CN114761394B

CN114761394B - Pyridine or pyrimidine derivative and preparation method and application thereof

Info

Publication number: CN114761394B
Application number: CN202180006863.8A
Authority: CN
Inventors: 曹琪; 别平彦; 黄贤贵; 邢庆娜; 王鑫; 晏青燕; 廖伟伟; 郭阳辉; 叶成; 胡泰山; 陈磊
Original assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Current assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Priority date: 2020-01-16
Filing date: 2021-01-15
Publication date: 2024-03-29
Anticipated expiration: 2041-01-15
Also published as: WO2021143823A1; CN114761394A

Abstract

The invention relates to pyridine or pyrimidine derivatives, a preparation method thereof and application thereof in medicines. In particular to pyridine or pyrimidine derivatives shown in a general formula (I), a preparation method and pharmaceutically acceptable salts thereof, and application of the pyridine or pyrimidine derivatives as therapeutic agents, particularly SHP2 allosteric inhibitors, wherein the definition of each substituent in the general formula (I) is the same as that in the specification,

Description

Pyridine or pyrimidine derivative and preparation method and application thereof

Technical Field

The present invention relates to a new pyridine or pyrimidine derivative, a process for its preparation, pharmaceutical compositions containing the derivative and its use as a therapeutic agent, in particular as an inhibitor of the SHP2 allosteric.

Background

Src homology-2 phosphatase (SHP 2) is one of the important members of the Protein Tyrosine Phosphatase (PTP) family, encoded by the protein tyrosine phosphatase non-receptor 11 (PTPN 11) gene, which catalyzes the dephosphorylation of tyrosine in proteins. The N-terminus of SHP2 comprises 2 SH2 domains, which control subcellular localization and functional regulation of SHP2, and the C-terminus comprises 1 catalytically active PTP domain and 2 tyrosine residues associated with its activity. SHP2 is normally in a self-inhibited state, and when stimulated by growth factors, cytokines, inflammatory factors, or the like, such as platelet-derived growth factors PDGF, FGF, or the like, exposes catalytic sites, resulting in activation of enzymes of SHP 2.

SHP2 is widely existed in human body, and participates in rat sarcoma (RAS) -extracellular signal related kinase (ERK), phosphatidylinositol 3 kinase (PI 3K) -protein kinase B and NF-KB, activates fibroblast growth factor, epidermal growth factor and insulin receptor downstream mitogen activated protein kinase (MAPK/ERK) and other signal paths, thereby regulating proliferation, differentiation, migration and apoptosis of cells. It has now been found that activating mutations in SHP2 are associated with the occurrence of noonan syndrome, leopard syndrome, monocytic leukemia, melanoma, solid tumors, cardiovascular diseases, immune disorders, fibrosis or vision disorders, and that overexpression of SHP2 increases the risk of chronic granulocytic leukemia, mastocytosis, glioblastoma, lung cancer, breast cancer and the like, indicating that SHP2 plays an important role in different types of cancer and different stages of cancer. Because of the multiple functions of SHP2 in tumors, research into SHP2 target inhibitors has also brought new hopes and directions for tumor treatment.

SHP2 inhibitors can be classified into competitive inhibitors (including allosteric mycin, phenylpyrazolyl hydrazinol sulfonate and NSC-87877), non-competitive inhibitors (including indosalicylic acid and fur Mo Sutong) and irreversible inhibitors (including sodium antimonate gluconate and cryptotanshinone), according to their mechanism of action, and cryptotanshinone has been reported to inhibit proliferation of rhabdomyosarcoma, melanoma, colon cancer and breast cancer in vitro, and in vivo studies have shown that it can inhibit proliferation of prostate cancer in mice, whether it can be further a clinically effective drug or not, and further require a number of experimental verification.

The compound RMC-4630 developed by REVOLUTION Medicines Inc has entered clinical stage II for the treatment of solid tumors, and 3 additional clinical stage I compounds JAB-3068, JAB-3312 and TNO-155, developed by Jacobio Pharmaceuticals Co Ltd and Novartis AG, respectively. REVOLUTION Medicines Inc and Novartis AG have disclosed a series of SHP2 inhibitor patents including WO-2019075265, WO-2018136265, WO-2018136264, WO-2017216706 and WO-2018013597, etc., and although research on SHP2 has been advanced to some extent, no effective drugs are currently marketed, so there is still a need to continue to research and develop new SHP2 inhibitors.

Disclosure of Invention

Aiming at the technical problems, the invention provides a new pyridine or pyrimidine compound shown in a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from aryl, heteroaryl or a bicyclic fused ring, wherein said bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with a monocyclic heterocyclyl or monocyclic cycloalkyl;

x is selected from CR ^e Or N;

R ^e selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, or an alkoxy group, wherein said alkyl group or alkoxy group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, or an alkoxy group;

R ¹ Selected from alkyl, cycloalkyl, heterocyclyl, cyano, alkenyl, alkynyl, -OR ⁶ 、-C(O)R ⁶ 、-SO ₂ R ⁶ 、-NR ⁷ R ⁸ 、-SO ₂ NR ⁷ R ⁸ 、-NHSO ₂ R ⁶ or-C (O) NR ⁷ R ⁸ Wherein said alkyl, cycloalkyl, heterocyclyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from hydroxy, halo, alkyl, alkoxy, cycloalkyl or-NR ⁷ R ⁸ Is substituted by a substituent of (2); preferably, R ¹ Selected from methyl;

R ² identical OR different, each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyano, halogen, nitro, cycloalkyl, heterocyclyl, -OR ⁶ 、-C(O)R ⁶ 、-SO ₂ R ⁶ 、-NR ⁷ R ⁸ 、-SO ₂ NR ⁷ R ⁸ 、-NHSO ₂ R ⁶ or-C (O) NR ⁷ R ⁸ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl OR heterocyclyl is optionally further substituted with one OR more substituents selected from halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-OC(O)R ⁶ 、-SO ₂ R ⁶ 、-NR ⁷ R ⁸ 、-SO ₂ NR ⁷ R ⁸ 、-NHSO ₂ R ⁶ or-C (O) NR ⁷ R ⁸ Is substituted by a substituent of (2);

R ³ selected from cyano, alkoxy, tetrazolyl, -C (O) R ⁶ 、-C(O)OR ⁶ or-C (O) NR ⁷ R ⁸ ；

With the proviso that when R ³ R is selected from alkoxy ¹ Not selected from-NR ⁷ R ⁸ ；

R ⁴ And R is ⁵ Together with the N atom to which it is attached form a 4-11 membered, preferably 5-11 membered, heterocyclic group containing one or more N, O, S atoms or SO ₂ And the heterocyclyl is optionally further substituted with one OR more substituents selected from halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-OC(O)R ⁶ 、-SO ₂ R ⁶ 、-NR ⁷ R ⁸ 、-SO ₂ NR ⁷ R ⁸ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁶ or-C (O) NR ⁷ R ⁸ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with a halogen, hydroxy, amino or alkoxy substituent;

alternatively, R ⁴ And R is ⁵ Together with the N atom to which it is attached, form a group:

is a single bond or a double bond;

when (when)When representing a single bond, G and M are each independently selected from N or CR ^j ；

When (when)When representing a double bond, G and M are each independently selected from C;

ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

e is selected from NR ^k 、(CR ^p R ^q ) _p O or S;

f is selected from (CR) ^p R ^q ) _q ；

Provided that when E is selected from (CR) ^p R ^q ) _p When p is 1, q is 1; alternatively, p is 2 and q is 0; when E is selected from NR ^k Q is 1 when O or S;

j is selected from CR ^p R ^q ；

K is selected from NR ^k 、(CR ^p R ^q ) _r O orS；

r is 0 or 1;

R ^m 、R ⁿ 、R ^p and R is ^q Identical or different, each independently selected from R ^A ；

Alternatively, R ^p And R is ^q Together with the carbon atoms to which they are attached form R ^B ；

R ^c And R is ^d Identical OR different, each independently selected from hydrogen, halogen, alkyl OR-OR ⁶ Wherein said alkyl is optionally further substituted with hydroxy, halogen, alkoxy, cycloalkyl or-NR ⁷ R ⁸ Is substituted by a substituent of (2);

alternatively, R ^c And R is ^d Together with the carbon atoms to which they are attached form R ^B ；

R ^g The same OR different are each independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-OC(O)R ⁶ 、-SO ₂ R ⁶ 、-NR ⁷ R ⁸ 、-SO ₂ NR ⁷ R ⁸ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁶ or-C (O) NR ⁷ R ⁸ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR ⁷ R ⁸ Is substituted by a substituent of (2);

alternatively, two R ^g Together with the same carbon atom to which it is attached, form c=o;

R ^j and R is ^k The same or different are each independently selected from a hydrogen atom or an alkyl group;

R ^A the same OR different are each independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-OC(O)R ⁶ 、-SO ₂ R ⁶ 、-NR ⁷ R ⁸ 、-SO ₂ NR ⁷ R ⁸ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁶ or-C (O) NR ⁷ R ⁸ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR ⁷ R ⁸ Is substituted by a substituent of (2);

R ^B identical OR different, each independently selected from 3-to 10-membered cycloalkyl OR 3-to 10-membered heterocyclyl, wherein said cycloalkyl OR heterocyclyl is optionally further substituted with one OR more substituents selected from halogen, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-OC(O)R ⁶ 、-SO ₂ R ⁶ 、-NR ⁷ R ⁸ 、-SO ₂ NR ⁷ R ⁸ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁶ or-C (O) NR ⁷ R ⁸ Is substituted by a substituent of (2);

R ⁶ 、R ⁷ and R is ⁸ Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, or a heterocyclic group, wherein the alkyl group, cycloalkyl group, or heterocyclic group is optionally further substituted with one or more groups selected from hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, -C (O) R ⁹ 、-C(O)OR ⁹ 、-OC(O)R ⁹ 、-SO ₂ R ⁹ 、-NR ¹⁰ R ¹¹ 、-C(O)NR ¹⁰ R ¹¹ 、-SO ₂ NR ¹⁰ R ¹¹ or-NR ¹⁰ C(O)R ¹¹ Is substituted by a substituent of (2);

alternatively, R ⁷ And R is ⁸ Together with the N atom to which it is attached form a 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic ring contains one or more N, O, S atoms or SO ₂ And optionally further substituted on the 3-to 8-membered heterocyclic ring with one or more substituents selected from hydroxy, halogen, amino, alkyl or alkoxy;

R ⁹ 、R ¹⁰ and R is ¹¹ Each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, whichOptionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;

m is selected from 0, 1, 2, 3, 4 or 5;

n is selected from 0, 1, 2, 3 or 4;

p is selected from 1 or 2.

In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

wherein: ring A, X, m, R ¹ 、R ² 、R ⁴ And R is ⁵ The definition of (C) is as described in the general formula (I).

In a preferred embodiment of the invention, the compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

In a preferred embodiment of the invention, the compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

In a preferred embodiment of the invention, the compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: r is R ⁴ And R is ⁵ Together with the N atom to which it is attached, form a 4-8 membered monocyclic heterocyclic group, preferably a 5-6 membered monocyclic heterocyclic group, more preferably a piperidinyl group, wherein said monocyclic heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁶ Is substituted by a substituent of (2); r is R ⁶ The definition of (C) is as described in the general formula (I).

In a preferred embodiment of the invention, the compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: r is R ⁴ And R is ⁵ Together with the N atom to which it is attached, form a 7-to 11-membered spiroheterocyclyl, wherein said spiroheterocyclyl is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁶ Is substituted by a substituent of (2); r is R ⁶ The definition of (a) is as described in a general formula (I); preferably, wherein said spiroheterocyclyl is selected from:

R ^a identical or different, each independently selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ OR-OR ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, two R ^a Together with the same carbon atom to which it is attached, form c=o; r is R ⁶ The definition of (a) is as described in a general formula (I); t is 1, 2 or 3.

In a preferred embodiment of the invention, the compounds of the general formulae (I), (II), (III) or (IV) or stereoisomers thereof, each otherAn stereoisomer or a pharmaceutically acceptable salt thereof, wherein: r is R ⁴ And R is ⁵ Together with the N atom to which it is attached, form a 7-to 11-membered bridged heterocyclic group, wherein said bridged heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁶ Is substituted by a substituent of (2); r is R ⁶ The definition of (C) is as described in the general formula (I).

In a preferred embodiment of the invention, the compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: r is R ⁴ And R is ⁵ Together with the N atom to which it is attached, form a 7-to 11-membered fused heterocyclic group, wherein said fused heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁶ Is substituted by a substituent of (2); r is R ⁶ The definition of (C) is as described in the general formula (I).

In a preferred embodiment of the invention, the compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (V):

wherein:

ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl;

e is selected from NR ^k 、(CR ^p R ^q ) _p O or S;

f is selected from (CR) ^p R ^q ) _q ；

R ^m selected from amino, -CH ₂ NH ₂ or-NHC (=nh) NH ₂ ；

R ⁿ Selected from hydrogen atoms, methyl groups, or-CH ₂ OH；

R ^p And R is ^q Each independently selected from hydrogen atom, halogen, amino group, C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ Alkyl, amino C ₁ -C ₄ Alkyl OR-OR ⁶ ；

Ring A, G, M, X, m, n, R ¹ ～R ³ 、R ⁶ 、R ^k And R is ^g The definition of (C) is as described in the general formula (I).

In a preferred embodiment of the invention, the compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (VI):

wherein:

J is selected from CR ^p R ^q ；

K is selected from NR ^k 、(CR ^p R ^q ) _r O or S;

r is 0 or 1;

R ^m selected from amino, -CH ₂ NH ₂ or-NHC (=nh) NH ₂ ；

R ⁿ Selected from hydrogen atoms, methyl groups, or-CH ₂ OH；

In a preferred embodiment of the invention, the compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (VII):

wherein:

R ^c and R is ^d Together with the attached atoms, form a 3-to 8-membered cycloalkyl group;

R ^m selected from amino, -CH ₂ NH ₂ or-NHC (=nh) NH ₂ ；

R ⁿ Selected from hydrogen atoms, methyl groups, or-CH ₂ OH；

Ring A, G, M, X, m, n, R ¹ ～R ³ And R is ^g The definition of (C) is as described in the general formula (I).

In a preferred embodiment of the invention, the compounds of the general formula (I), (II), (III), (IV), (V), (VI) or (VII) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ² Selected from the group consisting of hydrogen atom, F, cl, br, amino, hydroxy, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH ₃ or-N (CH) ₃ ) ₂ 。

In a preferred embodiment of the invention, the compounds of the general formula (V), (VI) or (VII) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof,wherein R is ³ Selected from the group consisting of-C (O) OH.

In a preferred embodiment of the invention, the compounds of the general formula (I), (II), (III), (IV), (V), (VI) or (VII) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ⁶ Selected from hydrogen atoms or alkyl groups.

In a preferred embodiment of the invention, the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring a is selected from phenyl.

In a preferred embodiment of the invention, the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from:

in a preferred embodiment of the invention, the compounds of the general formula (I), (II), (III), (IV), (V), (VI) or (VII) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ^g The same or different are each independently selected from hydrogen atom, F, cl, br, amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH ₃ or-N (CH) ₃ ) ₂ ；

Alternatively, two R ^g The same carbon atom as attached may together form c=o.

Typical compounds of the present invention include, but are not limited to:

/>

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Still further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

The invention provides an application of a compound shown in general formulas (I), (II), (III), (IV), (V), (VI) or (VII) or a stereoisomer, a tautomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing an SHP2 allosteric inhibitor.

The invention also provides the use of a compound of general formula (I), (II), (III), (IV), (V), (VI) or (VII), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a SHP2 mediated disease, preferably cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or vision disorder; wherein the SHP2 mediated disease is preferably 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 and glioblastoma.

The invention further provides the use of a compound of general formula (I), (II), (III), (IV), (V), (VI) or (VII), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or vision disorder.

The invention provides an application of a compound shown in a general formula (I), (II), (III), (IV), (V), (VI) or (VII) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of head and neck, gastric cancer, anaplastic large cell lymphoma and glioblastoma.

Detailed description of the invention

Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:

"alkyl" when taken as a group or part of a group is meant to include C ₁ -C ₂₀ Straight chain or branched aliphatic hydrocarbon groups. Preferably C ₁ -C ₁₀ Alkyl, more preferably C ₁ -C ₆ An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.

"alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Alkenyl groups may be optionally substituted or unsubstituted.

"alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond, which may be straight or branched. Preferably is C ₂ -C ₁₀ More preferably C ₂ -C ₆ Alkynyl, most preferably C ₂ -C ₄ Alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-,2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted.

"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. Preferably C ₃ -C ₁₂ Cycloalkyl, more preferably C ₃ -C ₈ Cycloalkyl, most preferably C ₃ -C ₆ Cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be optionally substituted or unsubstituted.

"spirocycloalkyl" refers to a 5 to 18 membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one carbon atom (called spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro group, a double spiro group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably single spiro group and double spirocycloalkyl group, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.

"fused ring alkyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl, or tetradecahydrophenanthryl.

"bridged cycloalkyl" means an aromatic system having 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups with one another that are not directly attached to a carbon atom, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron, preferably 6 to 12 members, more preferably 7 to 10 members. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1 s,4 s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1 s,5 s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1 r,5 r) -bicyclo [3.3.2] decyl.

"heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, and include monocyclic, polycyclic, fused, bridged and spiro rings. Preferably having a 5 to 7 membered mono-or 7 to 10 membered bi-or tri-ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, piperazinyl, and,The heterocyclic group may be substituted or unsubstituted.

"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, polycyclic group having single rings sharing one atom with each other, containing 1 or more double bonds in the ring, but no ring having a completely conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _n (wherein n is selected from 0, 1 or 2) heteroatoms, whichThe remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multiple spiro heterocyclic group according to the number of common spiro atoms between rings, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5 ] ]Decyl, 2-oxa-7-azaspiro [4.4 ]]Nonyl, 7-oxaspiro [3.5 ]]Nonyl, 5-oxaspiro [2.4 ]]Heptyl group,

"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, while at least one ring has a fully conjugated pi-electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo [3,4-c ]]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0 ]]Hexyl, octahydrobenzo [ b ]][1，4]Dioxin (dioxine)

"bridged heterocyclyl" means a 5 to 14 membered, 5 to 18 membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _n (wherein n is selected from 0, 1 or 2) heteroatoms, the remainder of the ring primordiaThe seed is carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl, 2-azabicyclo [3.3.2]Decyl group

"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C ₆ -C ₁₀ Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl groups may be substituted or unsubstituted.

"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" groups, which are preferably bicyclic heteroaryl groups, include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,

Heteroaryl groups may be substituted or unsubstituted.

"fused ring" means a polycyclic group having two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may containOne or more double bonds, but at least one ring not having a completely conjugated pi-electron aromatic system, wherein one or more ring atoms are selected from 0, oxygen or S (O) _n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. The fused ring preferably includes a double-or triple-ring fused ring, wherein the double-ring fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14 membered, more preferably 8 to 10 membered. Examples of "fused rings" include, but are not limited to:

/>

"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) ₁ -C ₆ Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"hydroxy" refers to an-OH group.

"halogen" refers to fluorine, chlorine, bromine and iodine.

"amino" means-NH ₂ 。

"cyano" refers to-CN.

"nitro" means-NO ₂ 。

"benzyl" means-CH ₂ -phenyl.

"carboxy" means-C (O) OH.

"carboxylate" refers to-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl, cycloalkyl are as defined above.

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to t-butoxycarbonyl.

"TFA" refers to trifluoroacetic acid.

"Ts" refers to p-toluenesulfonyl.

"hydroxy C ₁ -C ₄ Alkyl "refers to hydroxy-substituted C ₁ -C ₄ An alkyl group.

"amino C ₁ -C ₄ Alkyl "refers to amino substituted C ₁ -C ₄ An alkyl group.

The term "leaving group", or "leaving group", is used in the term nucleophilic substitution reaction and elimination reaction as an atom or functional group that is released from a larger molecule in a chemical reaction. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate (substrate), and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Groups that accept electrons easily and bear a strong negative charge are good leaving groups. The smaller the pKa of the leaving group conjugate acid, the easier the leaving group will be to disengage from the other molecule. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be bound to other atoms, and the tendency to exist in anionic (or charge neutral leaving group) form is enhanced. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -OTs, or-OH.

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, sterically hindered isomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, the structures described herein also include all isomeric (e.g., diastereomers, enantiomers, sterically hindered isomers and geometric (conformational) forms of such structures; e.g., R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, sterically hindered isomers of biphenyl structures (see basic organic chemistry (second edition) handbook, p104-105, criminal disclosure, et al), PAC,1996, 68, 2193 (Basic terminology of stereochemistry (IUPAC Recommendations 1996,on page 2201)), (Z) and (E) conformational isomers accordingly, individual stereoisomers as well as mixtures of enantiomers, mixtures of diastereomers, sterically hindered isomers and mixtures of geometric (conformational) isomers of the compounds of the invention are within the scope of the invention.

"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more groups selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =o, -OR ⁶ 、-C(O)R ⁶ 、-C(O)OR ⁶ 、-OC(O)R ⁶ 、-SO ₂ R ⁶ 、-NR ⁷ R ⁸ 、-SO ₂ NR ⁷ R ⁸ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁶ or-C (O) NR ⁷ R ⁸ Wherein said alkyl or alkoxy is optionally further substituted with halogen, hydroxy, amino or alkoxy substituents;

R ⁶ 、R ⁷ And R is ⁸ Each independently selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ⁹ 、-C(O)OR ⁹ 、-OC(O)R ⁹ 、-SO ₂ R ⁹ 、-NR ¹⁰ R ¹¹ 、-C(O)NR ¹⁰ R ¹¹ 、-SO ₂ NR ¹⁰ R ¹¹ or-NR ¹⁰ C(O)R ¹¹ Is substituted by a substituent of (2);

R ⁷ and R is ⁸ Together with the N atom to which it is attached form a 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic ring contains one or more N, O, S or SO ₂ An atom, and further substituted on the 3-to 8-membered heterocyclic ring with one or more substituents selected from hydroxy, halogen, amino, alkyl or alkoxy;

R ⁹ 、R ¹⁰ and R is ¹¹ Each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, and carboxylate.

"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by the general formula (I) may be metal salts, amine salts with suitable acids.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

Synthesis method of compound of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

the present invention provides a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:

compounds of formula (Ia) and NHR ⁴ R ⁵ Nucleophilic substitution reaction is carried out under alkaline condition to obtain a compound of a general formula (Ib); carrying out Suzuki reaction on a compound shown in a general formula (Ib) and a compound shown in a general formula (Ic) under a palladium catalyst and alkaline conditions, and optionally further removing a protecting group from the obtained compound to obtain a compound shown in a general formula (I);

wherein:

X ₂ selected from halogen;

X ₃ selected from leaving groups selected from halogen or-SO ₂ R ^t ；

R ³ Selected from alkoxy groups;

R ^t selected from alkyl groups;

ring A, X, m, R ¹ 、R ² 、R ⁴ And R is ⁵ The definition of (C) is as described in the general formula (I).

carrying out Suzuki reaction on a compound shown in a general formula (Ia) and a compound shown in a general formula (Ic) under a palladium catalyst and alkaline conditions to obtain a compound shown in a general formula (Id); compounds of formula (Id) and NHR ⁴ R ⁵ Carrying out nucleophilic substitution reaction under alkaline condition, and optionally removing protecting group to obtain compound of general formula (I);

wherein:

X ₂ selected from halogen;

X ₃ selected from leaving groups selected from halogen or-SO ₂ R ^t ；

R ³ Selected from alkoxy groups;

R ^t selected from alkyl groups;

The present invention provides a process for the preparation of a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:

/>

compounds of formula (IIa) and NHR ⁴ R ⁵ Nucleophilic substitution reaction is carried out under alkaline condition to obtain a compound of a general formula (IIb); carrying out Suzuki reaction on a compound shown in a general formula (IIb) and a compound shown in a general formula (Ic) under a palladium catalyst and alkaline conditions, and optionally further removing a protecting group from the obtained compound to obtain a compound shown in the general formula (IIc); hydrolyzing the compound of the general formula (IIc) under the condition of sodium hydroxide solution to obtain a compound of the general formula (II);

Wherein:

X ₂ selected from halogen;

X ₃ selected from leaving groups selected from halogen or-SO ₂ R ^t ；

R ^t Selected from alkyl groups;

ring A, X, m, R ¹ 、R ² 、R ⁴ And R is ⁵ The definition of (C) is as described in the general formula (II).

carrying out Suzuki reaction on a compound shown in a general formula (IIa) and a compound shown in a general formula (Ic) under a palladium catalyst and alkaline conditions to obtain a compound shown in a general formula (IId); compounds of formula (IId) and NHR ⁴ R ⁵ Nucleophilic substitution reaction is carried out under alkaline condition to obtain a compound of a general formula (IIc); hydrolyzing the compound of formula (IIc) in the presence of sodium hydroxide solution to give the compound of formula (II)A compound;

wherein:

X ₂ selected from halogen;

X ₃ selected from leaving groups selected from halogen or-SO ₂ R ^t ；

R ^t Selected from alkyl groups;

The present invention provides a process for the preparation of a compound of formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:

heating and hydrolyzing the compound of the general formula (IIc) under the condition of concentrated hydrochloric acid to obtain a compound of the general formula (III);

wherein: ring A, X, m, R ¹ 、R ² 、R ⁴ And R is ⁵ The definition of (C) is as described in the general formula (III).

The present invention provides a process for the preparation of a compound of formula (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:

reacting a compound of the general formula (IIc) in the presence of zinc chloride and sodium azide, and optionally further deprotecting the obtained compound to obtain a compound of the general formula (IV);

wherein: ring A, X, m, R ¹ 、R ² 、R ⁴ And R is ⁵ The definition of (a) is as described in the general formula (IV).

Detailed Description

The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.

Examples

The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. ¹ The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and, unless otherwise indicated, commercially available manufacturers include, but are not limited to, aldrich Chemical Company, ABCR GmbH & co.kg, acros Organics, praise chemical technology limited, and vision chemical technology limited, etc.

CD ₃ OD: deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

The argon atmosphere means that the reaction flask is connected to an argon balloon of about 1L volume.

The examples are not particularly described, and the solution in the reaction is an aqueous solution.

Purifying the compound by using a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: dichloromethane and ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.

Example 1

1- (5- (2, 3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-amine

First step

5-bromo-2-chloro-4-methoxy-6-methylpyrimidine

5-bromo-2, 4-dichloro-6-methylpyrimidine 1a (480 mg,2 mmol) was added to 5mL of methanol, and a solution of sodium methoxide (102.6 mg,1.9 mmol) in 5mL of methanol was slowly added dropwise thereto under ice-bath, followed by reaction at room temperature for 3 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, 10mL of water was added, extracted with methylene chloride (10 mL. Times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-bromo-2-chloro-4-methoxy-6-methylpyrimidine 1b (448.4 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI)：236.8[M+1]

Second step

(1- (5-bromo-4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Under argon, the above product, 5-bromo-2-chloro-4-methoxy-6-methylpyrimidine 1b (448.4 mg,1.9 mmol), tert-butyl (4-methylpiperidin-4-yl) carbamate 1c (470 mg,2.2 mmol) and 0.5mL of N, N-diisopropylethylamine were added to 5mL of dimethyl sulfoxide and heated to 130℃for 1 hour. After the completion of the reaction, it was cooled to room temperature, 30mL of water was added, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5-bromo-4-methoxy-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 1d (210 mg), yield: 26.7%.

MS m/z(ESI)：415.0[M+1]

Third step

(1- (5- (2, 3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (5-bromo-4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 1d (140 mg,0.338 mmol), (2, 3-dichlorophenyl) boronic acid 1e (128 mg,0.676 mmol), (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride (24 mg,0.0338 mmol), tetrakis (triphenylphosphine) palladium (39 mg,0.0338 mmol), sodium carbonate (143 mg,1.35 mmol) and 0.5mL of water were added to 3mL of N, N-dimethylformamide under argon and reacted for 4 hours. After the reaction was completed, cooled to room temperature, 20mL of water was added, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-methoxy-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 1f (110 mg), yield: 68.7%.

MS m/z(ESI)：480.9[M+1]

Fourth step

Tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 1f (110 mg,0.229 mmol) and 1mL of trifluoroacetic acid were added to 4mL of dichloromethane, reacted at room temperature for 2 hours, concentrated under reduced pressure, and the resulting residue was subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 1- (5- (2, 3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-amine 1 (60 mg), yield: 69%.

MS m/z(ESI)：380.9[M+1]

¹ H NMR(400MHz，CD ₃ OD)δ7.61(d，J＝8.0Hz，1H)，7.39(s，1H)，7.21-7.27(m，1H)，4.43(s，2H)，3.95(s，3H)，3.56-3.70(m，2H)，2.17(s，3H)，1.96(t，J＝5.8Hz，4H)，1.54(s，3H).

Example 2

2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methoxypyrimidin-4-amine

First step

5-bromo-2-chloro-6-methoxypyrimidin-4-amine

5-bromo-2, 4-dichloropyrimidin-4-amine 2a (971.56 mg,4 mmol) and sodium methoxide (216 mg,4 mmol) were added to 10mL of methanol, 1 equivalent of sodium methoxide was added every 3 hours, and the reaction was carried out at room temperature for 12 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, 20mL of water was added, extracted with methylene chloride (10 mL. Times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-bromo-2-chloro-6-methoxypyrimidin-4-amine 2b (800 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI)：237.8[M+1]

Second step

(1- (4-amino-5-bromo-6-methoxypyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl 5-bromo-2-chloro-6-methoxypyrimidin-4-amine 2b (473.86 mg,2 mmol), (4-methylpiperidin-4-yl) carbamate 1c (640 mg,3 mmol) and 1mL of N, N-diisopropylethylamine were added to 5mL of N-methylpyrrolidone, heated to 90℃and reacted for 2 hours. After the completion of the reaction, it was cooled to room temperature, 20mL of water was added, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (4-amino-5-bromo-6-methoxypyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 2c (360 mg), yield: 43.4%.

MS m/z(ESI)：415.8[M+1]

Third step

(1- (4-amino-5- (2, 3-dichlorophenyl) -6-methoxypyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (4-amino-5-bromo-6-methoxypyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 2c (100 mg,0.24 mmol), (2, 3-dichlorophenyl) boronic acid 1e (91.56 mg,0.48 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (35 mg,0.048 mmol), tetrakis (triphenylphosphine) palladium (55 mg,0.048 mmol), sodium carbonate (102 mg,0.96 mmol) and 0.5mL of water were added to 3mL of N, N-dimethylformamide under argon and the reaction was heated to 100 ℃ overnight. After the reaction was completed, cooled to room temperature, 20mL of water was added, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (4-amino-5- (2, 3-dichlorophenyl) -6-methoxypyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 2d (40 mg), yield: 34.8%.

MS m/z(ESI)：481.9[M+1]

Fourth step

Tert-butyl (1- (4-amino-5- (2, 3-dichlorophenyl) -6-methoxypyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 2d (40 mg,0.083 mmol) and 0.5mL of trifluoroacetic acid are added to 2mL of dichloromethane and reacted at room temperature for 2 hours, concentrated under reduced pressure, the resulting residue is subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methoxypyrimidin-4-amine 2 (30 mg), yield: 94%.

MS m/z(ESI)：381.9[M+1]

¹ H NMR(400MHz，CDCl ₃ )δ7.43-7.48(m，1H)，7.17-7.25(m，2H)，4.35(s，2H)，4.23(d，J＝14.0Hz，2H)，3.80(s，3H)，3.60(d，J＝11.2Hz，2H)，1.73-1.94(m，4H)，1.48(s，3H).

Example 3

2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid

First step

(1- (4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (400 mg,2.60 mmol), (4-methylpiperidin-4-yl) carbamate 1c (558.20 mg,2.60 mmol) and N, N-diisopropylethylamine (336.63 mg,2.60 mmol) were added sequentially to 20mL of N, N-dimethylacetamide and heated to 90℃for 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (30 mL. Times.2), and the combined organic phases were washed successively with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 3b (840 mg), yield 97.31%.

MS m/z(ESI)：332.2[M+1]

Second step

(1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 3b (840 mg,2.53 mmol) was added to 10mL of N, N-dimethylformamide, and bromosuccinimide (600.41 mg,3.37 mmol) was added at 0℃and reacted overnight at room temperature. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), and the combined organic phases were washed successively with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 3c (800 mg), yield 75.14%.

MS m/z(ESI)：355.9[M-56]

Third step

(1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 3c (800 mg,1.95 mmol), (2, 3-dichlorophenyl) boronic acid 1e (744.10 mg,3.90 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (163.25 mg,0.195 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (181.97 mg,0.390 mmol) and potassium phosphate (1.24 g,5.85 mmol) were added to a 12mL mixed solution (1, 4-dioxane: water=6:1) under argon atmosphere and heated to 130 ℃ for reaction for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 3d (900 mg), yield: 96.89%.

MS m/z(ESI)：476.1[M+1]

Fourth step

3d (380 mg,0.800 mmol) of tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate was added to 10mL of concentrated hydrochloric acid, heated to 110℃and reacted for 1.5 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 3 (300 mg), yield: 95.15%.

MS m/z(ESI)：394.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ7.62(dd，J＝8.1，1.4Hz，1H)，7.39(t，J＝7.9Hz，1H)，7.19(dd，J＝7.6，1.4Hz，1H)，7.06(s，1H)，4.10(dd，J＝13.6，3.7Hz，2H)，3.25-3.37(m，2H)，2.05(s，3H)，1.74(d，J＝4.2Hz，4H)，1.40(s，3H).

Example 4

2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

Tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 3d (170 mg,0.36 mmol) and 1.65mL of trifluoroacetic acid were added to 6mL of dichloromethane, reacted at room temperature for 40 minutes, concentrated under reduced pressure, and the resulting residue was subjected to liquid phase separation (separation column AKZONOBELKromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 4a (65.77 mg), yield: 49%.

MS m/z(ESI)：376.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ8.07(s，2H)，7.82(dd，J＝7.7，1.9Hz，1H)，7.48-7.64(m，2H)，4.27(s，2H)，3.50(t，J＝9.4Hz，2H)，2.09-2.24(m，3H)，1.63-1.86(m，4H)，1.40(s，3H).

Second step

2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 4a (20 mg,0.267 mmol) and 0.1mL of 6M sodium hydroxide solution were added to 1.5mL of ethanol, heated to 80℃and reacted for 40 minutes. Cooling after the reaction is finishedCooled to room temperature and concentrated under reduced pressure, the resulting residue was separated from the liquid phase (column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give the product 2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 4 (16.25 mg), yield: 49%.

MS m/z(ESI)：394.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ8.01(d，J＝9.7Hz，3H)，7.61(dd，J＝8.1，1.3Hz，1H)，7.45(s，1H)，7.37(t，J＝7.9Hz，1H)，7.16-7.24(m，1H)，4.41(d，J＝13.3Hz，2H)，3.46(dd，J＝14.0，5.8Hz，2H)，2.04(s，3H)，1.75(s，4H)，1.41(s，3H).

Example 5

6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methyliisonicotinic acid

First step

(1- (4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

2-chloro-6-methylisotropic nicotinonitrile 5a (230 mg,1.51mmol, self-made according to patent WO 2009016498), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 1c (389 mg,1.82 mmol) and N, N-diisopropylethylamine (399mg, 3.03 mmol) were added to 6mL of N-methylpyrrolidone, heated to 90℃and reacted for 5 hours, after the end of the reaction, 30mL of water was added, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the resulting residue was concentrated under reduced pressure and further purified by silica gel column chromatography (eluent: A system) to give (1- (4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 5b (245 mg), yield: 49%.

MS m/z(ESI)：331.2[M+1]

Second step

(1- (5-bromo-4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 5b (70 mg,0.212 mmol) and bromosuccinimide (42 mg,0.233 mmol) were added to 1.5mL of N, N-dimethylformamide and reacted overnight at room temperature. After the completion of the reaction, the organic phases were combined by extraction with ethyl acetate (30 mL. Times.2), washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5-bromo-4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 5c (64 mg), yield: 73%.

MS m/z(ESI)：409.1[M+1]

Third step

(1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (5-bromo-4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 5c (150 mg, 0.365 mmol) and 1e (140 mg, 0.730 mmol) of (2, 3-dichlorophenyl) boronic acid, methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (0.039 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (34 mg,0.074 mmol) and potassium phosphate (234 mg,1.104 mmol) were added to a 3.5mL mixture of (1, 4-dioxane: water=6:1) under argon and heated to 130℃for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 5d (170 mg), yield: 98%.

MS m/z(ESI)：475.0[M+1]

Fourth step

6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylisotope-nitrile

(1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) ammoniaTert-butyl benzoate 5d (170 mg, 0.399 mmol) and 1.5mL of trifluoroacetic acid were added to 6mL of dichloromethane, reacted at room temperature for 40 minutes, after the completion of the reaction, concentrated under reduced pressure, and the resulting residue was subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylisonicotinonitrile 5e (69.91 mg), yield: 52%. MS m/z (ESI): 375.0[ M+1 ]]

Fifth step

6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylisonicotinonitrile 5e (30 mg,0.08 mmol) was added to 0.5mL of concentrated hydrochloric acid and heated to 110℃for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was subjected to liquid phase separation (separation column AKZONOBELKromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methyliisonicotinic acid 5 (12.08 mg), yield: 39%.

MS m/z(ESI)：394.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ8.01(s，3H)，7.62(dd，J＝8.1，1.4Hz，1H)，7.39(t，J＝7.9Hz，1H)，7.19(dd，J＝7.6，1.4Hz，1H)，7.06(s，1H)，4.10(dd，J＝13.6，3.7Hz，2H)，3.25-3.37(m，2H)，2.05(s，3H)，1.74(d，J＝4.2Hz，4H)，1.40(s，3H).

Example 6

6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylisonicotinamide

First step

6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylisonicotinonitrile 5e (37.33 mg,0.1 mmol) and 0.1mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80℃and reacted for 40 min. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylisonicotinamide 6 (21.99 mg), yield: 56%.

MS m/z(ESI)：393.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ7.98(s，2H)，7.70(s，1H)，7.60(dd，J＝8.0，1.4Hz，1H)，7.36(t，J＝7.9Hz，1H)，7.30(s，1H)，7.20(dd，J＝7.6，1.5Hz，1H)，6.81(s，1H)，4.11(d，J＝13.9Hz，2H)，3.29(d，J＝5.1Hz，2H)，2.03(s，3H)，1.74(s，4H)，1.40(s，3H).

Example 7

1- (5- (2, 3-dichlorophenyl) -4-methyl-6- (2H-tetrazol-5-yl) pyrimidin-2-yl) -4-methylpiperidin-4-amine

First step

(1- (5- (2, 3-dichlorophenyl) -4-methyl-6- (2H-tetrazol-5-yl) pyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

3d (50 mg,0.105 mmol) of tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate, zinc chloride (14.30 mg,0.105 mmol) and sodium azide (6.82 mg,0.105 mmol) were added sequentially to 2mL of methanol and reacted at room temperature for 2 days. After the completion of the reaction, 2mL of 1M diluted hydrochloric acid was slowly added dropwise to the reaction mixture to quench the reaction, the reaction mixture was extracted with ethyl acetate (30 mL. Times.2), the combined organic phases were washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue to prepare a liquid fractionSeparation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give (1- (5- (2, 3-dichlorophenyl) -4-methyl-6- (2H-tetrazol-5-yl) pyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 7a (15 mg), yield: 27.51%.

MS m/z(ESI)：519.6[M+1]

Second step

Tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-methyl-6- (2H-tetrazol-5-yl) pyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 7a (15 mg,0.029 mmol) and 0.5mL of trifluoroacetic acid were added to 2mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the residue was concentrated under reduced pressure to give a liquid phase which was separated (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 1- (5- (2, 3-dichlorophenyl) -4-methyl-6- (2H-tetrazol-5-yl) pyrimidin-2-yl) -4-methylpiperidin-4-amine 7 (5 mg), yield: 40.4%.

MS m/z(ESI)：419.0[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ8.03(s，3H)，7.70-7.73(dd，J＝8.0，4.0Hz，1H)，7.43(t，J＝8.0Hz，1H)，7.28-7.31(dd，J＝8.0，4.0Hz，1H)，4.50(s，2H)，3.50-3.60(m，2H)，2.13(s，3H)，1.78(t，J＝4.0Hz，4H)，1.43(s，3H).

Example 8

(2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonyl) glycine

/>

First step

2- (4- ((tert-Butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid

2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 3 (80 mg,0.202 mmol), di-tert-butyl dicarbonate (88.34 mg,0.405 mmol) and sodium carbonate (85.8 mg, 0.09 mmol) were added to a 2mL mixed solution (1, 4-dioxane: water=5:1) and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, pH was adjusted to 2-3 by the addition of 1M diluted hydrochloric acid, extracted with ethyl acetate (30 mL. Times.2), the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: B system) to give 8a (40 mg) of 2- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid, yield: 39.9%.

MS m/z(ESI)：495.1[M+1]

Second step

(2- (4- ((tert-Butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonyl) glycine tert-butyl ester

2- (4- ((tert-Butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 8a (50 mg,0.128 mmol), tert-butyl 2-aminoacetate (33.52 mg,0.256 mmol), N-diisopropylethylamine (16.52 mg,0.128 mmol), benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (133.00 mg,0.256 mmol) was added to 2mL of N, N-dimethylformamide and reacted at room temperature for 2 hours. At the end of the reaction, the reaction mixture was extracted with ethyl acetate (30 mL. Times.2), the combined organic phases were washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (2- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonyl) glycine 8b (40 mg), yield: 62%.

MS m/z(ESI)：608.3[M+1]

Third step

Tert-butyl (2- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonyl) glycine 8b (40 mg,0.079 mmol) was added to 2mL of 6M diluted hydrochloric acid, heated to 90 ℃ and reacted for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give (2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonyl) glycine 8 (5 mg), yield: 13.84%.

MS m/z(ESI)：452.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ7.54(d，J＝8.0Hz，1H)，7.32(t，J＝8.0Hz，1H)，7.11(d，J＝8.0Hz，1H)，4.36(s，2H)，3.42(s，4H)，2.00(s，3H)，1.69-1.74(m，4H)，1.37(s，3H).

Example 9

2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] dec-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid

First step

(R) -2-methyl-N- ((3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) propane-2-sulfinamide

(3S, 4S) -4- (((R) -tert-butylsulfinyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester 9a (670 mg,1.79 mmol) and 1.5mL of trifluoroacetic acid were added to 6mL of dichloromethane and reacted at room temperature for 1.5 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure to give (R) -2-methyl-N- ((3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) propane-2-sulfinamide 9b (490 mg), and the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：275.1[M+1]

Second step

(R) -N- ((3S, 4S) -8- (4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide

(R) -2-methyl-N- ((3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) propane-2-sulfinamide 9b (490 mg,1.26 mmol), N-diisopropylethylamine (135.86 mg,1.05 mmol) and 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (161.43 mg,1.05 mmol) were added to 5mL of N, N-dimethylacetamide and heated to 110℃for 3 hours of reaction. After the completion of the reaction, 30mL of water was added, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give (R) -N- ((3S, 4S) -8- (4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide 9c (411 mg), yield: 99.86%.

MS m/z(ESI)：392.2[M+1]

Third step

2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] dec-8-yl) -6-methylpyrimidine-4-carbonitrile

(R) -N- ((3S, 4S) -8- (4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropane-2-sulfinamide 9c (375 mg,0.948 mmol) and bromosuccinimide (185.51 mg,1.04 mmol) were added to 5mL of N, N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to give the product 2- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6-methylpyrimidine-4-carbonitrile 9d (272.29 mg), yield: 100% of the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：288.1[M+1]

Fourth step

((3S, 4S) -8- (4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) carbamic acid tert-butyl ester

2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] dec-8-yl) -6-methylpyrimidine-4-carbonitrile 9d (272.29 mg,0.948 mmol), di-tert-butyl dicarbonate (827.20 mg,3.79 mmol) and triethylamine (287.65 mg,2.84 mmol) were added to 10mL of dichloromethane and reacted at room temperature for 3 hours. After the completion of the reaction, the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: A system) to give ((3S, 4S) -8- (4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) carbamic acid tert-butyl ester 9e (340 mg), yield: 92.6%.

MS m/z(ESI)：388.2[M+1]

Fifth step

((3S, 4S) -8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) carbamic acid tert-butyl ester

Tert-butyl ((3S, 4S) -8- (4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) carbamate 9e (340 mg,0.877 mmol) and bromosuccinimide (171.79 mg,0.965 mmol) were added to 5mL of N, N-dimethylformamide and reacted overnight at room temperature. After the completion of the reaction, 30mL of water was added, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give ((3S, 4S) -8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) carbamic acid tert-butyl ester 9f (390 mg), yield: 95.3%.

MS m/z(ESI)：466.1[M+1]

Sixth step

((3S, 4S) -8- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) carbamic acid tert-butyl ester

Tert-butyl ((3S, 4S) -8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) carbamate 9f (390 mg,0.836 mmol), (2, 3-dichlorophenyl) boronic acid 1e (319.14 mg,1.67 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (70.03 mg,0.084 mmol), tetrakis (triphenylphosphine) palladium (78.05 mg, 0.167mmol) and potassium phosphate (532.78 mg,2.51 mmol) were added to a 8mL mixed solution (1, 4-dioxane: water=7:1) under argon and heated to 135℃for 3.5 hours. After the reaction was completed, it was cooled, 30mL of water was added, extracted with ethyl acetate (30 mL. Times.3), and the saturated sodium chloride solution was washed, the organic phases were combined, dried over anhydrous sodium sulfate, and the obtained residue was concentrated under reduced pressure, and the further analyzed and purified by silica gel column chromatography (eluent: A system) to give ((3S, 4S) -8- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) carbamic acid tert-butyl ester 9g (380 mg), yield: 85.34%.

MS m/z(ESI)：532.2[M+1]

Seventh step

The ((3S, 4S) -8- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5)]Decyl-4-yl) carbamic acid tert-butyl ester 9g (29 mg,0.055 mmol) and 0.5mL of concentrated hydrochloric acid are added to the pressure tube and heated to 110℃for 1.5 h. After the reaction was completed, the residue was concentrated under reduced pressure to give a liquid phase which was separated (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give the product 2- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 9 (1.83 mg), yield: 5.91%.

MS m/z(ESI)：451.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ13.30(s，1H)，7.94(s，2H)，7.68(d，J＝8.1Hz，1H)，7.42(t，J＝7.8Hz，1H)，7.26(d，J＝7.6Hz，1H)，4.40-4.60(m，2H)，4.14-4.31(m，1H)，3.93(d，J＝9.2Hz，1H)，3.73(d，J＝9.1Hz，1H)，3.42(s，1H)，3.07-3.24(m，2H)，2.07(s，3H)，1.73(s，3H)，1.59(d，J＝13.7Hz，1H)，1.23(d，J＝6.5Hz，3H).

Example 10

2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] dec-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] dec-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

The ((3S, 4S) -8- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5) ]Decyl-4-yl) carbamic acid tert-butyl ester 9g (180 mg,0.338 mmol) and 1.5mL of trifluoroacetic acid are added to 6mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the residue was concentrated under reduced pressure to give a liquid phase which was separated (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give the product 2- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 10a (77.68 mg), yield: 41.5%.

MS m/z(ESI)：432.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ7.97(s，2H)，7.83(dd，J＝7.7，1.9Hz，1H)，7.45-7.62(m，2H)，4.42(s，2H)，4.16-4.29(m，1H)，3.92(d，J＝9.1Hz，1H)，3.73(d，J＝9.0Hz，1H)，3.44(s，1H)，3.13-3.29(m，2H)，2.15(s，3H)，1.72(d，J＝24.2Hz，3H)，1.61(d，J＝13.6Hz，1H)，1.23(d，J＝6.6Hz，3H).

Second step

2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 10a (30 mg,0.069 mmol) and 0.3mL of sodium hydroxide were added to 1.2mL of ethanol, heated to 80℃and reacted for 50 minutes. After the completion of the reaction, the residue obtained was concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil;250 x 21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% TFA+H ₂ O, mobile phase B: CH (CH) ₃ CN) to give the product 2- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5) ]Decan-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 10 (5.13 mg), yield: 16.2%.

MS m/z(ESI)：450.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ7.96(s，1H)，7.56-7.62(m，1H)，7.39(s，1H)，7.36(t，J＝7.8Hz，1H)，7.22(d，J＝6.2Hz，1H)，4.16(s，2H)，4.05-4.11(m，1H)，3.71(d，J＝8.4Hz，1H)，3.54(t，J＝12.9Hz，3H)，2.93(d，J＝5.0Hz，1H)，2.01(s，3H)，1.74(s，1H)，1.64(s，1H)，1.53(d，J＝18.7Hz，2H)，1.31(s，2H)，1.10(d，J＝6.4Hz，3H).

Example 11

2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

((1- (4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (100 mg,0.651 mmol), ((4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester 11a (178.42 mg,0.781 mmol) and N, N-diisopropylethylamine (252.47 mg,1.95 mmol) were added to 1.2mL of N, N-dimethylacetamide and heated to 90℃for 4 hours. After the completion of the reaction, 20mL of water was added, extraction was performed with ethyl acetate (20 mL. Times.3), the saturated sodium chloride solution was washed, the organic phases were combined, dried over anhydrous sodium sulfate, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((1- (4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamate 11b (223 mg), yield: 99.1%.

MS m/z(ESI)：346.2[M+1]

Second step

((1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester

Tert-butyl ((1- (4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamate 11b (223 mg,0.646 mmol) and bromosuccinimide (120.64 mg,0.678 mmol) were added to 4mL of N, N-dimethylformamide and reacted overnight at room temperature. After the completion of the reaction, 20mL of water was added, extraction was performed with ethyl acetate (20 mL. Times.3), the saturated sodium chloride solution was washed, the organic phases were combined, dried over anhydrous sodium sulfate, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give ((1- (5-bromo-4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester 11c (260 mg), yield: 94.91%.

MS m/z(ESI)：424.1[M+1]

Third step

((1- (4-cyano-5- (2, 3-dichlorophenyl) -6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester

Tert-butyl ((1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamate 11c (260 mg, 0.313 mmol), (2, 3-dichlorophenyl) boronic acid 1e (233.84 mg,1.23 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (51.31 mg,0.061 mmol), tetrakis (triphenylphosphine) palladium (57.18 mg,0.123 mmol) and potassium phosphate (390.37 mg,1.84 mmol) were added to a 3.5mL mixed solution (1, 4-dioxane: water=6:1) and heated to 130℃for 3.5 hours under argon. After the completion of the reaction, 30mL of water was added, extraction was performed with ethyl acetate (30 mL. Times.3), the saturated sodium chloride solution was washed, the organic phases were combined, dried over anhydrous sodium sulfate, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give ((1- (4-cyano-5- (2, 3-dichlorophenyl) -6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester 11d (280 mg), yield: 93.18%.

MS m/z(ESI)：490.1[M+1]

Fourth step

2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

Tert-butyl ((1- (4-cyano-5- (2, 3-dichlorophenyl) -6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamate 11d (80 mg,0.163 mmol) and 1mL of trifluoroacetic acid were added to 4mL of dichloromethane and reacted at room temperature for 50 minutes. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 11e (63 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI)：390.1[M+1]

Fifth step

2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 11e (63 mg,0.161 mmol) and 0.5mL of sodium hydroxide were added to 2mL of ethanol, heated to 80℃and reacted for 2 hours. The residue obtained was concentrated under reduced pressure to give a liquid phase (column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give the product 2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 11 (11.03 mg), yield: 16.4%.

MS m/z(ESI)：408.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ7.93(s，1H)，7.58(dd，J＝8.1，1.5Hz，1H)，7.38(s，1H)，7.34(dd，J＝9.6，6.1Hz，1H)，7.20(dd，J＝7.6，1.5Hz，1H)，4.16(d，J＝13.3Hz，2H)，3.44-3.52(m，2H)，2.42(s，2H)，2.00(s，3H)，1.44(t，J＝9.5Hz，2H)，1.29(d，J＝13.9Hz，2H)，0.95(s，3H).

Example 12

2- (4-amino-4-methylpiperidin-1-yl) -5- (2-chloro-3-methylphenyl) -6-methylpyrimidine-4-carboxamide

First step

(1- (5- (2-chloro-3-methylphenyl) -4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 3c (80 mg,0.195 mmol), (2-chloro-3-methylphenyl) boronic acid 12a (66.45 mg,0.390 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (16.33 mg,0.0195 mmol), 2-dicyclohexyl-phosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (18.20 mg,0.039 mmol) and potassium phosphate (124.22 mg,0.585 mmol) were added to a 1.5mL mixed solution (1, 4-dioxane: water=4:1) under argon atmosphere, and the mixture was heated to 130 ℃ for 5 hours. After the completion of the reaction, 20mL of water was added, extraction was performed with ethyl acetate (20 mL. Times.3), the saturated sodium chloride solution was washed, the organic phases were combined, dried over anhydrous sodium sulfate, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5- (2-chloro-3-methylphenyl) -4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 12b (86 mg), yield: 96.7%.

MS m/z(ESI)：456.2[M+1]

Second step

2- (4-amino-4-methylpiperidin-1-yl) -5- (2-chloro-3-methylphenyl) -6-methylpyrimidine-4-carbonitrile

Tert-butyl (1- (5- (2-chloro-3-methylphenyl) -4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 12b (86 mg,0.189 mmol) and 1.5mL of trifluoroacetic acid were added to 6mL of dichloromethane and reacted at room temperature for 40 minutes. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 2- (4-amino-4-methylpiperidin-1-yl) -5- (2-chloro-3-methylphenyl) -6-methylpyrimidine-4-carbonitrile 12c (67.12 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI)：356.1[M+1]

Third step

2- (4-amino-4-methylpiperidin-1-yl) -5- (2-chloro-3-methylphenyl) -6-methylpyrimidine-4-carbonitrile 12c (67.12 mg,0.189 mmol) and 0.5mL of sodium hydroxide were added to 2mL of ethanol, heated to 80℃and reacted for 40 minutes. The residue obtained was concentrated under reduced pressure to give a liquid phase (column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give the product 2- (4-amino-4-methylpiperidin-1-yl) -5- (2-chloro-3-methylphenyl) -6-methylpyrimidine-4-carboxamide 12 (43.69 mg), yield: 61.6%.

MS m/z(ESI)：374.1[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ7.83(s，1H)，7.30(d，J＝7.6Hz，2H)，7.22(t，J＝7.5Hz，1H)，7.06(d，J＝6.5Hz，1H)，3.90-4.14(m，2H)，3.60-3.76(m，2H)，2.37(s，3H)，1.99(s，3H)，1.45(dd，J＝14.8，10.6Hz，6H)，1.11(s，3H).

Example 13

2- ((R) -1-amino-8-azaspiro [4.5] dec-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

(R) -2-methyl-N- ((R) -8-azaspiro [4.5] dec-1-yl) propane-2-sulfinamide

(R) -1- (((R) -tert-butylsulfinyl) amino) tert-butyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester 13a (200 mg, 0.5538 mmol) and trifluoroacetic acid (636.03 mg,5.58 mmol) were added to 2mL of dichloromethane and reacted at room temperature for 1.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give (R) -2-methyl-N- ((R) -8-azaspiro [4.5] dec-1-yl) propane-2-sulfinamide 13b (144.15 mg), yield: 100.00% of the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：259.2[M+1]

Second step

(R) -2-methyl-N- ((R) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) -propane-2-sulfinamide

(R) -2-methyl-N- ((R) -8-azaspiro [4.5] dec-1-yl) propane-2-sulfinamide 13b (373.55 mg,1.04 mmol), 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (80 mg,0.521 mmol) and N, N-diisopropylethylamine (67.33 mg,0.521 mmol) were added sequentially to 2mL of N, N-dimethylacetamide and heated to 90℃for 3 hours. After completion of the reaction, cooled to room temperature, extracted with ethyl acetate (30 ml×2), the organic phases were combined, washed with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: a system) to give (R) -2-methyl-N- ((R) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) -propane-2-sulfinamide 13c (100 mg), yield: 51.12%.

MS m/z(ESI)：376.1[M+1]

Third step

(R) -2- (1-amino-8-azaspiro [4.5] dec-8-yl) -6-methylpyrimidine-4-carbonitrile

(R) -2-methyl-N- ((R) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) -propane-2-sulfinamide 13c (100 mg,0.266 mmol) and bromosuccinimide (52.13 mg,0.293 mmol) were added to 3mL of N, N-dimethylformamide and reacted overnight at room temperature. After the completion of the reaction, the mixture was concentrated under reduced pressure to give (R) -2- (1-amino-8-azaspiro [4.5] dec-8-yl) -6-methylpyrimidine-4-carbonitrile 13d (72 mg), yield: 99.64% of the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：272.2[M+1]

Fourth step

(R) - (8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamic acid tert-butyl ester

(R) -2- (1-amino-8-azaspiro [4.5] dec-8-yl) -6-methylpyrimidine-4-carbonitrile 13d (72 mg,0.265 mmol), di-tert-butyl dicarbonate (115.82 mg,0.531 mmol) and triethylamine (53.70 mg,0.531 mmol) were added to 2mL of dichloromethane and reacted overnight at room temperature. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) - (8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamate 13e (80 mg), yield: 81.17%.

MS m/z(ESI)：372.2[M+1]

Fifth step

(R) - (8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamic acid tert-butyl ester

Tert-butyl (R) - (8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamate 13e (72 mg,0.194 mmol) and bromosuccinimide (37.95 mg,0.213 mmol) were added to 2mL of N, N-dimethylformamide and reacted overnight at room temperature. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. Times.2), and dried over anhydrous sodium sulfate, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) - (8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamate 13f (80 mg). Yield: 91.65%.

MS m/z(ESI)：395.9[M-56]

Sixth step

((1R) -8- (4-cyano-5- (2, 3-dichlorophenyl) -6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamic acid tert-butyl ester

Tert-butyl (R) - (8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamate 13f (30 mg,0.067 mmol), (2, 3-dichlorophenyl) boronic acid 1e (25.42 mg,0.133 mmol), (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride (11.15 mg,0.013 mmol), tetrakis (triphenylphosphine) palladium (12.43 mg,0.027 mmol) and potassium phosphate (42.44 mg, 0.199mmol) were added to a 2mL mixed solution (1, 4-dioxane: water=5:1) under argon atmosphere and heated to 130℃for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give 13g (30 mg) of tert-butyl ((1R) -8- (4-cyano-5- (2, 3-dichlorophenyl) -6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamate, yield: 87.20%.

MS m/z(ESI)：515.9[M+1]

Seventh step

2- ((R) -1-amino-8-azaspiro [4.5] dec-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

13g (45 mg,0.087 mmol) of tert-butyl ((1R) -8- (4-cyano-5- (2, 3-dichlorophenyl) -6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamate and 0.5mL of trifluoroacetic acid were added to 2mL of dichloromethane and reacted at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to give 2- ((R) -1-amino-8-azaspiro [4.5] dec-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 13h (36 mg), yield: 99.24% of the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：416.1[M+1]

Eighth step

2- ((R) -1-amino-8-azaspiro [4.5]]Decan-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 13h (36 mg,0.086 mmol) and 0.5mL of 6M sodium hydroxide were added to 2mL of ethanol, heated to 80℃and reacted for 0.5 h. After the reaction was completed, the residue was concentrated under reduced pressure to give a liquid phase which was separated (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- ((R) -1-amino-8-azaspiro [4.5] ]Decan-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 13 (6 mg), yield: 15.70%.

MS m/z(ESI)：433.9[M+1]

¹ H NMR(400MHz，CD3OD)：δ7.52(d，J＝8.0Hz，1H)，7J1(t，J＝8.0Hz，1H)，7.15(d，J＝8.0Hz，1H)，4.72(s，2H)，3.21(d，J＝12.0Hz，2H)，2.82(s，1H)，2.09(s，3H)，1.59-1.79(m，5H)，1.32-1.48(m，5H).

Example 14

2- (4-aminopiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

(1- (4-cyano-6-methylpyrimidin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (80 mg,0.521 mmol), piperidine-4-carbamic acid tert-butyl ester 14a (125.20 mg,0.625 mmol) and N, N-diisopropylethylamine (201.98 mg,1.56 mmol) were added to 2mL of N, N-dimethylacetamide and heated to 90℃for 3 hours. After the completion of the reaction, 20mL of water was added, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (4-cyano-6-methylpyridin-2-yl) piperidin-4-yl) carbamate 14b (160 mg), yield: 96.77%.

MS m/z(ESI)：262.0[M+1-56]

Second step

(1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (4-cyano-6-methylpyrimidin-2-yl) piperidin-4-yl) carbamate 14b (160 mg,0.504 mmol) and bromosuccinimide (107.67 mg,0.605 mmol) were added to 2mL of N, N-dimethylformamide and reacted overnight at room temperature. After the completion of the reaction, 30mL of water was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) piperidin-4-yl) carbamate 14c (180 mg), yield: 90.1%.

MS m/z(ESI)：342.0[M+1-56]

Third step

(1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) piperidin-4-yl) carbamate 14c (100 mg,0.252 mmol), (2, 3-dichlorophenyl) boronic acid 1e (96.31 mg,0.505 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (21.13 mg,0.025 mmol), tetrakis (triphenylphosphine) palladium (23.55 mg,0.050 mmol) and potassium phosphate (160.69 mg,0.757 mmol) were added to a 2.2mL mixture (1, 4-dioxane: water=10:1) and heated to 130℃for 5 hours under argon. After the completion of the reaction, it was cooled to room temperature, 20mL of water was added, the mixture was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyridin-2-yl) piperidin-4-yl) carbamate 14d (100 mg), yield: 85.71%.

MS m/z(ESI)：406.0[M+1-56]

Fourth step

2- (4-aminopiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

Tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) piperidin-4-yl) carbamate 14d (100 mg,0.216 mmol) and trifluoroacetic acid (24.66 mg,0.216 mmol) were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give 2- (4-aminopiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 14e (100 mg), yield: 97.08% and the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：361.9[M+1]

Fifth step

2- (4-Aminopiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 14e (100 mg,0.210 mmol) and 0.3mL6M sodium hydroxide solution was added to 2mL of ethanol, heated to 80℃and reacted for 1 hour. After the reaction was completed, the residue was concentrated under reduced pressure to give a liquid phase which was separated (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-aminopiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 14 (40 mg), yield: 49.27%.

MS m/z(ESI)：379.9[M+1]

¹ H NMR(400MHz，CD3OD)δ7.50(dd，J＝8.0，1.6Hz，1H)，7.29(t，J＝7.9Hz，1H)，7.13(dd，J＝7.7，1.6Hz，1H)，4.84(d，J＝3.4Hz，2H)，3.02(ddd，J＝13.5，12.1，2.7Hz，2H)，2.93(ddd，J＝10.8，6.7，4.1Hz，1H)，2.08(s，3H)，1.93(dd，J＝13.3，3.7Hz，2H)，1.29-1.39(m，2H).

Example 15

2- ((R) -3- (aminomethyl) pyrrolidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

(R) - ((1- (4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (50 mg,0.326 mmol), (S) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester 15a (92.49 mg, 0.399 mmol) and N, N-diisopropylethylamine (126.24 mg,0.977 mmol) were added to 2mL of N, N-dimethylacetamide and heated to 90℃for 3 hours. After the completion of the reaction, 20mL of water was added, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) - ((1- (4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamate 15b (80 mg), yield: 77.42%.

MS m/z(ESI)：318.2[M+1]

Second step

(R) - ((1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester

Tert-butyl (R) - ((1- (4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamate 15b (80 mg,0.252 mmol) and bromosuccinimide (67.29 mg,0.378 mmol) were added to 2mL of N, N-dimethylformamide and reacted overnight at room temperature. After the completion of the reaction, 30mL of water was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) - ((1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamate 15c (80 mg), yield: 80.1%.

MS m/z(ESI)：341.9[M+1-56]

Third step

((3R) -1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester

Tert-butyl (R) - ((1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamate 15c (80 mg,0.202 mmol), (2, 3-dichlorophenyl) boronic acid 1e (96.31 mg,0.505 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (16.90 mg, 0.020mmol), tetrakis (triphenylphosphine) palladium (18.84 mg,0.040 mmol) and potassium phosphate (128.55 mg, 0.605 mmole) were added to a 2.2mL mixed solution (1, 4-dioxane: water=10:1) under argon atmosphere and heated to 130℃for 5 hours. After the completion of the reaction, it was cooled to room temperature, 20mL of water was added, the mixture was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give (((3R) -1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester 15d (70 mg), yield: 74.99%.

MS m/z(ESI)：461.9[M+1]

Fourth step

2- ((R) -3- (aminomethyl) pyrrolidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

Tert-butyl (((3R) -1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamate 15d (70 mg,0.151 mmol) and trifluoroacetic acid (1.53 g,13.42 mmol) were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to give 2- ((R) -3- (aminomethyl) pyrrolidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 15e (50 mg), yield: 91.17% and the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：362.1[M+1]

Fifth step

2- ((R) -3- (aminomethyl) pyrrolidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 15e (50 mg,0.138 mmol) and 0.3mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80℃and reacted for 1 hour. After the reaction was completed, the residue was concentrated under reduced pressure to give a liquid phase which was separated (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- ((R) -3- (aminomethyl) pyrrolidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 15 (20 mg), yield: 36.85%.

MS m/z(ESI)：380.0[M+1]

¹ H NMR(400MHz，CD3OD)δ7.51(dd，J＝8.1，1.5Hz，1H)，7.30(t，J＝7.9Hz，1H)，7.15(dd，J＝7.7，1.4Hz，1H)，3.90(dd，J＝11.4，7.3Hz，1H)，3.81(ddd，J＝11.8，8.2，4.0Hz，1H)，3.60(dt，J＝11.3，7.9Hz，1H)，3.35(d，J＝7.7Hz，1H)，2.76(d，J＝7.1Hz，2H)，2.44(dt，J＝14.4，7.1Hz，1H)，2.21(dt，J＝11.6，7.0Hz，1H)，2.09(d，J＝3.8Hz，3H)，1.72-1.85(m，1H).

Example 16

2- ((1 r,5 s) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

((1R, 5S) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (60 mg, 0.399mmol), ((1R, 5S) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 16a (106.11 mg,0.469 mmol) N, N-diisopropylethylamine (151.49 mg,1.17 mmol) was added to 2mL of N, N-dimethylacetamide and heated to 90℃for 3 hours. After completion of the reaction, 20mL of water was added, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give ((1R, 5S) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 16b (130 mg), yield: 96.89%.

MS m/z(ESI)：344.0[M+1]

Second step

((1R, 5S) -8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

Tert-butyl ((1R, 5S) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 16b (130 mg,0.379 mmol) and bromosuccinimide (80.85 mg,0.454 mmol) were added to 2mL of N, N-dimethylformamide and reacted overnight at room temperature. After the completion of the reaction, 30mL of water was added, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give ((1R, 5S) -8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 16c (150 mg), yield: 93.83%.

MS m/z(ESI)：365.9[M+1-56]

Third step

((1R, 5S) -8- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

Tert-butyl ((1R, 5S) -8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 16c (150 mg, 0.35mmol), (2, 3-dichlorophenyl) boronic acid 1e (169.44 mg,0.888 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (29.74 mg,0.036 mmol), tetrakis (triphenylphosphine) palladium (33.15 mg,0.071 mmol) and potassium phosphate (226.17 mg,1.07 mmol) were added to a 2.2mL mixed solution (1, 4-dioxane: water=10:1) under argon atmosphere and heated to 130℃for 5 hours. After the reaction was completed, cooled to room temperature, 20mL of water was added, extraction was performed with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: a system) to give ((1 r,5 s) -8- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 16d (150 mg), yield: 86.48%.

MS m/z(ESI)：488.1[M+1]

Fourth step

2- ((1 r,5 s) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

Tert-butyl ((1R, 5S) -8- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 16d (150 mg,0.307 mmol) and 1mL of trifluoroacetic acid were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give 2- ((1 r,5 s) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 16e (100 mg), yield: 83.86% and the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：387.9[M+1]

Fifth step

2- ((1R, 5S) -3-amino-8-azabicyclo [ 3.2.1)]Oct-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 16e (100 mg,0.258 mmol) and 0.3mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80℃and reacted for 1 hour. After the reaction was completed, the residue was concentrated under reduced pressure to give a liquid phase which was separated (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- ((1 r,5 s) -3-amino-8-azabicyclo [ 3.2.1)]Oct-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 16 (45 mg), yield: 41.75%.

MS m/z(ESI)：405.9[M+1]

¹ H NMR(400MHz，CD ₃ OD)δ7.51(dd，J＝8.1，1.5Hz，1H)，7.30(t，J＝7.9Hz，1H)，7.13(dd，J＝7.7，1.5Hz，1H)，4.87(s，2H)，3.33-3.38(m，1H)，2.08(d，J＝6.4Hz，5H)，1.83-1.96(m，4H)，1.59(dd，J＝17.5，6.6Hz，2H).

Example 17

5- (2, 3-dichlorophenyl) -2- (4-guanidino-4-methyl-1-piperidinyl) -6-methylpyrimidine-4-carboxamide

First step

N- [ (tert-Butoxycarbonylamino) - [ [1- [ 4-carbamoyl-5- (2, 3-dichlorophenyl) -6-methyl-pyrimidin-2-yl ] -4-methyl-4-piperidinyl ] amino ] methylene ] carbamic acid tert-butyl ester

2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 4 (14.0 mg, 35.51. Mu. Mol), 1, 3-bis (t-butoxycarbonyl) -2-methylisothiourea (11.34 mg, 39.06. Mu. Mol), cuprous iodide (13.52 mg, 71.01. Mu. Mol) and potassium carbonate (19.63 mg, 142.02. Mu. Mol) were added to 1mL of tetrahydrofuran in this order, nitrogen was replaced 3 times, and the mixture was heated to 60℃under external temperature for 24 hours. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (10 mL), the filtrates were combined and concentrated to dryness under reduced pressure to give crude tert-butyl N- [ (tert-butoxycarbonylamino) - [ [1- [ 4-carbamoyl-5- (2, 3-dichlorophenyl) -6-methyl-pyrimidin-2-yl ] -4-methyl-4-piperidinyl ] amino ] methylene ] carbamate 17a (oil) which was used in the next reaction without purification.

MS m/z(ESI)：537.2[M-100]

Second step

N- [ (tert-Butoxycarbonylamino) - [ [1- [ 4-carbamoyl-5- (2, 3-dichlorophenyl) -6-methyl-pyrimidin-2-yl ] -4-methyl-4-piperidinyl ] amino ] methylene ] carbamic acid tert-butyl ester 17a (22 mg, 34.56. Mu. Mol), TFA (1.54 g,13.51mmol,1 mL) was added sequentially to 3mL of dichloromethane and stirring continued at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (10 ml) was added to the residue, which was concentrated under reduced pressure, and the obtained residue was purified by preparative liquid chromatography, and after freeze-drying, 5- (2, 3-dichlorophenyl) -2- (4-guanidino-4-methyl-1-piperidinyl) -6-methylpyrimidine-4-carboxamide 17 (7.5 mg, 38.4% of total yield of the two steps) was obtained.

MS m/z(ESI)：435.9[M+1]

¹ H NMR(400MHz，CD ₃ OD)δ7.51(dd，J＝8.0，1.6Hz，1H)，7.30(t，J＝7.8Hz，1H)，7.13(dd，J＝7.6，1.6Hz，1H)，4.38-4.33(m，2H)，3.63-3.56(m，2H)，2.09-2.02(m，5H)，1.84-1.77(m，2H)，1.51(s，3H).

Example 18

2- (6-amino-3-azabicyclo [3.1.0] hex-3-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

(3- (4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6 yl) carbamic acid tert-butyl ester

Tert-butyl 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (70 mg,0.355 mmol) and (3-azabicyclo [3.1.0] hex-6-yl) carbamate 17a (91.48 mg, 0.463mmol) were added to 2mL of N, N-dimethylacetamide (137.62 mg,1.06 mmol) and reacted for 3 hours at 90 ℃. After the completion of the reaction, 20mL of water was added, extraction was performed with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (3- (4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6-yl) carbamate 17b (110 mg), yield: 98.27%.

MS m/z(ESI)：260.0[M+1-56]

Second step

(3- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6 yl) carbamic acid tert-butyl ester

Tert-butyl (3- (4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6 yl) carbamate 17b (110 mg,0.349 mmol) and bromosuccinimide (93.12 mg, 0.323 mmol) were added to 2mL of N, N-dimethylformamide and reacted overnight at room temperature. After completion of the reaction, 30mL of water was added, extraction was performed with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: a system) to give tert-butyl (3- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6-yl) carbamate 18c (110 mg), yield: 79.99%.

MS m/z(ESI)：340.0[M+1-56]

Third step

(3- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6 yl) carbamic acid tert-butyl ester

Tert-butyl (3- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6-yl) carbamate 18c (110 mg,0.279 mmol), (2, 3-dichlorophenyl) boronic acid 1e (122.45 mg,0.642 mmol), (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride (23.36 mg,0.028 mmol), tetrakis (triphenylphosphine) palladium (26.04 mg,0.056 mmol) and potassium phosphate (177.67 mg,0.837 mmol) were added to a 2.3mL mixed solution (1, 4-dioxane: water=7:1) under argon and heated to 130 ℃ for reaction for 5 hours. After the completion of the reaction, it was cooled to room temperature, 20mL of water was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (3- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6 yl) carbamate 18d (100 mg), yield: 77.86%. MS m/z (ESI): 403.8[ M+1-56]

Fourth step

2- (6-amino-3-azabicyclo [3.1.0] hex-3-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

Tert-butyl (3- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6 yl) carbamate 18d (100 mg,0.217 mmol) and trifluoroacetic acid (24.77 mg,0.21 mmol) were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give 2- (6-amino-3-azabicyclo [3.1.0] hex-3-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 18e (78 mg), yield: 99.68% and the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：359.7[M+1]

Fifth step

2- (6-amino-3-azabicyclo [ 3.1.0)]Hexal-3-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 18e (78 mg,0.217 mmol) and 0.3mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80℃and reacted for 1 hour. After the reaction was completed, the residue was concentrated under reduced pressure to give a liquid phase which was separated (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (6-amino-3-azabicyclo [ 3.1.0) ]Hex-3-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 18 (45 mg), yield: 41.74%.

MS m/z(ESI)：377.7[M+1]

¹ H NMR(400MHz，DMSO-d6)δ8.17(d，J＝97.0Hz，3H)，7.90(d，J＝10.2Hz，1H)，7.60(t，J＝6.6Hz，1H)，7.47(d，J＝21.5Hz，1H)，7.36(dq，J＝8.2，5.0，4.3Hz，1H)，7.23-7.08(m，1H)，3.89(d，J＝32.7Hz，3H)，3.60(d，J＝11.5Hz，2H)，2.13-1.90(m，5H).

Example 19

2- ((R) -6-amino-5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4 '-piperidin ] -1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

(R) -N- ((R) -5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4' -piperidin ] -6-yl) -2-methylpropan-2-sulfinamide

(R) -6- (((R) -tert-butylsulfinyl) amino) tert-butyl-5, 6-dihydrospiro [ cyclopenta [ b ] pyridine-7, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester 19a (150 mg, 0.365 mmol) and 1mL of trifluoroacetic acid were added to 6mL of dichloromethane and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give (R) -N- ((R) -5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4' -piperidin ] -6-yl) -2-methylpropane-2-sulfinamide 19b (113.15 mg), yield: 100.00% of the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：308.2[M+1]

Second step

(R) -N- ((R) -1'- (4-cyano-6-methylpyrimidin-2-yl) -5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4' -piperidin ] -6-yl) -2-methylpropan-2-sulfinamide

(R) -N- ((R) -5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4' -piperidin ] -6-yl) -2-methylpropane-2-sulfinamide 19b (113.15 mg, 0.365 mmol), 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (60 mg, 0.399 mmol) and N, N-diisopropylethylamine (50.49 mg, 0.399 mmol) were added sequentially to 3mL of N, N-dimethylacetamide, heated to 90℃and reacted for 3 hours. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (30 ml×2), the organic phases were combined, washed with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (R) -N- ((R) -1'- (4-cyano-6-methylpyrimidin-2-yl) -5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4' -piperidin ] -6-yl) -2-methylpropan-2-sulfinamide 19c (130 mg), yield: 78.37% of the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：424.9[M+1]

Third step

(R) - (1 '- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -5, 6-dihydrospiro [ cyclopent [ b ] pyridin-7, 4' -piperidin ] -6-yl) carbamic acid tert-butyl ester

(R) -N- ((R) -1'- (4-cyano-6-methylpyrimidin-2-yl) -5, 6-dihydrospiro [ cyclopent [ b ] pyridin-7, 4' -piperidin ] -6-yl) -2-methylpropane-2-sulfinamide 19c (130 mg,0.306 mmol) and iodosuccinimide (70.85 mg, 0.390 mmol) were added to 2mL of N, N-dimethylformamide and reacted at room temperature for 2 hours. After completion of the reaction, iodosuccinimide (70.85 mg,0.398 mmol) was added, the reaction was continued for 2 hours, and after completion of the reaction, 20mL of water was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed twice with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained, di-tert-butyl dicarbonate (200.48 mg,0.919 mmol) and N, N-diethylamine (154.92 mg,1.53 mmol) were added to 5mL of dichloromethane and reacted overnight at room temperature. After the completion of the reaction, 20mL of water was added, the organic phases were combined, washed twice with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) - (1 '- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4' -piperidin ] -6-yl) carbamate 19d (50 mg), yield: 32.7%.

MS m/z(ESI)：499.1[M+1]

Fourth step

(R) - (1 '- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -5, 6-dihydro-spiro [ cyclopenta [ b ] pyridin-7, 4' -piperidin ] -6-yl) carbamic acid tert-butyl ester

Tert-butyl (R) - (1 ' - (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4' -piperidin ] -6-yl) carbamate 19d (50 mg,0.100 mmol), (2, 3-dichlorophenyl) boronic acid 1e (47.76 mg,0.250 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (8.38 mg, 0.010mmol), tetrakis (triphenylphosphine) palladium (9.34 mg, 0.020mmol) and potassium phosphate (63.76 mg,0.300 mmol) were added to a 2.3mL mixed solution (1, 4-dioxane: water=7:1) under argon atmosphere and heated to 130℃for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) - (1 '- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4' -piperidin ] -6-yl) carbamate 19e (45 mg), yield: 79.48%.

MS m/z(ESI)：564.5[M+1]

Fifth step

2- ((R) -6-amino-5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4 '-piperidin ] -1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

Tert-butyl (R) - (1 '- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4' -piperidin ] -6-yl) carbamate 19e (45 mg,0.080 mmol) and 1mL of trifluoroacetic acid were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to give 2- ((R) -6-amino-5, 6-dihydrospiro [ cyclopenta [ b ] pyridin-7, 4 '-piperidin ] -1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 19f (37 mg), yield: 100% of the product was directly subjected to the next reaction without purification.

MS m/z(ESI)：465.1[M+1]

Sixth step

2- ((R) -6-amino-5, 6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7, 4' -piperidines]-1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 19f (37 mg,0.080mmol) and 0.3mL of 6M sodium hydroxide were added to 2mL of ethanol, heated to 80℃and reacted for 1 hour. After the reaction was completed, the residue was concentrated under reduced pressure to give a liquid phase which was separated (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- ((R) -6-amino-5, 6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7, 4' -piperidines]-1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 19 (20 mg), yield: 42.11%.

MS m/z(ESI)：482.7[M+1]

¹ H NMR(400MHz，CD ₃ OD)δ8.50(m，1H)，7.80(d，J＝7.6Hz，1H)，7.52(dd，J＝8.1，1.5Hz，1H)，7.36(m，2H)，7.15(dt，J＝7.6，1.7Hz，1H)，4.65-4.37(m，2H)，4.18-3.90(m，3H)，3.59(dd，J＝17.4，6.6Hz，1H)，3.11-2.97(m，1H)，2.25(t，J＝10.9Hz，1H)，2.10(s，3H)，1.94-1.67(m，3H).

Example 21

2- ((S) -1-amino-6-methoxy-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

(R) -N- ((S) -5-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -3-yl) -2-methylpropane-2-sulfinamide

Trifluoroacetic acid (1 mL) was added to a solution of (S) -1- (((R) -tert-butylsulfinyl) amino) -6-methoxy-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester 21a (200 mg, 455.97. Mu. Mol) in dichloromethane (5 mL) at room temperature, and reacted for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure to give the product (R) -N- ((S) -5-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -3-yl) -2-methylpropane-2-sulfinamide 21b (154.35 mg), yield: 100.00% of the product is directly used for the next reaction without separation and purification.

MS m/z(ESI)：337.2[M+1]

Second step

(R) -N- ((S) -1'- (4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -3-yl) -2-methylpropan-2-sulfinamide

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (63.66 mg, 414.52. Mu. Mol), (R) -N- ((S) -5-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -3-yl) -2-methylpropane-2-sulfinamide 21b (154.35 mg, 455.97. Mu. Mol), N-dimethylacetamide (2.5 mL), N-diisopropylethylamine (267.86 mg,2.07 mmol) were added sequentially to a 15mL single-necked flask at room temperature and the reaction was allowed to proceed at 100℃for 3.5 hours. After completion of the reaction, 20mL of water was added to the reaction mixture, extracted 3 times with ethyl acetate (20 ml×3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: eluent a) to give (R) -N- ((S) -1'- (4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -3-yl) -2-methylpropan-2-sulfinamide 21c (185 mg), yield: 98.39%.

MS m/z(ESI)：454.2[M+1]

Third step

(S) -2- (1-amino-6-methoxy-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -6-methylpyrimidine-4-carbonitrile

Bromosuccinimide (72.27 mg, 406.04. Mu. Mol) and (R) -N- ((S) -1'- (4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -3-yl) -2-methylpropane-2-sulfinamide 21c (184.18 mg, 406.04. Mu. Mol) were added to 2mL of N, N-dimethylformamide and the mixture was allowed to react gradually at room temperature for 2 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure to give (S) -2- (1-amino-6-methoxy-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -6-methylpyrimidine-4-carbonitrile 21d (141.88 mg), yield: 100% of the product was used directly in the next step without isolation and purification.

MS m/z(ESI)：333.1[M-17+1]

Fourth step

(S) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -3-yl) carbamic acid tert-butyl ester

(S) -2- (1-amino-6-methoxy-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -6-methylpyrimidine-4-carbonitrile 21d (141.07 mg, 403.71. Mu. Mol), di-tert-butyl dicarbonate (264.33 mg,1.21 mmol), triethylamine (204.25 mg,2.02 mmol) and methylene chloride (4 mL) were added to a 15mL single-necked flask and reacted at room temperature for 3 hours. After completion of the reaction, 20mL of water was added to the reaction mixture, extracted 3 times with methylene chloride (20 mL. Times.3), washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A)) to give tert-butyl (S) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -3-yl) carbamate 21e (130 mg), yield: 71.63%.

MS m/z(ESI)：450.3[M+1]

Fifth step

(S) - (1 '- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -3-yl) carbamic acid tert-butyl ester

Bromosuccinimide (51.47 mg, 289.18. Mu. Mol) and tert-butyl (S) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -3-yl) carbamate 21e (130 mg, 289.18. Mu. Mol)) were added to 2.5mL of N, N-dimethylformamide and the mixture was gradually warmed to room temperature and reacted for 5 hours. After completion of the reaction, 20mL of water was added to the reaction mixture, extracted with ethyl acetate (20 mL. Times.3), washed with a saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give tert-butyl (S) - (1 '- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -3-yl) carbamate 21f (150 mg), yield: 98.16%.

MS m/z(ESI)：472.1[M-56+1]

Sixth step

(S) - (1 '- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -3-yl) carbamic acid tert-butyl ester

Tert-butyl (S) - (1 ' - (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -3-yl) carbamate 21f (150 mg, 283.85. Mu. Mol), (2, 3-dichlorophenyl) boronic acid 1e (108.33 mg, 567.71. Mu. Mol), (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride (23.77 mg, 28.39. Mu. Mol), tetrakis (triphenylphosphine) palladium (26.49 mg, 56.77. Mu. Mol) and potassium phosphate (180.85 mg, 851.56. Mu. Mol) were added to a 2.3mL mixed solution (1, 4-dioxane: water=7:1) under argon atmosphere and the temperature was raised to 130℃for reaction for 4 hours. After completion of the reaction, 20mL of water was added to the reaction mixture, extracted with ethyl acetate (20 mL. Times.3), washed with a saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give (S) - (1 '- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -3-yl) carbamic acid tert-butyl ester 21g (140 mg), yield: 82.96%.

MS m/z(ESI)：594.2[M+1]

Seventh step

2- ((S) -1-amino-6-methoxy-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (S) - (1 '- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -3-yl) carbamate 21g (140 mg, 235.48. Mu. Mol) in dichloromethane (4 mL) at room temperature, and reacted for 40 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to give 2- ((S) -1-amino-6-methoxy-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 21h (116.42 mg), yield: 100% of the product was used directly in the next step without isolation and purification.

MS m/z(ESI)：477.1[M-17+1]

Eighth step

2- ((S) -1-amino-6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 21h (116.42 mg, 235.47. Mu. Mol) and 0.5mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80℃and reacted for 40 minutes. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give the product 2- ((S) -1-amino-6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 21 (24.32 mg), yield: 19.55%.

MS m/z(ESI)：512.2[M+1]

¹ H NMR(400MHz，DMSO-d ₆ )δ7.94(s，1H)，7.58(d，J＝8.0Hz，1H)，7.36(dd，J＝15.1，6.9Hz，2H)，7.21(d，J＝7.8Hz，1H)，7.09(d，J＝8.1Hz，1H)，6.89(s，1H)，6.71(d，J＝8.4Hz，1H)，4.63(t，J＝16.3Hz，2H)，3.80(s，1H)，3.73(s，3H)，3.18(dd，J＝24.7，12.4Hz，2H)，3.02(d，J＝15.2Hz，1H)，2.55(d，J＝15.0Hz，1H)，2.00(s，3H)，1.71-1.91(m，2H)，1.35-1.71(m，3H)，1.10(d，J＝13.6Hz，1H).

Example 22

(1S) -1'- (5- (2, 3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

First step

(R) -N- ((S) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide

Trifluoroacetic acid (1 mL) was added to a solution of (S) -1- (((R) -tert-butylsulfinyl) amino) -1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester 22a (260 mg, 639.48. Mu. Mol) in dichloromethane (4 mL) at room temperature, and reacted for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure to give the product (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 22b (195.98 mg), yield: 100.00% of the product is directly used for the next reaction without separation and purification.

MS m/z(ESI)：307.2[M+1]

Second step

(R) -N- ((1S) -1' - (5- (2, 3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -1' -yl) -2-methylpropan-2-sulfinamide

5- (2, 3-dichlorophenyl) -4-methoxy-6-methyl-2- (methylsulfonyl) pyrimidine 22c (75 mg, 216. Mu. Mol), (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 22b (79 mg, 260. Mu. Mol), N-methylpyrrolidone (1 mL), N-diisopropylethylamine (28 mg, 216. Mu. Mol) were added sequentially to a 15mL single-necked flask, heated to 100℃and reacted for 18 hours. After completion of the reaction, 5mL of water was added to the reaction mixture, extracted with ethyl acetate (20 ml×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: eluent a) to give (R) -N- ((1S) -1' - (5- (2, 3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1' -yl) -2-methylpropan-2-sulfinamide 22d (70 mg), yield: 56.5%.

MS m/z(ESI)：573.2[M+1]

Third step

Bromosuccinimide (20 mg, 115. Mu. Mol) and (R) -N- ((1S) -1'- (5- (2, 3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) -2-methylpropane-2-sulfinamide 22d (60 mg, 104. Mu. Mol) was added to 1mL of N, N-di-In methylformamide, the reaction is carried out for 2 hours at room temperature. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give the product (1S) -1'- (5- (2, 3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-amine 22 (5.0 mg), yield: 10%.

MS m/z(ESI)：468.5[M+1]

¹ H NMR(400MHz，Methanol-d ₄ )δ7.50(dd，J＝8.1，1.6Hz，1H)，7.33-7.40(m，1H)，7.29(t，J＝7.8Hz，1H)，7.10-7.24(m，4H)，4.63(dt，J＝13.5，4.1Hz，2H)，3.94(s，1H)，3.80(s，3H)，3.20-3.29(m，2H)，3.16(d，J＝15.7Hz，1H)，2.80(d，J＝15.7Hz，1H)，1.99(s，3H)，1.65-1.88(m，2H)，1.50-1.62(m，1H)，1.35-1.42(m，1H).

Example 23

2- ((R) -2-amino-2, 3-dihydrospiro [ indene-1, 4 '-piperidin ] -1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step

(R) -N- ((R) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-yl) -2-methylpropane-2-sulfinamide

Trifluoroacetic acid (1.53 g,13.42mmol,1 mL) and (R) -2- (((R) -tert-butylsulfinyl) amino) -2, 3-dihydrospiro [ indene-1, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester 23a (400 mg, 983.81. Mu. Mol) were added to 6mL of dichloromethane and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give the product (R) -N- ((R) -2, 3-dihydrospiro [ indene-1, 4' -piperidin ] -2-yl) -2-methylpropane-2-sulfinamide 23b (287 mg), yield: 95.19% of the purified product was used in the next step.

MS m/z(ESI)：307.3[M+1]

Second step

(R) -N- ((R) -1'- (4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ indene-1, 4' -piperidin ] -2-yl) -2-methylpropan-2-sulfinamide

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (120 mg, 781.41. Mu. Mol), (R) -N- ((R) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-yl) -2-methylpropane-2-sulfinamide 23b (287.37 mg, 937.69. Mu. Mol) and N, N-diisopropylethylamine (302.97 mg,2.34 mmol) were added sequentially to 2mL of N, N-dimethylacetamide, and the mixture was warmed to 90℃and reacted for 2 hours. After the completion of the reaction, 20mL of water was added to the reaction mixture, extracted with ethyl acetate (30 ml×2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: a system) to give (R) -N- ((R) -1'- (4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-yl) -2-methylpropan-2-sulfinamide 23c (170 mg), yield: 51.36%.

MS m/z(ESI)：424.0[M+1]

Third step

(R) -2- (2-amino-2, 3-dihydrospiro [ indene-1, 4 '-piperidin ] -1' -yl) -6-methylpyrimidine-4-carbonitrile

(R) -N- ((R) -1'- (4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-yl) -2-methylpropan-2-sulfinamide 23c (170 mg, 401.35. Mu. Mol) and bromosuccinimide (85.72 mg, 481.62. Mu. Mol) were added to 2mL of N, N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the product (R) -2- (2-amino-2, 3-dihydrospiro [ indene-1, 4 '-piperidin ] -1' -yl) -6-methylpyrimidine-4-carbonitrile 23d (128 mg), yield: 99.85% was used directly in the next step without purification.

MS m/z(ESI)：320.1[M+H]

Fourth step

(R) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydro-spiro [ indene-1, 4' -piperidin ] -2-yl) carbamic acid tert-butyl ester

(R) -2- (2-amino-2, 3-dihydrospiro [ indene-1, 4 '-piperidine ] -1' -yl) -6-methylpyrimidine-4-carbonitrile 23d (128 mg, 400.75. Mu. Mol), di-tert-butyl dicarbonate (262.39 mg,1.20mmol, 276.20. Mu.L) and triethylamine (202.76 mg,2.00mmol, 278.51. Mu.L) were successively added to 4mL of dichloromethane and reacted at room temperature for 3 hours. After the completion of the reaction, 20mL of water was added, extracted with methylene chloride (20 mL. Times.3), and the saturated sodium chloride solution (20 mL) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-yl) carbamate 23e (60 mg), yield: 35.69%.

MS m/z(ESI)：420.1[M+1]

Fifth step

(R) - (1 '- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-yl) carbamic acid tert-butyl ester

Tert-butyl (R) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ indene-1, 4' -piperidin ] -2-yl) carbamate 23e (60 mg, 143.02. Mu. Mol) and bromosuccinimide (33.09 mg, 185.93. Mu. Mol) were added to 2mL of N, N-dimethylformamide and reacted at room temperature for 2 hours. After completion of the reaction, 30mL of water was added to the reaction mixture, extracted with ethyl acetate (20 ml×3), and the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (R) - (1 '- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ indene-1, 4' -piperidin ] -2-yl) carbamate 23f (70 mg), yield: 98.20% was used directly in the next step without purification.

MS m/z(ESI)：498.1[M+1]

Sixth step

(R) - (1 '- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-yl) carbamic acid tert-butyl ester

Tert-butyl (R) - (1 ' - (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-yl) carbamate 23f (70 mg, 140.45. Mu. Mol), (2, 3-dichlorophenyl) boronic acid 1e (67.00 mg, 351.11. Mu. Mol), 2-dicyclohexyl-phosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (13.11 mg, 28.09. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (11.76 mg, 14.04. Mu. Mol) and potassium phosphate (89.44 mg, 421.34. Mu. Mol) were added to a 2.3mL mixed solution (1, 4-dioxane: water=7:1) under argon atmosphere, and the mixture was heated to 130℃for 4 hours. After completion of the reaction, 20mL of water was added to the reaction mixture, extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: a system) to give 23g (R) - (1 '- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-yl) carbamic acid tert-butyl ester (70 mg), yield: 88.29%.

MS m/z(ESI)：565.2[M+1]

Seventh step

2- ((R) -2-amino-2, 3-dihydrospiro [ indene-1, 4 '-piperidin ] -1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

(R) - (1 '- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ inden-1, 4' -piperidin ] -2-yl) carbamic acid tert-butyl ester 23g (80 mg, 141.72. Mu. Mol) and trifluoroacetic acid (1.53 g,13.42mmol,1 mL) were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to give 2- ((R) -2-amino-2, 3-dihydrospiro [ indene-1, 4 '-piperidin ] -1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 23h (65.8 mg), yield: 99.98%, without purification, was used directly in the next step.

MS m/z(ESI)：463.9[M+1]

Eighth step

2- ((R) -2-amino-2, 3-dihydrospiro [ indene-1, 4' -piperidine]-1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 23h (65.8 mg, 141.69. Mu. Mol) and 6M sodium hydroxide solution 0.3mL were added to 2mL of ethanol, heated to 80℃and reacted for 40 minutes. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20 mL/m) in; mobile phase a:0.05% TFA+H ₂ O, mobile phase B: CH (CH) ₃ CN) to give the product 2- ((R) -2-amino-2, 3-dihydrospiro [ indene-1, 4' -piperidine)]-1' -yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 23 (23 mg), yield: 33.31%.

MS m/z(ESI)：482.1[M+1]

¹ H NMR(400MHz，Methanol-d ₄ )δ7.51(dd，J＝8.0，1.5Hz，1H)，7.33-7.37(m，1H)，7.30(t，J＝7.8Hz，1H)，7.23-7.28(m，1H)，7.13-7.22(m，3H)，4.46(td，J＝12.7，12.2，6.3Hz，2H)，3.66-3.87(m，3H)，3.34(d，J＝6.2Hz，1H)，3.29(s，1H)，2.68-2.77(m，1H)，2.10(s，3H)，1.88-1.98(m，1H)，1.80(dt，J＝13.6，4.7Hz，1H)，1.64(ddd，J＝13.7，9.4，4.3Hz，1H).

Biological evaluation

Determination of the allosteric inhibitory Activity of the Compounds of the invention on SHP2

The following methods were used to determine the extent of inhibition of recombinant human full-length SHP2 activity by the compounds of the invention under in vitro conditions. SHP2 is allosterically activated by binding of a di-tyrosyl-phosphorylated peptide to its Src homology 2 (SH 2) domain. The latter activation step results in the release of the self-inhibiting interface of SHP2, which in turn activates SHP2 Protein Tyrosine Phosphatase (PTP), which is useful for substrate recognition and reaction catalysis.

The experimental procedure is briefly described as follows: test compounds were first dissolved in DMSO to prepare stock solutions. Reactions were performed in 384 well Small VolumeTM HiBase microwell plates (Greiner, 784075), to which were first added SHP2 (signalchem, P38-20G-10 ug) and SHP-2 Activating Peptide (IRS1_pY1172 (dPEG 8) pY 1222) (BPS, 79319-1) at final concentrations of 0.5nM and 0.5. Mu.M, respectively, followed by the addition of test compounds at concentrations ranging from 0.00004 to 10. Mu.M, and incubation for 60 min at 25 ℃. DiFMUP (Thermo, D6567) was then incubated in the reaction for 30 min at 25 ℃. After the incubation, the excitation and emission wavelengths were 340nm and 450nm, respectively, using a microplate reader (BMG) reading. The percent inhibition of the compounds at each concentration was calculated by comparison with the ratio of fluorescence intensity of the control group (0.1% dmso) and was measured by GraphPa d Prism 5 software performs nonlinear regression analysis on the numerical value-inhibition rate of compound concentration to obtain IC of the compound ₅₀ The values are shown in Table 1.

TABLE 1 IC for inhibition of full-length SHP2 enzyme Activity by Compounds of the invention ₅₀ Data

Numbering of compounds	SHP2/IC ₅₀ (nM)
		Example 1	＜500
Example 2	＜500
		Example 3	＜200
Example 4	＜500
		Example 5	＜200
Example 6	＜500
		Example 7	＜500
Example 9	＜200
		Implementation of the embodimentsExample 11	＜500
Example 12	＜500
		Example 13	＜200
Example 17	＜200
		Example 19	＜500
Example 21	0.71
		Example 22	16.61
Example 23	＜200

Conclusion: as can be seen from Table 1, the compounds of the present invention have a good allosteric inhibition on SHP2 enzyme.

Unless otherwise defined, all terms used herein are intended to have the meanings commonly understood by those skilled in the art.

The described embodiments of the present invention are intended to be illustrative only and not to limit the scope of the invention, and various other alternatives, modifications, and improvements may be made by those skilled in the art within the scope of the invention, and therefore the invention is not limited to the above embodiments but only by the claims.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from phenyl;

x is selected from CR ^e Or N;

R ^e selected from hydrogen atoms;

R ¹ selected from C _1-6 An alkyl group;

R ² the same or different are each independently selected from hydrogen atoms, C _1-6 Alkyl or halogen;

R ³ selected from C _1-6 Alkoxy, tetrazolyl, -C (O) OR ⁶ or-C (O) NR ⁷ R ⁸ ；

R ⁴ And R is ⁵ Together with the N atom to which it is attached form a 5-to 11-membered heterocyclic group, wherein said heterocyclic group contains one or more N, O, S atoms or SO ₂ And the heterocyclic groups are optionally further substituted with one or more groups selected from C _1-6 Alkyl, -NH ₂ or-NHC (=nh) NH ₂ Wherein said alkyl is optionally further substituted with a halogen, hydroxy or amino substituent;

is a double bond;

g and M are each independently selected from C;

ring B is selected from C _6-10 Aryl, 5 to 6 membered monocyclic heteroaryl, or 8 to 10 membered bicyclic heteroaryl;

j is selected from CR ^p R ^q ；

K is selected from (CR) ^p R ^q ) _r ；

r is 0;

R ^m 、R ⁿ identical or different, each independently selected from R ^A ；

R ^p And R is ^q Each independently selected from hydrogen atoms;

R ^c and R is ^d Each independently selected from hydrogen atoms;

R ^g identical OR different, each independently selected from hydrogen atoms OR-OR ⁶ ；

R ^A Selected from a hydrogen atom or an amino group;

R ⁶ selected from hydrogen atoms or C _1-6 An alkyl group;

R ⁷ selected from hydrogen atoms;

R ⁸ selected from hydrogen atoms or C _1-6 An alkyl group; wherein said C _1-6 Alkyl being interrupted by-C (O) OR ⁹ Substituted;

R ⁹ selected from hydrogen atoms;

m is selected from 0, 1, 2, 3, 4 or 5;

n is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, which is a compound of the formula (II) or a pharmaceutically acceptable salt thereof,

wherein: ring A, X, m, R ¹ 、R ² 、R ⁴ And R is ⁵ Is defined as in claim 1.

3. The compound according to claim 1, which is a compound of the formula (III) or a pharmaceutically acceptable salt thereof,

4. The compound according to claim 1, which is a compound of the formula (IV) or a pharmaceutically acceptable salt thereof,

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: r is R ¹ Selected from methyl groups.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴ and R is ⁵ Together with the N atom to which it is attached, form a 5-to 6-membered monocyclic heterocyclic group, wherein said monocyclic heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH or-NHC (=NH) NH ₂ Is substituted by a substituent of (2).

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein: r is R ⁴ And R is ⁵ Together with the N atom to which it is attached, forms a piperidinyl group.

8. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴ and R is ⁵ Together with the N atom to which it is attached, form a 7-to 11-membered spiroheterocyclic group, wherein said spiroheterocyclic group optionally furtherSubstituted with one or more substituents selected from methyl or amino.

9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein said spiroheterocyclyl is selected from the group consisting of:

R ^a the same or different are each independently selected from methyl or amino;

t is 1, 2 or 3.

10. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴ and R is ⁵ Together with the N atom to which it is attached, form a 7-to 11-membered bridged heterocyclic group, wherein said bridged heterocyclic group is optionally further substituted with an amino group.

11. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴ and R is ⁵ Together with the N atom to which it is attached, form a 6-to 11-membered fused heterocyclic group, wherein said fused heterocyclic group is optionally further substituted with an amino group.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of formula (VI):

Wherein:

ring B is selected from phenyl or 5-6 membered heteroaryl;

j is selected from CR ^p R ^q ；

K is selected from (CR) ^p R ^q ) _r ；

r is 0;

R ^m selected from amino groups;

R ⁿ selected from hydrogen atoms;

R ^p and R is ^q Each independently selected from hydrogen atoms;

ring A, G, M, X, m, n, R ¹ ～R ³ And R is ^g Is defined as in claim 1.

13. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from the group consisting of hydrogen atoms, methyl groups, F, cl, and Br.

14. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ⁶ Selected from hydrogen atoms or methyl groups.

15. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from:

16. a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ^g The same or different are each independently selected from a hydrogen atom or a methoxy group.

17. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

18. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

19. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the preparation of an inhibitor of SHP2 allosteric.

20. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for the treatment of a SHP2 mediated disease.

21. The use of claim 20, wherein the SHP2 mediated disease is cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or vision disorder.

22. The use of claim 20, wherein the SHP2 mediated disease 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.