Pyridine or pyrimidine derivatives and preparation method and use thereof

Abstract

The present invention relates to pyridine or pyrimidine derivatives, preparation methods and pharmaceutical applications thereof. Specifically, the present invention relates to a pyridine or pyrimidine derivative represented by general formula (I), preparation methods and pharmaceutically acceptable salts thereof, and their use as therapeutic agents, especially SHP2 allosteric inhibitors, wherein the definitions of the substituents in the general formula (I) are the same as those in the specification,

Description

Technical Field

[0001] The present invention relates to a novel pyridine or pyrimidine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and the use of the derivative as a therapeutic agent, in particular as a SHP2 allosteric inhibitor. Background Art

[0002] Src homology domain-2 phosphatase (SHP2) is an important member of the protein tyrosine phosphatase (PTP) family. It is encoded by the protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene and catalyzes the dephosphorylation reaction of tyrosine in proteins. The N-terminus of SHP2 contains two SH2 domains, which control the subcellular localization and functional regulation of SHP2. The C-terminus contains a catalytically active PTP domain and two tyrosine residues related to its activity. Under normal circumstances, SHP2 is in a state of autoinhibition. When stimulated by growth factors, cytokines or inflammatory factors, such as platelet-derived growth factor PDGF and FGF, the catalytic site is exposed, leading to the activation of the SHP2 enzyme.

[0003] SHP2 is widely present in the human body and participates in rat sarcoma (RAS)-extracellular signal-related kinase (ERK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B and NF-KB, activating multiple signaling pathways such as fibroblast growth factor, epidermal growth factor and insulin receptor downstream mitogen-activated protein kinase (MAPK / ERK), thereby regulating cell proliferation, differentiation, migration and apoptosis. It has been found that the activation mutation of SHP2 is closely related to the occurrence of Noonan syndrome, leopard spot syndrome, monocytic leukemia, melanoma, solid tumors, cardiovascular disease, immune disorders, fibrosis or visual disorders. Overexpression of SHP2 increases the risk of chronic myeloid leukemia, mastocytosis, malignant glioma, lung cancer, breast cancer and other cancers, indicating that SHP2 plays an important role in different types of cancer and different stages of cancer. Due to the multiple functions of SHP2 in tumors, the research on SHP2 target inhibitors also brings new hope and direction for the treatment of tumors.

[0004] According to their different mechanisms of action, SHP2 inhibitors can be divided into competitive inhibitors (including allosteric mycin, phenylpyrazole hydrazide sulfonate and NSC-87877), non-competitive inhibitors (including indole salicylic acid and furomonosulfuron) and irreversible inhibitors (including sodium antimony gluconate and cryptotanshinone). It is reported that cryptotanshinone, as an irreversible inhibitor of SHP2, can inhibit the proliferation of rhabdomyosarcoma, melanoma, colon cancer and breast cancer in vitro, and in vivo studies have shown that it can inhibit the proliferation of mouse prostate cancer. Whether it can further become a clinically effective drug still requires many experiments to verify.

[0005] At present, the compound RMC-4630 developed by REVOLUTION Medicines Inc has entered the clinical phase II for the treatment of solid tumors. There are also three clinical phase I compounds JAB-3068, JAB-3312 and TNO-155, which were developed by Jacobio Pharmaceuticals Co Ltd and Novartis AG respectively. REVOLUTION Medicines Inc and Novartis AG have disclosed a series of SHP2 inhibitor patents, including WO-2019075265, WO-2018136265, WO-2018136264, WO-2017216706 and WO-2018013597. Although some progress has been made in the research of SHP2, there is still no effective drug on the market, so it is still necessary to continue to research and develop new SHP2 inhibitors. Summary of the invention

[0006] In view of the above technical problems, the present invention provides a new class of pyridine or pyrimidine compounds or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof represented by general formula (I):

[0007]

[0008] in:

[0009] Ring A is selected from an aryl group, a heteroaryl group or a bicyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl group or a heteroaryl group and a monocyclic heterocyclyl group or a monocyclic cycloalkyl group;

[0010] X is selected from CR e or N;

[0011] R e is selected from hydrogen, alkyl, halogen or alkoxy, wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from hydroxy, halogen or alkoxy;

[0012] 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 7R 8 wherein the alkyl, cycloalkyl, heterocyclyl, alkenyl or alkynyl group is optionally further substituted by one or more selected from hydroxy, halogen, alkyl, alkoxy, cycloalkyl or -NR 7 R 8 Preferably, R 1 Selected from methyl;

[0013] R 2 are the same or different and are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cyano, halogen, nitro, cycloalkyl, heterocyclic, -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 the alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group is optionally further substituted by one or more selected from halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic group, 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 by a substituent;

[0014] R 3 Selected from cyano, alkoxy, tetrazolyl, -C(O)R 6 、-C(O)OR 6 or -C(O)NR 7 R 8 ;

[0015] The condition is that when R 3 When selected from alkoxy, R 1 Not selected -NR 7 R 8 ;

[0016] R 4 and R 5 Together with the nitrogen atom to which it is connected, it forms a 4- to 11-membered heterocyclic group, preferably a 5- to 11-membered heterocyclic group, wherein the heterocyclic group contains one or more nitrogen, oxygen, sulfur atoms or sulfur 2 , and the heterocyclyl is optionally further substituted by one or more 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by a halogen, hydroxyl, amino or alkoxy substituent;

[0017] Or, R 4 and R 5 Together with the N atom to which it is attached, it forms a group:

[0018]

[0019] is a single bond or a double bond;

[0020] when When it represents a single bond, G and M are each independently selected from N or CR j ;

[0021] when When it represents a double bond, G and M are each independently selected from C;

[0022] Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0023] E is selected from NR k , (CR p R q ) p , O or S;

[0024] F is selected from (CR p R q ) q;

[0025] Provided that, when E is selected from (CR p R q ) p When p is 1 and q is 1; or, p is 2 and q is 0; when E is selected from NR k , O or S, q is 1;

[0026] J is selected from CR p R q ;

[0027] K is selected from NR k , (CR p R q ) r , O or S;

[0028] r is 0 or 1;

[0029] R m , R n , R p and R q The same or different, each independently selected from R A ;

[0030] Or, R m and R n Together with the same carbon atom to which it is attached, it forms C=O;

[0031] Or, R p and R q Together with the carbon atom to which it is attached, it forms R B ;

[0032] R c and R d The same or different, each independently selected from hydrogen atom, halogen, alkyl or -OR 6 wherein the alkyl group is optionally further substituted with hydroxyl, halogen, alkoxy, cycloalkyl or -NR 7 R 8 substituted by a substituent;

[0033] Or, R c and R d Together with the carbon atom to which it is attached, it forms R B ;

[0034] R g are the same or different and are each independently selected from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclic, 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by hydroxy, halogen, alkyl, alkoxy, cycloalkyl or -NR 7 R 8 substituted by a substituent;

[0035] Or, two R g Together with the same carbon atom to which it is attached, it forms C=O;

[0036] R j and R k are the same or different, each independently selected from a hydrogen atom or an alkyl group;

[0037] R A are the same or different and are each independently selected from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclic, 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by hydroxy, halogen, alkyl, alkoxy, cycloalkyl or -NR 7 R 8 substituted by a substituent;

[0038] R Bthe same or different, each independently selected from 3-10 membered cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more selected from halogen, cyano, nitro, alkyl, cycloalkyl, heterocyclic group, 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 by a substituent;

[0039] R 6 , R 7 and R 8 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or a heterocyclic group, wherein the alkyl group, the cycloalkyl group or the heterocyclic group is optionally further substituted by one or more selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-SO 2 R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0040] Or, R 7 and R 8 Together with the nitrogen atom to which it is connected, it forms a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic ring contains one or more nitrogen, oxygen, sulfur atoms or sulfur 2 , and the 3- to 8-membered heterocyclic ring is optionally further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy;

[0041] R 9 , R 10 and R11 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0042] m is selected from 0, 1, 2, 3, 4 or 5;

[0043] n is selected from 0, 1, 2, 3 or 4;

[0044] p is selected from 1 or 2.

[0045] In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt is a compound of general formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt,

[0046]

[0047] Among them: Ring A, X, m, R 1 , R 2 , R 4 and R 5 The definition of is as described in the general formula (I).

[0048] In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt is a compound of general formula (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt,

[0049]

[0050] Among them: Ring A, X, m, R 1 , R 2 , R 4 and R 5 The definition of is as described in the general formula (I).

[0051] In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt is a compound of general formula (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt,

[0052]

[0053] Among them: Ring A, X, m, R 1 , R 2 , R 4 and R 5 The definition of is as described in the general formula (I).

[0054] In a preferred embodiment of the present invention, the compound described in general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R 4 and R 5 The N atom to which it is connected forms a 4-8 membered monocyclic heterocyclic group, preferably a 5-6 membered monocyclic heterocyclic group, more preferably a piperidinyl group, wherein the monocyclic heterocyclic group is optionally further substituted with one or more selected from methyl, amino, -CH 2 NH 2 、-CH 2 OH, -NHC(=NH)NH 2 , =O or -OR 6 Substituents; R 6 The definition of is as described in the general formula (I).

[0055] In a preferred embodiment of the present invention, the compound described by general formula (I), (II), (III) or (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0056] R 4 and R 5 Together with the N atom to which it is connected, it forms a 7-11-membered spiro heterocyclic group, wherein the spiro heterocyclic group is optionally further substituted with one or more selected from methyl, amino, -CH 2 NH 2 、-CH 2 OH, -NHC(=NH)NH 2 , =O or -OR 6 substituted by a substituent;

[0057] R 6 The definition of is as described in the general formula (I);

[0058] Preferably, the spiro heterocyclic group is selected from:

[0059]

[0060] R a are the same or different, each independently selected from methyl, amino, -CH 2 NH 2 、-CH 2 OH, -NHC(=NH)NH 2 OR 6 ; or, two R a Together with the carbon atom to which it is attached, it forms C=O; R 6 The definition of is as described in the general formula (I); t is 1, 2 or 3.

[0061] In a preferred embodiment of the present invention, the compound described in general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R 4 and R 5 Together with the N atom to which it is connected, it forms a 7-11-membered bridged heterocyclic group, wherein the bridged heterocyclic group is optionally further substituted with one or more selected from methyl, amino, -CH 2 NH 2 、-CH 2 OH, -NHC(=NH)NH 2 , =O or -OR 6 Substituents; R 6 The definition of is as described in the general formula (I).

[0062] In a preferred embodiment of the present invention, the compound described in general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R 4 and R 5 The N atom to which it is connected forms a 7-11-membered fused heterocyclic group, wherein the fused heterocyclic group is optionally further substituted with one or more selected from methyl, amino, -CH 2 NH 2 、-CH 2 OH, -NHC(=NH)NH 2 , =O or -OR 6 Substituents; R 6 The definition of is as described in the general formula (I).

[0063] In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of general formula (V) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0064]

[0065] in:

[0066] Ring B is selected from phenyl, 3- to 8-membered cycloalkyl, 4- to 8-membered heterocyclyl or 5- to 6-membered heteroaryl;

[0067] E is selected from NR k , (CR p R q ) p , O or S;

[0068] F is selected from (CR p R q ) q ;

[0069] Provided that, when E is selected from (CR p R q ) p When p is 1 and q is 1; or, p is 2 and q is 0; when E is selected from NR k , O or S, q is 1;

[0070] R m Selected from amino, -CH 2 NH 2 or -NHC(=NH)NH 2 ;

[0071] R n Selected from hydrogen atom, methyl or -CH 2 OH;

[0072] Or, R m and R n Together with the same carbon atom to which it is attached, it forms C=O;

[0073] R p and R q are independently selected from hydrogen, halogen, amino, C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, amino C 1 -C 4 Alkyl or -OR 6 ;

[0074] Ring A, G, M, X, m, n, R 1 ~R 3 , R 6 , R k and R g The definition of is as described in the general formula (I).

[0075] In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of general formula (VI) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0076]

[0077] in:

[0078] Ring B is selected from phenyl, 3- to 8-membered cycloalkyl, 4- to 8-membered heterocyclyl or 5- to 6-membered heteroaryl;

[0079] J is selected from CR p R q ;

[0080] K is selected from NRk , (CR p R q ) r , O or S;

[0081] r is 0 or 1;

[0082] R m Selected from amino, -CH 2 NH 2 or -NHC(=NH)NH 2 ;

[0083] R n Selected from hydrogen atom, methyl or -CH 2 OH;

[0084] Or, R m and R n Together with the same carbon atom to which it is attached, it forms C=O;

[0085] R p and R q are independently selected from hydrogen, halogen, amino, C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, amino C 1 -C 4 Alkyl or -OR 6 ;

[0086] Ring A, G, M, X, m, n, R 1 ~R 3 , R 6 , R k and R g The definition of is as described in the general formula (I).

[0087] In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of general formula (VII) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0088]

[0089] in:

[0090] Ring B is selected from phenyl, 3- to 8-membered cycloalkyl, 4- to 8-membered heterocyclyl or 5- to 6-membered heteroaryl;

[0091] R c and R d Together with the atoms to which it is attached, it forms a 3- to 8-membered cycloalkyl group;

[0092] Rm Selected from amino, -CH 2 NH 2 or -NHC(=NH)NH 2 ;

[0093] R n Selected from hydrogen atom, methyl or -CH 2 OH;

[0094] Or, R m and R n Together with the same carbon atom to which it is attached, it forms C=O;

[0095] Ring A, G, M, X, m, n, R 1 ~R 3 and R g The definition of is as described in the general formula (I).

[0096] In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt is a compound of general formula (VIII) or its stereoisomer, tautomer or pharmaceutically acceptable salt:

[0097]

[0098] in:

[0099] Ring B, n, R 1 ~R 2 and R g The definition of is as described in the general formula (I).

[0100] In a preferred embodiment of the present invention, the compound of formula (I), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 2 Selected from hydrogen, F, Cl, Br, amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH 3 or -N(CH 3 ) 2 .

[0101] In a preferred embodiment of the present invention, the compound of formula (V), (VI) or (VII) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 3 Selected from -C(O)OH.

[0102] In a preferred embodiment of the present invention, the compound of formula (I), (III), (IV), (V), (VI) or (VII) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 6 is selected from a hydrogen atom or an alkyl group.

[0103] In a preferred embodiment of the present invention, the compound described by general formula (I), (III), (IV), (V), (VI) or (VII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein ring A is selected from phenyl.

[0104] In a preferred embodiment of the present invention, the compound of formula (I), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein ring B is selected from:

[0105]

[0106] In a preferred embodiment of the present invention, the compound of formula (I), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R g are the same or different and are each independently selected from hydrogen, F, Cl, Br, amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH 3 or -N(CH 3 ) 2 ;

[0107] Or, two R g The same carbon atom connected to each other can form C=O together.

[0108] Typical compounds of the present invention include, but are not limited to:

[0109]

[0110]

[0111]

[0112]

[0113] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0114] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0115] The present invention provides a compound described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof (i.e., the pharmaceutical composition provided by the above technical scheme of the present invention) for use in preparing a SHP2 allosteric inhibitor.

[0116] The present invention also provides a use of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by SHP2, wherein the disease mediated by SHP2 is preferably cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder; wherein the disease mediated by SHP2 is preferably selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid 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.

[0117] The present invention further provides a compound of the general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder.

[0118] The present invention provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing a medicament for treating Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid 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.

[0119] The present invention also provides a compound of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, 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, cardiovascular disease, immune disorder, fibrosis or visual disorder; wherein the disease mediated by SHP2 is preferably selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid 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.

[0120] The present invention also provides a method for treating a disease mediated by SHP2, comprising administering to a subject a compound of 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; wherein the disease mediated by SHP2 is preferably cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder; wherein the disease mediated by SHP2 is preferably selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid 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.

[0121] Detailed description of the invention

[0122] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0123] "Alkyl" as a group or part of a group refers to a group comprising C 1 -C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6Alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-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, etc. Alkyl groups may be substituted or unsubstituted.

[0124] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups may be optionally substituted or unsubstituted.

[0125] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight chain or branched. 2 -C 10 Alkynyl, more preferably C 2 -C 6 Alkynyl, most preferably C 2 -C 4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. Alkynyl groups can be substituted or unsubstituted.

[0126] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 3 -C 6 Cycloalkyl. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl may be optionally substituted or unsubstituted.

[0127] "Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl is divided into single spiro, double spiro or multiple spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. 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.

[0128] "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, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" 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 tetradecahydrophenanthryl.

[0129] "Bridged cycloalkyl" refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s, 5s)-bicycloo[3.3.1]nonyl, bicyclo[22.2]octyl, (1r, 5r)-bicyclo[3.3.2]decyl.

[0130] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclic groups, wherein one or more of the atoms forming the ring are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, condensed, bridged and spirocyclic rings. Preferably, there are 5 to 7-membered monocyclic or 7 to 10-membered bi- or tricyclic rings, 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.

[0131] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and the single rings share one atom with each other, containing one or more double bonds in the ring, but no ring has a completely conjugated π-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) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spirocycloalkyl is divided into single spiro heterocyclic group, double spiro heterocyclic group or multi-spiro heterocyclic group, preferably single spiro heterocyclic group and double spiro heterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0132] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-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) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxine and

[0133] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-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) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, 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

[0134] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be fused together. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C 6 -C 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. Aryl may be substituted or unsubstituted.

[0135] "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. Preferably, it is a bicyclic heteroaryl. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,

[0136]

[0137] A heteroaryl group can be substituted or unsubstituted.

[0138] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, one or more rings may contain one or more double bonds, but at least one ring does not have a completely conjugated π-electron aromatic system, and at least one ring has a completely conjugated π-electron aromatic system, wherein 0, one or more ring atoms are selected from nitrogen, oxygen or S(O) n(where n is selected from 0, 1 or 2) heteroatoms, 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 and a monocyclic heterocyclic group or a monocyclic cycloalkyl. Preferably, it includes 7 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include, but are not limited to:

[0139]

[0140] "Alkoxy" refers to a group of (alkyl-O-) wherein alkyl is as defined herein. 1 -C 6 Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0141] "Hydroxy" refers to an -OH group.

[0142] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0143] "Amino" refers to -NH 2 .

[0144] "Cyano" refers to -CN.

[0145] "Nitro" refers to -NO 2 .

[0146] "Benzyl" refers to -CH 2 -phenyl.

[0147] "Carboxy" refers to -C(O)OH.

[0148] "Carboxylate" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[0149] "DMSO" refers to dimethyl sulfoxide.

[0150] "BOC" refers to tert-butoxycarbonyl.

[0151] "TFA" refers to trifluoroacetic acid.

[0152] "Ts" refers to p-toluenesulfonyl.

[0153] "Hydroxy C 1 -C 4 "Alkyl" refers to a hydroxy-substituted C 1 -C 4 alkyl.

[0154] "Amino C 1 -C 4 "Alkyl" refers to an amino-substituted C 1 -C4 alkyl.

[0155] "Leaving group", or leaving group, is an atom or functional group that detaches from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called a substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called a leaving group. Groups that are easy to accept electrons and have a strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to combine with other atoms, and the tendency to exist in the form of anions (or electrically neutral leaving groups) is enhanced. Common leaving groups include but are not limited to halogens, mesyl, -OTs or -OH.

[0156] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore 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, hindered isomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0157] Unless otherwise indicated, the structure described in the present invention also includes all isomers of the structure (e.g., diastereomers, enantiomers, steric isomers and geometric (conformation) isomer forms; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, steric isomers of biphenyl structures (see "Basic Organic Chemistry" (Second Edition) Volume 1, Xing Qiyi et al., p104-105); PAC, 1996, 68, 2193. (Basic terminology of stereochemistry (IUPAC Recommendations 1996, on page 2201)), (Z) and (E) conformational isomers. Therefore, single stereoisomers of the compounds of the present invention as well as enantiomeric mixtures, diastereomeric mixtures, steric isomers and geometric (conformation) isomer mixtures are all within the scope of the present invention.

[0158] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0159] The term "substituted" or "substituted" as used herein, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, 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 substituted by a substituent of, wherein the alkyl or alkoxy group is optionally further substituted by a halogen, hydroxyl, amino or alkoxy substituent;

[0160] R 6 , R 7 and R 8 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-SO 2 R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO 2 NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0161] R 7 and R 8 Together with the nitrogen atom to which it is connected, it forms a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic ring contains one or more N, O, S or SO2 Atoms, and the 3- to 8-membered heterocyclic ring is further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy;

[0162] R 9 , R 10 and R 11 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group.

[0163] "Pharmaceutically acceptable salts" refer to salts of the above compounds that can retain their original biological activity and are suitable for medical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0164] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0165] Synthesis method of the compound of the present invention

[0166] In order to achieve the purpose of the present invention, the present invention adopts the following technical scheme:

[0167] The present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

[0168]

[0169] Compounds of formula (Ia) and NHR 4 R 5 A nucleophilic substitution reaction is carried out under alkaline conditions to obtain a compound of the general formula (Ib); the compound of the general formula (Ib) and the compound of the general formula (Ic) are subjected to a Suzuki reaction under a palladium catalyst and alkaline conditions, and the obtained compound is optionally further freed of a protecting group to obtain a compound of the general formula (I);

[0170] in:

[0171] X 2 is selected from halogen;

[0172] X 3 Selected from a leaving group, wherein the leaving group is selected from halogen or -SO 2 Rt ;

[0173] R 3 Selected from alkoxy;

[0174] R t Selected from alkyl;

[0175] Ring A, X, m, R 1 , R 2 , R 4 and R 5 The definition of is as described in the general formula (I).

[0176] The present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

[0177]

[0178] The compound of the general formula (Ia) and the compound of the general formula (Ic) are subjected to Suzuki reaction under palladium catalyst and alkaline conditions to obtain the compound of the general formula (Id); the compound of the general formula (Id) and NHR 4 R 5 Carrying out a nucleophilic substitution reaction under alkaline conditions, and optionally further removing the protecting group of the obtained compound to obtain a compound of general formula (I);

[0179] in:

[0180] X 2 is selected from halogen;

[0181] X 3 Selected from a leaving group, wherein the leaving group is selected from halogen or -SO 2 R t ;

[0182] R 3 Selected from alkoxy;

[0183] R t Selected from alkyl;

[0184] Ring A, X, m, R 1 , R 2 , R 4 and R 5 The definition of is as described in the general formula (I).

[0185] The present invention provides a method for preparing a compound of general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

[0186]

[0187] Compounds of formula (IIa) and NHR4 R 5 A nucleophilic substitution reaction is carried out under alkaline conditions to obtain a compound of the general formula (IIb); the compound of the general formula (IIb) and the compound of the general formula (Ic) are subjected to a Suzuki reaction under a palladium catalyst and alkaline conditions, and the obtained compound is optionally further freed of a protecting group to obtain a compound of the general formula (IIc); the compound of the general formula (IIc) is hydrolyzed under sodium hydroxide solution to obtain a compound of the general formula (II);

[0188] in:

[0189] X 2 is selected from halogen;

[0190] X 3 Selected from a leaving group, wherein the leaving group is selected from halogen or -SO 2 R t ;

[0191] R t Selected from alkyl;

[0192] Ring A, X, m, R 1 , R 2 , R 4 and R 5 The definition of is as described in the general formula (II).

[0193] The present invention provides a method for preparing a compound of general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

[0194]

[0195] The compound of general formula (IIa) and the compound of general formula (Ic) are subjected to Suzuki reaction under palladium catalyst and alkaline conditions to obtain the compound of general formula (IId); the compound of general formula (IId) and NHR 4 R 5 A nucleophilic substitution reaction is carried out under alkaline conditions to obtain a compound of the general formula (IIc); the compound of the general formula (IIc) is hydrolyzed under sodium hydroxide solution conditions to obtain a compound of the general formula (II);

[0196] in:

[0197] X 2 is selected from halogen;

[0198] X 3 Selected from a leaving group, wherein the leaving group is selected from halogen or -SO 2 R t ;

[0199] R t Selected from alkyl;

[0200] Ring A, X, m, R 1 , R 2 , R 4 and R 5 The definition of is as described in the general formula (II).

[0201] The present invention provides a method for preparing a compound of general formula (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

[0202]

[0203] The compound of general formula (IIc) is heated and hydrolyzed under concentrated hydrochloric acid to obtain the compound of general formula (III);

[0204] Among them: Ring A, X, m, R 1 , R 2 , R 4 and R 5 The definition of is as described in the general formula (III).

[0205] The present invention provides a method for preparing a compound of general formula (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

[0206]

[0207] The compound of general formula (IIc) is reacted in the presence of zinc chloride and sodium azide, and the obtained compound is optionally further deprotected to obtain a compound of general formula (IV);

[0208] Among them: Ring A, X, m, R 1 , R 2 , R 4 and R 5 The definition of is as described in the general formula (IV). DETAILED DESCRIPTION

[0209] The present invention is further described below with reference to the embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0210] Example

[0211] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0212] The mass spectrum is obtained by LC / MS, and the ionization method can be ESI or APCI.

[0213] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0214] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0215] In the following examples, unless otherwise indicated, all temperatures are degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0216] CD 3 OD: deuterated methanol.

[0217] CDCl 3 : Deuterated chloroform.

[0218] DMSO-d 6 : Deuterated dimethyl sulfoxide.

[0219] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1L.

[0220] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0221] The compound is purified using a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, may also be added for adjustment.

[0222] Example 1

[0223] 1-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-amine

[0224]

[0225]

[0226] first step

[0227] 5-Bromo-2-chloro-4-methoxy-6-methylpyrimidine

[0228] 5-Bromo-2,4-dichloro-6-methylpyrimidine 1a (480 mg, 2 mmol) was added to 5 mL of methanol, and 5 mL of methanol solution containing sodium methoxide (102.6 mg, 1.9 mmol) was slowly added dropwise under ice bath, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-bromo-2-chloro-4-methoxy-6-methylpyrimidine 1b (448.4 mg), which was directly used for the next step without purification.

[0229] MS m / z(ESI):236.8[M+1]

[0230] Step 2

[0231] tert-Butyl (1-(5-bromo-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0232] Under argon protection, 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 (470 mg, 2.2 mmol) and 0.5 mL of N, N-diisopropylethylamine were added to 5 mL of dimethyl sulfoxide, heated to 130°C, and reacted for 1 hour. After the reaction was completed, it was cooled to room temperature, 30 mL of water was added, and extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(5-bromo-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 1d (210 mg), with a yield of 26.7%.

[0233] MS m / z(ESI):415.0[M+1]

[0234] Step 3

[0235] tert-Butyl (1-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0236] Under argon protection, tert-butyl (1-(5-bromo-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 1d (140 mg, 0.338 mmol), (2,3-dichlorophenyl)boronic acid 1e (128 mg, 0.676 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (24 mg, 0.0338 mmol), tetrakis(triphenylphosphine)palladium (39 mg, 0.0338 mmol), sodium carbonate (143 mg, 1.35 mmol) and 0.5 mL of water were added to 3 mL of N,N-dimethylformamide, heated to 110° C., and reacted for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl (1-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 1f (110 mg), with a yield of 68.7%.

[0237] MS m / z(ESI):480.9[M+1]

[0238] Step 4

[0239] 1-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-amine

[0240] Tert-butyl (1-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 1f (110 mg, 0.229 mmol) and 1 mL of trifluoroacetic acid were added to 4 mL of dichloromethane, reacted at room temperature for 2 hours, and concentrated under reduced pressure. The obtained residue was prepared by liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN), to give 1-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-amine 1 (60 mg), yield: 69%.

[0241] MS m / z(ESI):380.9[M+1]

[0242] 1 H NMR (400 MHz, CD 3 OD) δ7.61 (d, J=8.0Hz, 1H), 7.39 (s, 1H), 7.21-7.27 (m, 1H), 4.43 (s, 2H), 3.9 5(s, 3H), 3.56-3.70(m, 2H), 2.17(s, 3H), 1.96(t, J=5.8Hz, 4H), 1.54(s, 3H).

[0243] Example 2

[0244] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methoxypyrimidin-4-amine

[0245] first step

[0246] 5-Bromo-2-chloro-6-methoxypyrimidin-4-amine

[0247] 5-Bromo-2,4-dichloropyrimidine-4-amine 2a (971.56 mg, 4 mmol) and sodium methoxide (216 mg, 4 mmol) were added to 10 mL of methanol, and 1 equivalent of sodium methoxide was added every 3 hours. The reaction was allowed to react at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, 20 mL of water was added, and the mixture was extracted with dichloromethane (10 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-bromo-2-chloro-6-methoxypyrimidine-4-amine 2b (800 mg). The product was directly used for the next step without purification.

[0248] MS m / z(ESI):237.8[M+1]

[0249] Step 2

[0250] tert-Butyl (1-(4-amino-5-bromo-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0251] 5-Bromo-2-chloro-6-methoxypyrimidin-4-amine 2b (473.86 mg, 2 mmol), (4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 1c (642 mg, 3 mmol) and 1 mL of N,N-diisopropylethylamine were added to 5 mL of N-methylpyrrolidone, heated to 90°C, and reacted for 2 hours. After the reaction was completed, it was cooled to room temperature, 20 mL of water was added, and extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(4-amino-5-bromo-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 2c (360 mg), with a yield of 43.4%.

[0252] MS m / z(ESI):415.8[M+1]

[0253] Step 3

[0254] tert-Butyl (1-(4-amino-5-(2,3-dichlorophenyl)-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0255] Under argon protection, tert-butyl (1-(4-amino-5-bromo-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 2c (100 mg, 0.24 mmol), (2,3-dichlorophenyl)boronic acid 1e (91.56 mg, 0.48 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (35 mg, 0.048 mmol), tetrakis(triphenylphosphine)palladium (55 mg, 0.048 mmol), sodium carbonate (102 mg, 0.96 mmol) and 0.5 mL of water were added to 3 mL of N,N-dimethylformamide, heated to 100° C., and reacted overnight. After the reaction was completed, the mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl (1-(4-amino-5-(2,3-dichlorophenyl)-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 2d (40 mg), with a yield of 34.8%.

[0256] MS m / z(ESI):481.9[M+1]

[0257] Step 4

[0258] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methoxypyrimidin-4-amine

[0259] Tert-butyl (1-(4-amino-5-(2,3-dichlorophenyl)-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 2d (40 mg, 0.083 mmol) and 0.5 mL of trifluoroacetic acid were added to 2 mL of dichloromethane, reacted at room temperature for 2 hours, and concentrated under reduced pressure. The obtained residue was prepared by liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: 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%.

[0260] MS m / z(ESI):381.9[M+1]

[0261] 1 H NMR (400 MHz, 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).

[0262] Example 3

[0263] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid

[0264] first step

[0265] tert-Butyl (1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0266] 2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (400 mg, 2.60 mmol), (4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 1c (558.20 mg, 2.60 mmol) and N, N-diisopropylethylamine (336.63 mg, 2.60 mmol) were added to 20 mL of N, N-dimethylacetamide, heated to 90°C, and reacted for 3 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with saturated sodium chloride solution (30 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 3b (840 mg) with a yield of 97.31%.

[0267] MS m / z(ESI):332.2[M+1]

[0268] Step 2

[0269] tert-Butyl (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0270] Tert-butyl (1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3b (840 mg, 2.53 mmol) was added to 10 mL of N,N-dimethylformamide, and bromosuccinimide (600.41 mg, 3.37 mmol) was added at 0°C, and the mixture was reacted at room temperature overnight. The reaction solution was extracted with ethyl acetate (30 ml×2), and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3c (800 mg) with a yield of 75.14%.

[0271] MS m / z(ESI):355.9[M-56]

[0272] Step 3

[0273] tert-Butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0274] Under argon protection, tert-butyl (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3c (800 mg, 1.95 mmol), (2,3-dichlorophenyl)boronic acid 1e (744.10 mg, 3.90 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino- 1,1′-biphenyl-2-yl)palladium (163.25 mg, 0.195 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (181.97 mg, 0.390 mmol) and potassium phosphate (1.24 g, 5.85 mmol) were added to 12 mL of a mixed solution (1,4-dioxane: water = 6:1), heated to 130°C, and reacted for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3d (900 mg), with a yield of 96.89%.

[0275] MS m / z(ESI):476.1[M+1]

[0276] Step 4

[0277] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid

[0278] Tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3d (380 mg, 0.800 mmol) was added to 10 mL of concentrated hydrochloric acid, heated to 110°C, and reacted for 1.5 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The obtained residue was prepared by liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: 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%.

[0279] MS m / z(ESI):394.1[M+1]

[0280] 1 H NMR (400 MHz, 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).

[0281] Example 4

[0282] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0283]

[0284] first step

[0285] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0286] Tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3d (170 mg, 0.36 mmol) and 1.65 mL of trifluoroacetic acid were added to 6 mL of dichloromethane, reacted at room temperature for 40 minutes, and concentrated under reduced pressure. The obtained residue was prepared by liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: 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%.

[0287] MS m / z(ESI):376.1[M+1]

[0288] 1 H NMR (400 MHz, 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).

[0289] Step 2

[0290] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0291] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 4a (20 mg, 0.267 mmol) and 0.1 mL of 6 M sodium hydroxide solution were added to 1.5 mL of ethanol, heated to 80°C, and reacted for 40 minutes. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The obtained residue was subjected to preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: 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%.

[0292] MS m / z(ESI):394.1[M+1]

[0293] 1 H NMR (400 MHz, 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).

[0294] Example 5

[0295] 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinic acid

[0296]

[0297]

[0298] first step

[0299] tert-Butyl (1-(4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0300] 2-Chloro-6-methylisonicotinonitrile 5a (230 mg, 1.51 mmol, prepared according to patent WO 2009016498), tert-butyl (4-methylpiperidin-4-yl)carbamate 1c (389 mg, 1.82 mmol) and N,N-diisopropylethylamine (391 mg, 3.03 mmol) were added to 6 mL of N-methylpyrrolidone, heated to 90° C., and reacted for 5 hours. After the reaction, 30 mL of water was added, and the mixture was extracted 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. The residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (1-(4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate 5b (245 mg) with a yield of 49%.

[0301] MS m / z(ESI):331.2[M+1]

[0302] Step 2

[0303] tert-Butyl (1-(5-bromo-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0304] Tert-butyl (1-(4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate 5b (70 mg, 0.212 mmol) and bromosuccinimide (42 mg, 0.233 mmol) were added to 1.5 mL of N,N-dimethylformamide and reacted overnight at room temperature. After the reaction was completed, it was extracted with ethyl acetate (30 ml × 2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (1-(5-bromo-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate 5c (64 mg), yield: 73%.

[0305] MS m / z(ESI):409.1[M+1]

[0306] Step 3

[0307] tert-Butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0308] Under argon protection, tert-butyl (1-(5-bromo-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate 5c (150 mg, 0.368 mmol), (2,3-dichlorophenyl)boronic acid 1e (140 mg, 0.735 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium (31 mg, 0.039 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (34 mg, 0.074 mmol) and potassium phosphate (234 mg, 1.104 mmol) were added to 3.5 mL of a mixed solution (1,4-dioxane: water = 6:1), heated to 130° C., and reacted for 5 hours. After the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate 5d (170 mg) in a yield of 98%.

[0309] MS m / z(ESI):475.0[M+1]

[0310] Step 4

[0311] 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile

[0312] Tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate 5d (170 mg, 0.359 mmol) and 1.5 mL of trifluoroacetic acid were added to 6 mL of dichloromethane and reacted at room temperature for 40 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile 5e (69.91 mg), yield: 52%.

[0313] MS m / z(ESI):375.0[M+1]

[0314] Step 5

[0315] 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinic acid

[0316] 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile 5e (30 mg, 0.08 mmol) was added to 0.5 mL of concentrated hydrochloric acid, heated to 110°C, and reacted for 4 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The obtained residue was subjected to preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: 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%.

[0317] MS m / z(ESI):394.1[M+1]

[0318] 1 H NMR (400 MHz, 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).

[0319] Example 6

[0320] 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinamide

[0321]

[0322] first step

[0323] 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinamide

[0324] 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile 5e (37.33 mg, 0.1 mmol) and 0.1 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, heated to 80°C, and reacted for 40 minutes. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The obtained residue was subjected to preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN), to give 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinamide 6 (21.99 mg), yield: 56%.

[0325] MS m / z(ESI):393.1[M+1]

[0326] 1 H NMR (400 MHz, 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).

[0327] Example 7

[0328] 1-(5-(2,3-dichlorophenyl)-4-methyl-6-(2H-tetrazol-5-yl)pyrimidin-2-yl)-4-methylpiperidin-4-amine

[0329]

[0330] first step

[0331] tert-Butyl (1-(5-(2,3-dichlorophenyl)-4-methyl-6-(2H-tetrazol-5-yl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0332] Tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3d (50 mg, 0.105 mmol), zinc chloride (14.30 mg, 0.105 mmol) and sodium azide (6.82 mg, 0.105 mmol) were added to 2 mL of methanol in sequence and reacted at room temperature for 2 days. After the reaction was completed, 2 mL of 1 M dilute hydrochloric acid was slowly added dropwise to the reaction solution to quench the reaction. The reaction solution was extracted with ethyl acetate (30 mL×2), and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: 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%.

[0333] MS m / z(ESI):519.6[M+1]

[0334] Step 2

[0335] 1-(5-(2,3-dichlorophenyl)-4-methyl-6-(2H-tetrazol-5-yl)pyrimidin-2-yl)-4-methylpiperidin-4-amine

[0336] Tert-butyl (1-(5-(2,3-dichlorophenyl)-4-methyl-6-(2H-tetrazolyl-5-yl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 7a (15 mg, 0.029 mmol) and 0.5 mL of trifluoroacetic acid were added to 2 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: 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%.

[0337] MS m / z(ESI):419.0[M+1]

[0338] 1H NMR (400 MHz, 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).

[0339] Example 8

[0340] (2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonyl)glycine

[0341] first step

[0342] 2-(4-((tert-Butyloxycarbonyl)amino)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid

[0343] 2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 3 (80 mg, 0.202 mmol), di-tert-butyl dicarbonate (88.34 mg, 0.405 mmol) and sodium carbonate (85.8 mg, 0.809 mmol) were added to 2 mL of a mixed solution (1,4-dioxane: water = 5:1) and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, 1 M dilute hydrochloric acid was added to adjust the pH to 2-3, and then extracted with ethyl acetate (30 mL×2). The combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and 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) in a yield of 39.9%.

[0344] MS m / z(ESI):495.1[M+1]

[0345] Step 2

[0346] (2-(4-((tert-Butyloxycarbonyl)amino)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonyl)glycine tert-butyl ester

[0347] 2-(4-((tert-Butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 8a (50 mg, 0.128 mmol), tert-butyl 2-aminoacetate (33.52 mg, 0.256 mmol), N,N-diisopropylethylamine (16.52 mg, 0.128 mmol), and benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (133.00 mg, 0.256 mmol) were added to 2 mL 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), and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain (2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonyl)glycine tert-butyl ester 8b (40 mg) with a yield of 62%.

[0348] MS m / z(ESI):608.3[M+1]

[0349] Step 3

[0350] (2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonyl)glycine

[0351] (2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonyl)glycine tert-butyl ester 8b (40 mg, 0.079 mmol) was added to 2 mL of 6M dilute hydrochloric acid, heated to 90°C, and reacted for 3 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The obtained residue was prepared by liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: 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%.

[0352] MS m / z(ESI):452.1[M+1]

[0353] 1 H NMR (400 MHz, 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).

[0354] Example 9

[0355] 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid

[0356]

[0357] first step

[0358] (R)-2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)propane-2-sulfenamide

[0359] (3S, 4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester 9a (670 mg, 1.79 mmol) and 1.5 mL of trifluoroacetic acid were added to 6 mL of dichloromethane and reacted at room temperature for 1.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (R)-2-methyl-N-((3S, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)propane-2-sulfinamide 9b (490 mg), which was directly used for the next step without purification.

[0360] MS m / z(ESI):275.1[M+1]

[0361] Step 2

[0362] (R)-N-((3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0363] (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)propane-2-sulfinamide 9b (490 mg, 1.26 mmol), N,N-diisopropylethylamine (135.86 mg, 1.05 mmol) and 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (161.43 mg, 1.05 mmol) were added to 5 mL of N,N-dimethylacetamide, heated to 110°C and reacted for 3 hours. After the reaction was completed, 30 mL of water was added, and the mixture was extracted 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. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to give (R)-N-((3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfinamide 9c (411 mg) in a yield of 99.86%.

[0364] MS m / z(ESI):392.2[M+1]

[0365] Step 3

[0366] 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile

[0367] (R)-N-((3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfinamide 9c (371 mg, 0.948 mmol) and bromosuccinimide (185.51 mg, 1.04 mmol) were added to 5 mL of N,N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the product 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 9d (272.29 mg) with a yield of 100%. The product was directly subjected to the next step without purification.

[0368] MS m / z(ESI):288.1[M+1]

[0369] Step 4

[0370] tert-Butyl ((3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate

[0371] 2-((3S, 4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 9d (272.29 mg, 0.948 mmol), di-tert-butyl dicarbonate (827.20 mg, 3.79 mmol) and triethylamine (287.65 mg, 2.84 mmol) were added to 10 mL of dichloromethane and reacted at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by 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]dec-4-yl)carbamate 9e (340 mg), yield: 92.6%.

[0372] MS m / z(ESI):388.2[M+1]

[0373] Step 5

[0374] 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

[0375] Tert-butyl ((3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate 9e (340 mg, 0.877 mmol) and bromosuccinimide (171.79 mg, 0.965 mmol) were added to 5 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, 30 mL of water was added, and the mixture was extracted 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. The residue was further analyzed and purified by 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) with a yield of 95.3%.

[0376] MS m / z(ESI):466.1[M+1]

[0377] Step 6

[0378] 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

[0379] Under argon protection, tert-butyl ((3S,4S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate 9f (390 mg, 0.836 mmol), (2,3-dichlorophenyl)boronic acid 1e (319.14 mg, 1.67 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (70.03 mg, 0.084 mmol), tetrakis(triphenylphosphine)palladium (78.05 mg, 0.167 mmol) and potassium phosphate (532.78 mg, 2.51 mmol) were added to 8 mL of a mixed solution (1,4-dioxane: water = 7:1), heated to 135°C, and reacted for 3.5 hours. After the reaction, the mixture was cooled, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×3), washed with saturated sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain 9 g (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, with a yield of 85.34%.

[0380] MS m / z(ESI):532.2[M+1]

[0381] Step 7

[0382] 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid

[0383] 9 g (29 mg, 0.055 mmol) 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 and 0.5 mL of concentrated hydrochloric acid were added to a pressure tube, heated to 110°C, and reacted for 1.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give the product 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 9 (1.83 mg), yield: 5.91%.

[0384] MS m / z(ESI):451.1[M+1]

[0385] 1 H NMR (400 MHz, DMSO-d 6 )δ13.30(s, 1H), 7.94(s, 2H), 7.68(d, J=8.1Hz, 1H), 7.42(t, J=7.8Hz, 1 H), 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).

[0386] Example 10

[0387] 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0388]

[0389] first step

[0390] 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0391] 9 g (180 mg, 0.338 mmol) 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 and 1.5 mL of trifluoroacetic acid were added to 6 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3CN), and the product 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 10a (77.68 mg) was obtained with a yield of 41.5%.

[0392] MS m / z(ESI):432.1[M+1]

[0393] 1 H NMR (400 MHz, 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).

[0394] Step 2

[0395] 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0396] 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 10a (30 mg, 0.069 mmol) and 0.3 mL of sodium hydroxide were added to 1.2 mL of ethanol, heated to 80°C, and reacted for 50 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), and the product 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 10 (5.13 mg) was obtained with a yield of 16.2%.

[0397] MS m / z(ESI):450.1[M+1]

[0398] 1 H NMR (400 MHz, 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).

[0399] Embodiment 11

[0400] 2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0401]

[0402] first step

[0403] tert-Butyl ((1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0404] 2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (100 mg, 0.651 mmol), ((4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester 11a (178.42 mg, 0.781 mmol) and N, N-diisopropylethylamine (252.47 mg, 1.95 mmol) were added to 1.2 mL of N, N-dimethylacetamide, heated to 90°C, and reacted for 4 hours. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain ((1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester 11b (223 mg), yield: 99.1%.

[0405] MS m / z(ESI):346.2[M+1]

[0406] Step 2

[0407] tert-Butyl ((1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0408] Tert-butyl ((1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 11b (223 mg, 0.646 mmol) and bromosuccinimide (120.64 mg, 0.678 mmol) were added to 4 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl ((1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 11c (260 mg), with a yield of 94.91%.

[0409] MS m / z(ESI):424.1[M+1]

[0410] Step 3

[0411] tert-Butyl ((1-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0412] Under argon protection, tert-butyl ((1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 11c (260 mg, 0.613 mmol), (2,3-dichlorophenyl)boronic acid 1e (233.84 mg, 1.23 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (51.31 mg, 0.061 mmol), tetrakis(triphenylphosphine)palladium (57.18 mg, 0.123 mmol) and potassium phosphate (390.37 mg, 1.84 mmol) were added to 3.5 mL of a mixed solution (1,4-dioxane: water = 6:1), heated to 130°C, and reacted for 3.5 hours. After the reaction was completed, 30 mL of water was 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. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain 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%.

[0413] MS m / z(ESI):490.1[M+1]

[0414] Step 4

[0415] 2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0416] Tert-butyl ((1-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 11d (80 mg, 0.163 mmol) and 1 mL of trifluoroacetic acid were added to 4 mL of dichloromethane and reacted at room temperature for 50 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the product 2-(4-(aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 11e (63 mg), which was directly subjected to the next step without purification.

[0417] MS m / z(ESI):390.1[M+1]

[0418] Step 5

[0419] 2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0420] 2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 11e (63 mg, 0.161 mmol) and 0.5 mL of sodium hydroxide were added to 2 mL of ethanol, heated to 80°C, and reacted for 2 hours. The residue was concentrated under reduced pressure and subjected to preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: 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) with a yield of 16.4%.

[0421] MS m / z(ESI):408.1[M+1]

[0422] 1 H NMR (400 MHz, 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).

[0423] Example 12

[0424] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine-4-carboxamide

[0425] first step

[0426] tert-Butyl (1-(5-(2-chloro-3-methylphenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0427] Under argon protection, tert-butyl (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3c (80 mg, 0.195 mmol), (2-chloro-3-methylphenyl)boronic acid 12a (66.45 mg, 0.390 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl) (2-amino-1 , 1′-biphenyl-2-yl)palladium (16.33 mg, 0.0195 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (18.20 mg, 0.039 mmol) and potassium phosphate (124.22 mg, 0.585 mmol) were added to 1.5 mL of a mixed solution (1,4-dioxane: water = 4:1), heated to 130°C and reacted for 5 hours. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and 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%.

[0428] MS m / z(ESI):456.2[M+1]

[0429] Step 2

[0430] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine-4-carbonitrile

[0431] Tert-butyl (1-(5-(2-chloro-3-methylphenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 12b (86 mg, 0.189 mmol) and 1.5 mL of trifluoroacetic acid were added to 6 mL of dichloromethane and reacted at room temperature for 40 minutes. After the reaction was completed, the product was concentrated under reduced pressure to obtain the product 2-(4-amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine-4-carbonitrile 12c (67.12 mg), which was directly used for the next step without purification.

[0432] MS m / z(ESI):356.1[M+1]

[0433] Step 3

[0434] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine-4-carboxamide

[0435] 2-(4-amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine-4-carbonitrile 12c (67.12 mg, 0.189 mmol) and 0.5 mL of sodium hydroxide were added to 2 mL of ethanol, heated to 80°C, and reacted for 40 minutes. The residue was concentrated under reduced pressure and subjected to preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: 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) with a yield of 61.6%.

[0436] MS m / z(ESI):374.1[M+1]

[0437] 1 H NMR (400 MHz, 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).

[0438] Embodiment 13

[0439] 2-((R)-1-amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0440] first step

[0441] (R)-2-Methyl-N-((R)-8-azaspiro[4.5]dec-1-yl)propane-2-sulfenamide

[0442] (R)-1-(((R)-tert-butylsulfinyl)amino)tert-butyl-8-azaspiro[4.5]dec-8-carboxylic acid tert-butyl ester 13a (200 mg, 0.558 mmol) and trifluoroacetic acid (636.03 mg, 5.58 mmol) were added to 2 mL of dichloromethane and reacted at room temperature for 1.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (R)-2-methyl-N-((R)-8-azaspiro[4.5]dec-1-yl)propane-2-sulfinamide 13b (144.15 mg) with a yield of 100.00%. The product was directly subjected to the next step without purification.

[0443] MS m / z(ESI):259.2[M+1]

[0444] Step 2

[0445] (R)-2-Methyl-N-((R)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)-propane-2-sulfenamide

[0446] (R)-2-Methyl-N-((R)-8-azaspiro[4.5]dec-1-yl)propane-2-sulfinamide 13b (373.55 mg, 1.04 mmol), 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (80 mg, 0.521 mmol) and N,N-diisopropylethylamine (67.33 mg, 0.521 mmol) were added successively to 2 mL of N,N-dimethylacetamide, heated to 90°C and reacted for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (30 ml × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain (R)-2-methyl-N-((R)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)-propane-2-sulfenamide 13c (100 mg), yield: 51.12%.

[0447] MS m / z(ESI):376.1[M + 1]

[0448] Step 3

[0449] (R)-2-(1-amino-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile

[0450] (R)-2-methyl-N-((R)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)-propane-2-sulfinamide 13c (100 mg, 0.266 mmol) and bromosuccinimide (52.13 mg, 0.293 mmol) were added to 3 mL of N,N-dimethylformamide and reacted overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (R)-2-(1-amino-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 13d (72 mg) with a yield of 99.64%. The product was directly subjected to the next step without purification.

[0451] MS m / z(ESI):272.2[M+1]

[0452] Step 4

[0453] (R)-tert-Butyl (8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate

[0454] (R)-2-(1-amino-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 13d (72 mg, 0.265 mmol), di-tert-butyl dicarbonate (115.82 mg, 0.531 mmol) and triethylamine (53.70 mg, 0.531 mmol) were added to 2 mL of dichloromethane and reacted at room temperature overnight. After the reaction was completed, the product was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (R)-tert-butyl (8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate 13e (80 mg), with a yield of 81.17%.

[0455] MS m / z(ESI):372.2[M+1]

[0456] Step 5

[0457] (R)-tert-Butyl (8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate

[0458] (R)-(8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamic acid tert-butyl ester 13e (72 mg, 0.194 mmol) and bromosuccinimide (37.95 mg, 0.213 mmol) were added to 2 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), and dried over anhydrous sodium sulfate. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (R)-(8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamic acid tert-butyl ester 13f (80 mg). Yield: 91.65%.

[0459] MS m / z(ESI):395.9[M-56]

[0460] Step 6

[0461] tert-Butyl ((1R)-8-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate

[0462] Under argon protection, (R)-tert-butyl (8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate 13f (30 mg, 0.067 mmol), (2,3-dichlorophenyl)boronic acid 1e (25.42 mg, 0.133 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (11.15 mg, 0.013 mmol), tetrakis(triphenylphosphine)palladium (12.43 mg, 0.027 mmol) and potassium phosphate (42.44 mg, 0.199 mmol) were added to 2 mL of a mixed solution (1,4-dioxane: water = 5:1), heated to 130°C and reacted for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain 13 g (30 mg) of tert-butyl ((1R)-8-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate, with a yield of 87.20%.

[0463] MS m / z(ESI):515.9[M+1]

[0464] Step 7

[0465] 2-((R)-1-amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0466] 13 g (45 mg, 0.087 mmol) of tert-butyl ((1R)-8-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate and 0.5 mL of trifluoroacetic acid were added to 2 mL of dichloromethane and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 2-((R)-1-amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 13h (36 mg) with a yield of 99.24%. The product was directly subjected to the next step without purification.

[0467] MS m / z(ESI):416.1[M+1]

[0468] Step 8

[0469] 2-((R)-1-amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0470] 2-((R)-1-amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 13h (36 mg, 0.086 mmol) and 0.5 mL of 6M sodium hydroxide were added to 2 mL of ethanol, heated to 80°C, and reacted for 0.5 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN), to give 2-((R)-1-amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 13 (6 mg), yield: 15.70%.

[0471] MS m / z(ESI):433.9[M+1]

[0472] 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).

[0473] Embodiment 14

[0474] 2-(4-aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0475]

[0476] first step

[0477] tert-Butyl (1-(4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate

[0478] 2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (80 mg, 0.521 mmol), piperidine-4-carbamic acid tert-butyl ester 14a (125.20 mg, 0.625 mmol) and N, N-diisopropylethylamine (201.98 mg, 1.56 mmol) were added to 2 mL of N, N-dimethylacetamide, heated to 90°C, and reacted for 3 hours. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester 14b (160 mg), yield: 96.77%.

[0479] MS m / z(ESI):262.0[M+1-56]

[0480] Step 2

[0481] tert-Butyl (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate

[0482] Tert-butyl (1-(4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate 14b (160 mg, 0.504 mmol) and bromosuccinimide (107.67 mg, 0.605 mmol) were added to 2 mL of N,N-dimethylformamide and reacted overnight at room temperature. After the reaction was completed, 30 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate 14c (180 mg), yield: 90.1%.

[0483] MS m / z(ESI):342.0[M+1-56]

[0484] Step 3

[0485] tert-Butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate

[0486] Under argon protection, tert-butyl (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate 14c (100 mg, 0.252 mmol), (2,3-dichlorophenyl)boronic acid 1e (96.31 mg, 0.505 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (21.13 mg, 0.025 mmol), tetrakis(triphenylphosphine)palladium (23.55 mg, 0.050 mmol) and potassium phosphate (160.69 mg, 0.757 mmol) were added to 2.2 mL of a mixed solution (1,4-dioxane: water = 10:1), heated to 130°C and reacted for 5 hours. After the reaction, the mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate 14d (100 mg), with a yield of 85.71%.

[0487] MS m / z(ESI):406.0[M+1-56]

[0488] Step 4

[0489] 2-(4-aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0490] Tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate 14d (100 mg, 0.216 mmol) and trifluoroacetic acid (24.66 mg, 0.216 mmol) were added to 4 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 2-(4-aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 14e (100 mg) with a yield of 97.08%. The product was directly subjected to the next step without purification.

[0491] MS m / z(ESI):361.9[M+1]

[0492] Step 5

[0493] 2-(4-aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0494] 2-(4-aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 14e (100 mg, 0.210 mmol) and 0.3 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, heated to 80°C, and reacted for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μn, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN), to give 2-(4-aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 14 (40 mg), yield: 49.27%.

[0495] MS m / z(ESI):379.9[M+1]

[0496] 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).

[0497] Embodiment 15

[0498] 2-((R)-3-(Aminomethyl)pyrrolidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0499]

[0500]

[0501] first step

[0502] (R)-tert-Butyl ((1-(4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate

[0503] 2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (50 mg, 0.326 mmol), (S)-(pyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester 15a (92.49 mg, 0.391 mmol) and N,N-diisopropylethylamine (126.24 mg, 0.977 mmol) were added to 2 mL of N,N-dimethylacetamide, heated to 90°C, and reacted for 3 hours. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (R)-((1-(4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamic acid tert-butyl ester 15b (80 mg), with a yield of 77.42%.

[0504] MS m / z(ESI):318.2[M+1]

[0505] Step 2

[0506] (R)-tert-Butyl ((1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate

[0507] (R)-tert-butyl ((1-(4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate 15b (80 mg, 0.252 mmol) and bromosuccinimide (67.29 mg, 0.378 mmol) were added to 2 mL of N,N-dimethylformamide and reacted overnight at room temperature. After the reaction was completed, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (R)-((1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate 15c (80 mg) with a yield of 80.1%.

[0508] MS m / z(ESI):341.9[M+1-56]

[0509] Step 3

[0510] tert-Butyl (((3R)-1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate

[0511] Under argon protection, (R)-tert-butyl ((1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate 15c (80 mg, 0.202 mmol), (2,3-dichlorophenyl)boronic acid 1e (96.31 mg, 0.505 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (16.90 mg, 0.020 mmol), tetrakis(triphenylphosphine)palladium (18.84 mg, 0.040 mmol) and potassium phosphate (128.55 mg, 0.606 mmol) were added to 2.2 mL of a mixed solution (1,4-dioxane: water = 10:1), heated to 130°C and reacted for 5 hours. After the reaction, the mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and 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) with a yield of 74.99%.

[0512] MS m / z(ESI):461.9[M+1]

[0513] Step 4

[0514] 2-((R)-3-(Aminomethyl)pyrrolidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0515] Tert-butyl (((3R)-1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate 15d (70 mg, 0.151 mmol) and trifluoroacetic acid (1.53 g, 13.42 mmol) were added to 4 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 2-((R)-3-(aminomethyl)pyrrolidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 15e (50 mg) with a yield of 91.17%. The product was directly subjected to the next step without purification.

[0516] MS m / z(ESI):362.1[M+1]

[0517] Step 5

[0518] 2-((R)-3-(Aminomethyl)pyrrolidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0519] 2-((R)-3-(Aminomethyl)pyrrolidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 15e (50 mg, 0.138 mmol) and 0.3 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, heated to 80°C, and reacted for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: 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%.

[0520] MS m / z(ESI):380.0[M+1]

[0521] 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).

[0522] Example 16

[0523] 2-((1R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0524]

[0525]

[0526] first step

[0527] tert-Butyl ((1R,5S)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate

[0528] 2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (60 mg, 0.391 mmol), ((1R, 5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamic acid tert-butyl ester 16a (106.11 mg, 0.469 mmol), and N,N-diisopropylethylamine (151.49 mg, 1.17 mmol) were added to 2 mL of N,N-dimethylacetamide, heated to 90°C, and reacted for 3 hours. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl ((1R, 5S)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate 16b (130 mg) with a yield of 96.89%.

[0529] MS m / z(ESI):344.0[M+1]

[0530] Step 2

[0531] tert-Butyl ((1R,5S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate

[0532] Tert-butyl ((1R,5S)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate 16b (130 mg, 0.379 mmol) and bromosuccinimide (80.85 mg, 0.454 mmol) were added to 2 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and 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]octan-3-yl)carbamate 16c (150 mg) in a yield of 93.83%.

[0533] MS m / z(ESI):365.9[M+1-56]

[0534] Step 3

[0535] tert-Butyl ((1R,5S)-8-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate

[0536] Under argon protection, tert-butyl ((1R,5S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate 16c (150 mg, 0.355 mmol), (2,3-dichlorophenyl)boronic acid 1e (169.44 mg, 0.888 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (29.74 mg, 0.036 mmol), tetrakis(triphenylphosphine)palladium (33.15 mg, 0.071 mmol) and potassium phosphate (226.17 mg, 1.07 mmol) were added to 2.2 mL of a mixed solution (1,4-dioxane: water = 10:1), heated to 130°C and reacted for 5 hours. After the reaction, the mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl ((1R, 5S)-8-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate 16d (150 mg) in a yield of 86.48%.

[0537] MS m / z(ESI):488.1[M+1]

[0538] Step 4

[0539] 2-((1R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0540] Tert-butyl ((1R, 5S)-8-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate 16d (150 mg, 0.307 mmol) and 1 mL of trifluoroacetic acid were added to 4 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated 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) with a yield of 83.86%. The product was directly subjected to the next step without purification.

[0541] MS m / z(ESI):387.9[M+1]

[0542] Step 5

[0543] 2-((1R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0544] 2-((1R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 16e (100 mg, 0.258 mmol) and 0.3 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, heated to 80°C, and reacted for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN), to give 2-((1R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 16 (45 mg), yield: 41.75%.

[0545] MS m / z(ESI):405.9[M+1]

[0546] 1 H NMR (400 MHz, 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, 2 H), 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).

[0547] Embodiment 17

[0548] 5-(2,3-Dichlorophenyl)-2-(4-guanidino-4-methyl-1-piperidinyl)-6-methylpyrimidine-4-carboxamide

[0549]

[0550] first step

[0551] tert-Butyl N-[(tert-Butoxycarbonylamino)-[[1-[4-carbamoyl-5-(2,3-dichlorophenyl)-6-methyl-pyrimidin-2-yl]-4-methyl-4-piperidinyl]amino]methylene]carbamate

[0552] 2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 4 (14.0 mg, 35.51 μmol), 1,3-di(tert-butoxycarbonyl)-2-methylisothiourea (11.34 mg, 39.06 μmol), cuprous iodide (13.52 mg, 71.01 μmol) and potassium carbonate (19.63 mg, 142.02 μmol) were added successively to 1 mL of tetrahydrofuran, the atmosphere was replaced with nitrogen three times, the external temperature was heated to 60°C and stirring was continued for 24 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL), the filtrate was combined, and concentrated to dryness under reduced pressure to give crude 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 (oil), which was used directly in the next step without purification.

[0553] MS m / z(ESI):537.2[M-100]

[0554] Step 2

[0555] 5-(2,3-Dichlorophenyl)-2-(4-guanidino-4-methyl-1-piperidinyl)-6-methylpyrimidine-4-carboxamide

[0556] N-[(tert-butoxycarbonylamino)-[[1-[4-carbamoyl-5-(2,3-dichlorophenyl)-6-methyl-pyrimidin-2-yl]-4-methyl-4-piperidinyl]amino]methylene]carbamic acid tert-butyl ester 17a (22 mg, 34.56 μmol) and TFA (1.54 g, 13.51 mmol, 1 mL) were added to 3 mL of dichloromethane in sequence and stirred for 6 hours at room temperature. The reaction solution 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 obtain 5-(2,3-dichlorophenyl)-2-(4-guanidino-4-methyl-1-piperidinyl)-6-methylpyrimidine-4-carboxamide 17 (7.5 mg, total yield of two-step reaction 38.4%).

[0557] MS m / z(ESI):435.9[M+1]

[0558] 1 H NMR (400 MHz, CD 3OD) 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).

[0559] Embodiment 18

[0560] 2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0561]

[0562]

[0563] first step

[0564] tert-Butyl (3-(4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate

[0565] 2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (70 mg, 0.355 mmol), (3-azabicyclo[3.1.0]hexane-6-yl)carbamic acid tert-butyl ester 17a (91.48 mg, 0.461 mmol) and N,N-diisopropylethylamine (137.62 mg, 1.06 mmol) were added to 2 mL of N,N-dimethylacetamide, heated to 90°C and reacted for 3 hours. After the reaction, 20 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by 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) with a yield of 98.27%.

[0566] MS m / z(ESI):260.0[M+1-56]

[0567] Step 2

[0568] tert-Butyl (3-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate

[0569] Tert-butyl (3-(4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate 17b (110 mg, 0.349 mmol) and bromosuccinimide (93.12 mg, 0.523 mmol) were added to 2 mL of N,N-dimethylformamide and reacted overnight at room temperature. After the reaction was completed, 30 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) 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%.

[0570] MS m / z(ESI):340.0[M+1-56]

[0571] Step 3

[0572] tert-Butyl (3-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate

[0573] Under argon protection, tert-butyl (3-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate 18c (110 mg, 0.279 mmol), (2,3-dichlorophenyl)boronic acid 1e (122.45 mg, 0.642 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (23.36 mg, 0.028 mmol), tetrakis(triphenylphosphine)palladium (26.04 mg, 0.056 mmol) and potassium phosphate (177.67 mg, 0.837 mmol) were added to 2.3 mL of a mixed solution (1,4-dioxane: water = 7:1), heated to 130°C and reacted for 5 hours. After the reaction, the mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain 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) in a yield of 77.86%.

[0574] MS m / z(ESI):403.8[M+1-56]

[0575] Step 4

[0576] 2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0577] Tert-butyl (3-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate 18d (100 mg, 0.217 mmol) and trifluoroacetic acid (24.77 mg, 0.217 mmol) were added to 4 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated 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) with a yield of 99.68%. The product was directly subjected to the next step without purification.

[0578] MS m / z(ESI):359.7[M+1]

[0579] Step 5

[0580] 2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0581] 2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 18e (78 mg, 0.217 mmol) and 0.3 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, heated to 80°C, and reacted for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN), to give 2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 18 (45 mg), yield: 41.74%.

[0582] MS m / z(ESI):377.7[M+1]

[0583] 1H 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).

[0584] Embodiment 19

[0585] 2-((R)-6-amino-5,6-dihydrospiro[cyclopentyl[b]pyridine-7,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0586]

[0587]

[0588] first step

[0589] (R)-N-((R)-5,6-Dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidin]-6-yl)-2-methylpropane-2-sulfenamide

[0590] (R)-6-(((R)-tert-butylsulfinyl)amino)tert-butyl-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidine]-1′-carboxylic acid tert-butyl ester 19a (150 mg, 0.368 mmol) and 1 mL of trifluoroacetic acid were added to 6 mL of dichloromethane and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (R)-N-((R)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidine]-6-yl)-2-methylpropane-2-sulfinamide 19b (113.15 mg) with a yield of 100.00%. The product was directly subjected to the next step without purification.

[0591] MS m / z(ESI):308.2[M+1]

[0592] Step 2

[0593] (R)-N-((R)-1′-(4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidin]-6-yl)-2-methylpropane-2-sulfenamide

[0594] (R)-N-((R)-5,6-Dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidin]-6-yl)-2-methylpropane-2-sulfinamide 19b (113.15 mg, 0.368 mmol), 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (60 mg, 0.391 mmol) and N,N-diisopropylethylamine (50.49 mg, 0.391 mmol) were added successively to 3 mL of N,N-dimethylacetamide, heated to 90°C and reacted for 3 hours. After the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate (30 ml × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (R)-N-((R)-1′-(4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidin]-6-yl)-2-methylpropane-2-sulfenamide 19c (130 mg). Yield: 78.37%. The product was directly used for the next step without purification.

[0595] MS m / z(ESI):424.9[M+1]

[0596] Step 3

[0597] (R)-tert-Butyl (1′-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidin]-6-yl)carbamate

[0598] (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, 0.306 mmol) and iodosuccinimide (70.85 mg, 0.398 mmol) were added to 2 mL of N,N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction was completed, iodosuccinimide (70.85 mg, 0.398 mmol) was added and the reaction was continued for 2 hours. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed twice with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product, di-tert-butyl dicarbonate (200.48 mg, 0.919 mmol) and N,N-diethylethylamine (154.92 mg, 1.53 mmol) were added to 5 mL of dichloromethane and reacted at room temperature overnight. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed twice with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (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 (50 mg), yield: 32.7%.

[0599] MS m / z(ESI):499.1[M+1]

[0600] Step 4

[0601] (R)-tert-Butyl (1′-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidin]-6-yl)carbamate

[0602] Under argon protection, 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, 0.100 mmol), (2,3-dichlorophenyl)boronic acid 1e (47.76 mg, 0.250 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (8.38 mg, 0.010 mmol), tetrakis(triphenylphosphine)palladium (9.34 mg, 0.020 mmol) and potassium phosphate (63.76 mg, 0.300 mmol) were added to 2.3 mL of a mixed solution (1,4-dioxane: water = 7:1), heated to 130° C., and reacted for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain (R)-(1′-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidinyl]-6-yl)carbamic acid tert-butyl ester 19e (45 mg) in a yield of 79.48%.

[0603] MS m / z(ESI):564.5[M+1]

[0604] Step 5

[0605] 2-((R)-6-amino-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0606] 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, 0.080 mmol) and 1 mL of trifluoroacetic acid were added to 4 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated 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) with a yield of 100%. The product was directly subjected to the next step without purification.

[0607] MS m / z(ESI):465.1[M+1]

[0608] Step 6

[0609] 2-((R)-6-amino-5,6-dihydrospiro[cyclopentyl[b]pyridine-7,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0610] 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, 0.080 mmol) and 0.3 mL of 6M sodium hydroxide were added to 2 mL of ethanol, heated to 80°C, and reacted for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 2-((R)-6-amino-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 19 (20 mg), yield: 42.11%.

[0611] MS m / z(ESI):482.7[M+1]

[0612] 1 H NMR (400 MHz, 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, 2 H), 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).

[0613] Embodiment 20

[0614] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0615] first step

[0616] (R)-N-((S)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1-yl)-2-methylpropane-2-sulfenamide

[0617] At room temperature, 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 (260 mg, 639.48 μmol) in dichloromethane (4 mL), and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the product (R)-N-((S)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)-2-methylpropane-2-sulfinamide 20b (195.98 mg), with a yield of 100.00%. The product was used directly in the next step without separation and purification.

[0618] MS m / z(ESI):307.2[M+1]

[0619] Step 2

[0620] (R)-N-((S)-1′-(4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0621] At room temperature, 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (78.56 mg, 511.59 μmol), (R)-N-((S)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)-2-methylpropane-2-sulfenamide 20b (195.98 mg, 639.49 μmol), N,N-dimethylacetamide (2 mL), and N,N-diisopropylethylamine (247.94 mg, 1.92 mmol) were added sequentially into a 15 ml single-necked bottle, and the temperature was raised to 100° C. for reaction for 4 hours. 20 mL of water was added to the reaction solution, extracted three times with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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-sulfenamide 20c (265 mg), yield: 97.83%.

[0622] MS m / z(ESI):424.2[M+1]

[0623] Step 3

[0624] (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-6-methylpyrimidine-4-carbonitrile

[0625] Bromosuccinimide (122.48 mg, 688.19 μmol) 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 (265 mg, 0.626 mmol) were added to 3 mL of N,N-dimethylformamide and reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-methylpyrimidine-4-carbonitrile 20d (199.83 mg) with a yield of 100%. The product was used directly in the next step without separation and purification.

[0626] MS m / z(ESI):303.2[M-17+1]

[0627] Step 4

[0628] (S)-tert-Butyl (1′-(4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate

[0629] (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-6-methylpyrimidine-4-carbonitrile 20d (199.83 mg, 625.64 μmol), di-tert-butyl dicarbonate (409.64 mg, 1.88 mmol), triethylamine (189.92 mg, 1.88 mmol) and dichloromethane (4 mL) were added to a 15 ml single-necked bottle and reacted at room temperature for 2 hours. 20 mL of water was added to the reaction solution, extracted three times with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give (S)-(1′-(4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamic acid tert-butyl ester 20e (180 mg), yield: 68.58%.

[0630] MS m / z(ESI):420.2[M+1]

[0631] Step 5

[0632] (S)-tert-Butyl (1′-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate

[0633] Bromosuccinimide (84.00 mg, 471.97 μmol) and (S)-tert-butyl (1′-(4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 20e (180 mg, 429.06 μmol) were added to 2.5 mL of N,N-dimethylformamide and the temperature was gradually raised to room temperature for reaction overnight. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give (S)-(1′-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamic acid tert-butyl ester 20f (200 mg), yield: 93.52%.

[0634] MS m / z(ESI):498.1[M+1]

[0635] Step 6

[0636] (S)-tert-Butyl (1′-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate

[0637] Under argon protection, tert-butyl (S)-(1′-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 20f (200 mg, 401.27 μmol), (2,3-dichlorophenyl)boronic acid 1e (153.14 mg, 802.55 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (33.60 mg, 40.13 μmol), tetrakis(triphenylphosphine)palladium (37.45 mg, 80.25 μmol) and potassium phosphate (255.65 mg, 1.20 mmol) were added to 2.9 mL of a mixed solution (1,4-dioxane: water = 6:1), and the temperature was raised to 130° C. for reaction for 4 hours. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 20 g (190 mg) of tert-butyl (S)-(1′-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate, with a yield of 83.88%.

[0638] MS m / z(ESI):507.7[M-56+1]

[0639] Step 7

[0640] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0641] At room temperature, trifluoroacetic acid (1 mL) was added to a solution of 20 g (190 mg, 336.58 μmol) of tert-butyl (S)-(1′-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate in dichloromethane (4 mL), and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 20 h (156.3 mg), with a yield of 100%.

[0642] MS m / z(ESI):447.1[M-17+1]

[0643] Step 8

[0644] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0645] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 20h (156.3 mg, 336.57 μmol) and 0.5 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol and heated to 80°C for 40 minutes. The reaction solution was concentrated under reduced pressure and the obtained residue was subjected to preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give the product 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 20 (52.31 mg), yield: 32.09%.

[0646] MS m / z(ESI):482.2[M+1]

[0647] 1H NMR (400 MHz, 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).

[0648] Embodiment 21

[0649] 2-((S)-1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0650]

[0651] first step

[0652] (R)-N-((S)-5-Methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfenamide

[0653] At room temperature, trifluoroacetic acid (1 mL) was added to a solution of (S)-1-(((R)-tert-butylsulfinyl)amino)-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester 21a (200 mg, 455.97 μmol) in dichloromethane (5 mL), and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the product (R)-N-((S)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl)-2-methylpropane-2-sulfinamide 21b (154.35 mg), with a yield of 100.00%. The product was used directly in the next step without separation and purification.

[0654] MS m / z(ESI):337.2[M+1]

[0655] Step 2

[0656] (R)-N-((S)-1′-(4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)-2-methylpropane-2-sulfenamide

[0657] At room temperature, 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (63.66 mg, 414.52 μmol), (R)-N-((S)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl)-2-methylpropane-2-sulfinamide 21b (154.35 mg, 455.97 μmol), N,N-dimethylacetamide (2.5 mL), and N,N-diisopropylethylamine (267.86 mg, 2.07 mmol) were added sequentially into a 15 ml single-necked bottle, and the temperature was raised to 100°C for reaction for 3.5 hours. After the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: eluent A) to give (R)-N-((S)-1′-(4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl)-2-methylpropane-2-sulfenamide 21c (185 mg) with a yield of 98.39%.

[0658] MS m / z(ESI):454.2[M+1]

[0659] Step 3

[0660] (S)-2-(1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-6-methylpyrimidine-4-carbonitrile

[0661] Bromosuccinimide (72.27 mg, 406.04 μmol) 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 (184.18 mg, 406.04 μmol) were added to 2 mL of N,N-dimethylformamide and gradually heated to room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (S)-2-(1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-6-methylpyrimidine-4-carbonitrile 2Id (141.88 mg) with a yield of 100%. The product was used directly in the next step without separation and purification.

[0662] MS m / z(ESI):333.1[M-17 + 1]

[0663] Step 4

[0664] (S)-tert-Butyl (1′-(4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate

[0665] (S)-2-(1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-6-methylpyrimidine-4-carbonitrile 21d (141.07 mg, 403.71 μmol), di-tert-butyl dicarbonate (264.33 mg, 1.21 mmol), triethylamine (204.25 mg, 2.02 mmol) and dichloromethane (4 mL) were added to a 15 ml single-necked bottle and reacted at room temperature for 3 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted three times with dichloromethane (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain (S)-(1′-(4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl)carbamic acid tert-butyl ester 21e (130 mg) with a yield of 71.63%.

[0666] MS m / z(ESI):450.3[M+1]

[0667] Step 5

[0668] (S)-tert-Butyl (1′-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate

[0669] Bromosuccinimide (51.47 mg, 289.18 μmol) and (S)-tert-butyl (1′-(4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl)carbamate 21e (130 mg, 289.18 μmol) were added to 2.5 mL of N,N-dimethylformamide and the temperature was gradually raised to room temperature for 5 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain (S)-(1′-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl)carbamic acid tert-butyl ester 21f (150 mg), yield: 98.16%.

[0670] MS m / z(ESI):472.1[M-56+1]

[0671] Step 6

[0672] (S)-tert-Butyl (1′-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl)carbamate

[0673] Under argon protection, (S)-tert-butyl (1′-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl)carbamate 21f (150 mg, 283.85 μmol), (2,3-dichlorophenyl)boronic acid 1e (108.33 mg, 567.71 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (23.77 mg, 28.39 μmol), tetrakis(triphenylphosphine)palladium (26.49 mg, 56.77 μmol) and potassium phosphate (180.85 mg, 851.56 μmol) were added to 2.3 mL of a mixed solution (1,4-dioxane: water = 7:1), and the temperature was raised to 130° C. for 4 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 21 g (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′-piperidine]-3-yl)carbamate, with a yield of 82.96%.

[0674] MS m / z(ESI):594.2[M+1]

[0675] Step 7

[0676] 2-((S)-1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0677] At room temperature, trifluoroacetic acid (1 mL) was added to a solution of 21 g (140 mg, 235.48 μmol) of tert-butyl (S)-(1′-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl)carbamate in dichloromethane (4 mL), and the mixture was reacted at room temperature for 40 minutes. After the reaction, the reaction solution was concentrated under reduced pressure to obtain 2-((S)-1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 21 h (116.42 mg), with a yield of 100%. The product was used directly in the next step without separation and purification.

[0678] MS m / z(ESI):477.1[M-17+1]

[0679] Step 8

[0680] 2-((S)-1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0681] 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, 235.47 μmol) and 0.5 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, heated to 80°C, and reacted for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give the product 2-((S)-1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 21 (24.32 mg), yield: 19.55%.

[0682] MS m / z(ESI):512.2[M+1]

[0683] 1 H NMR (400 MHz, 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), 3.8 0 (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).

[0684] Embodiment 22

[0685] (1S)-1′-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

[0686]

[0687] first step

[0688] (R)-N-((1S)-1′-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-methylpropane-2-sulfenamide

[0689] At room temperature, 5-(2,3-dichlorophenyl)-4-methoxy-6-methyl-2-(methylsulfonyl)pyrimidine 22a (75 mg, 216 μmol), (R)-N-((S)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)-2-methylpropane-2-sulfinamide 20b (79 mg, 260 μmol), N-methylpyrrolidone (1 mL), and N,N-diisopropylethylamine (28 mg, 216 μmol) were added sequentially into a 15 mL single-necked bottle, heated to 100° C., and reacted for 18 hours. After the reaction, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: eluent A) to obtain (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-sulfenamide 22b (70 mg), yield: 56.5%.

[0690] MS m / z(ESI):573.2[M+1]

[0691] Step 2

[0692] (1S)-1′-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine

[0693] Bromosuccinimide (20 mg, 115 μmol) and (R)-N-((1S)-1′-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-methylpropane-2-sulfenamide 22b (60 mg, 104 μmol) were added to 1 mL of N,N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give the product (1S)-1′-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 22 (5.0 mg), yield: 10%.

[0694] MS m / z(ESI):468.5[M+1]

[0695] 1 H NMR (400 MHz, 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).

[0696] Embodiment 23

[0697] 2-((R)-2-amino-2,3-dihydrospiro[indene-1,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0698] first step

[0699] (R)-N-((R)-2,3-Dihydrospiro[indene-1,4′-piperidin]-2-yl)-2-methylpropane-2-sulfenamide

[0700] Trifluoroacetic acid (1.53 g, 13.42 mmol, 1 mL) and (R)-2-(((R)-tert-butylsulfinyl)amino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylic acid tert-butyl ester 23a (400 mg, 983.81 μmol) were added to 6 mL of dichloromethane and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the product (R)-N-((R)-2,3-dihydrospiro[indene-1,4′-piperidine]-2-yl)-2-methylpropane-2-sulfinamide 23b (287 mg) with a yield of 95.19%. The product was used directly in the next step without purification.

[0701] MS m / z(ESI):307.3[M+1]

[0702] Step 2

[0703] (R)-N-((R)-1′-(4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]-2-yl)-2-methylpropane-2-sulfenamide

[0704] 2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (120 mg, 781.41 μmol), (R)-N-((R)-2,3-dihydrospiro[indene-1,4′-piperidine]-2-yl)-2-methylpropane-2-sulfinamide 23b (287.37 mg, 937.69 μmol) [N,N-diisopropylethylamine (302.97 mg, 2.34 mmol) were added successively to 2 mL of N,N-dimethylacetamide, the temperature was raised to 90°C, and the reaction was carried out for 2 hours. After the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×2). The aqueous layer was separated and the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further analyzed and 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-sulfenamide 23c (170 mg) in a yield of 51.36%.

[0705] MS m / z(ESI):424.0[M+1]

[0706] Step 3

[0707] (R)-2-(2-Amino-2,3-dihydrospiro[indene-1,4′-piperidinyl]-1′-yl)-6-methylpyrimidine-4-carbonitrile

[0708] (R)-N-((R)-1′-(4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]-2-yl)-2-methylpropane-2-sulfinamide 23c (170 mg, 401.35 μmol) and bromosuccinimide (85.72 mg, 481.62 μmol) were added to 2 mL of N,N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated 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) with a yield of 99.85%. The product was used directly in the next step without purification.

[0709] MS m / z(ESI):320.1[M+H]

[0710] Step 4

[0711] (R)-tert-Butyl (1′-(4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]-2-yl)carbamate

[0712] (R)-2-(2-Amino-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-6-methylpyrimidine-4-carbonitrile 23d (128 mg, 400.75 μmol), di-tert-butyl dicarbonate (262.39 mg, 1.20 mmol, 276.20 μL) and triethylamine (202.76 mg, 2.00 mmol, 278.51 μL) were added successively to 4 mL of dichloromethane and reacted at room temperature for 3 hours. After the reaction, 20 mL of water was added, extracted with dichloromethane (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further analyzed and 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′-piperidine]-2-yl)carbamic acid tert-butyl ester 23e (60 mg) with a yield of 35.69%.

[0713] MS m / z(ESI):420.1[M+1]

[0714] Step 5

[0715] (R)-tert-Butyl (1′-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]-2-yl)carbamate

[0716] (R)-tert-Butyl (1′-(4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-2-yl)carbamate 23e (60 mg, 143.02 μmol) and bromosuccinimide (33.09 mg, 185.93 μmol) were added to 2 mL of N,N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction, 30 mL 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 obtain (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 (70 mg), yield: 98.20%, without purification, directly used in the next step.

[0717] MS m / z(ESI):498.1[M+1]

[0718] Step 6

[0719] (R)-tert-Butyl (1′-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]-2-yl)carbamate

[0720] Under argon protection, 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, 140.45 μmol), (2,3-dichlorophenyl)boronic acid 1e (67.00 mg, 351.11 μmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (13.1 1 mg, 28.09 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′, 6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium (11.76 mg, 14.04 μmol) and potassium phosphate (89.44 mg, 421.34 μmol) were added to 2.3 mL of a mixed solution (1,4-dioxane: water = 7:1), the temperature was raised to 130°C, and the reaction was carried out for 4 hours. After the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to obtain 23 g (70 mg) of tert-butyl (R)-(1′-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-2-yl)carbamate, with a yield of 88.29%.

[0721] MS m / z(ESI):565.2[M+1]

[0722] Step 7

[0723] 2-((R)-2-Amino-2,3-dihydrospiro[indene-1,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0724] 23 g (80 mg, 141.72 μmol) 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 (1.53 g, 13.42 mmol, 1 mL) were added to 4 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated 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), with a yield of 99.98%. The mixture was used directly in the next step without purification.

[0725] MS m / z(ESI):463.9[M+1]

[0726] Step 8

[0727] 2-((R)-2-amino-2,3-dihydrospiro[indene-1,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0728] 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, 141.69 μmol) and 0.3 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, heated to 80°C, and reacted for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give the product 2-((R)-2-amino-2,3-dihydrospiro[indene-1,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 23 (23 mg), yield: 33.31%.

[0729] MS m / z(ESI):482.1[M+1]

[0730] 1 H NMR (400 MHz, 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).

[0731] Embodiment 26

[0732] (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0733] first step

[0734] (R)-N-((S)-1′-(4-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1-yl)-2-methylpropane-2-sulfenamide

[0735] At room temperature, 2-chloropyrimidine-4-carbonitrile 26a (80 mg, 573.30 μmol), (R)-N-((S)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)-2-methylpropane-2-sulfenamide 20b (226 mg, 737.44 μmol), N,N-dimethylacetamide (3 mL) and N,N-diisopropylethylamine (370.48 mg, 2.87 mmol, 499.29 μL) were added sequentially into a 25 mL single-necked bottle, the temperature was raised to 90°C, and the reaction was carried out for 3 hours. After the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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-sulfenamide 26b (210 mg) with a yield of 89.44%.

[0736] MS m / z(ESI):410.2[M+1]

[0737] Step 2

[0738] (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)pyrimidine-4-carbonitrile

[0739] Under ice bath, bromosuccinimide (109.52 mg, 615.31 μmol) 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 (210 mg, 512.76 μmol) in N,N-dimethylformamide (2 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile 26c (156 mg) with a yield of 99.63%. The product was used directly in the next step without separation and purification.

[0740] MS m / z(ESI):289.1[M-17+1]

[0741] Step 3

[0742] (S)-tert-Butyl (1′-(4-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1-yl)carbamate

[0743] (S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)pyrimidine-4-carbonitrile 26c (156 mg, 510.85 μmol), di-tert-butyl dicarbonate (334.47 mg, 1.53 mmol), dichloromethane (5 mL) and triethylamine (258.46 mg, 2.55 mmol) were added sequentially into a 15 mL single-necked bottle and reacted at room temperature for 3 hours. After the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain (S)-tert-butyl (1′-(4-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 26d (120 mg) with a yield of 57.93%.

[0744] MS m / z(ESI):406.0[M+1]

[0745] Step 4

[0746] (S)-tert-Butyl (1′-(5-bromo-4-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1-yl)carbamate

[0747] To a solution of tert-butyl (S)-(1′-(4-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 26d (120 mg, 295.94 μmol) in dichloromethane (2 mL) was slowly added bromosuccinimide (63.21 mg, 355.12 μmol) at 0°C. After the addition was complete, the reaction solution was warmed to room temperature and reacted at room temperature for 2 hours. After the reaction, water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain (S)-(1′-(5-bromo-4-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamic acid tert-butyl ester 26e (140 mg) with a yield of 7.66%.

[0748] MS m / z(ESI):428.1[M+1-56]

[0749] Step 5

[0750] (S)-tert-Butyl (1′-(4-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate

[0751] Under argon protection, tert-butyl (S)-(1′-(5-bromo-4-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1-yl)carbamate 26e (140 mg, 289.02 μmol), (2,3-dichlorophenyl)boronic acid 1e (137.88 mg, 722.56 μmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (26. 97 mg, 57.80 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′, 6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl) palladium (II) (24.20 mg, 28.90 μmol), potassium phosphate (184.05 mg, 867.07 μmol) and 2.3 mL of a mixed solution (1,4-dioxane: water = 7:1), heated to 130°C, and reacted for 4 hours. After the reaction was completed, cooled to room temperature. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give (S)-tert-butyl (1′-(4-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 26f (150 mg) in a yield of 94.28%.

[0752] MS m / z(ESI):493.9[M+1-56]

[0753] Step 6

[0754] (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

[0755] Trifluoroacetic acid (1.53 g, 13.42 mmol, 1 mL) was added to a solution of (S)-(1′-(4-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamic acid tert-butyl ester 26f (150 mg, 272.49 μmol) in dichloromethane (4 mL) at room temperature and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile 26g (122 mg) with a yield of 99.41%.

[0756] MS m / z(ESI):433.1[M-17+1]

[0757] Step 7

[0758] (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0759] To a solution of 26 g (122 mg) of (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile in ethanol (2 mL) was added sodium hydroxide solution (6 M, 0.3 mL) and the mixture was reacted at 80° C. for 40 minutes. LC-MS detected that the reaction was incomplete, and sodium hydroxide solution (6 M, 0.3 mL) and ethanol (2 mL) were added, and the reaction was continued at 80° C. for 40 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide 26 (15 mg), yield: 95.41%.

[0760] MS m / z(ESI):468.2[M+1]

[0761] 1 H NMR (400 MHz, 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=1 4.0Hz, 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).

[0762] Embodiment 27

[0763] 2-((1R,3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0764]

[0765] first step

[0766] 8-Azaspiro[4.5]dec-2-en-1-one

[0767] 1-Oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester 27a (1.1 g, 4.38 mmol) and trifluoroacetic acid (499.05 mg, 4.38 mmol) were dissolved in 2 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 8-azaspiro[4.5]dec-2-ene-1-one 27b (661 mg) with a yield of 99.88%.

[0768] MS m / z(ESI):152.1[M+1]

[0769] Step 2

[0770] 6-Methyl-2-(1-oxo-8-azaspiro[4.5]dec-2-en-8-yl)pyrimidine-4-carbonitrile

[0771] 2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (479.52 mg, 3.12 mmol), 8-azaspiro[4.5]dec-2-en-1-one 27b (661 mg, 4.37 mmol) and N,N-diisopropylethylamine (403.56 mg, 3.12 mmol) were dissolved in 5 mL of N,N-dimethylacetamide and reacted at 55°C for 3 hours. After the reaction, the mixture was extracted with ethyl acetate (30 mL), the water layer was separated, and the organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-methyl-2-(1-oxo-8-azaspiro[4.5]dec-2-en-8-yl)pyrimidine-4-carbonitrile 27c (550 mg), with a yield of 65.65%.

[0772] MS m / z(ESI):269.1[M+1]

[0773] Step 3

[0774] (R)-2-(3-Hydroxy-1-oxo-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile

[0775] Under argon protection, cuprous chloride (6.09 mg, 61.50 μmol), [1-[2-(bis-p-tolylphosphonyl)-1-naphthyl]-2-naphthyl]-bis(p-tolyl)phosphine (41.74 mg, 61.50 μmol) and sodium tert-butoxide (5.91 mg, 61.50 μmol) were dissolved in 10 mL of tetrahydrofuran in sequence, argon was replaced, and after stirring at room temperature for 30 minutes, pinacol diboron (5 72.59 mg, 2.25 mmol) (dissolved in 2 mL tetrahydrofuran), continued stirring for 10 minutes, added 6-methyl-2-(1-oxo-8-azaspiro [4.5] dec-2-ene-8-yl) pyrimidine-4-carbonitrile 27c (550 mg, 2.05 mmol) (dissolved in 2 mL tetrahydrofuran), then added methanol (131.35 mg, 4.10 mmol), replaced argon, and reacted at room temperature overnight. After the reaction was completed, 7 mL of water was added, followed by sodium perborate (1.58 g, 10.25 mmol), and vigorously stirred at room temperature for 1 hour. The solid impurities were removed by filtration, and the filtrate was poured into 5 mL of a mixed solution of sodium bicarbonate and sodium sulfite (V:V=1:1), extracted with ethyl acetate (20 mL×2), and the organic phases were combined, washed with 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]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 27d (320 mg), with a yield of 54.54%.

[0776] MS m / z(ESI):287.2[M+1]

[0777] Step 4

[0778] (R)-2-(3-((tert-Butyldimethylsilyl)oxy)-1-oxo-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile

[0779] (R)-2-(3-Hydroxy-1-oxo-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 27d (210 mg, 733.42 μmol) was dissolved in 3 mL of dichloromethane, cooled to -78°C, 2,6-lutidine (157.17 mg, 1.47 mmol) was added, and then tert-butyldimethylsilyl trifluoromethanesulfonate (213.26 mg, 806.77 μmol) (dissolved in 3 mL of dichloromethane) was added dropwise, and the reaction was continued at -78°C for 1 hour. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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) in a yield of 77.60%.

[0780] MS m / z(ESI):401.2[M+1]

[0781] Step 5

[0782] (R)-N-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)-2-methylpropane-2-sulfenamide

[0783] (R)-2-(3-((tert-butyldimethylsilyl)oxy)-1-oxo-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 27e (236.27 mg, 589.81 μmol), (R)-2-methylpropane-2-sulfinamide (142.97 mg, 1.18 mmol) and ethyl titanate (269.13 mg, 1.18 mmol) were dissolved in 3 mL of tetrahydrofuran and reacted at 65° C. for 16 hours. Subsequently, 0.5 mL of methanol was added, and then lithium borohydride (16.70 mg, 766.76 μmol) was added and reacted for 1 hour. Saturated ammonium chloride solution (6 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (30 mL). The aqueous layer was separated and the organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The 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]dec-1-yl)-2-methylpropane-2-sulfinamide 27f (100 mg) in a yield of 33.52%.

[0784] MS m / z(ESI):506.3[M+1]

[0785] Step 6

[0786] 2-((1R,3R)-1-amino-3-((tert-butyldimethylsilyl)oxy)-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile

[0787] (R)-N-((1R, 3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)-2-methylpropane-2-sulfinamide 27f (100 mg, 197.71 μmol) was dissolved in 3 mL of N,N-dimethylformamide, cooled to 0°C, N-bromosuccinimide (38.71 mg, 217.48 μmol) was added, the mixture was heated to room temperature, and the reaction was allowed to proceed overnight. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product of 2-((1R, 3R)-1-amino-3-((tert-butyldimethylsilyl)oxy)-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 27g (79 mg), with a yield of 99.49%.

[0788] MS m / z(ESI):402.1[M+1]

[0789] Step 7

[0790] tert-Butyl ((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate

[0791] 27 g (79 mg, 196.70 μmol) of 2-((1R, 3R)-1-amino-3-((tert-butyldimethylsilyl)oxy)-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile, di-tert-butyl dicarbonate (85.86 mg, 393.41 μmol) and N,N-diethylethylamine (39.81 mg, 393.41 μmol) were dissolved in 3 mL of dichloromethane and reacted at room temperature overnight. After the reaction was completed, the product was concentrated under reduced pressure and the 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) with a yield of 78.02%.

[0792] MS m / z(ESI):502.3[M+1]

[0793] Step 8

[0794] 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

[0795] Dissolve 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, 153.47 μmol) in 2 mL of N,N-dimethylformamide, cool to 0°C, add N-bromosuccinimide (30.05 mg, 168.81 μmol), warm to room temperature, and react overnight. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL). The aqueous layer was separated, and the organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 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) in a yield of 97.63%.

[0796] MS m / z(ESI):524.2[M-56+1]

[0797] Step 9

[0798] tert-Butyl ((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate

[0799] 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, 149.84 μmol), (2,3-dichlorophenyl)boronic acid 1e (57.18 mg, 299.67 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropyloxy-1,1′-biphenyl) (2-amino 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (12.55 mg, 14.98 μmol, RuPhos-Pd-G3), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (13.98 mg, 29.97 μmol, RuPhos) and potassium phosphate (95.46 mg, 449.51 μmol) were successively dissolved in 2.5 mL of a mixed solvent (1,4-dioxane: water = 4:1) and reacted at 130°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (30 mL). The aqueous layer was separated and the organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl ((1R, 3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate 27j (70 mg) in a yield of 72.24%.

[0800] MS m / z(ESI):646.3[M+1]

[0801] Step 10

[0802] 2-((1R,3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0803] Tert-butyl ((1R, 3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate 27j (70 mg, 108.24 μmol) was dissolved in 2 mL of methanol, cooled to 0°C, and a methanol solution of hydrochloric acid (1.86 mL, 2M / MeOH) was added. The mixture was reacted at room temperature for 1 hour, and then concentrated under reduced pressure. 2 mL of trifluoroacetic acid and 0.5 mL of dichloromethane were added, and the reaction was continued at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 2-((1R, 3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 27k (40 mg) with a yield of 85.48%.

[0804] MS m / z(ESI):432.1[M+1]

[0805] Step 11

[0806] 2-((1R,3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0807] 2-((1R, 3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 27k (40 mg, 92.52 μmol) and 6M sodium hydroxide aqueous solution (0.3 mL) were dissolved in 2 mL of ethanol, heated to 80°C, and reacted for 0.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN), to give 2-((1R,3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 27 (7 mg), yield: 16.80%.

[0808] MS m / z(ESI):449.9[M+1]

[0809] 1 H NMR (400 MHz, CD 3OD) 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).

[0810] Example 28 (Comparative Example 4)

[0811] 6-amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0812] first step

[0813] (R)-N-((S)-1′-(4-amino-6-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1-yl)-2-methylpropane-2-sulfenamide

[0814] At room temperature, 6-amino-2-chloropyrimidine-4-carbonitrile 28a (100 mg, 647.01 μmol), (R)-N-((S)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)-2-methylpropane-2-sulfenamide 20b (218.11 mg, 711.71 μmol), N,N-dimethylacetamide (3 mL) and N,N-diisopropylethylamine (418.10 mg, 3.24 mmol, 563.47 μL) were added to a 25 mL single-necked bottle, and the temperature was raised to 90° C. for 3 hours. The reaction was incomplete as monitored by LC-MS, and the reaction was continued at 90° C. overnight. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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-sulfenamide 28b (274 mg) in a yield of 99.75%.

[0815] MS m / z(ESI):425.0[M+1]

[0816] Step 2

[0817] (S)-6-Amino-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-bromopyrimidine-4-carbonitrile

[0818] Under ice bath, N-bromosuccinimide (149.32 mg, 838.98 μmol) 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 (274 mg, 645.37 μmol) in dichloromethane (6 mL), and the mixture was heated to room temperature and reacted for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-bromopyrimidine-4-carbonitrile 28c (257 mg) with a yield of 99.73%, which was used directly in the next step.

[0819] MS m / z(ESI):381.9[M+H-17]

[0820] Step 3

[0821] (S)-tert-Butyl (1′-(4-amino-5-bromo-6-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1-yl)carbamate

[0822] (S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-5-bromopyrimidine-4-carbonitrile 28c (257 mg, 643.65 μmol), di-tert-butyl dicarbonate (421.43 mg, 1.93 mmol, 443.61 μL), dichloromethane (10 mL) and triethylamine (325.65 mg, 3.22 mmol, 446.10 μL) were added sequentially into a 25 mL single-necked bottle and reacted at room temperature for 2 hours. After the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain (S)-tert-butyl (1′-(4-amino-5-bromo-6-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 28d (150 mg) in a yield of 46.67%.

[0823] MS m / z(ESI):499.2[M+1]

[0824] Step 4

[0825] 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

[0826] Under argon protection, tert-butyl (S)-(1′-(4-amino-5-bromo-6-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1-yl)carbamate 28d (150 mg, 300.36 μmol), (2,3-dichlorophenyl)boronic acid 1e (143.29 mg, 750.90 μmol), 2-dicyclohexylphospho-2′,6′-diisopropoxy-1,1′-biphenyl (28.0 3mg, 60.07μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′, 6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl) palladium (II) (25.15mg, 30.04μmol), potassium phosphate (191.27mg, 901.08μmol), 1,4-dioxane (2mL) and water (0.3mL), blow argon for 1 minute, seal, heat to 130°C, and react for 4 hours. After the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL×2). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl ((1S)-1′-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 28e (150 mg) in a yield of 88.6%.

[0827] MS m / z(ESI):564.8[M+1]

[0828] Step 5

[0829] 6-amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

[0830] Trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL) 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 (150 mg, 265.26 μmol) in dichloromethane (4 mL) at room temperature and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give 6-amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile 28f (123 mg) in a yield of 99.64%.

[0831] MS m / z(ESI):464.9[M+1]

[0832] Step 6

[0833] 6-amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0834] 6M sodium hydroxide solution (0.3 mL) was added to a solution of 6-amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile 28f (123 mg, 265.08 μmol) in ethanol (2 mL), and the mixture was reacted at 80°C for 40 minutes. LC-MS detected that the reaction was incomplete, and sodium hydroxide solution (6M, 0.3 mL) and ethanol (2 mL) were added, and the reaction was continued at 80°C for 40 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 6-amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide 28 (85 mg), yield: 66.4%.

[0835] MS m / z(ESI):482.9[M+1]

[0836] 1 H NMR (400 MHz, 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).

[0837] Embodiment 29

[0838] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid

[0839]

[0840] 20 g (1.1 g, 1.95 mmol) 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 and concentrated hydrochloric acid (6 mL) were added to a 25 mL single-necked bottle, the temperature was raised to 110° C. and refluxed for 1.5 hours, and the mixture was concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 29 (370 mg), yield: 34.44%.

[0841] MS m / z(ESI):483.1[M+1]

[0842] 1H NMR (400 MHz, DMSO-d 6)δ13.37 (s, 1H), 8.27 (s, 2H), 7.67 (dd, J=8.1, 1.5Hz, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.47-7.29 (m, 4H), 7.25 (d, J=7.6Hz, 1H), 4.60 (dd, J=26.0, 13.5H z, 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).

[0843] Embodiment 30

[0844] 2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0845]

[0846]

[0847] first step

[0848] (R)-N-((S)-5,7-Dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfenamide

[0849] (S)-5-(((R)-tert-butylsulfinyl)amino)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylic acid tert-butyl ester 30a (200 mg, 490.71 μmol) was dissolved in 4 mL of dichloromethane, trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 40 minutes. LC-MS detected that the reaction was complete. The mixture was concentrated under reduced pressure to obtain (R)-N-((S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-5-yl)-2-methylpropane-2-sulfinamide 30b (150.87 mg), which was used directly in the next step.

[0850] MS m / z(ESI):308.2[M+1]

[0851] Steps 2 and 3

[0852] (S)-2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-methylpyrimidine-4-carbonitrile 30c

[0853] (S)-tert-Butyl (1′-(4-cyano-6-methylpyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)carbamate 30d

[0854] (R)-N-((S)-5,7-Dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide 30b (150.87 mg, 490.71 μmol), 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (75.36 mg, 490.71 μmol), N,N-dimethylacetamide (4 mL) and N,N-diisopropylethylamine (317.10 mg, 2.45 mmol) were added sequentially into a 15 mL single-necked bottle and the temperature was raised to 90°C for reaction for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature to obtain a reaction solution containing (S)-2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-methylpyrimidine-4-carbonitrile 30c. Without treatment, N,N-diisopropylethylamine (190.26 mg, 1.47 mmol) and di-tert-butyl dicarbonate (267.75 mg, 1.23 mmol) were directly added to the reaction solution and reacted at room temperature for 4 hours. LC-MS monitored the reaction to be complete. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give (S)-tert-butyl (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%.

[0855] MS m / z(ESI):421.2[M+1]

[0856] Step 4

[0857] (S)-tert-Butyl (1′-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)carbamate

[0858] 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, 190.25 μmol) was dissolved in 4 mL of dichloromethane, and N-bromosuccinimide (37.25 mg, 209.27 μmol) was added and reacted overnight. LC-MS showed that the reaction was complete. The product was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 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), with a yield of 63.15%.

[0859] MS m / z(ESI):499.1[M+1]

[0860] Step 5

[0861] 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

[0862] At room temperature, 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, 120.14 μmol), (2,3-dichlorophenyl)boronic acid 1e (68.78 mg, 360.43 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl) (2-amino-1,1′-biphenyl) Benzene-2-yl) palladium (II) (10.06 mg, 12.01 μmol, RuPhos-Pd-G3), 2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (11.21 mg, 24.03 μmol, RuPhos), potassium phosphate (76.54 mg, 360.43 μmol), 2 mL 1,4-dioxane and 0.3 mL water were added to a 10 mL microwave tube, argon was replaced 3 times, sealed, and heated to 140° C. for 4 hours. LC-MS monitored the reaction to be complete. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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) in a yield of 88.31%.

[0863] MS m / z(ESI):565.2[M+1]

[0864] Step 6

[0865] 2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0866] At room temperature, tert-butyl ((5S)-1′-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-5-yl)carbamate 30f (60 mg, 106.10 μmol) was dissolved in 4 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 40 minutes. LC-MS monitored the reaction to be complete. The mixture was concentrated under reduced pressure to obtain 2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 30 g (49.38 mg), which was used directly in the next step.

[0867] MS m / z(ESI):465.1[M+1]

[0868] Step 7

[0869] 2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0870] 2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 30 g (49.38 mg, 106.11 μmol), methanol (1.5 mL), saturated sodium hydroxide solution (1 mL) and hydrogen peroxide (0.5 mL) were added to a 15 mL single-mouth bottle in sequence and stirred at room temperature for 40 minutes. LC-MS monitored the reaction to be complete. The mixture was concentrated under reduced pressure and the obtained residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to afford 2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 30 (4.16 mg) in 7.67% yield.

[0871] MS m / z(ESI):483.1[M+1]

[0872] 1H NMR (400 MHz, 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, 3 H), 3.14 (d, J=16.8Hz, 1H), 2.03 (s, 3H), 1.74 (s, 2H), 1.56 (t, J=15.1Hz, 2H).

[0873] Embodiment 31

[0874] 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0875]

[0876]

[0877] first step

[0878] (R)-N-((S)-5,7-Dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfenamide

[0879] At room temperature, (S)-5-(((R)-tert-butylsulfinyl)amino)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidine]-1′-carboxylic acid tert-butyl ester 31a (300 mg, 736.07 μmol) was dissolved in 4 mL of dichloromethane and trifluoroacetic acid (1 mL) was added. The reaction was allowed to react at room temperature for 1 hour. LC-MS monitored the reaction to be complete. The reaction was concentrated under reduced pressure to give (R)-N-((S)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidine]-5-yl)-2-methylpropane-2-sulfinamide 31b (226 mg) with a yield of 99.86%. The crude product was used directly in the next step. MS m / z (ESI): 308.1 [M+1]

[0880] Step 2

[0881] (R)-N-((S)-1′-(4-amino-6-cyanopyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfenamide

[0882] (R)-N-((S)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide 31b (150 mg, 487.88 μmol), 1,2-dichloroethane (5 mL) and N,N-diisopropylethylamine (150.52 mg, 1.16 mmol) were added to a single-mouth bottle. After stirring for 1 minute, 6-amino-2-chloropyrimidine-4-carbonitrile 28a (60 mg, 388.21 μmol) was added and the temperature was raised to 66° C. for 3 hours. The reaction was complete by LC-MS. The reaction solution was concentrated under reduced pressure and the 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′-piperidine]-5-yl)-2-methylpropane-2-sulfenamide 31c (130 mg) in a yield of 78.69%.

[0883] MS m / z(ESI):426.0[M+1]

[0884] Step 3

[0885] 6-Amino-5-bromo-2-(5-oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile

[0886] (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, 305.49 μmol) was dissolved in 2 mL of dichloromethane, and N-bromosuccinimide (70.68 mg, 397.13 μmol) was added under ice bath, and the mixture was heated to room temperature for 3 hours. The reaction was completed after LC-MS monitoring, and the mixture was 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) with a yield of 90.19%, which was used directly in the next step.

[0887] MS m / z(ESI):399.0[M+H]

[0888] Step 4

[0889] 6-amino-5-(2,3-dichlorophenyl)-2-(5-oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile

[0890] 6-Amino-5-bromo-2-(5-oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile 31d (110 mg, 275.52 μmol), (2,3-dichlorophenyl)boronic acid 1e (131.44 mg, 688.80 μmol), 2-dicyclohexylphospho-2′,6′-diisopropoxy-1,1′-biphenyl (25.71 mg, 55 .10μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (23.07mg, 27.55μmol), potassium phosphate (175.45mg, 826.56μmol), 1,4-dioxane (2mL) and water (0.3mL), replace argon three times and seal the tube, heat to 130°C, and react for 4 hours. LC-MS monitors the reaction to be complete. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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%.

[0891] MS m / z(ESI):465.0[M+1]

[0892] Step 5

[0893] (R)-N-((Z)-1′-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)spiro[cyclopenta[c]pyridine-6,4′-piperidinyl]-5(7H)-alkylidene)-2-methylpropane-2-sulfenamide

[0894] 6-Amino-5-(2,3-dichlorophenyl)-2-(5-oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile 31e (160 mg, 343.84 μmol), (R)-2-methylpropane-2-sulfenamide (104.18 mg, 859.60 μmol) and tetraethyl titanate (2 mL) were dissolved in 1 mL of tetrahydrofuran in sequence and reacted at 90°C for 3 hours. After the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The aqueous layer was separated and the organic phase was washed with 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)-alkylidene)-2-methylpropane-2-sulfenamide 31f (195 mg) with a yield of 99.75%.

[0895] Step 6

[0896] (R)-N-((5S)-1′-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfenamide

[0897] (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-sulfenamide 31f (195 mg, 343.00 μmol) was dissolved in 8 mL of tetrahydrofuran, and 9-boranebicyclo[3.3.1]nonane (1.37 mL, 0.5 M in THF) was added at room temperature and reacted at room temperature for 2 hours. LC-MS monitored the reaction to be complete. 20 mL of water was added to the reaction solution, and the mixture was 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. The residue was purified by silica gel column chromatography (eluent: System B) to obtain 31 g (90 mg) of (R)-N-((5S)-1′-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfenamide, yield: 45.99%. MS m / z (ESI): 570.2 [M+1]

[0898] Step 7

[0899] 6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

[0900] At room temperature, (R)-N-((5S)-1′-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide 31 g (90.16 mg, 158.02 μmol) was dissolved in 4 mL of dichloromethane, and a methanol solution of hydrochloric acid (2 mL, 4 M) was added. The mixture was reacted at room temperature for 2 hours. LC-MS detected that the reaction was complete. The mixture was concentrated under reduced pressure to obtain 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile 31 h (70 mg), which was directly used in the next step.

[0901] MS m / z(ESI):466.1[M+1]

[0902] Step 8

[0903] 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0904] 6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile 31h (70 mg, 150.42 μmol) was dissolved in 2 mL of ethanol, and sodium hydroxide solution (0.3 mL, 6 M) was added and reacted at 80°C for 40 minutes. LC-MS detected that the reaction was complete. The residue was concentrated under reduced pressure and separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN) to afford 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide 31 (25 mg) in a yield of 27.77%.

[0905] MS m / z(ESI):484.1[M+1]

[0906] 1H NMR (400MHz, Methanol-d4 )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), 1.9 6(t, J=11.0Hz, 1H), 1.78 (dt, J=19.7, 8.4Hz, 2H), 1.61 (d, J=13.4Hz, 1H).

[0907] Embodiment 32

[0908] 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0909]

[0910]

[0911] first step

[0912] (R)-N-((S)-1′-(4-amino-6-cyanopyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfenamide

[0913] (R)-N-((S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide 30b (226 mg, 735.07 μmol), 1,2-dichloroethane (5 mL) and N,N-diisopropylethylamine (250.86 mg, 1.94 mmol) were added to a single-mouth bottle. After stirring for 1 minute, 6-amino-2-chloropyrimidine-4-carbonitrile 28a (100 mg, 647.01 μmol) was added and the temperature was raised to 66° C. for 3 hours. The reaction was complete by LC-MS. The reaction solution was concentrated under reduced pressure and the 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′-piperidine]-5-yl)-2-methylpropane-2-sulfenamide 32a (275 mg) in a yield of 99.88%.

[0914] MS m / z(ESI):425.9[M+1]

[0915] Step 2

[0916] 6-Amino-5-bromo-2-(5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile

[0917] (R)-N-((S)-1′-(4-amino-6-cyanopyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidinyl]-5-yl)-2-methylpropane-2-sulfinamide 32a (275 mg, 646.22 μmol) was dissolved in 5 mL of dichloromethane, and N-bromosuccinimide (172.53 mg, 969.34 μmol) was added under ice bath, and the temperature was raised to room temperature for reaction for 2 hours. The reaction was completed as monitored by LC-MS. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL×2). 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%.

[0918] MS m / z(ESI):399.1[M+H]

[0919] Step 3

[0920] 6-amino-5-(2,3-dichlorophenyl)-2-(5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile

[0921] 6-Amino-5-bromo-2-(5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile 32b (250 mg, 626.18 μmol), (2,3-dichlorophenyl)boronic acid 1e (298.72 mg, 1.57 mmol), 2-dicyclohexylphospho-2′,6′-diisopropoxy-1,1′-biphenyl (58.44 mg, 12 5.24 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (52.43 mg, 62.62 μmol), potassium phosphate (398.75 mg, 1.88 mmol), 1,4-dioxane (2 mL) and water (0.3 mL), argon was replaced 3 times and then the tube was sealed, the temperature was raised to 130 ° C, and the reaction was carried out for 4 hours. LC-MS monitored the reaction to be complete. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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) in a yield of 41.18%.

[0922] MS m / z(ESI):465.2[M+1]

[0923] Step 4

[0924] (R)-N-((Z)-1′-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)spiro[cyclopenta[b]pyridine-6,4′-piperidinyl]-5(7H)-alkylidene)-2-methylpropane-2-sulfenamide

[0925] 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, 257.88 μmol), (R)-2-methylpropane-2-sulfenamide (78.14 mg, 644.70 μmol) and tetraethyl titanate (2 mL) were dissolved in 1 mL of tetrahydrofuran in sequence and reacted at 90°C for 3 hours. After the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The aqueous layer was separated and the organic phase was washed with 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)-alkylidene)-2-methylpropane-2-sulfenamide 32d (146 mg) in a yield of 99.58%.

[0926] MS m / z(ESI):568.2[M+1]

[0927] Step 5

[0928] (R)-N-((5S)-1′-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfenamide

[0929] At room temperature, (R)-N-((Z)-1′-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)spiro[cyclopenta[b]pyridine-6,4′-piperidine]-5(7H)-ylidene)-2-methylpropane-2-sulfenamide 32d (146 mg, 256.81 μmol) was dissolved in 4 mL of tetrahydrofuran, and 9-borabicyclo[3.3.1]nonane (0.5 Min THF, 1.03 mL) was added. The reaction was allowed to react at room temperature for 2 h. The reaction was completed after monitoring by LC-MS. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) 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′-piperidin]-5-yl)-2-methylpropane-2-sulfenamide 32e (100 mg), yield: 68.25%.

[0930] MS m / z(ESI):570.2[M+1]

[0931] Step 6

[0932] 6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

[0933] At room temperature, (R)-N-((5S)-1′-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-yl)-2-methylpropane-2-sulfinamide 32e (100 mg, 175.27 μmol) was dissolved in 4 mL of dichloromethane, and a methanol solution of hydrochloric acid (2 mL, 4 M) was added and reacted at room temperature for 2 hours. LC-MS detection showed that the reaction was complete. The mixture was concentrated under reduced pressure to obtain 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 directly used in the next step.

[0934] MS m / z(ESI):466.1[M+1]

[0935] Step 7

[0936] 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0937] 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 (49 mg, 105.07 μmol) was dissolved in 3 mL of ethanol, and sodium hydroxide solution (0.3 mL, 6 M) was added and reacted at 80°C for 40 minutes. LC-MS detection showed that the reaction was complete. The residue was concentrated under reduced pressure and separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN) to give 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide 32 (20 mg) in a yield of 39.30%.

[0938] MS m / z(ESI):483.9[M+1]

[0939] 1 H NMR (400 MHz, 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).

[0940] Embodiment 35

[0941] 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinic acid

[0942] first step

[0943] (R)-N-((S)-1′-(4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0944] (R)-N-((S)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 20b (309 mg, 1.01 mmol), 2-chloro-6-methylisonicotinonitrile 5a (153.84 mg, 1.01 mmol), potassium carbonate (696.72 mg, 5.04 mmol) and N-methylpyrrolidone (8 mL) were added to a 25 mL microwave tube, sealed, heated to 130° C., and reacted for 5 hours. After the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give (R)-N-((S)-1′-(4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)-2-methylpropane-2-sulfenamide 35a (160 mg) in a yield of 37.55%.

[0945] MS m / z(ESI):423.2[M+1]

[0946] Step 2

[0947] (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-6-methylisonicotinonitrile

[0948] (R)-N-((S)-1′-(4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 35a (160 mg, 378.62 μmol) was dissolved in 3 mL of methanol, and concentrated hydrochloric acid (0.5 mL) was added and reacted at room temperature overnight. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-methylisonicotinonitrile 35b (120.56 mg), which was used directly in the next step.

[0949] MS m / z(ESI):319.2[M+1]

[0950] Step 3

[0951] (S)-tert-Butyl (1′-(4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate

[0952] (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-methylisonicotinonitrile 35b (120.56 mg, 378.63 μmol), dichloromethane (5 mL), triethylamine (191.49 mg, 1.89 mmol) and di-tert-butyl dicarbonate (247.91 mg, 1.14 mmol) were added to a 15 mL single-mouth bottle in sequence and reacted at room temperature for 4 hours. The reaction was complete when monitored by LC-MS. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give (S)-tert-butyl (1′-(4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 35c (100 mg). Yield: 63.10%.

[0953] MS m / z(ESI):419.2[M+1]

[0954] Step 4

[0955] (S)-tert-Butyl (1′-(5-bromo-4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate

[0956] (S)-tert-butyl (1′-(4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate 35c (100 mg, 238.93 μmol) was dissolved in dichloromethane (5 mL), and N-bromosuccinimide (42.53 mg, 238.93 μmol) was added and reacted at room temperature overnight. LC-MS monitored the reaction to be complete. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give (S)-tert-butyl (1′-(5-bromo-4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 35d (115 mg) in a yield of 96.76%.

[0957] MS m / z(ESI):497.1[M+1]

[0958] Step 5

[0959] tert-Butyl ((1S)-1′-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate

[0960] 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, 231.19 μmol), (2,3-dichlorophenyl)boronic acid 1e (88.23 mg, 462.38 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′ -biphenyl-2-yl)palladium (II) (19.36 mg, 23.12 μmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (21.58 mg, 46.24 μmol), potassium phosphate (147.29 mg, 693.57 μmol), 1,4-dioxane (2.5 mL) and water (0.3 mL) were added to a 10 mL microwave tube, purged with argon for 1 minute, sealed, heated to 130°C, and reacted for 3 hours. After the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl ((1S)-1′-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 35e (130 mg) in a yield of 99.79%.

[0961] MS m / z(ESI):563.2[M+1]

[0962] Step 6

[0963] 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinic acid

[0964] 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 (60 mg, 106.47 μmol) and concentrated hydrochloric acid (1.5 mL) were added to a 10 mL microwave tube and heated to 130° C. for 3 hours. The reaction was concentrated under reduced pressure and the residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinic acid 35 (10.55 mg), yield: 18%.

[0965] MS m / z(ESI):482.1[M+1]

[0966] 1 H NMR (400 MHz, DMSO-d 6 )δ13.04 (s, 1H), 8.25 (s, 2H), 7.62 (dd, J=8.1, 1.4Hz, 1H), 7.52 (d, J=7.3H z, 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 = 16.2H z, 1H), 2.04 (s, 3H), 1.74 (t, J=12.6Hz, 2H), 1.53 (dd, J=23.5, 13.1Hz, 2H).

[0967] Embodiment 36

[0968] 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinamide

[0969]

[0970]

[0971] first step

[0972] 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile

[0973] 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 (33 mg, 58.56 μmol) was dissolved in dichloromethane (2 mL), triethylamine (0.5 mL) was added, and the mixture was reacted at room temperature for 40 minutes. The mixture was concentrated under reduced pressure to obtain 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile 36a (27.14 mg), which was used directly in the next step.

[0974] MS m / z(ESI):463.1[M+1]

[0975] Step 2

[0976] 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinamide

[0977] At room temperature, 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile 36a (27.14 mg, 58.57 μmol), methanol (1.5 mL), saturated sodium hydroxide solution (1 mL) and hydrogen peroxide (0.5 mL) were added to a 15 mL single-mouth bottle in sequence and reacted at room temperature for 2 hours. LC-MS showed that the reaction was complete. The product was concentrated under reduced pressure and the obtained residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinamide 36 (11.02 mg) in a yield of 31.28%.

[0978] MS m / z(ESI):481.1[M+1]

[0979] 1 H NMR (400 MHz, 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=1 6.3Hz, 1H), 2.03 (s, 3H), 1.79-1.68 (m, 2H), 1.54 (dd, J=28.7, 13.3Hz, 2H).

[0980] Examples 37 and 38

[0981] (S)-6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide 37

[0982] (R)-6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide 38

[0983]

[0984] 6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide 32 (960 mg, 1.99 mmol) was chirally separated by SFC (column model: ChiralPak IC, 250×30 mm ID, 10 μm; mobile phase: Afor CO 2 and B for Ethanol(0.1%NH 3 H 2 O); column pressure: 100 bar; flow rate: 80 mL / min; detection wavelength: 220 nm; column temperature: 38°C), after purification, (S)-6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide 37 was obtained (retention time (T R ): 4.037 min; 360 mg) and (R)-6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide 38 (retention time (TR ): 6.957min; 564mg).

[0985] 37 MS m / z(ESI):483.9[M+1]

[0986] 1 H NMR (400 MHz, 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).

[0987] 38 MS m / z(ESI):483.9[M+1]

[0988] 1 H NMR (400 MHz, 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).

[0989] Examples 39 and 40

[0990] (R)-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39

[0991] (S)-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 40

[0992] first step

[0993] 2-((S)-1-((tert-Butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid

[0994] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 29 (350 mg, 724.05 μmol) was dissolved in 10 mL of dichloromethane, triethylamine (366.34 mg, 3.62 mmol) and di-tert-butyl dicarbonate (474.08 mg, 2.17 mmol) were added in sequence, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 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).

[0995] MS m / z(ESI):583.2[M+1]

[0996] Step 2

[0997] (R)-2-((S)-1-((tert-Butyloxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39b

[0998] (S)-2-((S)-1-((tert-Butyloxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39c

[0999] 2-((S)-1-((tert-Butyloxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39a (422.49 mg, 724.06 μmol) was chiral separated by SFC (column model: ChiralPak IC, 250×30 mm ID, 10 μm; mobile phase: Afor CO 2 and B for Methanol(0.1%NH 3 H 2O); ratio: B 40%; column pressure: 100 bar; flow rate: 60 mL / min; detection wavelength: 220 nm; column temperature: 38°C) was purified to obtain (R)-2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39b (retention time (T R ): 1.578 min; 147 mg) and (S)-2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39c (retention time (T R ): 2.389min; 107mg).

[1000] 39b MS m / z(ESI):583.2[M+1]

[1001] 39c MS m / z(ESI):583.2[M+1]

[1002] Step 3

[1003] (R)-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39

[1004] (R)-2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39b (140 mg, 239.93 μmol) was dissolved in 5 mL of dioxane, and a 4M solution of hydrogen chloride in 1,4-dioxane (43.74 mg, 1.20 mmol) was added, and the mixture was stirred and reacted overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained solid was dissolved in n-hexane, slurried, and concentrated to dryness to obtain (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), with a yield of 84.18%.

[1005] MS m / z(ESI):483.1[M+1]

[1006] 1 H NMR (400 MHz, 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, 1 3.4Hz, 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).

[1007] Step 4

[1008] (S)-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 40

[1009] (S)-2-((S)-1-((tert-Butyloxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39c (105 mg, 179.95 μmol) was dissolved in 5 mL of dioxane, and 4 M hydrogen chloride solution in 1,4-dioxane (32.80 mg, 899.74 μmol) 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 obtain (S)-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 40 (68 mg) with a yield of 72.69%.

[1010] MS m / z(ESI):483.1[M+1]

[1011] 1 H NMR (400 MHz, 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, 13.5Hz, 2H), 4.37 (d, J=5.4Hz, 1H), 3.22 (d, J=15.6Hz, 3H), 3.03 (d, J=16.2 Hz, 1H), 2.07 (s, 3H), 1.75 (dd, J=12.3, 4.1Hz, 2H), 1.55 (t, J=14.7Hz, 2H).

[1012] Embodiment 41

[1013] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3-chloro-2-fluoropyridin-4-yl)-6-methylpyrimidine-4-carboxamide

[1014]

[1015] first step

[1016] 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

[1017] Tert-butyl (S)-(1′-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate 20f (300 mg, 601.91 μmol), (3-chloro-2-fluoropyridin-4-yl)boronic acid 41a (158.32 mg, 902.86 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium (102.37 mg, 120.38 μmol) and potassium phosphate (510.42 mg, 144.8 μmol) were added. The residue was purified by silica gel column chromatography (eluent: system A) to give tert-butyl ((S)-1′-(5-(3-chloro-2-fluoropyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 41b (140 mg), with a yield of 42.36%.

[1018] MS m / z(ESI):549.2[M+1]

[1019] Step 2

[1020] tert-Butyl ((S)-1′-(5-(3-chloro-2-fluoropyridin-4-yl)-4-carbamoyl-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate

[1021] Potassium carbonate (7.54 mg, 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 (15 mg, 27.32 μmol) were added to 1 mL of dimethyl sulfoxide. Under ice bath, 0.25 mL of 30% hydrogen peroxide was slowly added dropwise to the reaction solution, and the mixture was stirred under ice bath for 3 hours. 0 minutes, after the reaction was completed, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated under reduced pressure to obtain tert-butyl ((S)-1′-(5-(3-chloro-2-fluoropyridin-4-yl)-4-carbamoyl-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 41c (15 mg), yield: 96.82%, without purification, directly carried out to the next step reaction.

[1022] MS m / z(ESI):567.2[M+1]

[1023] Step 3

[1024] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3-chloro-2-fluoropyridin-4-yl)-6-methylpyrimidine-4-carboxamide

[1025] Tert-butyl ((S)-1′-(5-(3-chloro-2-fluoropyridin-4-yl)-4-carbamoyl-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate 41c (15 mg, 26.45 μmol) and 0.5 mL of trifluoroacetic acid were added to 2 mL of dichloromethane and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3CN), to give the product 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3-chloro-2-fluoropyridin-4-yl)-6-methylpyrimidine-4-carboxamide 41 (5 mg), yield: 31.88%.

[1026] MS m / z(ESI):467.2[M+1]

[1027] Embodiment 42

[1028] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3-chloro-2-aminopyridin-4-yl)-6-methylpyrimidine-4-carboxamide

[1029]

[1030] first step

[1031] 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

[1032] 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 (80 mg, 145.71 μmol) and 8 mL of 28% ammonia monohydrate were added to 3 mL of dimethyl sulfoxide, sealed, heated to 115° C., reacted for 4.5 hours, cooled to room temperature, concentrated under reduced pressure, and adjusted to pH=7 with dilute hydrochloric acid. -8, and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain ((S)-1′-(5-(3-chloro-2-aminopyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamic acid tert-butyl ester 42a (10 mg), yield: 12.17%.

[1033] MS m / z(ESI):546.3[M+1]

[1034] Step 2

[1035] 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

[1036] Tert-butyl ((S)-1′-(5-(3-chloro-2-aminopyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 42a (12 mg, 26.73 μmol) and 0.5 mL of 6N sodium hydroxide solution were added to 2 mL of ethanol, heated to 80° C., and reacted for 1 hour. After the reaction was completed, it was directly concentrated under reduced pressure to obtain tert-butyl ((S)-1′-(5-(3-chloro-2-aminopyridin-4-yl)-4-carbamoyl-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate 42b (10 mg), yield: 66.33%, and was directly subjected to the next step reaction without purification.

[1037] MS m / z(ESI):564.2[M+1]

[1038] Step 3

[1039] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3-chloro-2-aminopyridin-4-yl)-6-methylpyrimidine-4-carboxamide

[1040] 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, 17.73 μmol) and 0.6 mL of trifluoroacetic acid were added to 2 mL of dichloromethane and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN), to give 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%.

[1041] MS m / z(ESI):464.1[M+1]

[1042] Embodiment 43

[1043] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidine-4-carboxamide

[1044]

[1045] first step

[1046] 5-(3-Chloro-2-methoxypyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)pyrimidine-4-carbonitrile

[1047] 5-Bromo-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile 43a (200 mg, 503.44 μmol), (3-chloro-2-methoxypyridin-4-yl)boronic acid 43b (141.51 mg, 755.16 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium (42.16 mg, 50.34 μmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl) Biphenyl (46.92 mg, 100.69 μmol) and potassium phosphate (320.19 mg, 1.51 mmol) were added successively to 1.2 mL of a mixed solution (1,4-dioxane: water = 5:1), the atmosphere was replaced with argon three times, the mixture was reacted at 115°C for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 5-(3-chloro-2-methoxypyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)pyrimidine-4-carbonitrile 43c (190 mg), yield: 82%.

[1048] MS m / z(ESI):460.2[M+1]

[1049] Step 2

[1050] 5-(3-Chloro-2-hydroxypyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile

[1051] 5-(3-Chloro-2-methoxypyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)pyrimidine-4-carbonitrile 43c (200 mg, 434.85 μmol) and 3 mL of 4M hydrochloric acid dioxane solution were added to 1 mL of dichloromethane, sealed and heated to 100° C. for 2 hours. After the reaction was completed, a small amount of ammonia methanol solution was added for neutralization, and the mixture was concentrated under reduced pressure. The 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′-piperidine]-1′-yl)pyrimidine-4-carbonitrile 43d (140 mg) in a yield of 72.20%.

[1052] MS m / z(ESI):446.1[M+1]

[1053] Step 3

[1054] 5-(2,3-dichloropyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrimidine-4-carbonitrile

[1055] 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, 313.97 μmol) was added to 3 mL of phosphorus oxychloride, heated to 90°C, reacted for 3 hours, cooled to room temperature, poured into ice water, stirred for 0.5 hours, extracted with ethyl acetate (20 mL×3) The organic phases were combined and washed with saturated sodium bicarbonate solution. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The 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 43e (90 mg) in a yield of 61.73%.

[1056] MS m / z(ESI):464.0[M+1]

[1057] Step 4

[1058] (R)-N-((Z)-1′-(4-cyano-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidin-2-yl)spiro[indene-2,4′-piperidinyl]-1(3H)-alkylidene)-2-methylpropane-2-sulfenamide

[1059] 5-(2,3-Dichloropyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)pyrimidine-4-carbonitrile 43e (90 mg, 193.82 μmol) and (R)-2-methylpropane-2-sulfenamide (70.47 mg, 581.46 μmol) were added to 1 mL of tetraethyl titanate, heated at 100°C, and reacted for 5 hours. After cooling to room temperature, 10 mL of water and 10 mL of ethyl acetate were added, and the insoluble solids were removed by filtration. The organic phase was separated from the filtrate, dried and filtered, and concentrated under reduced pressure. Thin layer chromatography was performed to obtain (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-sulfenamide 43f (20 mg), yield: 18.18%.

[1060] MS m / z(ESI):567.2[M+1]

[1061] Step 5

[1062] (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-sulfenamide

[1063] (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-sulfenamide 43f (100 mg, 176.20 μmol) was added to 2 mL of tetrahydrofuran, and 9-borabicyclo(3,3,1)-nonane (0.5 M, 704.81 μL) was added under ice bath, and the temperature was raised to room temperature for reaction for 2 hours. The mixture was quenched by adding 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 obtain 43 g (80 mg) of (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-sulfenamide with a yield of 79.72%. The mixture was directly used for the next step without purification.

[1064] MS m / z(ESI):568.8[M+1]

[1065] Step 6

[1066] 2-((S)-1-(((R)-tert-Butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidine-4-carboxamide

[1067] 43 g (80 mg, 140.46 μmol) of (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-sulfenamide and 0.5 mL of 6N sodium hydroxide solution were added to 2 mL of ethanol, heated to 80° C., reacted for 0.5 hour, and after the reaction was completed, the pH was adjusted with 1N dilute hydrochloric acid. =7-8, concentrated under reduced pressure, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 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 (50 mg), yield: 60.58%, without purification, directly carried out the next step reaction.

[1068] MS m / z(ESI):586.8[M+1]

[1069] Step 7

[1070] 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidine-4-carboxamide

[1071] 2-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidine-4-carboxamide 43h (50 mg, 85.10 μmol) was added to 4 mL of dichloromethane, and 0.4 mL of 4 M hydrochloric acid dioxane solution was added at room temperature, and stirred for 0.5 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN), to give the 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%.

[1072] MS m / z(ESI):482.9[M+1]

[1073] 1 H NMR (400 MHz, 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).

[1074] Embodiment 44

[1075] 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-carboxamide

[1076]

[1077] first step

[1078] 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]dec-4-yl)carbamate

[1079] 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 (90 mg, 192.98 μmol), (3-chloro-2-fluoropyridin-4-yl)boronic acid 41a (135.36 mg, 771.92 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium (32.82 mg, 38.60 μmol) and potassium phosphate (163.65 mg, 7 The residue was purified by silica gel column chromatography (eluent: system A) to give 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]dec-4-yl)carbamate 44a (30 mg), with a yield of 30.19%.

[1080] MS m / z(ESI):459.0[M+1-56]

[1081] Step 2

[1082] 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

[1083] 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]dec-4-yl)carbamate 44a (30 mg, 58.25 μmol) and 0.05 mL of N,N-diisopropylethylamine were added to 1 mL of phosphorus oxychloride, heated to 100° C., and stirred for 8 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into crushed ice, stirred for 0.5 h, 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-((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 (20 mg), yield: 79.23%, which was directly used for the next step without purification.

[1084] MS m / z(ESI):433.1[M+1]

[1085] Step 3

[1086] 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-carboxamide

[1087] 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 (20 mg, 46.15 μmol) and 0.5 mL of 5M sodium hydroxide solution were added to 0.5 mL of methanol, and 0.25 mL of 30% hydrogen peroxide was added under low temperature conditions, and stirred for 1 hour under ice bath. After the reaction was completed, a small amount of trifluoroacetic acid was added to adjust the pH value to 7-8, and the mixture was concentrated under reduced pressure. The residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give the product 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-carboxamide 44 (11 mg), yield: 33.72%.

[1088] MS m / z(ESI):450.9[M+1]

[1089] Embodiment 45

[1090] 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

[1091]

[1092] first step

[1093] tert-Butyl ((3S,4S)-8-(5-(3-chloro-2-fluoropyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate

[1094] 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 (120 mg, 257.31 μmol), (3-chloro-2-fluoropyridin-4-yl)boronic acid 41a (112.80 mg, 643.26 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium (43.76 mg, 51.46 μmol) and potassium phosphate (272.74 mg, 54.3 μmol) were added. g, 1.29 mmol) were added sequentially into 4.4 mL of a mixed solution (1,4-dioxane: water = 10:1), replaced with argon three times, refluxed with a condenser, stirred continuously at 100°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl ((3S,4S)-8-(5-(3-chloro-2-fluoropyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate 45a (75 mg), yield: 56.38%.

[1095] MS m / z(ESI):517.3[M+1]

[1096] Step 2

[1097] 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

[1098] Tert-butyl ((3S,4S)-8-(5-(3-chloro-2-fluoropyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate 45a (70 mg, 135.40 μmol) was added to 1 mL of 48% hydrobromic acid in acetic acid solution, sealed and heated to 90°C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, neutralized by adding saturated sodium bicarbonate, extracted with dichloromethane (10 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3CN), to give 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%.

[1099] MS m / z(ESI):495.0[M+1]

[1100] Embodiment 46

[1101] 2-((S)-3′-amino-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-1″-yl)-5-(2,3-(dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid

[1102]

[1103]

[1104] first step

[1105] 1-Methylene-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester

[1106] 1-Oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester 46a (4 g, 13.27 mmol) and methyltriphenylphosphonium bromide (11.85 g, 33.18 mmol) were added to 150 mL of tetrahydrofuran, the temperature was controlled at 0°C, potassium tert-butoxide (4.46 g, 39.82 mmol) was added, and the temperature was raised to 30°C and stirred for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, 1N dilute hydrochloric acid was added to adjust the pH to 8, and extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 1-methylene-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester 46b (3.8 g) with a yield of 95.63%.

[1107] Step 2

[1108] 3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]

[1109] A mixture of diethylzinc solution (2.31 g, 18.70 mmol) and dichloromethane (150 mL) was cooled to 0°C, and then trifluoroacetic acid (2.13 g, 18.70 mmol, 1.39 mL) was dissolved in 20 mL of dichloromethane and added to the reaction. After 15 minutes, diiodomethane (4.99 g, 18.70 mmol, 1.50 mL) was added, and the mixture was stirred at 0°C for 15 minutes. 1-Methylene-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylic acid was added. Tert-butyl ester 46b (1.4 g, 4.68 mmol) was dissolved in dichloromethane (5 mL), added to the above mixture while maintaining at 0°C, and stirred overnight at room temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine] 46c (550 mg) with a yield of 55.14%. The product was directly used for the next step without purification.

[1110] MS m / z(ESI):214.0[M+1]

[1111] Step 3

[1112] 3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-1″-carboxylic acid tert-butyl ester

[1113] 3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine] 46c (1.8 g, 8.44 mmol), di-tert-butyl dicarbonate (3.68 g, 16.88 mmol), 4-dimethylaminopyridine (51.54 mg, 421.91 μmol) and triethylamine (2.56 g, 25.31 mmol, 3.55 mL) were added to 20 mL of dichloromethane and stirred at room temperature for 4 hours. After the reaction was completed, 20 mL of water was added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-1″-carboxylate 46d (1.5 g) in a yield of 45.37%.

[1114] MS m / z(ESI):258.0[M+1-56]

[1115] 1H 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).

[1116] Step 4

[1117] 3′-Oxo-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-1″-carboxylic acid tert-butyl ester

[1118] 3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-1″-carboxylic acid tert-butyl ester 46d (1.5 g, 4.79 mmol), 1.5 M magnesium sulfate solution (5 mL) and potassium permanganate (3.02 g, 19.14 mmol) were added to 20 mL of acetone, heated to 40° C., and reacted for 8 hours. After the reaction was completed, celite was filtered, acetone was removed from the filtrate, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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″-carboxylic acid tert-butyl ester 46e (600 mg) in a yield of 38.29%.

[1119] MS m / z(ESI):272.0[M+1-56]

[1120] Step 5

[1121] (R,Z)-tert-Butyl 3′-((tert-butylsulfinyl)imino)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-1″-carboxylate

[1122] (R)-2-Methylpropane-2-sulfenamide (370.17 mg, 3.05 mmol) and tert-butyl 3′-oxo-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-1″-carboxylate 46e (400 mg, 1.22 mmol) were added to 2 mL of tetraethyl titanate and 0.5 mL of tetrahydrofuran, heated to 100° C., stirred for 18 hours, and after the reaction was completed, cooled to room temperature, and 10 mL of methyl tert-butyl ether was added. , cooled with an ice-water bath, added 10 mL of ice water, stirred for 15 minutes, filtered, the filtrate was separated from the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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: 55.13%.

[1123] MS m / z(ESI):331.0[M+1-100]

[1124] Step 6

[1125] (S)-tert-Butyl 3′-(((R)-tert-Butylsulfinyl)amino)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-1″-carboxylate

[1126] (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, 673.48 μmol) was added to 3 mL of tetrahydrofuran, cooled in an ice-water bath, 9-borabicyclo(3,3,1)-nonane (0.5 M, 2.69 mL) was added, the mixture was warmed to room temperature and stirred for 2 hours, saturated ammonium chloride solution was added to quench, the organic phase was 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 the mixture was directly subjected to the next step reaction without purification.

[1127] MS m / z(ESI):433.0[M+1]

[1128] Step 7

[1129] (R)-N-((S)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-3′-yl)-2-methylpropane-2-sulfenamide

[1130] 46 g (180 mg, 416.07 μmol) of (S)-3′-(((R)-tert-butylsulfinyl)amino)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-1″-carboxylic acid tert-butyl ester and 1 mL of trifluoroacetic acid were added to 4 mL of dichloromethane and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (R)-N-((S)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-3′-yl)-2-methylpropane-2-sulfinamide 46h (138 mg) with a yield of 99.75%. The mixture was directly subjected to the next step of reaction without purification.

[1131] MS m / z(ESI):333.2[M+1]

[1132] Step 8

[1133] (R)-N-((S)-1″-(4-cyano-6-methylpyrimidin-2-yl)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-3′-yl)-2-methylpropane-2-sulfenamide

[1134] 2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (63.74 mg, 415.03 μmol), (R)-N-((S)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-3′-yl)-2-methylpropane-2-sulfenamide 46h (138 mg, 415.03 μmol) and N,N-diisopropylethylamine (160.92 mg, 1.25 mmol) were added to 3 mL of N,N-dimethylformamide, and then heated to 90° C. for 1.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into 10 mL of water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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-1,1′-indene-2′,4″-piperidine]-3′-yl)-2-methylpropane-2-sulfinamide 46i (160 mg) in a yield of 85.74%.

[1135] MS m / z(ESI):450.1[M+1]

[1136] Step 9

[1137] (S)-2-(3′-amino-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-1″-yl)-6-methylpyrimidine-4-carbonitrile

[1138] (R)-N-((S)-1″-(4-cyano-6-methylpyrimidin-2-yl)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidin]-3′-yl)-2-methylpropane-2-sulfenamide 46i (160 mg, 355.86 μmol) and bromosuccinimide (69.67 mg, 391.45 μmol) were added to 2 mL of N,N-dimethylacetamide and reacted at low temperature for 1 hr. .5 hours after the reaction was completed, the reaction solution was poured into 10 mL of water and extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (S)-2-(3′-amino-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-1″-yl)-6-methylpyrimidine-4-carbonitrile 46j (123 mg) with a yield of 100%. The product was directly subjected to the next step of reaction without purification.

[1139] MS m / z(ESI):329.0[M+1-17]

[1140] Step 10

[1141] (S)-tert-Butyl (1″-(4-cyano-6-methylpyrimidin-2-yl)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-3′-yl)carbamate

[1142] (S)-2-(3′-amino-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-1″-yl)-6-methylpyrimidine-4-carbonitrile 46j (123 mg, 356.07 μmol), triethylamine (107.89 mg, 1.07 mmol) and di-tert-butyl dicarbonate (116.43 mg, 534.10 μmol) were added to 3 mL of dichloromethane, reacted at room temperature for 4 hours, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give (S)-tert-butyl(1″-(4-cyano-6-methylpyrimidin-2-yl)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidine]-3′-yl)carbamate 46k (110 mg), yield: 69.34%.

[1143] MS m / z(ESI):446.2[M+1]

[1144] Step 11

[1145] (S)-tert-Butyl (1″-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-3′-yl)carbamate

[1146] (S)-tert-butyl (1″-(4-cyano-6-methylpyrimidin-2-yl)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-3′-yl)carbamate 46k (110 mg, 246.88 μmol) was added to 3 mL of dichloromethane, cooled in an ice-water bath, and bromosuccinimide (48.33 mg, 271.57 μmol) was added. ), warmed to room temperature for 2 hours, concentrated under reduced pressure, and the 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)carbamic acid tert-butyl ester 461 (110 mg), yield: 84.96%.

[1147] MS m / z(ESI):524.0[M+1]

[1148] Step 12

[1149] (S)-tert-Butyl (1″-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-3′-yl)carbamate

[1150] Tert-butyl (S)-(1″-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidin]-3′-yl)carbamate 461 (89.31 mg, 170.29 μmol), 2,3-dichlorophenylboronic acid (48.74 mg, 255.44 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium (28.52 mg, 34.06 μmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (31 .74 mg, 68.12 μmol) and potassium phosphate (108.31 mg, 510.87 μmol) were added successively into 3.4 mL of a mixed solution (1,4-dioxane: water = 7.5: 1), argon was replaced three times, heated to 105°C, reacted for 2 hours, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain (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 (95 mg), yield: 94.47%.

[1151] MS m / z(ESI):[M+1]589.9

[1152] Step 13

[1153] 2-((S)-3′-amino-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-1″-yl)-5-(2,3-(dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid

[1154] tert-Butyl (S)-(1″-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-3′-yl)carbamate 46m (95 mg, 160.87 μmol) was added to 3 mL of concentrated hydrochloric acid, heated to 90° C., and stirred for 9 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was prepared by liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H 2 O, mobile phase B: CH 3 CN), to give the product 2-((S)-3′-amino-3′H-dispiro[cyclopropane-1,1′-indene-2′,4″-piperidinyl]-1″-yl)-5-(2,3-(dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 46 (2 mg), yield: 1.4%.

[1155] MS m / z(ESI):508.9[M+1]

[1156] Comparative Example 1

[1157] Comparative Example 1 is compound 4 of WO 2020063760, which is prepared according to Example 4 disclosed in WO 2020063760, and the specific structure is as follows:

[1158]

[1159] Comparative Example 2

[1160] Comparative Example 2 is the compound of Example 119 of WO 2020181283, which is prepared according to Example 119 of WO 2020181283, and the specific structure is as follows:

[1161]

[1162] Comparative Example 3

[1163] Comparative Example 3 is the compound of Example 117 of WO 2020181283, which is prepared according to Example 117 of WO 2020181283, and the specific structure is as follows:

[1164]

[1165] Comparative Example 4

[1166] Comparative Example 4 is a racemic compound of the compound in Example 117 of WO 2020181283. The operation steps are as shown in Example 28 of the present invention. The specific structure is as follows:

[1167]

[1168] Biological evaluation

[1169] Test Example 1 Determination of the Allosteric Inhibitory Activity of the Compounds of the Invention on SHP2

[1170] The following method is used to determine the degree of inhibition of the activity of recombinant human full-length SHP2 by the compounds of the present invention under in vitro conditions. SHP2 is allosterically activated by the binding of a di-tyrosyl-phosphorylated peptide to its Src homology 2 (SH2) domain. The latter activation step results in the release of the autoinhibitory interface of SHP2, which subsequently activates the SHP2 protein tyrosine phosphatase (PTP), which can be used for substrate recognition and reaction catalysis.

[1171] The experimental process is briefly described as follows: the test compound was first dissolved in DMSO to prepare a stock solution. The reaction was carried out in a 384-well Small VolumeTM HiBase microplate (Greiner, 784075). SHP2 (signalchem, P38-20G-10μg) and SHP-2Activating Peptide (IRS1_pY1172 (dPEG8) pY1222) (BPS, 79319-1) were first added to the wells at final concentrations of 0.5nM and 0.5μM, respectively, followed by the addition of the test compound at a concentration range of 0.00004-10μM and incubated at 25°C for 60 minutes. DiFMUP (Thermo, D6567) was then added to the reaction and incubated at 25°C for 30 minutes. After the incubation, the reaction was read using a microplate reader (BMG) with excitation and emission wavelengths of 340nm and 450nm, respectively. The percentage inhibition rate of the compound at each concentration was calculated by comparing the fluorescence intensity ratio with that of the control group (0.1% DMSO), and the IC value of the compound was obtained by nonlinear regression analysis of the compound concentration-inhibition rate using GraphPad Prism 5 software. 50 Values ​​are shown in Table 1.

[1172] Table 1 IC of the compounds of the present invention against the full-length SHP2 enzyme activity 50 data

[1173] Compound No. <![CDATA[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

[1174] Conclusion: It can be seen from Table 1 that the compounds of the present invention have good allosteric inhibition effect on SHP2 enzyme.

[1175] Test Example 2 Pharmacokinetic Test

[1176] 1. Purpose of the experiment

[1177] ICR mice were used as test animals, and comparative example 1, compound 29 and compound 37 were administered by gavage. The drug concentrations in plasma at different times were determined by LC / MS / MS method to study the pharmacokinetic characteristics of the compounds of the present invention and the comparative example compounds in mice.

[1178] 2. Experimental plan

[1179] 2.1 Experimental drugs and animals

[1180] Experimental drugs: Comparative Example 1, Compound 29 and Compound 37;

[1181] Animals: ICR mice, male, 29.0-33.8 g, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[1182] 2.2 Drug preparation

[1183] Weigh an appropriate amount of drug, add it to an appropriate amount of sodium carboxymethylcellulose (CMC-Na, containing 0.5% Tween 80), vortex and sonicate to prepare a 0.5 mg / mL suspension.

[1184] 2.3 Administration

[1185] ICR mice in each oral gavage group (9 mice in each group) were fasted overnight and then gavaged with the compound (PO, 5 mg / kg, volume 10 mL / kg), and were fed 4 hours after the administration.

[1186] 3. Operation

[1187] Before administration and at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, approximately 0.2 mL of blood was collected from the jugular vein and anticoagulated with sodium heparin. After blood sample collection, it was placed on ice and centrifuged to separate plasma (centrifugation conditions: 1500g, 10 minutes). The collected plasma was stored at -40 to -20°C before analysis.

[1188] The content of the test compound in mouse plasma after oral administration was determined by LC-MS / MS.

[1189] 4. Pharmacokinetic parameter results

[1190] The pharmacokinetic parameters of the compound of the present invention and comparative example 1 are shown in Table 2.

[1191] Table 2 Pharmacokinetic results

[1192]

[1193] Conclusion: Compared with Comparative Example 1, the blood drug concentration and the area under the curve of Compound 29, Compound 37 were significantly improved.

[1194] Test Example 3 hERG potassium channel inhibitory activity test of compounds

[1195] 1. Cell culture

[1196] 1.1 The cells used in this experiment were CHO cells transfected with hERG cDNA and stably expressing hERG channels (provided by Sophion Bioscience, Denmark), and the cell generation was P17. The cells were cultured in a medium containing the following ingredients (all from Invitrogen): Ham's F12 medium, 10% (v / v) inactivated fetal bovine serum, 100 μg / mL hygromycin B, and 100 μg / mL Geneticin.

[1197] 1.2 CHO hERG cells were grown in a culture dish containing the above culture medium and incubated at 37°C with 5% CO 2 24 to 48 hours before electrophysiological experiments, CHO hERG cells were transferred to round glass slides placed in culture dishes and grown in the same culture medium and conditions as above. The density of CHO hERG cells on each round glass slide should be such that most of the cells are independent and single.

[1198] 2. Experimental solution

[1199] The solutions of Table 3 (recommended by Sophion) were used for electrophysiological recordings.

[1200] Table 3 Composition of intracellular and extracellular fluids

[1201]

[1202] 3. Electrophysiological recording process

[1203] 3.1 Electrophysiological recording system

[1204] The fully automated QPatch system (Sophion, Denmark) was used to record whole-cell currents. Cells were clamped at -80 mV. The cell clamping voltage was depolarized to +20 mV to activate hERG potassium channels and then clamped to -50 mV 2.5 seconds later to eliminate inactivation and generate outward tail currents. The peak tail current was used as the value of the hERG current magnitude.

[1205] 3.2 QPatch Experimental Procedure

[1206] After reaching the whole-cell configuration with a ruptured membrane in the initial stage, the cells are recorded for at least 120 seconds to achieve stability. The above voltage pattern is then applied to the cells every 15 seconds throughout the process. Only stable cells recorded with the above parameter thresholds are allowed to enter the drug treatment process. An external solution containing 0.1% dimethyl sulfoxide (solvent) is applied to the cells to establish a baseline, and the current is allowed to stabilize for 3 minutes. After the compound solution is added, the cells are maintained in the test environment until the effect of the compound reaches a stable state or is limited to 4 minutes. In the test experiment with different compound concentration gradients, the compound is added to the clamped cells from low to high concentrations. After the compound test is completed, the cells are washed with external solution until the current returns to a stable state.

[1207] 4. Compound preparation

[1208] 4.1 Dilute the 10 mM compound stock solution in a serial dilution manner with extracellular fluid to a final μM concentration.

[1209] 4.2 The highest tested concentration was 30 μM, followed by 6 concentrations: 30, 10, 3, 1, 0.3 and 0.1 μM.

[1210] 4.3 Except for the 30 μM compound, the final DMSO concentration was 0.3%, and the final DMSO concentration in the other compound solutions was 0.1%. All compound solutions were routinely sonicated and shaken for 5 to 10 minutes to ensure that the compound was completely dissolved.

[1211] 5. Data Analysis

[1212] The experimental data were analyzed by Qpatch analysis software, Excel, and Graphpad Prism provided by Sophion.

[1213] 6. Quality Control

[1214] Reagents: All experimental reagents were purchased from Sigma.

[1215] The test data in the report needs to meet the following standards:

[1216] Membrane resistance Rm>100MΩ;

[1217] Access resistance (Ra) < 15MΩ;

[1218] Tail current amplitude > 200pA;

[1219] The spontaneous rundown of hERG current in cells is less than 2% per minute;

[1220] Leakage current less than 200 pA or less than 10% of the peak hERG current (during 90% of the recording time);

[1221] The inhibitory effects of Cisapride at different concentrations on hERG channels were used as positive controls.

[1222] 7. Experimental results

[1223] The results of the inhibition of hERG current by the compounds of the present invention and the comparative example compounds are shown in Table 4.

[1224] Table 4 Inhibition results of compounds on hERG current

[1225] Compound No. <![CDATA[hERG IC 50 (μM)]]> 1μM inhibition rate (%) 10μM inhibition rate (%) 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 -- --

[1226] Conclusion: The inhibition of cardiac hERG potassium ion channels by drugs is the main cause of drug-induced QT prolongation syndrome. From the experimental results, it can be seen that compared with comparative examples 2 and 3, Example compounds 29 and 39 of the present invention have no obvious inhibitory effect on cardiac hERG potassium ion channels, and can avoid cardiac toxic side effects at high doses.

[1227] Test Example 4 Toxicity Determination of Compounds on L-02 Hepatocytes and HK-2 Kidney Cells

[1228] The following method is used to determine the toxicity of the compounds of the present invention and the comparative example compounds to in vitro hepatic and renal cells. L-02 and HK-2 were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. The above two cell lines were used to determine the toxicity of the compounds to hepatic and renal cells. L-02 hepatocytes were cultured in DMEM medium containing 10% fetal bovine serum, and HK-2 renal cells were cultured in MEM medium containing 10% fetal bovine serum. Cell viability was determined by Cell Counting Kit-8 (DOJINDO, Cat. No. CK04).

[1229] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a stock solution, and then gradiently diluted with the culture medium of the corresponding cells to prepare the test sample. The final concentration of the compound ranged from 50 μM to 7.5 nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at an appropriate density and incubated at 37°C, 5% CO 2 After overnight incubation in the incubator, the test compound samples were added and the cells were cultured for 72 hours. After the culture was completed, 100 μL of Cell Counting Kit-8 colorimetric solution (10%) was added to each well and the cells were incubated at 37°C and 5% CO 2Incubate in an incubator for 1-3 hours, then read the light absorbance of each well of the sample at a wavelength of 450nm using the Absorbance mode on a microplate reader. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.5% DMSO), and then a nonlinear regression analysis was performed in GraphPad Prism 5 software using the logarithm of the compound concentration-inhibition rate to obtain the IC value of the compound's cytotoxicity. 50 Values ​​are shown in Table 5.

[1230] Table 5 IC values ​​of compounds for L-02 and HK-2 cell toxicity 50 data

[1231] Compound No. <![CDATA[IC 50 (μM) / L-02]]> <![CDATA[IC 50 (μM) / HK-2]]> Comparative Example 2 3.52 -- Comparative Example 4 29.12 3.87 Compound 29 ＞50 23.37

[1232] Conclusion: Compared with comparative examples 2 and 4, the example compound 29 of the present invention has lower liver and kidney toxicity and better safety.

[1233] Unless otherwise defined, the terms used in the present invention have the meanings commonly understood by those skilled in the art.

[1234] The embodiments described in the present invention are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Those skilled in the art may make various other substitutions, changes and improvements within the scope of the present invention. Therefore, the present invention is not limited to the above embodiments, but is only limited by the claims.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is selected from phenyl; X is selected from CR e or N; R e selected from hydrogen atoms; R 1 Selected from C1-C6 alkyl; R 2 are the same or different and are each independently selected from a hydrogen atom or a halogen; R 3 selected from -C(O)OR 6 ; R 4 and R 5 Together with the N atom to which it is attached, it forms a group: is a double bond; G and M are selected from C; Ring B is selected from phenyl; R m , R n The same or different, each independently selected from R A ; R c and R d selected from hydrogen atoms; Or, R c and R d Together with the carbon atom to which it is attached, it forms R B ; R g selected from hydrogen atoms; R A The same or different, each independently selected from a hydrogen atom or -NR 7 R 8 ; R B Selected from 3-6 membered cycloalkyl; R 6 , R 7 and R 8 selected from hydrogen atoms; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III) or a pharmaceutically acceptable salt thereof, in: Ring A, X, m, R 1 , R 2 , R 4 and R 5 The definition is as stated in claim 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound or a pharmaceutically acceptable salt thereof of the general formula (VII): in: Ring B is selected from phenyl; R c and R d Together with the atoms to which it is attached, it forms a 3-membered cycloalkyl group; R m Selected from amino groups; R n selected from hydrogen atoms; Ring A, G, M, X, m, n, R 1 ~R 3 and R g The definition is as stated in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound of general formula (VIII) or a pharmaceutically acceptable salt thereof: in: Ring B, n, R 1 ~R 2 and R g The definition is as stated in claim 1.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atom or Cl.

6. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from methyl.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound is selected from:

8. The compound shown below or a pharmaceutically acceptable salt thereof:

9. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

10. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a SHP2 allosteric inhibitor.

11. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, in the preparation of a medicament for treating a disease mediated by SHP2, wherein the disease mediated by SHP2 is cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder.

12. The use according to claim 11, wherein the disease mediated by SHP2 is selected from Noonan syndrome, Leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma or glioblastoma.

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