CN114761394A

CN114761394A - Pyridine or pyrimidine derivative and preparation method and application thereof

Info

Publication number: CN114761394A
Application number: CN202180006863.8A
Authority: CN
Inventors: 曹琪; 别平彦; 黄贤贵; 邢庆娜; 王鑫; 晏青燕; 廖伟伟; 郭阳辉; 叶成; 胡泰山; 陈磊
Original assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Current assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Priority date: 2020-01-16
Filing date: 2021-01-15
Publication date: 2022-07-15
Anticipated expiration: 2041-01-15
Also published as: CN114761394B; WO2021143823A1

Abstract

The invention relates to pyridine or pyrimidine derivatives, a preparation method thereof and application thereof in medicines. In particular to a pyridine or pyrimidine derivative shown in a general formula (I), a preparation method thereof, a medicinal salt thereof and application thereof as a therapeutic agent, in particular to an SHP2 allosteric inhibitor, wherein the definition of each substituent in the general formula (I) is the same as that in the specification,

Description

Pyridine or pyrimidine derivative and preparation method and application thereof

Technical Field

the invention relates to a novel pyridine or pyrimidine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof as a therapeutic agent, in particular as an SHP2 allosteric inhibitor.

Background

Src homeodomain-2 phosphatase (SHP2) is one of the important members of the Protein Tyrosine Phosphatase (PTP) family, 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 2 SH2 domains, the two SH2 domains control the subcellular localization and functional regulation of SHP2, and the C-terminus contains 1 PTP domain with catalytic activity and 2 tyrosine residues related to the activity. Normally, SHP2 is in a self-inhibitory state, and when stimulated by growth factors, cytokines, or inflammatory factors, such as platelet-derived growth factors PDGF and FGF, catalytic sites are exposed, resulting in activation of the enzyme SHP 2.

SHP2 is widely present in human body, and is involved in multiple signal pathways such as rat sarcoma (RAS) -extracellular signal-related kinase (ERK), phosphatidylinositol 3 kinase (PI3K) -protein kinase B and NF-KB, activation of fibroblast growth factor, epidermal growth factor, and downstream mitogen-activated protein kinase of insulin receptor (MAPK/ERK), and further regulation of proliferation, differentiation, migration, and apoptosis of cells. It has been found that the activating mutation of SHP2 is closely related to the occurrence of noonan syndrome, leopard syndrome, monocytic leukemia, melanoma, solid tumor, cardiovascular disease, immune disorder, fibrosis or visual disorder, and the overexpression of SHP2 increases the risk of cancers such as chronic granulocytic leukemia, mastocytosis, malignant glioma, lung cancer and breast cancer, indicating that SHP2 plays an important role in different types of cancers and different stages of cancers. Due to the multiple functions of SHP2 in tumors, studies on SHP2 target inhibitors have also brought new hopes and directions for the treatment of tumors.

The SHP2 inhibitor can be divided into competitive inhibitors (including allosteric mycin, phenyl pyrazole hydrazino sulfonate and NSC-87877), non-competitive inhibitors (including indole salicylic acid and furamectin ketone) and irreversible inhibitors (including sodium antimony gluconate and cryptotanshinone) according to different action mechanisms, cryptotanshinone is reported to be used as an irreversible inhibitor of SHP2, and can inhibit the proliferation of rhabdomyosarcoma, melanoma, colon cancer and breast cancer in vitro, and in vivo studies show that the inhibitor can inhibit the proliferation of prostate cancer in mice, and a plurality of tests are needed for verifying whether the inhibitor can further become a clinically effective medicament.

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

Disclosure of Invention

In view of the above technical problems, the present invention provides a novel pyridine or pyrimidine compound represented by general formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein:

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

x is selected from CR^eOr N;

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

R ¹Selected from alkyl, cycloalkyl, heterocyclyl, cyano, alkenyl, alkynyl, -OR⁶、-C(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Wherein said alkyl, cycloalkyl, heterocyclyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from hydroxy, halo, alkyl, alkoxy, cycloalkyl or-NR⁷R ⁸Substituted with the substituent(s); preferably, R¹Is selected from methyl;

R ²identical OR different, each independently selected from hydrogen atom, alkyl, alkenyl, alkynyl, cyano, halogen, nitro, cycloalkyl, heterocyclyl, -OR⁶、-C(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Wherein said alkyl, alkenyl, alkynyl, cycloalkyl OR heterocyclyl is optionally further substituted with one OR more substituents selected from halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Substituted with the substituent(s);

R ³selected from cyano, alkoxy, tetrazolyl, -C (O) R⁶、-C(O)OR ⁶or-C (O) NR⁷R ⁸；

Provided that when R is³When selected from alkoxy, R¹Is not selected from-NR⁷R ⁸；

R ⁴And R⁵Together with the N atom to which they are attached form a 4-11 membered heterocyclic group, preferably a 5-11 membered heterocyclic group, wherein the heterocyclic group contains one or more N, O, S atoms or SO₂And heterocyclyl is optionally further substituted with one OR more substituents selected from halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHC(＝NH)NH ₂、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with halo, hydroxy, amino or alkoxy substituents;

or, R⁴And R⁵Together with the N atom to which it is attached form a group:

is a single bond or a double bond;

when in use

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

When in use

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

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

e is selected from NR^k、(CR ^pR ^q) _pO or S;

f is selected from (CR)^pR ^q) _q；

Provided that when E is selected from (CR)^pR ^q) _pWhen p is 1, q is 1; or p is 2 and q is 0; when E is selected from NR^kQ is 1 when O or S;

j is selected from CR^pR ^q；

K is selected from NR^k、(CR ^pR ^q) _rO or S;

r is 0 or 1;

R ^m、R ⁿ、R ^pand R^qAre the same or different and are each independently selected from R^A；

Or, R^pAnd R^qTogether with the carbon atom to which they are attached form R^B；

R ^cAnd R^dSame or differentAnd each independently selected from hydrogen, halogen, alkyl OR-OR⁶Wherein said alkyl is optionally further substituted with hydroxy, halo, alkoxy, cycloalkyl or-NR⁷R ⁸Substituted with the substituent(s);

or, R^cAnd R^dTogether with the carbon atom to which they are attached form R^B；

R ^gIdentical OR different, each independently selected from hydrogen atom, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHC(＝NH)NH ₂、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR⁷R ⁸Substituted with the substituent(s);

or, two R^gTogether with the same carbon atom to which they are attached form C ═ O;

R ^jand R^kThe same or different, each independently selected from a hydrogen atom or an alkyl group;

R ^Aidentical OR different, each independently selected from hydrogen atom, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHC(＝NH)NH ₂、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Therein is describedSaid alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR⁷R ⁸Substituted with the substituent(s);

R ^Bthe same OR different, each is independently selected from 3-10 membered cycloalkyl OR 3-10 membered heterocyclyl, wherein the cycloalkyl OR heterocyclyl is optionally further substituted by one OR more groups selected from halogen, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -OR⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHC(＝NH)NH ₂、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Substituted with the substituent(s);

R ⁶、R ⁷and R⁸Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or a heterocyclyl group, wherein said alkyl, cycloalkyl or heterocyclyl group is optionally further substituted with one or more groups selected from hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ⁹、-C(O)OR ⁹、-OC(O)R ⁹、-SO ₂R ⁹、-NR ¹⁰R ¹¹、-C(O)NR ¹⁰R ¹¹、-SO ₂NR ¹⁰R ¹¹or-NR¹⁰C(O)R ¹¹Substituted with the substituent(s);

or, R⁷And R⁸Together with the N atom to which they are attached form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more N, O, S atoms or SO₂And the 3-to 8-membered heterocycle is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, alkyl, and alkoxy;

R ⁹、R ¹⁰and R¹¹Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;

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

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

p is selected from 1 or 2.

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

wherein: ring A, X, m, R¹、R ²、R ⁴And R⁵The definition of (A) is described in the general formula (I).

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

Wherein: ring A, X, m, R¹、R ²、R ⁴And R⁵The definition of (A) is as described in the general formula (I).

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

In a preferred embodiment of the invention, the compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: r⁴And R⁵Together with the N atom to which they are attached form a 4-8 membered monocyclic heterocyclyl group, preferably a 5-6 membered monocyclic heterocyclyl group, more preferably a piperidinyl group, wherein said monocyclic heterocyclyl group is optionally further substituted with one or more groups selected from methyl, amino, -CH₂NH ₂、-CH ₂OH、-NHC(＝NH)NH ₂OR ═ O OR-OR⁶Substituted with the substituent(s); r⁶The definition of (A) is described in the general formula (I).

In a preferred embodiment of the invention, the compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: r⁴And R⁵Together with the N atom to which they are attached form a 7-to 11-membered spiroheterocyclic group, wherein said spiroheterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂NH ₂、-CH ₂OH、-NHC(＝NH)NH ₂OR-O OR-OR⁶Substituted with a substituent of (a); r is⁶Is as defined in formula (I); preferably, wherein said spiroheterocyclyl is selected from:

R ^aidentical or different, each independently selected from methyl, amino, -CH₂NH ₂、-CH ₂OH、-NHC(＝NH)NH ₂OR-OR⁶(ii) a Or, two R^aTogether with the same carbon atom to which they are attached form C ═ O; r⁶Is as defined in formula (I); t is 1, 2 or 3.

In a preferred embodiment of the invention, the compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: r⁴And R⁵Together with the N atom to which they are attached form a 7-to 11-membered bridged heterocyclic group, wherein said bridged heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH₂NH ₂、-CH ₂OH、-NHC(＝NH)NH ₂OR ═ O OR-OR⁶Substituted with the substituent(s); r⁶The definition of (A) is described in the general formula (I).

In a preferred embodiment of the invention, the compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: r⁴And R⁵Together with the N atom to which they are attached form a 7-to 11-membered fused heterocyclic group, wherein said fused heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH₂NH ₂、-CH ₂OH、-NHC(＝NH)NH ₂OR ═ O OR-OR⁶Substituted with the substituent(s); r ⁶The definition of (A) is described in the general formula (I).

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

wherein:

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

e is selected from NR^k、(CR ^pR ^q) _pO or S;

f is selected from (CR)^pR ^q) _q；

R ^mselected from amino, -CH₂NH ₂or-NHC (═ NH) NH₂；

R ⁿSelected from hydrogen atom, methyl group or-CH₂OH；

R ^pAnd R^qEach independently selected from hydrogen atom, halogen, amino group, C₁-C ₄Alkyl, hydroxy C₁-C ₄Alkyl, amino C₁-C ₄Alkyl OR-OR⁶；

Ring A, G, M, X, M, n, R¹～R ³、R ⁶、R ^kAnd R^gThe definition of (A) is described in the general formula (I).

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

wherein:

J is selected from CR^pR ^q；

K is selected from NR^k、(CR ^pR ^q) _rO or S;

r is 0 or 1;

R ^mselected from amino, -CH₂NH ₂or-NHC (═ NH) NH₂；

R ⁿSelected from hydrogen atom, methyl group or-CH₂OH；

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

wherein:

R ^cand R^dTogether with the linking atoms form a 3-8 membered cycloalkyl group;

R ^mselected from amino, -CH₂NH ₂or-NHC (═ NH) NH₂；

R ⁿSelected from hydrogen atom, methyl group or-CH₂OH；

Ring A, G, M, X, M, n, R¹～R ³And R^gThe definition of (A) is described in the general formula (I).

In a preferred embodiment of the invention, the compounds of the general formula (I), (II), (III), (IV), (V), (VI) or (VII) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R is²Selected from hydrogen atom, F, Cl, Br, amino group, hydroxyl group, cyano group, nitro group, methoxy group, ethoxy group, methyl group, ethyl group, ethynyl group, ethenyl group, -NHCH ₃or-N (CH)₃) ₂。

In a preferred embodiment of the invention, the compound of formula (V), (VI) or (VII) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is³Selected from-C (O) OH.

In a preferred embodiment of the invention, the compounds of the general formula (I), (II), (III), (IV), (V), (VI) or (VII) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R is⁶Selected from hydrogen atoms or alkyl groups.

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

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

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

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

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

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

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

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

The invention also provides a compound of the general formula (I), (II), (III), (IV), (V), (VI) or (VII) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating a disease mediated by SHP2, wherein the disease mediated by SHP2 is preferably cancer, cancer metastasis, a cardiovascular disease, an immune disorder, fibrosis or a visual disorder; wherein said disease mediated by SHP2 is preferably selected from noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large-cell lymphoma and glioblastoma.

The invention further provides an application of the compound of the general formula (I), (II), (III), (IV), (V), (VI) or (VII) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating cancer, cancer metastasis, cardiovascular diseases, immune disorders, fibrosis or visual disorders.

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

Detailed description of the invention

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

"alkyl" when taken as a group or part of a group means including C₁-C ₂₀Straight-chain or branched aliphatic hydrocarbon groups. Preferably C ₁-C ₁₀Alkyl, more preferably C₁-C ₆An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted.

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

"alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, and can be straight or branched. Preferably selected is C₂-C ₁₀Alkynyl of (2), more preferably C₂-C ₆Alkynyl, most preferably C₂-C ₄Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted.

"cycloalkyl" refers to a saturated or partially saturated monoCarbocyclic rings of rings, fused rings, bridged rings, and spirocyclic rings. Preferably C₃-C ₁₂Cycloalkyl, more preferably C₃-C ₈Cycloalkyl, most preferably C₃-C ₆A cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be optionally substituted or unsubstituted.

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

"fused cycloalkyl" refers to a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls depending on the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl groups. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl or tetradecaphenanthryl.

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

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

The heterocyclic group may be substituted or unsubstituted.

"spiroheterocyclyl" refers to a 5-to 18-membered polycyclic group having two or more cyclic structures wherein the individual rings share an atom with one another and which contains 1 or more double bonds within the ring, but none of the rings have a fully conjugated pi-electron aromatic system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O)_n(wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. The spirocycloalkyl group is classified into a single spiroheterocyclic group, a double spiroheterocyclic group or a multiple spiroheterocyclic group, preferably a single spiroheterocyclic group and a double spiroheterocyclic group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered A 6-membered, 5-membered, or 5-membered, 6-membered, mono-spiroheterocyclyl group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5 ]]Decyl, 2-oxa-7-azaspiro [4.4]Nonyl, 7-oxaspiro [3.5 ]]Nonyl, 5-oxaspiro [2.4 ]]A heptyl radical,

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

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

"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C₆-C ₁₀Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. The aryl group may be substituted or unsubstituted.

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

Heteroaryl groups may be substituted or unsubstituted.

"fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, and one or more of the rings may contain one or more double bonds, but at least one of the rings is not fully conjugatedA pi-electron aromatic system wherein 0 or one or more of the ring atoms are selected from nitrogen, oxygen or S (O)_n(wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14, more preferably 8 to 10. Examples of "fused rings" include, but are not limited to:

"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. C₁-C ₆Alkoxy groups of (4) are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"hydroxy" refers to an-OH group.

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

"amino" means-NH₂。

"cyano" means-CN.

"nitro" means-NO₂。

"benzyl" means-CH₂-phenyl.

"carboxy" refers to-C (O) OH.

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

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to tert-butoxycarbonyl.

"TFA" refers to trifluoroacetic acid.

"Ts" refers to p-toluenesulfonyl.

"hydroxy group C₁-C ₄Alkyl "refers to hydroxy-substituted C₁-C ₄An alkyl group.

"amino group C₁-C ₄Alkyl "refers to amino-substituted C₁-C ₄An alkyl group.

A "leaving group", or leaving group, an atom or functional group that is removed from a larger molecule in a chemical reaction, is a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called the substrate (substrate), and the atom or group of atoms cleaved from the substrate molecule with a pair of electrons is called the leaving group. Groups that accept electrons easily and have a strong ability to bear negative charges are good leaving groups. The lower the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to be cleaved from other molecules. The reason is that the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced when the pKa of its conjugate acid is smaller, and the corresponding leaving group does not need to be bound to another atom. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -OTs, or-OH.

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

Unless otherwise indicated, the structures described herein also include all isomers of such structures (e.g., diastereomers, enantiomers, steric isomers, and geometric (conformational) isomeric forms; e.g., the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, steric isomers of biphenyl-like structures (see Basic organic chemistry, second edition, supra, prosecution, et al, p 104-105); PAC,1996,68,2193 (Basic nomenclature of steric (IUPAC Recommendations 1996, on Page 2201)), (Z) and (E) conformational isomers.) thus the individual stereoisomers as well as enantiomeric, diastereomeric, steric, and geometric (conformational) isomeric mixtures of the compounds of the invention are within the scope of the invention.

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

As used herein, "substituted" or "substituted," unless otherwise specified, means that the group may be substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, ═ O, -OR⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHC(＝NH)NH ₂、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Wherein said alkyl or alkoxy is optionally further substituted with a substituent of halo, hydroxy, amino or alkoxy;

R ⁶、R ⁷And R⁸Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group or the heteroaryl group is optionally further substituted by one or more groups selected from hydroxyl, amino, halogenElements, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R⁹、-C(O)OR ⁹、-OC(O)R ⁹、-SO ₂R ⁹、-NR ¹⁰R ¹¹、-C(O)NR ¹⁰R ¹¹、-SO ₂NR ¹⁰R ¹¹or-NR¹⁰C(O)R ¹¹Substituted with a substituent of (a);

R ⁷and R⁸Together with the N atom to which they are attached form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O, S or SO₂Atoms, and the 3-to 8-membered heterocyclic ring is further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy;

R ⁹、R ¹⁰and R¹¹Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate.

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

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

Synthesis of Compounds of the invention

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

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

compounds of the general formula (Ia) and NHR⁴R ⁵Carrying out nucleophilic substitution reaction under alkaline condition to obtain a compound with a general formula (Ib); carrying out Suzuki reaction on the compound of the general formula (Ib) and the compound of the general formula (Ic) under the conditions of palladium catalyst and alkali, and optionally further removing a protecting group from the obtained compound to obtain a compound of the general formula (I);

wherein:

X ₂selected from halogens;

X ₃selected from a leaving group selected from halogen or-SO₂R ^t；

R ³Is selected from alkoxy;

R ^tselected from alkyl groups;

ring A, X, m, R¹、R ²、R ⁴And R⁵The definition of (A) is described in the general formula (I).

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

carrying out Suzuki reaction on the compound of the general formula (Ia) and the compound of the general formula (Ic) under the conditions of palladium catalyst and alkali to obtain a compound of the general formula (Id); compounds of the general formula (Id) and NHR⁴R ⁵Nucleophilic extraction under alkaline conditionsCarrying out substitution reaction, and optionally further removing a protecting group from the obtained compound to obtain a compound of a general formula (I);

wherein:

X ₂selected from halogens;

X ₃selected from a leaving group selected from halogen or-SO₂R ^t；

R ³Is selected from alkoxy;

R ^tselected from alkyl groups;

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

compounds of the general formula (IIa) and NHR⁴R ⁵Carrying out nucleophilic substitution reaction under alkaline condition to obtain a compound with a general formula (IIb); carrying out Suzuki reaction on the compound of the general formula (IIb) and the compound of the general formula (Ic) under the conditions of palladium catalyst and alkali, and optionally further removing a protecting group from the obtained compound to obtain a compound of the general formula (IIc); hydrolyzing the compound of the general formula (IIc) in the presence of sodium hydroxide solution to obtain a compound of a general formula (II);

Wherein:

X ₂selected from halogens;

X ₃selected from a leaving group selected from halogen or-SO₂R ^t；

R ^tSelected from alkyl groups;

ring A, X, m, R¹、R ²、R ⁴And R⁵Is as defined in formula (II)(II) in the above-mentioned manner.

carrying out Suzuki reaction on the compound of the general formula (IIa) and the compound of the general formula (Ic) under the conditions of palladium catalyst and alkali to obtain a compound of the general formula (IId); compounds of the general formula (IId) and NHR⁴R ⁵Carrying out nucleophilic substitution reaction under alkaline condition to obtain a compound with a general formula (IIc); hydrolyzing the compound of the general formula (IIc) in the presence of sodium hydroxide solution to obtain a compound of a general formula (II);

wherein:

X ₂selected from halogens;

X ₃selected from a leaving group selected from halogen or-SO₂R ^t；

R ^tSelected from alkyl groups;

ring A, X, m, R¹、R ²、R ⁴And R⁵Is as defined in formula (II).

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

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

wherein: ring A, X, m, R ¹、R ²、R ⁴And R⁵Is as defined in formula (III)。

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

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

wherein: ring A, X, m, R¹、R ²、R ⁴And R⁵Is as defined in formula (IV).

Detailed Description

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

Examples

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

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

The thin-layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the thin-layer chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4 mm-0.5 mm.

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

In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification, and unless otherwise indicated, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Prov Chemical science Inc. and Sci Chemical science Inc., among others.

CD ₃OD: deuterated methanol.

CDCl ₃: deuterated chloroform.

DMSO-d ₆: deuterated dimethyl sulfoxide.

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

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

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

Example 1

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

First step of

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

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

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

Second step of

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

The above product, 5-bromo-2-chloro-4-methoxy-6-methylpyrimidine 1b (448.4mg,1.9mmol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 1c (470mg,2.2mmol) and 0.5mL of N, N-diisopropylethylamine were added to 5mL of dimethylsulfoxide under an argon atmosphere, heated to 130 ℃ and reacted for 1 hour. After the reaction was completed, it was cooled to room temperature, 30mL of water was added, extraction was performed with ethyl acetate (10 mL. times.3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further purified by analysis with a silica gel column chromatography (eluent: System A) to obtain tert-butyl (1- (5-bromo-4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 1d (210mg), yield: 26.7 percent.

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

The third step

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

Tert-butyl (1- (5-bromo-4-methoxy-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 1d (140mg,0.338mmol), 1e (128mg,0.676mmol) of (2, 3-dichlorophenyl) boronic acid, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (24mg,0.0338mmol), tetrakis (triphenylphosphine) palladium (39mg,0.0338mmol), sodium carbonate (143mg,1.35mmol) and 0.5mL of water were added to 3mL of N, N-dimethylformamide under argon protection, heated to 110 ℃ and reacted for 4 hours. After the reaction was completed, it was cooled to room temperature, 20mL of water was added, extraction was performed with ethyl acetate (10 mL. times.3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further purified by 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 (110mg), yield: 68.7 percent.

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

The fourth step

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

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

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

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

Example 2

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

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

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

The fourth step

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

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

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

Example 3

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

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

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

The fourth step

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

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

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

Example 4

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

First step of

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

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

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

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

Second step of

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

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

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

Example 5

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

Tert-butyl (1- (5-bromo-4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 5c (150mg,0.368mmol), 1e (140mg,0.735mmol) of (2, 3-dichlorophenyl) boronic acid, 2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl (2-amino-1, 1' -biphenyl-2-yl) palladium (31mg,0.039mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropoxy-1, 1' -biphenyl (34mg,0.074mmol) and potassium phosphate (234mg,1.104mmol) were added to 3.5mL of the mixed solution under argon (1, 4-dioxane and water 6:1), heated to 130 ℃, and reacted for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was further purified by silica gel column chromatography (eluent: system a) to give tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 5d (170mg), yield: 98 percent.

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

The fourth step

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

Tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyridin-2-yl) -4-methylpiperidin-4-yl) carbamate 5d (170mg,0.359mmol) and 1.5mL of trifluoroacetic acid were added to 6mL of dichloromethane, reacted at room temperature for 40 minutes, and after completion of the reaction, concentrated under reduced pressure to give a residue, which was subjected to liquid phase separation (column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA + H₂O, mobile phase B: CH (CH)₃CN) to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylisonicotinamide 5e (69.91mg), yield: 52 percent. MS M/z (ESI) 375.0[ M +1 ]]

The fifth step

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

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

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

example 6

First step of

6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylisonicotonitrile 5e (37.33mg,0.1mmol) and 0.1mL of a 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80 ℃ and reacted for 40 minutes. After the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was subjected to liquid phase separation (column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA + H)₂O, mobile phase B: CH (CH)₃CN) to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylisonicotinamide 6(21.99mg), yield: 56 percent. MS M/z (ESI) 393.1[ M +1 ]]

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

Example 7

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

First step of

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

Tert-butyl (1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 3d (50mg,0.105mmol), zinc chloride (14.30mg,0.105mmol) and sodium azide (6.82mg,0.105mmol) were successively added to 2mL of methanol and reacted at room temperature for 2 days. After the reaction, 2mL of 1M diluted hydrochloric acid was slowly dropped into the reaction solution to quench the reaction, the reaction solution was extracted with ethyl acetate (30 mL. times.2), the combined organic phases were washed with a saturated sodium chloride solution (30 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue, and liquid phase separation was performed (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5 μ M, 20 mL/min; mobile phase A: 0.05% TFA + H ₂O, mobile phase B: CH (CH)₃CN) 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 (15mg), yield: 27.51 percent.

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

Second step of

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

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

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

Example 8

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

First step of

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

2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxylic acid 3(80mg,0.202mmol), di-tert-butyl dicarbonate (88.34mg,0.405mmol) and sodium carbonate (85.8mg,0.809mmol) were added to a 2mL mixed solution (1, 4-dioxane: water ═ 5:1) and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, pH was adjusted to 2-3 by the addition of 1M dilute hydrochloric acid, extracted with ethyl acetate (30 mL. times.2), the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further purified by analysis 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 (40mg), yield: 39.9 percent.

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

Second step of

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

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

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

The third step

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

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

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

Example 9

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

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

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

The fourth step

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

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

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

The fifth step

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

Tert-butyl ((3S,4S) -8- (4-cyano-6-methylpyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate 9e (340mg,0.877mmol) and bromosuccinimide (171.79mg,0.965mmol) were added to 5mL of N, N-dimethylformamide and reacted overnight at room temperature. After the reaction was completed, 30mL of water was added, extraction was performed with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further 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] decan-4-yl) carbamate 9f (390mg), yield: 95.3 percent.

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

The sixth step

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

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

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

Step seven

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

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

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

Example 10

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

First step of

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

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

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

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

Second step of

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

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

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

Example 11

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

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

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

The fourth step

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

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

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

The fifth step

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

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

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

Example 12

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

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

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

Example 13

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

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

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

The fourth step

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

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

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

The fifth step

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

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

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

The sixth step

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

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

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

Step seven

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

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

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

Eighth step

2- ((R) -1-amino-8-azaspiro [4.5]]Decan-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carbonitrile 13h (36mg,0.086mmol) and 0.5mL of 6M sodium hydroxide were added to 2mL of ethanol, heated to 80 ℃ and reacted for 0.5 h. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to liquid phase separation (column AKZONOB)EL Kromasil; 250 × 21.2mm i.d.; 5 mu m, 20 mL/min; mobile phase A: 0.05% TFA + H₂O, mobile phase B: CH (CH)₃CN) to obtain 2- ((R) -1-amino-8-azaspiro [4.5 ]Dec-8-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrimidine-4-carboxamide 13(6mg), yield: 15.70 percent.

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

¹H NMR(400MHz,CD3OD):δ7.52(d,J＝8.0Hz,1H),7.31(t,J＝8.0Hz,1H),7.15(d,J＝8.0Hz,1H),4.72(s,2H),3.21(d,J＝12.0Hz,2H),2.82(s,1H),2.09(s,3H),1.59-1.79(m,5H),1.32-1.48(m,5H).

Example 14

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

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

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

The fourth step

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

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

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

The fifth step

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

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

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

Example 15

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

Tert-butyl (R) - ((1- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamate 15c (80mg,0.202mmol), (2, 3-dichlorophenyl) boronic acid 1e (96.31mg,0.505mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (16.90mg,0.020mmol), tetrakis (triphenylphosphine) palladium (18.84mg,0.040mmol) and potassium phosphate (128.55mg,0.606mmol) were added to 2.2mL of the mixed solution (1, 4-dioxane: water ═ 10:1) under argon, heated to 130 ℃ and reacted for 5 hours. After the reaction was completed, it was cooled to room temperature, 20mL of water was added, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl (((3R) -1- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) pyrrolidin-3-yl) methyl) carbamate 15d (70mg), yield: 74.99 percent.

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

The fourth step

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

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

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

The fifth step

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

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

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

Example 16

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

Tert-butyl ((1R,5S) -8- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 16c (150mg,0.355mmol), (2, 3-dichlorophenyl) boronic acid 1e (169.44mg,0.888mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (29.74mg,0.036mmol), tetrakis (triphenylphosphine) palladium (33.15mg,0.071mmol) and potassium phosphate (226.17mg,1.07mmol) were added to 2.2mL of a mixed solution (1, 4-dioxane: water ═ 10:1) under argon, heated to 130 ℃ and reacted for 5 hours. After the reaction was completed, it was cooled to room temperature, 20mL of water was added, extraction was performed with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((1R,5S) -8- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 16d (150mg), yield: 86.48 percent.

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

The fourth step

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

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

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

The fifth step

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

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

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

Example 17

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

First step of

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

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

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

Second step of

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

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

¹H NMR(400MHz,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).

Example 18

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

First step of

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

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (70mg,0.355mmol), (3-azabicyclo [3.1.0] hex-6-yl) carbamic acid tert-butyl ester 17a (91.48mg,0.461mmol) N, N-diisopropylethylamine (137.62mg,1.06mmol) was added to 2mL of N, N-dimethylacetamide, heated to 90 ℃ and reacted for 3 hours. After the reaction was completed, 20mL of water was added, extraction was performed with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analytically 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 (110mg), yield: 98.27 percent.

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

Second step of

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

Tert-butyl (3- (4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6-yl) carbamate 17b (110mg,0.349mmol) and bromosuccinimide (93.12mg,0.523mmol) were added to 2mL of N, N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, 30mL of water was added, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl (3- (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -3-azabicyclo [3.1.0] hex-6-yl) carbamate 18c (110mg), yield: 79.99 percent.

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

The third step

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

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

The fourth step

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

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

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

The fifth step

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

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

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).

Example 19

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

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

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

The fourth step

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

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

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

The fifth step

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

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

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

The sixth step

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

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

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

Example 21

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

First step of

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

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

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

Second step of

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

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

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

The third step

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

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

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

The fourth step

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

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

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

The fifth step

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

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

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

The sixth step

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

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

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

Step seven

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

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

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

The eighth step

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

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

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

Example 22

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

First step of

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

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

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

Second step of

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

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

The third step

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

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

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

Example 23

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

First step of

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

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

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

Second step of

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

2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (120mg, 781.41. mu. mol), (R) -N- ((R) -2, 3-dihydrospiro [ indene-1, 4' -piperidin ] -2-yl) -2-methylpropane-2-sulfinamide 23b (287.37mg, 937.69. mu. mol) and N, N-diisopropylethylamine (302.97mg,2.34mmol) were sequentially added to 2mL of N, N-dimethylacetamide, and the temperature was raised to 90 ℃ to react for 2 hours. After the reaction was completed, 20mL of water was added to the reaction solution, extracted with ethyl acetate (30mL × 2), the aqueous layer was separated, the combined organic phases were washed successively with a saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to give (R) -N- ((R) -1'- (4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ indene-1, 4' -piperidin ] -2-yl) -2-methylpropane-2-sulfinamide 23c (170mg), yield: 51.36 percent. MS M/z (ESI) 424.0[ M +1]

The third step

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

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

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

The fourth step

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

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

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

The fifth step

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

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

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

The sixth step

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

Under argon protection, (R) - (1' - (5-bromo-4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ indene-1, 4' -piperidin ] -2-yl) carbamic acid tert-butyl ester 23f (70mg, 140.45. mu. mol), (2, 3-dichlorophenyl) boronic acid 1e (67.00mg, 351.11. mu. mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropoxy-1, 1' -biphenyl (13.11mg, 28.09. mu. mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (11.76mg, 14.04. mu. mol) and potassium phosphate (89.44mg,421.34 μmol) was added to 2.3mL of the mixed solution (1, 4-dioxane: water: 7:1), and the temperature was raised to 130 ℃ to react for 4 hours. After the reaction was completed, 20mL of water was added to the reaction solution, extracted with ethyl acetate (30mL × 3), the organic phases were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to obtain 23g (70mg) of tert-butyl (R) - (1'- (5- (2, 3-dichlorophenyl) -4-cyano-6-methylpyrimidin-2-yl) -2, 3-dihydrospiro [ indene-1, 4' -piperidin ] -2-yl) carbamate, yield: 88.29 percent.

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

Step seven

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

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

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

The eighth step

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

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

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

Biological evaluation

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

The following method was used to determine the degree of inhibition of the activity of the recombinant human full-length SHP2 by the compounds of the present invention under in vitro conditions. SHP2 is allosterically activated by the binding of di-tyrosyl-phosphorylated peptide to its Src homology 2(SH2) domain. The latter activation step results in the release of the self-inhibiting interface of SHP2, which subsequently activates SHP2 Protein Tyrosine Phosphatase (PTP) for substrate recognition and reaction catalysis.

The experimental procedure is briefly described as follows: test compounds were first dissolved in DMSO to prepare stock solutions. The reaction was carried out in 384 well Small volume HiBase microplates (Greiner, 784075) by first adding SHP2(signalchem, P38-20G-10ug) and SHP-2Activating Peptide (IRS1_ pY1172(dPEG8) pY1222) (BPS, 79319-1) to the wells at final concentrations of 0.5nM and 0.5. mu.M, respectively, followed by addition of test compound at a concentration range of 0.00004-10. mu.M and incubation at 25 ℃ for 60 min. DiFMUP (Thermo, D6567) was then added to the reaction and incubated at 25 ℃ for 30 minutes. After the incubation was complete, the microplate reader (BMG) was used to read the excitation and emission wavelengths at 340nm and 450nm, respectively. The percent inhibition of the compound at each concentration was calculated by comparison with the fluorescence intensity ratio of the control (0.1% DMSO), and the IC of the compound was obtained by nonlinear regression analysis of the compound concentration log-inhibition by GraphPad Prism 5 software ₅₀Values, see table 1.

TABLE 1 IC inhibition of full-Length SHP2 enzymatic Activity by Compounds of the invention₅₀Data of

Compound number	SHP2/IC ₅₀(nM)
Example 1	<500
Example 2	<500
Example 3	<200
Example 4	<500
Example 5	<200
Example 6	<500
Example 7	<500
Example 9	<200
Example 11	<500
Example 12	<500
Example 13	<200
Example 17	<200
Example 19	<500
Example 21	0.71
Example 22	16.61
Example 23	<200

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

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

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

Claims

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

wherein:

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

x is selected from CR ^eOr N;

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

R ¹selected from alkyl, cycloalkyl, heterocyclyl, cyano, alkenyl, alkynyl, -OR⁶、-C(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Wherein said alkyl, cycloalkyl, heterocyclyl, alkenyl or alkynyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halo, alkyl, alkoxy, cycloalkyl and-NR⁷R ⁸Substituted with a substituent of (a); preferably, R¹Is selected from methyl;

R ²the same OR different, each independently selected from hydrogen atom, alkyl, alkenyl, alkynyl, cyano, halogen, nitro, cycloalkyl, heterocyclyl, -OR⁶、-C(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Wherein said alkyl, alkenyl, alkynyl, cycloalkyl OR heterocyclyl is optionally further substituted with one OR more substituents selected from halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Substituted with the substituent(s);

R ³selected from cyano, alkoxy, tetrazolyl, -C (O) R⁶、-C(O)OR ⁶or-C (O) NR⁷R ⁸；

Provided that when R is³When selected from alkoxy，R ¹Is not selected from-NR⁷R ⁸；

R ⁴And R⁵Together with the N atom to which they are attached form a 4-11 membered heterocyclic group, preferably a 5-11 membered heterocyclic group, wherein the heterocyclic group contains one or more N, O, S atoms or SO ₂And heterocyclyl is optionally further substituted by one OR more substituents selected from halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -OR⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHC(＝NH)NH ₂、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with a substituent of halo, hydroxy, amino, or alkoxy;

or, R⁴And R⁵Together with the N atom to which they are attached form a group:

is a single or double bond;

when the temperature is higher than the set temperature
When represents a single bond, G and M are each independently selected from N or CR^j；

When the temperature is higher than the set temperature
When representing a double bond, G and M are each independently selected from C;

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

e is selected from NR^k、(CR ^pR ^q) _pO or S;

f is selected from (CR)^pR ^q) _q；

Provided that when E is selected from (CR)^pR ^q) _pWhen p is 1, q is 1; or p is 2 and q is 0; when E is selected from NR^kQ is 1 when O or S;

j is selected from CR^pR ^q；

K is selected from NR^k、(CR ^pR ^q) _rO or S;

r is 0 or 1;

R ^m、R ⁿ、R ^pand R^qAre the same or different and are each independently selected from R^A；

Or, R^pAnd R^qTogether with the carbon atom to which they are attached form R^B；

R ^cAnd R^dIdentical OR different, each independently selected from a hydrogen atom, a halogen, an alkyl group OR-OR⁶Wherein said alkyl is optionally further substituted with hydroxy, halo, alkoxy, cycloalkyl or-NR ⁷R ⁸Substituted with a substituent of (a);

or, R^cAnd R^dTogether with the carbon atom to which they are attached form R^B；

R ^gIdentical or different, each independently from the hydrogen atomHalogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHC(＝NH)NH ₂、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR⁷R ⁸Substituted with a substituent of (a);

or, two R^gTogether with the same carbon atom to which they are attached form C ═ O;

R ^jand R^kThe same or different, each independently selected from a hydrogen atom or an alkyl group;

R ^Aidentical OR different, each independently selected from hydrogen atom, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHC(＝NH)NH ₂、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR⁷R ⁸Substituted with the substituent(s);

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 one Is substituted by one OR more groups selected from halogen, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -OR⁶、-C(O)R ⁶、-C(O)OR ⁶、-OC(O)R ⁶、-SO ₂R ⁶、-NR ⁷R ⁸、-SO ₂NR ⁷R ⁸、-NHC(＝NH)NH ₂、-NHSO ₂R ⁶or-C (O) NR⁷R ⁸Substituted with a substituent of (a);

R ⁶、R ⁷and R⁸Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or a heterocyclyl group, wherein said alkyl, cycloalkyl or heterocyclyl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R⁹、-C(O)OR ⁹、-OC(O)R ⁹、-SO ₂R ⁹、-NR ¹⁰R ¹¹、-C(O)NR ¹⁰R ¹¹、-SO ₂NR ¹⁰R ¹¹or-NR¹⁰C(O)R ¹¹Substituted with a substituent of (a);

or, R⁷And R⁸Together with the N atom to which they are attached form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more N, O, S atoms or SO₂And the 3-to 8-membered heterocycle is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, alkyl, and alkoxy;

R ⁹、R ¹⁰and R¹¹Each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, nitro, cyano, alkoxy, heteroaryl, alkoxy,Heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;

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

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

p is selected from 1 or 2.
The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (II), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,

wherein: ring A, X, m, R¹、R ²、R ⁴And R⁵Is defined as in claim 1.
The compound according to claim 1, which is a compound of the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

wherein: ring A, X, m, R¹、R ²、R ⁴And R⁵Is as defined in claim 1.
The compound according to claim 1, which is a compound of the general formula (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

wherein: ring A, X, m, R¹、R ²、R ⁴And R⁵Is as defined in claim 1.
A compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴and R⁵Together with the N atom to which they are attached form a 4-8 membered monocyclic heterocyclyl group, preferably a 5-6 membered monocyclic heterocyclyl group, more preferably a piperidinyl group, wherein said monocyclic heterocyclyl group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂NH ₂、-CH ₂OH、-NHC(＝NH)NH ₂OR-O OR-OR⁶Substituted with a substituent of (a);

R ⁶is defined as in claim 1.
A compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴and R⁵Together with the N atom to which they are attached form a 7-to 11-membered spiroheterocyclic group, wherein said spiroheterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH₂NH ₂、-CH ₂OH、-NHC(＝NH)NH ₂OR-O OR-OR⁶Substituted with a substituent of (a);

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

R ^aidentical or different, each independently selected from methyl, amino, -CH₂NH ₂、-CH ₂OH、-NHC(＝NH)NH ₂OR-OR⁶；

Or, two R^aTogether with the same carbon atom to which they are attached form C ═ O;

R ⁶as defined in claim 1;

t is 1, 2 or 3.
A compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴and R⁵Together with the N atom to which they are attached form a 7-to 11-membered bridged heterocyclic group, wherein said bridged heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂NH ₂、-CH ₂OH、-NHC(＝NH)NH ₂OR-O OR-OR⁶Substituted with a substituent of (a);

R ⁶is defined as in claim 1.
A compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

R ⁴and R⁵Together with the N atom to which they are attached form a 7-to 11-membered fused heterocyclic group, wherein said fused heterocyclic group is optionally further substituted by one or more groups selected from methyl, amino, -CH₂NH ₂、-CH ₂OH、-NHC(＝NH)NH ₂OR-O OR-OR⁶Substituted with a substituent of (a);

R ⁶is defined as in claim 1.
The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of general formula (V):

wherein:

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

e is selected from NR^k、(CR ^pR ^q) _pO or S;

f is selected from (CR)^pR ^q) _q；

Provided that when E is selected from (CR)^pR ^q) _pWhen p is 1, q is 1; or p is 2 and q is 0; when E is selected from NR^kQ is 1 when O or S;

R ^mselected from amino, -CH₂NH ₂or-NHC (═ NH) NH₂；

R ⁿSelected from hydrogen atom, methyl group or-CH₂OH；

R ^pAnd R^qEach independently selected from hydrogen atom, halogen, amino group, C₁-C ₄Alkyl, hydroxy C₁-C ₄Alkyl, amino C₁-C ₄Alkyl OR-OR ⁶；

Ring A, G, M, X, M, n, R¹～R ³、R ⁶、R ^kAnd R^gIs defined as in claim 1.
The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (VI):

wherein:

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

j is selected from CR^pR ^q；

K is selected from NR^k、(CR ^pR ^q) _rO or S;

r is 0 or 1;

R ^mselected from amino, -CH₂NH ₂or-NHC (═ NH) NH₂；

R ⁿSelected from hydrogen atom, methyl group or-CH₂OH；

R ^pAnd R^qEach independently selected from hydrogen atom, halogen, amino group, C₁-C ₄Alkyl, hydroxy C₁-C ₄Alkyl, amino C₁-C ₄Alkyl OR-OR⁶；

Ring A, G, M, X, M, n, R¹～R ³、R ⁶、R ^kAnd R^gIs as defined in claim 1.
The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (VII):

wherein:

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

R ^cand R^dTogether with the linking atoms form a 3-8 membered cycloalkyl group;

R ^mselected from amino, -CH₂NH ₂or-NHC (═ NH) NH ₂；

R ⁿSelected from a hydrogen atom, a methyl group or-CH₂OH；

Ring A, G, M, X, M, n, R¹～R ³And R^gIs defined as in claim 1.
A compound according to any one of claims 1 to 12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R²Selected from hydrogen atom, F, Cl, Br, amino group, hydroxyl group, cyano group, nitro group, methoxy group, ethoxy group, methyl group, ethyl group, ethynyl group, vinyl group, -NHCH₃or-N (CH)₃) ₂。
A compound according to any one of claims 10 to 12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R³Selected from-C (O) OH.
A compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R⁶Selected from a hydrogen atom or an alkyl group.
A compound according to any one of claims 1 to 12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from phenyl.
A compound according to any one of claims 10 to 12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from:
a compound according to any one of claims 10 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ^gThe same or different, each independently selected from hydrogen atom, F, Cl, Br, amino group, hydroxyl group, cyano group, nitro group, methoxy group, ethoxy group, methyl group, ethyl group, ethynyl group, vinyl group, -NHCH₃or-N (CH)₃) ₂；

Or, two R^gTogether with the same carbon atom to which it is attached, may form C ═ O.
A compound according to any one of claims 1 to 18, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
Use of a compound according to any one of claims 1 to 19, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the preparation of an allosteric inhibitor of SHP 2.
Use of a compound according to any one of claims 1 to 19, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20 for the manufacture of a medicament for the treatment of a disease mediated by SHP2, whereby said disease mediated by SHP2 is preferably cancer, cancer metastasis, cardiovascular disease, immune disorders, fibrosis or vision disorders.
The use according to claim 22, wherein the disease mediated by SHP2 is selected from noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large-cell lymphoma, and glioblastoma.