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-6 Alkyl radical, each R ₁₀ And R ₁₁ Independently optionally substituted by 1,2, 3, 4,5 or 6R ₁₉ Substituted or unsubstituted; or R ₁₀ And R ₁₁ Together with the N atom to which they are both attached form a 3-10 membered heterocyclic ring, which 3-10 membered heterocyclic ring may further comprise 1,2, 3 or 4 substituents selected from N, O, S, S (= O) or S (= O) ₂ And said 3-10 membered heterocyclic ring is independently optionally substituted with 1,2, 3, 4,5 or 6R ₂₀ Substituted or unsubstituted;

further preferably, each

Selected from the following structures:

in some embodiments, the compound of (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof described above is selected from the following compounds:

another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, optionally a therapeutically effective dose of 0.1-2000mg in the present disclosure, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The disclosure also relates to a process for preparing the pharmaceutical composition, which comprises mixing the compounds of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or the compound of formula (I) or tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, diluent or excipient.

The disclosure further relates to the use of compounds of general formula (I) and general formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same, for the preparation of SHP2 inhibitors.

The present disclosure further relates to the use of a compound of formula (I) and formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a disease or disorder mediated by SHP2 activity.

The disclosure further relates to the use of the compounds of general formula (I) and general formula (II), or tautomers, mesomers, racemates, enantiomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, as SHP2 inhibitors in the manufacture of a medicament for the prevention and/or treatment of tumors or cancers.

The disclosure further relates to the use of a compound of formula (I) and formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention or treatment of noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large-cell lymphoma, and glioblastoma.

The present disclosure further relates to compounds of general formula (I) and general formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The disclosure also relates to compounds of general formula (I) and general formula (II), or tautomers, mesomers, racemic enantiomers, diastereomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, as SHP2 inhibitors.

The disclosure also relates to compounds of general formula (I) and general formula (II) or tautomers, meso-racemates, enantiomers, diastereomers, atropisomers or mixtures thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are useful as SHP2 inhibitors for the prevention and/or treatment of tumors or cancers.

The present disclosure also relates to a method for the therapeutic prevention and/or treatment of tumors or cancers, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (la), or a tautomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, as a SHP2 inhibitor, or a pharmaceutical composition comprising the same, the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as a tableted dragee, lozenge, aqueous or oil suspension, dispersible powder or granule, emulsion, hard or soft gelatin capsule, or syrup or dosage form may be prepared as any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives to provide a visually pleasing and palatable pharmaceutical preparation, and the tablets may contain the active ingredient and non-toxic pharmaceutically acceptable excipients for mixing to make the tablet. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-hydrogenation agent.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion where the oil phase may be a vegetable oil, or a mineral oil or mixtures thereof suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion, in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection, or, preferably, the solution and microemulsion may be administered in such a manner as to maintain a constant circulating concentration of the compound of the present disclosure. To maintain such a constant concentration, a continuous intravenous delivery device may be used an example of such a device is an intravenous pump model Deltec CADD-plus. TM.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The mixtures can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents such as those described above, as well as sterile injectable preparations in the form of sterile injectable solutions or suspensions in parenterally-acceptable non-toxic diluents or solvents, and sterile fixed oils as solvents or suspending media, for which purpose any of the fixed oils may be used and, in addition, fatty acids may be used to prepare the injectables.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of the drug administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the rate of excretion, the combination of the drug, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amounts of the compounds of the general formulae (I) and (II) or the type of pharmaceutically acceptable salts can be verified according to conventional treatment protocols.

Certain chemical terms

Unless stated to the contrary, the following terms are used in the specification and claims.

Has the following meanings and is used herein in the manner of _x-y "denotes a range of numbers of carbon atoms wherein x and y are both integers, e.g. C _3-8 Cycloalkyl denotes cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3, 4,5, 6,7 or 8 carbon atoms. It is also understood that "C" is _3-8 "also includes any subrange therein, e.g. C _3-7 、C _3-6 、C _4-7 、C _4-6 、C _5-6 And the like.

"alkyl" refers to a straight or branched chain hydrocarbyl group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.

"alkenyl" refers to a straight or branched chain hydrocarbyl group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, e.g., 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1,4-pentadienyl, and 1,4-butadienyl. The alkenyl group may be substituted or unsubstituted.

"alkynyl" refers to a straight or branched chain hydrocarbyl group containing at least one carbon-carbon triple bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. The alkynyl group may be substituted or unsubstituted.

"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic and typically contain 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decahydronaphthyl, which may be substituted or unsubstituted.

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

"Spiroheterocyclyl" means 5 to 20 membered rings which share one atom in a single ring (referred to as the spiro atom)) Wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated electronic system, preferably 6 to 14, more preferably 7 to 10. The spirocycloalkyl group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro cycloalkyl group and a di-spiro cycloalkyl group, according to the number of spiro atoms shared between rings. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclic group. Non-limiting examples of spiroheterocyclyl radicals include:

"fused heterocyclyl" means a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

"aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.

"heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, at least one aromatic ring. Unless otherwise specified, heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may contain fused or bridged ring systems, provided that the point of attachment to the rest of the molecule is an aromatic ring atom, which may be selectively oxidized at nitrogen, carbon and sulfur atoms, and which may optionally be quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 4-11 membered monocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In the present application, heteroaryl is preferably 5-8 membered heteroaryl comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.

"halogen" means fluorine, chlorine, bromine or iodine.

"hydroxy" means-OH and "amino" means-NH ₂ "amido" means-NHCO-, "cyano" means-CN, and "nitro" means-NO ₂ "isocyano" means-NC and "trifluoromethyl" means-CF ₃ 。

The term "heteroatom" or "hetero", as used herein alone or as part of another ingredient, refers to atoms other than carbon and hydrogen, and is independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, and in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different.

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

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

"optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes where the event or circumstance occurs or does not occur-for example, "heterocyclic group optionally substituted with alkyl" means that alkyl may, but need not, be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

"substituted" means that one or more atoms, preferably 5, more preferably 1 to 3 atoms, in a group are independently substituted with a corresponding number of substituents. It goes without saying that the skilled person in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort, when the substituents are in their possible chemical positions. For example, having a free amine or hydroxyl group may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond. Such substituents include, but are not limited to, hydroxy, amine, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl groups, and the like.

"pharmaceutical composition" refers to a composition containing one or more compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, and other ingredients such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote administration to the organism, facilitate absorption of the active ingredient and further exert biological activity.

"isomers" refer to compounds having the same molecular formula but differing in the nature or order of the bonding of their atoms or in the arrangement of their atoms in space, and are referred to as "isomers"; isomers differing in the arrangement of their atoms in space are referred to as "stereoisomers". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are either in the "R" or "S" configuration. Optical isomers, including enantiomers and diastereomers, and methods of preparing and separating optical isomers are known in the art.

Geometric isomers may also exist for the compounds of the present invention. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as either the Z or E configuration, substituents around cycloalkyl or heterocyclic rings are designated as either the cis or trans configuration.

The compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.

It is to be understood that the present invention encompasses any tautomeric or stereoisomeric form and mixtures thereof and is not to be limited merely to any one tautomeric or stereoisomeric form employed in the nomenclature or chemical structure of the compounds.

"isotopes" are all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and ³⁶ and (4) Cl. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using appropriate isotopically-labeled reagents in place of non-isotopically-labeled reagents. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to favorably modify biological, pharmacological or pharmacokinetic properties。

By "prodrug" is meant that the compounds of the present invention can be administered in the form of a prodrug. Prodrugs refer to derivatives that are converted to the biologically active compounds of the present invention under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, and the like, each of which utilizes or proceeds without the participation of an enzyme. Examples of prodrugs are the following compounds: compounds in which the amine group in the compounds of the invention is acylated, alkylated or phosphorylated, for example eicosanoylamino, propylaminoylamino, pivaloyloxymethylamino, or in which the hydroxyl group is acylated, alkylated, phosphorylated or converted to a borate, for example acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, propylaminoyloxy, or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group forms a disulfide bridge with a carrier molecule, for example a peptide, which selectively delivers a drug to the target and/or to the cytosol of the cell, can be prepared from the compounds of the invention according to well-known methods.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable" refers to those made from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts. The compounds of the invention which contain acidic groups can therefore be present in salt form and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, caffeine, and the like, with particularly preferred organic bases being isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the invention containing basic groups can be present in the form of salts and can be used according to the invention in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention also includes inner salts or betaine salts in addition to the salt forms mentioned. The salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.

Thus, when reference is made in this application to "a compound", "a compound of the invention" or "a compound of the invention" all said compound forms are included, such as prodrugs, stable isotopic derivatives, pharmaceutically acceptable salts, isomers, meso forms, racemates, enantiomers, diastereomers and mixtures thereof.

In this context, the term "tumor" includes both benign tumors and malignant tumors (e.g., cancers).

Herein, the term "cancer" includes various malignancies in which SHP2 phosphatase is involved, including but not limited to non-small cell lung cancer, esophageal cancer, melanoma, striated muscle garnet, cell carcinoma, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (e.g. hepatocellular carcinoma), more specifically liver cancer, gastric cancer and bladder cancer.

The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.

The term "polymorph" or "polymorph" as used herein means that the compounds of the present invention have multiple crystal lattice forms, some of the compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

Crystallization often results in a solvate of a compound of the invention, and the term "solvate" as used herein refers to an association of one or more molecules of a compound of the invention and one or more molecules of a solvent.

The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent may be used. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may also be present only occasionally as water or as a mixture of water with some other solvent the compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonizing agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.

As used herein, the term "subject," "patient," "subject" or "individual" refers to an individual having a disease, disorder or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, and includes

(i) Preventing the development of a disease or condition in a mammal, particularly a mammal that has been previously exposed to the disease or condition but has not been diagnosed as having the disease or condition;

(ii) Inhibiting the disease or disorder, i.e., controlling its development;

(iii) Relieving the disease or condition, i.e., slowing the regression of the disease or condition;

(iv) Relieving symptoms caused by the disease or disorder.

The terms "disease" and "condition" as used herein may be used interchangeably and may have different meanings, as certain specific diseases or conditions have no known causative agent (and therefore the cause of the disease is not yet clear) and therefore are not considered as a disease but can be considered as an unwanted condition or syndrome, with more or less specific symptoms being confirmed by clinical researchers.

The terms "administering," "administration," "administering," and the like as used herein refer to methods that are capable of delivering a compound or composition to a desired site for a biological action. Including, but not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

Detailed description of the preferred embodiment

The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) and general formula (II) according to the invention can be carried out by the following exemplary methods and examples, which should not be construed as limiting the scope of the invention in any way. The compounds of the invention can also be synthesized using synthetic techniques known to those skilled in the art, or a combination of methods known in the art and those described herein can be used. The product of each step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatography, and the like. The starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased according to the literature (reaxys).

The pyrimidine heterocyclic compounds shown in the general formula (IIa) and the general formula (IIb) can be synthesized according to the following route

Unless otherwise indicated, temperatures are in degrees celsius. Reagents were purchased from commercial suppliers such as Chemblocks Inc, astatech Inc or mclin, and these reagents were used directly without further purification unless otherwise stated.

Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or argon, or using a drying tube; glassware was dried and/or heat dried.

Unless otherwise stated, column chromatography purification used 200-300 mesh silica gel from Qingdao oceanic plant; preparation of thin-layer chromatography silica gel precast slab (HSGF 254) produced by Nicoti chemical industry research institute was used; MS was measured using a Therno LCD flash model (ESI) liquid chromatography-mass spectrometer.

Nuclear magnetic data ( ¹ H NMR) Using a Bruker Avance-400MHz or Varian Oxford-400Hz Nuclear magnetic Analyzer, the Nuclear magnetic data were obtained using CDCl as the solvent ₃ 、CD ₃ OD、D ₂ O、DMSO-d ₆ Etc. based on tetramethylsilane (0.000 ppm) or based on residual solvent (CDCl) _3: 7.26ppm；CD ₃ OD:3.31ppm；D ₂ O:4.79ppm；DMSO-d ₆ 2.50 ppm) when indicating the diversity of the peak shapes, the following abbreviations indicate the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet triplet). If the coupling constant is given, it is in Hertz (Hz).

The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Preparation of intermediates

Preparation of intermediate 1-methyl-3- (tributylstannyl) -1H-pyrazole

The compound 1-methyl-3-bromopyrazole (5 g, 31.25mmol) was dissolved in 80mL of toluene, hexa-n-butylditin (18.05g, 31.25mmol) and tetratriphenylphosphine palladium (1.79g, 1.56mmol) were added, and the reaction was stirred at 120 ℃ for 5 hours. Cooled to room temperature, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 1-methyl-3- (tributylstannyl) -1H-pyrazole (2.9 g, 25% yield).

Preparation of intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol

Dissolving the compound 3-fluoro-2-chloroaniline (5 g, 34.35mmol) in 80mL of N, N-dimethylformamide, adding tert-butylmercaptan (9.29g, 103mmol), cesium carbonate (16.79g, 51.53mmol), and heatingThe reaction was stirred to 120 ℃ for 24 hours. After cooling to room temperature, the reaction mixture was poured into 150mL of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 3- (tert-butylmercapto) -2-chloroaniline (5.85 g, yield 79%). LC/MS (ESI) m/z =216.1[ 2[ M ] +H] ⁺ .

The compound 3- (tert-butylmercapto) -2-chloroaniline (5 g, 23.25mmol) was dissolved in 15mL of concentrated hydrochloric acid, 40mL of an aqueous solution of sodium nitrite (1.25g, 26.3mmol) was added dropwise at-5 ℃ and stirred for 1 hour, 40mL of an aqueous solution of potassium iodide (5.4 g,46.5 mmol) was added dropwise at-5 ℃ and stirred for reaction for 30 minutes. The reaction solution was extracted with ethyl acetate, and the organic phase obtained was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 3- (tert-butylmercapto) -2-chloro-1-iodobenzene (4.93 g, 65% yield). LC/MS (ESI) m/z =326.9[ m + H ]] ⁺ .

The compound 1-methyl-3- (tributylstannyl) -1H-pyrazole (2g, 5.39mmol) was dissolved in xylene 50mL, and the compounds 3- (tert-butylmercapto) -2-chloro-1-iodobenzene (1.76g, 5.39mmol), tetrakistriphenylphosphine palladium (312mg, 0.27mmol) and added, and the reaction was stirred at reflux for 2 hours. Cooled to room temperature, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (3- (3- (tert-butylmercapto) -2-chlorobenzene) -1-methyl-1H-pyrazole (1.14 g, yield 75%). LC/MS (ESI): m/z =281.1[ M + H ] +] ⁺ .

The compound 3- (3- (tert-butylmercapto) -2-chlorobenzene) -1-methyl-1H-pyrazole (1.12g, 4 mmol) was dissolved in 25mL of toluene, and anhydrous aluminum trichloride (2.13g, 16mmol) was added thereto, and the reaction was stirred at room temperature for 1 hour under nitrogen protection. Adding ice water for quenching, and extracting by ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Crude 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (0.89 g, 99% yield) was obtained and used directly in the next reaction. LC/MS (ESI) m/z =225.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (1-ethyl-1H-pyrazol-3-yl) -2-chloro-thiophenol

The compound 3- (1-ethyl-1H-pyrazol-3-yl) -2-chloro-thiophenol was obtained by a similar preparation method to that of the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was changed to 3-bromo-1-ethylpyrazole). LC/MS (ESI) m/z =240.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (1-isopropyl-1H-pyrazol-3-yl) -2-chloro-thiophenol

The compound 3- (1-isopropyl-1H-pyrazol-3-yl) -2-chloro-thiophenol was obtained using a similar preparation method to that of the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was 3-bromo-1-isopropylpyrazole). LC/MS (ESI) m/z =254.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (pyrimidin-5-yl) -2-chloro-thiophenol

The compound 3- (pyrimidin-5-yl) -2-chloro-thiophenol was obtained by a similar preparation method to that of intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was changed to 3-bromo-1-isopropylpyrazole). LC/MS (ESI) m/z =224.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (pyrazin-2-yl) -2-chloro-thiophenol

The compound 3- (pyrazin-2-yl) -2-chloro-thiophenol was obtained using a similar preparation to that for the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was 3-bromo-1-isopropylpyrazole). LC/MS (ESI) m/z =224.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (pyridin-3-yl) -2-chloro-thiophenol

The compound 3- (pyridin-2-yl) -2-chloro-thiophenol was obtained using a similar preparation to that for the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was 3-bromo-1-isopropylpyrazole). LC/MS (ESI) m/z =222.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (pyrimidin-4-yl) -2-chloro-thiophenol

The compound 3- (pyrimidin-4-yl) -2-chloro-thiophenol was obtained using a preparation method similar to that for the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was changed to 3-bromo-1-isopropylpyrazole). LC/MS (ESI) m/z =224.0[ m + H ]] ⁺ .

Preparation of intermediate ethyl 2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxylate

Compound 4c (4.64g, 20mmol) and 2-aminopyridine (0.94g, 10mmol) were dissolved in 40mL of xylene, and the reaction mixture was heated to 120 ℃ and stirred for 16 hours. Cooling to room temperature, filtering, washing the filter cake with methanol for 3 times, and drying to obtain the compound 2-hydroxy-4-oxo-pyridine [1,2-a]And pyrimidine-3-carboxylic acid ethyl ester (0.58 g, 25% yield). LC/MS (ESI) m/z =235.1[ 2 ] M + H] ⁺ .

Under the protection of nitrogen, the compound 2-hydroxy-4-oxo-pyridine [1,2-a]Ethyl pyrimidine-3-carboxylate (468mg, 2mmol) was dissolved in 4mL of methanol, and then palladium on carbon (40 mg) was added thereto and the mixture was replaced with hydrogen gas for 3 times, followed by stirring at room temperature for 2 hours. Filtering, concentrating under reduced pressure to obtain compound 2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine [1,2-a]Ethyl pyrimidine-3-carboxylate (452 mg, 95% yield). LC/MS (ESI) m/z =239.1[ 2 ] M + H] ⁺ .

Preparation of intermediate 3-amino-2-chloro-thiophenol

Dissolving the compound 3- (3- (tert-butylmercapto) -2-chloroaniline (10g, 46.4 mmol) in 100mL of concentrated hydrochloric acid, heating to 55 ℃, stirring for reaction overnight, cooling to room temperature, quenching sodium bicarbonate to neutrality, extracting the aqueous phase with ethyl acetate, washing the obtained organic phase with saturated saline solution, drying with anhydrous sodium sulfate, evaporating the organic phase under reduced pressure, purifying the residue by column chromatography to obtain the compound 3-amino-2-chloro-thiophenol (4.9 g, yield 66%). LC/MS (ESI): m/z =160.0 and M + H] ⁺ .

Preparation of intermediate 3- (pyridine-4-amino) -2-chloro-thiophenol

Compound 3-chloropyridine (1.14g, 10mmol) was dissolved in 15mL of toluene, and sodium t-butoxide (1.15g, 12mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (60 mg) was added thereto, and the mixture was purged with nitrogen 3 times, followed by addition of tris (dibenzylideneacetone) dipalladium (85 mg), followed by reflux reaction with stirring for 2 hours. Cooled to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound N- (3-tert-butylmercapto) -2-chloropyridin-3-amine (1.52 g, 52% yield). LC/MS (ESI) that m/z =293.1[ 2[ M ] +H] ⁺ .

The compound N- (3-tert-butylmercapto) -2-chloropyridin-3-amine (1.17g, 4 mmol) was dissolved in 30mL of concentrated hydrochloric acid and reacted at 50 ℃ for 2 hours. Cool to room temperature, quench sodium bicarbonate to neutral, and extract the aqueous phase with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 3- (pyridin-4-amino) -2-chloro-thiophenol (0.66 g, yield 70%). LC/MS (ESI): m/z＝237.0[M+H] ⁺ .

Preparation of intermediate 3- (pyrimidine-2-amino) -2-chloro-thiophenol

The compound 3- (pyrimidine-2-amino) -2-chloro-thiophenol is obtained by a preparation method similar to that of the intermediate 3- (pyridine-4-amino) -2-chloro-thiophenol (the raw material is 2-chloropyrimidine). LC/MS (ESI) m/z =239.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (pyrazine-4-amino) -2-chloro-thiophenol

The compound 3- (pyrazine-2-amino) -2-chloro-thiophenol is obtained by a preparation method similar to that of the intermediate 3- (pyridine-4-amino) -2-chloro-thiophenol (the raw material is 2-chloropyrazine). LC/MS (ESI) m/z =239.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (pyrimidine-4-amino) -2-chloro-thiophenol

The compound 3- (pyrimidine-4-amino) -2-chloro-thiophenol is obtained by a preparation method similar to that of the intermediate 3- (pyridine-4-amino) -2-chloro-thiophenol (the raw material is 4-chloropyrimidine). LC/MS (ESI) m/z =239.0[ m + H ]] ⁺ .

Preparation of intermediate (3S, 4S) -8- (5-chloropyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

2-chloro-5-iodopyrimidine (7.2g, 30mmol) was dissolved in 50mL of dichloromethane, and (3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] was added]Decane dihydrochloride (7.3g, 30m)mol), triethylamine (9.11g, 90mmol), and the reaction was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (3S, 4S) -8- (5-chloropyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5%]Decan-4-amine (5.34 g, 63% yield). LC/MS (ESI) that m/z =283.1[ 2[ M ] +H] ⁺ .

Preparation of intermediate (3S, 4S) -8- (6-chloropyridazin-3-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

2,6-dichloropyridazine (4.47g, 30mmol) was dissolved in 50mL of dichloromethane and (3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] was added]Decane dihydrochloride (7.3g, 30mmol), triethylamine (9.11g, 90mmol), and the reaction stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (3S, 4S) -8- (6-chloropyridazin-3-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5%]Decan-4-amine (5.77 g, 68% yield). LC/MS (ESI) that m/z =283.1[ 2[ M ] +H] ⁺ .

Preparation of intermediate (3S, 4S) -8- (6-chlorotetraoxazin-3-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

2,6-dichloropyromellizine (4.5g, 30mmol) was dissolved in 50mL of dichloromethane and (3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5%]Decane dihydrochloride (7.3g, 30mmol), triethylamine (9.11g, 90mmol), and the reaction stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound (3S, 4S) -8- (6-chlorotetrazin-3-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5%]Decan-4-amine (6.24 g, 73% yield))。LC/MS(ESI):m/z＝285.1[M+H] ⁺ .

Preparation of intermediate (3S, 4S) -8- (3-chloro-1,2,4-triazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

2,6-dichloro-1,2,4-triazine (4.5g, 30mmol) was dissolved in 50mL of methylene chloride, and (3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decane dihydrochloride (7.3g, 30mmol), triethylamine (9.11g, 90mmol), and the reaction was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (3S, 4S) -8- (6-chloro-1,2,4-triazin-3-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5%]Decan-4-amine (5.77 g, 68% yield). LC/MS (ESI) m/z =284.1[ 2[ M ] +H] ⁺ .

Preparation of intermediate N- (2-chloro-3-mercaptophenyl) pyrimidine-2-carboxamide

Adding pyrimidine-2-carboxylic acid (620mg, 5 mmol) to thionyl chloride 10mL, stirring at reflux for 2 hours, concentrating under reduced pressure to give acid chloride, adding dichloromethane 15mL, pyridine (593 mg,7.5 mmol), 3- (tert-butylmercapto) -2-chloroaniline (539mg, 2.5 mmol), 4-dimethylaminopyridine (153mg, 1.25mmol) to the acid chloride, stirring at room temperature for reaction for 2 hours, quenching with water, extracting with dichloromethane, washing the resulting organic phase with saturated brine, drying over anhydrous sodium sulfate, evaporating the organic phase under reduced pressure, and purifying the residue by column chromatography to give the compound N- (2-chloro-3- (3- (tert-butylmercapto) phenyl) pyrimidine-2-carboxamide (627 mg, yield 78%). LC/MS (ESI): m/z =322.1, [ M + H ], [ m/z =322.1 ]] ⁺ .

Dissolving the compound N- (2-chloro-3- (3- (tert-butylmercapto) phenyl) pyrimidine-2-formamide (578mg, 1.8mmol) in concentrated hydrochloric acid 30mL, reacting at 50 ℃ for 2 hours, cooling to room temperature, and quenching sodium bicarbonate toThe neutral, aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound N- (2-chloro-3-mercaptophenyl) pyrimidine-2-carboxamide (0.27 g, 56% yield). LC/MS (ESI) m/z =267.0[ m + H ]] ⁺ .

Preparation of intermediate N- (2-chloro-3-mercaptophenyl) pyrimidine-4-carboxamide

The compound N- (2-chloro-3-mercaptophenyl) pyrimidine-4-carboxamide is obtained by a similar preparation method (the raw material is replaced by pyrimidine-4-carboxylic acid) as the intermediate N- (2-chloro-3-mercaptophenyl) pyrimidine-2-carboxamide. LC/MS (ESI) m/z =267.0[ m + H ]] ⁺ .

Preparation of intermediate N- (2-chloro-3-mercaptophenyl) -2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide

The compound 3- (3- (tert-butylmercapto) -2-chloroaniline (1.08g, 5 mmol) and the compound 2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine [1,2-a]Ethyl pyrimidine-3-carboxylate (1.43g, 6 mmol) was dissolved in 20mL of chlorobenzene, and the reaction was stirred under reflux for 3 hours. Cooling to room temperature, filtering and drying to obtain the compound N- (3- (tert-butylmercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine [1,2-a]And pyrimidine-3-carboxamide (1.18 g, 58% yield). LC/MS (ESI) m/z =408.1[ 2 ] M + H] ⁺ .

The compound N- (3- (tert-butylmercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine [1,2-a]The 3-pyrimidinecarboxamide (1.02g, 2.5 mmol) was dissolved in 10mL of concentrated hydrochloric acid, and the reaction mixture was heated to 50 ℃ and stirred for 3 hours. Cool to room temperature, quench sodium bicarbonate to neutral, extract the aqueous phase with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue is passed throughPurifying by column chromatography to obtain N- (2-chloro-3-mercaptophenyl) -2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine [1,2-a]And pyrimidine-3-carboxamide (0.57 g, 65% yield). LC/MS (ESI) m/z =353.0[ M + H ]] ⁺ .

Example 1

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (1)

The compound 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (674mg, 3mmol) was dissolved in 8mL of ethanol, and 2-chloro-5-iodopyrimidine (864mg, 3.6 mmol) and sodium ethoxide (408mg, 6.0mmol) were added. The reaction was refluxed overnight with stirring. Cooled to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The resulting organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give intermediate 2- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) -5-iodopyrimidine (304 mg, yield 43%). LC/MS (ESI) m/z =471.2[ m + H ]] ⁺ .

The compound 2- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) -5-iodopyrimidine (506mg, 1.5mmol) was dissolved in 10mL of N, N-dimethylformamide, and (3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] was added]Decane dihydrochloride (438mg, 1.8mmol), potassium carbonate (829mg, 6.0mmol). The reaction was carried out at 120 ℃ for 6 hours with stirring. Cooled to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the objective product 1 (304 mg, yield 43%). ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.31(s,2H),7.78(d,1H),7.51(d,1H),7.23(t,1H),6.83(d,1H),6.60(d,1H),4.13-4.09(m,1H),3.92-3.75(m,5H),3.65(d,1H),3.47(d,1H),3.32-3.25(m,2H),2.90(d,1H),1.77-1.32(m,6H),1.13(d,3H)；LC/MS(ESI):m/z＝471.2[M+H] ⁺ .

Example 2

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-ethyl-1H-pyrazol-3-yl) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (2)

Compound 2 (327 mg, yield 45%, this is the final yield, the same below) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.31(s,2H),7.72(d,1H),7.51(d,1H),7.23(t,1H),6.83(d,1H),6.58(d,1H),4.13-4.09(m,1H),3.94-3.77(m,5H),3.65(d,1H),3.47(d,1H),3.32-3.25(m,2H),2.90(d,1H),1.77-1.33(m,6H),1.28(t,3H),1.13(d,3H)；LC/MS(ESI):m/z＝485.2[M+H] ⁺ .

Example 3

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-isopropyl-1H-pyrazol-3-yl) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (3)

Compound 3 (381 mg, 51% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.31(s,2H),7.70(s,1H),7.51(d,1H),7.23(t,1H),6.83(d,1H),6.54(d,1H),4.14-4.07(m,2H),3.92-3.75(m,5H),3.65(d,1H),3.47(d,1H),3.32-3.25(m,2H),2.90(d,1H),1.77-1.32(m,12H),1.13(d,3H)；LC/MS(ESI):m/z＝499.2[M+H] ⁺ .

Example 4

Preparation of N- (3- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-2-yl) mercapto) -2-chlorobenzene) -2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (4)

The compound 3-amino-2-chloro-thiophenol (3.19g, 20mmo)l) was dissolved in 60mL of dimethyl sulfoxide, followed by addition of 2-chloro-5-iodopyrimidine (4.8g, 20mmol) and cesium carbonate (13.0g, 40mmol), heating to 80 ℃ and stirring for reaction for 6 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 2-chloro-3- ((5-iodopyrimidin-2-yl) mercapto) aniline (2.45 g, 45% yield). LC/MS (ESI) m/z =272.0[ m + H ]] ⁺ .

The compound 2-hydroxy-4-oxo-pyridine [1,2-a]Ethyl pyrimidine-3-carboxylate (408mg, 1.5mmol) and the compound 2-chloro-3- ((5-iodopyrimidin-2-yl) mercapto) aniline (429mg, 1.8mmol) were dissolved in chlorobenzene 5mL, heated to 130 ℃ and reacted with stirring for 5 hours. Cooling to room temperature, filtering and drying to obtain the compound N- (2-chloro-3- ((5-iodopyrimidin-2-yl) mercapto) phenyl) -2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridine [1,2-a]Pyrimidine-3-carboxamide (474 mg, 68% yield). LC/MS (ESI) m/z =464.0[ m + H ]] ⁺ .

The compound N- (2-chloro-3- ((5-iodopyrimidin-2-yl) mercapto) phenyl) -2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridine [1,2-a]Pyrimidine-3-carboxamide (464mg, 1mmol) was dissolved in 4mL of N, N-dimethylformamide and (3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] was added]Decane dihydrochloride (292mg, 1.2mmol) and potassium carbonate (553mg, 4.0 mmol) were reacted at 120 ℃ for 8 hours with stirring. Cooled to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the objective product 4 (191 mg, yield 32%). ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.5(br s,1H),8.35-8.23(m,3H),7.23(s,1H),6.58(d,1H),5.54(br s,3H),4.13-4.09(m,1H),3.92-3.55(m,7H),3.32-3.25(m,3H),2.92(d,1H),1.82-1.43(m,8H),1.13(d,3H)；LC/MS(ESI):m/z＝598.2[M+H] ⁺ .

Example 5

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrimidin-5-yl) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (5)

Compound 5 (205 mg, 38% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:9.22(s,1H),8.89(s,2H),8.31(s,2H),7.50(d,1H),7.21(t,1H),6.86(d,1H),4.13-4.09(m,1H),3.94-3.75(m,5H),3.65(d,1H),3.47(d,1H),3.32-3.25(m,2H),2.90(d,1H),1.77-1.33(m,3H),1.13(d,3H)；LC/MS(ESI):m/z＝469.1[M+H] ⁺ .

Example 6

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrazin-2-yl) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (6)

Compound 6 (189 mg, 35% yield) was obtained in a similar manner to example 5. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.81(s,1H),8.75(s,2H),8.31(s,2H),7.50(d,1H),7.21(t,1H),6.86(d,1H),4.13-4.09(m,1H),3.94-3.75(m,5H),3.65(d,1H),3.47(d,1H),3.32-3.25(m,2H),2.90(d,1H),1.77-1.33(m,3H),1.13(d,3H)；LC/MS(ESI):m/z＝469.1[M+H] ⁺ .

Example 7

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyridin-3-yl) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (7)

Compound 7 (327 mg, 42% yield) was obtained in a similar manner to example 5. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.85(s,1H),8.70(d,1H),8.32-8.30(m,3H),7.53-7.50(m,2H),7.21(t,1H),6.86(d,1H),4.13-4.09(m,1H),3.94-3.75(m,5H),3.65(d,1H),3.47(d,1H),3.32-3.25(m,2H),2.90(d,1H),1.77-1.33(m,3H),1.13(d,3H)；LC/MS(ESI):m/z＝468.2[M+H] ⁺ .

Example 8

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrimidin-4-yl) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (8)

Compound 8 (216 mg, 40% yield) was obtained in a similar manner to example 5. ¹ H NMR(400MHz,DMSO-d ₆ )δ:9.23(s,1H),8.85(d,1H),8.31(s,2H),8.12(d,1H),7.50(d,1H),7.21(t,1H),6.86(d,1H),4.13-4.09(m,1H),3.94-3.75(m,5H),3.65(d,1H),3.47(d,1H),3.32-3.25(m,2H),2.90(d,1H),1.77-1.33(m,3H),1.13(d,3H)；LC/MS(ESI):m/z＝469.1[M+H] ⁺ .

Example 9

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyridin-3-ylamino) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (9)

The compound 3- (pyridin-4-ylamino) -2-chloro-thiophenol (592mg, 2.5mmol) was dissolved in 6mL of methanol, and 2-chloro-5-iodopyrimidine (720mg, 3mmol) and potassium carbonate (830mg, 6.0mmol) were added thereto, and the reaction was refluxed for 5 hours with stirring. Cooled to room temperature, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound N- (2-chloro-3- ((5-iodopyrimidin-2-yl) mercapto) phenyl) pyridin-3-amine (463 mg, 53% yield). LC/MS (ESI) m/z =349.0[ m + H ]] ⁺ .

The compound N- (2-chloro-3- ((5-iodopyrimidin-2-yl) mercapto) phenyl) pyridin-3-amine (419mg, 1.2mmol) was dissolved in 5mL of N-methylpyrrolidinone and (3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] added]Decane dihydrochloride (365mg, 1.5mmol) and triethylamine (486mg, 4.8mmol) were reacted at 120 ℃ overnight with stirring. Cooled to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. Washing the obtained organic phase with water and saturated brine, drying with anhydrous sodium sulfate, and collecting organic phaseThe phases are evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the objective product 9 (203 mg, yield 35%). ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.43(s,1H),8.32-8.25(m,3H),7.63-7.03(m,5H),6.05(s,1H),4.13-4.09(m,1H),3.94-3.75(m,5H),3.65(d,1H),3.46(d,1H),3.33-3.25(m,2H),2.90(d,1H),1.77-1.34(m,3H),1.13(d,3H)；LC/MS(ESI):m/z＝483.2[M+H] ⁺ .

Example 10

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrimidin-2-ylamino) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (10)

Compound 10 (186 mg, 32% yield) was obtained in a similar manner to example 9. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.45(d,2H),8.30-8.22(m,3H),7.52-7.03(m,3H),6.17(s,1H),4.14-4.09(m,1H),3.95-3.75(m,5H),3.65(d,1H),3.46(d,1H),3.33-3.25(m,2H),2.92(d,1H),1.77-1.34(m,3H),1.13(d,3H)；LC/MS(ESI):m/z＝484.2[M+H] ⁺ .

Example 11

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrazin-2-amino) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (11)

Compound 11 (174 mg, 30% yield) was obtained in a similar manner to example 9. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.40-8.35(m,3H),8.28(s,2H),7.52-7.09(m,3H),6.23(s,1H),4.14-4.09(m,1H),3.92-3.75(m,5H),3.64(d,1H),3.46(d,1H),3.35-3.25(m,2H),2.92(d,1H),1.77-1.34(m,3H),1.13(d,3H)；LC/MS(ESI):m/z＝484.2[M+H] ⁺ .

Example 12

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrimidin-4-ylamino) phenyl) mercapto) pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (12)

Compound 12 (186 mg, 32% yield) was obtained in a similar manner to example 9. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.43(s,1H),8.40(d,1H),8.29(s,2H),7.52-6.93(m,4H),6.05(s,1H),4.13-4.09(m,1H),3.94-3.75(m,5H),3.65(d,1H),3.46(d,1H),3.33-3.24(m,2H),2.88(d,1H),1.79-1.34(m,3H),1.13(d,3H)；LC/MS(ESI):m/z＝484.2[M+H] ⁺ .

Example 13

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (13)

The compound (3S, 4S) -8- (5-chloropyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decane-4-amine (1.13g, 4 mmol) was dissolved in 1,4-dioxane 10mL, and the compounds 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (1.08g, 4.8mmol), potassium tert-butoxide (0.67g, 6.0mmol), cuprous iodide (76mg, 0.4mmol) and nitrogen were added thereto and the reaction was refluxed for 24 hours with stirring. Cooling to room temperature, passing the reaction solution through a silica gel short column, leaching with ethyl acetate, and evaporating to dryness under reduced pressure. The residue was purified by column chromatography to give compound 13 (810 mg, yield 43%). ¹ H NMR(400MHz,DMSO-d6)δ:8.33(s,2H),7.77(d,1H),7.51(d,1H),7.23(t,1H),6.83(d,1H),6.58(d,1H),4.13-4.09(m,1H),3.94-3.75(m,5H),3.63(d,1H),3.47(d,1H),3.34-3.25(m,2H),2.92(d,1H),1.77-1.32(m,6H),1.15(d,3H)；LC/MS(ESI):m/z＝471.2[M+H] ⁺ .

Example 14

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (1-ethyl-1H-pyrazol-3-yl) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (14)

Compound 14 (912 mg, 47% yield) was obtained in a similar manner to example 13. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.32(s,2H),7.77(d,1H),7.52(d,1H),7.23(t,1H),6.85(d,1H),6.57(d,1H),4.13-4.09(m,1H),3.98-3.77(m,5H),3.65(d,1H),3.49(d,1H),3.34-3.25(m,2H),2.90(d,1H),1.78-1.33(m,6H),1.28(t,3H),1.15(d,3H)；LC/MS(ESI):m/z＝485.2[M+H] ⁺ .

Example 15

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (1-isopropyl-1H-pyrazol-3-yl) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (15)

Compound 15 (799 mg, 40% yield) was obtained in a similar manner to example 13. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.32(s,2H),7.78(s,1H),7.51(d,1H),7.23(t,1H),6.83(d,1H),6.57(d,1H),4.14-4.07(m,2H),3.97-3.74(m,5H),3.64(d,1H),3.47(d,1H),3.34-3.25(m,2H),2.90(d,1H),1.79-1.32(m,12H),1.15(d,3H)；LC/MS(ESI):m/z＝499.2[M+H] ⁺ .

Example 16

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-5-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (16)

The compound (3S, 4S) -8- (5-iodopyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decane-4-amine (748mg, 2mmol) was dissolved in 1,4-dioxane 6mL, and the compound N- (2-chloro-3-mercaptophenyl) -2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine [1,2-a ] was added]And pyrimidine-3-carboxamide (504mg, 2.4mmol), potassium tert-butoxide (335mg, 3mmol), cuprous iodide (38mg, 0.2mmol), nitrogen was substituted for 3 times, and the reaction was refluxed for 24 hours with stirring. Cooling to room temperature, passing the reaction solution through a silica gel short column, leaching with ethyl acetate, and evaporating to dryness under reduced pressure. The residue was purified by column chromatography to give compound 16 (538 mg, yield 45%). ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.7(br s,1H),8.35-8.23(m,3H),7.24(s,1H),6.59(d,1H),5.52(br s,3H),4.13-4.09(m,1H),3.92-3.55(m,7H),3.32-3.25(m,3H),2.93(d,1H),1.87-1.35(m,8H),1.15(d,3H)；LC/MS(ESI):m/z＝598.2[M+H] ⁺ .

Example 17

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (pyrimidin-5-yl) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (17)

Compound 17 (441 mg, 47% yield) was obtained in a similar manner to the last step of example 16. ¹ H NMR(400MHz,DMSO-d ₆ )δ:9.22(s,1H),8.90(s,2H),8.33(s,2H),7.51(d,1H),7.21(t,1H),7.06(d,1H),4.13-4.09(m,1H),3.94-3.45(m,7H),3.34-3.25(m,2H),2.90(d,1H),1.81-1.33(m,3H),1.13(d,3H)；LC/MS(ESI):m/z＝469.1[M+H] ⁺ .

Example 18

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (pyrazin-2-yl) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (18)

Compound 18 (422 mg, 45% yield) was obtained in a similar manner to the last step of example 16. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.80(s,1H),8.75(s,2H),8.32(s,2H),7.51(d,1H),7.23(t,1H),7.05(d,1H),4.13-4.09(m,1H),3.94-3.43(m,7H),3.32-3.23(m,2H),2.91(d,1H),1.79-1.33(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝469.1[M+H] ⁺ .

Example 19

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (pyridin-3-yl) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (19)

Compound 19 (393 mg, 42% yield) was obtained in a similar manner to the last step of example 16. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.87(s,1H),8.71(d,1H),8.34-8.30(m,3H),7.55-7.51(m,2H),7.22(t,1H),7.04(d,1H),4.13-4.08(m,1H),3.94-3.45(m,7H),3.31-3.25(m,2H),2.91(d,1H),1.78-1.31(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝468.2[M+H] ⁺ .

Example 20

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (pyrimidin-4-yl) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (20)

Compound 20 (431 mg, 46% yield) was obtained in a similar manner to the last step of example 16. ¹ H NMR(400MHz,DMSO-d ₆ )δ:9.25(s,1H),8.86(d,1H),8.32(s,2H),8.12(d,1H),7.51(d,1H),7.22(t,1H),7.06(d,1H),4.13-4.10(m,1H),3.94-3.45(m,7H),3.32-3.25(m,2H),2.90(d,1H),1.78-1.31(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝469.1[M+H] ⁺ .

Example 21

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (pyridin-3-ylamino) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (21)

Compound 21 (347 mg, 36% yield) was obtained in a similar manner to the last step of example 16. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.43(s,1H),8.35-8.25(m,3H),7.58-6.89(m,5H),6.11(s,1H),4.13-4.09(m,1H),3.94-3.45(m,7H),3.33-3.25(m,2H),2.91(d,1H),1.76-1.32(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝483.2[M+H] ⁺ .

Example 22

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (pyrimidin-2-ylamino) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (22)

Compound 22 (386 mg, 40% yield) was obtained in a similar manner to the last step of example 16. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.46(d,2H),8.33(s,2H),8.05(d,1H),7.32-6.95(m,3H),6.15(s,1H),4.14-4.10(m,1H),3.95-3.45(m,7H),3.33-3.25(m,2H),2.93(d,1H),1.75-1.31(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝484.2[M+H] ⁺ .

Example 23

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (pyrazin-2-amino) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (23)

Compound 23 (405 mg, 42% yield) was obtained in a similar manner to the last step of example 16. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.41-8.35(m,3H),8.31(s,2H),7.41-6.94(m,3H),6.21(s,1H),4.14-4.10(m,1H),3.92-3.75(m,5H),3.64(d,1H),3.46(d,1H),3.35-3.25(m,2H),2.92(d,1H),1.75-1.31(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝484.2[M+H] ⁺ .

Example 24

Preparation of (3S, 4S) -8- (5- ((2-chloro-3- (pyrimidin-4-ylamino) phenyl) mercapto) pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (24)

Compound 24 (424 mg, 44% yield) was obtained in a similar manner to the last step of example 16. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.43(s,1H),8.41(d,1H),8.31(s,2H),7.64-6.93(m,4H),6.12(s,1H),4.15-4.11(m,1H),3.93-3.45(m,7H),3.33-3.23(m,2H),2.90(d,1H),1.74-1.31(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝484.2[M+H] ⁺ .

Example 25

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-5-yl) mercapto) -2-chlorophenyl) pyrimidine-2-carboxamide (25)

The subsequent two steps gave compound 25 (266 mg, 52% yield) in a similar manner to the last two steps of example 16. ¹ H NMR(400MHz,DMSO-d ₆ )δ:9.93(s,1H),8.91(d,2H),8.31(s,2H),7.64-6.93(m,4H),4.15-4.11(m,1H),3.93-3.45(m,7H),3.33-3.23(m,2H),2.90(d,1H),1.74-1.31(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝512.2[M+H] ⁺ .

Example 26

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-5-yl) mercapto) -2-chlorophenyl) pyrimidine-4-carboxamide (26)

Using a method similar to example 25 (starting material was changed to pyrimidine-4-carboxylic acid), compound 26 (282 mg, yield 55%) was obtained. ¹ H NMR(400MHz,DMSO-d ₆ )δ:9.88(s,1H),9.31(s,1H),9.01(d,1H),8.31(s,2H),8.21(d,1H),7.75(d,1H),7.42(t,1H),7.15(d,1H),4.15-4.11(m,1H),3.93-3.45(m,7H),3.33-3.23(m,2H),2.90(d,1H),1.74-1.31(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝512.2[M+H] ⁺ .

Example 27

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-5-yl) mercapto) -2-chlorophenyl) pyridine-2-carboxamide (27)

In a similar manner to example 25 (starting material was changed to pyridine-2-carboxylic acid), compound 27 (245 mg, yield 48%) was obtained. ¹ H NMR(400MHz,DMSO-d ₆ )δ:10.02(s,1H),8.61-8.59(m,1H),8.32-8.30(m,3H),7.75-7.55(m,3H),7.44-7.39(m,1H),7.14-7.03(m,1H),4.15-4.11(m,1H),3.93-3.45(m,7H),3.32-3.21(m,2H),2.90(d,1H),1.73-1.30(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝511.2[M+H] ⁺ .

Example 28

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-5-yl) mercapto) -2-chlorophenyl) pyrazine-2-carboxamide (28)

In a similar manner to example 25 (starting material was changed to pyrazine-2-carboxylic acid), compound 28 (261 mg, 51% yield) was obtained. ¹ H NMR(400MHz,DMSO-d ₆ )δ:9.68(s,1H),9.51(s,1H),8.81(d,1H),8.55-8.52(m,1H),8.31(s,2H),7.71-7.62(m,1H),7.43-7.39(m,1H),7.15(d,1H),4.15-4.11(m,1H),3.93-3.45(m,7H),3.33-3.23(m,2H),2.90(d,1H),1.74-1.31(m,3H),1.15(d,3H)；LC/MS(ESI):m/z＝512.2[M+H] ⁺ .

Example 29

Preparation of (3S, 4S) -8- (3- ((2-chloro-3- (1-ethyl-1H-pyrazol-3-yl) phenyl) mercapto) pyridazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (29)

Compound 29 (320 mg, yield 44%, this is the final yield, the same applies below) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =486.2[ 2 ], [ M + H ]] ⁺ .

Example 30

Preparation of (3S, 4S) -8- (3- ((2-chloro-3- (1-ethyl-1H-pyrazol-3-yl) phenyl) mercapto) s-tetrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (30)

Compound 30 (358 mg, yield 49%, this is the final yield, the same below) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =488.2[ 2 ], [ M + H ]] ⁺ .

Example 31

Preparation of (3S, 4S) -8- (3- ((2-chloro-3- (1-ethyl-1H-pyrazol-3-yl) phenyl) mercapto) -1,2,4-triazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (31)

Compound 31 (350 mg, yield 48%, this is the final yield, the same applies below) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =487.2[ 2 ], [ M + H ]] ⁺ .

Example 32

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -1,2,4-triazin-6-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (32)

Compound 32 (299 mg, yield 41%, this is the last step yield, the same applies to below) was obtained in a similar manner to example 16. LC/MS (ESI) m/z =600.2[ m + H ]] ⁺ .

Example 33

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (1-ethyl-1H-pyrazol-3-yl) phenyl) mercapto) -1,2,4-triazin-3-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (33)

Compound 33 (283 mg, 39% yield, which is the final yield, the same applies to below) was obtained in a similar manner to example 16. LC/MS (ESI) m/z =487.2[ M + H ]] ⁺ .

Example 34

Preparation of (3S, 4S) -8- (3- ((2-chloro-3- (pyrazin-2-yl) phenyl) mercapto) pyridazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (34)

Compound 34 (200 mg, 37% yield) was obtained in a similar manner to example 5. LC/MS (ESI) m/z =470.1[ m + H ]] ⁺ .

Example 35

Preparation of (3S, 4S) -8- (3- ((2-chloro-3- (pyrazin-2-yl) phenyl) mercapto) s-tetrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (35)

Compound 35 (211 mg, 39% yield) was obtained in a similar manner to example 5. LC/MS (ESI) m/z =472.1[ m + H ]] ⁺ .

Example 36

Preparation of (3S, 4S) -8- (3- ((2-chloro-3- (pyrazin-2-yl) phenyl) mercapto) -1,2,4-triazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (36)

Compound 36 (227 mg, yield 42%) LC/MS (ESI) of m/z =471.1[ 2M + H ] is obtained in a similar manner to example 5] ⁺ .

Example 37

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (pyrazin-2-yl) phenyl) mercapto) -1,2,4-triazin-3-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (37)

Compound 37 (384 mg, 41% yield) was obtained in a similar manner to the last step of example 16. LC/MS (ESI) m/z =471.1[ m + H ]] ⁺ .

Example 38

Preparation of N- (3- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyridazin-3-yl) mercapto) -2-chlorobenzene) -2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (38)

Compound 38 (197 mg, 32% yield) was obtained in a similar manner to example 4. LC/MS (ESI) m/z =499.1[ m + H ]] ⁺ .

Example 39

Preparation of N- (3- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) s-tetrazin-3-yl) mercapto) -2-chlorobenzene) -2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (40)

Compound 39 (159 mg, 25% yield) was obtained in a similar manner to example 4. LC/MS (ESI) m/z =601.1[ 2 ] M + H] ⁺ .

Example 40

Preparation of N- (3- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -1,2,4-triazin-3-yl) mercapto) -2-chlorobenzene) -2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (40)

Compound 40 (178 mg, 29% yield) was obtained in a similar manner to example 4. LC/MS (ESI) m/z =600.1[ 2 ] M + H] ⁺ .

Example 41 biological Activity assay

The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.

Experiment for inhibition of SHP2 allosteric

Determination of the inhibition of SHP-2 kinase Activity by Compounds

Experiment for inhibition of SHP2 allosteric

Determination of SHP-2 kinase Activity inhibition by Compounds

The purpose of this test was to measure the inhibitory ability of compounds on the allosteric activity of the full-length SHP-2 protein.

An experimental instrument: the centrifuge (5810R) is purchased from Eppendorf corporation, the pipettor is purchased from Eppendor Domain Rainin corporation, and the microplate reader is purchased from BioTek corporation, USA, and the model is SynergyHl full-function microplate reader.

The experimental method comprises the following steps: in vitro SHP-2 activity assays were performed using the Homogeneous Full Length SHP-2 Assay Kit (BPS Bioscience, # 79330). 18 μ L of Master Mix, i.e. 0.5 μ M SHP-2 activating Peptide and 5mM DTT in a reaction buffer solution with a final concentration of 1 × was added to a 96-well low adsorption microplate (NUNC, # 267342), 5 μ L of test compound/DMSO per well (final DMSO content 1%, V/V, test compound dissolved in DMSO as ImM, three-fold serial dilutions, 10 concentrations, reaction system final concentration ranging from 1 μ M to 0.05 nM) was added after centrifugation, SHP-2 was diluted to a final concentration of 0.06nM in 1X reaction buffer solution, 2 μ L per well was added to the reaction microplate, and the reaction mixture was centrifuged at room temperature after setting a full activity control (compound plus DMSO only) and a full inhibition control (without SHP-2) on the reaction plate for 60 minutes.

After the incubation was complete, 25. Mu.L of Substrate solution containing Substrate at a final concentration of 10. Mu.M and 5mM DTT was added to each well and incubation continued for 30 minutes at room temperature after centrifugation. After the reaction is finished, the excitation wavelength is set to be 340nM, the emission wavelength is set to be 455nM, and the gain value is set to be 75 for reading on a Synergy H1 full-function microplate reader (Biotek).

The experimental data processing method comprises the following steps:

the percent inhibition ratio data {% inhibition =100- [ (test compound-Min average)/(Max average-Min average) ] X100} for wells treated with compound was calculated from the values of full activity control and full inhibition control as Max and Min by positive control wells (DMSO control wells) and negative control wells (no kinase added) on the reaction plate. IC50 values for test compounds were calculated using GraphPad prism to fit the percent inhibition and ten-point concentration data to a 4-parameter nonlinear logistic formula.

And (4) experimental conclusion:

it was concluded from the above protocol that the compounds of the examples shown in the present invention show biological activities in the SHP-2 kinase activity assay as shown in table 1 below. Wherein "A" represents IC ₅₀ Less than or equal to 10nM; "B" means 10<IC ₅₀ Less than or equal to 100nM; "C" means 100<IC ₅₀ Less than or equal to 1000nM; "D" denotes 1000<IC ₅₀ nM。

IC inhibition of SHP2 by Compounds of Table 1 ₅₀ Value of

Numbering	IC ₅₀	Numbering	IC ₅₀	Number of	IC ₅₀
						1	A	15	B	29	A
2	A	16	B	30	A
						3	A	17	A	31	A
4	A	18	A	32	A
						5	A	19	A	33	A
6	A	20	A	34	A
						7	A	21	A	35	A
8	A	22	A	36	A
						9	B	23	A	37	A
10	B	24	A	38	A
						11	B	25	A	39	A
12	B	26	A	40	A
						13	B	27	A
14	B	28	A

Claims

1. A compound having the general formula (I) and the general formula (II) or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, polymorph or isomer thereof,

wherein:

each Ar ₁ Independently at each occurrence is selected from

each Ar ₃ Independently at each occurrence selected from H, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence comprising 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₃ Optionally at each occurrence independently by 1,2, 3, 4,5 or 6R ₁₉ Substituted or unsubstituted;

Each R ₅ Independently at each occurrence selected from H, deuterium, OH, C _1-6 Alkyl radical, C _1-6 Alkyl substituted by 1,2, 3, 4,5 or 6 deuterium, OH, methyl, OCH ₃ 5-10 membered heteroaryl;

R ₂ and R ₃ Can adopt NH ₂ Substituted alkylene groups are linked to form a spiro ring,

R ₄ and R ₅ Can be connected to form C _3-12 Cycloalkyl of, C _3-12 Heterocycloalkyl of (A), C _3-12 Bicycloalkyl of, C _3-12 In which C is _3-12 Heterocycloalkyl of (A), C _3-12 Each occurrence of heterobicycloalkyl is independentlyContaining 1,2, 3 or 4 heteroatoms selected from N, O, or S, each C _3-12 Cycloalkyl of, C _3-12 Heterocycloalkyl of (C) _3-12 Bicycloalkyl of, C _3-12 Independently at each occurrence, optionally deuterium, halogen, OH, CH ₃ 、OCH ₃ 、NH ₂ The substitution forms a spiro ring,

R ₂ and R ₆ May be linked through an alkylene group to form bridged bicyclic rings,

each a, b, c, d is independently selected at each occurrence from 0, 1.

2. The compound of (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein,

selected from the following structures:

3. a compound of (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein Ar ₂ Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence comprising 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₃ Is optionally independently at each occurrence1.2, 3, 4,5 or 6R ₁₉ Substituted or unsubstituted;

each Ar ₃ Independently at each occurrence selected from H, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence comprising 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₂ Optionally at each occurrence independently by 1,2, 3, 4,5 or 6R ₁₉ Substituted or unsubstituted;

each R ₁₀ And R ₁₁ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-6 Alkyl radical, each R ₁₀ And R ₁₁ Independently optionally substituted by 1,2, 3, 4,5 or 6R ₁₉ Substituted or unsubstituted; or R ₁₀ And R ₁₁ Together with the N atom to which they are jointly attached form3-10 membered heterocycle, said 3-10 membered heterocycle may further comprise 1,2, 3, or 4 substituents selected from N, O, S, S (= O) or S (= O) ₂ And said 3-10 membered heterocyclic ring is independently optionally substituted with 1,2, 3, 4,5 or 6R ₂₀ Substituted or unsubstituted;

further preferably, each

Selected from the following structures:

4. the compound according to claim 1, or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, polymorph or isomer thereof, and mixtures thereof, selected from the group consisting of:

or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer, and mixtures and forms thereof.

5. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-4 or a pharmaceutically acceptable prodrug, stable isotopic derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof.

6. A pharmaceutical formulation comprising a compound of formula (I) as described in any one of claims 1-4 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof or a pharmaceutical composition as described in claim 5, said formulation being any one of a tablet, capsule, injection, granule, powder, suppository, pill, cream, paste, gel, powder, oral solution, inhalant, suspension, dry suspension, patch, lotion.

7. A compound of formula (I) as described in any one of claims 1-4 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof, or a pharmaceutical composition as described in claim 5, or a pharmaceutical formulation as described in claim 6 for use in the prevention and treatment of non-receptor protein tyrosine phosphatase mediated or dependent diseases or conditions.

8. Use of a compound of formula (I) as described in any one of claims 1-4 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof, or of a pharmaceutical composition as described in claim 5, or of a pharmaceutical formulation as described in claim 6, for the prevention and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.

9. Use of a compound of formula (I) as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof, or a pharmaceutical formulation as claimed in claim 4 in the manufacture of a medicament for the prophylaxis and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.

10. Use of a compound of formula (I) according to any one of claims 1 to 4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, in the manufacture of a medicament for the prevention or treatment of noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute bone leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large-cell lymphoma and glioblastoma.