CN115916765A

CN115916765A - Pyridine or pyrimidine derivative and preparation method and application thereof

Info

Publication number: CN115916765A
Application number: CN202180044805.4A
Authority: CN
Inventors: 黄贤贵; 曹琪; 别平彦; 邢庆娜; 王鑫; 晏青燕; 廖伟伟; 郭阳辉; 叶成; 胡泰山; 钱文建; 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: 2020-07-10
Filing date: 2021-07-08
Publication date: 2023-04-04
Also published as: WO2022007869A1

Abstract

The invention relates to pyridine or pyrimidine derivatives, a preparation method thereof and application thereof in medicines. In particular to a pyridine or pyrimidine derivative shown in a general formula (I), a preparation method thereof, a medicinal salt thereof and application thereof as a therapeutic agent, in particular to an SHP2 allosteric inhibitor, 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 invention relates to a novel pyridine or pyrimidine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof as a therapeutic agent, in particular as an SHP2 allosteric inhibitor.

Background

Src homeodomain-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 type 11 (PTPN 11) gene, and catalyzes the dephosphorylation reaction of tyrosine in proteins. The N-terminus of SHP2 contains 2 SH2 domains that control subcellular localization and functional regulation of SHP2, and the C-terminus contains 1 catalytically active PTP domain and 2 tyrosine residues associated with its activity. Normally, SHP2 is in a self-inhibitory state, which when stimulated by growth factors, cytokines, or inflammatory factors, such as platelet-derived growth factors PDGF and FGF, exposes catalytic sites, resulting in activation of the SHP2 enzyme.

SHP2 is widely present in human body, and participates in a plurality of signal paths such as rat sarcoma (RAS) -extracellular signal related kinase (ERK), phosphatidylinositol 3 kinase (PI 3K) -protein kinase B and NF-KB, and activates fibroblast growth factor, epidermal growth factor and downstream mitogen-activated protein kinase (MAPK/ERK) of insulin receptor, and the like, thereby regulating proliferation, differentiation, migration and apoptosis of cells. It has been found that the activating mutation of SHP2 is closely linked to the occurrence of noonan syndrome, leopard syndrome, monocytic leukemia, melanoma, solid tumor, cardiovascular disease, immune disorder, fibrosis or visual disorder, and the overexpression of SHP2 increases the risk of cancers such as chronic myelogenous leukemia, mastocytosis, malignant glioma, lung cancer, breast cancer, etc., indicating that SHP2 plays an important role in different types of cancers and different stages of cancers. Due to the multiple functions of SHP2 in tumors, studies on inhibitors of SHP2 targets have also brought new hopes and directions for the treatment of tumors.

The SHP2 inhibitors can be classified into competitive inhibitors (including allosteric mycin, phenylpyrazole hydrazino sulfonate and NSC-87877), non-competitive inhibitors (including indole salicylic acid and furs Mo Sutong) and irreversible inhibitors (including antimony sodium gluconate and cryptotanshinone) according to the difference of action mechanism, and cryptotanshinone is reported to be used as an irreversible inhibitor of SHP2 and can inhibit the proliferation of rhabdomyosarcoma, melanoma, colon cancer and breast cancer in vitro, and in vivo studies show that the inhibitor can inhibit the proliferation of prostate cancer in mice, and further needs a plurality of tests to verify whether the inhibitor can become a clinically effective medicament.

The compound RMC-4630 developed by REVOLUTION MEDICINES Inc. has now entered clinical stage II for the treatment of solid tumors, and there are 3 additional clinical stage I compounds, JAB-3068, JAB-3312 and TNO-155, developed by Jacobio Pharmaceuticals Co Ltd and Novartis AG, respectively. A series of SHP2 inhibitor patents have been disclosed by REVOLUTION MEDICINES Inc and Novartis AG, including WO-2019075265, WO-2018136265, WO-2018136264, WO-2017216706 and WO-2018013597, etc., and although some progress has been made in the study of SHP2, there are no effective drugs on the market at present, so it is necessary to continue to research and develop new SHP2 inhibitors.

Disclosure of Invention

In view of the above technical problems, the present invention provides a novel pyridine or pyrimidine compound represented by 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 the bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with a monocyclic heterocyclic group or a monocyclic cycloalkyl group;

x is selected from CR ^e Or N;

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

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 by one or more substituents selected from the group consisting of hydroxy, halo, alkyl, alkoxy, cycloalkyl and-NR ⁷ R ⁸ Substituted with the substituent(s); preferably, R ¹ Is selected from methyl;

R ² identical OR different, each independently selected from hydrogen atom, 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 Substituted with the substituent(s);

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 When selected from alkoxy, R ¹ Is not selected from-NR ⁷ R ⁸ ；

R ⁴ And R ⁵ Together with the N atom to which they are attached form a 4-to 11-membered heterocyclic group, preferably a 5-to 11-membered heterocyclic group, wherein said heterocyclic group contains one or moreMultiple N, O, S atoms or SO ₂ And 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 substituent of halo, hydroxy, amino, or alkoxy;

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

is a single bond or a double bond;

when in use

When represents a single bond, G and M are each independently selected from N or CR ^j ；

When in use

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,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 or S;

r is 0 or 1;

R ^m 、R ⁿ 、R ^p and R ^q Are the same or different and are each independently selected from R ^A ；

Or, R ^m And R ⁿ Together with the same carbon atom to which they are attached form C = O;

or, R ^p And R ^q Together with the carbon atom to which they are attached form R ^B ；

R ^c And R ^d Identical OR different, each independently selected from a hydrogen atom, a halogen, an alkyl group OR-OR ⁶ Wherein said alkyl is optionally further substituted with hydroxy, halo, alkoxy, cycloalkyl or-NR ⁷ R ⁸ Substituted with the substituent(s);

or, R ^c And R ^d Together with the carbon atom to which they are attached form R ^B ；

R ^g Identical OR different, each independently selected from hydrogen atom, 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 Substituted with the substituent(s);

or, two R ^g Together with the same carbon atom to which it is attached form C = O;

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

R ^A identical OR different, each independently selected from hydrogen atom, 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 Substituted with the substituent(s);

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 by 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 Substituted with the substituent(s);

R ⁶ 、R ⁷ and R ⁸ Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or a heterocyclyl group, wherein said alkyl, cycloalkyl or heterocyclyl group 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 Substituted with a substituent of (a);

or, R ⁷ And R ⁸ Together with the N atom to which they are attached form a 3-to 8-membered heterocyclic group in which the 3-to 8-membered heterocyclic group contains one or more N, O, S atoms or SO ₂ And the 3-to 8-membered heterocycle is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, alkyl or alkoxy;

R ⁹ 、R ¹⁰ and R ¹¹ Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of 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, a tautomer, or a pharmaceutically acceptable salt thereof, which is the compound of formula (II), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

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

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

In a preferred embodiment of the present invention, the compound of formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV), or a stereoisomer, a tautomer, or a 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 ⁴ And R ⁵ Together with the N atom to which they are attached form a 4-to 8-membered monocyclic heterocyclyl group, preferably a 5-to 6-membered monocyclic heterocyclyl group, more preferably a piperidinyl group, wherein said monocyclic heterocyclyl 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 Substituted with a substituent of (a); r ⁶ The definition of (A) 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 ⁴ and R ⁵ Together with the N atom to which they are 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 Substituted with the substituent(s);

R ⁶ is as defined in 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 (ii) a Or, two R ^a Together with the same carbon atom to which it is attached form C = O; r is ⁶ Is as defined in formula (I); t is 1,2 or 3.

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 ⁴ And R ⁵ Together with the N atom to which they are attached form a 7-to 11-membered bridged heterocyclyl group, wherein said bridged heterocyclyl 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 Substituted with a substituent of (a); r ⁶ The definition of (A) is 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 ⁴ And R ⁵ Together with the N atom to which they are attached form a 7-to 11-membered fused heterocyclic group, wherein said fused heterocyclic group is optionally further substituted by one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ , = O OR-OR ⁶ Substituted with the substituent(s); r is ⁶ The definition of (A) is as described in the general formula (I).

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

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 atom, methyl group or-CH ₂ OH；

Or, R ^m And R ⁿ Together with the same carbon atom to which it is attached form C = O;

R ^p and R ^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 ^g The definition of (A) is described in the general formula (I).

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

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 atom, methyl group or-CH ₂ OH；

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

wherein:

R ^c and R ^d Together with the linking 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 a hydrogen atom, a methyl group or-CH ₂ OH；

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

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

wherein:

ring B, n, R ¹ ～R ² And R ^g The definition of (A) is described in the general formula (I).

In a preferred embodiment of the invention, the compound of formula (I), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is ² Selected from hydrogen atom, F, cl, br, amino group, hydroxyl group, cyano group, nitro group, methoxy group, ethoxy group, methyl group, ethyl group, ethynyl group, ethenyl group, -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-C (O) OH.

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

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

in a preferred embodiment of the invention, the compound of formula (I), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is ^g The same or different, each independently selected from hydrogen atom, F, cl, br, amino group, hydroxyl group, cyano group, nitro group, methoxy group, ethoxy group, methyl group, ethyl group, ethynyl group, ethenyl group, -NHCH ₃ or-N (CH) ₃ ) ₂ ；

Or, two R ^g Together with the same carbon atom to which it is attached, may form C = O.

Typical compounds of the 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), (VII), or (VIII), 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 a general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (namely the pharmaceutical composition provided by the technical scheme of the invention) in preparing an SHP2 allosteric inhibitor.

The invention also provides an application of the compound of the general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating the diseases mediated by the SHP2, wherein the diseases mediated by the SHP2 are preferably cancer, cancer metastasis, cardiovascular diseases, immune disorders, fibrosis or visual disorders; wherein said SHP 2-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 an application of the compound of the general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating cancer, cancer metastasis, cardiovascular diseases, immune disorders, fibrosis or visual disorders.

The invention provides an application of a compound shown as a general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing a medicament for treating 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 also provides a compound of the general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a disease mediated by SHP2, wherein the disease mediated by SHP2 is preferably cancer, cancer metastasis, a cardiovascular disease, an immune disorder, fibrosis or a visual disorder; wherein said SHP 2-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 present invention also provides a method of treating a SHP2 mediated disease, comprising administering to a subject a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; wherein the SHP 2-mediated disease is preferably cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or vision disorder; wherein said SHP 2-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.

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 means including 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, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.

"alkenyl" means 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 ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be optionally substituted or unsubstituted.

"alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, and can be straight or branched. Preferred is that C ₂ -C ₁₀ Alkynyl of (2), more preferably C ₂ -C ₆ Alkynyl, most preferably C ₂ -C ₄ Alkynyl. Implementation of the alkynyl radicalExamples 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 carbocyclic rings. Preferably C ₃ -C ₁₂ Cycloalkyl, more preferably C ₃ -C ₈ Cycloalkyl, most preferably C ₃ -C ₆ A cycloalkyl group. Examples of monocyclic cycloalkyl 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 polycyclic group having two or more cyclic structures with single rings sharing a single carbon atom (called the 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, more preferably 7 to 10. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-spiro, di-spiro, or multi-spiro cycloalkyl groups, preferably mono-spiro and di-spiro cycloalkyl groups, 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 cycloalkyl" refers to a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more 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, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. 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, decahydronaphthyl or tetradecaphenanthryl.

"bridged cycloalkyl" means a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing two non-directly attached carbon atoms with each other, one or more 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, more preferably 7 to 10. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to: (1s, 4s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1s, 5s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1r, 5r) -bicyclo [3.3.2] decyl.

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

The heterocyclic group may be substituted or unsubstituted.

"spiroheterocyclyl" refers to a 5-to 18-membered polycyclic group having two or more cyclic structures wherein the individual rings share an atom with one another and 1 or more double bonds are present within the ring, but none of the rings has a completely conjugated pi electronWherein one or more ring atoms are 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, more preferably 7 to 10. The spirocycloalkyl group is classified into a single spiroheterocyclic group, a double spiroheterocyclic group or a multiple spiroheterocyclic group, preferably a single spiroheterocyclic group and a double spiroheterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. 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]]A heptyl radical,

"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 which rings may contain one or more double bonds, but none of which rings has a fully conjugated pi-electron aromatic system, wherein one or more ring atoms are 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, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo [3,4-c]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0]Hexyl, octahydrobenzo [ b ]][1,4]Dioxins (dioxines) and

"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 hasAromatic systems with fully conjugated pi-electrons, 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) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl, 2-azabicyclo [3.3.2]Decyl and

"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. 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. The aryl group 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. Preferred examples of bicyclic heteroaryls, "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridinyl, 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, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyrazolinyl, dihydropyridyl, pyridazinyl, and the like,

Heteroaryl groups may be substituted or unsubstituted.

"fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but at least one ring does not have an aromatic system of fully conjugated pi electrons, while at least one ring has an aromatic system of fully conjugated pi electrons, wherein 0, one or more of the ring atoms are selected from nitrogen, 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 bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14, more preferably 8 to 10. Examples of "fused rings" include, but are not limited to:

"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. C ₁ -C ₆ Alkoxy groups of (4) are preferred. 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" means-CN.

"nitro" means-NO ₂ 。

"benzyl" means-CH ₂ -a phenyl group.

"carboxy" means-C (O) OH.

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

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to tert-butoxycarbonyl.

"TFA" refers to trifluoroacetic acid.

"Ts" refers to p-toluenesulfonyl.

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

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

A "leaving group", or leaving group, an atom or functional group that is removed from a larger molecule in a chemical reaction, is a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called the substrate (substrate), and the atom or group of atoms cleaved from the substrate molecule with a pair of electrons is called the leaving group. Groups that accept electrons easily and have a strong ability to bear negative charges are good leaving groups. The lower the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to be cleaved from other molecules. The reason is that the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced when the pKa of its conjugate acid is smaller, and the corresponding leaving group does not need to be bound to another atom. 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, steric 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 isomers of such structures (e.g., diastereomers, enantiomers, steric isomers, and geometric (conformational) isomeric forms; e.g., the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, steric isomers of biphenyl-like structures (see Basic organic chemistry, second edition, supra, prosecution, et al, p 104-105); PAC,1996,68,2193. (Basic nomenclature of stereochemistry, 1996, on page 2201)), (Z) and (E) conformational isomers.

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

As used herein, "substituted" or "substituted," unless otherwise specified, means that the group may be substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, 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 a substituent of halo, hydroxy, amino or alkoxy;

R ⁶ 、R ⁷ and R ⁸ Each independently selected from a hydrogen atom, an alkyl group,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 Substituted with a substituent of (a);

R ⁷ and R ⁸ Together with the N atom to which they are attached form a 3-to 8-membered heterocyclic group in which the 3-to 8-membered heterocyclic group contains one or more of N, O, S or SO ₂ Atom, and the 3-to 8-membered heterocyclic ring is further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, alkyl, or alkoxy;

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

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

"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

Synthesis of the Compounds 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 general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which process comprises:

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

wherein:

X ₂ selected from halogens;

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

R ³ Is selected from alkoxy;

R ^t selected from alkyl groups;

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

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

a compound of the formula (Ia) with a compound of the formula (Ic) catalyzed by palladiumCarrying out Suzuki reaction on a reagent and an alkaline condition to obtain a compound with a general formula (Id); compounds of the general formula (Id) and NHR ⁴ R ⁵ Nucleophilic substitution reaction is carried out under alkaline condition, and the obtained compound is optionally subjected to further deprotection to obtain a compound of a general formula (I);

wherein:

X ₂ selected from halogens;

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

R ³ Is selected from alkoxy;

R ^t selected from alkyl groups;

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

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

wherein:

X ₂ selected from halogens;

X ₃ selected from a leaving group 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 ⁵ Is as defined in formula (II).

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

wherein:

X ₂ selected from halogens;

X ₃ selected from a leaving group 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 ⁵ Is as defined in formula (II).

The present invention provides a process for the preparation of a compound of general formula (III) or a stereoisomer, tautomer or a 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 a general formula (III);

wherein: ring A, X, m, R ¹ 、R ² 、R ⁴ And R ⁵ Is as defined in formula (III).

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

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

wherein: ring A, X, m, R ¹ 、R ² 、R ⁴ And R ⁵ Is as defined in formula (IV).

Detailed Description

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

Examples

The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention. ¹ The H NMR spectrum was obtained using a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ Method for H NMR expression: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If a coupling constant is provided, it is 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 adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by 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.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents 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, prov Chemical science Inc. and Sci Chemical science Inc., and the like.

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 with an argon balloon having a volume of about 1L.

In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.

Purifying the compound by silica gel column chromatography using an eluent system selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: dichloromethane and ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for adjustment.

Example 1

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

First step of

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

5-bromo-2,4-dichloro-6-methylpyrimidine 1a (480mg, 2mmol) was added to 5mL of methanol, and a 5mL methanol solution containing sodium methoxide (102.6mg, 1.9mmol) dissolved therein was slowly added dropwise thereto in an ice bath, followed by reaction at room temperature for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, 10mL of water was added, extraction was performed 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 used in the next reaction without purification.

MS m/z(ESI):236.8[M+1]

Second step of

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

The above product, 5-bromo-2-chloro-4-methoxy-6-methylpyrimidine 1b (448.4 mg,1.9 mmol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 1c (470mg, 2.2 mmol), and 0.5mL of N, N-diisopropylethylamine were added to 5mL of dimethylsulfoxide under an argon atmosphere, and the mixture was heated to 130 ℃ for 1 hour. After the reaction was completed, it was cooled to room temperature, 30mL of water was added, extraction was performed with ethyl acetate (10 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 obtained residue was further analytically purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (1- (5-bromo-4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 1d (210 mg), yield: 26.7 percent.

MS m/z(ESI):415.0[M+1]

The third step

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

Under the protection of argon, (1- (5-bromo-4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 1d (140mg, 0.338mmol), (2,3-dichlorophenyl) boronic acid 1e (128mg, 0.676mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (24mg, 0.0338mmol), tetrakis (triphenylphosphine) palladium (39mg, 0.0338mmol), sodium carbonate (143mg, 1.35mmol) and 0.5mL of water were added to 3mL of N, N-dimethylformamide, heated to 110 ℃ and reacted for 4 hours. After the reaction was completed, it was cooled to room temperature, 20mL of water was added, extraction was performed with ethyl acetate (10 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 obtained residue was further purified by analysis with a silica gel column chromatography (eluent: system A) to give tert-butyl (1- (5- (2,3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 1f (110 mg), yield: 68.7 percent.

MS m/z(ESI):480.9[M+1]

The fourth step

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

(1- (5- (2,3-dichlorophenyl) -4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 1f (110mg, 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: and 69 percent.

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 of

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

5-bromo-2,4-dichloropyrimidin-4-amine 2a (971.56mg, 4 mmol) and sodium methoxide (216mg, 4 mmol) were added to 10mL of methanol, and 1 equivalent of sodium methoxide was added thereto every 3 hours, followed by reaction at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 20mL of water was added, the mixture was 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 of

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

5-bromo-2-chloro-6-methoxypyrimidin-4-amine 2b (473.86mg, 2mmol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 1c (642mg, 3mmol) and 1mL of N, N-diisopropylethylamine were added to 5mL of N-methylpyrrolidone, heated to 90 ℃ and reacted for 2 hours. After the reaction was completed, it was cooled to room temperature, 20mL of water was added, extraction was performed with ethyl acetate (10 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 obtained residue was further purified by analysis with a silica gel column chromatography (eluent: system A) to obtain tert-butyl (1- (4-amino-5-bromo-6-methoxypyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 2c (360 mg), yield: 43.4 percent.

MS m/z(ESI):415.8[M+1]

The third step

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

Under the protection of argon, (1- (4-amino-5-bromo-6-methoxypyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 2c (100mg, 0.24mmol), (2,3-dichlorophenyl) boronic acid 1e (91.56mg, 0.48mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (35mg, 0.048mmol), tetrakis (triphenylphosphine) palladium (55mg, 0.048mmol), sodium carbonate (102mg, 0.96mmol) and 0.5mL of water were added to 3mL of N, N-dimethylformamide, heated to 100 ℃ and reacted overnight. After the reaction was completed, it was cooled to room temperature, 20mL of water was added, extraction was performed with ethyl acetate (10 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 obtained residue was further purified by analysis with a 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 percent.

MS m/z(ESI):481.9[M+1]

The fourth step

Tert-butyl (1- (4-amino-5- (2,3-dichlorophenyl) -6-methoxypyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 2d (40mg, 0.083mmol) and 0.5mL of trifluoroacetic acid were added to 2mL of dichloromethane, reacted at room temperature for 2 hours, and concentrated under reduced pressure to give a residue, which was subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05 and 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 percent.

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 of

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

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

MS m/z(ESI):332.2[M+1]

Second step of

(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, 2.53mmol) was added to 10mL of N, N-dimethylformamide, and bromosuccinimide (600.41mg, 3.37mmol) was added thereto at 0 ℃ and reacted at room temperature overnight. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), 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 obtained residue was further purified by analysis by silica gel column chromatography (eluent: system A) to give tert-butyl (1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 3c (800 mg) in 75.14% yield.

MS m/z(ESI):355.9[M-56]

The 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 (800mg, 1.95mmol), (2,3-dichlorophenyl) boronic acid 1e (744.10mg, 3.90mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (163.25mg, 0.195mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropoxy-1,1 ' -biphenyl (181.97mg, 0.390mmol), and potassium phosphate (1.24g, 5.85mmol) were added to 12mL of a mixed solution (1,4-dioxane: water = 6:1) under argon protection, heated to 130 ℃ and reacted for 5 hours. After completion of the reaction, it was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was further purified by analysis with silica gel column chromatography (eluent: system a) 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 percent.

MS m/z(ESI):476.1[M+1]

The fourth step

Tert-butyl (1- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 3d (380mg, 0.800mmol) was added to 10mL of concentrated hydrochloric acid, heated to 110 ℃ and reacted for 1.5 hours. After the reaction, the reaction 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 of

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 (170mg, 0.36mmol) and 1.65mL of trifluoroacetic acid were added to 6mL of dichloromethane, reacted at room temperature for 40 minutes, and concentrated under reduced pressure to give a residue, which was subjected to liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05 and 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 percent.

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 of

2- (4-amino-4-methylpiperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 4a (20mg, 0.267mmol) and 0.1mL of a 6M sodium hydroxide solution were added to 1.5mL of ethanol, heated to 80 ℃ and reacted for 40 minutes. After completion of the reaction, it 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 the product 2- (4-amino-4-methylpiperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 4 (16.25 mg), yield: 49 percent.

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-methylisonicotinic acid

First step of

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

2-chloro-6-methylisonicotonitrile 5a (230mg, 1.51mmol, self-made according to patent WO 2009016498), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 1c (389mg, 1.82mmol) and N, N-diisopropylethylamine (391mg, 3.03mmol) were added to 6mL of N-methylpyrrolidone, heated to 90 ℃ for 5 hours, after completion of the reaction, 30mL of water was added, extraction was performed with ethyl acetate (30 mL. Times.3), organic phases were combined, washed with a saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was further purified by silica gel column chromatography (eluent: A system) to obtain (1- (4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 5b (245 mg), yield: 49 percent.

MS m/z(ESI):331.2[M+1]

Second step of

(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 (70mg, 0.212mmol) and bromosuccinimide (42mg, 0.233mmol) were added to 1.5mL of N, N-dimethylformamide and reacted at room temperature overnight. After the completion of the reaction, 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 purified by analysis with a silica gel column chromatography (eluent: system A) to give tert-butyl (1- (5-bromo-4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 5c (64 mg), yield: 73 percent.

MS m/z(ESI):409.1[M+1]

The 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 (150mg, 0.368mmol), (2,3-dichlorophenyl) boronic acid 1e (140mg, 0.735mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (31mg, 0.039mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropoxy-1,1 ' -biphenyl (34mg, 0.074mmol), and potassium phosphate (234mg, 1.104mmol) were added to a 3.5mL mixed solution (1,4-dioxane: water = 6:1) under argon protection and reacted for 5 hours at 130 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was further purified by silica gel column chromatography (eluent: system a) 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 percent.

MS m/z(ESI):475.0[M+1]

The fourth step

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

Tert-butyl (1- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 5d (170mg, 0.359mmol) and 1.5mL of trifluoroacetic acid were added to 6mL of dichloromethane, reacted at room temperature for 40 minutes, and after completion of the reaction, concentrated under reduced pressure to give a residue, which was subjected to liquid phase separation (AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05 TFA + H TFA + ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (2,3-dichlorophenyl) -2-methylisonicotinamide 5e (69.91 mg), yield: 52 percent.

MS m/z(ESI):375.0[M+1]

The fifth step

6- (4-amino-4-methylpiperidin-1-yl) -3- (2,3-dichlorophenyl) -2-methylisonicotinamide 5e (30mg, 0.08mmol) was added to 0.5mL of concentrated hydrochloric acid, heated to 110 ℃ and reacted for 4 hours. After the reaction, the reaction 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-methylisonicotinic acid 5 (12.08 mg), yield: 39 percent.

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

First step of

6- (4-amino-4-methylpiperidin-1-yl) -3- (2,3-dichlorophenyl) -2-methylisonicotinamide 5e (37.33mg, 0.1 mmol) and 0.1mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80 ℃ and reacted for 40 minutes. After the reaction, the reaction 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 obtain 6- (4-amino-4-methylpiperPyridin-1-yl) -3- (2,3-dichlorophenyl) -2-methylisonicotinamide 6 (21.99 mg), yield: 56 percent.

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 of

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

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

MS m/z(ESI):519.6[M+1]

Second step of

Tert-butyl (1- (5- (2,3-dichlorophenyl) -4-methyl-6- (2H-tetrazol-5-yl) pyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 7a (15mg, 0.029 mmol) and 0.5mL of trifluoroacetic acid were added to 2mL of dichloromethane and reacted at room temperature for 1 hour. After completion of the reaction, concentration was carried out 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 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 percent.

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 of

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 (80mg, 0.202mmol), di-tert-butyl dicarbonate (88.34mg, 0.405mmol) and sodium carbonate (85.8mg, 0.809mmol) 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, adjusted to pH 2-3 by addition of 1M dilute hydrochloric acid, extracted with ethyl acetate (30 mL × 2), the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further purified by silica gel column chromatography (eluent: system B) to give 2- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 8a (40 mg), yield: 39.9 percent.

MS m/z(ESI):495.1[M+1]

Second step of

(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 (50mg, 0.128mmol), tert-butyl 2-aminoacetate (33.52mg, 0.256 mmol), N-diisopropylethylamine (16.52mg, 0.128mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (133.00mg, 0.256 mmol) were added to 2mL of N, N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL × 2), the combined organic phases were washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl (2- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonyl) glycinate 8b (40 mg), yield: 62 percent.

MS m/z(ESI):608.3[M+1]

The third step

Tert-butyl (2- (4- ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonyl) glycinate 8b (40mg, 0.079mmol) was added to 2mL of 6M dilute hydrochloric acid, heated to 90 ℃ and reacted for 3 hours. After the reaction, the reaction 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 percent。

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] decan-8-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid

First step of

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

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

MS m/z(ESI):275.1[M+1]

Second step of

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

(R) -2-methyl-N- ((3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide 9b (490mg, 1.26mmol), N-diisopropylethylamine (135.86mg, 1.05mmol) and 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (161.43mg, 1.05mmol) were added to 5mL of N, N-dimethylacetamide, heated to 110 ℃ and reacted for 3 hours. At the end of the reaction, 30mL of water was added, extraction was performed with ethyl acetate (30 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 resulting residue was further analytically purified by silica gel column chromatography (eluent: system a) to give (R) -N- ((3s, 4 s) -8- (4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropane-2-sulfinamide 9c (411 mg), yield: 99.86 percent.

MS m/z(ESI):392.2[M+1]

The third step

2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-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] decan-4-yl) -2-methylpropane-2-sulfinamide 9c (371mg, 0.948mmol) and bromosuccinimide (185.51mg, 1.04mmol) were added to 5mL of N, N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction was completed, concentration was performed under reduced pressure to obtain 2- ((3s, 4s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6-methylpyrimidine-4-carbonitrile 9d (272.29 mg), yield: 100 percent, the product is directly used for the next reaction without purification.

MS m/z(ESI):288.1[M+1]

The fourth step

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

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

MS m/z(ESI):388.2[M+1]

The fifth step

((3S, 4S) -8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-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] decan-4-yl) carbamate 9e (340mg, 0.877mmol) and bromosuccinimide (171.79mg, 0.965mmol) were added to 5mL of N, N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, 30mL of water was added, extraction was performed 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 obtained residue was further purified by analysis with a silica gel column chromatography (eluent: system A) to obtain 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), yield: 95.3 percent.

MS m/z(ESI):466.1[M+1]

The sixth step

((3S, 4S) -8- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-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 (390mg, 0.836 mmol), (2,3-dichlorophenyl) boronic acid 1e (319.14mg, 1.67mmol), (1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (70.03mg, 0.084mmol), tetrakis (triphenylphosphine) palladium (78.05mg, 0.167mmol) and potassium phosphate (532.78mg, 2.51mmol) were added to 8mL of a mixed solution (1,4-dioxane: water = 7:1), heated to 135 ℃ and reacted for 3.5 hours under argon protection. After the reaction was completed, it was cooled, 30mL of water was added, extracted with ethyl acetate (30 mL. Times.3), washed with a saturated sodium chloride solution, the organic phases were combined, 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 9g (380 mg) of tert-butyl ((3S, 4S) -8- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) carbamate (yield: 85.34%.

MS m/z(ESI):532.2[M+1]

Seventh 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 9g (29mg, 0.055mmol) and 0.5mL of concentrated hydrochloric acid were added to a pressure tube, heated to 110 ℃ and reacted for 1.5 hours. After completion of the reaction, concentration was carried out 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 obtain the product 2- ((3S, 4S) -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 percent.

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] decan-8-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step of

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

(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 (180mg, 0.338mmol) and 1.5mL of trisThe fluoroacetic acid was added to 6mL of dichloromethane, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, concentration was carried out 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 obtain the product 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 (77.68 mg), yield: 41.5 percent.

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 of

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 (30mg, 0.069 mmol) and 0.3mL sodium hydroxide were added to 1.2mL ethanol, heated to 80 ℃ and reacted for 50 min. After completion of the reaction, concentration was carried out 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 obtain a product 2- ((3S, 4S) -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 percent.

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 of

((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 (100mg, 0.651mmol), ((4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester 11a (178.42mg, 0.781mmol) and N, N-diisopropylethylamine (252.47mg, 1.95mmol) were added to 1.2mL of N, N-dimethylacetamide, heated to 90 ℃ and reacted for 4 hours. After the reaction was completed, 20mL of water was added, extraction was performed with ethyl acetate (20 mL × 3), washing was performed with a saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl ((1- (4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamate 11b (223 mg), yield: 99.1 percent.

MS m/z(ESI):346.2[M+1]

Second step of

((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 (223mg, 0.646 mmol) and bromosuccinimide (120.64mg, 0.678mmol) were added to 4mL of N, N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, 20mL of water was added, extraction was performed with ethyl acetate (20 mL × 3), washing was performed with a saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl ((1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamate 11c (260 mg), yield: 94.91%.

MS m/z(ESI):424.1[M+1]

The 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 (260mg, 0.613mmol), (2,3-dichlorophenyl) boronic acid 1e (233.84mg, 1.23mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (51.31mg, 0.061mmol), tetrakis (triphenylphosphine) palladium (57.18mg, 0.123mmol) and potassium phosphate (390.37mg, 1.84mmol) were added to 3.5mL of a mixed solution (1,4-dioxane: water = 6:1) under argon, heated to 130 ℃ and reacted for 3.5 hours. At the end of the reaction, 30mL of water were added, extracted with ethyl acetate (30 mL × 3), washed with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was further purified analytically by silica gel column chromatography (eluent: system a) to give tert-butyl ((1- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamate 11d (280 mg), yield: 93.18 percent.

MS m/z(ESI):490.1[M+1]

The 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 (80mg, 0.163mmol) and 1mL of trifluoroacetic acid were added to 4mL of dichloromethane and reacted at room temperature for 50 minutes. After 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 used in the next reaction without purification.

MS m/z(ESI):390.1[M+1]

The fifth step

2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5-(2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 11e (63mg, 0.161mmol) and 0.5mL of sodium hydroxide were added to 2mL of ethanol, heated to 80 ℃ and reacted for 2 hours. Concentration under reduced pressure, liquid phase separation of the obtained residue was performed (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- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 11 (11.03 mg), yield: 16.4 percent.

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 of

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

Under argon protection, (1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 3c (80mg, 0.195mmol), (2-chloro-3-methylphenyl) boronic acid 12a (66.45mg, 0.390mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (16.33mg, 0.0195 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropoxy-1,1 ' -biphenyl (18.20mg, 0.039mmol) and potassium phosphate (124.22mg, 0.585mmol) were added to 1.5mL of a mixed solution (1,4-dioxane: water = 3732 zxft), and heated to 130 ℃ for 5 hours. After the reaction was completed, 20mL of water was added, extraction was performed with ethyl acetate (20 mL. Times.3), washing was performed with a saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl (1- (5- (2-chloro-3-methylphenyl) -4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 12b (86 mg), yield: 96.7 percent.

MS m/z(ESI):456.2[M+1]

Second step of

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 (86mg, 0.189mmol) and 1.5mL of trifluoroacetic acid were added to 6mL of dichloromethane and reacted at room temperature for 40 minutes. After 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 used without purification for the next reaction.

MS m/z(ESI):356.1[M+1]

The third step

2- (4-amino-4-methylpiperidin-1-yl) -5- (2-chloro-3-methylphenyl) -6-methylpyrimidine-4-carbonitrile 12c (67.12mg, 0.189mmol) and 0.5mL of sodium hydroxide were added to 2mL of ethanol, heated to 80 ℃ and reacted for 40 minutes. Concentration under reduced pressure, liquid phase separation of the obtained residue was performed (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- (4-amino-4-methylpiperidin-1-yl) -5- (2-chloro-3-methylphenyl) -6-methylpyrimidine-4-carboxamide 12 (43.69 mg), yield: 61.6 percent.

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] decan-8-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step of

(R) -2-methyl-N- ((R) -8-azaspiro [4.5] decan-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 (200mg, 0.558 mmol) and trifluoroacetic acid (636.03mg, 5.58mmol) were added to 2mL of dichloromethane and reacted at room temperature for 1.5 hours. After the reaction was completed, concentration under reduced pressure was performed to obtain (R) -2-methyl-N- ((R) -8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide 13b (144.15 mg), yield: 100.00%, the product was not purified and was directly subjected to the next reaction.

MS m/z(ESI):259.2[M+1]

Second step of

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

(R) -2-methyl-N- ((R) -8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide 13b (373.55mg, 1.04mmol), 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (80mg, 0.521mmol) and N, N-diisopropylethylamine (67.33mg, 0.521mmol) were added in that order to 2mL 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 a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analytically purified by silica gel column chromatography (eluent: system a) to give (R) -2-methyl-N- ((R) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) -propane-2-sulfinamide 13c (100 mg), yield: 51.12 percent.

MS m/z(ESI):376.1[M+1]

The third step

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

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

MS m/z(ESI):272.2[M+1]

The fourth step

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

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

MS m/z(ESI):372.2[M+1]

The fifth step

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

(R) - (8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) carbamic acid tert-butyl ester 13e (72mg, 0.194mmol) and bromosuccinimide (37.95mg, 0.213mmol) were added to 2mL of N, N-dimethylformamide and reacted at room temperature overnight. After 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), dried over anhydrous sodium sulfate, and the resulting residue was further purified by analysis 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] decan-1-yl) carbamate 13f (80 mg). Yield: 91.65 percent.

MS m/z(ESI):395.9[M-56]

The sixth step

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

Tert-butyl (R) - (8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) carbamate 13f (30mg, 0.067mmol), (2,3-dichlorophenyl) boronic acid 1e (25.42mg, 0.133mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (11.15mg, 0.013mmol), tetrakis (triphenylphosphine) palladium (12.43mg, 0.027mmol) and potassium phosphate (42.44mg, 0.199mmol) were added to 2mL of the mixed solution under argon protection (1,4-dioxane: water = 5:1), heated to 130 ℃ and reacted for 4 hours. After completion of the reaction, it was cooled to room temperature, 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 purified by analysis by silica gel column chromatography (eluent: A system) to give tert-butyl ((1R) -8- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) carbamate 13g (30 mg), yield: 87.20 percent.

MS m/z(ESI):515.9[M+1]

Seventh step

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

Tert-butyl ((1R) -8- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) carbamate 13g (45mg, 0.087 mmol) 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, concentration was performed under reduced pressure to obtain 2- ((R) -1-amino-8-azaspiro [4.5] decan-8-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 13h (36 mg), yield: 99.24%, and the product is directly used for the next reaction without purification.

MS m/z(ESI):416.1[M+1]

The eighth step

2- ((R) -1-amino-8-azaspiro [4.5]]Decan-8-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 13h (36mg, 0.086 mmol) and 0.5mL of 6M sodium hydroxide were added to 2mL of ethanol, heated to 80 ℃ and reacted for 0.5 hour. After completion of the reaction, concentration under reduced pressure was carried out, 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 obtain 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 percent.

MS m/z(ESI):433.9[M+1]

¹ H NMR(400MHz,CD3OD):δ7.52(d,J＝8.0Hz,1H),7.31(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 of

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

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (80mg, 0.521mmol), piperidine-4-carbamic acid tert-butyl ester 14a (125.20mg, 0.625mmol), and N, N-diisopropylethylamine (201.98mg, 1.56mmol) were added to 2mL of N, N-dimethylacetamide, heated to 90 ℃ and reacted for 3 hours. After the reaction was completed, 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 purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl (1- (4-cyano-6-methylpyrimidin-2-yl) piperidin-4-yl) carbamate 14b (160 mg), yield: 96.77 percent.

MS m/z(ESI):262.0[M+1-56]

Second step of

(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 (160mg, 0.504mmol) and bromosuccinimide (107.67mg, 0.605mmol) were added to 2mL of N, N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, 30mL of water was added, extraction was performed 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 purified by analysis with a silica gel column chromatography (eluent: system A) to obtain tert-butyl (1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) piperidin-4-yl) carbamate 14c (180 mg), yield: 90.1 percent.

MS m/z(ESI):342.0[M+1-56]

The 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 (100mg, 0.252mmol), (2,3-dichlorophenyl) boronic acid 1e (96.31mg, 0.505mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (21.13mg, 0.025mmol), tetrakis (triphenylphosphine) palladium (23.55mg, 0.050mmol), and potassium phosphate (160.69mg, 0.757mmol) were added to 2.2mL of a mixed solution (1,4-dioxane: water = 10) under argon, heated to 130 ℃ and reacted for 5 hours. After the reaction was completed, 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 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 purified by silica gel column chromatography (eluent: system A) to give tert-butyl (1- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) piperidin-4-yl) carbamate 14d (100 mg), yield: 85.71 percent.

MS m/z(ESI):406.0[M+1-56]

The 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 (100mg, 0.216mmol) and trifluoroacetic acid (24.66mg, 0.216mmol) were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, concentration was performed under reduced pressure to obtain 2- (4-aminopiperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 14e (100 mg), yield: 97.08% and the product is not purified and is directly used for the next step.

MS m/z(ESI):361.9[M+1]

The fifth step

2- (4-Aminopiperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 14e (100mg, 0.210mmol) and 0.3mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80 ℃ and reacted for 1 hour. After completion of the reaction, concentration was carried out 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-aminopiperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 14 (40 mg), yield: 49.27 percent.

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 of

(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 (50mg, 0.326mmol), (S) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester 15a (92.49mg, 0.391mmol) and N, N-diisopropylethylamine (126.24mg, 0.977 mmol) were added to 2mL of N, N-dimethylacetamide, heated to 90 ℃ and reacted for 3 hours. After the reaction was completed, 20mL of water was added, extraction was performed with ethyl acetate (30 mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl (R) - ((1- (4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamate 15b (80 mg), yield: 77.42 percent.

MS m/z(ESI):318.2[M+1]

Second step of

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

MS m/z(ESI):341.9[M+1-56]

The third step

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

Under argon protection, (R) - ((1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester 15c (80mg, 0.202mmol), (2,3-dichlorophenyl) boronic acid 1e (96.31mg, 0.505mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (16.90mg, 0.020mmol), tetrakis (triphenylphosphine) palladium (18.84mg, 0.040mmol), and potassium phosphate (128.55mg, 0.606mmol) were added to 2.2mL of a mixed solution (1,4-dioxane: water = 10), heated to 130 ℃ and reacted for 5 hours. After the reaction was completed, it was 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 a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl (((3R) -1- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamate 15d (70 mg), yield: 74.99%.

MS m/z(ESI):461.9[M+1]

The 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 (70mg, 0.151mmol) and trifluoroacetic acid (1.53g, 13.42mmol) were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was complete, concentration under reduced pressure gave 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 used in the next step without purification.

MS m/z(ESI):362.1[M+1]

The fifth step

2- ((R) -3- (aminomethyl) pyrrolidin-1-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 15e (50mg, 0.138mmol) 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, 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,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 percent.

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

First step of

((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 (60mg, 0.391mmol), ((1R, 5S) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 16a (106.11mg, 0.469mmol), N-diisopropylethylamine (151.49mg, 1.17mmol) were added to 2mL of N, N-dimethylacetamide, heated to 90 ℃ and reacted for 3 hours. After the reaction was completed, 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 analytically purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl ((1R, 5S) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 16b (130 mg), yield: 96.89 percent.

MS m/z(ESI):344.0[M+1]

Second step of

((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 (130mg, 0.379mmol) and bromosuccinimide (80.85mg, 0.454mmol) were added to 2mL of N, N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, 30mL of water was added, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to obtain 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), yield: 93.83 percent.

MS m/z(ESI):365.9[M+1-56]

The 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 (150mg, 0.355mmol), (2,3-dichlorophenyl) boronic acid 1e (169.44mg, 0.888mmol), (1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (29.74mg, 0.03mmol), tetrakis (triphenylphosphine) palladium (33.15mg, 0.071mmol) and potassium phosphate (226.17mg, 1.07mmol) were added to a 2.2mL mixed solution (1,4-dioxane: water = 10) under argon protection, heated to 130 ℃ and reacted for 5 hours. After the reaction was completed, 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 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 purified by analysis with a silica gel column chromatography (eluent: A system) to give 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), yield: 86.48%.

MS m/z(ESI):488.1[M+1]

The fourth step

2- ((1R, 5S) -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 (150mg, 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, concentration was performed under reduced pressure to obtain 2- ((1r, 5s) -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 is not purified and is directly used for the next step.

MS m/z(ESI):387.9[M+1]

The fifth step

2- ((1R, 5S) -3-amino-8-azabicyclo [ 3.2.1)]Oct-8-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 16e (100mg, 0.258mmol) and 0.3mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80 ℃ and reacted for 1 hour. After completion of the reaction, concentration was carried out 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 obtain 2- ((1R, 5S) -3-amino-8-azabicyclo [ 3.2.1)]Oct-8-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 16 (45 mg), yield: 41.75 percent.

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 of

N- [ (tert-Butoxycarbonylamino) - [ [1- [ 4-carbamoyl-5- (2,3-dichlorophenyl) -6-methyl-pyrimidin-2-yl ] -4-methyl-4-piperazino ] 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 (tert-butoxycarbonyl) -2-methylisothiourea (11.34mg, 39.06. Mu. Mol), cuprous iodide (13.52mg, 71.01. Mu. Mol) and potassium carbonate (19.63mg, 142.02. Mu. Mol) were added to 1mL of tetrahydrofuran in this order, replaced with nitrogen 3 times, and the external temperature was heated to 60 ℃ and stirred for 24 hours. The reaction 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 of

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 (22mg, 34.56. Mu. Mol), TFA (1.54g, 13.51mmol, 1mL) was sequentially added to 3mL of dichloromethane and stirring was continued at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate (10 ml), concentrated under reduced pressure, and the obtained residue was purified by preparative liquid chromatography and freeze-dried to give 5- (2,3-dichlorophenyl) -2- (4-guanidino-4-methyl-1-piperidinyl) -6-methylpyrimidine-4-carboxamide 17 (7.5 mg, total yield in two steps 38.4%).

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 of

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

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (70mg, 0.355mmol), (3-azabicyclo [3.1.0] hex-6-yl) carbamic acid tert-butyl ester 17a (91.48mg, 0.461mmol) N, N-diisopropylethylamine (137.62mg, 1.06mmol) was added to 2mL of N, N-dimethylacetamide, heated to 90 ℃ and reacted for 3 hours. After the reaction was completed, 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 purified by analysis with a silica gel column chromatography (eluent: system A) to obtain tert-butyl (3- (4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6-yl) carbamate 17b (110 mg), yield: 98.27 percent.

MS m/z(ESI):260.0[M+1-56]

Second step of

(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 (110mg, 0.349mmol) and bromosuccinimide (93.12mg, 0.523mmol) were added to 2mL of N, N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, 30mL of water was added, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to obtain 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 percent.

MS m/z(ESI):340.0[M+1-56]

The 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 (110mg, 0.279mmol), (2,3-dichlorophenyl) boronic acid 1e (122.45mg, 0.642mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (23.36mg, 0.028mmol), tetrakis (triphenylphosphine) palladium (26.04mg, 0.056 mmol) and potassium phosphate (177.67mg, 0.837mmol) were added to 2.3mL of a mixed solution (1,4-dioxane: water = 7:1) under argon protection, heated to 130 ℃ and reacted for 5 hours. After the reaction was completed, 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 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 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]

The 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 (100mg, 0.217mmol) and trifluoroacetic acid (24.77mg, 0.217mmol) were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, concentration was performed under reduced pressure to obtain 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 is directly used for the next reaction without purification.

MS m/z(ESI):359.7[M+1]

The fifth step

2- (6-amino-3-azabicyclo [3.1.0]]Hex-3-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 18e (78mg, 0.217mmol) and 0.3mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80 ℃ and reacted for 1 hour. After completion of the reaction, concentration was carried out 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 obtain 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 percent.

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 ] pyridine-7,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step of

(R) -N- ((R) -5,6-dihydrospiro [ cyclopenta [ b ] pyridine-7,4' -piperidin ] -6-yl) -2-methylpropane-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 (150mg, 0.368mmol) and 1mL of trifluoroacetic acid were added to 6mL of dichloromethane and reacted at room temperature for 2 hours. After the reaction was completed, concentration was performed under reduced pressure to obtain (R) -N- ((R) -5,6-dihydrospiro [ cyclopenta [ b ] pyridine-7,4' -piperidin ] -6-yl) -2-methylpropane-2-sulfinamide 19b (113.15 mg), yield: 100.00%, and the product is directly used for the next reaction without purification.

MS m/z(ESI):308.2[M+1]

Second step of

(R) -N- ((R) -1'- (4-cyano-6-methylpyrimidin-2-yl) -5,6-dihydrospiro [ cyclopenta [ b ] pyridine-7,4' -piperidine ] -6-yl) -2-methylpropane-2-sulfinamide

(R) -N- ((R) -5,6-dihydrospiro [ cyclopenta [ b ] pyridine-7,4' -piperidine ] -6-yl) -2-methylpropane-2-sulfinamide 19b (113.15mg, 0.368mmol), 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (60mg, 0.391mmol) and N, N-diisopropylethylamine (50.49mg, 0.391mmol) were added in this order 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 a 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 ] pyridine-7,4' -piperidin ] -6-yl) -2-methylpropane-2-sulfinamide 19c (130 mg), yield: 78.37%, the product was not purified and was directly subjected to the next reaction.

MS m/z(ESI):424.9[M+1]

The third step

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

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

MS m/z(ESI):499.1[M+1]

The fourth step

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

(R) - (1 ' - (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -5,6-dihydrospiro [ cyclopenta [ b ] pyridine-7,4 ' -piperidin ] -6-yl) carbamic acid tert-butyl ester 19d (50mg, 0.100mmol), (2,3-dichlorophenyl) boronic acid 1e (47.76mg, 0.250mmol), (1,1 ' -bis (diphenylphosphino) ferrocene ] dichloropalladium (8.38mg, 0.010mmol), tetrakis (triphenylphosphine) palladium (9.34mg, 0.020mmol), and potassium phosphate (63.76mg, 0.300mmol) were added to 2.3mL of a mixed solution (1,4-dioxane: water = 7:1), heated to 130 ℃ and reacted for 4 hours under argon. After the reaction was completed, it was cooled to room temperature, 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 obtained residue was further purified by analysis 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 ] pyridine-7,4' -piperidin ] -6-yl) carbamate 19e (45 mg), yield: 79.48%.

MS m/z(ESI):564.5[M+1]

The fifth step

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

(R) - (1 '- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -5,6-dihydrospiro [ cyclopenta [ b ] pyridine-7,4' -piperidin ] -6-yl) carbamic acid tert-butyl ester 19e (45mg, 0.080mmol) and 1mL of trifluoroacetic acid were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, concentration was performed under reduced pressure to obtain 2- ((R) -6-amino-5,6-dihydrospiro [ cyclopenta [ b ] pyridine-7,4 '-piperidin ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 19f (37 mg), yield: 100 percent, the product is not purified and is directly subjected to the next reaction.

MS m/z(ESI):465.1[M+1]

The sixth step

2- ((R) -6-amino-5,6-dihydrospiro [ cyclopentyl [ b)]Pyridine-7,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 19f (37mg, 0.080mmol) and 0.3mL of 6M sodium hydroxide were added to 2mL of ethanol, heated to 80 ℃ and reacted for 1 hour. After completion of the reaction, concentration was carried out 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 obtain 2- ((R) -6-amino-5,6-dihydrospiro [ cyclopentyl [ b ]]Pyridine-7,4' -piperidine]-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 20

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

First step of

(R) -N- ((S) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -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 20a (260mg, 639.48. Mu. Mol) in dichloromethane (4 mL) at room temperature and reacted for 1 hour at room temperature. The reaction 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 20b (195.98 mg), yield: 100.00 percent, and the product is directly used for the next reaction without separation and purification.

MS m/z(ESI):307.2[M+1]

Second step of

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

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (78.56mg, 511.59. Mu. Mol), (R) -N- ((S) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 20b (195.98mg, 639.49. Mu. Mol), N-dimethylacetamide (2 mL), N-diisopropylethylamine (247.94mg, 1.92mmol) were added in this order to a 15mL single vial at room temperature, and the temperature was raised to 100 ℃ for 4 hours. To the reaction solution was added 20mL of water, extracted 3 times with ethyl acetate (20 mL × 3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: eluent a) to give (R) -N- ((S) -1'- (4-cyano-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide 20c (265 mg), yield: 97.83%.

MS m/z(ESI):424.2[M+1]

The third step

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

Bromosuccinimide (122.48mg, 688.19. Mu. Mol) and (R) -N- ((S) -1'- (4-cyano-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 20c (265mg, 0.626 mmol) were added to 3mL of N, N-dimethylformamide and reacted at room temperature for 2 hours. Concentration under reduced pressure gave (S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) -6-methylpyrimidine-4-carbonitrile 20d (199.83 mg), yield: 100%, the product is used in the next step without separation and purification.

MS m/z(ESI):303.2[M-17+1]

The fourth step

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

(S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -6-methylpyrimidine-4-carbonitrile 20d (199.83mg, 625.64. Mu. Mol), di-tert-butyl dicarbonate (409.64mg, 1.88mmol), triethylamine (189.92mg, 1.88mmol), and dichloromethane (4 mL) were added to a 15mL one-neck flask and reacted at room temperature for 2 hours. To the reaction solution was added 20mL of water, extracted 3 times with ethyl acetate (20 mL × 3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and 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) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 20e (180 mg), yield: 68.58%.

MS m/z(ESI):420.2[M+1]

The fifth step

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

Bromosuccinimide (84.00mg, 471.97. Mu. Mol) and tert-butyl (S) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 20e (180mg, 429.06. Mu. Mol) were added to 2.5mL of N, N-dimethylformamide and gradually warmed to room temperature for overnight reaction. To the reaction solution was added 20mL of water, extracted with ethyl acetate (20 mL × 3), washed with a saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained 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) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 20f (200 mg), yield: 93.52%.

MS m/z(ESI):498.1[M+1]

The sixth step

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

Under argon protection, (S) - (1 ' - (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4 ' -piperidin ] -1-yl) carbamic acid tert-butyl ester 20f (200mg, 401.27. Mu. Mol), (2,3-dichlorophenyl) boronic acid 1e (153.14mg, 802.55. Mu. Mol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (33.60mg, 40.13. Mu. Mol), tetrakis (triphenylphosphine) palladium (37.45mg, 80.25. Mu. Mol), and potassium phosphate (255.65mg, 1.20mmol) were added to 2.9mL of a mixed solution (1,4-dioxane: water = 6:1) and the temperature was raised to 130 ℃ for 4 hours. To the reaction solution was added 20mL of water, extracted with ethyl acetate (20 mL. Times.3), washed with a saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give 20g (190 mg) of tert-butyl (S) - (1 '- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate, yield: 83.88%.

MS m/z(ESI):507.7[M-56+1]

Step seven

2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -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) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate (20 g (190mg, 336.58. 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 2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile for 20h (156.3 mg), yield: 100 percent.

MS m/z(ESI):447.1[M-17+1]

The eighth step

2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 20h (156.3mg, 336.57. Mu. Mol) and 0.5mL of 6M sodium hydroxide solution were added to 2mL of ethanol and the reaction was allowed to warm to 80 ℃ for 40 min. The reaction solution 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,20mL/min; mobile phase A:0.05% TFA +H ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain a product 2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 20 (52.31 mg), yield: 32.09 percent.

MS m/z(ESI):482.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ7.94(s,1H),7.58(d,J＝8.0Hz,1H),7.26-7.43(m,3H),7.18(dt,J＝17.4,6.5Hz,4H),4.62(t,J＝16.8Hz,2H),3.84(s,1H),3.05-3.26(m,3H),2.64(d,J＝15.6Hz,1H),2.01(s,3H),1.69-1.94(m,3H),1.64(t,J＝12.6Hz,1H),1.52(d,J＝13.3Hz,1H),1.11(d,J＝13.2Hz,1H).

Example 21

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

First step of

(R) -N- ((S) -5-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine ] -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 (200mg, 455.97. Mu. Mol) in methylene chloride (5 mL) at room temperature, and reacted for 1 hour at room temperature. The reaction 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 percent, and the product is directly used for the next reaction without separation and purification.

MS m/z(ESI):337.2[M+1]

Second step of

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

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

MS m/z(ESI):454.2[M+1]

The third step

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

Bromosuccinimide (72.27mg, 406.04. Mu. Mol) and (R) -N- ((S) -1'- (4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidine ] -3-yl) -2-methylpropane-2-sulfinamide 21c (184.18mg, 406.04. Mu. Mol) were added to 2mL of N, N-dimethylformamide and allowed to gradually warm to room temperature for 2 hours. After the reaction was completed, concentration was performed under reduced pressure to obtain (S) -2- (1-amino-6-methoxy-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -6-methylpyrimidine-4-carbonitrile 21d (141.88 mg), yield: 100%, the product is used in the next step without separation and purification.

MS m/z(ESI):333.1[M-17+1]

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

MS m/z(ESI):450.3[M+1]

The 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 (51.47mg, 289.18. Mu. Mol) and tert-butyl (S) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidin ] -3-yl) carbamate 21e (130mg, 289.18. Mu. Mol) were added to 2.5mL of N, N-dimethylformamide and gradually warmed to room temperature for 5 hours. After the reaction was completed, 20mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), washed with a saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained 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 percent.

MS m/z(ESI):472.1[M-56+1]

The sixth step

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

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

MS m/z(ESI):594.2[M+1]

Step seven

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

Trifluoroacetic acid (1 mL) was added to a solution of 21g (140mg, 235.48. Mu. Mol) of tert-butyl (S) - (1 '- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -5-methoxy-1,3-dihydrospiro [ indene-2,4' -piperidin ] -3-yl) carbamate in dichloromethane (4 mL) at room temperature for 40 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 2- ((S) -1-amino-6-methoxy-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 21h (116.42 mg), yield: 100%, the product was used 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 (116.42mg, 235.47. Mu. Mol) and 0.5mL of 6M sodium hydroxide solution were added to 2mL of ethanol, and the temperature was raised to 80 ℃ for 40 minutes. After 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,20mL/min; mobile phase A:0.05% TFA +H ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain a 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 percent.

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 [ indene-2,4' -piperidine ] -1-amine

First step of

(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

5- (2,3-dichlorophenyl) -4-methoxy-6-methyl-2- (methylsulfonyl) pyrimidine 22a (75mg, 216. Mu. Mol), (R) -N- ((S) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide 20b (79mg, 260. Mu. Mol), N-methylpyrrolidone (1 mL), N-diisopropylethylamine (28mg, 216. Mu. Mol) were added sequentially to a 15mL one-port bottle at room temperature, heated to 100 ℃ and reacted for 18 hours. After the reaction was completed, 5mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), washed with a saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained 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 [ indene-2,4 ' -piperidine ] -1' -yl) -2-methylpropane-2-sulfinamide 22b (70 mg), yield: and 56.5 percent.

MS m/z(ESI):573.2[M+1]

Second step of

Bromosuccinimide (20mg, 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 22b (60mg, 104. Mu. Mol) was added to 1mL of N, N-dimethylformamide and reacted at room temperature for 2 hours. After 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,20mL/min; mobile phase A:0.05% TFA + H + ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain 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 percent.

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 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step of

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

Trifluoroacetic acid (1.53g, 13.42mmol, 1mL) and (R) -2- (((R) -tert-butylsulfinyl) amino) -2,3-dihydrospiro [ indene-1,4 '-piperidine ] -1' -carboxylic acid tert-butyl ester 23a (400mg, 983.81. Mu. Mol) were added to 6mL of dichloromethane and reacted at room temperature for 2 hours. After the reaction was completed, concentration was performed under reduced pressure to obtain the product (R) -N- ((R) -2,3-dihydrospiro [ indene-1,4' -piperidin ] -2-yl) -2-methylpropane-2-sulfinamide 23b (287 mg), yield: 95.19%, without purification, was used directly in the next step.

MS m/z(ESI):307.3[M+1]

Second step of

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

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

MS m/z(ESI):424.0[M+1]

The third step

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

(R) -N- ((R) -1'- (4-cyano-6-methylpyrimidin-2-yl) -2,3-dihydrospiro [ indene-1,4' -piperidin ] -2-yl) -2-methylpropane-2-sulfinamide 23c (170mg, 401.35. Mu. Mol) and bromosuccinimide (85.72mg, 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, concentration was performed under reduced pressure to obtain 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% without purification, was used directly in the next step.

MS m/z(ESI):320.1[M+H]

The fourth step

(R) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -2,3-dihydrospiro [ 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 (128mg, 400.75. Mu. Mol), di-tert-butyl dicarbonate (262.39mg, 1.20mmol, 276.20. Mu.L) and triethylamine (202.76mg, 2.00mmol, 278.51. Mu.L) were added in this order to 4mL of dichloromethane and reacted at room temperature for 3 hours. After the reaction was completed, 20mL of water was added, extraction was performed with dichloromethane (20 mL × 3), saturated sodium chloride solution (20 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to obtain (R) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -2,3-dihydrospiro [ indene-1,4' -piperidin ] -2-yl) carbamic acid tert-butyl ester 23e (60 mg), yield: 35.69%.

MS m/z(ESI):420.1[M+1]

The fifth step

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

(R) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -2,3-dihydrospiro [ indene-1,4' -piperidin ] -2-yl) carbamic acid tert-butyl ester 23e (60mg, 143.02. Mu. Mol) and bromosuccinimide (33.09mg, 185.93. Mu. Mol) were added to 2mL of N, N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction was completed, 30mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), 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 in the next step without purification.

MS m/z(ESI):498.1[M+1]

The sixth step

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

Under argon protection, (R) - (1 ' - (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -2,3-dihydrospiro [ indene-1,4 ' -piperidine ] -2-yl) carbamic acid tert-butyl ester 23f (70mg, 140.45. Mu. Mol), (2,3-dichlorophenyl) boronic acid 1e (67.00mg, 351.11. Mu. Mol), 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1,1 ' -biphenyl (13.111mg, 28.09. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (11.76mg, 14.04. Mu. Mol) and potassium phosphate (89.44mg, 421.34. Mu. Mol) were added to a 2.3mL mixed solution (3425 zxft 5732:. Mu. Deg.25-hexahydro), and the temperature was raised to 345732 ℃. After the reaction was completed, 20mL of water was added to the reaction solution, extraction was performed with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further purified by analysis with a silica gel column chromatography (eluent: A system) to obtain 23g (70 mg) of tert-butyl (R) - (1 '- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -2,3-dihydrospiro [ indene-1,4' -piperidin ] -2-yl) carbamate, yield: 88.29%.

MS m/z(ESI):565.2[M+1]

Seventh step

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

23g (80mg, 141.72. Mu. Mol) of tert-butyl (R) - (1 '- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -2,3-dihydrospiro [ indene-1,4' -piperidin ] -2-yl) carbamate and trifluoroacetic acid (1.53g, 13.42mmol, 1mL) were added to 4mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, concentration was performed under reduced pressure to obtain 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]

The eighth step

Mixing 2- ((R) -2-amino-2,3-dihydrospiro [ indene-1,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 23h (65.8mg, 141.69. Mu. Mol) and 0.3mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80 ℃ and reacted for 40 minutes. After 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,20mL/min; mobile phase A:0.05% TFA + H + ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain a 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).

Example 26

(S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide

First step of

(R) -N- ((S) -1'- (4-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide

2-Chloropyrimidine-4-carbonitrile 26a (80mg, 573.30. Mu. Mol), (R) -N- ((S) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 20b (226mg, 737.44. Mu. Mol), N-dimethylacetamide (3 mL) and N, N-diisopropylethylamine (370.48mg, 2.87mmol, 499.29. Mu.L) were added sequentially to a 25mL one-port flask at room temperature, warmed to 90 ℃ and reacted for 3 hours. After the reaction was completed, 20mL of water was added to the reaction solution, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give (R) -N- ((S) -1'- (4-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide 26b (210 mg), yield: 89.44 percent.

MS m/z(ESI):410.2[M+1]

Second step of

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

Bromosuccinimide (109.52mg, 615.31. Mu. Mol) was added to a solution of (R) -N- ((S) -1'- (4-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 26b (210mg, 512.76. Mu. Mol) in N, N-dimethylformamide (2 mL) under ice-bath and reacted at room temperature for 2 hours. After the reaction was completed, concentration was performed under reduced pressure to obtain (S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile 26c (156 mg), yield: 99.63%, and the product was used in the next step without isolation and purification.

MS m/z(ESI):289.1[M-17+1]

The third step

(S) - (1 '- (4-Cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamic acid tert-butyl ester

(S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile 26c (156mg, 510.85. Mu. Mol), di-tert-butyl dicarbonate (334.47mg, 1.53mmol), methylene chloride (5 mL) and triethylamine (258.46mg, 2.55mmol) were successively charged into a 15mL one-necked flask and reacted at room temperature for 3 hours. After the reaction was completed, 20mL of water was added to the reaction solution, extraction was performed with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain (S) - (1 '- (4-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamic acid tert-butyl ester 26d (120 mg), yield: 57.93%.

MS m/z(ESI):406.0[M+1]

The fourth step

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

Bromosuccinimide (63.21mg, 355.12. Mu. Mol) was slowly added to a solution of tert-butyl (S) - (1 '- (4-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 26d (120mg, 295.94. Mu. Mol) in dichloromethane (2 mL) at 0 ℃ and the reaction solution was warmed to room temperature and reacted at room temperature for 2 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, extraction was performed with dichloromethane (20 mL × 3), the organic phases were combined, the organic phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl (S) - (1 '- (5-bromo-4-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 26e (140 mg), yield: 7.66 percent.

MS m/z(ESI):428.1[M+1-56]

The fifth step

(S) - (1 '- (4-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) carbamic acid tert-butyl ester

Under the protection of argon, tert-butyl (S) - (1 ' - (5-bromo-4-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4 ' -piperidine ] -1-yl) carbamate 26e (140mg, 289.02. Mu. Mol), (2,3-dichlorophenyl) borate 1e (137.88mg, 722.56. Mu. Mol), 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1,1 ' -biphenyl (26.97mg, 57.80. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (II) (24.2mg, 28.90. Mu. Mol), potassium phosphate (867.07. Mu. Mol) and a mixed solution of 2.3mL (3425 zxft 5732:. Mu. Deg.31) were added to a microwave tube in sequence, and the temperature was raised to react at 34054 ℃ for 3432 ℃. After the reaction was completed, it was cooled to room temperature. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl (S) - (1 '- (4-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 26f (150 mg), yield: 94.28%.

MS m/z(ESI):493.9[M+1-56]

The sixth step

(S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile

Trifluoroacetic acid (1.53g, 13.42mmol, 1mL) was added to a solution of tert-butyl (S) - (1 '- (4-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 26f (150mg, 272.49. Mu. Mol) in dichloromethane (4 mL) at room temperature and reacted for 1 hour at room temperature. After the completion of the reaction, concentration was carried out under reduced pressure to obtain 26g (122 mg) of (S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile, yield: 99.41 percent.

MS m/z(ESI):433.1[M-17+1]

Step seven

To (S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine](E) -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile 26g (122 mg) in ethanol (2 mL) was reacted with sodium hydroxide solution (6M, 0.3 mL) at 80 ℃ for 40 minutes. The reaction was checked by LC-MS for incomplete reaction and supplemented with sodium hydroxide solution (6M, 0.3mL) and ethanol (2 mL) and the reaction was continued for 40 min at 80 ℃. After completion of the reaction, concentration was carried out under reduced pressure, and the obtained residue was separated by preparative 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 obtain (S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide 26 (15 mg), yield: 95.41 percent.

MS m/z(ESI):468.2[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ8.30(d,J＝1.0Hz,1H),7.54-7.47(m,2H),7.43-7.40(m,2H),7.37-7.29(m,2H),7.22(dd,J＝7.6,1.6Hz,1H),4.82(d,J＝14.0Hz,1H),4.73(d,J＝14.2Hz,1H),4.41(s,1H),3.48-3.35(m,3H),3.23(s,2H),1.89-1.72(m,3H),1.65(d,J＝13.8Hz,1H).

Example 27

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

First step of

8-azaspiro [4.5] dec-2-en-1-one

Tert-butyl 1-oxo-8-azaspiro [4.5] dec-2-ene-8-carboxylate 27a (1.1g, 4.38mmol) and trifluoroacetic acid (499.05mg, 4.38mmol) were dissolved in 2mL of dichloromethane and reacted at room temperature for 1 hour. After the completion of the reaction, concentration was carried out under reduced pressure to obtain 8-azaspiro [4.5] dec-2-en-1-one 27b (661 mg), yield: 99.88 percent.

MS m/z(ESI):152.1[M+1]

Second step of

6-methyl-2- (1-oxo-8-azaspiro [4.5] dec-2-en-8-yl) pyrimidine-4-carbonitrile

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (479.52mg, 3.12mmol), 8-azaspiro [4.5] dec-2-en-1-one 27b (661mg, 4.37mmol) and N, N-diisopropylethylamine (403.56mg, 3.12mmol) were dissolved in this order in 5mL of N, N-dimethylacetamide and reacted at 55 ℃ for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate (30 mL), the aqueous layer was separated, and the organic phase was washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6-methyl-2- (1-oxo-8-azaspiro [4.5] dec-2-en-8-yl) pyrimidine-4-carbonitrile 27c (550 mg), yield: 65.65 percent.

MS m/z(ESI):269.1[M+1]

The third step

(R) -2- (3-hydroxy-1-oxo-8-azaspiro [4.5] decan-8-yl) -6-methylpyrimidine-4-carbonitrile

Cuprous chloride (6.09mg, 61.50. Mu. Mol), [1- [2- (bis-p-tolylphosphono) -1-naphthyl ] -2-naphthyl ] -bis (p-tolyl) phosphine (41.74mg, 61.50umol) and sodium tert-butoxide (5.91mg, 61.50. Mu. Mol) were dissolved in 10mL of tetrahydrofuran successively under argon atmosphere, argon was replaced, pinacol diboron (572.59mg, 2.25mmol) was added (dissolved in 2mL of tetrahydrofuran) after stirring at room temperature for 30 minutes, 6-methyl-2- (1-oxo-8-azaspiro [4.5] dec-2-en-8-yl) pyrimidine-4-carbonitrile 27c (550mg, 2.05mmol) was added (dissolved in 2mL of tetrahydrofuran) after stirring for 10 minutes, methanol (131.35mg, 4.10mmol) was added to replace argon and the reaction was performed at room temperature overnight. After the reaction was completed, 7mL of water was added, followed by sodium perborate (1.58g, 10.25mmol) and vigorously stirred at room temperature for 1 hour. Solid impurities were removed by filtration, the filtrate was poured into 5mL of a mixed solution of sodium bicarbonate and sodium sulfite (V: V = 1:1), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R) -2- (3-hydroxy-1-oxo-8-azaspiro [4.5] decan-8-yl) -6-methylpyrimidine-4-carbonitrile 27d (320 mg), yield: 54.54 percent.

MS m/z(ESI):287.2[M+1]

The fourth step

(R) -2- (3- ((tert-butyldimethylsilyl) oxy) -1-oxo-8-azaspiro [4.5] decan-8-yl) -6-methylpyrimidine-4-carbonitrile

(R) -2- (3-hydroxy-1-oxo-8-azaspiro [4.5] decan-8-yl) -6-methylpyrimidin-4-carbonitrile 27d (210mg, 733.42. Mu. Mol) was dissolved in 3mL of dichloromethane, cooled to-78 ℃ and 2,6-lutidine (157.17mg, 1.47mmol) was added followed by dropwise addition of tert-butyldimethylsilyl triflate (213.26mg, 806.77. Mu. Mol) (dissolved in 3mL of dichloromethane) -78 ℃ the reaction was continued for 1 hour. After the reaction was completed, the reaction was quenched by dropwise addition of a saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (30 mL), the organic phase was washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give (R) -2- (3- ((tert-butyldimethylsilyl) oxy) -1-oxo-8-azaspiro [4.5] dec-8-yl) -6-methylpyrimidine-4-carbonitrile 27e (228 mg), yield: 77.60%.

MS m/z(ESI):401.2[M+1]

The fifth step

(R) -N- ((1R, 3R) -3- ((tert-butyldimethylsilyl) oxy) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide

(R) -2- (3- ((tert-butyldimethylsilyl) oxy) -1-oxo-8-azaspiro [4.5] decan-8-yl) -6-methylpyrimidine-4-carbonitrile 27e (236.27mg, 589.81. Mu. Mol), (R) -2-methylpropane-2-sulfinamide (142.97mg, 1.18mmol) and ethyl titanate (269.13mg, 1.18mmol) were dissolved in this order in 3mL tetrahydrofuran and reacted at 65 ℃ for 16 hours. Then, 0.5mL of methanol was added, and lithium borohydride (16.70mg, 766.76. Mu. Mol) was further added to the mixture to react for 1 hour. The reaction was quenched by addition of saturated ammonium chloride solution (6 mL), the reaction solution was extracted with ethyl acetate (30 mL), the aqueous layer was separated, the organic phase was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give (R) -N- ((1r, 3r) -3- ((tert-butyldimethylsilyl) oxy) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide 27f (100 mg), yield: 33.52%.

MS m/z(ESI):506.3[M+1]

The sixth step

2- ((1R, 3R) -1-amino-3- ((tert-butyldimethylsilyl) oxy) -8-azaspiro [4.5] decan-8-yl) -6-methylpyrimidine-4-carbonitrile

(R) -N- ((1R, 3R) -3- ((tert-butyldimethylsilyl) oxy) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide 27f (100mg, 197.71. Mu. Mol) was dissolved in 3mL N, N-dimethylformamide, cooled to 0 ℃, N-bromosuccinimide (38.71mg, 217.48. Mu. Mol) was added, warmed to room temperature, and reacted overnight. After the reaction was completed, concentration was performed under reduced pressure to obtain 27g (79 mg) of crude 2- ((1R, 3R) -1-amino-3- ((tert-butyldimethylsilyl) oxy) -8-azaspiro [4.5] dec-8-yl) -6-methylpyrimidine-4-carbonitrile (yield: 99.49 percent.

MS m/z(ESI):402.1[M+1]

Seventh step

((1R, 3R) -3- ((tert-butyldimethylsilyl) oxy) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) carbamic acid tert-butyl ester

27g (79mg, 196.70. Mu. Mol) of 2- ((1R, 3R) -1-amino-3- ((tert-butyldimethylsilyl) oxy) -8-azaspiro [4.5] decan-8-yl) -6-methylpyrimidine-4-carbonitrile, di-tert-butyl dicarbonate (85.86mg, 393.41. Mu. Mol) and N, N-diethylethylamine (39.81mg, 393.41. Mu. Mol) were dissolved in 3mL of dichloromethane and reacted at room temperature overnight. After the reaction was completed, concentration was performed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl ((1r, 3r) -3- ((tert-butyldimethylsilyl) oxy) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamate 27h (77 mg), yield: 78.02%.

MS m/z(ESI):502.3[M+1]

Eighth step

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

Tert-butyl ((1R, 3R) -3- ((tert-butyldimethylsilyl) oxy) -8- (4-cyano-6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) carbamate 27h (77mg, 153.47. Mu. Mol) was dissolved in 2mL of N, N-dimethylformamide, cooled to 0 ℃, N-bromosuccinimide (30.05mg, 168.81. Mu. Mol) was added, warmed to room temperature, and reacted overnight. After the reaction was completed, 20mL of water was added, and extraction was performed with ethyl acetate (30 mL), the aqueous layer was separated, the organic phase was washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl ((1r, 3r) -8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3- ((tert-butyldimethylsilyl) oxy) -8-azaspiro [4.5] dec-1-yl) carbamate 27i (87 mg), yield: 97.63%.

MS m/z(ESI):524.2[M-56+1]

The ninth step

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

Tert-butyl ((1R, 3R) -8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3- ((tert-butyldimethylsilyl) oxy) -8-azaspiro [4.5] decan-1-yl) carbamate 27i (87mg, 149.84. Mu. Mol), (2,3-dichlorophenyl) boronic acid 1e (57.18mg, 299.67. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (II) (12.55mg, 14.98. Mu. Mol, ruPhos-Pd-G3), 2-dicyclohexylphosphorus-2 ',6' -diisopropoxy-1,1 ' -biphenyl (13.98mg, 29.97. Mu. Mol, ruPhos) and potassium phosphate (95.46449.449) were dissolved in succession in dioxane 3951. Mu. Mol at 3936. Deg.3536. C in dioxane (3926. Multidot. Boiling). After completion of the reaction, it was cooled to room temperature, extracted with ethyl acetate (30 mL), the aqueous layer was separated, the organic phase was washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give tert-butyl ((1R, 3R) -3- ((tert-butyldimethylsilyl) oxy) -8- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyrimidin-2-yl) -8-azaspiro [4.5] decan-1-yl) carbamate 27j (70 mg) in yield: 72.24 percent.

MS m/z(ESI):646.3[M+1]

The tenth step

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

((1R, 3R) -3- ((tert-butyldimethylsilyl) oxy) -8- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyrimidin-2-yl) -8-azaspiro [4.5] dec-1-yl) carbamic acid tert-butyl ester 27j (70mg, 108.24. Mu. Mol) was dissolved in 2mL of methanol, cooled to 0 ℃, and a hydrochloric acid methanol solution (1.86mL, 2M/MeOH) was added, and after 1 hour of reaction at room temperature, concentration was performed under reduced pressure, 2mL of trifluoroacetic acid and 0.5mL of dichloromethane were added, and the reaction was continued at room temperature for 1 hour. After the reaction was completed, concentration was performed under reduced pressure to obtain 2- ((1r, 3r) -1-amino-3-hydroxy-8-azaspiro [4.5] decan-8-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 27k (40 mg), yield: 85.48 percent.

MS m/z(ESI):432.1[M+1]

The eleventh step

2- ((1R, 3R) -1-amino-3-hydroxy-8-azaspiro [4.5]]Dec-8-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 27k (40mg, 92.52. Mu. Mol) and 6M aqueous sodium hydroxide (0.3 mL) were dissolved in 2mL of ethanol, warmed to 80 ℃ and reacted for 0.5 hour. After completion of the reaction, concentration was carried out under reduced pressure, and the obtained residue was separated by preparative 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 obtain 2- ((1R, 3R) -1-amino-3-hydroxy-8-azaspiro [ 4.5)]Decan-8-yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 27 (7 mg), yield: 16.80 percent.

MS m/z(ESI):449.9[M+1]

¹ H NMR(400MHz,CD ₃ OD)δ7.50-7.48(m,1H),7.28(t,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),4.79-4.68(m,2H),4.32(s,1H),3.19-3.13(m,2H),2.87(s,1H),2.36-2.33(m,2H),2.06(s,3H),1.66(s,4H),1.32-1.29(d,J＝12.0Hz,4H).

Example 28 (comparative example 4)

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

First step of

(R) -N- ((S) -1'- (4-amino-6-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide

6-amino-2-chloropyrimidine-4-carbonitrile 28a (100mg, 647.01. Mu. Mol), (R) -N- ((S) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 20b (218.11mg, 711.71. Mu. Mol), N-dimethylacetamide (3 mL) and N, N-diisopropylethylamine (418.10mg, 3.24mmol, 563.47. Mu.L) were added to a 25mL single vial at room temperature, and the reaction was warmed to 90 ℃ for 3 hours, and LC-MS monitored for incomplete reaction and continued overnight at 90 ℃. After the reaction was completed, 20mL of water was added, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give (R) -N- ((S) -1'- (4-amino-6-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide 28b (274 mg), yield: 99.75 percent.

MS m/z(ESI):425.0[M+1]

Second step of

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

N-bromosuccinimide (149.32mg, 838.98. Mu. Mol) was added to a solution of (R) -N- ((S) -1'- (4-amino-6-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 28b (274mg, 645.37. Mu. Mol) in dichloromethane (6 mL) under ice-bath, warmed to room temperature, and reacted for 3 hours. After the reaction was completed, concentration was performed under reduced pressure to obtain (S) -6-amino-2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5-bromopyrimidine-4-carbonitrile 28c (257 mg), yield: 99.73%, which was used directly in the next step.

MS m/z(ESI):381.9[M+H-17]

The third step

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

(S) -6-amino-2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5-bromopyrimidine-4-carbonitrile 28c (257 mg, 643.65. Mu. Mol), di-tert-butyl dicarbonate (421.43mg, 1.93mmol, 443.61. Mu.L), methylene chloride (10 mL) and triethylamine (325.65mg, 3.22mmol, 446.10. Mu.L) were sequentially added to a 25mL single-necked flask and reacted at room temperature for 2 hours. After the reaction was completed, 20mL of water was added to the reaction solution, extraction was performed with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give tert-butyl (S) - (1 '- (4-amino-5-bromo-6-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 28d (150 mg), yield: 46.67 percent. .

MS m/z(ESI):499.2[M+1]

The fourth step

((1S) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) carbamic acid tert-butyl ester

Under the protection of argon, (S) - (1 '- (4-amino-5-bromo-6-cyanopyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamic acid tert-butyl ester 28d (150mg, 300.36. Mu. Mol), (2,3-dichlorophenyl) boronic acid 1e (143.29 mg, 750.90. Mu. Mol), 2-dicyclohexyl phosphorus-2 ',6' -diisopropoxy-1,1 '-biphenyl (28.03mg, 60.07. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2', 6 '-diisopropoxy-1,1' -biphenyl) (2-amino-1,1 '-biphenyl-2-yl) palladium (II) (25.15mg, 30.04. Mu. Mol), potassium phosphate (191.27mg, 901.08. Mu. Mol), 1,4' -dioxane-2-yl) palladium (II) (25.15, 30.04. Mu. Mol), argon gas (2 mL), argon gas (0.3 mL), and argon gas (0.130 min), followed by sealing and heating to react at a temperature of 1.130 ℃ for 4 hours. After completion of the reaction, 20mL of water was added to the reaction solution, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl ((1S) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 28e (150 mg), yield: 88.6 percent.

MS m/z(ESI):564.8[M+1]

The fifth step

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

Trifluoroacetic acid (1.54g, 13.51mmol, 1mL) was added to a solution of tert-butyl ((1S) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 28e (150mg, 265.26. Mu. Mol) in dichloromethane (4 mL) at room temperature for 1 hour at room temperature. After the reaction was completed, concentration was performed under reduced pressure to obtain 6-amino-2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile 28f (123 mg), yield: 99.64 percent.

MS m/z(ESI):464.9[M+1]

The sixth step

To 6-amino-2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]To a solution of (E) -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile 28f (123mg, 265.08. Mu. Mol) in ethanol (2 mL) was added 6M sodium hydroxide solution (0.3 mL) and the reaction was carried out at 80 ℃ for 40 minutes. The reaction was not completed as detected by LC-MS, and supplemented with sodium hydroxide solution (6M, 0.3 mL) and ethanol (2 mL) and the reaction was continued at 80 ℃ for 40 minutes. After completion of the reaction, concentration was performed under reduced pressure, and the obtained residue was separated by preparative 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 obtain 6-amino-2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide 28 (85 mg), yield: 66.4 percent.

MS m/z(ESI):482.9[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.56(d,J＝8.1Hz,1H),7.50(d,J＝7.5Hz,1H),7.41(d,J＝6.1Hz,2H),7.34(dd,J＝10.0,6.0Hz,2H),7.21(d,J＝7.6Hz,1H),4.67(d,J＝13.9Hz,1H),4.55(d,J＝14.2Hz,1H),4.41(s,1H),3.44-3.32(m,2H),3.20(s,2H),1.91-1.68(m,3H),1.61(d,J＝13.5Hz,1H).

Example 29

2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid

Mixing (S) - (1' - (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -1,3-dihydrospiro[ indene-2,4' -piperidine]20g (1.1 g, 1.95mmol) of t-butyl-1-yl carbamate and concentrated hydrochloric acid (6 mL) were added to a 25mL single-necked flask, the mixture was heated to 110 ℃ and refluxed for 1.5 hours, and concentrated under reduced pressure, and the resulting residue was separated by preparative liquid phase separation (column AKZONOBEL Kromasil;250 × 21.2mm i.d.;5 mu m,20mL/min; a mobile phase A:0.05% of TFA + H ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain 2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 29 (370 mg), yield: 34.44 percent.

MS m/z(ESI):483.1[M+1]

1H NMR(400MHz,DMSO-d ₆ )δ13.37(s,1H),8.27(s,2H),7.67(dd,J＝8.1,1.5Hz,1H),7.52(d,J＝7.3Hz,1H),7.47-7.29(m,4H),7.25(d,J＝7.6Hz,1H),4.60(dd,J＝26.0,13.5Hz,2H),4.41(d,J＝5.2Hz,1H),3.30-3.21(m,2H),3.18(s,1H),3.05(d,J＝16.2Hz,1H),2.07(s,3H),1.72(q,J＝12.4Hz,2H),1.54(d,J＝11.1Hz,2H).

Example 30

2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide

First step of

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

(S) -5- (((R) -tert-butylsulfinyl) amino) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidine ] -1' -carboxylic acid tert-butyl ester 30a (200mg, 490.71. Mu. Mol) was dissolved in 4mL of dichloromethane, and trifluoroacetic acid (1 mL) was added to react at room temperature for 40 minutes. The LC-MS detection reaction is complete. Concentration under reduced pressure afforded (R) -N- ((S) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide 30b (150.87 mg) which was used directly in the next step.

MS m/z(ESI):308.2[M+1]

Second and third steps

(S) -2- (5-amino-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidin ] -1' -yl) -6-methylpyrimidine-4-carbonitrile 30c

(S) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) carbamic acid tert-butyl ester 30d

(R) -N- ((S) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidine ] -5-yl) -2-methylpropane-2-sulfinamide 30b (150.87mg, 490.71. Mu. Mol), 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (75.36mg, 490.71. Mu. Mol), N-dimethylacetamide (4 mL) and N, N-diisopropylethylamine (317.10mg, 2.45mmol) were added in this order to a 15mL single-necked flask, and the mixture was raised to 90 ℃ for reaction at 6 hours. After the reaction, the reaction mixture was cooled to room temperature to obtain a reaction mixture containing (S) -2- (5-amino-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidine ] -1' -yl) -6-methylpyrimidine-4-carbonitrile 30c, and N, N-diisopropylethylamine (190.26mg, 1.47mmol) and di-tert-butyl dicarbonate (267.75mg, 1.23mmol) were directly added to the reaction mixture without further treatment, and the reaction was carried out at room temperature for 4 hours. The reaction was monitored by LC-MS for completion. To the reaction solution was added 20mL of water, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and 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) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) carbamate 30d (80 mg), yield: 38.77 percent.

MS m/z(ESI):421.2[M+1]

The fourth step

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

Tert-butyl (S) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) carbamate 30d (80mg, 190.25. Mu. Mol) was dissolved in 4mL of dichloromethane, N-bromosuccinimide (37.25mg, 209.27. Mu. Mol) was added, and the reaction was allowed to proceed overnight. LC-MS showed the reaction was complete. 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) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) carbamate 30e (60 mg), yield: 63.15 percent.

MS m/z(ESI):499.1[M+1]

The fifth step

((5S) -1'- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) carbamic acid tert-butyl ester

Tert-butyl (S) - (1 ' - (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 ' -piperidin ] -5-yl) carbamate 30e (60mg, 120.14. Mu. Mol), (2,3-dichlorophenyl) boronic acid 1e (68.78mg, 360.43. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (II) (10.06mg, 12.01. Mu. Mol, ruPhos-Pd-G3), 2-dicyclohexylphos-2 ',6' -diisopropoxy-1,1 ' -biphenyl (11.21mg, 24.03. Mu. Mol, ruPhos), microwave (76.43 mg, 43. Mol), potassium hexoxide-32360.360. Mu. Mol), argon (1.140 mL) and argon (1 mL) were added to the tube at room temperature for displacement reaction, and the temperature was increased to react at a temperature of 4. Mu. Mol. The reaction was monitored by LC-MS for completion. To the reaction solution was added 20mL of water, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl ((5S) -1'- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) carbamate 30f (60 mg), yield: 88.31%.

MS m/z(ESI):565.2[M+1]

The sixth step

2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile

Tert-butyl ((5S) -1'- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) carbamate 30f (60mg, 106.10. Mu. Mol) was dissolved in 4mL of dichloromethane at room temperature, and 1mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction was monitored by LC-MS for completion. Concentration under reduced pressure gave 30g (49.38 mg) of 2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidin ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile, which was used directly in the next step.

MS m/z(ESI):465.1[M+1]

Seventh step

2- ((S) -5-amino-5,7-dihydrospiro [ cyclopentyl [ b)]Pyridine-6,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 30g (49.38mg, 106.11. Mu. Mol), methanol (1.5 mL), saturated sodium hydroxide solution (1 mL), and hydrogen peroxide (0.5 mL) were added sequentially to a 15mL single-neck flask and stirred at room temperature for 40 minutes. The reaction was monitored by LC-MS for completion. Concentrating under reduced pressure, separating the obtained residue with preparative liquid phase (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 obtain 2- ((S) -5-amino-5,7-dihydrospiro [ cyclopentyl [ b ]]Pyridine-6,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 30 (4.16 mg), yield: 7.67 percent.

MS m/z(ESI):483.1[M+1]

1H NMR(400MHz,DMSO-d ₆ )δ8.62-8.51(m,1H),8.37(s,2H),8.00(s,1H),7.92(d,J＝7.7Hz,1H),7.60(dd,J＝8.1,1.5Hz,1H),7.43(s,1H),7.40-7.30(m,2H),7.20(d,J＝7.5Hz,1H),4.75(d,J＝12.4Hz,1H),4.67(s,1H),4.48(s,1H),3.25(q,J＝15.3,12.3Hz,3H),3.14(d,J＝16.8Hz,1H),2.03(s,3H),1.74(s,2H),1.56(t,J＝15.1Hz,2H).

Example 31

6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide

First step of

(R) -N- ((S) -5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide

Tert-butyl (S) -5- (((R) -tert-butylsulfinyl) amino) -5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4 '-piperidine ] -1' -carboxylate 31a (300mg, 736.07. Mu. Mol) was dissolved in 4mL of dichloromethane at room temperature, and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction was monitored by LC-MS for completion. Concentration under reduced pressure gave (R) -N- ((S) -5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide 31b (226 mg), yield: 99.86% of the crude product was used directly in the next reaction.

MS m/z(ESI):308.1[M+1]

Second step of

(R) -N- ((S) -1'- (4-amino-6-cyanopyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide

To a single neck flask was added (R) -N- ((S) -5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide 31b (150mg, 487.88. Mu. Mol), 1,2-dichloroethane (5 mL) and N, N-diisopropylethylamine (150.52mg, 1.16mmol), and after stirring for 1 minute, 6-amino-2-chloropyrimidine-4-carbonitrile 28a (60mg, 388.21. Mu. Mol) was added, and the temperature was raised to 66 ℃ for reaction for 3 hours. The LC-MS detection reaction is complete. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (R) -N- ((S) -1'- (4-amino-6-cyanopyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide 31c (130 mg), yield: 78.69%.

MS m/z(ESI):426.0[M+1]

The third step

6-amino-5-bromo-2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile

(R) -N- ((S) -1'- (4-amino-6-cyanopyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide 31c (130mg, 305.49. Mu. Mol) was dissolved in 2mL of dichloromethane, and N-bromosuccinimide (70.68mg, 397.13. Mu. Mol) was added under ice bath and warmed to room temperature for 3 hours. LC-MS monitored the reaction completion and concentrated under reduced pressure to give 6-amino-5-bromo-2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile 31d (110 mg), yield: 90.19% for direct use in the next step.

MS m/z(ESI):399.0[M+H]

The fourth step

6-amino-5- (2,3-dichlorophenyl) -2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4 '-piperidine ] -1' -yl) pyrimidine-4-carbonitrile

6-amino-5-bromo-2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4 ' -piperidin ] -1' -yl) pyrimidine-4-carbonitrile 31d (110mg, 275.52. Mu. Mol), (2,3-dichlorophenyl) boronic acid 1e (131.44mg, 688.80. Mu. Mol), 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1,1 ' -biphenyl (25.71mg, 55.10. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (II) (23.07mg, 27.55. Mu. Mol), potassium phosphate (175.45mg, 826.56. Mu. Mol), 1,4-dioxane (2 mL) and argon (3 mL) were sequentially added to the microwave tube, and the temperature was raised to replace the tube with water (3.130 mL) for 4 hours. The reaction was monitored by LC-MS for completion. To the reaction mixture was added water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give 6-amino-5- (2,3-dichlorophenyl) -2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile 31e (100 mg), yield: 78.00 percent.

MS m/z(ESI):465.0[M+1]

The fifth step

(R) -N- ((Z) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) spiro [ cyclopenta [ c ] pyridine-6,4' -piperidine ] -5 (7H) -alkylidene) -2-methylpropane-2-sulfinamide

6-amino-5- (2,3-dichlorophenyl) -2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4 '-piperidine ] -1' -yl) pyrimidine-4-carbonitrile 31e (160mg, 343.84. Mu. Mol), (R) -2-methylpropane-2-sulfinamide (104.18mg, 859.60. Mu. Mol), and tetraethyltitanate (2 mL) were dissolved in this order in 1mL tetrahydrofuran and reacted at 90 ℃ for 3 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (20 mL), the aqueous layer was separated, and the organic phase was washed with a saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R) -N- ((Z) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) spiro [ cyclopenta [ c ] pyridine-6,4' -piperidine ] -5 (7H) -alkylene) -2-methylpropane-2-sulfinamide 31f (195 mg), yield: 99.75 percent.

The sixth step

(R) -N- ((5S) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4' -piperidine ] -5-yl) -2-methylpropane-2-sulfinamide

(R) -N- ((Z) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) spiro [ cyclopenta [ c ] pyridine-6,4' -piperidine ] -5 (7H) -alkylene) -2-methylpropane-2-sulfinamide 31f (195mg, 343.00. Mu. Mol) was dissolved in 8mL of tetrahydrofuran, and 9-borabicyclo [3.3.1] nonane (1.37mL, 0.5M in THF) was added at room temperature, and reacted at room temperature for 2 hours. The reaction was monitored by LC-MS for completion. To the reaction solution was added 20mL of water, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (R) -N- ((5S) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4' -piperidine ] -5-yl) -2-methylpropane-2-sulfinamide 31g (90 mg) in yield: 45.99 percent.

MS m/z(ESI):570.2[M+1]

Step seven

6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile

(R) -N- ((5S) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4' -piperidine ] -5-yl) -2-methylpropane-2-sulfinamide 31g (90.16mg, 158.02. Mu. Mol) was dissolved in 4mL of dichloromethane at room temperature, and methanol hydrochloride solution (2mL, 4M) was added and reacted at room temperature for 2 hours. The LC-MS detection reaction is complete. Vacuum concentration to obtain 6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ c ] pyridine-6,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile 31h (70 mg) which was used directly in the next reaction.

MS m/z(ESI):466.1[M+1]

The eighth step

Reacting 6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ c)]Pyridine-6,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile 31h (70mg, 150.42. Mu. Mol) was dissolved in 2mL ethanol, and sodium hydroxide solution (0.3 mL, 6M) was added and reacted at 80 ℃ for 40 minutes. The LC-MS detection reaction is complete. Concentration under reduced pressure, the residue obtained was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain 6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopentyl [ c ]]Pyridine-6,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide 31 (25 mg), yield: 27.77 percent.

MS m/z(ESI):484.1[M+1]

1H NMR(400MHz,Methanol-d ₄ )δ8.81-8.69(m,2H),7.88(d,J＝5.5Hz,1H),7.56(dd,J＝8.1,1.5Hz,1H),7.34(t,J＝7.9Hz,1H),7.21(dd,J＝7.7,1.5Hz,1H),4.73(d,J＝6.7Hz,3H),3.49(d,J＝16.8Hz,1H),3.35(d,J＝2.6Hz,2H),3.27(d,J＝9.6Hz,1H),1.96(t,J＝11.0Hz,1H),1.78(dt,J＝19.7,8.4Hz,2H),1.61(d,J＝13.4Hz,1H).

Example 32

6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide

First step of

(R) -N- ((S) -1'- (4-amino-6-cyanopyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide

To a single vial was added (R) -N- ((S) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide 30b (226mg, 735.07. Mu. Mol), 1,2-dichloroethane (5 mL) and N, N-diisopropylethylamine (250.86mg, 1.94mmol), and after stirring for 1 minute, 6-amino-2-chloropyrimidine-4-carbonitrile 28a (100mg, 647.01. Mu. Mol) was added and the temperature was raised to 66 ℃ for reaction for 3 hours. The LC-MS detection reaction is complete. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (R) -N- ((S) -1'- (4-amino-6-cyanopyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ B ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide 32a (275 mg), yield: 99.88 percent.

MS m/z(ESI):425.9[M+1]

Second step of

6-amino-5-bromo-2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile

(R) -N- ((S) -1'- (4-amino-6-cyanopyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide 32a (275mg, 646.22. Mu. Mol) was dissolved in 5mL of dichloromethane, and N-bromosuccinimide (172.53mg, 969.34. Mu. Mol) was added under ice bath, and allowed to warm to room temperature for 2 hours. LC-MS monitored the reaction completion, water (10 mL) was added to the reaction solution, extracted with dichloromethane (10 mL × 2), and the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6-amino-5-bromo-2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile 32b (258 mg), yield: 99.74 percent.

MS m/z(ESI):399.1[M+H]

The third step

6-amino-5- (2,3-dichlorophenyl) -2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidine ] -1' -yl) pyrimidine-4-carbonitrile

6-amino-5-bromo-2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 ' -piperidin ] -1' -yl) pyrimidine-4-carbonitrile 32b (250mg, 626.18. Mu. Mol), (2,3-dichlorophenyl) boronic acid 1e (298.72mg, 1.57mmol), 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1,1 ' -biphenyl (58.44mg, 125.24. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (II) (52.43mg, 62.62. Mu. Mol), potassium phosphate (398.75mg, 1.88mmol), 1,4-dioxane (2 mL) and water (0.3 mL) were added to the microwave tube in this order, and the tube was purged with argon gas for 4 hours, followed by heating to 130 hours. The reaction was monitored by LC-MS for completion. To the reaction mixture was added water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give 6-amino-5- (2,3-dichlorophenyl) -2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile 32c (120 mg), yield: 41.18%.

MS m/z(ESI):465.2[M+1]

The fourth step

(R) -N- ((Z) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) spiro [ cyclopenta [ b ] pyridine-6,4' -piperidine ] -5 (7H) -alkylidene) -2-methylpropane-2-sulfinamide

6-amino-5- (2,3-dichlorophenyl) -2- (5-oxo-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidine ] -1' -yl) pyrimidine-4-carbonitrile 32c (120mg, 257.88. Mu. Mol), (R) -2-methylpropane-2-sulfinamide (78.14mg, 644.70. Mu. Mol), and tetraethyltitanate (2 mL) were dissolved in this order in 1mL tetrahydrofuran and reacted at 90 ℃ for 3 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (20 mL), the aqueous layer was separated, and the organic phase was successively washed with a saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R) -N- ((Z) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) spiro [ cyclopenta [ b ] pyridine-6,4' -piperidine ] -5 (7H) -alkylene) -2-methylpropane-2-sulfinamide 32d (146 mg), yield: 99.58 percent.

MS m/z(ESI):568.2[M+1]

The fifth step

(R) -N- ((5S) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidine ] -5-yl) -2-methylpropane-2-sulfinamide

(R) -N- ((Z) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) spiro [ cyclopenta [ b ] pyridine-6,4' -piperidine ] -5 (7H) -alkylidene) -2-methylpropane-2-sulfinamide 32d (146mg, 256.81. Mu. Mol) was dissolved in 4mL tetrahydrofuran at room temperature, 9-borabicyclo [3.3.1] nonane (0.5M in THF, 1.03mL) was added and the reaction was allowed to react for 2 hours at room temperature and LC-MS monitored for completion. To the reaction solution was added 20mL of water, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (R) -N- ((5S) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ B ] pyridine-6,4' -piperidine ] -5-yl) -2-methylpropane-2-sulfinamide 32e (100 mg), yield: 68.25 percent.

MS m/z(ESI):570.2[M+1]

The sixth step

6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile

(R) -N- ((5S) -1'- (4-amino-6-cyano-5- (2,3-dichlorophenyl) pyrimidin-2-yl) -5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4' -piperidine ] -5-yl) -2-methylpropane-2-sulfinamide 32e (100mg, 175.27. Mu. Mol) was dissolved in 4mL of dichloromethane at room temperature, and methanol hydrochloride solution (2mL, 4M) was added thereto and reacted at room temperature for 2 hours. LC-MS detection showed the reaction was complete. Concentration under reduced pressure gave 6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidin ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile 32f (81 mg) which was used directly in the next reaction.

MS m/z(ESI):466.1[M+1]

Seventh step

Reacting 6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carbonitrile 32f (49mg, 105.07. Mu. Mol) was dissolved in 3mL ethanol, and sodium hydroxide solution (0.3 mL, 6M) was added and reacted at 80 ℃ for 40 minutes. LC-MS detection showed the reaction was complete. Concentration under reduced pressure and separation of the resulting residue by preparative 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 obtain 6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopentyl [ b ]]Pyridine-6,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide 32 (20 mg), yield: 39.30 percent.

MS m/z(ESI):483.9[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.31(d,J＝5.0Hz,1H),7.74(s,1H),7.65(d,J＝7.5Hz,1H),7.51(dd,J＝8.1,1.5Hz,1H),7.29(t,J＝7.8Hz,1H),7.23-7.08(m,3H),6.12(s,2H),4.56(t,J＝13.3Hz,2H),3.88(s,1H),3.10(dd,J＝15.2,4.8Hz,3H),2.74(d,J＝16.3Hz,1H),1.80-1.70(m,2H),1.63(dd,J＝13.3,9.6Hz,1H),1.49(d,J＝13.4Hz,2H),1.06(dd,J＝15.6,9.8Hz,1H).

Example 35

6- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -3- (2,3-dichlorophenyl) -2-methylisonicotinic acid

First step of

(R) -N- ((S) -1'- (4-cyano-6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide

(R) -N- ((S) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide 20b (309mg, 1.01mmol), 2-chloro-6-methylisonicotinamide 5a (153.84mg, 1.01mmol), potassium carbonate (696.72mg, 5.04mmol) and N-methylpyrrolidone (8 mL) were added to a 25mL microwave tube, sealed, brought to 130 ℃ and reacted for 5 hours. After the reaction was completed, 20mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain (R) -N- ((S) -1'- (4-cyano-6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide 35a (160 mg), yield: 37.55 percent.

MS m/z(ESI):423.2[M+1]

Second step of

(S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -6-methylisonicotrione

(R) -N- ((S) -1'- (4-cyano-6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 35a (160mg, 378.62. Mu. Mol) was dissolved in 3mL of methanol, concentrated hydrochloric acid (0.5 mL) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure to give (S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) -6-methylisonicotonitrile 35b (120.56 mg) which was used as it was in the next step.

MS m/z(ESI):319.2[M+1]

The third step

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

(S) -2- (1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) -6-methylisonicotonitrile 35b (120.56mg, 378.63. Mu. Mol), methylene chloride (5 mL), triethylamine (191.49mg, 1.89mmol) and di-tert-butyl dicarbonate (247.91mg, 1.14mmol) were successively charged into a 15mL single-necked flask and reacted at room temperature for 4 hours. The reaction was monitored by LC-MS for completion. To the reaction solution was added 20mL of water, extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl (S) - (1 '- (4-cyano-6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 35c (100 mg), yield: 63.10 percent.

MS m/z(ESI):419.2[M+1]

The fourth step

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

Tert-butyl (S) - (1 '- (4-cyano-6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 35c (100mg, 238.93. Mu. Mol) was dissolved in dichloromethane (5 mL), N-bromosuccinimide (42.53mg, 238.93. Mu. Mol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LC-MS for completion. To the reaction solution was added 20mL of water, extraction was performed with dichloromethane (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl (S) - (1 '- (5-bromo-4-cyano-6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 35d (115 mg), yield: 96.76%.

MS m/z(ESI):497.1[M+1]

The fifth step

((1S) -1'- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) carbamic acid tert-butyl ester

Tert-butyl (S) - (1 ' - (5-bromo-4-cyano-6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4 ' -piperidin ] -1-yl) carbamate 35d (115mg, 231.19. Mu. Mol), (2,3-dichlorophenyl) boronic acid 1e (88.23mg, 462.38. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (II) (19.36mg, 23.12. Mu. Mol), 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1,1 ' -biphenyl (21.58mg, 46.24. Mu. Mol), potassium phosphate (147.29mg, 693.57. Mu. Mol), 1,4-dioxane (2.5. Mu. Mol) and argon (0.5 mL) were added to a microwave tube and the reaction was sealed for 1 hour, and the reaction was carried out at 130 mL. After the reaction was completed, 20mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl ((1S) -1'- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 35e (130 mg), yield: 99.79 percent.

MS m/z(ESI):563.2[M+1]

The sixth step

((1S) -1'- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine)]Tert-butyl-1-yl) carbamate 35e (60mg, 106.47. Mu. Mol) and concentrated hydrochloric acid (1.5 mL) were added to a 10mL microwave tube and the reaction was allowed to warm to 130 ℃ for 3 hours. Concentration under reduced pressure, the residue obtained was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain 6- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -3- (2,3-dichlorophenyl) -2-methylisonicotinic acid 35 (10.55 mg), yield: 18 percent.

MS m/z(ESI):482.1[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ13.04(s,1H),8.25(s,2H),7.62(dd,J＝8.1,1.4Hz,1H),7.52(d,J＝7.3Hz,1H),7.46-7.27(m,4H),7.23-7.15(m,1H),7.05(s,1H),4.37(dd,J＝16.4,9.7Hz,2H),4.24(d,J＝13.5Hz,1H),3.23-3.10(m,3H),3.05(d,J＝16.2Hz,1H),2.04(s,3H),1.74(t,J＝12.6Hz,2H),1.53(dd,J＝23.5,13.1Hz,2H).

Example 36

6- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -3- (2,3-dichlorophenyl) -2-methylisonicotinamide

First step of

6- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -3- (2,3-dichlorophenyl) -2-methylisonicotonitrile

Tert-butyl ((1S) -1'- (4-cyano-5- (2,3-dichlorophenyl) -6-methylpyridin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 35e (33mg, 58.56. Mu. Mol) was dissolved in dichloromethane (2 mL), triethylamine (0.5 mL) was added, and the reaction was carried out at room temperature for 40 minutes. Concentration under reduced pressure gave 6- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) -3- (2,3-dichlorophenyl) -2-methylisonicotonitrile 36a (27.14 mg) which was used directly in the next step.

MS m/z(ESI):463.1[M+1]

Second step of

At room temperature, the 6- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -3- (2,3-dichlorophenyl) -2-methylisonicotonitrile 36a (27.14mg, 58.57. Mu. Mol), methanol (1.5 mL), saturated sodium hydroxide solution (1 mL) and hydrogen peroxide (0.5 mL) were sequentially added to a 15mL single-neck flask and reacted at room temperature for 2 hours. LC-MS showed the reaction was complete. Concentration under reduced pressure and separation of the resulting residue by preparative 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 obtain 6- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -3- (2,3-dichlorophenyl) -2-methylisonicotinamide 36 (11.02 mg), yield: 31.28 percent.

MS m/z(ESI):481.1[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.24(s,2H),7.67(s,1H),7.59(d,J＝8.1Hz,1H),7.52(d,J＝7.4Hz,1H),7.45-7.31(m,4H),7.28(s,1H),7.20(d,J＝7.5Hz,1H),6.79(s,1H),4.48-4.30(m,2H),4.29-4.17(m,1H),3.16(q,J＝14.9,13.2Hz,3H),3.04(d,J＝16.3Hz,1H),2.03(s,3H),1.79-1.68(m,2H),1.54(dd,J＝28.7,13.3Hz,2H).

Examples 37 and 38

(S) -6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide 37

(R) -6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ] pyridine-6,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide 38

6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide 32 (960mg, 1.99mmol) was purified by SFC chiral resolution (column type no: chiralPak IC,250 × 30mm I.D.,10 μm; mobile phase: a for CO ₂ and B for Ethanol(0.1％NH ₃ H ₂ O); column pressure: 100bar; flow rate: 80mL/min; detection wavelength: 220nm; column temperature: purification at 38 ℃ to give (S) -6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ] b)]Pyridine-6,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide 37 (retention time (T) _R ): 4.037min;360 mg) and (R) -6-amino-2- ((S) -5-amino-5,7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) pyrimidine-4-carboxamide 38 (Retention time (T) _R )：6.957min；564mg)。

37 MS m/z(ESI):483.9[M+1]

¹ H NMR(400MHz,CD ₃ OD)δ8.34(d,J＝5.2Hz,1H),7.83(d,J＝7.6Hz,1H),7.49(dd,J＝8.1,1.5Hz,1H),7.35–7.23(m,2H),7.14(dd,J＝7.6,1.5Hz,1H),4.67(d,J＝14.3Hz,3H),4.02(s,1H),3.28–3.17(m,3H),2.92(d,J＝16.5Hz,1H),1.82(dtd,J＝31.3,12.6,4.4Hz,2H),1.64–1.51(m,1H),1.42–1.33(m,1H).

38 MS m/z(ESI):483.9[M+1]

¹ H NMR(400MHz,CD ₃ OD)δ8.55(d,J＝5.0Hz,1H),8.00(d,J＝7.7Hz,1H),7.50(dd,J＝8.1,1.4Hz,1H),7.44–7.26(m,2H),7.15(dd,J＝7.6,1.5Hz,1H),4.73(ddt,J＝37.2,14.3,4.2Hz,2H),4.52(s,1H),3.36–3.31(m,1H),3.26(ddd,J＝13.7,9.7,7.3Hz,3H),1.83(dtd,J＝26.0,12.4,4.4Hz,2H),1.75–1.67(m,1H),1.66–1.56(m,1H).

Examples 39 and 40

(R) -2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 39

(S) -2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 40

First step of

2- ((S) -1- ((tert-butoxycarbonyl) amino) -1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid

2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 29 (350mg, 724.05. Mu. Mol) was dissolved in 10mL of dichloromethane, triethylamine (366.34mg, 3.62mmol) and di-tert-butyl dicarbonate (474.08mg, 2.17mmol) were added in this order, and the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to give 2- ((S) -1- ((tert-butoxycarbonyl) amino) -1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 39a (422.49 mg).

MS m/z(ESI):583.2[M+1]

Second step of

(R) -2- ((S) -1- ((tert-butoxycarbonyl) amino) -1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 39b

(S) -2- ((S) -1- ((tert-butoxycarbonyl) amino) -1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 39c

2- ((S) -1- ((tert-butoxycarbonyl) amino) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 39a (422.49mg, 724.06 μmol) was resolved by SFC chirality (column No.: chiralPak IC,250 × 30mm I.D.,10 μm; mobile phase: a for CO ₂ and B for Methanol(0.1％NH ₃ H ₂ O); the proportion is as follows: b, 40 percent; column pressure: 100bar; flow rate: 60mL/min; detection wavelength: 220nm; column temperature: after purification at 38 ℃ C., (R) -2- ((S) -1- ((tert-butoxycarbonyl) ammonia was obtainedYl) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 39b (retention time (T) _R ): 1.578min;147 mg) and (S) -2- ((S) -1- ((tert-butoxycarbonyl) amino) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 39c (retention time (T) _R )：2.389min；107mg)。

39b MS m/z(ESI):583.2[M+1]

39c MS m/z(ESI):583.2[M+1]

The third step

(R) -2- ((S) -1- ((tert-butoxycarbonyl) amino) -1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 39b (140mg, 239.93. Mu. Mol) was dissolved in 5mL dioxane, 4M 1,4-dioxane solution of hydrogen chloride (43.74mg, 1.20mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained solid was dissolved in n-hexane, slurried and concentrated to dryness to give (R) -2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 39 (105 mg), yield: 84.18%.

MS m/z(ESI):483.1[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.75-8.36(m,3H),7.67(d,J＝8.0Hz,1H),7.62(d,J＝7.4Hz,1H),7.46-7.29(m,4H),7.26(d,J＝7.4Hz,1H),4.60(dd,J＝29.3,13.4Hz,2H),4.37(d,J＝5.4Hz,1H),3.31-3.15(m,3H),3.07-3.03(m,1H),2.07(s,3H),1.87-1.66(m,2H),1.55(t,J＝15.2Hz,2H).

The fourth step

(S) -2- ((S) -1- ((tert-butoxycarbonyl) amino) -1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 39c (105mg, 179.95. Mu. Mol) was dissolved in 5mL dioxane, 4M 1,4-dioxane solution of hydrogen chloride (32.80mg, 899.74. Mu. Mol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained solid was dissolved in n-hexane, slurried and concentrated to dryness to give (S) -2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) -5- (2,3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 40 (68 mg), yield: 72.69 percent.

MS m/z(ESI):483.1[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.52(s,3H),7.67(dd,J＝8.1,1.5Hz,1H),7.61(d,J＝7.4Hz,1H),7.42(t,J＝7.9Hz,1H),7.36(d,J＝6.0Hz,2H),7.30-7.20(m,2H),4.61(dd,J＝28.3,13.5 Hz,2H),4.37(d,J＝5.4Hz,1H),3.22(d,J＝15.6Hz,3H),3.03(d,J＝16.2Hz,1H),2.07(s,3H),1.75(dd,J＝12.3,4.1Hz,2H),1.55(t,J＝14.7Hz,2H).

Example 41

2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (3-chloro-2-fluoropyridin-4-yl) -6-methylpyrimidine-4-carboxamide

First step of

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

Tert-butyl (S) - (1 '- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 20f (300mg, 601.91 μmol), (3-chloro-2-fluoropyridin-4-yl) boronic acid 41a (158.32mg, 902.86 μmol), methanesulfonic acid (2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl) (2 '-methylamino-1,1' -biphenyl-2-yl) palladium (102.37mg, 120.38 μmol), and potassium phosphate (510.42mg, 2.41mmol) were added sequentially to a 3.6mL mixed solution (1,4-dioxane: water = 3835 zxft), argon was replaced three times, reflux was continued with a condenser tube for 1 hour at 100 ℃, cooled to room temperature, concentrated under reduced pressure to give a residual chromatography column (3524 mg) containing tert-butyl (3524-dihydropyrimidine-2-yl) -2-piperidine-1-yl) to obtain a purified (3524 zxft-cyano-piperidine system ((3534-cyano-piperidine) eluent: 1-cyano-2-yl) -1-piperidine-1-cyano-34-piperidine-cyano-6-hydroxy-pyridine-1-pyridine-carboxylic acid (1-2-base): 42.36 percent.

MS m/z(ESI):549.2[M+1]

Second step of

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

Potassium carbonate (7.54mg, 54.64 μmol) and tert-butyl ((S) -1'- (5- (3-chloro-2-fluoropyridin-4-yl) -4-cyano-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 41b (15mg, 27.32 μmol) were added to 1mL of dimethyl sulfoxide, 0.25mL of 30% hydrogen peroxide was slowly added dropwise to the reaction solution under ice bath, and after completion of the reaction, water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL × 3), combination of the organic phases, and concentration were carried out to obtain ((S) -1'- (5- (3-chloro-2-fluoropyridin-4-yl) -4-carbamoyl-6-methylpyrimidin-2-yl) -3532 zft 3532-dihydrospiro [ indene-25 z3425' -piperidin-1-yl) carbamate (15 mg: 96.82%, without purification, the reaction was carried out directly in the next step.

MS m/z(ESI):567.2[M+1]

The third step

((S) -1'- (5- (3-chloro-2-fluoropyridin-4-yl) -4-carbamoyl-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine)]-1-yl) carbamic acid tert-butyl ester 41c (15mg, 26.45. Mu. Mol) and 0.5mL of trifluoroacetic acid were added to 2mL of dichloromethane, stirred at room temperature for 2 hours, and after completion of the reaction, concentrated under reduced pressure, and the obtained residue was subjected to liquid phase separation (separation column AKZONOBEL Kromasil;250 × 21.2mm i.d.;5 mu m,20mL/min; mobile phase A:0.05% of TFA + H ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain a product 2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (3-chloro-2-fluoropyridin-4-yl) -6-methylpyrimidine-4-carboxamide 41 (5 mg) yield: 31.88 percent.

MS m/z(ESI):467.2[M+1]

Example 42

2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (3-chloro-2-aminopyridin-4-yl) -6-methylpyrimidine-4-carboxamide

First step of

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

Tert-butyl ((S) -1' - (5- (3-chloro-2-fluoropyridin-4-yl) -4-cyano-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4 ' -piperidin ] -1-yl) carbamate 41b (80mg, 145.71 μmol) and 8mL of 28% ammonia monohydrate were added to 3mL of dimethyl sulfoxide, sealed, heated to 115 ℃, reacted for 4.5 hours, cooled to room temperature, concentrated under reduced pressure, adjusted to pH =7-8 with dilute hydrochloric acid, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give ((S) -1' - (5- (3-chloro-2-aminopyridin-4-yl) -4-cyano-6-methylpyrimidin-2-yl) -3532 zxft [ indene-3425 zft ] piperidine-1-yl) carbamate (yield: 10 mg: 12.17 percent.

MS m/z(ESI):546.3[M+1]

Second step of

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

Tert-butyl ((S) -1'- (5- (3-chloro-2-aminopyridin-4-yl) -4-cyano-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 42a (12mg, 26.73 μmol) and 0.5mL of 6N sodium hydroxide solution were added to 2mL of ethanol, heated to 80 ℃, reacted for 1 hour, and after completion of the reaction, directly concentrated under reduced pressure to give tert-butyl ((S) -1'- (5- (3-chloro-2-aminopyridin-4-yl) -4-carbamoyl-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) carbamate 42b (10 mg), yield: 66.33% and was carried on to the next step without purification.

MS m/z(ESI):564.2[M+1]

The third step

(S) -1'- (5- (3-chloro-2-aminopyridin-4-yl) -4-carbamoyl-6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine]T-butyl-1-yl) carbamate 42b (10mg, 17.73. Mu. Mol) and 0.6mL of trifluoroacetic acid were added to 2mL of dichloromethane, stirred at room temperature for 1 hour, and after the reaction was completed, concentrated under reduced pressure, and the obtained residue was subjected to liquid phase separation (column AKZONOBEL Kromasil;250 × 21.2mm i.d.;5 mu m,20mL/min; a mobile phase A:0.05% of TFA + H ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain the product 2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (3-chloro-2-aminopyridin-4-yl) -6-methylpyrimidine-4-carboxamide 42 (3 mg) yield: 34.65 percent.

MS m/z(ESI):464.1[M+1]

Example 43

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

First step of

5- (3-chloro-2-methoxypyridin-4-yl) -6-methyl-2- (1-oxo-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile

5-bromo-6-methyl-2- (1-oxo-1,3-dihydrospiro [ indene-2,4 ' -piperidine ] -1' -yl) pyrimidine-4-carbonitrile 43a (200mg, 503.44 μmol), (3-chloro-2-methoxypyridin-4-yl) boronic acid 43b (141.51mg, 755.16 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (42.16mg, 50.34 μmol), 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1,1 ' -biphenyl (46.92mg, 100.69 μmol), and potassium phosphate (320.19mg, 1.51mmol) were sequentially added to a 1.2mL mixed solution (3862 zxft-silica-2-dioxane-2- (4232: 4232 μmol), and the residue was purified by a cold-silica gel chromatography (4264-4232-column chromatography) to obtain a solution: 82 percent.

MS m/z(ESI):460.2[M+1]

Second step of

5- (3-chloro-2-hydroxypyridin-4-yl) -6-methyl-2- (1-oxo-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile

5- (3-chloro-2-methoxypyridin-4-yl) -6-methyl-2- (1-oxo-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile 43c (200mg, 434.85. Mu. Mol) and 3mL of 4M dioxane hydrochloride solution were added to 1mL of dichloromethane, heated to 100 ℃ under sealed conditions, reacted for 2 hours, followed by addition of a little methanolic ammonia solution for neutralization and concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give 5- (3-chloro-2-hydroxypyridin-4-yl) -6-methyl-2- (1-oxo-1,3-dihydrospiro [ indene-2,4 '-piperidin ] -1' -yl) pyrimidine-4-carbonitrile 43d (140 mg) in yield: 72.20%.

MS m/z(ESI):446.1[M+1]

The third step

5- (2,3-dichloropyridin-4-yl) -6-methyl-2- (1-oxo-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) pyrimidine-4-carbonitrile

5- (3-chloro-2-hydroxypyridin-4-yl) -6-methyl-2- (1-oxo-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) pyrimidine-4-carbonitrile 43d (140mg, 313.97. Mu. Mol) was added to 3mL of phosphorus oxychloride, heated to 90 ℃ for 3 hours, cooled to room temperature, poured into ice water, stirred for 0.5 hour, extracted with ethyl acetate (20 mL. Times.3), the organic phases combined, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give 5- (2,3-dichloropyridin-4-yl) -6-methyl-2- (1-oxo-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) pyrimidine-4-carbonitrile (90 mg): 61.73 percent.

MS m/z(ESI):464.0[M+1]

The fourth step

(R) -N- ((Z) -1'- (4-cyano-5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidin-2-yl) spiro [ indene-2,4' -piperidine ] -1 (3H) -alkylidene) -2-methylpropane-2-sulfinamide

5- (2,3-dichloropyridin-4-yl) -6-methyl-2- (1-oxo-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) pyrimidine-4-carbonitrile 43e (90mg, 193.82. Mu. Mol) and (R) -2-methylpropane-2-sulfinamide (70.47mg, 581.46. Mu. Mol) were added to 1mL of tetraethyl titanate, heated to 100 ℃ and reacted for 5 hours. After cooling to room temperature, 10mL of water and 10mL of ethyl acetate were added, the insoluble solids were removed by filtration, the organic phase was separated from the filtrate, dried, filtered, concentrated under reduced pressure, and prepared by thin layer chromatography to give (R) -N- ((Z) -1'- (4-cyano-5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidin-2-yl) spiro [ indene-2,4' -piperidine ] -1 (3H) -alkylene) -2-methylpropane-2-sulfinamide 43f (20 mg), yield: 18.18 percent.

MS m/z(ESI):567.2[M+1]

The fifth step

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

(R) -N- ((Z) -1'- (4-cyano-5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidin-2-yl) spiro [ indene-2,4' -piperidine ] -1 (3H) -alkylidene) -2-methylpropane-2-sulfinamide 43f (100mg, 176.20. Mu. Mol) was added to 2mL tetrahydrofuran, and 9-borabicyclo (3,3,1) -nonane (0.5M, 704.81. Mu.L) was added under ice bath and allowed to warm to room temperature for 2 hours. Quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (R) -N- ((S) -1'- (4-cyano-5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 43g (80 mg), yield: 79.72%, without purification, were directly subjected to the next reaction.

MS m/z(ESI):568.8[M+1]

The sixth step

2- ((S) -1- (((R) -tert-butylsulfinyl) amino) -1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidine-4-carboxamide

Adding (R) -N- ((S) -1'- (4-cyano-5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidin-2-yl) -1,3-dihydrospiro [ indene-2,4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide 43g (80mg, 140.46. Mu. Mol) and 0.5mL of 6N sodium hydroxide solution into 2mL of ethanol, heating to 80 ℃, reacting for 0.5 hour, adjusting pH to 7-8 with 1N diluted hydrochloric acid after the reaction is finished, concentrating under reduced pressure, extracting an aqueous phase with ethyl acetate (10 mL. Times.3), combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 2- ((S) -1- (((R) -tert-butylsulfinyl) amino) -1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -yl) -5- (3926 zxft) -pyridine-4-yl) -5- (3926 zxft) pyridine-6-4-methyl formamide yield of 50 mg: 60.58% and was carried on to the next step without purification.

MS m/z(ESI):586.8[M+1]

Step seven

2- ((S) -1- (((R) -tert-butylsulfinyl) amino) -1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidine-4-carboxamide 43h (50mg, 85.10 μmol) was added to 4mL of dichloromethane, 0.4mL of 4M dioxane hydrochloride solution was added at room temperature, stirring was performed for 0.5 hour, after the reaction was completed, concentration was performed under reduced pressure, and the obtained residue was subjected to liquid phase separation (column akzo nobel Kromasil;250 × 21.2mm i.d.;5 mu m,20mL/min; mobile phase A:0.05% of TFA + H ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain a product 2- ((S) -1-amino-1,3-dihydrospiro [ indene-2,4' -piperidine]-1' -yl) -5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidine-4-carboxamide 43 (11 mg), yield: 24.52 percent.

MS m/z(ESI):482.9[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ8.28(d,J＝4.9Hz,1H),7.47(d,J＝7.3Hz,1H),7.33(dd,J＝19.9,4.4Hz,3H),7.23(dd,J＝4.9,1.9Hz,1H),4.68-4.85(m,3H),3.38(d,J＝8.6Hz,2H),3.13(s,1H),2.10(s,3H),1.79(tt,J＝11.8,6.4Hz,2H),1.64(t,J＝12.8Hz,3H).

Example 44

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

First step of

((3S, 4S) -8- (5- (3-chloro-2-hydroxypyridin-4-yl) -4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-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 (90mg, 192.98 μmol), (3-chloro-2-fluoropyridin-4-yl) boronic acid 41a (135.36mg, 771.92 μmol), methanesulfonic acid (2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl) (2 '-methylamino-1,1' -biphenyl-2-yl) palladium (32.82mg, 38.60 μmol) and potassium phosphate (163.65mg, 771.92 μmol) were added in this order to a 2.2mL mixed solution (1,4-dioxane: water = 10), argon was replaced three times, refluxed with a condenser, stirred continuously at 100 ℃ for 1.5 hours, cooled to a residue, concentrated under reduced pressure to give a silica gel column (eluent: 3.4-azaspiro [ 3-4-yl) -3-methyl-4-yl) and purified ((3s, 5-azaspiro [ 4-yl) -8-azaspiro [ 3-methyl-4-yl) pyridine-yl) as a: 30.19 percent.

MS m/z(ESI):459.0[M+1-56]

Second step of

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

Tert-butyl ((3S, 4S) -8- (5- (3-chloro-2-hydroxypyridin-4-yl) -4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate 44a (30mg, 58.25. Mu. Mol) and 0.05mL of N, N-diisopropylethylamine were added to 1mL of phosphorus oxychloride, heated to 100 ℃ and stirred for 8 hours. After the reaction was completed, cooled to room temperature, the reaction solution was poured into crushed ice, stirred for 0.5 hour, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] dec-8-yl) -5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidine-4-carbonitrile 44b (20 mg), yield: 79.23%, and the next reaction was carried out without purification.

MS m/z(ESI):433.1[M+1]

The third step

2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Dec-8-yl) -5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidine-4-carbonitrile 44b (20mg, 46.15. Mu. Mol) and 0.5mL of a 5M sodium hydroxide solution were added to 0.5mL of methanol, and 0.25mL of 30% hydrogen peroxide was further added under low temperature conditions, followed by stirring for 1 hour in ice bath. After the reaction was completed, a small amount of trifluoroacetic acid was added to adjust the pH to 7-8, and the mixture was concentrated under reduced pressure to obtain a residue, which was subjected to liquid phase separation (column: AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain the product 2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -5- (2,3-dichloropyridin-4-yl) -6-methylpyrimidine-4-carboxamide 44 (11 mg), yield: 33.72 percent.

MS m/z(ESI):450.9[M+1]

Example 45

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

First step of

((3S, 4S) -8- (5- (3-chloro-2-fluoropyridin-4-yl) -4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-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 (120mg, 257.31 μmol), (3-chloro-2-fluoropyridin-4-yl) boronic acid 41a (112.80mg, 643.26 μmol), methanesulfonic acid (2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl) (2 '-methylamino-1,1' -biphenyl-2-yl) palladium (43.76mg, 51.46 μmol) and potassium phosphate (272.74mg, 1.29mmol) were added in this order to a 4.4mL mixed solution (1,4-dioxane: water = 10), argon gas was replaced three times, reflux was performed with a condenser, stirring was continued for 1 hour at 100 ℃, cooled to room temperature, concentrated, the resulting residue was purified by silica gel column chromatography (3242: silica gel column, eluent) to obtain tert-butyl ((3s) -3-methyl-2-oxaspiro [ 4-yl) -8-azaspiro [ 3.5-methyl-4-yl ] -2-azaspiro [ 3-oxapyridine-4-yl) (3.5-chloro-4-yl): 56.38%.

MS m/z(ESI):517.3[M+1]

Second step of

(3S, 4S) -8- (5- (3-chloro-2-fluoropyridin-4-yl) -4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decyl-4-yl) carbamic acid tert-butyl ester 45a (70mg, 135.40. Mu. Mol) was added to 1mL of a 48% hydrobromic acid solution in acetic acid, the mixture was heated to 90 ℃ under sealed conditions, reacted for 1 hour, cooled to room temperature after completion of the reaction, concentrated under reduced pressure, neutralized with saturated sodium bicarbonate, extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was subjected to liquid phase separation (column ZOAKNOBEL Kromasil;250 × 21.2mm i.d.;5 mu m,20mL/min; mobile phase A:0.05% of TFA + H ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain the product 2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Dec-8-yl) -5- (2-bromo-3-chloropyridin-4-yl) -6-methylpyrimidine-4-carboxamide 45 (12 mg), yield: 10.90 percent.

MS m/z(ESI):495.0[M+1]

Example 46

2- ((S) -3 '-amino-3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 "-piperidine ] -1" -yl) -5- (2,3- (dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid

First step of

1-methylene-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -carboxylic acid tert-butyl ester

1-oxo-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -carboxylic acid tert-butyl ester 46a (4g, 13.27mmol) and methyltriphenylphosphonium bromide (11.85g, 33.18mmol) were added to 150mL of tetrahydrofuran, the temperature was controlled at 0 ℃, potassium tert-butoxide (4.46g, 39.82mmol) was added thereto, the mixture was further raised to 30 ℃, the mixture was stirred for 4 hours, after the completion of the reaction, the mixture was concentrated under reduced pressure, 1N diluted hydrochloric acid was added to adjust the pH to 8, the mixture was extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give 1-methylene-1,3-dihydrospiro [ indene-2,4 '-piperidine ] -1' -carboxylic acid tert-butyl ester 46b (3.8 g) in a yield: 95.63 percent.

Second step of

3'H-dispiro [ cyclopropane-1,1' -indene-2 ', 4' -piperidine ]

A mixture of diethyl zinc solution (2.31g, 18.70mmol) and dichloromethane (150 mL) was cooled to 0 ℃, then trifluoroacetic acid (2.13g, 18.70mmol, 1.39ml) was dissolved in 20mL dichloromethane and added to the reaction, after 15 minutes, diiodomethane (4.99g, 18.70mmol, 1.50ml) was added, stirring was continued at 0 ℃ for another 15 minutes, 1-methylene-1,3-dihydrospiro [ indene-2,4 ' -piperidine ] -1' -carboxylic acid tert-butyl ester 46b (1.4 g, 4.68mmol) was dissolved in dichloromethane (5 mL), kept at 0 ℃ and added to the above mixture, stirring was continued overnight at room temperature after addition, after completion of the reaction, saturated ammonium chloride solution was added and extracted with dichloromethane (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 3532-bis-spiro [ cyclopropane-25 ' -25 zxft-piperidine ] -46 mg, yield was quenched (46 ″ -550 mg: 55.14% and was not purified and directly subjected to the next step.

MS m/z(ESI):214.0[M+1]

The third step

3'H-dispiro [ cyclopropane-1,1 ' -indene-2 ',4 "-piperidine ] -1" -carboxylic acid tert-butyl ester

3'H-dispiro [ cyclopropane-1,1' -indene-2 ',4 "-piperidine ]46c (1.8g, 8.44mmol), di-tert-butyl dicarbonate (3.68g, 16.88mmol), 4-dimethylaminopyridine (51.54mg, 421.91. Mu. Mol), and triethylamine (2.56g, 25.31mmol, 3.55mL) were added to 20mL of dichloromethane, and after the reaction was completed, 20mL of water was added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent: system A) to give 3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4" -piperidine ] -1 "-carboxylic acid tert-butyl ester 46d (1.5 g), yield: 45.37 percent.

MS m/z(ESI):258.0[M+1-56]

¹ H NMR(400MHz,Chloroform-d)δ7.15-7.23(m,1H),7.12(ddd,J＝6.5,4.4,1.4Hz,2H),6.69(dd,J＝6.4,2.0Hz,1H),4.11(s,2H),2.86(s,2H),1.46(s,9H),1.39(dd,J＝14.2,3.1Hz,2H),1.23-1.34(m,2H),1.18(td,J＝13.2,4.9Hz,2H),0.87(t,J＝3.3Hz,2H),0.74(q,J＝4.6Hz,2H).

The fourth step

3 '-oxo-3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester

3'H-dispiro [ cyclopropane-1,1 ' -indene-2 ',4 "-piperidine ] -1" -carboxylic acid tert-butyl ester 46d (1.5g, 4.79mmol), 1.5M magnesium sulfate solution (5 mL), and potassium permanganate (3.02g, 19.14mmol) were added to 20mL of acetone, heated to 40 ℃ and reacted for 8 hours. After the reaction was completed, celite was filtered, the filtrate was acetone-removed, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain 3 '-oxo-3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 "-piperidine ] -1" -tert-butyl formate 46e (600 mg), yield: 38.29%.

MS m/z(ESI):272.0[M+1-56]

The fifth step

(R, Z) -3'- ((tert-butylsulfinyl) imino) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester

(R) -2-methylpropane-2-sulfinamide (370.17mg, 3.05mmol), 3 '-oxo-3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 "-piperidine ] -1" -carboxylic acid tert-butyl ester 46e (400mg, 1.22mmol) were added to 2mL tetraethyl titanate and 0.5mL tetrahydrofuran, heated to 100 ℃ and stirred for 18 hours, after completion of the reaction, cooled to room temperature, 10mL methyl tert-butyl ether was added, cooled with an ice water bath, 10mL ice water was added, stirred for 15 minutes, filtered, the filtrate was separated from the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give (R, Z) -3'- ((tert-butylsulfinyl) imino) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 "-piperidine ] -1-carboxylic acid tert-butyl ester 46f (290 mg), yield: and (5) 55.13%.

MS m/z(ESI):331.0[M+1-100]

The sixth step

(S) -3'- (((R) -tert-butylsulfinyl) amino) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 "-piperidine ] -1" -carboxylic acid tert-butyl ester

(R, Z) -3'- ((tert-butylsulfinyl) imino) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 "-piperidine ] -1" -carboxylic acid tert-butyl ester 46f (290mg, 673.48. Mu. Mol) was added to 3mL tetrahydrofuran, cooled with an ice-water bath, 9-borobicyclo (3,3,1) -nonane (0.5M, 2.69mL) was added, allowed to stir at room temperature for 2 hours, quenched with saturated ammonium chloride solution, the organic phase separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S) -3'- (((R) -tert-butylsulfinyl) amino) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 "-piperidine ] -1" -carboxylic acid tert-butyl ester 46g (180 mg), yield: 61.78% and was not purified and directly subjected to the next step.

MS m/z(ESI):433.0[M+1]

Seventh step

(R) -N- ((S) -3'H-dispiro [ cyclopropane-1,1 ' -indene-2 ', 4' -piperidine ] -3' -yl) -2-methylpropane-2-sulfinamide

(S) -3'- (((R) -tert-butylsulfinyl) amino) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 "-piperidine ] -1" -carboxylic acid tert-butyl ester 46g (180mg, 416.07. Mu. Mol) and 1mL trifluoroacetic acid were added to 4mL of dichloromethane, stirred at room temperature for 1 hour, and after completion of the reaction, concentrated under reduced pressure to give (R) -N- ((S) -3'H-dispiro [ cyclopropane-1,1' -indene-2 ',4 "-piperidine ] -3' -yl) -2-methylpropane-2-sulfinamide 46h (138 mg), yield: 99.75%, and directly carrying out the next reaction without purification.

MS m/z(ESI):333.2[M+1]

Eighth step

(R) -N- ((S) -1'- (4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 '-piperidine ] -3' -yl) -2-methylpropane-2-sulfinamide

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (63.74mg, 415.03. Mu. Mol), (R) -N- ((S) -3'H-dispiro [ cyclopropane-1,1 ' -indene-2 ',4 "-piperidine ] -3' -yl) -2-methylpropane-2-sulfinamide 46h (138mg, 415.03. Mu. Mol) and N, N-diisopropylethylamine (160.92mg, 1.25mmol) were added to 3mL of N, N-dimethylformamide, then heated to 90 ℃ for 1.5 hours, after completion of the reaction, cooled to room temperature, poured into 10mL of water, extracted with ethyl acetate (10 mL. Times.3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: system A) to give (R) -N- ((S) -1" - (4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-160 ' -spiro [ 2' -cyclopropane-5 ' -cyclopropane-3446 ″ -2' -sulfinamide: 85.74%.

MS m/z(ESI):450.1[M+1]

The ninth step

(S) -2- (3 '-amino-3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 "-piperidine ] -1" -yl) -6-methylpyrimidine-4-carbonitrile

(R) -N- ((S) -1'- (4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 '-piperidine ] -3' -yl) -2-methylpropane-2-sulfinamide 46i (160mg, 355.86. Mu. Mol) and bromosuccinimide (69.67mg, 391.45. Mu. Mol) were added to 2mL of N, N-dimethylacetamide, and after the reaction was completed, the reaction liquid was poured into 10mL of water, ethyl acetate (10 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S) -2- (3 '-amino-3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 '-piperidine ] -1' -yl) -6-methylpyrimidine-4-nitrile 46j (123 mg) in yield: 100%, and the reaction product is directly subjected to the next reaction without purification.

MS m/z(ESI):329.0[M+1-17]

The tenth step

(S) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 '-piperidine ] -3' -yl) carbamic acid tert-butyl ester

(S) -2- (3 '-amino-3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 "-piperidine ] -1" -yl) -6-methylpyrimidine-4-carbonitrile 46j (123mg, 356.07. Mu. Mol), triethylamine (107.89mg, 1.07mmol) and di-tert-butyl dicarbonate (116.43mg, 534.10. Mu. Mol) were added to 3mL of dichloromethane, reacted at room temperature for 4 hours, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give (S) - (1 "- (4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1' -indene-2 ',4" -piperidine ] -3' -yl) carbamic acid tert-butyl ester 46k (110 mg), yield: 69.34%.

MS m/z(ESI):446.2[M+1]

The eleventh step

(S) - (1 '- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 '-piperidine ] -3' -yl) carbamic acid tert-butyl ester

Tert-butyl (S) - (1 '- (4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 '-piperidine ] -3' -yl) carbamate 46k (110mg, 246.88. Mu. Mol) was added to 3mL of methylene chloride, cooled with an ice-water bath, bromo-succinimide (48.33mg, 271.57. Mu. Mol) was added, allowed to react at room temperature for 2 hours, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give (S) - (1 '- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1 '-indene-2', 4 '-piperidine ] -3' -yl) carbamate 46l (110 mg), yield: 84.96%.

MS m/z(ESI):524.0[M+1]

Twelfth step

(S) - (1 "- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1' -indene-2 ',4" -piperidine ] -3' -yl) carbamic acid tert-butyl ester

(S) - (1 ' - (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1 ' -indene-2 ', 4' -piperidine ] -3' -yl) carbamic acid tert-butyl ester 46l (89.31mg, 170.29. Mu. Mol), 2,3-dichlorophenylboronic acid (48.74mg, 255.44. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 ' -biphenyl) (2-amino-1,1 ' -biphenyl-2-yl) palladium (28.5252mg, 34.86506. Mu. Mol), 2-dicyclohexylphosphonium-2 ',6' -diisopropoxy-1,1 ' -biphenyl (31.mg, 7468.12. Mu. Mol) and potassium phosphate (108.31mg, 510.87. Mu. Mol) were added to 3.4mL of the mixed solution in sequence (2 zxft: water = 7.5), argon replacement three times, heating to 105 ℃, reaction for 2 hours, concentration under reduced pressure, and purification of the obtained residue by silica gel column chromatography (eluent: system a) to obtain (S) -tert-butyl (1 "- (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1 ' -indene-2 ',4" -piperidin ] -3' -yl) carbamate 46m (95 mg), yield: 94.47 percent.

MS m/z(ESI):[M+1]589.9

Thirteenth step

Mixing (S) - (1 ' - (5- (2,3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -3'H-dispiro [ cyclopropane-1,1 ' -indene-2 ', 4' -piperidine]-3' -yl) carbamic acid tert-butyl ester 46m (95mg, 160.87. Mu. Mol) was added to 3mL of concentrated hydrochloric acid, heated to 90 ℃ and stirred for 9 hours, after completion of the reaction, cooled to room temperature and concentrated under reduced pressure, and the obtained residue was subjected to liquid phase separation (column AKZONOBEL Kromasil;250 × 21.2mm i.d.;5 mu m,20mL/min; mobile phase A:0.05% of TFA +H ₂ O, mobile phase B: CH (CH) ₃ CN) to obtain the product 2- ((S) -3' -amino-3'H-dispiro [ cyclopropane-1,1 ' -indene-2 ', 4' -piperidine]-1 "-yl) -5- (2,3- (dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 46 (2 mg), yield: 1.4 percent.

MS m/z(ESI):508.9[M+1]

Comparative example 1

Comparative example 1 was compound 4 of WO 2020063760, prepared according to example 4 disclosed in WO 2020063760, and has the following specific structure:

comparative example 2

Comparative example 2 is the compound of example 119 of WO 2020181283, prepared according to example 119 of WO 2020181283, with the following specific structure:

comparative example 3

Comparative example 3 was the compound of example 117 of WO 2020181283 prepared according to example 117 of WO 2020181283 and has the following specific structure:

comparative example 4

Comparative example 4 is the racemate of the compound of WO 2020181283, example 117, the procedure is as in example 28 of the present invention, with the following specific structure:

biological evaluation

Test example 1 measurement of the allosteric inhibitory Activity of the inventive Compounds on SHP2

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

The experimental procedure is briefly described as follows: test compoundsStock solutions were prepared by first dissolving in DMSO. The reaction was carried out in 384 well Small volume HiBase microplates (Greiner, 784075) to which SHP2 (signalchem, P38-20G-10. Mu.g) and SHP-2 Activating Peptide (IRS 1_ pY1172 (dPEG 8) pY 1222) (BPS, 79319-1) were first added to final concentrations of 0.5nM and 0.5. Mu.M, followed by the test compound in the range of 0.00004-10. Mu.M and incubated at 25 ℃ for 60 min. DiFMUP (Thermo, D6567) was then added to the reaction and incubated at 25 ℃ for 30 min. After the incubation was complete, the microplate reader (BMG) was used to read the excitation and emission wavelengths at 340nm and 450nm, respectively. The percentage inhibition of the compound at each concentration was calculated by comparison with the fluorescence intensity ratio of a control group (0.1% DMSO), and the IC of the compound was obtained by nonlinear regression analysis using GraphPad Prism 5 software at the logarithmic value-inhibition of the compound concentration ₅₀ Values, see table 1.

TABLE 1 inhibition of full-Length SHP2 enzymatic Activity IC by Compounds of the invention ₅₀ Data of

Compound numbering	SHP2/IC ₅₀ (nM)
26	4.51
29	0.98
30	11.37
31	5.60
32	3.58
36	4.69
37	1.55
39	0.74
40	19.4

And (4) conclusion: as can be seen from Table 1, the compounds of the present invention all have a good allosteric inhibitory effect on SHP2 enzyme.

Test example 2 pharmacokinetic testing

1. Purpose of experiment

The comparative examples 1, 29 and 37 were administered to ICR mice as test animals by gavage, and the pharmacokinetic characteristics of the compounds of the present invention and the comparative examples in the mice were investigated by measuring the drug concentration in the plasma at different times by the LC/MS method.

2. Experimental protocol

2.1 Experimental drugs and animals

Experimental drugs: comparative example 1, compound 29 and compound 37;

animals: ICR mouse, male, 29.0-33.8 g, purchased from Experimental animals technology, inc. of Wei Tong Hua, beijing.

2.2 pharmaceutical preparation

An appropriate amount of the drug was weighed, added to an appropriate amount of sodium carboxymethylcellulose (CMC-Na, 0.5% Tween 80), vortexed, and sonicated to prepare a 0.5mg/mL suspension.

2.3 administration of drugs

ICR mice from each of the test compound gavage groups (9 mice per group) were gavaged overnight (PO, dose 5mg/kg, dose volume 10 mL/kg) and fed 4 hours after dosing.

3. Operation of

Approximately 0.2mL of blood was collected via jugular vein and anticoagulated with heparin sodium at 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours before and after administration. After the blood sample was collected, it was placed on ice, and plasma was centrifuged (centrifugation conditions: 1500g,10 minutes). The collected plasma was stored at-40 to-20 ℃ before analysis.

The content of the test compound in the plasma of the mice after the gavage administration was determined by LC-MS/MS.

4. Pharmacokinetic parameter results

The pharmacokinetic parameters of the compounds of the invention and comparative example 1 are shown in table 2.

Table 2 pharmacokinetic results

And (4) conclusion: compared with the compound 29 and the compound 37, the blood concentration and the area under the curve are obviously improved.

Test example 3 hERG Potassium ion channel inhibitory Activity test of the Compound

1. Cell culture

1.1 the experiment used cells were transfected with hERG cDNA and stable expression of hERG channel CHO cell line (Danish Sophion Bioscience company, P17). Cells were cultured in media containing the following components (all from Invitrogen): ham's F medium, 10% (v/v) inactivated fetal bovine serum, 100 μ g/mL hygromycin B,100 μ g/mL Geneticin.

1.2 CHO hERG cells were grown in a petri dish containing the above culture medium and contained 5% CO at 37 ℃% ₂ The incubator of (2) for cultivation. 24 to 48 hours before the electrophysiological experiment, CHO hERG cells were transferred to a round glass slide placed in a petri dish and grown in the same culture medium and culture conditions as above. The density of CHO hERG cells on each circular slide is required to achieve the requirement that most cells are independent and individual.

2. Test solutions

The solutions of table 3 (recommended by Sophion) were used for electrophysiological recording.

TABLE 3 composition of intracellular and extracellular fluids

3. Electrophysiological recording procedure

3.1 electrophysiological recording System

The fully automated QPatch system (Sophion, denmark) was used to record the whole-cell currents. The cells were clamped at-80 mV. The cell clamp voltage depolarized to +20mV to activate the hERG potassium channel, and clamped to-50 mV after 2.5 seconds to eliminate inactivation and generate an outward tail current. The tail current peak value was used as a value for the magnitude of the hERG current.

3.2 QPatch Experimental procedure

After reaching the membrane-rupture whole-cell configuration state in the initial stage, the cells were recorded for at least 120 seconds to reach stabilization. The voltage pattern described above was then applied to the cells every 15 seconds throughout the process. Only stable cells in the above parameter threshold records are allowed to enter the process of drug treatment. An external solution containing 0.1% dimethylsulfoxide (solvent) was applied to the cells, a baseline was established, and the current was allowed to stabilize for 3 minutes. The cells were kept in the test environment after the compound solution was added until the effect of the compound reached steady state or 4 minutes limit. In the test experiments of different concentration gradients of the compound, the compound is added to the clamped cells from low to high concentration. After completion of the compound test, the cells were washed with external liquid until the current returned to a steady state.

4. Compound preparation

4.1 stock solutions of 10mM compound were diluted in a gradient fashion with extracellular fluid to final. Mu.M concentration.

4.2 the highest concentration tested was 30. Mu.M, 6 concentrations in the order of 30, 10, 3,1, 0.3 and 0.1. Mu.M.

4.3 the final concentration of DMSO was 0.1% in compound solutions at all concentrations except for 30. Mu.M compound DMSO at 0.3%. All compound solutions were subjected to conventional 5 to 10 minutes sonication and shaking to ensure complete dissolution of the compound.

5. Data analysis

The test data was analyzed by Qpatch analysis software supplied by Sophion, excel, graphpad Prism, and the like.

6. Quality control

Reagent: the test reagents used were purchased from Sigma.

The test data in the report need to meet the following criteria:

the membrane resistance Rm is more than 100 MOmega;

an access resistance (Ra) <15M Ω;

tail current amplitude >200pA;

cell hERG current spontaneous decrease (rundown) by <2% per minute;

leakage current is less than 200pA or less than 10% of the hERG current peak (within 90% of the recording time);

the inhibitory effect of multiple concentrations of Cisapride on the hERG channel was a positive control.

7. Results of the experiment

The results of the inhibition of hERG current by the compounds of the present invention and the comparative compounds are shown in Table 4.

TABLE 4 inhibition of hERG Current by Compounds

Compound numbering	hERG IC ₅₀ (μM)	1 μ M inhibition (%)	10 μ M inhibition (%)
Comparative example 2	2.03	28.1	91.9
Comparative example 3	--	8.1	69.9
Compound 29	--	0.77	21.98
Compound 39	>30	--	--

And (4) conclusion: inhibition of cardiac hERG potassium channel by drugs is the major cause of QT prolongation syndrome by drugs. As can be seen from the experimental results, the compounds 29 and 39 of examples of the present invention have no significant inhibitory effect on the cardiac hERG potassium channel and can avoid the cardiotoxic side effects at high doses, as compared with the compounds of comparative examples 2 and 3.

Test example 4 determination of toxicity of Compounds on L-02 hepatocytes and HK-2 Kidney cells

The following methods were used to determine the toxicity of the compounds of the invention and the comparative compounds on liver and kidney cells in vitro. L-02 and HK-2 were purchased from the cell resource center of Shanghai Life sciences research institute of Chinese academy of sciences. The two cell lines were used for hepatorenal cytotoxicity assay of compounds, L-02 hepatocytes were cultured in DMEM medium containing 10% fetal bovine serum, and HK-2 kidney cells were cultured in MEM medium containing 10% fetal bovine serum. Cell viability was determined by Cell Counting Kit-8 Kit (DOJINDO, cat # CK 04).

The experimental method is operated according to the steps of the kit specification, and is briefly as follows: test compounds were first dissolved in DMSO to prepare stock solutions, which were then diluted in a gradient of the corresponding cell culture medium to prepare test samples, with final concentrations of compounds ranging from 50 μ M to 7.5nM. Cells in logarithmic growth phase were seeded at appropriate density into 96-well cell culture plates and at 37 ℃ C. 5% CO ₂ After overnight in the incubator, cells were incubated for a further 72 hours after addition of test compound samples. After the culture was completed, 100. Mu.L of Cell Counting Kit-8 color developing solution (10%) was added to each well, and after shaking, the total volume of CO was 5% at 37 ℃% ₂ Incubate in incubator for 1-3h, then use the Absorbance mode 450nm wavelength on the plate reader to read the sample each hole light absorption value. The percent inhibition of the compounds at each concentration point was calculated by comparison with the values of the control (0.5% DMSO), after which non-linear regression analysis was performed in GraphPad Prism 5 software at the compound concentration log-inhibition to obtain the IC of compound cytotoxicity ₅₀ Values, see table 5.

TABLE 5 IC of compound cytotoxicity to L-02 and HK-2 ₅₀ Data of

Compound numbering	IC ₅₀ (μM)/L-02	IC ₅₀ (μM)/HK-2
Comparative example 2	3.52	--
Comparative example 4	29.12	3.87
Compound 29	>50	23.37

And (4) conclusion: compared with comparative examples 2 and 4, the compound 29 of the embodiment of the invention has lower liver and kidney toxicity and better safety.

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

The described embodiments of the present invention are for illustrative purposes only and are not intended to limit the scope of the present invention, and those skilled in the art may make various other substitutions, alterations, and modifications within the scope of the present invention, and thus, the present invention is not limited to the above-described embodiments but only by the claims.

Claims

A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein:

ring A is selected from aryl, heteroaryl or a bicyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with a monocyclic heterocyclic group or a monocyclic cycloalkyl group;

x is selected from CR ^e Or N;

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

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 Substituted with the substituent(s); preferably, R ¹ Is selected from methyl;

R ² identical OR different, each independently selected from hydrogen atom, 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 by one OR more substituents selected from the group consisting of 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 Substituted with the substituent(s);

R ³ selected from cyano, alkoxyRadical, tetrazolyl, -C (O) R ⁶ OR-C (O) OR ⁶ ；

Provided that when R is ³ When selected from alkoxy, R ¹ Is not selected from-NR ⁷ R ⁸ ；

R ⁴ And R ⁵ Together with the N atom to which they are attached form a 4-to 11-membered heterocyclic group, preferably a 5-to 11-membered heterocyclic group, wherein one or more N, O, S atoms or SO are contained in said heterocyclic group ₂ And 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 halo, hydroxy, amino or alkoxy substituents;

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

is a single bond or a double bond;

when in use
When represents a single bond, G and M are each independently selected from N or CR ^j ；

When in use
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,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 or S;

r is 0 or 1;

R ^m 、R ⁿ 、R ^p and R ^q Are the same or different and are each independently selected from R ^A ；

Or, R ^m And R ⁿ Together with the same carbon atom to which it is attached form C = O;

or, R ^p And R ^q Together with the carbon atom to which they are attached form R ^B ；

R ^c And R ^d Identical OR different, each independently selected from a hydrogen atom, a halogen, an alkyl group OR-OR ⁶ Wherein said alkyl is optionally further substituted with hydroxy, halogen, alkoxy, cycloalkyl or-NR ⁷ R ⁸ Substituted with the substituent(s);

or, R ^c And R ^d Together with the carbon atom to which they are attached form R ^B ；

R ^g Identical OR different, each independently selected from hydrogen atom, 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 Substituted with the substituent(s);

or, two R ^g Together with the same carbon atom to which it is attached form C = O;

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

R ^A identical OR different, 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 isOptionally further substituted by hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR ⁷ R ⁸ Substituted with the substituent(s);

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 by 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 Substituted with the substituent(s);

R ⁶ 、R ⁷ and R 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 hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, 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 Substituted with the substituent(s);

or, R ⁷ And R ⁸ Together with the N atom to which they are attached form a 3-to 8-membered heterocyclic group in which the 3-to 8-membered heterocyclic group contains one or more N, O, S atoms or SO ₂ And the 3-to 8-membered heterocycle is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, alkyl or alkoxy;

R ⁹ 、R ¹⁰ and R ¹¹ Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of 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.
The compound according to claim 1, which is a compound of the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

wherein: ring A, X, m, R ¹ 、R ² 、R ⁴ And R ⁵ Is as defined in claim 1.
The compound according to claim 1, which is a compound of the general formula (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

wherein: ring A, X, m, R ¹ 、R ² 、R ⁴ And R ⁵ Is as defined in claim 1.
A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴ and R ⁵ Together with the N atom to which they are attached form a 4-to 8-membered monocyclic heterocyclyl group, preferably a 5-to 6-membered monocyclic heterocyclyl group, more preferably a piperidinyl group, wherein said monocyclic heterocyclyl 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 Substituted with the substituent(s);

R ⁶ is as defined in claim 1.
A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴ and R ⁵ Together with the N atom to which they are 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 Substituted with the substituent(s);

R ⁶ is as defined in claim 1.
A compound according to claim 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said spiroheterocyclyl is selected from the group consisting of:

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 ；

Or, two R ^a Together with the same carbon atom to which it is attached form C = O;

R ⁶ as defined in claim 1;

t is 1,2 or 3.
A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴ and R ⁵ Together with the N atom to which they are attached form a 7-to 11-membered bridged heterocyclic group, wherein said bridged heterocyclic group is optionally further substituted by one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ , = O OR-OR ⁶ Substituted with the substituent(s);

R ⁶ is as defined in claim 1.
A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴ and R ⁵ Together with the N atom to which they are attached form a 7-to 11-membered fused heterocyclic group, wherein said fused heterocyclic group is optionally further substituted by one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ , = O OR-OR ⁶ Substituted with the substituent(s);

R ⁶ is as defined in claim 1.
The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of general 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 ；

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

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

R ⁿ Selected from a hydrogen atom, a methyl group or-CH ₂ OH；

Or, R ^m And R ⁿ Together with the same carbon atom to which it is attached form C = O;

R ^p and R ^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 ^g Is as defined in claim 1.
The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of general formula (VI):

wherein:

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

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 atom, methyl group or-CH ₂ OH；

Or, R ^m And R ⁿ Together with the same carbon atom to which it is attached form C = O;

R ^p and R ^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 ^g Is as defined in claim 1.
The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (VII):

wherein:

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

R ^c and R ^d Together with the linking 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 atom, methyl group or-CH ₂ OH；

Or, R ^m And R ⁿ Together with the same carbon atom to which it is attached form C = O;

ring A, G, M, X, M, n, R ¹ ～R ³ And R ^g Is defined as in claim 1.
The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of general formula (VIII):

wherein:

ring B, n, R ¹ ～R ² And R ^g Is defined as in claim 1.
The compound of any one of claims 1-3, 9-12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ² Selected from hydrogen atom, F, cl, br, amino group, hydroxyl group, cyano group, nitro group, methoxy group, ethoxy group, methyl group, ethyl group, ethynyl group, ethenyl group, -NHCH ₃ or-N (CH) ₃ ) ₂ 。
The compound according to any one of claims 9 to 11, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R ³ Selected from-C (O) OH.
The compound according to any one of claims 1 to 10, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R ⁶ Selected from a hydrogen atom or an alkyl group.
The compound of any one of claims 1-4, 9-11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring a is selected from phenyl.
A compound according to any one of claims 9 to 12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from:
the compound of any one of claims 9-12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ^g The same or different, each independently selected from hydrogen atom, F, cl, br, amino group, hydroxyl group, cyano group, nitro group, methoxy group, ethoxy group, methyl group, ethyl group, ethynyl group, ethenyl group, -NHCH ₃ or-N (CH) ₃ ) ₂ ；

Or, two R ^g Together with the same carbon atom to which it is attached, may form C = O.
A compound according to any one of claims 1 to 18, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
a pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
Use of a compound according to any one of claims 1 to 19, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the preparation of an SHP2 allosteric inhibitor.
Use of a compound according to any one of claims 1 to 19, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the manufacture of a medicament for the treatment of a disease mediated by SHP2, preferably cancer, cancer metastasis, cardiovascular disease, immune disorders, fibrosis or vision disorders.
The use according to claim 22, wherein the disease mediated by SHP2 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, and glioblastoma.