CN115448923B

CN115448923B - Pyrimidine-fused ring compound, preparation method and application thereof

Info

Publication number: CN115448923B
Application number: CN202210427468.3A
Authority: CN
Inventors: 邹斌; 张睿; 付贤磊; 马世超
Original assignee: Shanghai Blueray Biopharma Co ltd
Current assignee: Shanghai Blueray Biopharma Co ltd
Priority date: 2018-02-13
Filing date: 2018-02-13
Publication date: 2024-03-22
Anticipated expiration: 2038-02-13
Also published as: CN110156786B; CN115448923A; CN110156786A

Abstract

The invention discloses a pyrimidine-fused ring compound, and a preparation method and application thereof. The pyrimidine-fused ring compound has a structure shown in a formula (II), and can be used for preparing medicines for treating diseases or symptoms related to abnormal SHP2 activity.

Description

Pyrimidine-fused ring compound, preparation method and application thereof

Technical Field

Pyrimidine-fused ring compounds, pharmaceutically acceptable salts thereof, and solvates thereof are disclosed. The invention also provides a preparation method of the compound, a composition containing the compound and application of the compound in preparing medicines for treating diseases or symptoms related to abnormal SHP2 activity.

Background

The tyrosine phosphatase SHP2 consists of two N-terminal Src homology 2 domains (N-SH 2 and C-SH 2) and one protein tyrosine phosphatase catalytic domain (PTP). In the basal state, N-SH2 can combine with PTP to form a cyclic structure, thereby preventing the combination of PTP and a substrate, and inhibiting the catalytic activity of enzyme; when the tyrosine of the upstream receptor protein is phosphorylated, N-SH2 binds thereto, and the PTP catalytic domain is released to exert phosphatase activity.

At the cellular level, SHP2 is involved in multiple tumor cell signaling pathways, such as RTK/Ras/MAPK, JAK/STAT, PI3K/Akt, and the like, through functional roles downstream of the cytoplasm of many receptor tyrosine kinases. By modulating these kinases and signaling pathways, SHP2 is intimately involved in many important cellular vital activities, such as cell proliferation, migration, differentiation, death, cytokine regulation, and tumorigenesis, among others.

At the same time, SHP2 is also involved in the programmed death receptor 1 (PD 1) -mediated suppression of the immune system. After binding of PD-1 to PD-L1, T cells can recruit a large amount of SHP2 in the cell. SHP2 is capable of dephosphorylating antigen receptor pathway proteins within T cells, thereby inhibiting activation of T cells. Thus, inhibition of SHP2 activity can reverse immunosuppression in tumor microenvironment.

SHP2 is an important member of the protein tyrosine phosphatase family, associated with a variety of diseases in humans, such as Noonan Syndrome (Noonan Syndrome), leopard Syndrome (Leopard Syndrome), juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, glioblastoma, and the like.

Recently issued patents such as WO2018/013597A1, WO2017/210134A1, WO2017/211303A1, WO 2017/216706A1, WO 2016/203406A1, WO 2016/203405A1, WO 2016/203404A1, WO2015/107495A1, WO2015/107494A1 and WO2015/107493A1, and the like, indicate that SHP2 is attracting increasing attention as a novel patentable drug target. Around the development of SHP2 inhibitors, there are two major strategies for inhibitor development for the PTP catalytic region of SHP2 and allosteric inhibitor development for the non-catalytic region; because of the poor selectivity and formation of inhibitors in the PTP catalytic region, more research is currently being directed towards the development of allosteric inhibitors. The patent publications are all allosteric inhibition, but most of the inhibition activities on tumor cells are not high, such as SHP099 (6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine) disclosed in WO2015/107493A1, etc., which is a compound to be further developed into SHP2 inhibitors with novel structure, good biological activity and high patentability.

Disclosure of Invention

The pyrimidine fused ring compound provided by the invention is a brand new SHP2 inhibitor, shows good inhibition activity on tumor cells and good drug-forming property, and has wide drug development prospect. And the preparation method of the compound is simple and is beneficial to industrial production.

In a first aspect, the present invention provides a pyrimido ring compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt.

Wherein the method comprises the steps of

Z ₁ 、Z ₂ At the same time, C or one of them is N;

x is independently S or absent;

y is independently C or N;

n is independently 0, 1 or 2;

R ¹ independently 0 to 4R ^1a Substituted phenyl, 0 to 4R ^1a Substituted containing 1-4 aza-aryl groups, 0 to 4R ^1a Substituted naphthyl, 0 to 4R ^1a Substituted 1-4 azanaphthylaryl groups, 0 to 4R ^1a Substituted or substitutedUnsubstituted benzoheterocycle, 0 to 4R ^1a Substituted or unsubstituted containing 1-4 azaaromatic rings, 0 to 4R ^1a Substituted containing 1-4N, NR ^1b Heteroaromatic rings of hetero atoms, e.g. O or S (O) m, R ^1c Substituted or unsubstituted C _1-8 Alkyl, R ^1c Substituted or unsubstituted C _1-8 A haloalkyl group; wherein m is selected from 0, 1 and 2;

R ^1a independently is halogen, R ^1a1 Substituted or unsubstituted C _1-4 Alkoxy, R ^1a1 Substituted or unsubstituted C _1-4 Alkyl, trifluoromethyl, C (=o) OR ^1a2 、NR ^1a2 R ^1a3 、NHC(＝O)R ^1a4 、R ^1a1 Substituted or unsubstituted C _3-8 Cycloalkyl; r is R ^1a1 Independently halogen or C _1-4 An alkyl group; r is R ^1a2 、R ^1a3 Independently hydrogen, C _1-4 An alkyl group; r is R ^1a4 Independently C _1-4 Alkyl, substituted or unsubstituted alkenyl, amide, C _3-12 Mono-or poly-heterocyclic ring;

R ^1b independently is hydrogen, R ^1a1 Substituted or unsubstituted C _1-4 An alkyl group;

R ^1c independently hydrogen, -C (=o) OR ^1a2 、R ^1a1 Substituted or unsubstituted C _1-4 An alkyl group;

R ^2a 、R ^2b 、R ^3a and R is ^3b Independently is hydrogen, R ^1a1 Substituted or unsubstituted C _1-4 An alkyl group;

when y=n, R ⁴ Independently is hydrogen, R ^1a1 Substituted or unsubstituted C _1-4 An alkyl group; r is R ⁵ Absence of;

when y=c, R ⁴ 、R ⁵ Independently hydrogen, aryl, C _1-4 Alkyl, C _1-4 Alkoxy, -O-C _1-4 Alkyl, amino, C _1-4 Alkyl substituted amino, -O-C _1-4 Alkyl substituted amino, or R ⁴ And R is ⁵ Together with Y, form 0 to 3R ^4a Substituted 3-to 7-membered saturated or partially unsaturated spiro rings, which rings may optionally contain 1 to 3 groups independently selected from N, C (=o) andheteroatoms or groups such as O;

R ^4a independently is hydrogen, halogen, R ^1a1 Substituted or unsubstituted C _1-4 Alkoxy, R ^1a1 Substituted or unsubstituted C _1-4 Alkyl, hydroxy, amino, C _1-4 An alkylamino group.

In one preferred embodiment, the pyrimido-cyclic compound of the invention has the structure of formula (II)

In another preferred embodiment, R ¹ Selected from the following structures:

wherein o is 0, 1, 2, 3 or 4; ring a is heteroaryl containing 1 to 4N atoms; ring B is heteroaryl containing 1 to 4 heteroatoms such as N, S, O; g is independently a heteroatom or group such as C, C (=o), N, S, or O; r is R ^1aa 、R ^1ab Independently R is ^1a ；R ^1ac Independently R is ^1c Substituted or unsubstituted C _1-8 Alkyl, R ^1c Substituted or unsubstituted C _1-8 An alkyl halide;

in another preferred embodiment, R ^2a 、R ^2b 、R ^3a And R is ^3b Independently hydrogen or methyl;

in another preferred embodiment, when y=n, R ⁴ Independently hydrogen, methyl; r is R ⁵ Absence of;

in another preferred embodiment, when y=c, R ⁴ 、R ⁵ Independently hydrogen, methyl, ethyl, phenyl, amino, methylamino or ethylamino; in another preferred embodiment, when y=c, R ⁴ And R is ⁵ The ring formed with Y is selected from the following structures:

wherein p is 0, 1, 2 or 3; r is R ^4a As defined above;

in another preferred embodiment, when y=c, R ⁴ And R is ⁵ The ring formed with Y is selected from the following configurations:

wherein p, R ^4a As defined above;

in another preferred embodiment, the compound is selected from any one of the following compounds:

in another aspect, the present invention provides isotopically-labeled compounds of pyrimido-ring compounds represented by formula (I), pharmaceutically acceptable salts thereof, or solvates thereof. Atoms in the compounds of formula (I) that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. They can be respectively isotopically substituted with ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ Cl and Cl ¹²⁵ I, etc.

In another aspect, the present invention provides a method for preparing a pyrimido-ring compound represented by formula (I) and an intermediate thereof, which mainly comprises the following aspects:

The invention provides a preparation method of a formula (I), which comprises the following steps:

halogenated intermediate compoundsCoupling reaction with boric acid, mercaptan or sodium sulfate (F) to obtain the formula (I), wherein the reaction equation is as follows:

wherein W is ¹ Represents halogen, preferably Br, I; z is Z ₁ 、Z ₂ 、X、Y、n、R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as above.

In one preferred embodiment, the process for the preparation of formula (II) comprises the steps of:

coupling reaction of halogenated intermediate compound A with boric acid, mercaptan or sodium sulfide (F) to obtain formula (II), wherein the reaction equation is as follows:

wherein W is ¹ Represents halogen, preferably Br, I; x, Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as above.

The present invention also provides a compound of formula a,

wherein W is ¹ Represents halogen, preferably Br, I; r is R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ The definition of Y, n is as described above.

The invention also provides a preparation method of the compound A, which comprises the following steps:

the halogenated intermediate E is substituted by intermediate amine C under alkaline conditions to obtain an intermediate compound A, and the reaction equation is as follows:

wherein W is ¹ Represents halogen, preferably Br, I; w (W) ² Represents halogen, preferably Cl, br, I; y, n, R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as above.

The present invention also provides a compound C-1,

wherein U is independently C or O; q is selected from 0, 1 or 2; pg is selected from protecting groups Boc, ac, S (=O) ^t Bu；n、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ^4a Is defined as above.

The invention also provides a preparation method of the compound C-1, which comprises the following steps:

reductive amination of the spirocyclic ketone compound C-1a to obtain an intermediate C-1b; c-1 is obtained after selective deprotection of C-1b, and the reaction equation is as follows:

wherein Pg1 is selected from protecting groups Boc, benzoyl and benzyl; pg, U, q, n, R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ^4a Is defined as above.

The present invention also provides a compound C-2,

wherein R is ⁶ Independently C _1-8 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl; u, q, pg, n, R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ^4a Is defined as above.

The invention also provides a preparation method of the compound C-2, which comprises the following steps:

spirocyclic ketone compounds C-1a and R ⁶ Adding the substituted nucleophilic reagent to obtain a hydroxyl compound C-2a; the compound C-2a is converted into an amino compound C-2b, and then the protecting group Pg1 is selectively removed to obtain C-2, and the reaction equation is as follows:

wherein R is ⁶ 、U、q、Pg1、Pg、n、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ^4a Is defined as above.

The present invention also provides a compound C-3,

wherein R is ⁶ 、Pg、n、R ^2a 、R ^2b 、R ^3a And R is ^3b Is defined as above.

The invention also provides a preparation method of the compound C-3, which comprises the following steps:

ortho-dehydrogenation of ester group of compound C-3a and R ⁶ The substituted electrophile is substituted to obtain a compound C-3b; hydrolyzing the ester group of the compound C-3b to obtain acid C-3C; the acid C-3C is rearranged to obtain amine C-3d, and then the protecting group Pg1 is selectively removed to obtain C-3, and the reaction equation is as follows:

Wherein R is ⁶ 、Pg1、Pg、n、R ^2a 、R ^2b 、R ^3a And R is ^3b Is defined as above.

The present invention also provides a compound C-4,

The invention also provides a preparation method of the compound C-4, which comprises the following steps:

the cyano compound C-4a is reduced and protected with amino to obtain an intermediate C-4b, and then the protecting group Pg1 is selectively removed to obtain C-4, wherein the reaction equation is as follows:

wherein Pg1, pg, R ⁶ 、n、R ^2a 、R ^2b 、R ^3a And R is ^3b Is defined as above.

The present invention also provides a compound E which,

wherein W is ¹ Represents halogen, preferably Br, I; w (W) ² Represents halogen, preferably Cl, br, I;

the invention also provides a preparation method of the compound E, which comprises the following steps:

the hydroxy intermediate B-3 is halogenated to obtain a dihalogen substituted compound E, and the reaction equation is as follows:

the invention also provides compounds F-1, F-2,

wherein V is independently C or N; r is R ^1a Is defined as above.

The invention also provides a preparation method of the compound F-1, which comprises the following steps:

the intermediate F-1b is obtained under the condition of catalytic coupling of the halogenated compound F-1a and methyl mercaptopropionate, and then the corresponding sodium sulfate compound F-1 is obtained under the alkaline condition;

the invention also provides a preparation method of the compound F-2, which comprises the following steps:

The halogen compound F-1a is condensed with mercaptan to obtain an intermediate F-2b, and then the thiol compound F-2 is obtained under acidic conditions.

The reaction equations for the preparation of F-1 and F-2 are as follows:

wherein W is ³ Halogen, preferably Br, I; v, R ^1a Is defined as above.

The invention also provides another preparation method of the pyrimido-ring compound shown in the formula (I), which comprises the following steps:

intermediate productsSubstituted with amine C to give formula (I), the reaction equation is as follows: />

Wherein W is ² Represents halogen, preferably Cl, br, I; z is Z ₁ 、Z ₂ 、X、Y、n、R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as above.

the substitution of the halogenated intermediate compound B with the amine C gives the formula (II) as follows:

wherein W is ² Represents halogen, preferably Cl, br, I; x, Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as above.

The present invention also provides a compound B,

wherein W is ² Represents halogen, preferably Cl, br, I; r is R ¹ And X is as defined above;

the invention also provides a preparation method of the compound B, which comprises the following steps:

substitution of dichloropyrimidine compound B-1 with an amine to give intermediate B-2; condensing, cyclizing and hydrolyzing the intermediate B-2 under the condition of strong acid to obtain a halogenated intermediate B-3; the halogenated intermediate B-3 is obtained as an intermediate B-4 under the condition of catalytic coupling, and then is converted into the intermediate B, and the reaction equation is as follows:

Wherein W is ¹ Represents halogen, preferably Br, I; w (W) ² Represents halogen, preferably Cl, br, I; r is R ¹ And X is as defined above.

In another preferred embodiment, the process for the preparation of compound II-A comprises the steps of:

coupling of sodium sulfide intermediate compound D with a halide gives the formula (II-A) as follows:

wherein Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as above.

The present invention also provides a compound D,

wherein Y, n, R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as above.

The invention also provides a preparation method of the compound D, which comprises the following steps:

intermediate compound A and methyl mercaptopropionate are subjected to catalytic coupling to obtain an intermediate D-1, and then a corresponding sodium sulfate compound D is obtained under alkaline conditions, wherein the reaction equation is as follows:

wherein W is ¹ Represents halogen, preferably Br, I; y, n, R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as above.

In another preferred embodiment, the process for the preparation of compound II-B comprises the steps of:

removing amino protecting group of intermediate II-B1 under acidic or alkaline condition to obtain compound II-B, the reaction equation is as follows:

wherein Pg is selected from protecting groups Boc, ac, S (=O) ^t Bu；R ^4Pg 、R ^5Pg Together with the linking carbon, selected from the following structures:

R ⁴ 、R ⁵ together with the linking carbon, selected from the following structures:

X、n、R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ And R is ^4a As defined above; p is 0, 1,2 or 3.

In another preferred embodiment, the process for the preparation of compound II-C comprises the steps of:

the intermediate II-C1 is aminoacylated to obtain a compound II-C, and the reaction equation is as follows:

therein, X, Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ 、R ^1a And R is ^1a4 Is defined as above.

The solvents involved in the present invention are selected from: dichloromethane, chloroform, 1, 2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP, THF, or a combination thereof.

The bases to which the present invention relates include organic bases and inorganic bases.

The organic base according to the invention is preferably: TEA, DIPEA, or combinations thereof.

The inorganic base according to the present invention is preferably: sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium t-butoxide, sodium t-butoxide, liHMDS, LDA, butyllithium, or combinations thereof.

Isotopically-labeled compounds of the pyrimido-ring compounds of formula (I) according to the present invention can be prepared by a synthesis analogous to those of unlabeled compounds, except that the unlabeled starting materials and/or reagents are replaced by isotopically-labeled starting materials and/or reagents.

In another aspect, the present invention also provides a pharmaceutical composition comprising a pyrimido-ring compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof or an isotopically-labeled compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable adjuvant. The pharmaceutically acceptable auxiliary materials are preferably selected from diluents, absorbents, wetting agents, binders, disintegrants and lubricants.

In another aspect, the invention also provides the use of the pyrimidyl ring compound shown in the formula (I), the pharmaceutically acceptable salt or the solvate thereof for preparing medicines for treating diseases or symptoms related to abnormal SHP2 activity. Preferably, the disease or disorder includes, but is not limited to, a disease or disorder including noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, or glioblastoma.

In another aspect, the invention provides a pharmaceutical formulation comprising a pyrimido-cyclic compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, and is administered in a suitable manner, such as in the form of tablets, capsules (e.g., sustained release or time release capsules), pills, powders, granules (e.g., small particles), elixirs, tinctures, suspensions (e.g., nanosuspensions, microsuspensions) and spray-dried dispersions, and the like, in the form of syrups, emulsions, solutions, and the like, and is administered orally, sublingually, including subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and the like, nasal administration (e.g., nasal inhalation), topical surfaces (e.g., creams and ointments), rectal administration (e.g., suppositories), and the like. The compounds disclosed herein may be administered alone or in combination with a suitable pharmaceutical carrier.

In another aspect, the invention provides that the pharmaceutical formulation of the previous aspect may be formulated in appropriate doses to facilitate and control the dosage of the drug. The dosage regimen of the disclosed compounds will vary depending upon the particular factors such as pharmacodynamics and mode of administration, subject, sex, age, health condition and weight of the subject, condition characteristics, other conditions of concurrent administration, frequency of administration, liver and kidney function and desired effect, etc. The disclosed compounds may be administered in a single dose per day, or in multiple doses (e.g., two to four times per day).

In another aspect, the present invention also provides a pyrimido-ring compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, for use in combination with other drugs selected from the group consisting of: anticancer drugs, tumor immunity drugs, antiallergic drugs, antiemetics, analgesics, cytoprotective drugs, etc., have better effects when used together. It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

The invention has the following advantages:

1. the pyrimidine fused ring compound disclosed by the invention is a novel allosteric inhibitor, and can be used for inhibiting the activity of SHP2 by combining with a non-catalytic region of the SHP2 and locking a basic state with weak SHP2 activity. The pyrimidine fused ring compound disclosed by the invention overcomes the defects of general selectivity, poor drug-forming property and the like of PTP catalytic region inhibitors, shows good biological activity and patentability, and has good drug development prospect.

2. In the same conditions of the evaluation systems of the SHP2 enzyme activity inhibition experiment, the phosphoprotein kinase (p-ERK) cell experiment, the MOLM-13 cell proliferation experiment and the like, the invention shows more superior activity compared with the compound SHP099 (6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine) disclosed in WO 2015/107493 A1 and literature (Nature 2016,535, 148-152).

Description of the terms

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, when used in reference to a specifically recited value, the term "about" means that the value can vary no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….

Definition of groups

The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY TH ED." vols. A (2000) and B (2001), plenum Press, new York). Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH ₂ O-is equivalent to OCH ₂ -。

The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C _1-6 Alkyl means having a total ofAlkyl of 1 to 6 carbon atoms as defined below. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.

In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below, unless specifically indicated otherwise.

In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

"hydroxy" refers to an-OH group. Alkoxy "refers to an alkyl group as defined below substituted with a hydroxy (-OH).

"carbonyl" refers to a-C (=o) -group. "cyano" refers to-CN.

"amino" means-NH 2.

"substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., mono-alkylamino, di-alkylamino, alkylamido, aralkylamino, heteroaralkylamino.

"carboxy" refers to-COOH.

In this application, as part of a group or other group (e.g., as used in halogen substituted alkyl groups and the like), the term "alkyl" refers to a straight or branched hydrocarbon chain radical that is fully saturated, consisting of only carbon and hydrogen atoms, having, for example, from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6) carbon atoms, and being attached to the remainder of the molecule by a single bond, including, for example, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like. For the purposes of the present invention, the term "alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms.

In the present application, the term "alkenyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being linked to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.

In this application, as part of a group or other group, the term "cycloalkyl" means a stable, non-aromatic, mono-or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the present specification, carbon atoms in the cycloalkyl group may optionally be oxidized. Examples of cyclic hydrocarbyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7 dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [ 2.2.2.2 ] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [ 2.2.2.2 ] octenyl, bicyclo [ 2.1.1 ] octadienyl, adamantylene, and the like.

In the present application, the term "heterocyclyl" as part of a group or other group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless specifically indicated otherwise in the present specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include fused, bridged or spiro ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclyl may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl groups are preferably stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxacyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.

In this application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are linked to the remainder of the molecule by single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.

In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In this application, as part of a group or other group, the term "heteroaryl" means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthyridinyl, [1,2,4] triazolo [4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [1, 4] triazolo [1, 4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [ 2,4] a ] 1, 4-imidazo [ 2, 4-a ] and the like.

In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above. In this application, "optionally" or "optionally" means that the subsequently described event or condition may or may not occur, and that the description includes both cases where the event or condition occurs and where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

The "optional" substituents described in the claims and the description section of the invention are selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.

The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.

When an olefinic double bond is contained in the compounds of the present invention, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.

"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule.

All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention. The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Substituents or representative symbols of the invention, e.g. Z ₁ 、Z ₂ 、X、Y、U、V、W ¹ 、W ² 、W ³ 、n、o、p、q、R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ Pg1, pg, etc., the same symbols, unless otherwise indicated, represent the same definition at different places.

Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example, gerald gabiz and Martin g.schmid (eds.), chiral Separations, methods and Protocols, methods in Molecular Biology, vol.243,2004; m.stalcup, chiral Separations, annu.rev.animal.chem.3:341-63, 2010; fumigs et al (EDs.), VOGEL' S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY.sup.TH ED, longman Scientific and Technical Ltd., essex,1991,809-816; heller, acc.chem.Res.1990,23,128.

In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2 dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.

By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

In this application, "pharmaceutical composition" refers to a formulation of a compound of the invention with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.

The term "pharmaceutically acceptable" as used herein refers to a material (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 material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition. In this application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are approved by the relevant government agency as acceptable for human or livestock use.

The term "tumor" as used herein includes, but is not limited to, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, sarcomas, melanomas, joint chondriomas, cholangioma, leukemia, gastrointestinal stromal tumors, diffuse large B-cell lymphoma, follicular lymphoma and other lymphomas, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, lung squamous carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal carcinoma, brain cancer, bone cancer, esophagus cancer, melanoma, kidney cancer, oral cancer, multiple myeloma, mesothelioma, malignant rhabdoid tumor, endometrial cancer, head and neck cancer, thyroid cancer, parathyroid tumor, uterine tumor, and soft tissue sarcoma.

The terms "prevent", "preventing" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition.

The term "treatment" and other similar synonyms as used herein include the following meanings:

(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;

(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;

(iii) Alleviating a disease or condition, even if the state of the disease or condition subsides; or alternatively

(iv) Alleviating symptoms caused by the disease or condition.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers 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 of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test. The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Application techniques useful in the compounds and methods described herein are well known to those skilled in the art, for example, at Goodman and Gilman, the Pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, pharmaceutical Sciences (current edition), mack Publishing co., easton, pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

The terms "pharmaceutical combination", "co-administration", "administration of other treatments", "administration of other therapeutic agents" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals. These also apply to cocktail therapies, for example, administration of three or more active ingredients. It will also be appreciated by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto-protecting groups include-C (O) -R "(wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters. Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, t.w. and p.g.m. wuts, protective Groups in Organi Synthesis, (1999), 4th Ed. The protecting group may also be a polymeric resin.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The starting materials used in the examples described below are commercially available from chemical vendors such as Aldrich, TCI, alfa Aesar, piobtained, an Naiji, etc., or can be synthesized by known methods.

In the following examples, ice bath means-5 to 0 degrees celsius, room temperature means 10 to 30 degrees celsius, and reflux temperature generally means the reflux temperature of the solvent under normal pressure. Overnight reaction means a period of 8-15 hours. In the examples below, the specific operating temperatures are not limited, and are all carried out at room temperature.

In the examples described below, the isolation and purification of the intermediates and final products is by normal or reverse phase chromatographic column separation or other suitable method. The normal phase flash column uses ethyl acetate and normal hexane or methanol and methylene chloride as mobile phase. Reverse phase preparative High Pressure Liquid Chromatography (HPLC) was performed on a C18 column with UV 214nm and 254nm and the mobile phases were A (water and 0.1% formic acid), B (acetonitrile) or mobile phases A (water and 0.1% ammonium bicarbonate), B (acetonitrile).

In various embodiments: LCMS instrument: pump Agilent 1260 UV detector: agilent 1260 DAD Mass Spectrometer API 3000

Chromatography column: waters canfire C18, 4.6X105 mm,5um

Mobile phase: a-H2O (0.1% hcooh); b-acetonitrile NMR

Instrument: bruker Assetnd 400M% ¹ H NMR:400MHz； ¹³ C NMR:100MHz)。

Example 1: preparation of intermediate 5-chloro-8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidine (B1)

Step one: 2-chloro-N- (2, 2-dimethoxyethyl) -5-iodopyrimidin-4-amine

To a dry 2L flask was added 2, 4-dichloro-5-iodopyrimidine (110 g,400 mmol) followed by 2, 2-dimethoxyethylamine (84 g,800 mmol) and absolute ethanol (1.2L). Triethylamine (109 ml,800 mmol) was slowly added dropwise thereto under nitrogen at 0 ℃ and the mixture was stirred at room temperature for reaction for 10 hours. After the completion of the reaction, the resultant concentrate was concentrated in vacuo, 1L of water was added, and extracted with methylene chloride (3X 300 mL), the saturated brine was washed and the organic layer was mixed, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting tan solid was washed with anhydrous ethanol (3X 50 mL) to give 2-chloro-N- (2, 2-dimethoxyethyl) -5-iodopyrimidin-4-amine (110 g, yield: 78%) as a brown solid.

¹ H NMR(400MHz,DMSO-d6)δ8.35(s,1H),4.58(t,J＝5.4Hz,1H),3.47(t,J＝5.6Hz,2H),3.29(s,6H)ppm；LC-MS:m/z 344.1[M+H] ⁺ 。

Step two: 8-iodoimidazo [1,2-c ] pyrimidin-5-ols

To a dry 2L flask was added 2-chloro-N- (2, 2-dimethoxyethyl) -5-iodopyrimidin-4-amine (110 g,317 mmol) and 800mL of concentrated sulfuric acid in sequence. The mixture was heated to 65 ℃ under nitrogen and stirred for 2 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, the mixture was slowly poured into ice water, then the pH was adjusted to about 6.0 with 4M NaOH solution, and extracted with ethyl acetate (3X 300 mL), the organic layer was mixed and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 8-iodoimidazo [1,2-c ] pyrimidin-5-ol (70 g, yield 84.5%).

¹ H NMR(400MHz,DMSO-d6)δ11.80(s,1H),7.92(d,J＝1.5Hz,1H),7.60(d,J＝3.9Hz,1H),7.40(d,J＝1.5Hz,1H)；LC-MS:m/z 262.1[M+H] ⁺ 。

Step three: 8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-ol

Into a dry 250mL three-necked flask, 8-iodoimidazo [1,2-c ] was sequentially added]Pyrimidine-5-ol (2.61 g,10 mmol), cuprous iodide (190 mg,1 mmol), 1, 10-phenanthroline (360 mg,2 mmol), 2, 3-dichlorobenzothiool (2.15 g,12 mmol), potassium phosphate (4.2 g,20 mmol) and 50mL dioxane solvent. The mixture was heated under nitrogen for 3 hours. After the reaction is finished, saturated NH is added ₄ Cl solution (200 mL). It was extracted with ethyl acetate (3×200 mL). The combined organic phases were taken up with Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, purification of the resulting residue by silica gel chromatography (0 to 10% gradient of methanol: ethyl acetate) afforded 8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c as a pale yellow solid ]Pyrimidin-5-ol (2.3 g, yield: 74%).

LC-MS:m/z 312.1[M+H] ⁺ .

Step four: 5-chloro-8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidine (B1)

To a dry 100mL single-neck flask was added 8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-ol (2.3 g,7.3 mmol) and phosphorus oxychloride (30 mL) in sequence, then N, N-diisopropylethylamine (1 mL) was slowly added dropwise under nitrogen, after which the mixture was heated to 120℃and stirred for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, and then concentrated in vacuo, and the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×30 mL), washed with saturated brine and mixed with an organic layer, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel chromatography (0 to 10% gradient of methanol: ethyl acetate) to give 5-chloro-8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidine B1 (660 mg, yield: 27.4%) as a white solid.

¹ H NMR(400MHz,DMSO-d6)δ8.18(d,J＝1.4Hz,1H),8.07(s,1H),7.76(d,J＝1.4Hz,1H),7.52(dd,J＝8.0,1.3Hz,1H),7.17(t,J＝8.0Hz,1H),7.00(dd,J＝8.1,1.2Hz,1H)ppm；LC-MS:m/z 330.1[M+H] ⁺ .

Example 2: preparation of intermediate 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine (E1)

To a dry 250mL single-neck flask, 8-iodo imidazo [1,2-c ] pyrimidin-5-ol (5 g,19.1 mmol) and phosphorus oxychloride (50 mL) were added sequentially, N-diisopropylethylamine (1 mL) was slowly added dropwise under nitrogen, and the mixture was heated to 120℃and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated in vacuo, then quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×100 mL), the mixed organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by column chromatography to give 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine E1 (1.6 g, yield: 29.8%) by silica gel chromatography (0 to 10% gradient of methanol: ethyl acetate).

¹ H NMR(400MHz,Methanol-d4)δ8.28(s,1H),8.16(d,J＝1.6Hz,1H),7.81(d,J＝1.6Hz,1H)ppm；LC-MS:m/z 280.1[M+H] ⁺ .

Example 3: preparation of intermediate (R) -2-methyl-N- ((R) -8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1A)

Step one: (R) -1- ((R) -1, 1-dimethylethylsulfinylamino) -8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

1-carbonyl-8-azaspiro [4.5] was added sequentially to a dry 100mL single vial]Decane-8-carboxylic acid tert-butyl ester (2.53 g,10 mmol), tetraethoxytitanium (6.84 g,30 mmol) and 50mL of tetrahydrofuran were reacted under stirring under reflux with heating for 4 hours. After cooling to room temperature, methanol (10 mL) was added followed by lithium borohydride (0.65 g,30 mmol). The resulting mixture was stirred at room temperature for 3 hours. Methanol was slowly added to quench excess borohydride, followed by brine. The resulting mixture was stirred for 15 minutes and then filtered through celite. The aqueous mixture was extracted with ethyl acetate (3×50 mL). The organic phase was treated with MgSO ₄ Dried, filtered, and volatiles removed under reduced pressure. The resulting residue was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate: petroleum ether) to give (R) -1- ((R) -1, 1-dimethylethylsulfinylamino) -8-azaspiro [4.5] as a white solid]Decane-8-carboxylic acid tert-butyl ester (2.86 g, yield: 80%).

LC-MS:m/z 359.1[M+H] ⁺ .

Step two: (R) -2-methyl-N- ((R) -8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1A)

(R) -1- ((R) -1, 1-dimethylethylsulfinylamino) -8-azaspiro [4.5]A solution of tert-butyl decane-8-carboxylate (2.86 g,8 mmol) and dioxane (50 mL) of concentrated sulfuric acid (2.0 mL,32 mmol) was stirred at room temperature for 2 hours. Adding Na ₂ CO ₃ The aqueous solution was saturated until pH 11 and the aqueous mixture was extracted with DCM (3×50 mL). The combined organic phases were washed with brine, with Na ₂ SO ₄ Drying, filtration, and removal of volatiles under reduced pressure gives (R) -2-methyl-N- ((R) -8-azaspiro [4.5] as a white solid]Decane-1-yl) propane-2-sulfinamide C-1A (1.86 g, yield: 90%)

¹ H NMR(400MHz,DMSO-d ₆ )δ4.82(d,J＝7.5Hz,1H),3.04(d,J＝7.6Hz,1H),2.81(ddd,J＝12.1,8.0,4.0Hz,2H),2.60-2.51(m,2H),1.92-1.14(m,10H),1.12(s,9H)ppm；LC-MS:m/z 259.1[M+H] ⁺ .

The following intermediates C-1B, C-1C, C-1D, C-1E, C-1F, C-1G were obtained by reacting similar starting materials according to the synthetic method of example 1.

Example 4: preparation of intermediate (R) -2-methyl-N- ((S) -2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1H)

Step one: 4- (2- (benzyloxy) -1-hydroxyethyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl-4-methyl ester

To a dry 500mL three-necked flask under nitrogen atmosphere was added 1-tert-butyl-4-methylpiperidine-1, 4-dicarboxylic acid ester (45 g,180 mmol) and tetrahydrofuran (400 mL) in this order, and the solution was cooled to-78℃and LiHMDS (261 mL,261 mmol) was added dropwise. After the completion of the dropwise addition, the mixture was warmed to room temperature and stirred at room temperature for 3 hours. Then cooled again to-78℃and a solution of benzyloxyacetaldehyde (46 g,300 mmol) in tetrahydrofuran (50 mL) was slowly added dropwise. The reaction was slowly warmed to room temperature and stirred for 2.5 hours. After the reaction is finished, saturated NH is added ₄ The reaction was quenched with Cl solution (200 mL). It was extracted with ethyl acetate (3×200 mL). The combined organic phases were taken up with Na ₂ SO ₄ Drying, filtering, concentrating the filtrate under reduced pressure, purifying the residue by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) to obtain 4- (2- (benzyloxy) -1-hydroxyethyl) piperidine-1, 4-dicarboxylic acid1-tert-butyl-4-methyl ester (52 g, yield: 73.3%).

¹ H NMR(400MHz,CDCl ₃ )δ7.36-7.30(m,5H),4.50(s,2H),3.97(s,2H),3.73-3.65(m,2H),3.62(s,3H),3.59-3.48(m,3H),2.88(d,J＝6.2Hz,1H),2.23(dd,J＝13.7,2.7Hz,1H),2.04-1.88(m,2H),1.74(d,J＝14.7Hz,1H),1.56(d,J＝4.2Hz,1H),1.44(s,9H)ppm；LC-MS:m/z 294.1[M+H] ⁺ .

Step two: 4- (2- (benzyloxy) -1-hydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester

To a dry 500mL three-necked flask, a solution of 4- (2- (benzyloxy) -1-hydroxyethyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl-4-methyl ester (51.4 g,130 mmol) and tetrahydrofuran (500 mL) were sequentially added LiBH ₄ (11.44 g,520 mmol) and stirred at room temperature for 6 hours. After the reaction was completed, saturated NaHCO was used ₃ (200 mL) quench the reaction. Extracted with ethyl acetate (3 x200 mL). The combined organic phases were taken up in Na ₂ S0 ₄ Dried, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) to give tert-butyl 4- (2- (benzyloxy) -1-hydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylate (27 g, yield: 57%).

LC-MS:m/z 266.1[M+H] ⁺ .

Step three: 4- (1, 2-Dihydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester

To a dry 500mL single-necked flask was successively added tert-butyl 4- (2- (benzyloxy) -1-hydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylate (27 g,74 mmol), methanol (270 mL) and Pd/C (20 g), followed by three replacements with a hydrogen balloon and stirring at room temperature for 12 hours. The reaction solution was concentrated by filtration to give tert-butyl 4- (1, 2-dihydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylate (18.9 g, yield: 93%).

LC-MS:m/z 176.1[M+H] ⁺ .

Step four: 4-hydroxy-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

To a dry 500mL one-necked flask was successively added tert-butyl 4- (1, 2-dihydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylate (18.9 g,69 mmol), triphenylphosphine (25.2 g,86.25 mmol) and tetrahydrofuran (350 mL), and the reaction solution was cooled to 0℃and DEAD (12.46 mL,86 mmol) was added, followed by stirring at room temperature for 5 hours. After the completion of the reaction, saturated water (200 mL) was added to quench the reaction. It was extracted with ethyl acetate (3×200 mL). The organic phases were combined and taken up with Na ₂ SO ₄ Drying, filtering, concentrating the filtrate under reduced pressure and purifying the residue by silica gel chromatography (0 to 2% gradient of methanol/dichloromethane) to give 4-hydroxy-2-oxa-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester (13.2 g, yield: 74%).

¹ H NMR(400MHz,CDCl ₃ )δ4.04(dd,J＝10.0,4.6Hz,1H),3.98-3.90(m,1H),3.71-3.63(m,2H),3.64-3.49(m,3H),3.20(dt,J＝13.4,6.3Hz,1H),3.07(ddd,J＝13.2,9.2,3.5Hz,1H),1.95(d,J＝5.2Hz,1H),1.74-1.66(m,1H),1.53-1.46(m,1H),1.39(s,9H),1.27-1.11(m,1H)ppm；LC-MS:m/z 202.1[M-56+H] ⁺ .

Step five: 4-carbonyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

To a dry 500mL single-necked flask was successively added 4-hydroxy-2-oxa-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester (13.2 g,51 mmol), methylene chloride (280 mL) and Dess-Martin oxidant (32.2 g,76.5 mmol) were stirred for 5 hours in an ice bath. After the reaction is finished, naHCO is added ₃ ：Na ₂ S ₂ O ₃ (1:1) saturated solution (200 mL), the organic phase was separated and the aqueous phase extracted with DCM (3×100 mL). The combined organic phases were taken up with Na ₂ SO ₄ Drying, and concentrating the filtrate under reduced pressure. The residue obtained was purified by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give 4-carbonyl-2-oxa-8-azaspiro [4.5] as a colorless solid]Decane-8-carboxylic acid tert-butyl ester (12 g, yield: 92.1%).

¹ H NMR(400MHz,CDCl ₃ )δ4.05(d,J＝13.6Hz,4H),3.87(d,J＝12.9Hz,2H),3.09(ddd,J＝13.5,9.8,3.5Hz,2H),1.73(ddd,J＝13.9,9.8,4.3Hz,2H),1.53(d,J＝15.1Hz,2H),1.46(s,9H)ppm；LC-MS:m/z200.0[M-56+H] ⁺ 。

Step six: (S) -4- ((R) -1, 1-dimethylethylsulfinylamino) -2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

The same procedures used in example 3, intermediate C-1A, step one, were used to effect reductive amination of tert-butyl 4-carbonyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylate to give tert-butyl (S) -4- ((R) -1-methylethylsulfinyl amino) -2-oxa-8-azaspiro [4.5] decane-8-carboxylate as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ4.14(dd,J＝9.3,6.2Hz,1H),3.90(d,J＝13.8Hz,2H),3.77(s,2H),3.70(dd,J＝9.2,5.3Hz,1H),3.63(q,J＝6.1Hz,1H),3.27(d,J＝6.4Hz,1H),2.90(t,J＝12.4Hz,2H),1.71(dt,J＝16.6,7.9Hz,2H),1.51(s,2H),1.45(s,9H),1.22(s,9H)ppm；LC-MS:m/z 361.1[M-100] ⁺ 。

Step seven: (R) -2-methyl-N- ((S) -2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1H)

The same synthesis procedure used intermediate C-1A, step two, example 3 was followed to remove the Boc protecting group from tert-butyl (S) -4- ((R) -1-methylethylsulfinyl amino) -2-oxa-8-azaspiro [4.5] decane-8-carboxylate to give (R) -2-methyl-N- ((S) -2-oxa-8-azaspiro [4.5] decane-4-yl) propane-2-sulfinamide C-1H as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ5.30(s,1H),5.23(d,J＝8.9Hz,1H),3.93(dd,J＝8.6,7.2Hz,1H),3.69(d,J＝8.6Hz,1H),3.58(d,J＝8.6Hz,1H),3.46(dd,J＝8.5,7.0Hz,2H),2.89-2.73(m,2H),2.48-2.42(m,1H),1.69-1.50(m,2H),1.39-1.21(m,3H),1.12(s,9H)ppm；LC-MS:m/z 261.1[M+H] ⁺ .

Example 5: preparation of Synthesis (C-1I) of (R) -2-methyl-N- ((R) -1-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide

Step one: 3-methoxyprop-1-yne

To a stirred solution of propan-2-yn-1-ol (50 g,892.8 mmol) in water (40 mL) was added 50% aqueous NaOH (98.2 g) and the reaction mixture was heated to 70 ℃. Dimethyl sulfate (67.4 g,535.7 mmol) was slowly added to the reaction mixture at below 70 ℃. The reaction mixture was stirred at 60℃for 2h. The product was distilled from the reaction mass at 60 ℃ and collected in a receiving flask cooled at-70 ℃. The distillate was dried over calcium chloride overnight and distilled again to give 3-methoxyprop-1-yne (30 g, yield: 48%) as a colorless liquid.

¹ H NMR(CDCl _3, 400MHz)δ4.10(d,J＝2.0Hz,2H),3.39(s,3H),2.43(t,J＝2.0Hz,1H)ppm.

Step two: 1-methoxy-1, 2-propadiene

A suspension of potassium tert-butoxide (3.9 g,35.7 mmol) and 3-methoxyprop-1-yne (50 g,714.2 mmol) was stirred at 70℃for 2 hours. The product was distilled from the reaction mass at 50℃and collected in a receiver cooled at-70℃to give 1-methoxypropa-1, 2-diene (35 g, yield: 70%) as a colorless liquid. The compound was dried over KOH and kept at 0 ℃.

¹ H NMR(CDCl _3, 400MHz)δ6.76(t,J＝8.0Hz,1H),5.48(d,J＝6.0Hz,2H),3.41(s,3H)ppm。

Step three: 4-hydroxy-4- (1-methoxypropan-1, 2-dien-1-yl) piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 1-methoxypropyl-1, 2-diene (0.227 g,7.5 mmol) in THF (10 mL) was slowly added dropwise n-butyllithium (2.5M solution in THF) (2.8 mL,7.0 mmol) at-78deg.C, and the reaction stirred at this temperature for an additional 30 min. A solution of tert-butyl 4-carbonylpiperidine-1-carboxylate (1.0 g,5.0 mmol) in THF (5 mL) was then added to the reaction mixture and stirring was continued for 4 hours at-78deg.C. The reaction mixture was saturated with NaHCO ₃ The aqueous solution was quenched and extracted with ethyl acetate (3X 10 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave 4-hydroxy-4- (1-methoxypropan-1, 2-dien-1-yl) piperidine-1-carboxylic acid tert-butyl ester (1.0 g, yield: 90%) as a brown gum

Step four: 4-methoxy-1-oxa-8-azaspiro [4.5] dec-3-ene-8-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 4-hydroxy-4- (1-methoxypropan-1, 2-dien-1-yl) piperidine-1-carboxylate (6.0 g,22.3 mmol) in tert-butanol (60 mL) was added potassium tert-butoxide (12.5 g,111.5 mmol) and dicyclohexyl-18-crown-6 (0.42 g,1.1 mmol). The reaction mixture was stirred at reflux for 9 hours. The reaction mixture was cooled to 10 ℃, neutralized with 5% hcl (ph=7.0) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give tert-butyl 4-methoxy-1-oxa-8-azaspiro [4.5] dec-3-en-8-carboxylate (4.0 g), which was used in the next step without purification.

¹ H NMR(CDCl _3, 400MHz)δ4.56(s,2H),3.97(s,1H),3.69(s,3H),3.08(s,1H),1.79-1.74(m,1H),1.52(s,9H),1.45-1.26(m,1H)ppm；LCMS:m/z 214[M-55] ⁺ .

Step five: 4-carbonyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

4-methoxy-1-oxa-8-azaspiro [4.5]]Decane-3-ene-8-carboxylic acid tert-butyl ester (38.0 g,141.3 mmol) and p-TSA.H ₂ O (29.6 g,155.4 mmol), a mixture of acetone (400 mL) was stirred at room temperature for 1 hour, and the reaction mixture was saturated with NaHCO ₃ Quenched with water, extracted with ethyl acetate (3X 500 mL), the combined organic phases were washed with brine (1000 mL), dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to give 4-carbonyl-1-oxa-8-azaspiro [4.5] as a brown gum]Decane-8-carboxylic acid tert-butyl ester (25 g), which was used directly in the next reaction.

LCMS:m/z 278[M+Na] ⁺ .

Step six and seven: synthesis of (R) -2-methyl-N- ((R) -1-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1I)

Following the same procedure for the synthesis of intermediate C-1A, example 3, ketone intermediate 4-carbonyl-1-oxa-8-azaspiro [4.5]]De-decane-8-carboxylic acid tert-butyl ester is subjected to reductive amination and removal of Boc protecting group to give (R) -2-methyl-N- ((R) -1-oxa-8-azaspiro [4.5]]Synthesis of decane-4-yl) propane-2-sulfinamide (C-1I). LCMS: m/z 261[ M+Na ]] ⁺ .

Example 6: preparation of (R) -2-methyl-N- ((3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1J)

Step one: (S) -2- ((tert-Butyldimethylsilyl) oxy) propanoic acid ethyl ester

To a solution of ethyl (S) -2-hydroxypropionate (30 g,254 mmol) in methylene chloride (300 mL) was added imidazole (2.75 g,304.9 mmol) and cooled to 0deg.C. To the solution was added t-butyldimethylsilyl chloride (46.0 g,304.9 mmol) in portions and stirred at room temperature for 16 hours. After completion of the reaction as judged by TLC analysis, the reaction mixture was quenched with water and extracted with dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave ethyl (S) -2- ((tert-butyldimethylsilyl) oxy) propionate (50 g, 84% yield) as a colorless liquid.

¹ H NMR(400MHz,CDCl ₃ )δ4.32-4.27(m,1H),4.21-4.12(m,2H),1.37(d,J＝6.8Hz,3H),1.27(d,J＝7.2Hz,3H),0.90(s,9H),0.08(s,6H)ppm.

Step two: (S) -2- ((tert-butyldimethylsilyl) oxy) propanal

To a solution of ethyl (S) -2- ((tert-butyldimethylsilyl) oxy) propionate (25 g,107.6 mmol) in diethyl ether (500 mL) was slowly added dropwise diisobutylaluminum hydride (1M in hexane) (129 mL,129.1 mmol) at-78℃and stirred for 1 hour. After confirming completion of the reaction by TLC analysis, the reaction mixture was warmed to-40 ℃, quenched with a saturated aqueous solution of rochelle salt (1L), and then diethyl ether (500 mL) was added. The resulting mixture was stirred at room temperature for 2 hours. Then extracted with diethyl ether (200 mL). The organic layer was washed with saturated brine (250 mL) and was washed with Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give (S) -2- ((tert-butyldimethylsilyl) oxy) propanal (19 g, yield: 94%).

¹ H NMR(400MHz,CDCl ₃ )δ9.61(s,1H),4.12-4.06(m,1H),1.27(d,J＝6.8Hz,3H),0.91(s,9H),0.10(s,6H)ppm.

Step three: 4- ((2S) -2- ((tert-Butyldimethylsilyl) oxy) -1-hydroxypropyl) piperidine-1, 4-dicarboxylic acid 1- (tert-butyl)

To a stirred solution of 1- (tert-butyl) -4-ethylpiperidine-1, 4-dicarboxylic acid ester (30 g,116.6 mmol) in THF (250 mL) was added lithium diisopropylamide (2M in THF) (93.3 mL,186.6 mmol) at 0deg.C and stirring continued for 30 min at 0deg.C. A solution of (S) -2- ((tert-butyldimethylsilyl) oxy) propanal (22 g,116.6 mmol) in THF (50 mL) was then added. The resulting reaction mixture was stirred at 0 ℃ for 1 hour and then maintained at room temperature for 1 hour. After completion of the reaction by TLC analysis, the reaction mixture was taken up in saturated NH ₄ The Cl solution was quenched and extracted with ethyl acetate (2X 250 mL). The combined organic layers were washed with water (150 mL), brine (150 mL) and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) using a solvent gradient mixture of 25% ethyl acetate in petroleum ether as eluent to give 1- (tert-butyl) 4- ((2S) -2- ((tert-butyldimethylsilyl) oxy) -1-hydroxypropyl) piperidine-1, 4-dicarboxylic acid (17 g, yield: 32%) as a pale red oil.

¹ H NMR(400MHz,CDCl ₃ )δ4.29-4.09(m,2H),3.96-3.94(m,2H),3.86-3.80(m,1H),3.56-3.54(m,1H),2.86-2.76(m,2H),2.46(d,J＝5.2Hz,1H),2.16-2.13(m,1H),2.13-2.04(m,1H),1.77-1.60(m,2H),1.46(s,9H),1.29-1.24(m,3H),1.12(d,J＝4Hz,3H),0.89(s,9H),0.05(s,6H)ppm；LCMS:m/z 346[M-100] ⁺ .

Step four: ((2S) -2- ((tert-Butyldimethylsilyl) oxy) -1-hydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester

To the stirred solution was added 1- (tert-butyl) (5 g,11.21 mmol) 4- ((2S) -2- ((tert-butyldimethylsilyl) oxy) -1-hydroxypropyl) piperidine-1, 4-dicarboxylic acid 1- (tert-butyl) to a solution of LiBH in THF (50 mL) ₄ (0.73 g,33.65 mmol) and stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was quenched with saturated NaHCO at 0deg.C ₃ The solution was quenched and stirred at room temperature for 15 minutes. The precipitated solid was filtered off and the aqueous phase was extracted with ethyl acetate (2X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained was purified by column chromatography on silica gel (100-200 mesh) using a gradient mixture of 25% ethyl acetate in petroleum ether as eluent to give tert-butyl ((2S) -2- ((tert-butyldimethylsilyl) oxy) -1-hydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylate (3 g, yield: 66%).

¹ H NMR(400MHz,CDCl ₃ )δ4.55(t,J＝4.8Hz,1H),4.43(d,J＝6.4Hz,1H),3.52-3.47(m,5H),3.31-3.28(m,1H),3.05-3.01(m,2H),1.58-1.49(m,2H),1.42-1.38(m,11H),1.11(d,J＝6.4Hz,3H),0.85(m,9H),0.04(s,6H)ppm；LC-MS:m/z 404.3[M+H] ⁺ 。

Step five: 4- ((2S) -1, 2-dihydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl ((2S) -2- ((tert-butyldimethylsilyl) oxy) -1-hydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylate (25 g,61.93 mmol) in THF (500 mL) was added tetrabutylammonium fluoride (1M in THF) (93 mL,92.89 mmol) and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by TLC analysis, the reaction mixture was taken up in saturated NaHCO ₃ The solution was quenched and extracted with ethyl acetate (2X 500 mL). The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained is filtered and concentrated under reduced pressure and purified by column chromatography on silica gel (60-120 mesh) using a solvent gradient mixture of 70-90% ethyl acetate in petroleum etherAs an eluent, tert-butyl 4- ((2S) -1, 2-dihydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylate (12 g, yield: 67%) was obtained as a colorless liquid.

¹ H NMR(400MHz,DMSO-d ₆ )δ4.72(t,J＝4.8Hz,1H),4.61(d,J＝5.2Hz,1H),4.50(d,J＝7.2Hz,1H),3.72-3.68(m,1H),3.53-3.44(m,4H),3.11-2.98(m,3H),1.68-1.53(m,2H),1.42-1.35(m,11H),1.10(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 290.1[M+H] ⁺ 。

Step six: (3S) -4-hydroxy-3-methyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

To a stirred suspension of NaH (60% in mineral oil) (1.45 g,60.5 mmol) in THF (30 mL) was added tert-butyl 4- ((2S) -1, 2-dihydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylate (5 g,17.3 mmol) and p-toluenesulfonyl chloride (3.29 g,17.3 mmol) in THF (20 mL) at 0deg.C and the resulting reaction mixture was reacted for 3 hours at 0deg.C. After the reaction was completed, the reaction mixture was treated with saturated NH at-20 ℃ ₄ The Cl solution (250 mL) was quenched and extracted with ethyl acetate (2X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by column chromatography on silica gel (100-200 mesh) using a solvent gradient mixture of 40% ethyl acetate in petroleum ether as eluent to give (3S) -4-hydroxy-3-methyl-2-oxa-8-azaspiro [4.5] ]Decane-8-carboxylic acid tert-butyl ester (2.1 g, yield: 44%).

¹ H NMR(400MHz,CDCl ₃ )δ3.83-3.62(m,5H),3.43(d,J＝6.0,1H),3.07-2.97(m,2H),1.72-1.55(m,3H),1.51-1.42(m,11H),1.33(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 172.2[M-100] ⁺ 。

Step seven: (S) -tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid ester

(3S) -4-hydroxy-3-methyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (2.1 g,7.74 mmol) was added to a solution of tetrahydrofuran (50 mL) and stirred for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel (100-200 mesh) using a solvent gradient mixture of 30% ethyl acetate in petroleum ether as eluent, followed by flash chromatography with 0.1% formic acid and acetonitrile as eluent to give (S) -tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylate (1.2 g, yield: 57%).

¹ H NMR(400MHz,CDCl ₃ )δ4.20(d,J＝9.5Hz,1H),3.94-3.90(m,4H),3.16-3.10(m,1H),3.03-2.97(m,1H),1.81-1.75(m,1H),1.67-1.62(m,1H),1.61-1.57(m,1H),1.42-1.45(m,10H),1.32(d,J＝6.0Hz,3H)ppm；LC-MS:m/z 214.1[M-55] ⁺ 。

Step eight: (3S, 4S) -4- ((R) -tert-butylsulfinyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

(S) -tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro [4.5]A stirred solution of decane-8-carboxylic acid ester (1.2 g,4.46 mmol) in THF (15 mL) was added (R) -2-methylpropan-2-sulfinamide (1.07 g,8.91 mmol) and tetraethyltitanate (4.07 g,17.84 mmol), respectively. The resulting reaction mixture was stirred at 90℃for 20 hours. The reaction mixture was cooled to-4 ℃, meOH (2 mL) was added, followed by LiBH addition in portions ₄ (282 mg,12.99 mmol) and kept stirring at the same temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with saturated brine solution at 0 ℃ and stirred at room temperature for 15 minutes. The solution was filtered and extracted with ethyl acetate (2X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained was filtered and concentrated under reduced pressure and purified by flash chromatography with GRACE with 0.1% formic acid and acetonitrile as eluent to give (3S, 4S) -4- ((R) -tert-butylsulfinyl) amino) -3-methyl-2-oxa-8-aza-nitrogenHeterospiro [4.5]]Decane-8-carboxylic acid tert-butyl ester (1.2 g, yield: 72%).

¹ H NMR(400MHz,CDCl ₃ )δ4.20-4.15(m,1H),3.90-3.84(m,2H),3.63-3.59(m,1H),3.49-3.43(m,1H),3.31-3.29(m,1H),2.95-2.81(m,2H),1.90-1.71(m,2H),1.49-1.40(m,11H),1.25(s,9H),1.19(d,J＝6.5Hz,3H)ppm；LC-MS:m/z 375.2[M+H] ⁺ 。

Step nine: (R) -2-methyl-N- ((3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1J)

To a solution of tert-butyl (3 s,4 s) -4- ((R) -tert-butylsulfinyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylate (1.1 g,2.936 mmol) in dichloromethane (10 mL) was added dropwise trifluoroacetic acid (1.12 mL,14.68 mmol) and stirred at room temperature for 6 hours. After the completion of the reaction, the crude product obtained by concentrating the reaction mixture under reduced pressure was purified by chromatography with 0.1% formic acid and acetonitrile to give (R) -2-methyl-N- ((3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide C-1J (850 mg, yield: 72%).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.40(brs,D ₂ O Exchangeable,1H),8.30(brs,D ₂ O Exchangeable,1H),5.28(d,J＝12.0Hz,1H),4.13-4.09(m,1H),3.77(d,J＝9.0Hz,1H),3.50-3.45(m,2H),3.29-3.26(m,1H),3.19-3.15(m,1H),2.94-2.85(m,2H),1.87-1.80(m,2H),1.69-1.59(m,2H),1.17(s,9H),1.08(d,J＝6.0Hz,3H)ppm；LC-MS:m/z 275.2[M+H] ⁺ 。

Example 7: preparation of intermediate (R) -2-methyl-N- ((1R) -2-methyl-8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1K)

Step one: 2-methyl-1-carbonyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

Under the condition of 0 ℃ and nitrogen protection, sequentially adding 1-carbonyl-8-azaspiro [4.5] into a 100mL dry single-neck flask]To tert-butyl decane-8-carboxylate (1 g,3.95 mmol) and dried tetrahydrofuran (15 mL) was then slowly added dropwise LiHMDS (3.95 mL,3.95 mmol), after stirring at this temperature for 1 hour, methyl iodide (0.25 mL,3.95 mmol) was added thereto, and stirring was continued for 2 hours. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×20 mL), and the combined organic phases were taken up in Na ₂ SO ₄ Drying, concentrating the filtrate under reduced pressure and purifying by column chromatography (0 to 20% gradient of ethyl acetate/petroleum ether) to give 2-methyl-1-carbonyl-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester. LCMS: m/z 368.0[ M+H ]] ⁺ .

Step two and three: (R) -2-methyl-N- ((1R) -2-methyl-8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1K)

Following the same procedure as described in example 3, intermediate C-1A, tert-butyl ester of the ketone intermediate 2-methyl-1-carbonyl-8-azaspiro [4.5] decane-8-carboxylate was subjected to reductive amination and removal of the Boc protecting group to give (R) -2-methyl-N- ((1R) -2-methyl-8-azaspiro [4.5] decane-1-yl) propane-2-sulfinamide C-1K.

¹ H NMR(400MHz,CDCl ₃ )δ5.07-4.97(m,1H),3.32-3.20(m,1H),3.01-2.84(m,2H),2.81-2.61(m,2H),2.20-2.11(m,1H),2.02-1.34(m,8H),1.25-1.20(m,9H),1.06-0.99(m,3H)ppm；LCMS:m/z 273.0[M+H] ⁺ Example 8: (R) -N- ((R) -3, 3-dimethyl-1-oxa-8-azaspiro [ 4.5)]Preparation of decan-4-yl) -2-methylpropan-2-sulfinamide (C-1L)

Step one: 3, 3-dimethyl-4-oxo-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

Nitrogen protectionNext, the mixture was introduced into 4-carbonyl-1-oxa-8-azaspiro [4.5] at-78deg.C]To a solution of tert-butyl decane-8-carboxylate (5 g,19.6 mmol) in THF (50 mL) was slowly added LiHMDS (1M in THF; 19.6mL,19.6 mmol) and maintained stirring at-78℃for 2 hours. Then, after the reaction mixture was warmed to room temperature, methyl iodide (1.22 mL,19.6 mmol) was added thereto in portions. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and saturated NaHCO ₃ The solution (150 mL) was quenched and then extracted with ethyl acetate (2X 300 mL). The combined organic phases were dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (0 to 15% gradient of ethyl acetate/petroleum ether) to give 3, 3-dimethyl-4-carbonyl 1-oxa-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester (1 g, yield: 18%) and 3-methyl-4-carbonyl-1-oxa-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester (0.7 g, yield: 14%)

3, 3-dimethyl-4-carbonyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester:

¹ HNMR(400MHz,CDCl ₃ )δ3.94(brs,2H),3.89(s,2H),3.16-3.10(m,2H),1.70-1.61(m,4H),1.48(s,9H),1.14(s,6H)ppm；LCMS:m/z 306[M+Na] ⁺ .

3-methyl-4-carbonyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester:

¹ H-NMR(400MHz,CDCl ₃ )δ4.38(t,J＝8.8Hz,1H),3.96(brs,2H),3.67(t,J＝9.6Hz,1H),3.14-3.09(m,2H),2.65-2.58(m,1H),1.75-1.46(m,13H),1.15(d,J＝7.2Hz,3H)ppm；LCMS:m/z 292[M+Na] ⁺ .

step two: (S) -4- ((tert-butylsulfinyl) imino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 3, 3-dimethyl-4-carbonyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylate (2.0 g,7.1 mmol) in THF (5.0 mL) was added (R) -2-methylpropane-2-sulfinamide (2.56 g,21.2 mmol) and tetraethyltitanate (8.05 g,35.3 mmol). The resulting reaction mixture was stirred at 90℃for 48 hours. The reaction mixture was quenched with methanol (10 mL), diluted with ethyl acetate (50 mL), then filtered through celite, and the crude product obtained was concentrated by reverse phase flash chromatography using 0.1% formic acid and acetonitrile as eluent to give tert-butyl (S) -4- ((tert-butylsulfinyl) imino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylate (1.5 g, yield: 55%).

¹ HNMR(400MHz,CDCl ₃ )δ4.10-3.88(brs,2H),3.80-3.72(m,2H),3.04(brs,2H),1.70-1.59(m,5H),1.46-1.41(m,14H),1.24-1.14(m,9H)ppm；LCMS:m/z 331[M-55] ⁺ .

Step three: (R) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester and (S) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

To (S) -4- ((tert-butylsulfinyl) imino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5]To a mixed solvent of MeOH and THF (3:1; 30 mL) was added NaBH t-butyl decane-8-carboxylate (1.5 g,3.88 mmol) ₄ (886 mg,23.3 mmol) was then stirred under reflux for 16 hours. After cooling to room temperature, part of the solvent was concentrated under reduced pressure to 10mL, and then the mixture was poured into ice water (100 mL) and stirred for 10 minutes. The resulting solid precipitate was removed by filtration and extracted with ethyl acetate (3X 50 mL) and the combined organic phases concentrated by drying. The obtained crude product is purified and separated to obtain (R) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester (350 mg, yield: 23%) and (S) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester (350 mg, yield: 23%) and a mixture of both (400 mg, yield: 28%).

(S) -4- (((R) -tert-butylsulfinyl) amino) -3,3-dimethyl-1-oxa-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester: ¹ H NMR(400MHz,CDCl ₃ )δ3.94(brs,2H),3.61(d,J＝9.2Hz,1H),3.54(d,J＝9.2Hz,1H),3.22(d,J＝10Hz,1H),3.07-3.00(m,3H),1.54-1.49(m,4H),1.45(s,9H),1.24(s,9H),1.21(s,3H),1.03(s,3H)ppm；LCMS:m/z 411[M+Na] ⁺ ；[α] ²⁵ _D ＝+19.62(c 0.25,MeOH)；retention time:1.835min

(R) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [ 4.5)]Decane-8-carboxylic acid tert-butyl ester: ¹ HNMR(400MHz,CDCl ₃ )δ4.03-3.93(m,2H),3.62-3.58(m,1H),3.50-3.47(m,1H),3.30(brs,1H),3.11-2.96(m,3H),1.91-1.76(m,2H),1.54-1.56(m,merged in DMSO,2H)1.43(s,9H),1.25(s,9H),1.03(s,3H),0.99(s,3H)ppm；LCMS:m/z 411[M+Na] ⁺ ；[α] ²⁵ _D ＝-43.56(c 0.25,MeOH)；retention time:2.009min.

step four: (R) -N- ((R) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropan-2-sulfinamide (C-1L)

The same synthesis method used for step nine of intermediate C-1J of synthesis example 6 was followed by removal of the Boc protecting group from tert-butyl (R) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylate to give (R) -N- ((R) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-4-yl) -2-methylpropan-2-sulfinamide C-1L.

¹ H-NMR(400MHz,DMSO-d ₆ )δ4.92(d,D ₂ O Exchangeable,J＝11.5Hz,1H),3.50(d,J＝9.0Hz,1H),3.43(d,J＝9.0Hz,1H),3.20-3.14(m,2H),3.09(d,J＝12.0,1H),3.00-2.89(m,2H),1.92-1.86(m,1H),1.82-1.80(m,2H),1.73-1.70(m,1H),1.19(s,9H),0.97(s,3H),0.94(s,3H)ppm；LCMS:m/z 289[M+H] ⁺ 。

Example 9: preparation of (R) -N- ((S) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropane-2-sulfinamide (C-1M)

The same synthesis method used for step nine of intermediate C-1J of synthesis example 6 was followed by removal of the Boc protecting group from tert-butyl (S) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylate to give (R) -N- ((S) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-4-yl) -2-methylpropan-2-sulfinamide C-1M.

¹ HNMR(400MHz,DMSO-d ₆ )δ8.40(brs,D ₂ O Exchangeable,1H),8.40(brs,D ₂ O Exchangeable,1H),5.27(d,J＝11.0Hz,1H),4.12-4.10(m,1H),3.77(d,J＝8.5Hz,1H),3.47-3.44(m,2H),3.28-3.24(m,1H),3.17-3.15(m,1H),2.95-2.87(m,2H),1.86-1.82(m,2H),1.69-1.59(m,2H),1.17(s,9H),1.08(d,J＝6.0Hz,3H)ppm；LCMS:m/z 289[M+H] ⁺ .

Example 10: preparation of intermediate (R) -2-methyl-N- ((1R) -3-methyl-8-aza-spiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1N)

Step one: 4-allyl-4-formylpiperidine-1-carboxylic acid tert-butyl ester

To a dry 1L flask was added tert-butyl 4-formylpiperidine-1-carboxylate (35.0 g,164 mmol), lithium tert-butoxide (15.77 g, 197mmol) and allyl bromide (11.54 mL,189 mmol) and DMF (328 mL) in this order, and the mixture was stirred at 0deg.C for 1 hour. After the reaction, the mixture was poured into a reactor containing saturated NH ₄ Aqueous Cl solution H2O (1:1,500 mL) in a separatory funnel was treated with Et ₂ O (5X 50 mL) extraction. The combined organic phases were dried over MgSO ₄ Drying, filtering, and concentrating the filtrate under reduced pressure. The resulting residue was purified by silica gel chromatography (0 to 25% gradient of ethyl acetate/petroleum ether) to give 4-allyl-4-formylpiperidine-1-carboxylic acid tert-butyl ester (24 g, yield: 48%) as a colorless oil.

¹ H NMR(400MHz,CDCl ₃ )δ9.52(s,1H),5.53-5.76(m,1H),4.96-5.19(m,2H),3.80(br.s.,2H),2.97(t,J＝11.49Hz,2H),2.26(d,J＝7.33Hz,2H),1.95(dt,J＝13.71,3.13Hz,2H),1.38-1.58(m,11H)ppm.

Step two: 4-allyl-4- (1-hydroxy-allyl) piperidine-1-carboxylic acid tert-butyl ester (C-1N-C)

To a dry 1L three-necked flask was added tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (24 g,95 mmol) and THF (300 mL), the solution was cooled to-78deg.C and vinylmagnesium bromide (1M in THF, 118mL,118 mmol) was slowly added dropwise under nitrogen. The resulting solution was allowed to slowly warm to room temperature over 1 hour. After the reaction, the mixture was poured into a reactor containing saturated NH ₄ Aqueous Cl (250 mL) was extracted with EtOAc (4X 50 mL) in a separatory funnel. The combined organic phases were dried over MgSO ₄ Drying, filtration and concentration of the filtrate under reduced pressure gave tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (26.7 g) which was used in the next step without further purification.

¹ H NMR(400MHz,CDCl ₃ )δ6.05-5.83(m,2H),5.32-5.21(m,2H),5.12(s,1H),5.08(d,J＝3.5Hz,1H),4.05-3.97(m,1H),3.71(s,2H),3.12(ddd,J＝13.8,10.4,3.6Hz,2H),2.33(dd,J＝14.3,7.8Hz,1H),2.20(dd,J＝14.3,7.2Hz,1H),1.60(q,J＝4.3Hz,2H),1.57-1.50(m,2H),1.45(s,9H)ppm.

Step three: 4-allyl-4-allyl piperidine-1-carboxylic acid tert-butyl ester

To a dry 1L three-necked flask was added, in order, tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (26.7 g,95 mmol), dess-Martin oxidant (44.3 g,105 mmol) and anhydrous dichloromethane (380 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction, the mixture was poured intoContaining NaHCO ₃ :Na ₂ SO ₃ Saturated aqueous (1:1, 300 mL) was added to the separatory funnel and extracted with DCM (4X 50 mL). The combined organic phases were dried over MgSO ₄ Drying, filtering, and concentrating the filtrate under reduced pressure to obtain white solid. The white solid was suspended in petroleum ether (250 mL) and sonicated for 20 minutes. The white suspension was filtered through a celite pad and removed under reduced pressure, and the filtrate was concentrated under reduced pressure to give 4-allylic-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (25 g, two-step yield: 94%).

¹ H NMR(400MHz,CDCl ₃ )δ6.80(dd,J＝16.8,10.3Hz,1H),6.39(dd,J＝16.8,1.9Hz,1H),5.70(dd,J＝10.3,1.9Hz,1H),5.55(ddt,J＝17.5,10.2,7.4Hz,1H),5.09-4.98(m,2H),3.77(s,2H),2.94(s,2H),2.31(d,J＝7.4Hz,2H),2.08(d,J＝13.8Hz,2H),1.47-1.41(m,11H)ppm。

Step four: 1-carbonyl-8-azaspiro [4.5] dec-2-ene-8-carboxylic acid tert-butyl ester

To a dry 1L three-necked flask was added a solution of tert-butyl 4-allylpiperidine-1-carboxylate (25 g,89.6 mmol), toluene (degassed, 850 mL) and Grubbs' second generation catalyst (2.02 g,2.38 mmol) in toluene (degassed, 100 mL) in sequence. The resulting mixture was stirred for 45 minutes under nitrogen at 85 ℃. After the reaction was completed, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give tert-butyl 1-carbonyl-8-azaspiro [4.5] dec-2-ene-8-carboxylate (19 g,83 mmol) as a brown solid. A solution of this compound and DDQ (560 mg,2.49 mmol) in toluene (540 mL) was stirred at room temperature for 15 minutes. The resulting bright red solution was filtered through a pad of celite. Charcoal (100 g) was added and the resulting suspension was stirred at room temperature for 2 hours. The mixture was filtered through a pad of celite, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give tert-butyl 1-carbonyl-8-azaspiro [4.5] dec-2-ene-8-carboxylate as a white solid (12 g, yield: 53.3%).

Step five: 3-methyl-1-carbonyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

To a nitrogen-protected 250mL dry three-necked flask, cuI (3.8 g,20 mmol) and anhydrous tetrahydrofuran (100 mL) were sequentially added, the solution was cooled to-20℃and MeLi (1.6M solution in THF, 25mL,40 mmol) was slowly added dropwise thereto, and after the dropwise addition was completed, the reaction solution was reacted at-20℃until the solution became clear. Then 1-carbonyl-8-azaspiro [4.5] was slowly added dropwise at this temperature]A solution of tert-butyl decane-2-ene-8-carboxylate (2.51 g,10 mmol) in tetrahydrofuran (20 mL). After the reaction, the mixture was poured into a reactor containing saturated NH ₄ In a separation funnel of aqueous Cl solution, it was extracted with ethyl acetate (3X 15 mL). The combined organic phases were dried over MgSO ₄ Drying, filtering and concentrating the filtrate under reduced pressure, purifying by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) to give 3-methyl-1-carbonyl-8-azaspiro [4.5]]Decane-2-ene-8-carboxylic acid tert-butyl ester (1.6 g, yield: 60%).

¹ H NMR(400MHz,CDCl ₃ )δ3.92(s,1H),3.81(s,1H),3.55(d,J＝5.0Hz,1H),3.13-3.04(m,1H),2.96(t,J＝10.9Hz,1H),2.56-2.46(m,1H),2.31-2.21(m,2H),1.94-1.75(m,2H),1.62-1.49(m,1H),1.45(s,9H),1.41-1.35(m,2H),1.15(d,J＝6.0Hz,3H),0.90(t,J＝6.9Hz,3H)ppm.

Step six and seven: (R) -2-methyl-N- ((1R) -3-methyl-8-aza-spiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1N)

The same synthetic procedure as used in steps eight and nine of the synthetic intermediate C-1J was used to obtain (R) -2-methyl-N- ((1R) -3-methyl-8-aza-spiro [4.5] decan-1-yl) propane-2-sulfinamide C-1N after reductive amination of the ketone intermediate tert-butyl 3-methyl-1-carbonyl-8-azaspiro [4.5] decan-2-ene-8-carboxylate and removal of the Boc protecting group.

¹ H NMR(400MHz,CDCl ₃ )δ ¹ H NMR(400MHz,DMSO-d ₆ )δ3.04-2.95(m,1H),2.75(s,2H),2.62-2.53(m,2H),1.93-1.57(m,5H),1.52-1.27(m,13H),0.96(d,J＝6.5Hz,3H)ppm；LCMS:m/z 273[M+H] ⁺ .

Example 11: preparation of intermediate (R) -2-methyl-N- ((1R, 3R) -3-methyl-8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1O)

Step one: (R) -3- ((tert-Butyldimethylsilyl) oxy) -1-carbonyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

To a dry 100mL three-necked flask, cuCl (19 mg,0.19 mmol),(s) -TolBlNAP (129 mg,0.19 mmol), sodium t-butoxide (18 mg,0.19 mmol) and THF (9 mL) were successively added, and the mixture was stirred at room temperature for 30 minutes. Adding B ₂ Pin ₂ (1.78 g,7.01 mmol) in THF (2.5 mL) and the resulting mixture was stirred at room temperature for 10 min. 1-carbonyl-8-azaspiro [4.5] was then added]A solution of tert-butyl decane-2-ene-8-carboxylate (1.60 g,6.37 mmol) in THF (9 mL) was then added with MeOH (0.53 mL,12.74 mmol). The resulting mixture was stirred at room temperature for 16 hours. After the reaction is finished, H is added ₂ O (20 mL), followed by sodium perborate (4.84 g,32 mmol) and the resulting mixture was vigorously stirred at room temperature for l hours. The green suspension obtained was filtered through a pad of celite and poured into a container containing NaHCO ₃ Saturated aqueous solution: na (Na) ₂ SO ₃ A saturated aqueous (40 mL) separating funnel was extracted with EtOAc (4X 40 mL). The combined organic phases were dried over MgSO ₄ Drying, filtering and concentrating the filtrate under reduced pressure to obtain crude (R) -3-hydroxy-1-carbonyl-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester.

Sequentially adding crude (R) -3-hydroxy-1-carbonyl-8-azaspiro [4.5] into a 100mL single-neck flask]Decane-8-carboxylic acid tert-butyl ester (theory, 6.37 mmol), imidazole (650 mg,9.56 mmol), TBSCl (1.20 g,7.96 mmol) and DMF (16 mL), the mixture was in a chamberThe reaction was stirred at room temperature for 16 hours. After the reaction, the reaction mixture was poured into a reactor containing saturated NH ₄ Aqueous Cl (30 mL) was extracted with ethyl acetate (5X 50 mL) in a separatory funnel. The combined organic phases were dried over MgSO ₄ The residue obtained was dried, filtered and concentrated under reduced pressure was purified by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give (R) -3- ((tert-butyldimethylsilyl) oxy) -1-carbonyl-8-azaspiro [4.5]Decane-8-carboxylic acid tert-butyl ester (1.26 g, yield: 51.6%) was a colorless oil.

LCMS:m/z 328[M-56+H] ⁺ .

Step di (1R, 3R) -3- ((tert-Butyldimethylsilyl) oxy) -1- ((R) -1, 1-dimethylethylsulfinylamino) -8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

The same synthetic procedure as used in step eight of synthetic intermediate C-1J was used to give, after reductive amination of tert-butyl ester of the ketone intermediate (R) -3- ((tert-butyldimethylsilyl) oxy) -1-carbonyl-8-azaspiro [4.5] decane-8-carboxylate, tert-butyl ester of (1R, 3R) -3- ((tert-butyldimethylsilyl) oxy) -1- ((R) -1, 1-dimethylethylsulfinylamino) -8-azaspiro [4.5] decane-8-carboxylate as a white solid (1.24 g, yield: 77%).

¹ H NMR(400MHz,CDCl ₃ )δ4.23(s,1H),3.84(d,J＝13.6Hz,2H),3.24(s,1H),2.77(td,J＝12.7,12.0,3.0Hz,2H),2.27(d,J＝8.8Hz,1H),1.72-1.54(m,5H),1.38(s,9H),1.19(d,J＝2.5Hz,3H),1.14(s,9H),0.80(s,9H),-0.03(s,6H)ppm；LCMS:m/z 488.9[M+H] ⁺ .

Step three: (R) -N- ((1R, 3R) -3-hydroxy-8-azaspiro [4.5] decan-1-yl) -2-methylpropan-2-sulfinamide (C-1O)

(1R) -3- ((tert-Butyldimethylsilyl) oxy) -1-((R) -1, 1-dimethylethylsulfinylamino) -8-azaspiro [4.5]]To a solution of tert-butyl decane-8-carboxylate (49 mg,0.1 mmol) in 1, 4-dioxane (1 mL) was added concentrated sulfuric acid (0.023 mL,0.4 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was brought to ph=12 with sodium hydroxide solution and then extracted with DCM (4×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the volatiles removed under reduced pressure to give (R) -N- ((1R, 3R) -3-hydroxy-8-azaspiro [ 4.5)]Decane-1-yl) -2-methylpropan-2-sulfinamide C-1O (20 mg, yield: 70%). LC-MS m/z 275[ M+H ]] ⁺ 。

Example 12: preparation of intermediate (R) -1- ((tert-butoxycarbonyl) amino) -3, 3-difluoro-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (C-1P)

Step one: (1R, 3R) -1-amino) -3-hydroxy-8-azaspiro [4.5] decane

To a solution of tert-butyl (1R, 3R) -3- ((tert-butyldimethylsilyl) oxy) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] decane-8-carboxylate (100 mg,0.2 mmol) in methanol (5 mL) at room temperature was slowly added a solution of 1, 4-dioxane hydrochloride (4M, 2mmol,0.5 mL) and the reaction mixture was heated at 40℃for 1 hour. Concentrating under reduced pressure to obtain (1R, 3R) -1-amino) -3-hydroxy-8-azaspiro [4.5] decane, which is directly used for the next reaction.

LC-MS:m/z 171.0

Step two: (1R, 3R) -1- ((tert-Butoxycarbonyl) amino) -3-hydroxy-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (C-1P-b)

The above (1R, 3R) -1-amino) -3-hydroxy-8-azaspiro [4.5]]Decane (0.2 mmol) was dissolved in tetrahydrofuran (10 mL) and then added (Boc) ₂ O (109 mg,0.5 mmol) and then DIPEA (516 mg,4.0 mmol) were added and the reaction stirred at room temperature for 16 hours. After the completion of the reaction, the reaction mixture,the reaction was quenched with saturated ammonium chloride, then extracted with diethyl ether (5×50 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) to give (1 r,3 r) -1- ((tert-butoxycarbonyl) amino) -3-hydroxy-8-azaspiro [ 4.5)]Decane-8-carboxylic acid tert-butyl ester C-1P-b (60 mg, two-step yield: 80%).

¹ H NMR(400MHz,CDCl ₃ )δ5.11(s,1H),4.36(s,1H),3.86-3.62(m,3H),2.94(t,J＝11.7Hz,2H),2.20-2.08(m,1H),1.81(d,J＝8.5Hz,1H),1.64-1.55(m,3H),1.49-1.42(m,3H),1.37(d,J＝4.9Hz,18H)ppm；LC-MS:m/z 393.2[M+H] ⁺ .

Step three: (R) -1- ((tert-Butoxycarbonyl) amino) -3-carbonyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

(1R, 3R) -1- ((tert-Butoxycarbonyl) amino) -3-hydroxy-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (60 mg,0.16 mmol) was dissolved in dichloromethane (5 mL) at 0deg.C, then Dess-Martin (76 mg,0.18 mmol) was slowly added at 0deg.C, and the reaction was kept at 0deg.C for 2 hours. After the reaction was completed, water (4 mL) was added to quench, followed by extraction with methylene chloride (5×50 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by silica gel chromatography (0 to 80% gradient of ethyl acetate/petroleum ether) to give tert-butyl (R) -1- ((tert-butoxycarbonyl) amino) -3-carbonyl-8-azaspiro [4.5] decane-8-carboxylate (30 mg, yield: 50%).

¹ H NMR(400MHz,CDCl ₃ )δ4.46(d,J＝9.4Hz,1H),4.07(d,J＝7.0Hz,1H),3.92(s,2H),2.73(t,J＝12.7Hz,2H),2.63(dd,J＝19.0,8.1Hz,1H),2.41(d,J＝18.3Hz,1H),2.14-2.01(m,2H),1.68(td,J＝12.9,4.6Hz,1H),1.59(d,J＝4.8Hz,1H),1.39(d,J＝2.5Hz,18H),1.26(d,J＝2.9Hz,1H)ppm；LC-MS:m/z 369.1[M+H] ⁺ .

Step four: (R) -1- ((tert-Butoxycarbonyl) amino) -3, 3-difluoro-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

(R) -1- ((tert-Butoxycarbonyl) amino) -3-carbonyl 8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (80 mg,0.22 mmol) was dissolved in dichloromethane (10 mL), then DeoxyFluor (162. Mu.L, 0.88 mmol) was added and the reaction mixture was heated and stirred at 50℃for a further 48 h. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution at 0℃and extracted with ethyl acetate (3X 20 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R) -1- ((tert-butoxycarbonyl) amino) -3, 3-difluoro-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (46 mg, yield: 54%)

¹ H NMR(400MHz,CDCl ₃ )δ4.49(d,J＝9.9Hz,1H),3.92(dd,J＝24.5,15.9Hz,3H),2.87-2.68(m,2H),2.58-2.42(m,1H),2.21(td,J＝17.7,16.8,9.6Hz,1H),2.06-1.86(m,2H),1.60(t,J＝6.6Hz,1H),1.38(d,J＝4.0Hz,21H)ppm；LC-MS:m/z 391.1[M+H] ⁺

Step five: (R) -1-amino) -3, 3-difluoro-8-azaspiro [4.5] decane (C-1P)

(R) -1- ((tert-Butoxycarbonyl) amino) -3, 3-difluoro-8-azaspiro [4.5] at room temperature]To a solution of tert-butyl decane-8-carboxylate (46 mg,0.12 mmol) in methanol (5 mL) was slowly added a solution of 1, 4-dioxane hydrochloride (4M, 1.2mmol,0.3 mL), and the reaction mixture was reacted at room temperature for 1 hour. Concentrating under reduced pressure to obtain (R) -1-amino) -3, 3-difluoro-8-azaspiro [4.5]]Decane (C-1P). LC-MS: m/z 191.1[ M+H ]] ⁺ .

Example 13: preparation of intermediate 1-methyl-8-azaspiro [4.5] decan-1-amine (C-2A)

Step one: 1-hydroxy-1-methyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

To a solution of tert-butyl 1-carbonyl-8-azaspiro [4.5] decane-8-carboxylate (500 mg,2.0 mmol) in toluene (20 mL) at 0deg.C was slowly added dropwise a solution of methyl magnesium bromide in tetrahydrofuran (1M, 2.2mmol,2.2 mL), and the reaction solution was stirred at 0deg.C for 1 hour. After the reaction was completed, a saturated aqueous ammonium chloride solution was added to quench it, followed by extraction with ethyl acetate (3×20 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) to give tert-butyl 1-hydroxy-1-methyl-8-azaspiro [4.5] decane-8-carboxylate (410 mg, yield: 77%).

¹ H NMR(400MHz,CDCl ₃ )δ4.16-4.04(m,2H),3.12-2.56(m,2H),1.98-1.49(m,8H),1.49(s,9H),1.42-1.29(m,2H),1.16(s,3H)ppm；LC-MS:m/z 270.2[M+H] ⁺ .

Step two: n- (1-methyl-8-azaspiro [4.5] decan-1-yl) acetamides

1-hydroxy-1-methyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (410 mg,1.52 mmol) was dissolved in acetonitrile (1.82 mL), then concentrated sulfuric acid (1.56 mL) was added at 0℃and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into ice water, then alkalified to ph=12 with NaOH (50%) aqueous solution, followed by extraction with ethyl acetate (3×20 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product N- (1-methyl-8-azaspiro [4.5] decan-1-yl) acetamide (260 mg, yield: 81%), which was directly used for the next reaction.

LC-MS:m/z 211.0[M+H] ⁺ .

Step three: 1-methyl-8-azaspiro [4.5] decan-1-amine (C-2A)

The crude N- (1-methyl-8-azaspiro [4.5] decan-1-yl) acetamide (260 mg,1.23 mmol) was dissolved in 6M hydrochloric acid solution (5 mL) at room temperature, and the reaction mixture was reacted at 120℃for 4 hours under microwave heating. After completion, the reaction solution was concentrated under reduced pressure and then lyophilized to give a crude product of 1-methyl-8-azaspiro [4.5] decan-1-amine C-2A (200 mg, yield: 97%), which was used in the next reaction without purification.

LC-MS:m/z 169.1[M+H] ⁺ .

Example 14: preparation of intermediate tert-butyl (4-ethylpiperidin-4-yl) carbamate (C-3A)

Step one: 1-benzyl-4-ethylpiperidine-4-carboxylic acid methyl ester

LDA in tetrahydrofuran (1M, 5.1mmol,5.1 mL) was slowly added dropwise to a solution of methyl 1-benzylpiperidine-4-carboxylate (1 g,4.3 mmol) in tetrahydrofuran (10 mL) at-78deg.C under nitrogen, the reaction mixture was stirred for further 1 hour at-78deg.C, and then ethyl iodide (795 mg,5.1 mmol) in tetrahydrofuran (1 mL) was slowly added, and the reaction mixture was continued at-78deg.C for 4 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution was added to quench, followed by extraction with ethyl acetate (3×30 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) to give methyl 1-benzyl-4-ethylpiperidine-4-carboxylate (800 mg, yield: 71%).

LC-MS:m/z 262.2[M+H] ⁺ .

Step two: 1-benzyl-4-ethylpiperidine-4-carboxylic acid

1-benzyl-4-ethylpiperidine-4-carboxylic acid methyl ester (800 mg,3.23 mmol) was dissolved in an aqueous solution of ethanol (ethanol: water=4:1, 20 ml), followed by addition of NaOH (517 mg,12.9 mmol), and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, then acidified to ph=3 with 1N hydrochloric acid, then extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the product 1-benzyl-4-ethylpiperidine-4-carboxylic acid (720 mg, yield: 90%), which was directly used for the next reaction.

LC-MS:m/z 248.2[M+H] ⁺ .

Step three: 1-methyl-8-azaspiro [4.5] decan-1-amine

1-benzyl-4-ethylpiperidine-4-carboxylic acid (250 mg,1.0 mmol) was dissolved in tert-butanol (5 mL) at room temperature, then triethylamine (306 mg,3.0 mmol) and diphenyl azide phosphate (330 mg,2.0 mmol) were added, and the reaction solution was then heated under reflux for 8 hours. After the reaction was completed, the reaction was quenched with water, then extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by silica gel chromatography (0 to 70% gradient of ethyl acetate/petroleum ether) to give 1-methyl-8-azaspiro [4.5] decan-1-amine (160 mg, yield: 50%).

LC-MS:m/z 319.2[M+H] ⁺ .

Step four: (4-Ethylpiperidin-4-yl) carbamic acid tert-butyl ester

1-methyl-8-azaspiro [4.5] decan-1-amine (160 mg,0.5 mmol) was dissolved in 10mL of methanol at room temperature, pd/C (16 mg, 10%) was then added, and the reaction mixture was reacted under a hydrogen atmosphere for 16 hours. The resulting mixture was filtered through celite, then washed with ethyl acetate, and concentrated under reduced pressure to give tert-butyl (4-ethylpiperidin-4-yl) carbamate (110 mg, yield: 95%). The product was used directly in the next reaction.

LC-MS:m/z 229.2[M+H] ⁺ .

Step five: (4-Ethylpiperidin-4-yl) carbamic acid tert-butyl ester (C-3A)

Tert-butyl (4-ethylpiperidin-4-yl) carbamate (110 mg,0.5 mmol) was dissolved in methanol (3 mL) at room temperature, then 1, 4-dioxane hydrochloride solution (4N, 5mmol,1.1 mL) was added, the reaction solution was stirred at room temperature for 2 hours, and concentrated under reduced pressure to give tert-butyl (4-ethylpiperidin-4-yl) carbamate (C-3A) (50 mg, yield: 95%) as a product which was directly used in the next reaction.

LC-MS:m/z 128.2[M+H] ⁺ .

Example 15: preparation of intermediate tert-butyl ((4-methylpiperidin-4-yl) methyl) carbamate (C-4A)

Step one: 1-benzoyl-4-methylpiperidine-4-carbonitrile

To a 100mL dry one-necked flask under nitrogen was added 4-methylpiperidine-4-carbonitrile (496 mg,4 mmol), DCM (10 mL) and triethylamine (611 mg,6 mmol) in sequence, followed by slow dropwise addition of benzoyl chloride (670 mg,4.8 mmol) at room temperature. The mixture was stirred at room temperature for a further 1 hour and TLC monitored the reaction until the starting material was reacted. After quenching the reaction with 1N HCl solution, dichloromethane (3X 20 mL) was extracted and the combined organic phases were taken up in Na ₂ SO ₄ Dried, the filtrate was concentrated under reduced pressure and purified by column chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give 1-benzoyl-4-methylpiperidine-4-carbonitrile (650 mg, yield: 70.72%).

LC-MS:m/z 229[M+H] ⁺ .

Step two: 1-benzoyl- ((4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester

To a 100mL dry flask at 0deg.C under nitrogen was added, in order, 1-benzoyl-4-methylpiperidine-4-carbonitrile (650 mg,2.85 mmol), nickel chloride hexahydrate (135 mg,0.67 mmol), di-tert-butyl dicarbonate (1.86 g,8.54 mmol) and methanol (12 mL), and sodium borohydride (754 mg,20 mmol). The reaction was then stirred at room temperature for 12 hours and TLC monitored the reaction until the starting material was complete. After the reaction was completed, the reaction solution was concentrated and extracted with dichloromethane (3×20 mL), and the combined organic phases were extracted with Na ₂ SO ₄ Drying, concentrating the filtrate under reduced pressure and purifying by column chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give tert-butyl 1-benzoyl- ((4-methylpiperidin-4-yl) methyl) carbamate (620 mg, yield: 65.50%)

LC-MS:m/z 333[M+H] ⁺ .

Step three: (4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester (C-4A)

To a 100mL one-necked flask was successively added tert-butyl ((1-benzoyl-4-methylpiperidin-4-yl) methyl) carbamate (620 mg,1.87 mmol), ethanol (8 mL) and 7N NaOH (2 mL), and the mixture was heated to 90℃under the protection of nitrogen and stirred for 8 hours, cooled to room temperature, filtered, diluted with water and extracted with ethyl acetate (3X 20 mL), and the combined organic phases were taken up in Na ₂ SO ₄ Dried, the filtrate was concentrated under reduced pressure and purified by column chromatography (0 to 80% gradient of ethyl acetate/petroleum ether) to give tert-butyl ((4-methylpiperidin-4-yl) methyl) carbamate C-4A (300 mg, yield: 70.5%).

¹ H NMR(400MHz,DMSO-d ₆ )δ3.97(q,J＝7.0Hz,2H),2.80(d,J＝6.4Hz,2H),2.65(d,J＝30.3Hz,2H),1.38(s,9H),1.27(dd,J＝16.2,7.0Hz,2H),1.10(d,J＝12.8Hz,2H),0.81(s,3H)ppm；LC-MS:m/z 229[M+H] ⁺ .

EXAMPLE 16 preparation of intermediate tert-butyl ((4-phenylpiperidin-4-yl) methyl) carbamate (C-4B)

Step one: 4-cyano-4-phenylpiperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (2-chloroethyl) carbamate (2 g,8.26 mmol) and 2-benzyl cyanide (968 mg,8.26 mmol) in anhydrous DMF (20 mL) was added NaH (60% dispersed in mineral oil, 1.6g,41.3 mmol) in portions at 0deg.C. The reaction mixture was heated at 60 ℃ for 16 hours. After the reaction was completed, the mixture was quenched with ice-water (30 mL) and then extracted with 3X 50 mL. The combined organic layers were washed with saturated brine (2×50 mL), then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give tert-butyl 4-cyano-4-phenylpiperidine-1-carboxylate (500 mg, yield: 21%).

LCMS:m/z 187.2[M-100] ⁺ .

Step two: 4- (aminomethyl) -4-phenylpiperidine-1-carboxylic acid tert-butyl ester

4-cyano-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (0.5 g,1.75 mmol) was dissolved in 20mL of methanol, followed by addition of palladium on carbon (50 mg) and reaction mixture was reacted under hydrogen for 16 hours. After the completion of the reaction, the mixture was filtered and concentrated under reduced pressure to give tert-butyl 4- (aminomethyl) -4-phenylpiperidine-1-carboxylate (0.4 g, yield: 80%).

¹ H NMR(400MHz,CDCl ₃ )δ7.38(t,J＝7.6Hz,2H),7.30(d,J＝7.5Hz,2H),7.24(d,J＝7.2Hz,1H),3.75(d,J＝7.8Hz,2H),3.04(t,J＝11.2Hz,2H),2.58(brs,2H),2.21(d,J＝13.9Hz,2H),1.76-1.61(m,2H),1.44(s,9H)ppm；LC-MS:m/z 191.0[M-100] ⁺ .

Step two: (4-phenylpiperidin-4-yl) methylamine (C-4B)

Tert-butyl 4- (aminomethyl) -4-phenylpiperidine-1-carboxylate (0.4 g,1.37 mmol) was dissolved in 10mL of methanol, then 1, 4-dioxane solution (4M, 13.7 mmol) of hydrochloric acid was added at room temperature, and the reaction was continued at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give (4-phenylpiperidin-4-yl) methylamine C-4B (0.25 g, yield: 95%) and the crude product was used directly in the next reaction.

LC-MS:m/z 191.2[M+H] ⁺ .

EXAMPLE 17 preparation of intermediate 6- ((tert-Butoxycarbonyl) amino) -2, 3-dichloropyridine-4-thiol sodium (F-1A)

Step one: (6-Chloropyridin-2-yl) carbamic acid tert-butyl ester

To a dry 250mL three-necked flask under nitrogen atmosphere was added 6-chloropyridin-2-amine (8 g,62.2 mmol) and THF (80 mL), and the mixture was stirred at 0deg.C for 10 min, then NaHDMS (124.4mL,1.0M in THF) was added, then a solution of di-tert-butyl dicarbonate (16.3 g,74.7 mmol) in tetrahydrofuran (50 mL) was slowly added while maintaining the system at 0deg.C, and the reaction was continued at 0deg.C for 4 hours. After the reaction is finished, H is added ₂ O (40 mL) was then extracted with EtOAc (3X 100 mL). The combined organic phases were dried over MgSO ₄ The residue obtained was dried, filtered and concentrated under reduced pressure was purified by silica gel chromatography (0 to 10% gradient of ethyl acetate/petroleum ether) to give tert-butyl (6-chloropyridin-2-yl) carbamate (7 g, yield: 49%).

¹ H NMR(400MHz,DMSO-d6)δ10.04(s,1H),7.79-7.58(m,2H),7.02(dd,J＝5.5,2.9Hz,1H),1.38(s,9H)ppm；LCMS:m/z 288.1[M+H] ⁺ .

Step two: (5, 6-dichloropyridin-2-yl) carbamic acid tert-butyl ester

To a dry 100mL round bottom flask was added tert-butyl (6-chloropyridin-2-yl) carbamate (7 g,30.6 mmol) and N, N-dimethylformamide (50 mL), the mixture was stirred at room temperature for 10 min, then N-chlorosuccinimide (4.50 g,33.67 mmol) was added and the mixture was reacted at 100℃for 4 h. After the reaction is finished, H is added after the reaction night temperature is reduced to room temperature ₂ O (50 mL), then extracted with ethyl acetate (3X 80 mL), then washed with saturated aqueous lithium chloride (2X 40 mL). The organic phase was treated with MgSO ₄ Dried, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (0 to 5% gradient of ethyl acetate/petroleum ether) to give tert-butyl (5, 6-dichloropyridin-2-yl) carbamate (5.3 g, yield: 65.8%).

¹ H NMR(400MHz,CDCl ₃ )δ7.86(d,J＝8.7Hz,1H),7.69(d,J＝8.7Hz,1H),7.24(s,1H),1.51(s,9H)；LCMS:m/z 207.1[M-55] ⁺ .

Step three: (5, 6-dichloro-4-iodopyridin-2-yl) carbamic acid tert-butyl ester

To a dry 100mL round bottom flask under nitrogen was added tert-butyl (5, 6-dichloropyridin-2-yl) carbamate (5.3 g,20.14 mmol) and tetrahydrofuran (50 mL), n-butyllithium (44.3mmol,2.5M in THF) was slowly added dropwise at-78℃and the reaction stirred at this temperature for 1 hour. A solution of iodine (3.07 g,24.17 mmol) in tetrahydrofuran (20 mL) was then slowly added dropwise, and the reaction was continued at-78℃for 3 hours. After the reaction is finished, H is added ₂ O (50 mL) was followed by extraction with EtOAc (3X 80 mL). The combined organic phases were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (0 to 5% gradient of ethyl acetate/petroleum ether) to give tert-butyl (5, 6-dichloro-4-iodopyridin-2-yl) carbamate (4.3 g, yield: 55%).

¹ H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.36(s,1H),1.46(s,9H)ppm；LCMS:m/z 334.1[M-55] ⁺ .

Step four: 3- ((6- ((tert-Butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) propanoic acid methyl ester

To a dry 100mL round bottom flask under nitrogen was added tert-butyl (5, 6-dichloro-4-iodopyridin-2-yl) carbamate (3.2 g,8.22 mmol), palladium acetate (92 mg,0.41 mmol), xantphos (284 mg,0.49 mmol), DIPEA (2.12 g,16.46 mmol) and 1, 4-dioxane (30 mL) in sequence. The reaction mixture was stirred with heating at 100℃for 2 hours. Filtration and concentration under reduced pressure gave a residue which was purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/petroleum ether) to give methyl 3- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) propanoate (3 g, yield: 96%).

¹ H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.73(s,1H),3.64(s,3H),3.26(t,J＝6.9Hz,2H),2.82(t,J＝6.9Hz,2H),1.46(s,9H)ppm；LCMS:m/z 326.3[M-55] ⁺ .

Step five: 6- ((tert-Butoxycarbonyl) amino) -2, 3-dichloropyridine-4-thiol sodium (F-1A)

To a dried 100mL round bottom flask was added methyl 3- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) propanoate and tetrahydrofuran (30 mL) in sequence, and then a solution of sodium ethoxide in ethanol (21%, 6 mL) was slowly added dropwise at room temperature and the reaction solution was stirred at room temperature for 1 hour. Concentrated under reduced pressure, then dichloromethane (10 mL) was added to precipitate a large amount of brown solid, which was filtered and washed with dichloromethane, and dried to give sodium 6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridine-4-thiol F-1A (2.1 g, yield: 84%).

¹ H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.61(s,1H),1.41(s,9H)ppm；LCMS:m/z 262.2[M-55] ⁺ The following intermediates F-1B, F-1C, F-1D, F-1E, F-1F, F-1G, F-1H, F-1I, F-1J, F-1K, F-1L, F-1M, F-1N, F-1O, F-1P were obtained by reacting similar intermediate starting materials according to the synthetic procedure of example 17.

EXAMPLE 18 preparation of the intermediate sodium 3-chloro-2-methylpyridine-4-thiolate (F-1Q)

Step one: 3- ((3-chloro-2-methylpyridin-4-yl) thio) propanoic acid methyl ester

Intermediate 3- ((2, 3-dichloropyridin-4-yl) thio) propanoic acid methyl ester obtained during the synthesis of intermediate F-1G was used in the following reaction.

To a dry 100mL round bottom flask under nitrogen was added methyl 3- ((2, 3-dichloropyridin-4-yl) thio) propanoate (500 mg,1.88 mmol), pd (PPh) ₃ ) ₄ (217 mg,0.188 mmol), trimethylboroxine (354 mg,2.82 mmol), potassium carbonate (389 mg,2.82 mmol) and 1, 4-dioxane (10 mL). The reaction mixture was stirred under nitrogen at 100℃for 6 hours. The residue obtained was filtered and concentrated under reduced pressure was purified by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give methyl 3- ((3-chloro-2-methylpyridin-4-yl) thio) propionate (320 mg, yield: 69%).

Step two: 3-chloro-2-methylpyridine-4-thiol sodium (F-1Q)

To a dried 100mL round bottom flask was added methyl 3- ((3-chloro-2-methylpyridin-4-yl) thio) propionate (320 mg,1.30 mmol) and tetrahydrofuran (10 mL) in sequence, and then a solution of sodium ethoxide in ethanol (21%, 2 mL) was slowly added dropwise at room temperature, and the reaction solution was stirred at room temperature for 1 hour. Concentrated under reduced pressure, then dichloromethane (10 mL) was added, a large amount of brown solid was precipitated, filtered, and washed with dichloromethane, and dried to give 3-chloro-2-methylpyridine-4-thiol sodium F-1Q (200 mg, yield: 85%).

¹ H NMR(400MHz,DMSO-d6)δ7.37(d,J＝4.8Hz,1H),6.97(d,J＝4.8Hz,1H),2.31(s,3H)ppm；LCMS:m/z 160.0[M+H] ⁺ .

The following intermediate F-1R was obtained by following the synthetic procedure of example 18, using similar intermediate starting materials.

Example 19: preparation of intermediate 6- ((tert-butoxycarbonyl) amino) -3-chloro-2-methylpyridine-4-thiol sodium (F-1S)

Step one: 3- ((6- ((tert-Butoxycarbonyl) amino) -3-chloro-2-methylpyridin-4-yl) thio) propanoic acid methyl ester

Intermediate 3- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) propanoic acid methyl ester obtained during the synthesis of intermediate F-1A was used in the following reaction.

To a dry 100mL round bottom flask under nitrogen was added methyl 3- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) propanoate (600 mg,1.57 mmol), [1,1' -bis (tert-butylphosphine) ferrocene palladium dichloride (103 mg,0.157 mmol), trimethylcyclotriboroxane (301 mg,2.4 mmol), potassium carbonate (331 mg,2.4 mmol), 1, 4-dioxane (10 mL) and water (1 mL) in sequence. The reaction mixture was stirred under nitrogen at 100℃for 6 hours. The residue obtained was filtered and concentrated under reduced pressure was purified by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give methyl 3- ((6- ((tert-butoxycarbonyl) amino) -3-chloro-2-methylpyridin-4-yl) thio) propanoate (420 mg, yield: 74%).

¹ H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.64(s,1H),3.64(s,3H),3.21(t,J＝6.9Hz,2H),2.80(t,J＝6.9Hz,2H),1.46(s,9H)ppm；LCMS:m/z 361.1[M+H] ⁺ .

Step two: 6- ((tert-Butoxycarbonyl) amino) -3-chloro-2-methylpyridine-4-thiol sodium (F-1S)

To a dried 100mL round bottom flask was added methyl 3- ((6- ((tert-butoxycarbonyl) amino) -3-chloro-2-methylpyridin-4-yl) thio) propanoate (420 mg,1.17 mmol) and tetrahydrofuran (10 mL) in sequence, then a solution of sodium ethoxide in ethanol (21%, 2 mL) was slowly added dropwise at room temperature and the reaction stirred at room temperature for 1 hour. Concentrated under reduced pressure, then dichloromethane (10 mL) was added, a large amount of brown solid was precipitated, filtered, and washed with dichloromethane, and dried to give sodium 6- ((tert-butoxycarbonyl) amino) -3-chloro-2-methylpyridine-4-thiolate F-1S (320 mg, yield: 92%).

¹ H NMR(400MHz,DMSO-d ₆ )δ9.87(s,1H),7.63(s,1H),3.64(s,3H),1.46(s,9H)ppm；LCMS:m/z275.0[M+H] ⁺ .

EXAMPLE 20 preparation of intermediate 3-amino-2-chlorobenzothiolate hydrochloride (F-2A)

Step one: 2-chloro-3-aminobenzenethiol tert-butyl ester

To a dry 100mL round bottom flask under nitrogen was added 2-chloro-3-fluoroaniline (5 g,34.3 mmol) and N-methylpyrrolidone (50 mL) in sequence followed by 2-methylpropane-2-thiol (8.66 g,96.04 mmol) and cesium carbonate (22.36 g,68.6 mmol) and the reaction mixture was heated at 120℃for 16 h. After cooling to room temperature, the reaction solution was diluted with 60mL of ethyl acetate and washed with a saturated aqueous lithium chloride solution (30 mL), water (30 mL) and a saturated aqueous sodium chloride solution (30 mL) in this order, and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 2-chloro-3-aminobenzene thiol (6.04 g, yield: 82%).

LCMS:m/z 216.1[M+H] ⁺ .

Step two: 3-amino-2-chlorobenzothiolate hydrochloride (F-2A)

To a dry 100mL round bottom flask was added tert-butyl 2-chloro-3-aminobenzene thiol (6.04 g,28 mmol) and concentrated hydrochloric acid (50 mL) and the reaction mixture was heated and stirred at 45℃for 8 hours. After naturally cooling to room temperature, the reaction solution was further cooled to 0℃and a large amount of white solid was precipitated, filtered, and washed with concentrated hydrochloric acid and petroleum ether in this order to give 3-amino-2-chlorobenzothiolate hydrochloride F-2A (4.9 g, yield: 90%).

LCMS:m/z 160.0[M+H] ⁺ .

EXAMPLE 21 preparation of the Compound 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-methylpiperidin-4-amine

Step one: (1- (8-iodoimidazo [1,2-c ] pyrimidin-5-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Under the protection of nitrogen, sequentially adding 5-chloro-8-iodoimidazo [1,2-c ] into a dry 50mL single-neck flask]Pyrimidine E1 (50 mg,0.18 mmol), tert-butyl (4-methylpiperidin-4-yl) carbamate (77 mg,0.36 mmol), DIEA (46 mg,0.36 mmol) and NMP (5 mL) were then reacted at 90℃with stirring for 2 hours. After the reaction was completed, the obtained residue was poured into water (10 mL) and stirred at room temperature for 5 minutes. Then extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with MgSO ₄ The residue obtained is dried, filtered and concentrated under reduced pressure and purified by chromatography on silica gel (gradient 0 to 80% of ethyl acetate) Ethyl acetate/petroleum ether) to give a pale yellow solid (1- (8-iodoimidazo [1, 2-c)]Pyrimidin-5-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (70 mg, yield: 43%)

¹ H NMR(400MHz,DMSO-d ₆ )δ8.02(s,1H),7.89(d,J＝1.5Hz,1H),7.62(d,J＝1.4Hz,1H),3.49(d,J＝13.4Hz,2H),3.21(ddd,J＝13.3,10.8,2.6Hz,2H),2.18(d,J＝13.9Hz,2H),1.65(ddd,J＝14.1,10.7,3.8Hz,2H),1.40(s,9H),1.28(s,3H)ppm；LCMS:m/z 458.1[M+H] ⁺ .

Step two: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Into a dry 50mL three-necked flask was successively charged (1- (8-iodoimidazo [1, 2-c)]Pyrimidin-5-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (70 mg,0.15 mmol), cuprous iodide (3 mg,0.015 mmol), 1, 10-phenanthroline (6 mg,0.030 mmol), 2, 3-dichlorobenzothiool (32 mg,0.18 mmol), potassium phosphate (66 mg,0.30 mmol) and 5mL dioxane. The mixture was heated under nitrogen for 3 hours. After the reaction is finished, saturated NH is added ₄ Cl solution (10 mL). Then extracted with ethyl acetate (3×50 mL). The combined organic phases were taken up with Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, purification of the resulting residue by silica gel chromatography (0 to 60% gradient of ethyl acetate/petroleum ether) to give imidazo [1,2-c ] as a pale yellow solid (1- (8- ((2, 3-dichlorophenyl) thio)]Pyrimidin-5-) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (30 mg, yield: 39%).

LC-MS:m/z 508.1[M+H] ⁺ .

Step three: 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-methylpiperidin-4-amine

To a dried 50mL round bottom flask was added tert-butyl (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-) -4-methylpiperidin-4-yl) carbamate (30 mg,0.059 mmol) and a solution of 1, 4-dioxane (7M, 5 mL) of hydrochloric acid, which were reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by high performance liquid chromatography to give the product 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-methylpiperidin-4-amine (15 mg, yield: 62%).

¹ H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.84(d,J＝1.3Hz,1H),7.55(d,J＝1.2Hz,1H),7.41(dd,J＝8.0,1.2Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(dd,J＝8.1,1.2Hz,1H),3.60(t,J＝4.2Hz,4H),1.73-1.60(m,4H),1.19(s,3H)ppm；LC-MS:m/z 408.1[M+H] ⁺ .

Using the synthetic method of example 21, the following compounds can be synthesized:

EXAMPLE 22- ((2, 3-dichlorophenyl) thio) -5- (1, 8-diazaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidine

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.89(s,1H),7.57(s,1H),7.41(d,J＝8.1Hz,1H),7.12(t,J＝8.0Hz,1H),6.72(d,J＝8.1Hz,1H),3.79(ddd,J＝13.9,7.1,3.7Hz,2H),3.49(ddd,J＝12.8,8.0,3.4Hz,2H),3.19(t,J＝6.9Hz,2H),2.04(ddd,J＝12.3,8.1,3.5Hz,2H),1.93(dt,J＝20.5,6.5Hz,6H)ppm；LC-MS:m/z434.1[M+H] ⁺ .

EXAMPLE 23 preparation of Compound 8- ((2, 3-dichlorophenyl) thio) -5- (piperidin-1-yl) imidazo [1,2-c ] pyrimidine

To a dry 50mL single neck flask was added sequentially 5-chloro-8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c]Pyrimidine B1 (50 mg,0.15 mmol), piperidine (20 mg,0.23 mmol), DIEA (39 mg,0.3 mmol) and NMP (5 mL) were reacted at 90℃with stirring for 2 hours. ReactionAfter completion, the obtained residue was poured into water (100 mL) and stirred at room temperature for 5 minutes. Then extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with MgSO ₄ The residue obtained was dried, filtered and concentrated under reduced pressure was purified by chromatography on silica gel (0 to 80% gradient of ethyl acetate/petroleum ether) and purified by high performance liquid chromatography to give the product ((1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1, 2-c)]Pyrimidin-5-yl) pyrrolidin-3-yl-methyl-carbamic acid tert-butyl ester (20 mg, yield: 35%)

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.83(d,J＝1.4Hz,1H),7.55(d,J＝1.4Hz,1H),7.41(dd,J＝8.0,1.3Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(dd,J＝8.1,1.3Hz,1H),3.50(d,J＝5.6Hz,4H),1.79-1.63(m,6H)ppm；LC-MS:m/z 378.7[M+H] ⁺ .

Using the synthetic method of example 23, the following compounds can be synthesized:

example 24:8- ((2, 3-dichlorophenyl) thio) -5- (3, 5-dimethylpiperazin-1-yl) imidazo [1,2-c ] pyrimidine

¹ H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.03(s,1H),7.92(d,J＝1.2Hz,1H),7.55(d,J＝1.2Hz,1H),7.44-7.37(m,1H),7.12(t,J＝8.1Hz,1H),6.69(dd,J＝8.1,1.1Hz,1H),3.89(d,J＝12.0Hz,2H),3.02(d,J＝6.6Hz,2H),2.72-2.59(m,2H),1.05(t,J＝6.0Hz,7H)ppm；LC-MS:m/z 407.7[M+H] ⁺ .

Example 25:8- ((2, 3-dichlorophenyl) thio) -5- (4-methylpiperazin-1-yl) imidazo [1,2-c ] pyrimidine

¹ H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.04(s,1H),7.91(d,J＝1.4Hz,1H),7.57(d,J＝1.4Hz,1H),7.41(dd,J＝8.0,1.2Hz,1H),7.12(t,J＝8.0Hz,1H),6.70(dd,J＝8.1,1.2Hz,1H),3.59-3.50(m,4H),2.59-2.53(m,4H),2.27(s,3H)ppm；LC-MS:m/z 393.8[M+H] ⁺ .

Example 26: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-phenylpiperidin-4-yl) methylamine

¹ H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.88(s,1H),7.54(s,1H),7.50-7.33(m,5H),7.28(t,J＝6.8Hz,1H),7.10(t,J＝8.0Hz,1H),6.67(d,J＝8.1Hz,1H),3.77(d,J＝12.5Hz,2H),3.31-3.22(m,2H),3.09(s,1H),2.82(s,1H),2.32(s,2H),2.06(t,J＝10.3Hz,2H)；LC-MS:m/z 484.7[M+H] ⁺ .

Example 27: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ8.03(s,1H),7.81(d,J＝1.5Hz,1H),7.57(d,J＝1.4Hz,1H),7.42(dd,J＝8.0,1.3Hz,1H),7.12(t,J＝8.1Hz,1H),6.69(dd,J＝8.1,1.4Hz,1H),3.93(t,J＝14.9Hz,2H),3.31(d,J＝19.3Hz,2H),3.28-3.16(m,3H),2.252.06(m,2H),1.90(dd,J＝32.1,11.8Hz,2H),1.61-1.45(m,2H)ppm；LC-MS:m/z 484.1[M+H] ⁺ .

Example 28: (R) -3- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-azaspiro [5.5] undecan-7-amine

¹ H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.82(d,J＝1.2Hz,1H),7.56(d,J＝1.2Hz,1H),7.41(dd,J＝8.0,1.2Hz,1H),7.12(t,J＝8.1Hz,1H),6.68(dd,J＝8.1,1.2Hz,1H),3.80(d,J＝4.8Hz,2H),3.33(dd,J＝29.0,11.6Hz,2H),2.77(d,J＝5.2Hz,1H),2.04(dd,J＝30.0,14.7Hz,2H),1.85-1.12(m,10H)ppm；LC-MS:m/z 461.7[M+H] ⁺ .

Example 29:1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-ethylpiperidin-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.88(d,J＝1.5Hz,1H),7.58(d,J＝1.4Hz,1H),7.42(dd,J＝8.0,1.3Hz,1H),7.12(t,J＝8.1Hz,1H),6.70(dd,J＝8.1,1.4Hz,1H),3.71-3.64(m,4H),1.90-1.73(m,4H),1.69(q,J＝7.3Hz,2H),0.93(t,J＝7.5Hz,3H)ppm；LC-MS:m/z 422.1[M+H] ⁺ .

Example 30:8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -1-methyl-8-aza-spiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.83(s,1H),7.56(s,1H),7.41(d,J＝8.1Hz,1H),7.17-7.08(m,1H),6.69(d,J＝8.2Hz,1H),4.08-3.93(m,2H),3.18-3.04(m,2H),3.04-2.94(m,1H),2.45(s,1H),1.90-1.29(m,8H),0.95(t,J＝6.3Hz,3H)ppm；LC-MS:m/z 462.1[M+H] ⁺ .

Example 31: preparation of the Compound 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-amine

Step one: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-yl) carbamic acid tert-butyl ester

Using the same method as example 23, B1 was substituted with the corresponding amine to give tert-butyl (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-yl) carbamate.

LC-MS:m/z 424.1[M+H] ⁺ .

Step two: the compound 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-amine

The same procedure as in step three of example 21 was used to remove the Boc protecting group from tert-butyl (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-yl) carbamate to give the compound 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-amine.

¹ H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.93(d,J＝1.1Hz,1H),7.46(s,1H),7.40(d,J＝8.0Hz,1H),7.13(t,J＝8.0Hz,1H),6.63(d,J＝8.1Hz,1H),4.14(d,J＝9.3Hz,1H),4.05(d,J＝5.9Hz,1H),3.82(d,J＝11.2Hz,3H),2.24(d,J＝7.3Hz,1H),2.02(s,1H)ppm；LC-MS:m/z 379.9[M+H] ⁺ .

Using the synthetic method of example 31, the following compounds can be synthesized:

example 32:1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) piperidin-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.03(s,1H),7.86(s,1H),7.57(s,1H),7.42(d,J＝7.6Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(d,J＝8.1Hz,1H),4.00(d,J＝13.0Hz,2H),3.13(d,J＝11.5Hz,2H),2.02-1.86(m,3H),1.62(dd,J＝21.0,9.8Hz,2H),1.23(s,1H)；LC-MS:m/z 394.7[M+H] ⁺ .

Example 33: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-yl) methylamine

¹ H NMR(400MHz,DMSO-d6)δ8.17(d,J＝1.6Hz,1H),7.91(s,1H),7.45(d,J＝1.5Hz,1H),7.39(d,J＝7.7Hz,1H),7.12(t,J＝8.0Hz,1H),6.63(d,J＝8.1Hz,1H),4.04(ddd,J＝11.5,8.9,5.5Hz,2H),3.94-3.86(m,1H),3.72(dd,J＝10.8,7.6Hz,2H),2.93(d,J＝7.2Hz,2H),2.16(dq,J＝11.9,6.2Hz,1H),1.79(dq,J＝12.3,8.3Hz,1H)ppm；LC-MS:m/z 394.1[M+H] ⁺ .

Example 34: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-methylpiperidin-4-yl) methylamine

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.83(d,J＝1.5Hz,1H),7.57(d,J＝1.4Hz,1H),7.42(dd,J＝8.0,1.3Hz,1H),7.12(t,J＝8.1Hz,1H),6.69(dd,J＝8.1,1.3Hz,1H),3.68(dt,J＝13.7,4.6Hz,2H),3.44(td,J＝9.6,4.8Hz,2H),2.76(s,2H),1.70(ddd,J＝13.3,9.2,3.7Hz,2H),1.62-1.49(m,2H),1.08(s,3H)ppm；LC-MS:m/z 422.1[M+H] ⁺ .

Example 35: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) piperidin-4-yl) methylamine

¹ H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.03(s,1H),7.83(s,1H),7.57(s,1H),7.42(d,J＝7.7Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),4.05(d,J＝13.2Hz,2H),3.07(t,J＝12.3Hz,2H),2.75(d,J＝5.9Hz,2H),1.88(d,J＝11.8Hz,3H),1.53-1.35(m,2H)ppm；LC-MS:m/z 409.8[M+H] ⁺ .

Example 36:2- (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) piperidin-4-yl) ethan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.85(d,J＝1.2Hz,1H),7.56(d,J＝1.2Hz,1H),7.41(dd,J＝8.0,1.2Hz,1H),7.12(t,J＝8.1Hz,1H),6.69(dd,J＝8.1,1.2Hz,1H),4.02(d,J＝12.9Hz,2H),3.03(t,J＝12.0Hz,2H),2.87-2.78(m,2H),1.82(d,J＝12.5Hz,2H),1.70(s,1H),1.55(dd,J＝14.7,6.9Hz,2H),1.40(dd,J＝21.6,11.5Hz,2H)ppm；LC-MS:m/z 422.7[M+H] ⁺ .

Example 37: synthesis of the Compound (S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine

Step one: (R) -N- ((S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropan-2-sulfinamide

The same procedures used in example 23 were repeated except for using the corresponding amine to give (R) -N- ((S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropan-2-sulfinamide.

LC-MS:m/z 554.1[M+H] ⁺ .

Step two: (S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine

To a 50mL one-necked flask under nitrogen atmosphere were successively added (R) -N- ((S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropan-2-sulfinamide (70 mg,0.13 mmol) and methanol (0.5 mL), and a 1, 4-dioxane solution (0.05 mL, 4M) of hydrochloric acid was added dropwise at room temperature, and the mixture was stirred at room temperature for reaction for 1 hour. After the reaction was completed, cooled to room temperature, filtered and the resulting residue was concentrated under reduced pressure and purified by high performance liquid chromatography to give (S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine (10 mg, yield: 17%).

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.83(d,J＝1.5Hz,1H),7.57(d,J＝1.4Hz,1H),7.42(dd,J＝8.0,1.4Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(dd,J＝8.1,1.4Hz,1H),4.00(dd,J＝8.8,6.4Hz,1H),3.87-3.71(m,2H),3.66(d,J＝8.5Hz,1H),3.29-3.27(m,1H),3.17(t,J＝5.8Hz,2H),1.92-1.76(m,2H),1.57(dd,J＝12.5,5.8Hz,2H),1.24(d,J＝3.2Hz,1H)ppm；LC-MS:m/z 450.1[M+H] ⁺ .

Following the synthetic method of example 37, the following compounds may be synthesized:

example 38: (R) -1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) azepan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.95(s,2H),7.48(s,1H),7.40(d,J＝7.9Hz,1H),7.12(t,J＝8.0Hz,1H),6.66(d,J＝8.0Hz,1H),4.03-3.89(m,2H),3.81-3.61(m,2H),3.20(s,1H),2.15(s,1H),1.95(d,J＝14.1Hz,4H),1.56(d,J＝10.7Hz,1H)ppm；LC-MS:m/z 409.8[M+H] ⁺ .

Example 39: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.03(s,1H),7.84(s,1H),7.56(s,1H),7.41(d,J＝7.9Hz,1H),7.12(t,J＝8.1Hz,1H),6.70(d,J＝8.1Hz,1H),3.94(t,J＝13.7Hz,2H),3.54(d,J＝8.7Hz,1H),3.45(d,J＝8.7Hz,1H),3.32(d,J＝12.2Hz,2H),2.68(s,1H),1.98-1.88(m,2H),1.65(s,2H),1.02(s,3H),0.95(s,3H)；LC-MS:m/z 479.7[M+H] ⁺ .

Example 40: (S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.84(s,1H),7.56(s,1H),7.41(d,J＝7.9Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(d,J＝8.1Hz,1H),3.94(t,J＝14.1Hz,2H),3.54(d,J＝8.7Hz,1H),3.45(d,J＝8.7Hz,1H),3.35-3.25(m,2H),2.69(s,1H),1.98-1.85(m,2H),1.71-1.59(m,2H),1.03(s,3H),0.95(s,3H)；LC-MS:m/z 479.7[M+H] ⁺ .

Example 41: (1R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-methyl-8-aza-spiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.81(dd,J＝7.4,1.6Hz,1H),7.56(d,J＝1.6Hz,1H),7.41(dd,J＝8.0,1.4Hz,1H),7.12(t,J＝8.0Hz,1H),6.68(dd,J＝8.1,1.4Hz,1H),3.95(d,J＝11.9Hz,2H),3.12(t,J＝12.0Hz,2H),2.89(d,J＝5.8Hz,1H),2.08-1.44(m,9H),1.00(dd,J＝31.0,6.6Hz,3H)ppm；LC-MS:m/z462.1[M+H] ⁺ .

Example 42: (1R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-8-aza-spiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.80(s,1H),7.56(s,1H),7.41(d,J＝8.0Hz,1H),7.12(t,J＝8.1Hz,1H),6.69(d,J＝8.1Hz,1H),3.99-3.80(m,2H),3.24-2.98(m,3H),2.27-1.14(m,9H),1.04-0.95(m,3H)ppm；LC-MS:m/z 462.1[M+H] ⁺ .

Example 43: (4R) -4-amino-8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-2-ol

¹ H NMR(400MHz,DMSO-d6)δ8.37(s,1H),8.04(s,1H),7.81(s,1H),7.57(s,1H),7.42(d,J＝7.9Hz,1H),7.12(t,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),4.15(d,J＝6.5Hz,1H),3.91(d,J＝14.3Hz,2H),3.22(s,2H),2.93(t,J＝7.3Hz,1H),2.27-2.20(m,1H),1.89-1.66(m,5H),1.54(dt,J＝13.4,6.7Hz,1H),1.35(d,J＝12.9Hz,1H)ppm；LC-MS:m/z 465.7[M+H] ⁺ .

Example 44: (3S, 4S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.84(s,1H),7.56(s,1H),7.41(d,J＝7.9Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),4.15-4.06(m,1H),3.73(s,2H),3.56(d,J＝8.5Hz,1H),3.42-3.27(m,3H),3.05(d,J＝4.8Hz,1H),1.91(dt,J＝39.6,9.8Hz,2H),1.67(dd,J＝25.7,13.7Hz,2H),1.12(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 463.7[M+H] ⁺ .

Example 45: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -1-oxa-8-aza-spiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.60(s,1H),7.48(s,1H),7.20(d,J＝6.4Hz,1H),6.95(t,J＝6.4Hz,1H),6.70(d,J＝6.4Hz,1H),4.00-3.85(m,4H),3.46(t,J＝8.8Hz,2H),3.20(t,J＝5.2Hz,1H),2.39-2.35(m,1H),1.94-1.89(m,2H),1.80-1.74(m,2H),1.68-1.65(m,1H)ppm；LCMS:m/z 450.1[M+H] ⁺ .

Example 46: synthesis of the Compound (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -N-methyl-8-aza-spiro [4.5] decan-1-amine

Step one: (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide

Using the same method as example 23, B1 was substituted with amine to give (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropan-2-sulfinamide (70 mg, yield: 80%)

LC-MS:m/z 552.1[M+H] ⁺ .

Step two: (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -N, 2-dimethylpropane-2-sulfinamide

To a dry 50mL round bottom flask was added sequentially (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1, 2-c)]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-yl) -2-methylpropan-2-sulfinamide (70 mg,0.13 mmol) and DMF (5 mL). NaH (10.4 mg,0.26 mmol) was then slowly added at 0deg.C, the mixture was stirred at this temperature for 10 minutes, and then CH was slowly added while maintaining 0deg.C ₃ I (28 mg,0.20 mmol) and then stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (3X 10 mL) and the combined organic phases were separated over MgSO ₄ The residue obtained was dried, filtered and concentrated under reduced pressure was purified by silica gel chromatography (0 to 80% gradient of ethyl acetate/petroleum ether) to give (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1, 2-c) as a pale yellow solid]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-yl)-N, 2-dimethylpropane-2-sulfinamide (50 mg, yield: 49%)

LC-MS:m/z 566.1[M+H] ⁺ .

Step three: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -N-methyl-8-aza-spiro [4.5] decan-1-amine

The same procedures used in example 37 step two were repeated except for removing sulfinyl groups from (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -N, 2-dimethylpropane-2-sulfinamide to give (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -N-methyl-8-aza-spiro [4.5] decan-1-amine.

¹ H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.03(s,1H),7.82(s,1H),7.55(s,1H),7.41(d,J＝8.0Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(d,J＝8.1Hz,1H),3.87(d,J＝13.2Hz,2H),3.22(dd,J＝22.1,10.8Hz,2H),2.56(t,J＝7.3Hz,1H),2.35(s,3H),1.89(ddd,J＝33.1,16.7,7.8Hz,4H),1.72-1.33(m,6H)ppm；LC-MS:m/z461.7[M+H] ⁺ .

Example 47: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

Step one: (R) -N- ((R) -8- (8-iodoimidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfonamide

To a dry 50mL single-necked flask was successively added 5-chloro-8-iodoimidazo [1,2-c ] ]Pyrimidine E1 (50 mg,0.18 mmol), (R) -2-methyl-N- ((R) -8-azaspiro [ 4.5)]Decane-1-yl) propane-2-sulfinamide (C-1A) (93 mg,0.36 mmol), DIEA (46 mg,0.36 mmol) and NMP (5 mL) were then reacted with stirring at 90℃for 2 hours. After the reaction was completed, the obtained residue was poured into water (10 mL) and stirred at room temperature for 5 minutes. Then use BEthyl acetate (3×20 mL) and the combined organic phases were extracted with MgSO ₄ The residue obtained was dried, filtered and concentrated under reduced pressure was purified by silica gel chromatography (0 to 80% gradient of ethyl acetate/petroleum ether) to give (R) -N- ((R) -8- (8-iodoimidazo [1, 2-c) as a pale yellow solid]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-yl) -2-methylpropan-2-sulfonamide (80 mg, yield: 88%)

¹ H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.79(d,J＝1.4Hz,1H),7.64(d,J＝1.4Hz,1H),4.97(d,J＝8.0Hz,1H),3.77-3.65(m,2H),3.23-3.13(m,1H),3.04(dd,J＝30.0,11.5Hz,2H),2.03-1.78(m,4H),1.67-1.31(m,6H),1.13(s,9H)ppm；LC-MS:m/z 502.1[M+H] ⁺ .

Step two: (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide

(R) -N- ((R) -8- (8-iodoimidazo [1, 2-c) was sequentially added to a dry 50mL three-necked flask]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-yl) -2-methylpropane-2-sulfonamide (80 mg,0.16 mmol), cuprous iodide (3 mg,0.016 mmol), 1, 10-phenanthroline (6 mg,0.032 mmol), 2, 3-dichlorobenzothiool (34 mg,0.192 mmol), potassium phosphate (68 mg,0.32 mmol) and 10mL dioxane solution. The mixture was heated under nitrogen for 3 hours. After the reaction is finished, saturated NH is added ₄ Cl solution (50 mL). It was extracted with ethyl acetate (3×20 mL). The combined organic phases were taken up with Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, purification of the resulting residue by silica gel chromatography (0 to 10% gradient of methanol/ethyl acetate) afforded (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1, 2-c) as a pale yellow solid]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-yl) -2-methylpropan-2-sulfinamide (60 mg, yield: 68%).

¹ H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.76(d,J＝1.4Hz,1H),7.56(d,J＝1.4Hz,1H),7.40(dd,J＝8.0,1.3Hz,1H),7.11(t,J＝8.0Hz,1H),6.68(dd,J＝8.1,1.3Hz,1H),5.00(d,J＝8.1Hz,1H),3.94(dd,J＝12.8,3.4Hz,2H),3.26-3.14(m,3H),2.08-1.84(m,4H),1.69-1.36(m,6H),1.14-1.11(m,9H)ppm；LC-MS:m/z552.1[M+H] ⁺ .

Step three: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

To a dry 50mL round bottom flask was added successively (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropan-2-sulfinamide (example 17-2) (60 mg,0.11 mmol) and a 1, 4-dioxane solution of hydrochloric acid (7M, 5 mL) and reacted at room temperature for 1 hour. The reaction solution was distilled under reduced pressure, and the obtained crude product was purified by reverse phase high performance liquid chromatography to give the product (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine (25 mg, yield: 51%).

¹ H NMR(400MHz,CD ₃ OD-d4)δ8.54(s,2H),8.04(s,1H),7.81(s,1H),7.58(s,1H),7.33(dd,J＝8.0,1.3Hz,1H),7.05(t,J＝8.0Hz,1H),6.68(dd,J＝8.1,1.3Hz,1H),4.03(t,J＝14.7Hz,2H),3.38(s,2H),2.27(d,J＝5.4Hz,1H),1.97-1.63(m,9H)ppm；LC-MS:m/z 448.1[M+H] ⁺ .

Following the synthetic method of example 47, the following compounds can be synthesized:

Example 48: (R) -7- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -7-aza-spiro [3.5] nonan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.02(s,1H),7.82(d,J＝1.6Hz,1H),7.55(s,1H),7.41(d,J＝7.8Hz,1H),7.12(t,J＝8.1Hz,1H),6.69(d,J＝7.9Hz,1H),3.91(d,J＝13.2Hz,1H),3.84-3.73(m,1H),3.18-3.08(m,3H),2.13(q,J＝8.0Hz,1H),1.83(td,J＝10.7,8.5,4.2Hz,2H),1.80-1.69(m,3H)ppm；LC-MS:m/z 434.1[M+H] ⁺ .

Example 49:7- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -7-aza-spiro [3.5] nonan-2-amine

¹ H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.83(d,J＝1.6Hz,1H),7.56(d,J＝1.5Hz,1H),7.41(dd,J＝8.0,1.4Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(dd,J＝8.1,1.4Hz,1H),3.50(d,J＝10.2Hz,2H),3.41(s,2H),2.71-2.64(m,1H),2.36-2.30(m,1H),2.21(s,2H),1.81(d,J＝26.6Hz,5H)ppm；LC-MS:m/z 434.1[M+H] ⁺ .

Example 50: (7R) -2- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-aza-spiro [4.4] nonan-7-ylamine

¹ H NMR(400MHz,DMSO-d ₆ )δ8.36(brs,1H),8.18(s,1H),7.89(d,J＝2.4Hz,1H),7.43(s,1H),7.38(d,J＝6.0Hz,1H),7.11(t,J＝6.4Hz,1H),6.64(d,J＝6.0Hz,1H),3.96-3.74(m,4H),3.53-3.51(m,1H),2.00-1.60(m,8H)ppm；LCMS:m/z 434.2[M+H] ⁺ .

Example 51: (R) -8- (8- ((6-amino-3-chloro-2-methyl-pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl 1-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.17(s,2H),8.08(s,1H),7.90(s,1H),7.65(s,1H),5.67(s,1H),

4.09-3.93(m,2H),3.61(dd,J＝14.2,9.1Hz,4H),3.10(d,J＝5.4Hz,1H),2.35(d,J＝15.8Hz,3H),2.03-1.71(m,4H),1.16(s,3H),1.07(s,3H)ppm；LCMS:m/z 474.1[M+H] ⁺ .

Example 52: (S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(DMSO-d6)δ8.43(s,1H),8.02(s,1H),7.79-7.80(d,1H),7.56-7.57(d,1H),7.40-7.42(d,1H),7.11-7.15(t,1H),6.68-6.71(d,1H),3.88(t,2H),3.24(t,2H),3.01(t,1H),1.60-1.90(m,5H),1.30-1.59(m,5H)ppm；LC-MS:m/z 448.1[M+H] ⁺ .

Example 53: (R) -8- (8- ((2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.80(d,J＝1.5Hz,1H),7.57(d,J＝1.4Hz,1H),7.49(dd,J＝7.7,1.6Hz,1H),7.15(dtd,J＝19.6,7.4,1.6Hz,2H),6.76(dd,J＝7.7,1.7Hz,1H),3.93-3.80(m,2H),3.21(td,J＝11.2,2.7Hz,2H),3.00(s,1H),2.05-1.75(m,4H),1.75-1.35(m,6H)ppm；LCMS:m/z 414.1[M+H] ⁺ .

Example 54: (R) -8- (8- ((3-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(CD ₃ OD-d4)δ7.96(s,1H),7.78(s,1H),7.58(s,1H),7.23-7.27(m,3H),7.14-7.16(m,1H),3.83(m,2H),3.24(m,2H),2.89(m,1H),1.77-1.83(m,4H),1.51-1.62(m,2H),1.354-1.46(m,4H)ppm；LCMS:m/z414.1[M+H] ⁺ .

Example 55: (R) -8- (8- ((4-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.79-7.75(m,1H),7.58(d,J＝1.2Hz,1H),7.33(d,J＝8.5Hz,2H),7.23(d,J＝8.5Hz,2H),3.91-3.71(m,2H),3.18(t,J＝12.3Hz,2H),3.00(s,1H),2.05-1.66(m,5H),1.64-1.34(m,5H)ppm；LCMS:m/z 414.1[M+H] ⁺ .

Example 56: (R) -8- (8- ((2, 6-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.66(s,1H),7.64(s,1H),7.60(s,1H),7.51(t,J＝8.1Hz,1H),7.09(s,1H),3.64(s,2H),3.04(q,J＝12.4Hz,2H),2.74(t,J＝7.2Hz,1H),1.89-1.74(m,4H),1.52(s,2H),1.42-1.24(m,4H)ppm；LCMS:m/z 450.0[M+H] ⁺ .

Example 57: (R) -8- (8- ((2, 4-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.81(d,J＝1.6Hz,1H),7.69(d,J＝2.3Hz,1H),7.56(d,J＝1.4Hz,1H),7.20(dd,J＝8.6,2.3Hz,1H),6.75(d,J＝8.6Hz,1H),3.94-3.79(m,2H),3.20(q,J＝11.9Hz,2H),2.77(t,J＝7.3Hz,1H),1.90-1.77(m,4H),1.67-1.52(m,2H),1.37(td,J＝27.0,26.1,12.9Hz,4H)ppm；LCMS:m/z 450.0[M+H] ⁺ .

Example 58: (R) -8- (8- ((2, 5-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(CD ₃ OD-d4)δ8.02(s,1H),7.82(s,1H),7.52-7.58(m,2H),7.22-7.25(m,1H),6.71(s,1H),3.88-3.89(m,2H),3.22-3.24(m,2H),2.81-2.83(m,1H),1.77-1.83(m,4H),1.51-1.62(m,2H),1.354-1.46(m,4H)ppm；LCMS:m/z 450.0[M+H] ⁺ .

Example 59: (R) -8- (8- ((2-isopropylphenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ7.76(s,1H),7.58(s,2H),7.37(d,J＝7.7Hz,1H),7.24(s,1H),7.06(d,J＝6.1Hz,2H),3.73(s,2H),3.52(s,1H),3.11(d,J＝12.8Hz,2H),2.76(s,1H),1.83(d,J＝31.7Hz,4H),1.58(d,J＝42.0Hz,2H),1.36(s,4H),1.24(d,J＝7.0Hz,6H)ppm；LCMS:m/z 423.2[M+H] ⁺ .

Example 60: (R) -8- (8- ((2-methoxyphenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ7.77(s,1H),7.73(s,1H),7.58(s,1H),7.19(t,J＝7.9Hz,1H),7.05(d,J＝8.2Hz,1H),6.82-6.69(m,2H),3.87(s,3H),3.77(d,J＝12.4Hz,2H),3.17(s,2H),2.97(s,2H),1.97(s,1H),1.77-1.30(m,9H)ppm；LCMS:m/z 410.1[M+H] ⁺ .

Example 61: (R) -methyl 2- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) benzoic acid ester

¹ H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.95(dd,J＝7.8,1.6Hz,1H),7.78(d,J＝1.5Hz,1H),7.53(d,J＝1.4Hz,1H),7.30(td,J＝7.7,1.6Hz,1H),7.21(t,J＝7.5Hz,1H),6.77(d,J＝8.1Hz,1H),3.91(s,3H),3.85(d,J＝13.4Hz,2H),3.23(d,J＝12.8Hz,2H),2.97(t,J＝7.0Hz,1H),1.97(d,J＝7.0Hz,2H),1.82-1.40(m,8H)ppm；LC-MS:m/z 438.1[M+H] ⁺ .

Example 62: (R) -8- (8- ((4-aminophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.61(s,1H),7.24(d,J＝7.5Hz,2H),7.13(s,1H),6.58(d,J＝7.5Hz,2H),5.48(s,2H),3.60(s,2H),3.17(s,2H),3.04-3.01(m,1H),1.40(s,10H)ppm；LC-MS:m/z 396.2[M+H] ⁺ .

Example 63: (R) -8- (8- ((3-amino-2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.31(s,2H),7.85(s,1H),7.78(s,1H),7.58(s,1H),6.80(t,J＝7.9Hz,1H),6.59(d,J＝8.0Hz,1H),5.94(d,J＝7.8Hz,1H),5.50(s,2H),3.84(t,J＝13.1Hz,2H),3.17(s,2H),3.04(s,1H),2.00(q,J＝7.2Hz,2H),1.83-1.37(m,10H)ppm；LC-MS:m/z 429.1[M+H] ⁺ .

Example 64: (R) -8- (8- ((3- (trifluoromethyl) phenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.31(s,2H),8.00(s,1H),7.79(d,J＝1.6Hz,1H),7.59-7.52(m,1H),7.47(dd,J＝16.9,9.2Hz,5H),3.84(t,J＝13.0Hz,2H),3.22(d,J＝13.1Hz,2H),2.98(s,1H),1.79(d,J＝13.8Hz,5H),1.60-1.36(m,5H)ppm；LC-MS:m/z 448.1[M+H] ⁺ .

Example 65: (R) -N- (4- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) phenyl) acetamide

¹ H NMR(400MHz,DMSO-d6)δ10.04(d,J＝5.3Hz,1H),8.35(s,1H),7.74(s,1H),7.61(d,J＝13.9Hz,2H),7.54(d,J＝8.5Hz,2H),7.31(d,J＝8.4Hz,2H),3.73(t,J＝12.0Hz,2H),3.12(s,2H),2.97(s,1H),2.02(s,3H),1.96(s,1H),1.74(dt,J＝53.1,26.6Hz,5H),1.50(d,J＝35.3Hz,4H)ppm；LC-MS:m/z 396.2[M+H] ⁺ .

Example 66: (R) -5- ((5- (1-amino-8-aza-spiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -1,3, 4-thiadiazol-2-amine

¹ H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.96(s,1H),7.81(d,J＝1.5Hz,1H),7.66(d,J＝1.4Hz,1H),7.33(s,2H),3.83(td,J＝11.2,9.7,4.9Hz,2H),3.20(s,2H),3.05(d,J＝6.9Hz,1H),1.99(t,J＝6.5Hz,1H),1.86-1.69(m,4H),1.62-1.38(m,5H)ppm；LC-MS:m/z 403.1[M+H] ⁺ .

Example 67: (R) -8- (8- ((1-methyl-1H-imidazol-2-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ7.76(d,J＝1.5Hz,1H),7.60(dd,J＝6.8,1.4Hz,1H),7.39(d,J＝1.1Hz,1H),7.35(d,J＝7.0Hz,1H),7.00(d,J＝1.1Hz,1H),3.80(d,J＝2.6Hz,3H),3.63(d,J＝10.4Hz,2H),3.08(t,J＝12.2Hz,2H),2.73(t,J＝7.3Hz,1H),1.90-1.67(m,4H),1.65-1.51(m,2H),1.50-1.29(m,4H)ppm；LC-MS:m/z 384.1[M+H] ⁺ .

Example 68: (R) -8- (8- (naphthalen-1-ylsulfanyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(CD ₃ OD-d4)δ8.35-8.40(m,2H),7.99-8.02(m,1H),7.89-7.91(m,1H),7.76(m,1H),7.57-7.64(m,4H),7.43-7.47(m,2H),3.73(m,2H),3.11(m,2H),2.95(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LC-MS:m/z 430.2[M+H] ⁺ .

Example 69: (R) -8- (8- (thiazol-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.35(s,1H),8.11(s,1H),7.82(s,1H),7.69(d,J＝3.3Hz,1H),7.62(s,1H),7.58(d,J＝3.3Hz,1H),3.89(d,J＝4.1Hz,2H),3.25(t,J＝12.2Hz,2H),3.07(s,1H),2.32-2.25(m,2H),2.06-1.69(m,5H),1.65-1.40(m,5H)ppm；LC-MS:m/z 387.1[M+H] ⁺ .

Example 70: (R) -8- (8- (oxazol-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(CD ₃ OD-d4)δ8.12(s,1H),8.04(s,1H),7.80(s,1H),7.60(s,1H),7.22(s,1H),3.86(m,2H),3.22(m,2H),2.98(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LC-MS:m/z 371.1[M+H] ⁺ .

Example 71: synthesis of the Compound (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) acrylamide

Step one: n- (2-chloro-3- ((5- ((R) -1, 1-dimethylethylidene) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2d ] pyrimidin-8-yl) thio) phenyl) acrylamide

During the course of synthesis example 63, the intermediate (R) -N- ((R) -8- (8- ((3-amino-2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decylcyclobutan-1-yl) -2-methylpropan-2-sulfinamide obtained was used for the following reaction.

To a 100mL round bottom flask at 0deg.C was added successively (R) -N- ((R) -8- (8- ((3-amino-2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decacyclobutan-1-yl) -2-methylpropan-2-sulfinamide (60 mg,0.11 mmol), triethylamine (22 mg,0.22 mmol) and dichloromethane (5 mL), and then acryloyl chloride (23 mg,0.22 mmol) was slowly added dropwise to the reaction solution at 0deg.C, and the reaction solution was reacted at room temperature for 2 hours after the dropwise addition. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (3X 20 mL), and the organic phase was washed with water (20 mL. Times.1) and saturated brine (20 mL. Times.1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Chromatography (petroleum ether: ethyl acetate=1:1) afforded the crude product N- (2-chloro-3- ((5- ((R) -1, 1-dimethylethylidene) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2d ] pyrimidin-8-yl) thio) phenyl) acrylamide (30 mg, yield: 46%).

LC-MS:m/z 587.2[M+H] ⁺ .

Step two: (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) acrylamide

Following the same procedure as in step two of example 37, sulfinyl group was removed to give (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) acrylamide.

¹ H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.99(s,1H),7.80(s,1H),7.57(s,1H),7.49(s,1H),7.10(t,J＝8.0Hz,1H),6.72-6.51(m,2H),6.29(d,J＝16.9Hz,1H),5.81(d,J＝10.3Hz,1H),3.87(dd,J＝14.9,10.9Hz,2H),3.20(s,2H),3.01(t,J＝6.8Hz,1H),2.05-1.34(m,10H)ppm；LC-MS:m/z 482.8[M+H] ⁺ .

Following the synthetic method of example 71, the following compounds may be synthesized:

example 72: (R) -N1- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -N2, N2-dimethyloxyacetamide

¹ H NMR(400MHz,DMSO-d ₆ )δ8.00(s,1H),7.80(s,1H),7.57(s,1H),7.41(d,J＝8.0Hz,1H),7.13(t,J＝8.0Hz,1H),6.62(d,J＝8.2Hz,1H),5.49(s,1H),3.86(d,J＝12.7Hz,2H),3.81(s,3H),3.23(t,J＝12.7Hz,2H),3.11(s,3H),3.02(d,J＝6.8Hz,1H),2.05-1.75(m,5H),1.54(dd,J＝41.2,13.2Hz,5H)ppm；LC-MS:m/z528.2[M+H] ⁺ .

Example 73: synthesis of the Compound (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide

Step one: 2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxylic acid ethyl ester

To a solution of pyridin-2-amine (940 mg,10 mmol) in xylene (10 mL) under nitrogen was added triethyl methane tricarboxylate (4.64 g,20 mmol). The mixture was stirred at 140℃for a further 4 hours, TLC monitored until the starting material had reacted, and the reaction mixture was filtered and washed with ethyl acetate to give ethyl 2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxylate (1.95 g, yield: 83%)

¹ H NMR(400MHz,DMSO-d ₆ )δ12.47(s,1H),8.93(dd,J＝7.4,1.5Hz,1H),8.19(ddd,J＝8.6,7.1,1.6Hz,1H),7.43-7.34(m,2H),4.15(q,J＝7.1Hz,2H),1.23(t,J＝7.1Hz,3H)ppm；LCMS:m/z 235[M+H] ⁺ .

Step two: n- (2-chloro-3- ((5- ((R) -1, 1-dimethylethylidene) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2d ] pyrimidin-8-yl) thio) phenyl) -2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide

To a solution of ethyl 2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxylate (40 mg,0.169 mmol) in DMF (2 mL) was added (R) -N- ((R) -8- (8- ((3-amino-2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decacyclobutan-1-yl) -2-methylpropane-2-sulfinamide (60 mg,0.113 mmol) under nitrogen. The mixture was reacted at 160℃for 1 hour under microwaves. After the mixture was cooled to room temperature, the mixture was filtered, diluted with water and extracted with ethyl acetate (20 ml×3), the saturated brine was washed and the organic layer was mixed, dried over anhydrous sodium sulfate, filtered and concentrated to give N- (2-chloro-3- ((5- ((R) -1, 1-dimethylethylidene) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2d ] pyrimidin-8-yl) thio) phenyl) -2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide (20 mg, yield 21.7%).

LCMS:m/z 721[M+H] ⁺ .

Step three: (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide

The same procedures used in step two of example 37 were repeated except for removing sulfinyl group to give (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide.

¹ H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.43(s,1H),7.94(s,1H),7.79(s,1H),7.63(d,J＝34.6Hz,2H),7.03(d,J＝8.2Hz,1H),6.61-6.51(m,1H),6.40(d,J＝8.2Hz,1H),6.00(d,J＝6.9Hz,1H),5.45(s,1H),3.94-3.80(m,2H),3.23(s,2H),3.05(s,1H),2.09-1.34(m,10H)ppm；LC-MS:m/z 617.1[M+H] ⁺ .

Example 74: synthesis of the Compound (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -2-hydroxy-4-carbonyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide

Step one: 2-hydroxy-4-carbonyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxylic acid ethyl ester

To a 100mL round bottom flask was added ethyl 2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxylate (obtained in example 69, step one) (1 g,4.12 mmol), methanol (25 mL), and 10% Pd/C (862 mg) in sequence. The mixture was stirred further under hydrogen (hydrogen balloon) at room temperature for 2.5 hours, and TLC monitored the reaction until the starting material was reacted, and the reaction mixture was filtered through celite and concentrated in vacuo to give ethyl 2-hydroxy-4-carbonyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxylate (700 mg, yield: 69.4%).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.39(s,1H),4.09(q,J＝7.1Hz,2H),3.66(t,J＝6.0Hz,2H),2.77(t,J＝6.4Hz,2H),1.88-1.80(m,2H),1.78-1.71(m,2H),1.19(t,J＝7.1Hz,3H)ppm；LCMS:m/z[M+H] ⁺ .

The procedure was followed in the same manner as in step two and step three of example 73 to give (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -2-hydroxy-4-carbonyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide.

¹ H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.24(s,1H),7.96(s,1H),7.85(s,1H),7.81-7.72(m,2H),7.58(s,1H),3.86(dd,J＝30.5,16.1Hz,4H),3.29-3.15(m,4H),2.85-2.78(m,1H),2.11-1.61(m,14H)；LC-MS:m/z 621.1[M+H] ⁺ .

Example 75: synthesis of (R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

Step one: (R) -N- ((R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropan-2-sulfinamide

To a 20mL lock tube was added successively (R) -N- ((R) -8- (8-iodoimidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfonamide (60 mg,0.12 mmol), 1, 4-dioxane (2 mL), purified water (0.5 mL), (2, 3-dichlorophenyl) boronic acid (50 mg,0.24 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (9 mg,0.012 mmol) and potassium carbonate (50 mg,0.36 mmol) at room temperature. Nitrogen was bubbled for one minute and the tube was capped and heated to 80 degrees celsius for 6 hours. After completion of the reaction, 20mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL. Times.3). The organic phase was washed with water (20 mL. Times.1) and saturated brine (20 mL. Times.1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Chromatography (petroleum ether: ethyl acetate=1:1) afforded the crude product (R) -N- ((R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropan-2-sulfinamide. (30 mg, yield: 48%) as a pale yellow solid.

LC-MS:m/z 520.1[M+H] ⁺ .

Step two: (R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

The same procedures used in step two of example 37 were repeated except for removing sulfinyl groups from (R) -N- ((R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropan-2-sulfinamide to give (R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine.

¹ H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.75(s,3H),7.60(s,1H),7.49(s,1H),3.79(s,2H),3.21-3.12(m,2H),2.93(s,1H),1.82(s,5H),1.46(s,7H)ppm；LCMS:m/z 416.1[M+H] ⁺ .

Example 76: synthesis of the Compound (R) -8 (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

Step one: (R) -N- ((R) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropan-2-sulfinamide

The crude product (R) -N- ((R) -8- (8-iodoimidazo [1, 2-c) is added into a 100mL single-neck flask in sequence under the protection of nitrogen]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-yl) -2-methylpropane-2-sulfonamide (100 mg,0.20 mmol), sodium 2-amino-3-chloropyridine-4-thiolate (43 mg,0.26 mmol), pd ₂ (dba) ₃ (20 mg,0.02 mmol), xantphos (23 mg,0.040 mmol), DIPEA (52 mg,0.40 mmol) and 1, 4-dioxane solution(10 mL) and the mixture was heated to 100deg.C under nitrogen and stirred for 6 hours. After completion of the reaction, cooled to room temperature, filtered and the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/methanol) to give (R) -N- ((R) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1, 2-c) ]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-yl) -2-methylpropan-2-sulfinamide (40 mg, yield: 37%).

LC-MS:m/z 534.2[M+H] ⁺ .

Step two: (R) -8 (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

The same procedures used in step two of example 37 were repeated except for using (R) -N- ((R) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropan-2-sulfinamide to remove sulfinyl groups to give (R) -8 (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine.

¹ H NMR(400MHz,DMSO-d6)δ8.32(d,J＝6.9Hz,1H),8.02(s,1H),7.81(s,1H),7.58(d,J＝1.4Hz,1H),7.54(d,J＝5.4Hz,1H),6.35(s,1H),5.78(d,J＝5.4Hz,1H),3.89(t,J＝12.5Hz,2H),3.29-3.17(m,3H),3.00(s,1H),1.97(s,1H),1.89-1.33(m,6H)ppm；LCMS:m/z 430.1[M+H] ⁺ .

Following the synthetic method of example 76, the following compounds may be synthesized:

example 77: (R) -8- (8- ((3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(CD ₃ OD-d4)δ8.54(s,1H),8.35(s,1H),8.15-8.16(m,1H),8.09(s,1H),7.83-7.84(m,1H),7.57-7.58(m,1H),6.67-6.68(m,1H),3.92(m,2H),3.26(m,2H),3.00(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LCMS:m/z 415.1[M+H] ⁺ .

Example 78: (R) -8- (8- ((3- (trifluoromethyl) pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.41(d,J＝5.5Hz,1H),8.31(s,1H),8.10(s,1H),7.84(s,1H),7.57(s,1H),6.90(d,J＝5.4Hz,1H),3.93(s,2H),3.28-3.20(m,2H),2.94(s,1H),1.90-1.32(m,10H)；LCMS:m/z 449.1[M+H] ⁺ .

Example 79: (3S, 4S) -8- (8- ((2-amino-5-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.87(s,1H),7.83(s,1H),7.62(d,J＝1.3Hz,1H),5.91(s,2H),5.65(s,1H),4.13(d,J＝5.2Hz,1H),3.77(d,J＝8.5Hz,3H),3.60(d,J＝8.6Hz,1H),3.40(s,1H),3.14(s,1H),1.81(dd,J＝82.1,33.6Hz,5H),1.14(d,J＝6.3Hz,3H)ppm；LC-MS:m/z 462.1[M+H] ⁺ .

EXAMPLE 80 (3S, 4S) -8- (8- ((6-amino-3-chloro-2-methyl-pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.04(s,1H),7.85(s,1H),7.63(s,1H),5.82(s,2H),5.51(s,1H),4.26-4.18(m,1H),3.88(t,J＝13.0Hz,3H),3.70(d,J＝8.9Hz,1H),3.42(d,J＝4.3Hz,1H),3.27(s,2H),2.31(s,3H),1.99(d,J＝10.0Hz,2H),1.80(d,J＝13.5Hz,1H),1.69(d,J＝12.8Hz,1H),1.23(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 459.8[M+H] ⁺ .

Example 81: (R) -8- (8- ((3-chloro-2-cyclopropylpyrimidin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.97(d,J＝5.3Hz,1H),7.82(d,J＝1.5Hz,1H),7.57(d,J＝1.4Hz,1H),6.40(d,J＝5.3Hz,1H),3.91(t,J＝13.1Hz,2H),3.25(t,J＝11.7Hz,2H),3.02(t,J＝6.6Hz,1H),2.03-1.65(m,5H),1.67-1.37(m,5H),1.04(ddt,J＝8.0,5.6,2.4Hz,2H),0.97(dq,J＝6.9,4.2,3.4Hz,2H)ppm；LCMS:m/z 455.1[M+H] ⁺ .

Example 82: (R) -8- (8- ((3-chloro-2-methyl-pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.35-8.29(m,1H),8.07(s,1H),8.02(d,J＝5.4Hz,1H),7.83(s,1H),7.57(d,J＝1.4Hz,1H),6.50(d,J＝5.3Hz,1H),3.91(t,J＝12.9Hz,2H),3.26(t,J＝12.3Hz,2H),3.01(s,1H),2.55(s,3H),2.02-1.77(m,4H),1.75-1.38(m,6H)ppm；LCMS:m/z 429.1[M+H] ⁺ .

Example 83: (R) -8- (8- ((2-amino-5-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(CD ₃ OD-d4)δ8.38(s,1H),8.04(s,1H),7.82-7.84(m,2H),7.61(m,1H),5.93(s,2H),5.66(m,1H),3.87-3.93(m,2H),3.21-3.28(m,2H),2.98(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LCMS:m/z430.1[M+H] ⁺ .

Example 84: (R) -8- (8- ((2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.10(s,1H),8.00(d,J＝5.3Hz,1H),7.83(d,J＝1.5Hz,1H),7.59(d,J＝1.4Hz,1H),6.72(d,J＝5.3Hz,1H),4.03-3.87(m,2H),3.27(d,J＝13.6Hz,2H),3.14(t,J＝6.3Hz,1H),2.05(q,J＝6.4Hz,1H),1.87-1.42(m,9H)ppm；LCMS:m/z 449.1[M+H] ⁺ .

Example 85: (R) -8- (8- ((2-methylpyridin-3-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.25(dd,J＝4.7,1.5Hz,1H),7.89(s,1H),7.79(d,J＝1.4Hz,1H),7.56(d,J＝1.4Hz,1H),7.23(dd,J＝7.9,1.5Hz,1H),7.06(dd,J＝7.9,4.7Hz,1H),3.89-3.70(m,2H),3.17(dd,J＝22.2,10.5Hz,2H),2.80(t,J＝7.2Hz,1H),2.60(s,3H),1.88-1.20(m,10H)ppm；LCMS:m/z 395.2[M+H] ⁺ .

Example 86: (R) -8- (8- ((2- (trifluoromethyl) pyridin-3-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.35(s,1H),7.75(s,1H),7.21(d,J＝8.2Hz,2H),6.52(d,J＝8.4Hz,2H),5.39(s,2H),4.69(s,2H),2.87(s,1H),1.93-1.30(m,10H)ppm；LCMS:m/z 449.1[M+H] ⁺ .

Example 87: (R) -8- (8- ((2-chloropyridin-3-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(CD ₃ OD-d4)δ8.38(s,1H),8.16-8.18(m,1H),8.06(s,1H),7.81(m,2H),7.23(m,1H),7.14-7.22(m,2H),3.88(m,2H),3.23(m,2H),2.97(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LCMS:m/z 415.1[M+H] ⁺ .

Example 88: (R) -8- (8- ((6-amino-2-chloropyridin-3-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.74(d,J＝1.4Hz,1H),7.61(d,J＝1.4Hz,1H),7.51(d,J＝8.5Hz,1H),7.40(s,1H),6.73(s,2H),6.38(d,J＝8.4Hz,1H),3.68(d,J＝12.5Hz,3H),3.10(s,2H),2.97(t,J＝6.8Hz,1H),2.01-1.31(m,10H)ppm.LC-MS:m/z 431.1[M+H] ⁺ .

Example 89: (R) -8- (8- (benzo [ d ] thiazol-7-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ HNMR(CD ₃ OD-d4)δ9.43(m,1H),8.35(s,3H),8.00-8.02(m,1H),7.88(s,1H),7.76(m,1H),7.56-7.58(m,1H),7.47-7.51(m,1H),7.38-7.40(m,1H),3.80(m,2H),3.17(m,2H),2.98(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LC-MS:m/z 437.1[M+H] ⁺ .

Example 90: (R) -8- (8- (phenylsulfanyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.83(s,1H),7.76(s,1H),7.59(s,1H),7.25(tq,J＝14.0,7.4Hz,5H),3.84-3.70(m,2H),3.16(d,J＝12.4Hz,2H),3.01(t,J＝6.8Hz,1H),1.97(dd,J＝13.2,7.2Hz,1H),1.86-1.26(m,9H)ppm；LCMS:m/z 380.1[M+H] ⁺ .

Example 91: (R) -8- (8- ((1-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.97(d,J＝5.1Hz,1H),7.80(s,1H),7.61-7.49(m,2H),6.56-6.39(m,2H),3.84(d,J＝22.6Hz,5H),3.22(t,J＝12.5Hz,2H),2.98(t,J＝6.9Hz,1H),2.03-1.33(m,10H)ppm；LC-MS:m/z 433.9[M+H] ⁺ .

Example 92: (R) -8- (8- ((2, 3-dihydrobenzofuran-5-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.62(s,1H),7.46(s,1H),7.39(s,1H),7.27(d,J＝8.2Hz,1H),6.77(d,J＝8.3Hz,1H),4.54(t,J＝8.7Hz,2H),3.69(t,J＝11.9Hz,2H),3.11(dt,J＝29.5,12.5Hz,6H),1.99(s,1H),1.87-1.36(m,9H)ppm；LC-MS:m/z 422.1[M+H] ⁺ .

Example 93: (R) -8- (8- (quinolin-4-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.52(d,J＝4.8Hz,1H),8.26(dd,J＝8.4,1.3Hz,1H),8.12(s,1H),8.04(dd,J＝8.5,1.2Hz,1H),7.89-7.79(m,2H),7.73(ddd,J＝8.2,6.8,1.3Hz,1H),7.56(d,J＝1.4Hz,1H),6.82(d,J＝4.8Hz,1H),3.91(dd,J＝15.3,11.3Hz,2H),3.37-3.16(m,2H),3.05(t,J＝6.5Hz,1H),2.10-1.65(m,5H),1.67-1.38(m,5H)ppm；LC-MS:m/z 431.2[M+H] ⁺ .

Example 94: (1R) -8- (8- ((2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.09(d,J＝6.5Hz,1H),8.00(d,J＝5.3Hz,1H),7.84(s,1H),7.57(s,1H),6.71(d,J＝5.3Hz,1H),4.03-3.85(m,2H),3.26-3.15(m,2H),2.98(d,J＝21.9Hz,1H),2.14(dd,J＝25.3,11.9Hz,2H),1.87(dd,J＝41.5,14.7Hz,3H),1.43(dd,J＝32.2,18.7Hz,2H),1.28(dd,J＝18.2,8.7Hz,1H),1.12(d,J＝12.5Hz,1H),1.05-0.93(m,3H)ppm；LC-MS:m/z 462.8[M+H] ⁺ .

Example 95: (1R) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.36(s,1H),8.02(s,1H),7.80(s,1H),7.63-7.49(m,2H),6.34(s,2H),5.78(d,J＝5.4Hz,1H),3.98-3.83(m,2H),3.18(dd,J＝27.6,14.3Hz,2H),3.06-2.94(m,1H),2.23-2.07(m,2H),1.96-1.89(m,1H),1.86-1.67(m,2H),1.51-1.33(m,2H),1.33-1.20(m,1H),1.21-1.09(m,1H),1.08-0.94(m,3H)ppm；LC-MS:m/z 443.8[M+H] ⁺ .

Example 96: (1R) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-8-aza-spiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.06(s,1H),7.84(s,1H),7.61(s,1H),6.33(s,2H),5.62(s,1H),4.00-3.86(m,2H),3.17(d,J＝13.0Hz,1H),3.07-2.95(m,1H),2.25-2.07(m,2H),1.94(dd,J＝12.0,8.2Hz,2H),1.79(dd,J＝28.2,13.0Hz,2H),1.45(dd,J＝33.4,19.7Hz,2H),1.34-1.11(m,2H),1.01(dd,J＝18.3,10.3Hz,3H)；LCMS:m/z 447.8[M+H] ⁺ .

Example 97: (S) -8- (8- ((2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.10(s,1H),8.00(d,J＝5.3Hz,1H),7.86(s,1H),7.58(s,1H),6.72(d,J＝5.3Hz,1H),4.02(dd,J＝8.8,6.4Hz,1H),3.85(dd,J＝17.4,13.7Hz,2H),3.72(dd,J＝21.2,8.6Hz,2H),3.43(dd,J＝9.0,4.8Hz,2H),3.25(dd,J＝15.2,9.6Hz,2H),1.98-1.86(m,1H),1.85-1.73(m,1H),1.61(s,2H)；LC-MS:m/z 451.7[M+H] ⁺ .

Example 98: (S) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.04(s,1H),7.83(s,1H),7.60(s,1H),7.55(d,J＝5.4Hz,1H),6.35(s,2H),5.78(d,J＝5.4Hz,1H),4.10(dd,J＝9.9,6.0Hz,1H),3.92-3.76(m,4H),3.69(dd,J＝10.1,3.1Hz,1H),3.53(s,1H),3.24(d,J＝10.8Hz,1H),1.99-1.83(m,2H),1.73(d,J＝12.0Hz,2H),1.24(d,J＝6.4Hz,1H)ppm；LC-MS:m/z 431.8[M+H] ⁺ .

Example 99: (3S, 4S) -8- (8- ((2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.17(s,1H),8.10(s,1H),8.00(d,J＝5.3Hz,1H),7.87(s,1H),7.57(d,J＝1.0Hz,1H),6.72(d,J＝5.3Hz,1H),4.12(dt,J＝12.1,6.1Hz,1H),3.85-3.67(m,3H),3.57(d,J＝8.5Hz,1H),3.41(dd,J＝26.4,9.0Hz,2H),3.06(d,J＝4.9Hz,1H),1.99-1.81(m,2H),1.68(dd,J＝27.9,14.6Hz,2H),1.13(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 464.8[M+H] ⁺ .

Example 100: (3S, 4S) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.02(s,1H),7.84(s,1H),7.61-7.50(m,2H),6.34(s,2H),5.79(d,J＝5.4Hz,1H),4.11(dt,J＝12.3,6.3Hz,1H),3.73(d,J＝8.5Hz,3H),3.56(d,J＝8.5Hz,1H),3.38-3.26(m,2H),3.05(d,J＝4.9Hz,1H),1.99-1.81(m,2H),1.67(dd,J＝26.4,15.3Hz,2H),1.18-1.02(m,3H)ppm；LC-MS:m/z 445.8[M+H] ⁺ .

Example 101:4- ((5- (4-amino-4-methylpiperidin-1-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -3-chloropyridin-2-amine

¹ H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.83(s,1H),7.54(d,J＝5.8Hz,2H),6.29(s,2H),5.79(d,J＝5.4Hz,1H),3.60(d,J＝4.3Hz,4H),1.77-1.53(m,4H),1.19(s,3H)ppm；LC-MS:m/z 390.1[M+H] ⁺ .

Example 102: (R) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.85(d,J＝1.5Hz,1H),7.60(d,J＝1.4Hz,1H),6.32(s,2H),5.62(s,1H),3.90(dd,J＝13.2,8.5Hz,2H),3.23(q,J＝11.9,11.0Hz,2H),2.77(t,J＝7.3Hz,1H),1.90-1.77(m,4H),1.67-1.53(m,2H),1.45-1.28(m,4H)ppm；LCMS:m/z 466.1[M+H] ⁺ .

Example 103: (R) -8- (8- ((6-amino-3-chloro-2-methyl-pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ7.88(s,4H),7.66(d,J＝11.1Hz,1H),5.81(s,1H),3.96(t,J＝13.9Hz,2H),3.37-3.23(m,3H),2.42(s,3H),2.14-2.05(m,1H),1.88-1.46(m,9H)；LC-MS:m/z 443.8[M+H] ⁺ .

Example 104: (S) -8- (8- ((6-amino-3-chloro-2-methylpyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.17(d,J＝4.9Hz,3H),7.91(s,1H),7.68(s,1H),5.81(s,1H),4.13(dd,J＝10.4,5.8Hz,1H),3.90(d,J＝9.0Hz,3H),3.80(d,J＝9.0Hz,1H),3.74(dd,J＝10.3,2.6Hz,1H),3.63(s,1H),3.40(dd,J＝12.6,8.6Hz,1H),3.30(dd,J＝12.6,9.4Hz,1H),2.42(s,3H),1.95-1.81(m,2H),1.75(d,J＝10.3Hz,2H)；LC-MS:m/z 445.8[M+H] ⁺ .

Example 105: (S) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.07(s,1H),7.87(s,1H),7.63(s,1H),6.33(s,2H),5.62(s,1H),4.06(dd,J＝9.6,6.2Hz,1H),3.93-3.74(m,4H),3.56(dd,J＝9.5,4.0Hz,1H),3.26(s,3H),1.98-1.80(m,2H),1.67(s,2H)ppm；LC-MS:m/z 466.6[M+H] ⁺ .

Example 106: (3S, 4S) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.18(s,3H),8.08(s,1H),7.87(s,1H),7.65(s,1H),6.35(s,2H),5.64(s,1H),4.31-4.16(m,1H),4.03-3.83(m,3H),3.71(d,J＝9.0Hz,1H),3.46(s,1H),3.24(d,J＝11.2Hz,2H),2.03(t,J＝12.3Hz,2H),1.75(dd,J＝41.2,13.7Hz,2H),1.24(d,J＝6.5Hz,3H)；LCMS:m/z 479.7[M+H] ⁺ .

Example 107: (3S, 4S) -8- (8- ((3-chloro-2-methylpyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.06(s,1H),8.01(d,J＝5.3Hz,1H),7.85(d,J＝1.5Hz,1H),7.56(d,J＝1.4Hz,1H),6.50(d,J＝5.3Hz,1H),4.15-4.05(m,1H),3.74-3.66(m,5H),3.45-3.42(m,1H),3.03(d,J＝4.9Hz,1H),2.55(s,3H),2.00-1.60(m,4H),1.12(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 445.2[M+H] ⁺ .

Example 108: (S) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.06(s,1H),7.88(s,1H),7.61(s,1H),6.34(s,2H),5.64(s,1H),3.95(d,J＝14.3Hz,2H),3.55(s,1H),3.44(s,1H),3.31(d,J＝11.5Hz,2H),2.69(s,1H),1.94(d,J＝12.4Hz,2H),1.66(t,J＝11.9Hz,2H),1.06-0.99(m,3H),0.94(d,J＝14.9Hz,3H)；LC-MS:m/z 493.7[M+H] ⁺ .

Example 109: (S) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.15(s,2H),7.89(s,1H),7.64(s,1H),6.33(s,1H),5.63(s,1H),4.03(s,2H),3.59(d,J＝14.4Hz,2H),3.38(s,2H),3.09(s,1H),1.83(s,4H),1.16(s,3H),1.07(s,3H)；LC-MS:m/z493.7[M+H] ⁺ .

Example 110: (S) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.02(s,1H),7.84(s,1H),7.61-7.51(m,2H),6.33(s,2H),5.80(d,J＝5.4Hz,1H),4.00-3.88(m,2H),3.55(d,J＝8.7Hz,1H),3.46(d,J＝8.8Hz,1H),3.32-3.27(m,2H),2.73(s,1H),1.98-1.86(m,2H),1.68(s,2H),1.00(d,J＝29.6Hz,6H)；LC-MS:m/z 459.8[M+H] ⁺ .

Example 111: (R) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine

¹ H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.84(s,1H),7.57(s,1H),7.55(d,J＝5.4Hz,1H),6.33(s,2H),5.80(d,J＝5.3Hz,1H),4.01-3.91(m,2H),3.56(d,J＝8.8Hz,1H),3.48(d,J＝8.9Hz,1H),3.32-3.26(m,2H),2.80(s,1H),1.97-1.88(m,2H),1.70(d,J＝12.3Hz,2H),1.06(s,3H),0.99(s,3H)；LC-MS:m/z 459.8[M+H] ⁺ .

EXAMPLE 112 Synthesis of (R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

Step one methyl (((R) -1- ((R) -tert-butylsulfinyl) amino) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8 yl) thio) propanoate

(R) -N- ((R) -8- (8-iodoimidazo [1, 2-c) was sequentially added to a 100mL single-necked flask under a nitrogen atmosphere ]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-yl) -2-methylpropan-2-sulfonamide (500 mg,1.0 mmol), methyl mercaptopropionate (132 mg,1.1 mmol), pd ₂ (dba) ₃ (46 mg,0.05 mmol), xantphos (58 mg,0.10 mmol), DIPEA (258 mg,2.0 mmol) and 1, 4-dioxane solution (30 mL) were heated under nitrogen and the mixture was stirred at 100deg.C for 4 hours. After completion of the reaction, cooled to room temperature, filtered and concentrated under reduced pressure to give a residue which is purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/petroleum ether) to give ((R) -1- ((R) -tert-butylsulfinyl) amino) -8-azaspiro [ 4.5)]Decan-8-yl) imidazo [1,2-c]Pyrimidin-8-yl) methyl propionate (380 mg, yield: 77%).

LCMS:m/z 494.2[M+H] ⁺ .

Step two, ((R) -1- ((R) -1, 1-dimethylethylsulfinylamino) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidine-8-thiolate

To a dried 100mL round bottom flask was added sequentially ((R) -1- ((R) -tert-butylsulfinyl) amino) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8 yl) thio) methyl propionate (380 mg,0.77 mmol) and tetrahydrofuran (20 mL), and then a sodium ethoxide solution (21%, 3 mL) was slowly added dropwise at room temperature, and the reaction solution was stirred at room temperature for 1 hour. Concentration under reduced pressure afforded crude ((R) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidine-8-thiolate (400 mg) without purification.

LC-MS:m/z 408.2[M+H] ⁺ .

Step three (R) -N- ((R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropan-2-sulfinamide

To a 100mL one-necked flask under nitrogen was successively added crude ((R) -1- ((R) -1, 1-dimethylethylsulfinylamino) -8-azaspiro [ 4.5)]Decan-8-yl) imidazo [1,2-c]Pyrimidine-8-thiolate (100 mg,0.23 mmol), 3-chloro-4-iodo-2-methoxypyridine (71 mg,0.26 mmol), pd ₂ (dba) ₃ (22 mg,0.024 mmol), xantphos (28 mg,0.048 mmol), DIPEA (62 mg,0.48 mmol) and 1, 4-dioxane solution (10 mL) were heated under nitrogen and the mixture was stirred at 100deg.C for 4 hours. After completion of the reaction, cooled to room temperature, filtered and the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/methanol) to give (R) -N- ((R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1, 2-c)]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-yl) -2-methylpropan-2-sulfinamide (51 mg, yield: 40%).

LCMS:m/z 549.2[M+H] ⁺ .

Step four (R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

To a 100mL one-necked flask under nitrogen atmosphere was successively added (R) -N- ((R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropan-2-sulfinamide (40 mg,0.09 mmol) and methanol (2.3 mL), and a 1, 4-dioxane solution (0.23 mL, 4M) of hydrochloric acid was added dropwise at room temperature, and the mixture was stirred at room temperature for reaction for 1 hour. After the reaction was completed, cooled to room temperature, filtered and the resulting residue was purified by high performance liquid chromatography to give (R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine (15 mg, yield: 37%).

¹ H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.83(d,J＝1.6Hz,1H),7.77(d,J＝5.5Hz,1H),7.56(d,J＝1.5Hz,1H),6.28(d,J＝5.5Hz,1H),3.93(s,3H),3.88(d,J＝9.4Hz,2H),3.23(d,J＝11.6Hz,2H),2.76(t,J＝7.2Hz,1H),1.80(d,J＝11.4Hz,4H),1.66-1.52(m,2H),1.44-1.29(m,4H).LCMS:m/z 445.1[M+H] ⁺ Following the synthetic method of example 112, the following compounds may be synthesized:

EXAMPLE 113 methyl (R) -3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) propanoate

¹ H NMR(400MHz,DMSO-d6)δ7.73(d,J＝2.7Hz,2H),7.64(d,J＝1.3Hz,1H),3.70(d,J＝4.0Hz,2H),3.56(s,3H),3.26(t,J＝7.0Hz,2H),3.15-3.04(m,3H),2.61(t,J＝7.0Hz,2H),2.05-1.68(m,5H),1.66-1.37(m,5H)ppm；LC-MS:m/z 390.1[M+H] ⁺ .

Example 114: (R) -8- (8- ((3-chloro-2-fluoropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.86-7.80(m,2H),7.58(d,J＝1.4Hz,1H),6.66(d,J＝5.4Hz,1H),3.95(d,J＝12.7Hz,2H),3.28(s,2H),2.95(s,1H),1.97-1.80(m,4H),1.66(d,J＝32.2Hz,2H),1.56-1.41(m,4H)ppm；LCMS:m/z 434.1[M+H] ⁺ .

Example 115: (R) -8- (8- ((3-chloro-2- (dimethylamino) pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.83(d,J＝1.6Hz,1H),7.79(d,J＝5.3Hz,1H),7.56(d,J＝1.4Hz,1H),6.15(d,J＝5.3Hz,1H),3.98-3.79(m,2H),3.23(d,J＝11.6Hz,3H),2.90(s,6H),2.77(t,J＝7.3Hz,1H),1.83-1.74(m,7H),1.69-1.51(m,3H),1.49-1.27(m,5H)ppm；LCMS:m/z 458.2[M+H] ⁺ .

Example 116: (R) -4- ((5- (1-amino-8-aza-spiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) indoline-2, 3-dione

¹ H NMR(400MHz,DMSO-d6)δ8.28(s,1H),8.02(s,1H),7.81(s,1H),7.58(s,1H),7.24(t,J＝8.0Hz,1H),6.58(d,J＝7.7Hz,2H),6.21(d,J＝8.3Hz,1H),3.90(s,3H),3.24(s,3H),2.97(s,1H),1.69(d,J＝93.3Hz,9H)ppm；LC-MS:m/z 449.1[M+H] ⁺ .

EXAMPLE 117 Synthesis of the Compound (R) -8- (8- ((3-Chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

Step one (R) -N- ((R) -8- (8- ((3-Chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decylcyclobutane-1-yl) -2-methylpropane-2-sulfinamide

To a 100mL one-necked flask under nitrogen atmosphere was successively added crude ((R) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidine-8-thiolate (50 mg,0.12 mmol), 3, 4-dichloropyridazine (19 mg,0.13 mmol) and acetonitrile (3 mL), followed by DIPEA (31 mg,0.24 mmol) and the reaction mixture was heated at 80℃and stirred for 16 hours. After the reaction solution was cooled, the resulting residue was compressed under reduced pressure and purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/methanol) to give (R) -N- ((R) -8- (8- ((3-chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decacyclobutan-1-yl) -2-methylpropan-2-sulfinamide (10 mg, yield: 16%).

LCMS:m/z 520.2[M+H] ⁺ .

Step two (R) -8- (8- ((3-Chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

To a 50mL one-necked flask under nitrogen atmosphere were successively added (R) -N- ((R) -8- (8- ((3-chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decacyclobutan-1-yl) -2-methylpropan-2-sulfinamide (10 mg,0.02 mmol) and methanol (0.5 mL), and a 1, 4-dioxane solution (0.05 mL, 4M) of hydrochloric acid was added dropwise at room temperature, and the mixture was stirred at room temperature for reaction for 1 hour. After the reaction was completed, cooled to room temperature, filtered and the resulting residue was concentrated under reduced pressure and purified by high performance liquid chromatography to give (R) -8- (8- ((3-chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine (2 mg, yield: 24%).

¹ H NMR(400MHz,DMSO-d6)δ8.79(d,J＝5.4Hz,1H),8.36(s,2H),8.12(s,1H),7.84(s,1H),7.58(s,1H),7.01(d,J＝5.4Hz,1H),3.88(d,J＝9.4Hz,2H),3.23(d,J＝11.6Hz,2H),2.76(t,J＝7.2Hz,1H),1.70-1.32(m,9H)；LCMS:m/z 416.1[M+H] ⁺ .

Following the synthetic method of example 117, the following compounds may be synthesized:

example 118 (R) -8- (8- ((2-Chloropyrimidin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.37(d,J＝5.5Hz,1H),8.29(s,1H),8.09(s,1H),7.84(s,1H),7.61(d,J＝1.2Hz,1H),7.06(d,J＝5.5Hz,1H),3.93(t,J＝12.9Hz,2H),3.25(s,2H),3.09(s,1H),2.03(s,1H),1.81(dd,J＝19.3,13.3Hz,4H),1.65-1.46(m,5H)ppm；LCMS:m/z 416.1[M+H] ⁺ .

EXAMPLE 119 preparation of the Compound (R) -8- (8- (pyridin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

Step one: (R) -2-methyl-N- (R) -8- (8- (pyridin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decylpiperazin-1-yl) propane-2-sulfinamide

(R) -N- ((R) -8- (8-iodoimidazo [1, 2-c) was sequentially added to a 100mL single-necked flask under a nitrogen atmosphere]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-yl) -2-methylpropan-2-sulfonamide (50 mg,0.10 mmol), pyridine-2-thiol (13 mg,0.12 mmol), cu (OTf) ₂ (4 mg,0.01 mmol), BINAM (3 mg,0.01 mmol) and 1, 4-dioxane (3 mL), then cesium carbonate (65 mg,0.2 mmol) was added and the reaction was heated at 100deg.C and stirred for 16h. After the reaction solution was cooled, the residue obtained by compression was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate/methanol) to give (R) -2-methyl-N- (R) -8- (8- (pyridin-2-ylthio) imidazo [1, 2-c)]Pyrimidin-5-yl) -8-azaspiro [4.5]Decylpiperazin-1-yl) propane-2-sulfinamide (20 mg, yield: 41%).

LCMS:m/z 485.2[M+H] ⁺ .

Step two: (R) -8- (8- (pyridin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

The same procedures used in example 37, step two, were repeated except for removing sulfinyl groups from (R) -2-methyl-N- (R) -8- (8- (pyridin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decane piperazin-1-yl) propane-2-sulfinamide to give (R) -8- (8- (pyridin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine. .

¹ H NMR(400MHz,DMSO-d6)δ8.34(d,J＝3.1Hz,2H),8.02(s,1H),7.78(s,1H),7.63-7.48(m,2H),7.11(dd,J＝7.3,4.9Hz,1H),6.93(d,J＝8.1Hz,1H),3.86(t,J＝13.0Hz,2H),3.22(t,J＝12.4Hz,2H),3.03(t,J＝6.5Hz,1H),2.04-1.35(m,10H)ppm；LCMS:m/z 381.2[M+H] ⁺ .

Following the synthetic method of example 119, the following compounds may be synthesized:

example 120 (R) -8- (8- (pyridazin-3-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.97(d,J＝4.8Hz,1H),8.09(s,1H),7.80(s,1H),7.58(s,1H),7.48(dd,J＝8.9,4.9Hz,1H),7.33(d,J＝8.8Hz,1H),3.90(s,2H),3.25(d,J＝12.2Hz,3H),3.18(s,1H),1.86-1.46(m,9H)；LCMS:m/z 382.1[M+H] ⁺ .

EXAMPLE 121 (R) -8- (8- (pyrazin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.36(s,1H),8.31(s,1H),8.07(s,1H),7.79(s,1H),7.58(s,1H),3.89(t,J＝12.8Hz,2H),3.24(d,J＝12.2Hz,2H),2.06-1.46(m,9H)；LCMS:m/z 382.1[M+H] ⁺ .

Example 122: preparation of the Compound 8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -1-methyl-8-azaspiro [4.5] decan-1-amine

Step one: 8- (8-iodoimidazo [1,2-c ] pyrimidin-5-yl) -1-methyl-spiro [4.5] decan-1-amine

To a solution of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine (56 mg,0.2 mmol) in anhydrous DMF (10 mL) at 0deg.C was added 1-methyl-8-azaspiro [4.5] decan-1-amine (40 mg,0.24 mmol), followed by diisopropylethylamine (51.6 mg,0.4 mmol), and the reaction stirred at 0deg.C for 1 hour. After the reaction is completed, the reaction solution is directly used for the next reaction.

LCMS:m/z 412.0[M+H] ⁺ .

Step two: (8- (8-iodoimidazo [1,2-c ] pyrimidin-5-yl) -1-methyl-spiro [4.5] decan-1-yl) carbamic acid tert-butyl ester

Adding (Boc) to the solution obtained in the previous step ₂ O (87 mg,0.4 mmol) then diisopropylethylamine (51.6 mg,0.4 mmol) was added and the reaction stirred at room temperature for 4 hours. After the reaction was completed, the reaction was quenched with water and then extracted with ethyl acetate (3X 10 mL). The combined organic phases were dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/petroleum ether) to give (8- (8-iodoimidazo [1, 2-c) ]Pyrimidin-5-yl) -1-methyl-spiro [4.5]Decane-1-yl) carbamic acid tert-butyl esterButyl ester (15 mg, above two step yield: 7%)

LC-MS:m/z＝512.0[M+H] ⁺ .

Step three: (8- (8- ((6- ((tert-Butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -methyl spiro [4.5] decan-1-yl) carbamic acid tert-butyl ester.

Following the synthesis of step one of example 76, (8- (8-iodoimidazo [1, 2-c)]Pyrimidin-5-yl) -1-methyl-spiro [4.5]Deck-1-yl) carbamic acid tert-butyl ester is coupled with sodium 6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridine-4-thiol to give (8- (8- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c]Pyrimidin-5-yl) -methyl spirocycles [4.5]Decane-1-yl) carbamic acid tert-butyl ester (4 mg, yield: 15%). LC-MS: m/z 678.2[ M+H ]] ⁺ .

Step four: 4- ((5- (1-amino-1-methyl-spiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -5, 6-dichloropyridin-2-amine.

Following the synthesis of step three of example 21, tert-butyl (8- (8- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -methyl spiro [4.5] decan-1-yl) carbamate is deprotected by Boc to give 4- ((5- (1-amino-1-methylpara [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -5, 6-dichloropyridin-2-amine (2 mg, yield: 60%)

¹ HNMR(400MHz,DMSO-d6)δ8.10(s,1H),7.87(s,1H),7.64(s,1H),6.42(s,2H),5.63(s,1H),4.06(s,2H),3.18(t,J＝12.4Hz,2H),1.96-1.37(m,9H),1.26(s,3H),0.98-0.84(m,1H)ppm；LC-MS:m/z＝478.2

[M+H] ⁺ 。

Following the synthetic method of example 122, the following compounds may be synthesized:

example 123 (R) -8- (8- ((6-amino-3-chloro-2-methyl-pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ8.19(s,2H),8.07(s,1H),7.84(s,1H),7.65(s,1H),5.65(s,1H),3.99(t,J＝15.1Hz,2H),3.62-3.55(m,3H),2.74-2.63(m,2H),2.44-2.33(m,5H),2.01(t,J＝11.8Hz,1H),1.85-1.60(m,3H)ppm；LC-MS:m/z＝480.2[M+H] ⁺ .

Example 124: preparation of the Compound (R) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine

Step one and step two: 5, 6-dichloro-4- ((5-chloroimidazo [1,2-c ] pyrimidin-8-yl) thio) pyridin-2-amine

Following the procedure for the synthesis of step three and step four of example 1, 8-iodoimidazo [1,2-c ] pyrimidin-5-ol was coupled with sodium 6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridine-4-thiolate and halogenated to give 5, 6-dichloro-4- ((5-chloroimidazo [1,2-c ] pyrimidin-8-yl) thio) pyridin-2-amine.

LC-MS:m/z 347.9[M+H] ⁺

Step three: (R) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine

Following the synthesis of example 23, 5, 6-dichloro-4- ((5-chloroimidazo [1,2-c ] pyrimidin-8-yl) thio) pyridin-2-amine was substituted with (R) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine to give (R) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine.

¹ H NMR(400MHz,DMSO-d6)δ8.35(s,2H),8.06(s,1H),7.86(s,1H),7.61(s,1H),6.31(s,2H),5.62(s,1H),3.92(d,J＝14.9Hz,2H),3.21(d,J＝12.8Hz,3H),3.07(t,J＝8.1Hz,2H),2.12-1.98(m,3H),1.91(d,J＝12.4Hz,2H),1.47(t,J＝16.6Hz,3H)ppm；LC-MS:m/z 501.7[M+H] ⁺ .

Examples 125-127 pharmacological related examples

Example 125: SHP2 enzyme Activity inhibition assay

The compound powder was dissolved in DMSO to prepare a mother liquor. In the experiments, compound stock solutions were subjected to 3-fold gradient dilutions in DMSO, and 10 different test concentrations of the same compound were set. mu.L of each concentration point of compound was taken into wells of a detection plate (Corning, costar 3915), and 2 replicates were set per concentration point. The protein used is active protein SHP2 with 76 th amino acid mutation ^E76A The substrate used was DiFMUP (Invitrogen, E12020). SHP2 ^E76A The protein and substrate were diluted to 1.2nM and 20. Mu.M with buffer (0.1M NaAc (pH 7.2), 0.02%Tween 20,0.1%BSA,1mM EDTA,5mM DTT), respectively. To the assay wells, 50. Mu.L of enzyme solution was added followed by 50. Mu.L of substrate. Fluorescence signals were recorded (Ex 358nm/Em 455 nm) on a Spectra max i3 (Molecular Devices) instrument every 1 minute to calculate the rate of accumulation of the product to characterize the enzyme activity. Nonlinear regression analysis was performed using GraphPad Prism 5, and a curve of enzyme activity as a function of compound concentration was fitted by the equation y=bottom+ (Top-Bottom)/(1+10 + (log ic 50-X) HillSlope). IC for determining each Compound ₅₀ Values.

Results

The following table shows the IC of some of the compounds of the invention ₅₀ Values.

Letter A represents IC ₅₀ Less than 100nM;

letter B represents IC ₅₀ 100nM to 1000nM;

example 126: phosphorylated protein kinase (p-ERK) cell assay

Compounds were tested for inhibition of intracellular protein kinase (ERK) phosphorylation levels by the AlphaLISA method.

The first step of the compound treats the cells. The compound to be tested is firstly diluted 3-times by 100% DMSO, and 9 different concentration gradients are arranged in total; the MOLM13 cells were then seeded into 96-well plates at a cell density of 30000 cells per well, with a volume of 100 μl per well; then 0.5 μl of DMSO or test compounds at different concentrations, each concentration set 2 replicates, was added to each well, and the final concentration of DMSO was controlled to be 0.5%.

The second step lyses the cells. After 2 hours of cell treatment, the medium was removed, the cells were washed 3 times with phosphate buffered saline, 50 μl of freshly prepared lysis buffer was added to each well, shaken and left at room temperature for 10 minutes.

Third stepUltra ^TM The p-ERK 1/2 (Thr 202/Tyr 204) kit (Perkin Elmer, ALSU-PERK-A10K)) detects phosphorylated extracellular signal-regulated kinase (p-ERK). Mu.l of the above lysates were taken into 384 well plates (Perkin Elmer, 6005350) and samples were tested for extracellular signal-regulated kinase phosphorylation levels according to the product instructions. The signal was read using an AlphaScreen detector on Spectra max i3 (Molecular Devices). Percent (%) inhibition was calculated by the following formula:

Percent inhibition (%) = (p-ERK signal of 1-compound-treated cells/p-ERK signal of DMSO-treated cells) ×100

Results

Letter A represents IC ₅₀ Less than 100nM;

letter B represents IC ₅₀ 100nM to 1000nM;

example 127: MOLM-13 cell proliferation assay

MOLM-13 cells suspended in medium (RPMI-1640, containing 10% FBS and 1% Penicillin-Streptomycin, gibco) were plated at 800 cells (40. Mu.L/well) onto 384-well plates. The cells were immediately treated with the test compound at 50, 16.67,5.56,1.85,0.617,0.206,0.069,0.023,0.0076 μm concentration, respectively. After 3 days, 5. Mu.L of CellTiter-Glo reagent (Promega, ZG 7572) was added to each well and left at room temperature for 10 minutes in the absence of light. The fluorescent signal was detected by Spectra max i3 (Molecular Devices). The relative growth rate of the treated cells was compared to DMSO control.

Results

Letter A represents IC ₅₀ Less than 100nM;

letter B represents IC ₅₀ 100nM to 1000nM;

according to the same test methods as the SHP2 enzyme activity inhibition test described in example 125, the phosphoprotein kinase (p-ERK) cell test described in example 126 and the MOLM-13 cell proliferation test described in example 127, the applicant conducted corresponding experiments on the compound SHP099 (6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine) disclosed in WO 2015/107493 A1 or document (Nature 2016,535, 148-152), and the comparative experimental data of the compound obtained in the examples of the present invention and SHP099 were shown in the following table, and it was found that the pyrimido-cyclic compound according to the present invention has more excellent activity by comparison.

The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims

1. Pyrimidine ring compound shown in formula (II) or pharmaceutically acceptable salt thereof,

wherein the method comprises the steps of

X is independently S or absent;

y is independently C;

n is independently 0, 1 or 2;

R ¹ selected from the following structures:

wherein o is independently 0, 1, 2, 3 or 4; ring a is independently a 6 membered heteroaryl group containing 1 to 4N atoms; ring B is independently a 5 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, S and O; g is independently C, C (=o), N, S or an O heteroatom or group;

R ^1aa 、R ^1ab and R is ^1a Independently is halogen, C _1-4 Alkoxy, R ^1a1 Substituted or unsubstituted C _1-4 Alkyl, NR ^1a2 R ^1a3 、NHC(＝O)R ^1a4 、C _3-8 Cycloalkyl;

R ^1a1 independently halogen or C _1-4 An alkyl group;

R ^1a2 、R ^1a3 independently hydrogen, C _1-4 An alkyl group;

R ^1a4 independently C _1-4 Alkyl, C _2-6 Alkenyl groups;

R ⁴ 、R ⁵ independently hydrogen, C _1-4 Alkyl, amino, C _1-4 Alkyl substituted amino, or R ⁴ And R is ⁵ Together with Y, form 0 to 3R ^4a A substituted 3-to 7-membered saturated or partially unsaturated spiro ring, which ring may optionally contain 1 to 3 heteroatoms or groups independently N, C (=o) or O;

R ^4a independently hydrogen, C _1-4 Alkyl, hydroxy, amino, C _1-4 An alkylamino group;

and the pyrimidocyclic compound shown in the formula (II) is not any one of the following compounds:

2. a pyrimido compound of formula (II) according to claim 1 or a pharmaceutically acceptable thereofSalts, R ^1aa 、R ^1ab And R is ^1a In the formula, R is ^1a1 Substituted C _1-4 The alkyl group is trifluoromethyl.

3. The pyrimido compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^2a 、R ^2b 、R ^3a And R is ^3b Independently hydrogen or methyl.

4. The pyrimido compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, R ⁴ 、R ⁵ Independently hydrogen, methyl, ethyl, amino, methylamino or ethylamino.

5. The pyrimido compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, R ⁴ And R is ⁵ The ring formed with Y is selected from the following structures:

wherein p is independently 0, 1, 2 or 3; r is R ^4a As defined in claim 1.

6. The pyrimido compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, R ⁴ And R is ⁵ The ring formed with Y is of the following configuration:

wherein p is independently 0, 1, 2 or 3; r is R ^4a As defined in claim 1.

7. A pyrimido-cyclic compound or a pharmaceutically acceptable salt thereof, said pyrimido-cyclic compound being selected from any one of the following compounds：

8. An isotopically-labeled compound of a pyrimido-ring compound as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, said isotope being selected from the group consisting of ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ Cl and Cl ¹²⁵ I。

9. A process for preparing a pyrimido-cyclic compound represented by formula (II), which is process 1 or process 2:

the method 1 comprises the following steps:

the halogenated intermediate compound A is subjected to coupling reaction with boric acid, mercaptan or sodium sulfate to obtain a formula (II), and the reaction equation is as follows:

wherein W is ¹ Represents halogen; x, Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as in claim 1;

the method 2 comprises the following steps:

wherein W is ² Represents halogen; x, Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as in claim 1.

10. The process for producing a pyrimido-cyclic compound represented by the formula (II) according to claim 9,

in the method 1, W ¹ Represents Br, I;

And/or, in the method 2, W ² Represents Cl, br, I.

11. A process for the preparation of intermediate compound A, B or D, wherein,

the preparation method of the compound A comprises the following steps:

the halogenated intermediate E is substituted by intermediate amine C under alkaline conditions to obtain halogenated intermediate compound A, and the reaction equation is as follows:

wherein Y, n, R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as in claim 1; w (W) ¹ Represents halogen; w (W) ² Represents halogen; the intermediate compound A is not

The preparation method of the compound B comprises the following steps:

substitution of dichloropyrimidine compound B-1 with an amine to give intermediate B-2; condensing, cyclizing and hydrolyzing the intermediate B-2 under the condition of strong acid to obtain a halogenated intermediate B-3; the halogenated intermediate B-3 is obtained as an intermediate B-4 under the condition of catalytic coupling, and then is converted into the halogenated intermediate B, and the reaction equation is as follows:

therein, X, R ¹ Is defined as in claim 1; w (W) ¹ Represents halogen; w (W) ² Represents halogen;

the preparation method of the compound D comprises the following steps:

Wherein Y, n, R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as in claim 1; w (W) ¹ Represents halogen.

12. A process for the preparation of intermediate compounds A, B or D as claimed in claim 11,

in the preparation method of the compound A, W ¹ Represents Br, I;

and/or, in the preparation method of the compound A, W ² Represents Cl, br, I;

and/or, in the preparation method of the compound B, W ¹ Represents Br, I;

and/or, in the preparation method of the compound B, W ² Represents Cl, br, I

And/or, in the preparation method of the compound D, W ¹ Represents Br, I.

13. A process for preparing a pyrimido-cyclic compound of formula (II-a), comprising the steps of:

wherein Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as in claim 1.

14. A preparation method of pyrimidine-fused ring compound shown in formula (II-B) comprises the following steps:

removing the protecting group of the intermediate II-B1 under acidic or alkaline conditions to obtain a compound II-B, wherein the reaction equation is as follows:

wherein Pg is selected from protecting groups Boc, ac, S (=O) ^t Bu；R ^4Pg 、R ^5Pg Together with the attached carbon, selected from the following structures:

R ⁴ 、R ⁵ together with the attached carbon, selected from the following structures:

X、n、R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b As defined in claim 1; r is R ^4a As defined in claim 1; p is independently 0, 1, 2 or 3; r is R ^4x Is hydrogen, C _1-4 Alkyl, amino, C _1-4 Alkyl substituted amino; the pyrimido-ring compound shown in the formula (II-B) is not

15. A preparation method of pyrimidine-fused ring compounds shown in formula (II-C) comprises the following steps:

therein, X, Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ 、R ⁵ 、R ^1a And R is ^1a4 Is defined as in claim 1.

16. An intermediate for preparing the pyrimido-ring compound of claim 1, said intermediate compound being selected from the group consisting of:

therein X, Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as in claim 1; w (W) ¹ Represents halogen;

W ² represents halogen; the intermediate compound A is not

17. The intermediate for preparing a pyrimido-ring compound according to claim 1, as set forth in claim 16,

W ¹ represents Br, I;

and/or W ² Represents Cl, br, I.

18. A process for the preparation of a pyrimido-cyclic compound of formula (I), which is process 1 or process 2:

the method 1 comprises the following steps:

halogenated intermediate compoundsCoupling reaction with boric acid, mercaptan or sodium sulfate to obtain the formula (I), wherein the reaction equation is as follows:

Wherein W is ¹ Represents halogen; x, Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Is defined as in claim 1; z is Z ₁ And Z ₂ C at the same time;

the method 2 comprises the following steps:

intermediate productsSubstituted with amine C to give formula (I), the reaction equation is as follows:

wherein W is ² Represents halogen; x, Y, n, R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ⁴ And R is ⁵ Z as defined in claim 1 ₁ And Z ₂ And is C at the same time.

19. A process for the preparation of pyrimidine-fused ring compounds of formula (I) according to claim 18, wherein:

in the method 1, W ¹ Represents Br, I;

and/or, in the method 2, W ² Represents Cl, br, I.

20. Use of a pyrimido-cyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 or the isotopically-labeled compound according to claim 8 for the manufacture of a medicament for the treatment of a disease or disorder associated with aberrant SHP2 activity.

21. The use of claim 20, wherein the disease or condition is selected from noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, or glioblastoma.

22. A pharmaceutical composition comprising a pyrimido-cyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 or the isotopically labeled compound of claim 8, and a pharmaceutically acceptable adjuvant.

23. A pharmaceutical formulation comprising the pyrimido-cyclic compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 or the isotopically labeled compound of claim 8, selected from the group consisting of tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, solutions.

24. The pharmaceutical formulation of claim 23, which is administered in a manner selected from the group consisting of: oral, sublingual, subcutaneous, intravenous, intramuscular, intrasternal, nasal, topical or rectal administration, and/or said pharmaceutical formulation is administered in a single or multiple doses per day.