CN116323622A

CN116323622A - Bicyclic heteroaryl derivatives, preparation method and application thereof

Info

Publication number: CN116323622A
Application number: CN202180062798.0A
Authority: CN
Inventors: 黄贤贵; 别平彦; 郭阳辉; 晏青燕; 曹琪; 刑庆娜; 王鑫; 孟力陈; 吴诺毅; 李文朋; 仇宗兴; 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: 2021-05-14
Filing date: 2021-12-24
Publication date: 2023-06-23
Also published as: CN115340545A; WO2022237178A1

Abstract

The invention relates to a bicyclic heteroaryl derivative, a preparation method thereof and application thereof in medicines. Specifically, the invention relates to a bicyclic heteroaryl derivative shown in a formula (AI), a preparation method and pharmaceutically acceptable salts thereof, and application of the bicyclic heteroaryl derivative as a therapeutic agent, particularly an SHP2 allosteric inhibitor, wherein each substituent in the formula (AI) is defined as the specification.

Description

Bicyclic heteroaryl derivatives, preparation method and application thereof

Technical Field

The present invention relates to a novel bicyclic heteroaryl derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, in particular as SHP2 allosteric inhibitors.

Background

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

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

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

The compound RMC-4630 developed by REVOLUTION Medicines Inc company has entered clinical stage II for the treatment of solid tumors, including preclinical RMC-4550, and 3 additional clinical stage I compounds JAB-3068, JAB-3312 and TNO-155, developed by Calif. (Jacobio Pharmaceuticals Co Ltd) and Novartis AG), respectively, including the NoHua preclinical drug SHP-099; REVOLUTION Medicines Inc and Novartis AG have disclosed a series of SHP2 inhibitor patents including WO-2019075265, WO-2018136265, WO-2018136264, WO-2017216706 and WO-2018013597, etc., and although research on SHP2 has been advanced to some extent, no effective drugs are currently marketed, so there is still a need to continue to research and develop new SHP2 inhibitors.

Disclosure of Invention

Aiming at the technical problems, the invention provides a novel bicyclic heteroaryl compound shown in a formula (AI) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

wherein:

when Z is selected from-NH-; v is selected from-N-or-CH-; or alternatively; when Z is selected from-O-; v is selected from-N-;

q and T are each independently selected from N or CH; wherein at least one of Q and T is selected from N;

Ring a is selected from naphthyl, bicyclic heteroaryl;

R ¹ identical OR different, each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyano, halogen, nitro, cycloalkyl, heterocyclyl, -OR ⁵ 、-C(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ WhereinThe alkyl, alkenyl, alkynyl, cycloalkyl OR heterocyclyl is optionally further substituted with one OR more groups selected from deuterium, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Is substituted by a substituent of (2);

R ² selected from cyano, tetrazolyl, -C (O) R ⁵ 、-C(O)OR ⁵ or-C (O) NR ⁶ R ⁷ ；

R ³ And R is ⁴ Together with the N atom to which it is attached form a 4-11 membered heterocyclic group, preferably a 5-11 membered heterocyclic group, wherein said heterocyclic group contains one or more N, O, S or SO ₂ An atom, and optionally further substituted on the heterocyclyl with one or more groups selected from halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CH ₂ R ⁵ 、-CH(OH)R ⁵ 、-CH ₂ OR ⁵ 、＝O、-OR ⁵ 、-SR ⁵ 、-SOR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, amino, halo, nitro, cyano, alkyl, haloalkyl, haloalkoxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-SO ₂ R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

alternatively, R ³ And R is ⁴ Together with the N atom to which it is attached, form a group:

is a single bond or a double bond;

when (when)

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

When (when)

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

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

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

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

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

j is selected from CR ^p R ^q ；

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

r is 0 or 1;

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

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

R ^c And R is ^d Identical OR different, each independently selected from hydrogen, halogen, alkyl OR-OR ⁵ Wherein said alkyl is optionally further substituted with hydroxy, halogen, alkoxy, cycloalkyl or-NR ⁶ R ⁷ Is substituted by a substituent of (2);

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

R ^g The same OR different are each independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR ⁶ R ⁷ Is substituted by a substituent of (2);

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

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

R ^A the same OR different are each independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR ⁶ R ⁷ Is substituted by a substituent of (2);

R ^B identical OR different, each independently selected from 3-to 10-membered cycloalkyl OR 3-to 10-membered heterocyclyl, wherein said cycloalkyl OR heterocyclyl is optionally further substituted with one OR more substituents selected from halogen, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Is substituted by a substituent of (2);

R ⁵ 、R ⁶ and R is ⁷ Each independently selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-SO ₂ R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

alternatively, R ⁶ And R is ⁷ Together with the N atom to which it is attached form a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic ring contains one or more N, O, S or SO ₂ An atom, and optionally further substituted on the 3-to 8-membered heterocyclic ring with one or more substituents selected from hydroxy, halogen, amino, alkyl or alkoxy;

R ⁸ 、R ⁹ and R is ¹⁰ Each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, and carboxylate;

m is 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 (AI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (AII) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

wherein: ring A, m, V, R ¹ ～R ⁴ The definition of (2) is as described in formula (AI).

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

Wherein: ring A, V, m, R ¹ 、R ³ And R is ⁴ Is defined as in formula (AII).

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

R ³ and R is ⁴ Together with the N atom to which it is attached, form a 4-8 membered monocyclic heterocyclic group, preferably a 5-6 membered monocyclic heterocyclic group, more preferably a piperidinyl group, wherein said monocyclic heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, cycloalkyl, phenyl, halophenyl, heteroaryl, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁵ Is substituted by a substituent of (2); wherein said methyl, cycloalkyl, phenyl or heteroaryl is optionally further substituted with one or more substituents selected from methanesulfonyl, hydroxy, amino, halogen, haloalkyl, alkoxy, haloalkoxy, pyridinyl or pyrimidinyl; wherein the heteroaryl is preferably pyridyl, pyrimidylmethylpyrazolyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, benzimidazolyl, benzofuryl or benzoxazolyl;

R ⁵ the definition of (2) is as described in formula (AI).

R ³ And R is ⁴ Together with the N atom to which it is attached form a 7-to 11-membered spiroheterocyclic group, wherein said spiroheterocyclic ringThe radicals are optionally further substituted by one or more radicals selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁵ Is substituted by a substituent of (2); r is R ⁵ Is defined as in formula (AI); preferably, wherein said spiroheterocyclyl is selected from:

R ^a identical or different, each independently selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ OR-OR ⁵ The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, two R ^a Together with the same carbon atom to which it is attached, form c=o; t is 1, 2 or 3; r is R ⁵ The definition of (2) is as described in formula (AI).

In a preferred embodiment of the invention, the compounds of formula (AI), (AII) or (I) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ³ And R is ⁴ Together with the N atom to which it is attached, form a 7-to 11-membered bridged heterocyclic group, wherein said bridged heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁵ Is substituted by a substituent of (2); r is R ⁵ The definition of (2) is as described in formula (AI).

In a preferred embodiment of the invention, a compound of formula (AI), (AII) or (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ³ And R is ⁴ Together with the N atom to which it is attached, form a 7-to 11-membered fused heterocyclic group, wherein said fused heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁵ Is substituted by a substituent of (2); r is R ⁵ Is fixed to (1)The meaning is as described in formula (AI).

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

wherein:

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

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

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

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

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

R ^p And R is ^q Each independently selected from hydrogen atom, halogen, amino group, C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ Alkyl, amino C ₁ -C ₄ Alkyl OR-OR ⁵ ；

Ring A, V, G, M, m, n, R ¹ ～R ² 、R ⁵ 、R ^k And R is ^g Is defined as in formula (AII).

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

wherein:

J is selected from CR ^p R ^q ；

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

r is 0 or 1;

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

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

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

wherein:

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

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

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

Ring A, V, G, M, m, n, R ¹ ～R ² And R is ^g Is defined as in formula (AII).

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

wherein:

L ₁ selected from the group consisting of absence, - (c=o) -, - (CR ^w R ^v ) _u -, any one of which- (CR) ^w R ^v ) -optionally further by-N (R ^z )-、-O-、-S-、-SO-、-SO ₂ -replaced;

each R ^w And R is ^v The same or different, each independently selected from hydrogen atom, halogen, hydroxy, alkyl or alkoxy;

each R ^z The same or different are each independently selected from a hydrogen atom or an alkyl group;

ring E is selected from 4-11 membered N-containing monocyclic heterocyclyl, 4-11 membered N-containing fused heterocyclyl OR 4-11 membered N-containing bridged heterocyclyl, wherein said monocyclic heterocyclyl, fused heterocyclyl, bridged heterocyclyl is optionally further substituted with one OR more substituents selected from halogen, alkyl, -OR ⁵ Or = O;

ring K is selected from the group consisting of absent, cycloalkyl, aryl, and heteroaryl, wherein said cycloalkyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-SO ₂ R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

wherein-L ₁ -ring K and- (CH) ₂ ) _W -NH ₂ Attached to the same carbon atom of ring E;

w is 0,1 or 2;

u is 0,1,2 or 3;

ring A, V, Q, T, m, R ¹ ～R ² 、R ⁵ 、R ⁸ ～R ¹⁰ Is defined as in formula (AII).

In a preferred embodiment of the invention, the compound of formula (AI), (AII), (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ¹ Selected from hydrogen atomsSon, F, cl, br, amino, hydroxy, cyano, nitro, methoxy, ethoxy, methyl, ethyl, difluoromethyl, cyclopropyl, d ₃ -methyl, ethynyl, vinyl, -NHCH ₃ or-N (CH) ₃ ) ₂ 。

In a preferred embodiment of the invention, the compound of formula (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ² Selected from-C (O) NH ₂ Or cyano.

In a preferred embodiment of the invention, the compound of formula (AI), (AII), (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ⁵ Selected from hydrogen atoms or alkyl groups.

In a preferred embodiment of the invention, the compound of formula (AI), (AII), (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring a is selected from naphthyl, benzopyrazolyl or benzothiazolyl.

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

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

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

In a preferred embodiment of the invention, the compound of formula (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring E is selected from

In a preferred embodiment of the invention, the compound of formula (AI) is selected from:

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

Further, the present invention provides a process for preparing a compound of formula (AII), or a stereoisomer, tautomer thereof, comprising:

compounds of formula (AIIa) and NHR ³ R ⁴ Nucleophilic substitution reaction is carried out under alkaline condition to obtain a compound of formula (Ib); carrying out Suzuki reaction on a compound shown in a formula (AIIb) and a compound shown in a formula (AIic) under a palladium catalyst and alkaline conditions, and optionally further removing a protecting group from the obtained compound to obtain a compound shown in a formula (AII);

wherein:

M ₁ selected from-B (OH) ₂ Or (b)

X ₁ Selected from leaving groups selected from halogen or-SO ₂ R ^t ；

X ₂ Selected from halogen;

R ^t Selected from alkyl groups;

rings A, V, m and R ¹ ～R ⁴ Is defined as in formula (AII).

Still further, the present invention provides a process for preparing a compound of formula (AII), or stereoisomers, tautomers thereof, comprising:

carrying out Suzuki reaction on the compound shown in the formula (AIIa) and the compound shown in the formula (AIic) under palladium catalyst and alkaline condition to obtain the compound shown in the formula (AIId); compounds of formula (AIId) and NHR ³ R ⁴ Carrying out nucleophilic substitution reaction under alkaline condition, and optionally removing protecting group to obtain compound of formula (AII);

wherein:

M ₁ selected from-B (OH) ₂ Or (b)

X ₁ Selected from leaving groups selected from halogen or-SO ₂ R ^t ；

X ₂ Selected from halogen;

R ^t selected from alkyl groups;

rings A, V, m and R ¹ ～R ⁴ Is defined as in formula (AII).

Still further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (AI), (AII), (I), (II), (III), (IV) or (V), 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 formula (AI), (AII), (I), (II), (III), (IV) or (V) or a stereoisomer, a tautomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing an SHP2 allosteric inhibitor.

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

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

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

The present invention provides a method for inhibiting an SHP2 receptor in vitro, which comprises contacting the SHP2 receptor with a compound of formula (AI), (AII), (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The present invention provides a method of treating a disorder mediated by SHP2, which comprises administering to a patient in need thereof an effective amount of a compound of formula (AI), (AII), (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; wherein the SHP2 mediated disease is preferably cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or vision disorder; wherein the SHP2 mediated disease is more preferably selected from the group consisting of noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma and glioblastoma.

Detailed description of the invention

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

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

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

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

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

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

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

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

"heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, and include monocyclic, polycyclic, fused, bridged and spiro rings. Preferably a 4-11 membered heterocyclic ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulphur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, piperazinyl, and,

The heterocyclic group may be substituted or unsubstituted.

"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one atom with each otherA group containing 1 or more double bonds within the ring, but no ring having a completely conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multiple spiro heterocyclic group according to the number of common spiro atoms between rings, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably a 7-to 11-membered spiroheterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5 ] ]Decyl, 2-oxa-7-azaspiro [4.4 ]]Nonyl, 7-oxaspiro [3.5 ]]Nonyl, 5-oxaspiro [2.4 ]]Heptyl group,

"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 7-11 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo [3,4-c ]]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0 ]]Hexyl, octahydrobenzo [ b ]][1,4]Dioxin (dioxine)

"bridged heterocyclyl" means a 5 to 14 membered, 5 to 18 membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain one or more double bonds, but no An aromatic system having a ring with fully conjugated pi electrons, 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 7-11 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl, 2-azabicyclo [3.3.2]Decyl group,

"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Aryl groups may be substituted or unsubstituted.

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

Heteroaryl groupMay be substituted or unsubstituted.

"fused ring" means a polycyclic group having two or more cyclic structures sharing a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring does not have a fully conjugated pi-electron aromatic system, while at least one ring has a fully conjugated pi-electron aromatic system, wherein 0, 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. The fused ring preferably includes a double-or triple-ring fused ring, wherein the double-ring fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14 membered, more preferably 8 to 10 membered. Examples of "fused rings" include, but are not limited to:

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

"hydroxy" refers to an-OH group.

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

"amino" means-NH ₂ 。

"cyano" refers to-CN.

"nitro" means-NO ₂ 。

"benzyl" and "Bn" refer to-CH ₂ -phenyl.

"carboxy" means-C (O) OH.

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

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to t-butoxycarbonyl.

"TFA" refers to trifluoroacetic acid.

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

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

"SEM" refers to (trimethylsilyl) ethoxymethyl.

"THP" refers to tetrahydropyranyl.

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

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

As used herein, "substituted" or "substituted", unless otherwise indicated, means that the group may be substituted with one or moreA plurality of substitutions selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =o, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Is substituted by a substituent of (2);

R ⁵ 、R ⁶ and R is ⁷ Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, or a heterocyclic group, wherein the alkyl group, cycloalkyl group, or heterocyclic group is optionally further substituted with one or more groups selected from hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-SO ₂ R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

alternatively, R ⁶ And R is ⁷ Together with the N atom to which it is attached form a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic ring contains one or more N, O, S or SO ₂ An atom, and further substituted on the 3-to 8-membered heterocyclic ring with one or more substituents selected from hydroxy, halogen, amino, alkyl or alkoxy;

R ⁸ 、R ⁹ and R is ¹⁰ Each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, and arylThe group or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate groups.

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

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

Synthesis method of compound of the invention

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

the present invention provides a process for the preparation of a compound of formula (AII) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, said process comprising:

wherein:

M ₁ selected from-B (OH) ₂ Or (b)

X ₁ Selected from leaving groups selected from halogen or-SO ₂ R ^t ；

X ₂ Selected from halogen;

R ^t selected from alkyl groups;

rings A, V, m and R ¹ ～R ⁴ Is defined as in formula (AII).

Wherein:

M ₁ selected from-B (OH) ₂ Or (b)

X ₁ Selected from leaving groups selected from halogen or-SO ₂ R ^t ；

X ₂ Selected from halogen;

R ^t selected from alkyl groups;

rings A, V, m and R ¹ ～R ⁴ Is defined as in formula (AII).

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

carrying out nucleophilic substitution reaction on the compound shown in the formula (Ia) and NHR3R4 under alkaline conditions to obtain a compound shown in the formula (Ib); carrying out Suzuki reaction on a compound shown in a formula (Ib) and a compound shown in a formula (AIic) under a palladium catalyst and alkaline conditions, and optionally further removing a protecting group from the obtained compound to obtain the compound shown in the formula (Ic); hydrolyzing the compound of formula (Ic) to obtain the compound of formula (I);

wherein:

M ₁ selected from-B (OH) ₂ Or (b)

X ₁ Selected from leaving groups selected from halogen or-SO ₂ R ^t ；

X ₂ Selected from halogen;

R ^t selected from alkyl groups;

rings A, V, m, R ¹ ，R ³ And R is ⁴ The definition is as described in formula (I).

carrying out Suzuki reaction on a compound shown in the formula (Ia) and a compound shown in the formula (AIic) under a palladium catalyst and alkaline conditions to obtain a compound shown in the formula (Id); compounds of formula (Id) and NHR ³ R ⁴ Nucleophilic substitution reaction is carried out under alkaline condition to obtain compound of formula (Ic); hydrolyzing the compound of formula (Ic) to obtain the compound of formula (I);

wherein:

M ₁ selected from-B (OH) ₂ Or (b)

X ₁ Selected from leaving groups selected from halogen or-SO ₂ R ^t ；

X ₂ Selected from halogen;

R ^t selected from alkyl groups;

Detailed Description

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

Examples

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

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

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

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

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

Methanol-d ₄ : deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

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

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

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

Example 1

6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tetrabutylammonium cyanide 1a (2.81 g,10.48 mmol), 4, 6-dichloro-1H-pyrazolo [3,4-d ] pyrimidine 1b (1.8 g,9.52 mmol) and triethylenediamine (213.65 mg,1.90 mmol) were added sequentially to dichloromethane (30 mL) and stirring was continued at room temperature for 2 hours. After the completion of the reaction, the residue was further analyzed and purified by silica gel column chromatography (eluent: B system), and a small amount of triethylamine was added to the system to give 6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1c (741 mg), yield: 43.33%.

MS m/z(ESI):179.9[M+1]

Second step

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1c (200 mg,1.11 mmol), N-bromosuccinimide (218.06 mg,1.23 mmol) was added sequentially to acetonitrile (4 mL), heated to 90℃and reacted for 4 hours. After the reaction was completed, the residue was further purified by silica gel column chromatography (eluent: B system) to give 3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (280 mg), yield: 97.26%.

MS m/z(ESI):257.7[M+1]

Third step

(1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (150 mg, 580.35. Mu. Mol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 1e (186.56 mg, 870.53. Mu. Mol) and diisopropylethylamine (375.03 mg,2.90mmol, 506.79. Mu.L) were added to N, N-dimethylacetamide (5 mL), and the mixture was heated to 80℃for 1 hour. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate 1f (200 mg), yield: 78.99%.

MS m/z(ESI):436.1[M+1]

Fourth step

(1- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate 1f (200 mg, 458.39. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (336.74 mg,1.38mmol, obtained according to the homemade patent WO 2019167000), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (76.77 mg, 91.68. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (85.56 mg, 183.36. Mu. Mol) and potassium phosphate (292.05 mg,1.38 mmol) were added to a mixed solution of 1, 4-dioxane (2.5 mL) and water (0.5 mL). Argon was replaced three times, heated to 110℃and reacted for 16 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate for 1H (58 mg), yield: 22.74%.

MS m/z(ESI):556.2[M+1]

Fifth step

6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl (1- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate for 1H (58 mg,104.23 μmol) in dichloromethane (2.5 mL) and the reaction was continued for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1i (47.56 mg), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification.

MS m/z(ESI):456.1[M+1]

Sixth step

5M sodium hydroxide solution (0.25 mL) was added to 6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dichloro-2)-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 1i (47.56 mg, 104.22. Mu. Mol) in methanol (2 mL) was then added with 30% hydrogen peroxide (0.5 mL), stirred at room temperature for 0.5 hours, after completion of the reaction, pH was adjusted to acidity by adding trifluoroacetic acid, and concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 1 (20 mg), yield: 31.85%.

MS m/z(ESI):474.1[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.05(s,1H),7.97(s,3H),7.53-7.61(m,2H),7.29(d,J＝8.8Hz,1H),4.44(s,2H),4.16(s,3H),1.74(t,J＝5.8Hz,4H),1.41(s,3H),1.24(d,J＝3.7Hz,2H).

Example 2

2- (4-amino-4-methylpiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine 2a (4 g,21.28 mmol), tetrakis triphenylphosphine palladium (2.46 g,2.13 mmol) and zinc cyanide (5.00 g,42.55 mmol) were added to N, N-dimethylformamide (40 mL), replaced with argon, heated to 110℃and stirred for 4 hours. After the completion of the reaction, 30mL of water was added, extraction was performed with ethyl acetate (30 mL. Times.3), and the saturated sodium chloride solution (20 mL) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 2b (3.79 g), yield: 99.76%.

MS m/z(ESI):179.1[M+1]

Second step

5-bromo-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

N-bromosuccinimide (2.32 g,13.03 mmol) was added to a solution of 2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 2b (1.79 g,10.02 mmol) in acetonitrile (30 mL), heated to 95℃and reacted for 2 hours, after which the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: A system) to give 5-bromo-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 2c (790 mg), yield: 30.61%.

MS m/z (ESI) 256.9[ M+1] third step

(1- (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (4-methylpiperidin-4-yl) carbamate 1e (262.18 mg,1.22 mmol), diisopropylethylamine (451.76 mg,3.50 mmol) and 5-bromo-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 2c (300 mg,1.17 mmol) were added to N, N-dimethylacetamide (3 mL), heated to 80℃and stirred for 1 hour. After the completion of the reaction, ethyl acetate (30 mL) was added, followed by washing with a saturated sodium chloride solution (30 mL. Times.2), drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 2d (120 mg), yield: 23.66%.

MS m/z(ESI):435.1[M+1]

Fourth step

(1- (5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 2d (120 mg, 275.66. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) borate 1g (202.50 mg, 826.98. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (46.17 mg, 55.13. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (51.45 mg, 110.26. Mu. Mol) and potassium phosphate (175.63 mg, 826.98. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (2.5 mL) and water (0.5 mL). Argon was replaced three times, heated to 110℃and reacted for 16 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 2e (23 mg), yield: 15.02%.

MS m/z(ESI):554.9[M+1]

Fifth step

2- (4-amino-4-methylpiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl (1- (5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-methylpiperidin-4-yl) carbamate 2e (23 mg,41.41 μmol) in dichloromethane (2.5 mL) and the reaction was continued for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give 2- (4-amino-4-methylpiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 2f (18 mg), yield: 95.47 percent, the reaction is directly carried out to the next reaction without purification.

MS m/z(ESI):455.1[M+1]

Sixth step

5M sodium hydroxide solution (0.25 mL) was added to 2- (4-amino-4-methylpiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 2f (18 mg, 39.53. Mu. Mol) in methanol (2 mL) was added with 30% hydrogen peroxide (0.5 mL) and stirred at room temperature for 0.5 hours, after completion of the reaction, trifluoroacetic acid was added to adjust pH to acidity, and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4-methylpiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carboxamide 2 (6 mg), yield: 24.94%.

MS m/z(ESI):473.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ11.72-11.88(m,1H),8.01(s,2H),7.86(s,1H),7.49(d,J＝8.8Hz,1H),7.35(s,1H),7.29(d,J＝2.3Hz,1H),7.22(d,J＝8.8Hz,1H),4.39(dt,J＝14.5,4.7Hz,2H),4.14(s,3H),3.43(ddd,J＝13.6,8.3,4.8Hz,2H),1.74(dt,J＝9.7,5.0Hz,4H),1.40(s,3H).

Example 3

6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dichloro-1-methyl-1H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

5-bromo-4-chloro-1-methyl-indazole

5-bromo-4-chloro-1H-indazole 3a (2 g,8.64 mmol) was added to sodium hydride (247.20 mg,9.50 mmol) in tetrahydrofuran (20 mL) and after 15 minutes of reaction, methyl iodide (1.84 g,12.96mmol, 806.82. Mu.L) was added at low temperature and the reaction was continued at 0℃for 2 hours. The reaction solution was added with 1N diluted hydrochloric acid (6 mL), extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: A system) to give 5-bromo-4-chloro-1-methyl-indazole 3b (850 mg), yield: 40.07%.

MS m/z(ESI):245.0[M+1]

Second step

5-bromo-3, 4-dichloro-1-methyl-indazole

5-bromo-4-chloro-1-methyl-indazole 3b (480 mg,3.99 mmol) and chlorosuccinimide (639.63 mg,4.79 mmol) were added to N, N-dimethylformamide (15 mL) and stirred overnight at room temperature. After completion of the reaction, 20mL of water was added, extraction was performed with ethyl acetate (20 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: a system) to obtain 5-bromo-3, 4-dichloro-1-methyl-indazole 3c (1 g), yield: 89.49%. MS m/z (ESI): 278.9[ M+1]

Third step

3, 4-dichloro-1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indazole

5-bromo-3, 4-dichloro-1-methyl-indazole 3c (400 mg,1.43 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (471.69 mg,1.86 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (209.10 mg, 285.77. Mu. Mol) and potassium acetate (420.68 mg,4.29 mmol) were dissolved in dioxane (6 mL), argon was replaced 3 times, and the temperature was raised to 100℃for 2 hours. After the completion of the reaction, 10mL of water was added, extraction was performed with ethyl acetate (30 mL), the aqueous layer was removed, the combined organic phases were sequentially washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: A system) to give 3, 4-dichloro-1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indazole 3d (400 mg), yield: 85.61%.

MS m/z(ESI):327.1[M+1]

Fourth step

(1- (4-cyano-3- (3, 4-dichloro-1-methyl-1H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate 1f (150 mg, 343.80. Mu. Mol), 3, 4-dichloro-1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indazole 3d (337.28 mg,1.03 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (57.58 mg, 68.76. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (64.17 mg, 137.52. Mu. Mol) and potassium phosphate (219.04 mg,1.03 mmol) were added to a mixed solution of 1, 4-dioxane (6 mL) and 1mL water. Argon was replaced three times, heated to 110℃and reacted for 16 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (4-cyano-3- (3, 4-dichloro-1-methyl-1H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate 3e (80 mg), yield: 41.82%.

MS m/z(ESI):556.1[M+1]

Fifth step

6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dichloro-1-methyl-1H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl (1- (4-cyano-3- (3, 4-dichloro-1-methyl-1H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate 3e (80 mg,143.77 μmol) in dichloromethane (2.5 mL) and the reaction was continued for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dichloro-1-methyl-1H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 3f (65.61 mg), yield: 100% of the reaction was directly carried out in the next step without purification.

MS m/z(ESI):456.1[M+1]

Sixth step

5M sodium hydroxide solution (0.25 mL) was added to 6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dichloro-1-methyl-1H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 3f (65 mg, 142.44. Mu. Mol) in methanol (2 mL) was then added with 30% hydrogen peroxide (0.5 mL), stirred at room temperature for 0.5 hours, after completion of the reaction, pH was adjusted to acidity by adding trifluoroacetic acid, and concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dichloro-1-methyl-1H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 3 (30 mg), yield: 35.02%.

MS m/z(ESI):474.1[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ13.55(s,1H),8.08(s,1H),7.96(s,3H),7.71(d,J＝8.7Hz,1H),7.61(s,1H),7.48(d,J＝8.7Hz,1H),4.45(s,2H),4.08(s,3H),1.99(s,1H),1.74(t,J＝5.8Hz,4H),1.41(s,3H).

Example 4

6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(R) -N- ((3S, 4S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (150 mg, 580.35. Mu. Mol), (R) -2-methyl-N- ((3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) propane-2-sulfinamide 4a (238.89 mg, 870.53. Mu. Mol, prepared according to the preparation of patent CN 110156786) and diisopropylethylamine (375.03 mg,2.90mmol, 506.79. Mu. L) were added to N, N-dimethylacetamide (5 mL) and the reaction was warmed to 80℃for 1 hour. After the completion of the reaction, the resulting residue was concentrated under reduced pressure and further purified by silica gel column chromatography (eluent: a system) to give (R) -N- ((3 s,4 s) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide 4b (200 mg), yield: 69.42%. MS m/z (ESI): 496.1[ M+1]

Second step

(R) -N- ((3S, 4S) -8- (4-cyano-3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide

1g (123.32 mg, 503.60. Mu. Mol) of (R) -N- ((3S, 4S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide 4b (100 mg, 201.44. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boric acid, 1g (123.32 mg, 503.60. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (33.74 mg, 40.29. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (37.60 mg, 80.58. Mu. Mol) and potassium phosphate (128.34.32. Mu. Mol) were added to a mixture of 1, 4-dicyclohexylphosphino-2 ', 1' -biphenyl-2-yl) and (0.5 mL) water. Argon was replaced three times, heated to 110℃and reacted for 16 hours. After the reaction was completed, the resulting residue was concentrated under reduced pressure and further separated and purified by silica gel column chromatography (eluent: a system) to give (R) -N- ((3 s,4 s) -8- (4-cyano-3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec 4-yl) -2-methylpropan-2-sulfinamide 4c (36 mg), yield: 28.99%.

MS m/z(ESI):616.2[M+1]

Third step

6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

To a solution of (R) -N- ((3S, 4S) -8- (4-cyano-3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec 4-yl) -2-methylpropan-2-sulfinamide 4c (36 mg, 58.39. Mu. Mol) in dichloromethane (2 mL) was slowly added dropwise a solution of 4M methanolic hydrochloride (4M, 58.39. Mu. L) at room temperature and reacted for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to give 6- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 4d (29 mg), yield: 96.93%, the reaction was directly carried out for the next reaction without purification.

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

Fourth step

5M sodium hydroxide solution (0.15 mL) was added to 6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ]Pyrimidine-4-carbonitrile 4d (29 mg, 56.60. Mu. Mol) in methanol (2 mL) was followed by 30% hydrogen peroxide (0).3 mL), stirring at room temperature for 0.5 hours, and after the reaction, adding trifluoroacetic acid to adjust the pH to acidity, concentrating under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil;250 x 21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% TFA+H ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 4 (10 mg), yield: 27.21%.

MS m/z(ESI):530.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.04(s,1H),7.82-7.93(m,3H),7.53-7.61(m,2H),7.29(d,J＝8.8Hz,1H),4.60(s,3H),4.19-4.25(m,1H),4.16(s,3H),3.93(d,J＝9.1Hz,1H),3.73(d,J＝9.0Hz,1H),3.20(d,J＝11.4Hz,2H),1.74(d,J＝13.4Hz,4H),1.22(d,J＝6.5Hz,3H).

Example 5

(S) -6- (4-amino-2-oxa-8-azaspiro [4.5] dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(R) -N- ((S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (150 mg, 580.35. Mu. Mol), (R) -2-methyl-N- ((S) -2-oxa-8-azaspiro [4.5] dec-4-yl) propane-2-sulfinamide 5a (196.46 mg, 754.46. Mu. Mol, obtained as per the homemade patent CN 110156786) and diisopropylethylamine (375.03 mg,2.90mmol, 506.79. Mu. L) were added to N, N-dimethylacetamide (1.49 mL) and the reaction was warmed to 80℃for 1 hour. After the completion of the reaction, the resulting residue was concentrated under reduced pressure and further purified by silica gel column chromatography (eluent: a system) to give (R) -N- ((S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide 5b (190 mg), yield: 67.87%.

MS m/z(ESI):482.0[M+1]

Second step

(R) -N- ((S) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide

(R) -N- ((S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide 5b (190 mg, 393.87. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (192.89 mg, 787.73. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (65.96 mg, 78.77. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (73.52 mg, 157.55. Mu. Mol) and potassium phosphate (250.94 mg,1.18 mmol) were added to a mixture of 1, 4-dioxane (2.5 mL) and water (0.5 mL). Argon was replaced three times, heated to 110℃and reacted for 16 hours. After the completion of the reaction, the resulting residue was concentrated under reduced pressure and further separated and purified by silica gel column chromatography (eluent: a system) to give (R) -N- ((S) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide 5c (40 mg), yield: 16.85%.

MS m/z(ESI):601.9[M+1]

Third step

(S) -6- (4-amino-2-oxa-8-azaspiro [4.5] dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

To a solution of (R) -N- ((S) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -2-oxa-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide 5c (40 mg, 66.39. Mu. Mol) in dichloromethane (2 mL) was slowly added dropwise a solution of hydrochloric acid in methanol (4M, 66.39. Mu. L) at room temperature, followed by a reaction for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give (S) -6- (4-amino-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 5d (33 mg), yield: 99.74% and the reaction was carried out directly to the next reaction without purification.

MS m/z(ESI):498.2[M+1]

Fourth step

5M sodium hydroxide solution (0.15 mL) was added to (S) -6- (4-amino-2-oxa-8-azaspiro [ 4.5)]Dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 5d (33 mg, 66.22. Mu. Mol) in methanol (2 mL) was added followed by 30% hydrogen peroxide (0.3 mL), stirred at room temperature for 0.5 hours, and after completion of the reaction, trifluoroacetic acid was added to adjust pH to acidity, concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give (S) -6- (4-amino-2-oxa-8-azaspiro [4.5]]Dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 5 (8.5 mg), yield: 20%.

MS m/z(ESI):516.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ13.50(s,1H),8.04(s,3H),7.57(s,1H),7.28(s,1H),6.86(s,1H), 5.32(s,1H),4.52(s,2H),4.16(s,2H),3.61-3.88(m,4H),1.98(s,1H),1.63(s,3H),1.24(s,3H).

Example 6

(R) -6- (1-amino-8-azaspiro [4.5] dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(R) -N- ((R) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azaspiro [4.5] dec-1-yl) -2-methylpropan-2-sulfinamide

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (150 mg, 580.35. Mu. Mol), (R) -2-methyl-N- ((R) -8-azaspiro [4.5] dec-1-yl) propane-2-sulfinamide 6a (209.97 mg, 812.50. Mu. Mol, prepared according to patent CN 110156786) and diisopropylethylamine (375.03 mg,2.90 mmol) were added to N, N-dimethylacetamide (3 mL) and the reaction was warmed to 80℃for 1 hour. After the completion of the reaction, the resulting residue was concentrated under reduced pressure and further purified by silica gel column chromatography (eluent: a system) to give (R) -N- ((R) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azaspiro [4.5] dec-1-yl) -2-methylpropan-2-sulfinamide 6b (180 mg), yield: 64.56%.

MS m/z(ESI):479.9[M+1]

Second step

(R) -N- ((R) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azaspiro [4.5] dec-1-yl) -2-methylpropan-2-sulfinamide

(R) -N- ((R) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azaspiro [4.5] dec-1-yl) -2-methylpropan-2-sulfinamide 6b (180 mg, 374.67. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (229.36 mg, 936.67. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (62.75 mg, 74.93. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (69.93 mg, 149.87. Mu. Mol) and potassium phosphate (238.71 mg,1. Mu. Mmol) were added to a mixed solution of 1, 4-dioxane (2.5 mL) and water (0.5 mL). Argon was replaced three times, heated to 110℃and reacted for 16 hours. After the completion of the reaction, the resulting residue was concentrated under reduced pressure and further purified by silica gel column chromatography (eluent: a system) to give (R) -N- ((R) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azaspiro [4.5] dec-1-yl) -2-methylpropan-2-sulfinamide 6c (70 mg), yield: 31.11%.

MS m/z(ESI):600.2[M+1]

Third step

(R) -6- (1-amino-8-azaspiro [4.5] dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

To a solution of (R) -N- ((R) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azaspiro [4.5] dec-1-yl) -2-methylpropan-2-sulfinamide 6c (70 mg, 116.56. Mu. Mol) in dichloromethane (2 mL) was slowly added dropwise a solution of hydrochloric acid in methanol (4M, 116.56. Mu. L) at room temperature, followed by reaction for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give (R) -6- (1-amino-8-azaspiro [4.5] dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 6d (57.86 mg), yield: 100% of the reaction was directly carried out in the next step without purification.

MS m/z(ESI):496.2[M+1]

Fourth step

5M sodium hydroxide (0.25 mL) was added to (R) -6- (1-amino-8-azaspiro [ 4.5)]Dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 6d (57.86 mg, 116.56. Mu. Mol) in methanol (2.5 mL) was added with 30% hydrogen peroxide (0.5 mL), stirred at room temperature for 0.5 hours, and after completion of the reaction, trifluoroacetic acid was added to adjust pH to acidity, and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give (R) -6- (1-amino-8-azaspiro [4.5 ]]Dec-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 6 (19 mg), yield: 25.72%.

MS m/z(ESI):514.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ13.45(s,1H),8.00(s,2H),7.21-7.32(m,2H),4.67(s,2H),4.17(s,3H),3.10-3.22(m,5H),2.06(d,J＝7.8Hz,1H),1.85(d,J＝11.2Hz,1H),1.59-1.79(m,5H),1.34-1.53(m,3H).

Example 7

(S) -2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

(R) -N- ((S) -1'- (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

(R) -N- ((S) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 7a (301.5 mg, 983.80. Mu. Mol, prepared according to patent WO 2020156242), 5-bromo-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 2c (253.30 mg, 983.80. Mu. Mol) and N, N-diisopropylethylamine (635.73 mg,4.92 mmol) were added to N, N-dimethylacetamide (5 mL) and the reaction was heated to 130℃overnight. After the completion of the reaction, 20mL of water was added, ethyl acetate (20 mL. Times.3) was extracted, a saturated sodium chloride solution (20 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: A system) to give (R) -N- ((S) -1'- (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide 7b (120 mg), yield: 23.12%.

MS m/z(ESI):527.1[M+1]

Second step

(R) -N- ((S) -1'- (5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

(R) -N- ((S) -1' - (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide 7b (120 mg, 227.50. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (139.27 mg, 568.74. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (38.10 mg, 45.50. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (42.46 mg, 91.00. Mu. Mol) and potassium phosphate (144.87 mg, 682.49. Mu. Mol) were added to a mixed aqueous solution of 1, 4-dioxane (3.3 mL). Argon was displaced three times, heated to 130 ℃, and reacted overnight. After the completion of the reaction, the resulting residue was concentrated under reduced pressure and further separated and purified by silica gel column chromatography (eluent: a system) to give (R) -N- ((S) -1'- (5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide 7c (20 mg), yield: 13.57%.

MS m/z(ESI):647.2[M+1]

Third step

(S) -2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

Concentrated hydrochloric acid (4.50 mg, 123.53. Mu. Mol) was added to a dichloromethane solution (1 mL) of (R) -N- ((S) -1'- (5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide 7c (20 mg, 30.88. Mu. Mol) and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give (S) -2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 7d (16.7 mg), yield: 99.51% and the reaction was carried out directly to the next step without purification.

MS m/z(ESI):543.2[M+1]

Fourth step

5M sodium hydroxide solution (0.2 mL) was added to (S) -2- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 7d (16 mg, 29.44. Mu. Mol) in methanol (2 mL) was added with 30% hydrogen peroxide (0.5 mL), stirred at room temperature for 1.5 hours, and after completion of the reaction, trifluoroacetic acid was added to adjust pH to acidity, and concentrated under reduced pressure to prepare a liquid phase Separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give (S) -2- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carboxamide 7 (3.15 mg), yield: 14.9%.

MS m/z(ESI):561.2[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.24-7.68(m,7H),7.17(s,1H),4.69(d,J＝13.7Hz,1H),4.37(s,1H),4.15(s,3H),3.37(t,J＝12.7Hz,2H),3.21(s,2H),1.66-1.93(m,3H),1.61(d,J＝13.1Hz,1H),1.29(s,1H).

Example 8

2- (4-amino-4-phenylpiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

4-Phenylpiperidin-4-amine 8a (212 mg,1.20 mmol), 5-bromo-2-chloro-7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 2C (309.69 mg,1.20 mmol) and N, N-diisopropylethylamine (777.24 mg,6.01 mmol) were added to N, N-dimethylacetamide (6 mL), heated to 130℃for 2 hours, concentrated under reduced pressure after completion of the reaction, C ₁₈ Reversed phase chromatography column separation (C) ₁₈ Separating column 20-45 μm; mobile phase a: h ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7H-pyrrolo [2, 3-d)]Pyrimidine-4-carbonitrile 8b (150 mg), yield: 31.57%.

MS m/z(ESI):380.0[M-16]

Second step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 8b (150 mg, 377.58. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (231.14 mg, 943.94. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (63.23 mg, 75.52. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (70.48 mg, 151.03. Mu. Mol) and potassium phosphate (400.93 mg,1.89 mmol) were added to a mixed solution of 1, 4-dioxane (4 mL) and water (0.4 mL). Argon was replaced three times, heated to 130 ℃, and reacted for 4 hours. After the reaction, concentrating under reduced pressure, C ₁₈ Reversed phase chromatography column separation (C) ₁₈ Separating column 20-45 μm; mobile phase a: h ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 8c (80 mg), yield: 40.95%.

MS m/z(ESI):500.1[M-16]

Third step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 8c (80 mg, 108.23. Mu. Mol), 5M sodium hydroxide solution (0.5 mL) and 30% hydrogen peroxide (0.5 mL) were added to methanol (1.5 mL), stirred at room temperature for 1 hour, after completion of the reaction, pH was adjusted to acidity by adding trifluoroacetic acid, and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carboxamide 8 (5.34 mg), yield: 7.6%.

MS m/z(ESI):535.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.34(s,3H),7.85(d,J＝2.5Hz,1H),7.71(dd,J＝7.5,1.8Hz,2H),7.44-7.59(m,4H),7.35(d,J＝2.5Hz,1H),7.30(d,J＝2.3Hz,1H),7.22(d,J＝8.8Hz,1H),4.33(d,J＝13.5Hz,2H),4.14(s,3H),3.41(s,2H),2.51-2.61(m,2H),2.09(td,J＝10.9,10.1,5.5Hz,2H).

Example 9

6- (4-amino-3-fluoro-4-phenylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6- (4-amino-3-fluoro-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

To a solution of 3-fluoro-4-phenylpiperidin-4-amine 9a (110 mg, 566.29. Mu. Mol) in N, N-dimethylacetamide (2 mL) was added N, N-diisopropylethylamine (219.56 mg,1.70 mmol), and after stirring at room temperature for 5 minutes, 3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (146.36 mg, 566.29. Mu. Mol) was added, and the reaction was warmed to 90℃and stirred for 1 hour. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: a system) to give 6- (4-amino-3-fluoro-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 9b (170 mg), yield: 72.12%.

MS m/z(ESI):416.0[M+1]

Second step

6- (4-amino-3-fluoro-4-phenylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-3-fluoro-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 9b (100 mg, 240.24. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (176.48 mg, 720.72. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (40.23 mg, 48.05. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (44.84 mg, 96.10. Mu. Mol) and potassium phosphate (152.98 mg, 720.72. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL). Argon was replaced three times, heated to 130 ℃, and reacted for 20 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: a system) to give 6- (4-amino-3-fluoro-4-phenylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 9c (40 mg), yield: 31.04%.

MS m/z(ESI):518.8[M-16]

Third step

To sodium hydroxide solution (5M, 0.5 mL) and 6- (4-amino-3-fluoro-4-phenylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ]Pyrimidine-4-carbonitrile 9c (60 mg, 124.39. Mu. Mol) in methanol (2 mL) was slowly added dropwise 30% hydrogen peroxide (0.5 mL) and reacted at room temperature for 30 minutes. After the reaction, trifluoroacetic acid was added to adjust the pH to be acidic, and the mixture was concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-3-fluoro-4-phenylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 9 (30 mg), yield: 39.25%.

MS m/z(ESI):553.8[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.76(dt,J＝6.4,1.2Hz,2H),7.51-7.67(m,4H),7.36(d,J＝8.8Hz,1H),5.67(d,J＝47.9Hz,1H),5.25(s,1H),4.98(dd,J＝12.6,6.1Hz,1H),4.18(s,3H),3.33-3.47(m,2H),2.80(d,J＝14.2Hz,1H),2.46(t,J＝12.6Hz,1H),1.92(d,J＝11.9Hz,2H),1.77(d,J＝8.5Hz,2H).

Example 10

6- (4-amino-4-cyclopropylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6- (4-amino-4-cyclopropylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (400 mg,1.55 mmol), 4-cyclopropylpiperidin-4-amine 10a (600 mg,4.28 mmol) and N, N-diisopropylethylamine (600.04 mg,4.64 mmol) were added to N, N-dimethylacetamide (2.5 mL), the temperature was raised to 100℃for 1 hour, after the reaction was completed, the reaction was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: A system) to give 6- (4-amino-4-cyclopropylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 10b (560 mg), yield: 99.9%.

MS m/z(ESI):345.0[M-16]

Second step

6- (4-amino-4-cyclopropylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4-cyclopropylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 10b (70 mg, 193.25. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (189.28 mg, 773.00. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (32.36 mg, 38.65. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (36.02 mg, 77.30. Mu. Mol) and potassium phosphate (204.84 mg, 966.24. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (2 mL) and water (0.2 mL). Argon was replaced three times, heated to 130 ℃, and reacted for 18 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: a system) to give 6- (4-amino-4-cyclopropylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 10c (28 mg), yield: 30.04%.

MS m/z(ESI):464.9[M-16]

Third step

To 5M sodium hydroxide solution (0.5 mL) and 6- (4-amino-4-cyclopropylpiperidin-1-yl) -3 - (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]To a solution of pyrimidine-4-carbonitrile 10c (28 mg, 58.05. Mu. Mol) in methanol (3 mL) was slowly added dropwise 30% hydrogen peroxide (0.5 mL) and reacted at room temperature for 30 minutes. After the reaction, trifluoroacetic acid was added to adjust the pH to be acidic, and the mixture was concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-cyclopropylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 10 (11 mg), yield: 39.25%.

MS m/z(ESI):499.9[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.70-7.78(m,2H),7.52-7.65(m,4H),7.32-7.41(m,2H),5.56-5.75(m,1H),5.25(s,1H),4.92-5.01(m,1H),3.32-3.43(m,2H),2.80(d,J＝14.2Hz,1H),2.38-2.52(m,1H).

Example 11

6- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl-3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl-3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

To a solution of (3R, 4R) -3-fluoropiperidin-4-amine 11a (270 mg,2.29 mmol) in N, N-dimethylacetamide (3 mL) was added N, N-diisopropylethylamine (450.04 mg,3.48 mmol), and after stirring at room temperature for 10 minutes, 3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (300 mg,1.16 mmol) was added and the reaction warmed to 90℃and stirred for 1 hour. After the completion of the reaction, the residue was concentrated under reduced pressure and the resulting residue was further separated and purified by silica gel column chromatography (eluent: A system) to give 6- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl-3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 11b (390 mg) in 98.78% yield.

MS m/z(ESI):339.9[M+1]

Second step

6- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl-3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

1g (359.94 mg,1.47 mmol) of 6- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl-3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 11b (200 mg, 587.97. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid, 1g (359.94 mg,1.47 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (98.47 mg, 117.59. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (109.60 mg, 235.19. Mu. Mol) and potassium phosphate (623.25 mg,2.94 mmol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL), argon was replaced three times, heated to 120℃and at the end of reaction time, 18H, and the reaction system was purified by vacuum chromatography to give 3- ((3, 1' -bipiperidin-1, 1' -yl) -3-2-bromo-1, 1-4-carbonitrile (117. Mu. Mol) and 3-d) pyridine-4-carbonitrile (109. Mu. Mol),

MS m/z(ESI):459.9[M+1]

third step

To sodium hydroxide solution (5M, 0.5 mL) and 6- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl-3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 11c (150 mg, 325.88. Mu. Mol) in methanol (3 mL) was slowly added dropwise 30% hydrogen peroxide (1 mL) and reacted at room temperature for 30 minutes. After the reaction, trifluoroacetic acid was added to adjust the pH to be acidic, and the mixture was concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- ((3 r,4 r) -4-amino-3-fluoropiperidin-1-yl-3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3, 4-d)]Pyrimidine-4-carboxamide 11 (15 mg), yield: 7.26%.

MS m/z(ESI):477.9[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.57(dd,J＝8.9,2.3Hz,1H),7.36(dd,J＝8.8,2.4Hz,1H),5.41(d,J＝13.1Hz,1H),5.09(d,J＝14.3Hz,1H),4.47-4.68(m,1H),4.18(d,J＝2.3Hz,3H),3.62(dt,J＝14.3,7.0Hz,1H),3.03-3.19(m,2H),2.23(d,J＝13.4Hz,1H),1.64-1.81(m,1H).

Example 12

(S) -6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(R) -N- ((S) -1'- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To a solution of (R) -N- ((S) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide 7a (306 mg, 998.48. Mu. Mol) in N, N-dimethylacetamide (3 mL) was added N, N-diisopropylethylamine (107.54 mg, 832.07. Mu. Mol), and after stirring at room temperature for 10 minutes, 3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (215.06 mg, 832.07. Mu. Mol) was added and the reaction was warmed to 90℃and stirred for 1 hour. After the reaction was completed, the resulting residue was concentrated under reduced pressure, and the residue was further separated and purified by silica gel column chromatography (eluent: a system) to give (R) -N- ((S) -1'- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide 12a (280 mg), yield: 63.68%.

MS m/z(ESI):528.1[M+1]

Second step

(R) -N- ((S) -1'- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

(R) -N- ((S) -1' - (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide 12a (280 mg, 529.83. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (324.35 mg,1.32 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (98.90 mg, 211.93. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (88.73 mg, 105.97. Mu. Mol) and potassium phosphate (337.40 mg,1.59 mmol) were added to a mixed aqueous solution of 1, 4-dioxane (10 mL). Argon was replaced three times, heated to 130 ℃, and reacted for 18 hours. After the completion of the reaction, the resulting residue was concentrated under reduced pressure and further separated and purified by silica gel column chromatography (eluent: a system) to give (R) -N- ((S) -1'- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide 12b (190 mg), yield: 55.29%.

MS m/z(ESI):647.8[M+1]

Third step

(S) -6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

To (R) -N- ((S) -1'- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide 12b (190 mg, 292.94. Mu. Mol) in dichloromethane (4 mL) was slowly added dropwise dioxane hydrochloride solution (4M, 366.17. Mu.L) and reacted for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give (S) -6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 12c (159 mg), yield: 99.7% and the reaction was carried out directly to the next reaction without purification.

MS m/z(ESI):527.1[M-16]

Fourth step

To sodium hydroxide solution (5M, 292.04. Mu.L) and (S) -6- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 12c (159 mg, 292.04. Mu. Mol) in methanol (4 mL) was slowly added dropwise 30% hydrogen peroxide (1 mL) and reacted at room temperature for 1 hour. After the reaction, trifluoroacetic acid was added to adjust the pH to be acidic, and the mixture was concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give (S) -6- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 12 (38 mg), yield: 19.23%.

MS m/z(ESI):561.9[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.56(dd,J＝8.9,3.2Hz,1H),7.50(d,J＝7.5Hz,1H),7.29-7.45(m,4H),4.75-4.89(m,2H),4.40(s,1H),4.18(d,J＝2.8Hz,3H),3.35-3.51(m,2H),3.23(s,2H),1.57-1.89(m,4H).

Example 13

6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Diisopropylethylamine (375 mg,2.9 mmol) and 4- (2, 2-difluoroethyl) piperidin-4-amine 13a were added to 3-bromo-6-chloro-1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 1d (250 mg, 967. Mu. Mol) in N-methylpyrrolidone (3 mL) was heated to 100deg.C and stirred for 1 hour. After the reaction is completed, C ₁₈ Reversed phase chromatography column separation (C) ₁₈ Separating column 20-45 μm; mobile phase a: h ₂ O, mobile phase B: CH (CH) ₃ CN) to give the product 6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 13b (300 mg), yield: 80.3%.

MS m/z(ESI):385.9[M+1]

Second step

6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

1g (329.7 mg,1.35 mmol) of 6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 13b (130 mg, 337. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (56.4 mg, 67. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (62.8 mg, 135. Mu. Mol) and potassium phosphate (214.4 mg,1.01 mmol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL). Argon was substituted three times and the reaction was heated at 100 ℃ overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the layers were extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give 6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 13c (100 mg), yield: 58.7%.

MS m/z(ESI):505.9[M+1]

Third step

Potassium hydroxide (22.2 mg, 395. Mu. Mol) and 6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 13c (100 mg, 198. Mu. Mol) were added to a solution of dimethyl sulfoxide (2 mL), hydrogen peroxide (30%, 1 mL) was slowly added dropwise to the reaction solution, stirred for 1 hour after the dropwise addition was completed, and after the completion of the reaction, trifluoroacetic acid was added dropwise to adjust the pH to 3-4 to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5. Mu.m, 20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-indazol-5-pyrazolo [3,4-d ] (3 mg) and the yield of 5-formyl ] pyrimidine-1-d (3 mg): 23.6%.

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

¹ H NMR(400MHz,DMSO-d ₆ )δ8.25(br,3H),8.06(s,1H),7.58(d,J＝8.8Hz,1H),7.54(s,1H),7.29(d,J＝8.8Hz,1H),6.19-6.66(m,1H),4.19-4.44(m,2H),4.16(s,3H),3.67-3.93(m,2H),2.38-2.49(m,2H),1.87-2.02(m,2H),1.71-1.86(m,2H).

Example 14

6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 13b (120 mg, 311. Mu. Mol), 7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole 14a (144.3 mg, 466. Mu. Mol, prepared according to patent WO 2019167000), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (52.0 mg, 62. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (58.0 mg, 124. Mu. Mol) and potassium phosphate (197.9 mg,0.93 mmol) were added to a mixed aqueous solution of 1, 4-dioxane (5 mL). Argon was substituted three times and the reaction was heated at 100 ℃ overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give 6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 14b (55 mg), yield: 36.2%.

MS m/z(ESI):490.9[M+1]

Second step

Potassium hydroxide (12.6 mg, 225. Mu. Mol) and 6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 14B (55 mg, 112. Mu. Mol) were added to a solution of dimethyl sulfoxide (1 mL), hydrogen peroxide (30%, 0.5 mL) was slowly added dropwise to the reaction mixture, stirred for 1 hour after the dropwise addition was completed, and after the completion of the reaction, trifluoroacetic acid was added dropwise to adjust the pH to 3-4 to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-1H-pyrazolo [ 14 mg ] pyrimidine (4 mg) yield) 14 mg). 31.1%.

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

¹ H NMR(400MHz,DMSO-d ₆ )δ8.23(br,3H),8.10(s,1H),7.90(d,J＝8.3Hz,1H),7.58(s,1H),7.54(d,J＝8.3Hz,1H),6.22-6.62(m,1H),4.12-4.47(m,2H),3.71-3.90(m,2H),2.87(s,3H),2.39-2.49(m,2H),1.87-2.03(m,2H),1.70-1.86(m,2H).

Example 15

6- ((1R, 3r, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

((1R, 3r, 5S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (656.82 mg,2.54 mmol), ((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 15a (400 mg,1.77 mmol) and N, N-diisopropylethylamine (456.85 mg,3.53 mmol) were added to N, N-dimethylacetamide (3 mL) and heated to 100deg.C for 1 hour. After the reaction was completed, the organic phases were combined by extraction with ethyl acetate and water, washed with saturated sodium chloride, 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 ((1R, 3r, 5S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 15b (696 mg), yield: 87.84%.

MS m/z(ESI):447.9[M+1]

Second step

((1R, 3r, 5S) -8- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] thiazole 14a (207.19 mg, 669.17. Mu. Mol), ((1R, 3r, 5S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 15b (150 mg, 334.59. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (56.03 mg, 66.92. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (62.45 mg, 133.83. Mu. Mol) and potassium phosphate (142.17.17 mg, 6. Mu. Mol) were added to a solution of water and mixed (1.4 mL). Argon was displaced three times and the reaction was heated at 110℃overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give ((1R, 3r, 5S) -8- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 15c (88 mg), yield: 47.73%.

MS m/z(ESI):550.9[M-16]

Third step

6- ((1R, 3r, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl ((1R, 3r, 5S) -8- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 15c (138 mg, 250.43. Mu. Mol) in dichloromethane (1.5 mL) was added to the mixture, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to give 6- ((1 r,3r,5 s) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 15d (110 mg), yield: 97.41%, without purification, the next reaction was directly carried out.

MS m/z(ESI):450.9[M-16]

Fourth step

6- ((1R, 3r, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 15d (110 mg, 243.93. Mu. Mol) and sodium hydroxide solution (1M, 975.73. Mu.L) were added to methanol (2 mL), 30% hydrogen peroxide (1 mL) was slowly added dropwise, and after completion of the reaction, trifluoroacetic acid was added dropwise to adjust the pH to 3-4 to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5. Mu.m, 20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- ((1R, 3r, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (7-chloro-2-methylbenzo [ 3-d ] thiazol-6-4-yl) pyrimidine-1, 4-carboxamide (4 mg): 4.3%.

MS m/z(ESI):469.1[M-16]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.89(d,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),5.02(s,2H),3.84-3.75Hz(m,1H),2.88(s,3H),2.14-2.28(m,2H),1.98-2.10(m,2H),1.93(d,J＝8.0Hz,4H).

Example 16

6- (4-amino-4- (fluoro (phenyl) methyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

4-carboxamide-4- (fluoro (phenyl) methyl) piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4-cyano-4- (fluoro (phenyl) methyl) piperidine-1-carboxylate 16a (0.92 g,2.89mmol, prepared according to patent WO 2010068881), potassium hydroxide (324.2 mg,5.78 mmol) was added sequentially to N, N-dimethyl sulfoxide (10 mL), hydrogen peroxide (15 mL) was added dropwise in a water bath, and the reaction was carried out overnight at room temperature. After the completion of the reaction, a small amount of water was added to the reaction mixture, and a white solid was precipitated and filtered to give tert-butyl 4-carboxamide-4- (fluoro (phenyl) methyl) piperidine-1-carboxylate 16b (312 mg), yield: 32.1%.

MS m/z(ESI):261.1[M-75]

Second step

4-amine-4- (fluoro (phenyl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To a mixed solution of acetonitrile (5 mL) and water (5 mL) was successively added 4-formamide-4- (fluoro (phenyl) methyl) piperidine-1-carboxylic acid tert-butyl ester 16b (312 mg, 927.47. Mu. Mol), potassium hydroxide (234.18 mg,4.17 mmol), 1, 3-dibromo-5, 5-dimethylhydantoin (132.59 mg, 463.73. Mu. Mol) and reacted at room temperature for 3 hours, the reaction was completed, ethyl acetate and water were extracted, and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-amine-4- (fluoro (phenyl) methyl) piperidine-1-carboxylic acid tert-butyl ester 16c (167 mg), yield: 58.39%.

MS m/z(ESI):253.0[M-55]

Third step

4- (fluoro (phenyl) methyl) piperidin-4-amines

Tert-butyl 4-amine-4- (fluoro (phenyl) methyl) piperidine-1-carboxylate 16c (167 mg, 541.52. Mu. Mol) and trifluoroacetic acid (0.5 mL) were added to dichloromethane (1.5 mL), reacted at room temperature for 1 hour, the reaction was complete, a small amount of water was added to quench it, saturated sodium bicarbonate solution was added, ethyl acetate was used for extraction, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4- (fluoro (phenyl) methyl) piperidin-4-amine 16d (109 mg), yield: 96.64%.

MS m/z(ESI):209.1[M+1]

Fourth step

6- (4-amino-4- (fluoro (phenyl) methyl) piperidin-1-yl) -3-iodo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

3-iodo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 16e (159.86 mg, 523.35. Mu. Mol), 4- (fluoro (phenyl) methyl) piperidin-4-amine 16d (109 mg, 523.35. Mu. Mol), N, N-diisopropylethylamine (202.91 mg,1.57 mmol) was added sequentially to N, N-dimethylacetamide (2 mL), and the mixture was heated to 100℃for 1 hour. The reaction was complete, extracted with ethyl acetate (30 mL) and water, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give 6- (4-amino-4- (fluoro (phenyl) methyl) piperidin-1-yl) -3-iodo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 16f (118 mg), yield: 47.24%.

MS m/z(ESI):477.8[M+1]

Fifth step

6- (4-amino-4- (fluoro (phenyl) methyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

1g (60.54 mg, 247.24. Mu. Mol) of (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid, 6- (4-amino-4- (fluoro (phenyl) methyl) piperidin-1-yl) -3-iodo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 16f (59 mg, 123.62. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (20.70 mg, 24.72. Mu. Mol) and 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (28.84 mg, 61.81. Mu. Mol) and potassium phosphate (52.48 mg, 247.24. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (2 mL) and water (0.2 mL). Argon was substituted three times and the reaction was heated at 110℃for 3 hours. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give 16g (32 mg) of 6- (4-amino-4- (fluoro (phenyl) methyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile, yield: 47.03%.

MS m/z(ESI):549.8[M+1]

Sixth step

6- (4-amino-4- (fluoro (phenyl) methyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 16g (64 mg, 116.28. Mu. Mol) and sodium hydroxide (1M, 465.10. Mu.L) were added sequentially to methanol (2 mL), 30% hydrogen peroxide (1 mL) was slowly added, reacted at room temperature for 0.5 hours, and the reaction was completed with dropwise addition of trifluoroacetic acid to adjust the pH to 3-4, to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- (4-amino-4- (fluoro (phenyl) methyl) piperidin-1-yl) -3- (3, 4-dichloro-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-16-mg (9.45 mg): 10%.

MS m/z(ESI):567.8[M+1]

Example 17

6- ((1R, 3s, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

((1R, 3s, 5S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (411.14 mg,1.59 mmol), ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 17a (300 mg,1.33 mmol) and N, N-diisopropylethylamine (342.64 mg,2.65 mmol) were added to N, N-dimethylacetamide (3 mL), heated to 100℃and reacted for 1 hour. After the reaction was completed, the organic phases were combined by extraction with ethyl acetate and water, washed with saturated sodium chloride, 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 ((1R, 3s, 5S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 17b (500 mg), yield: 84.13%.

MS m/z(ESI):448.1[M+1]

Second step

((1R, 3s, 5S) -8- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] thiazole 14a (276.25 mg, 892.23. Mu. Mol), ((1R, 3s, 5S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 17b (150 mg, 334.59. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (74.71 mg, 89.22. Mu. Mol) and 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (83.27 mg, 178.45. Mu. Mol) and potassium phosphate (39 mg, 89.23. Mu. Mol) were added to a solution of 1, 2mL of water and 0mL of the solution. Argon was displaced three times and the reaction was heated at 110℃overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give ((1R, 3s, 5S) -8- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 17c (120 mg), yield: 48.81%.

MS m/z(ESI):553.2[M+1]

Third step

6- ((1R, 3s, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl ((1R, 3s, 5S) -8- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 17c (120 mg, 217.76. Mu. Mol) was added to dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL) was further added, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to give 6- ((1 r,3s,5 s) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 17d (98 mg), yield: 99.8%, and the next reaction was directly carried out without purification.

MS m/z(ESI):453.1[M+1]

Fourth step

6- ((1R, 3s, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 17d (98 mg, 210.67. Mu. Mol) in sodium hydroxide solution (1M, 842.67. Mu. L) was added to methanol (2 mL), 30% hydrogen peroxide (1 mL) was slowly added, and after completion of the reaction, the reaction was allowed to react at room temperature for 1 hour, trifluoroacetic acid was added dropwise to adjust the pH to 3-4 to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5. Mu.m, 20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- ((1R, 3s, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (7-chloro-2-methylbenzo [ 6-d ] thiazol-6-yl) -1H-pyrazolo [ 18.2.2 m ] 2mg, 5 mg: 14.52%.

MS m/z(ESI):471.1[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.88(d,J＝9.0Hz,1H),7.58(d,J＝8.8Hz,1H),5.01(s,3H),2.87(s,3H),2.67-2.62(br,2H),2.24-2.37(m,2H),1.96(d,J＝8.2Hz,2H),1.74(dd,J＝16.0,4.0Hz,2H).

Example 18

6- ((1R, 3s, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

((1R, 3s, 5S) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

1g (218.83 mg, 669.17. Mu. Mol) of (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid, ((1R, 3s, 5S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 17b (150 mg, 334.59. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (56.03 mg, 66.92. Mu. Mol) and 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (62.45 mg, 133.83. Mu. Mol) and potassium phosphate (142.04 mg, 669.17. Mu. Mol) were added to a mixed aqueous solution of 1, 4-dioxane (2 mL). Argon was displaced three times and the reaction was heated at 110℃overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give ((1R, 3s, 5S) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 18a (95 mg), yield: 49.95%.

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

Second step

6- ((1R, 3s, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl ((1R, 3s, 5S) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 18a (95 mg, 167.12. Mu. Mol) was added to dichloroethane (1.5 mL), trifluoroacetic acid (0.5 mL) was added and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to give 6- ((1 r,3s,5 s) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 18b (78 mg), yield: 99% of the reaction mixture was directly subjected to the next reaction without purification.

MS m/z(ESI):468.1[M+1]

Third step

6- ((1R, 3s, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 18b (78 mg, 166.55. Mu. Mol) and sodium hydroxide solution (1M, 333.09. Mu. L) were added to methanol (1.5 mL), 30% hydrogen peroxide (0.5 mL) was slowly added, and the reaction was carried out at room temperature for 0.5 hours. After completion of the reaction, trifluoroacetic acid was added dropwise to adjust the pH to 3-4 to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- ((1R, 3s, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide 18 (2.07 mg), yield: 1.84%.

MS m/z(ESI):485.9[M+1]

Example 19

6- ((1R, 3r, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

((1R, 3r, 5S) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

1g (218.83 mg, 669.17. Mu. Mol) of (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid, ((1R, 3r, 5S) -8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 15b (150 mg, 334.59. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (56.03 mg, 66.92. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (62.45 mg, 133.83. Mu. Mol) and potassium phosphate (142.04 mg, 669.17. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (2 mL) and 0.2mL of water. Argon was displaced three times and the reaction was heated at 110℃overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give ((1R, 3r, 5S) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 19a (100 mg), yield: 52.58%.

MS m/z(ESI):567.9[M+1]

Second step

6- ((1R, 3r, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl ((1R, 3r, 5S) -8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -8-azabicyclo [3.2.1] oct-3-yl) carbamate 19a (100 mg, 175.91. Mu. Mol was added to dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL) was added, and after completion of the reaction at room temperature for 1 hour, the reaction was concentrated under reduced pressure to give 6- ((1R, 3r, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 19b (82 mg), yield: 99.53%, and the next reaction was directly carried out without purification.

MS m/z(ESI):467.9[M+1]

Third step

6- ((1R, 3r, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 19b (82 mg, 175.09. Mu. Mol) in sodium hydroxide solution (1M, 350.17. Mu. L) was added to methanol (1.5 mL), 30% hydrogen peroxide (0.5 mL) was added, and the reaction time was 3 hours at room temperature. After completion of the reaction, trifluoroacetic acid was added dropwise to adjust pH to 3-4 to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- ((1R, 3r, 5S) -3-amino-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide 19 (14.06 mg), yield: 11.89%.

MS m/z(ESI):485.9[M+1]

Example 20

6- (3-amino-3-methyl-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (225.83 mg, 873.76. Mu. Mol), tert-butyl (3-methyl-8-azabicyclo [3.2.1] oct-3-yl) carbamate 20a (210 mg, 873.76. Mu. Mol, prepared according to patent WO 2005042533), and N, N-diisopropylethylamine (225.85 mg,1.75 mmol) were added sequentially to N, N-dimethylacetamide (2 mL), heated to 100deg.C and reacted for 1 hour. After the completion of the reaction, extraction with ethyl acetate and water, combination of the organic phases, washing with saturated sodium chloride, drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give tert-butyl 8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-8-azabicyclo [3.2.1] oct-3-yl) carbamate 20b (210 mg), yield: 51.98%.

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

Second step

(8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

1g (222.44 mg, 908.42. Mu. Mol) of (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid, (8- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester 20b (210 mg, 454.21. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (76.07 mg, 90.84. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (84.66 mg, 181.68. Mu. Mol) and potassium phosphate (192.83 mg, 908.42. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (3 mL) and water (0.3 mL). Argon was substituted three times and the reaction was heated at 110℃for 3 hours. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give tert-butyl (8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-8-azabicyclo [3.2.1] oct-3-yl) carbamate 20c (112 mg), yield: 42.33%.

MS m/z(ESI):582.2[M+1]

Third step

6- (3-amino-3-methyl-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl (8- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-8-azabicyclo [3.2.1] oct-3-yl) carbamate 20c (112 mg,192.28 μmol) was added to dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give 6- (3-amino-3-methyl-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 20d (92 mg), yield: 99% of the reaction mixture was directly subjected to the next reaction without purification.

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

Fourth step

Sodium hydroxide solution (1M, 381.45. Mu.L) of 6- (3-amino-3-methyl-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 20d (92 mg, 190.73. Mu. Mol) was added to methanol (1.5 mL), and 30% hydrogen peroxide (1 mL) was added to react at room temperature for 4 hours. After completion of the reaction, trifluoroacetic acid was added dropwise to adjust pH to 3-4 to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- (3-amino-3-methyl-8-azabicyclo [3.2.1] oct-8-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide 20 (1.82 mg), yield: 1.52%.

MS m/z(ESI):483.0[M-16]

Example 21

6- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

1-benzyl-4- (2, 4-difluorophenyl) piperidine-4-carbonitrile

2- (2, 4-difluorophenyl) acetonitrile 21a (3 g,19.59 mmol), N-benzyl-2-chloro-N- (2-chloroethyl) ethan-1-amine 21b (5.00 g,21.55 mmol) was added to N, N-dimethylformamide (30 mL), stirred at 0deg.C for 10 min, sodium hydride (5.10 g,127.41mmol,60% purity) was added, stirred for 1 hour, and the temperature was raised to 60deg.C for overnight reaction. After the completion of the reaction, the reaction mixture was poured into ice water and stirred, solids were precipitated, the filtrate was extracted with ethyl acetate, 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-benzyl-4- (2, 4-difluorophenyl) piperidine-4-carbonitrile 21c (2.2 g), yield: 35.95%.

MS m/z(ESI):313.2[M+1]

Second step

1-benzyl-4- (2, 4-difluorophenyl) piperidine-4-carboxamide

1-benzyl-4- (2, 4-difluorophenyl) piperidine-4-carbonitrile 21c (2.2 g,7.04 mmol), potassium hydroxide (790.39 mg,14.09 mmol) was added sequentially to dimethyl sulfoxide (15 mL), hydrogen peroxide (15 mL) was slowly added dropwise, and the reaction was allowed to react overnight at room temperature. After the reaction was completed, the reaction solution was poured into ice water and stirred, solids were precipitated, the solution was filtered, the filtrate was extracted with ethyl acetate, 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-benzyl-4- (2, 4-difluorophenyl) piperidine-4-carboxamide 21d (1 g), yield: 42.98%.

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

Third step

1-benzyl-4- (2, 4-difluorophenyl) piperidin-4-amine

1-benzyl-4- (2, 4-difluorophenyl) piperidine-4-carboxamide 21d (1 g,3.03 mmol), potassium hydroxide (764.28 mg,13.62 mmol) was added to a mixed solution of acetonitrile (3 mL) and water (3 mL), and 1, 3-dibromo-5, 5-dimethylhydantoin (476.00 mg,1.66 mmol) was added. The reaction was carried out at room temperature overnight. After the completion of the reaction, sodium sulfite (38.15 mg, 302.69. Mu. Mol) and potassium phosphate (706.76 mg,3.33 mmol) were added thereto and stirred for 20 minutes. Extraction with ethyl acetate and water separated the aqueous layer and the combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-benzyl-4- (2, 4-difluorophenyl) piperidin-4-amine 21e (500 mg), yield: 54.63%.

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

Fourth step

(1-benzyl-4- (2, 4-difluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

1-benzyl-4- (2, 4-difluorophenyl) piperidin-4-amine 21e (500 mg,1.65 mmol), di-t-butyl dicarbonate (721.82 mg,3.31 mmol) and sodium hydroxide (79.38 mg,1.98 mmol) were added to a mixed solution of dioxane (6 mL) and water (3 mL), reacted at room temperature for 4 hours, and the reaction was completed, extracted with ethyl acetate and water, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give (1-benzyl-4- (2, 4-difluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester 21f (430 mg), yield: 64.61%.

MS m/z(ESI):403.0[M+1]

Fifth step

(4- (2, 4-difluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1-benzyl-4- (2, 4-difluorophenyl) piperidin-4-yl) carbamate 21f (430 mg,1.07 mmol) and palladium on carbon (129.76 mg,1.07 mmol) were added to methanol (20 mL) and after hydrogen displacement, reacted at room temperature for 48 hours. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure to give 21g (300 mg) of t-butyl (4- (2, 4-difluorophenyl) piperidin-4-yl) carbamate, yield: 89.9%.

MS m/z(ESI):313.0[M+1]

Sixth step

(1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (248.24 mg, 960.45. Mu. Mol), (4- (2, 4-difluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester 21g (300 mg, 960.45. Mu. Mol) and N, N-diisopropylethylamine (124.13 mg, 960.45. Mu. Mol) were added sequentially to N, N-dimethylacetamide (2 mL) and heated to 100℃overnight. The reaction was completed, extracted with ethyl acetate and water, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-yl) carbamate 21H (151 mg), yield: 29%.

MS m/z(ESI):534.1[M+1]

Seventh step

(1- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

1g (91.65 mg, 374.28. Mu. Mol) of (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid, (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester (100 mg, 187.14. Mu. Mol), 2-dicyclohexyl-2 ',6' -diisopropyloxy-1, 1' -biphenyl (34.93 mg, 74.86. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (31.34 mg, 37.43. Mu. Mol) and potassium phosphate (79.45 mg, 374.28. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (3 mL) and water (0.3 mL). Argon was substituted three times and the reaction was heated at 110℃for 3 hours. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-yl) carbamate 21i (60 mg), yield: 48.99%.

MS m/z(ESI):653.8[M+1]

Eighth step

6- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl (1- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-yl) carbamate 21i (60 mg,91.67 μmol) was added to dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give 6- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 21j (50 mg), yield: 98.38%. MS m/z (ESI): 536.8[ M-16]

Ninth step

6- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 21j (66 mg, 119.05. Mu. Mol) and sodium hydroxide (48.0 mg,1.2 mmol) were added to methanol (1.5 mL), 30% hydrogen peroxide (0.5 mL) was slowly added and the reaction was continued for 4 hours at room temperature. After completion of the reaction, trifluoroacetic acid was added dropwise to adjust pH to 3-4 to prepare a liquid phase for separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide 21 (1.87 mg), yield: 2.06%.

MS m/z(ESI):571.8[M+1]

Example 22

6- (4-amino-4-phenylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(1- (4-cyano-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-phenylpiperidin-4-yl) carbamic acid tert-butyl ester

N, N-diisopropylethylamine (1.27 g,9.82mmol,1.62 mL) was added to a solution of 3-iodo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 16e (1 g,3.27 mmol) and tert-butyl (4-phenylpiperidin-4-yl) carbamate 22a (995 mg,3.6 mmol) in N, N-dimethylacetamide (5 mL), heated to 100℃and stirred for 1 hour. After the completion of the reaction, the mixture was poured into 100mL of water, extracted with ethyl acetate (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (4-cyano-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-phenylpiperidin-4-yl) carbamate 22b (1.15 g), yield: 64.41%.

MS m/z(ESI):546.1[M+1]

Second step

(1- (4-cyano-3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-phenylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (4-cyano-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-phenylpiperidin-4-yl) carbamate 22b (100 mg, 183.36. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) borate 1g (112.25 mg, 458.40. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (30.71 mg, 36.67. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (34.18 mg, 73.34. Mu. Mol), potassium phosphate (194.36 mg, 916.80. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (2 mL) and water (0.2 mL). Argon was replaced three times, heated to 110℃and reacted for 4 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (4-cyano 3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-phenylpiperidin-4-yl) carbamate 22c (80 mg), yield: 70.54%.

MS m/z(ESI):618.2[M+1]

Third step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

(1- (4-cyano-3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-phenylpiperidin-4-yl) carbamic acid tert-butyl ester 22c (80 mg, 129.34. Mu. Mol) and trifluoroacetic acid (1 mL) were added to dichloromethane (3 mL) and stirred at room temperature for 1 hour. After the reaction, the mixture was concentrated under reduced pressure to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 22d, which was directly subjected to the next reaction without purification.

MS m/z(ESI):518.1[M+1]

Fourth step

The crude product of the above-mentioned 6- (4-amino-4-phenylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 22d was dissolved in methanol (3 mL), sodium hydroxide (51.70 mg,1.29 mmol), hydrogen peroxide (0.5 mL) was added sequentially, and stirring was continued at room temperature for an additional 2 hours. After the reaction, pH=7 was adjusted with trifluoroacetic acid, and the mixture was concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 22 (25 mg), yield: 36%.

MS m/z(ESI):536.1[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.72(d,J＝7.9Hz,2H),7.46-7.62(m,4H),7.35(d,J＝8.8Hz,1H),4.65-4.71(m,2H),4.17(d,J＝2.6Hz,3H),3.46(ddd,J＝13.7,10.2,2.9Hz,2H),2.77(dt,J＝14.3,3.2Hz,2H),2.16(ddd,J＝14.3,10.4,4.3Hz,2H).

Example 23

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(1- (3- (4-chloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-phenylpiperidin-4-ylcarbamic acid tert-butyl ester

Tert-butyl (1- (4-cyano-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-phenylpiperidin-4-yl) carbamate 22b (100 mg, 183.36. Mu. Mol), (4-chloro-2-methyl-2H-indazol-5-yl) boronic acid 23a (96.46 mg, 458.40. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (30.71 mg, 36.67. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (34.18 mg, 73.34. Mu. Mol) and potassium phosphate (194.36 mg, 916.80. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (2.5 mL) and water (0.25 mL). Argon was replaced three times, heated to 110℃and reacted for 4 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give (1- (3- (4-chloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-phenylpiperidin-4-ylcarbamic acid tert-butyl ester 23b (90 mg), yield: 84.04%.

MS m/z(ESI):584.3[M+1]

Second step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

(1- (3- (4-chloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-phenylpiperidin-4-ylcarbamic acid tert-butyl ester 23b (100 mg, 171.21. Mu. Mol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (3 mL) and stirred at room temperature for 1.5 hours after the completion of the reaction, concentrated under reduced pressure to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 23c (80 mg) which was directly subjected to the next reaction without purification.

MS m/z(ESI):467.1[M-16]

Third step

To prepare 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 23c (80 mg, 165.30. Mu. Mol), sodium hydroxide (66.12 mg,1.65 mmol) were dissolved in methanol (2 mL), hydrogen peroxide (0.5 mL) was added and stirred at room temperature for 1 hour, after completion of the reaction, pH=7 was adjusted with trifluoroacetic acid and concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 23 (41 mg), yield: 39.7%.

MS m/z(ESI):501.9[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ8.33(s,1H),7.71-7.75(m,2H),7.49-7.61(m,4H),7.37(d,J＝8.8Hz,1H),4.69(d,J＝14.1Hz,2H),4.25(s,3H),3.45-3.50(m,2H),2.77(d,J＝13.6Hz,2H),2.13-2.18(m,2H).

Example 24

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

(1- (4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-phenylpiperidin-4-yl) carbamic acid tert-butyl ester

2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 2b (147 mg, 821.09. Mu. Mol), (4-phenylpiperidin-4-yl) carbamic acid tert-butyl ester 22a (249.62 mg, 903.20. Mu. Mol), N, N-diisopropylethylamine (529.60 mg,4.11 mmol), N, N-dimethylacetamide (3 mL) were heated to 90℃for 1.5 hours, after completion of the reaction 10mL of water was added, extracted with ethyl acetate (20 mL X2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give (1- (4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-phenylpiperidin-4-yl) carbamic acid tert-butyl ester 24a (200 mg), yield: 58.2%.

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

Second step

(1- (4-cyano-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-phenylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-phenylpiperidin-4-yl) carbamate 24a (200 mg, 477.91. Mu. Mol) was dissolved in N, N-dimethylformamide (1 mL), iodosuccinimide (129.02 mg, 573.49. Mu. Mol) was added, stirred at room temperature for 2 hours, after completion of the reaction 10mL of water was added, extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (4-cyano-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-phenylpiperidin-4-yl) carbamate 24b (150 mg), yield: 57.66%. MS m/z (ESI): 545.0[ M+1]

Third step

(1- (4-cyano-5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-phenylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (4-cyano-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-phenylpiperidin-4-yl) carbamate 24b (10 mg, 18.37. Mu. Mol), (4-chloro-2-methyl-2H-indazol-5-yl) boronic acid 23a (13.44 mg, 45.92. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (3.08 mg, 3.67. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (3.42 mg, 7.35. Mu. Mol) and potassium phosphate (11.68 mg, 55.11. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (1.5 mL) and water (0.15 mL). Argon was replaced three times, heated to 110℃and reacted for 4 hours. After the reaction was completed, the residue was concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (4-cyano-5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-phenylpiperidin-4-yl) carbamate 24c (100 mg), yield: 66.69%.

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

Fourth step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

Tert-butyl (1- (4-cyano-5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4-phenylpiperidin-4-yl) carbamate 24c (100 mg,171.50 μmol) and trifluoroacetic acid (0.5 mL) were added to dichloromethane (1.5 mL), reacted at room temperature for 2 hours, after the end of the reaction, concentrated under reduced pressure to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 24d (80 mg), yield: 96.58%, and the next reaction was directly carried out without purification.

MS m/z(ESI):466.1[M-16]

Fifth step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 24d (80 mg, 165.64. Mu. Mol) and sodium hydroxide (66.26 mg,1.66 mmol) were added to methanol (3 mL), hydrogen peroxide (1 mL) was added and stirred at room temperature for 2 hours, after completion of the reaction, pH=7 was adjusted with trifluoroacetic acid, concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carboxamide 24 (24 mg), yield: 22.92%.

MS m/z(ESI):501.2[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ8.23(s,1H),7.69-7.74(m,2H),7.57(t,J＝7.6Hz,2H),7.47-7.52(m,2H),7.31(d,J＝8.8Hz,1H),7.19(s,1H),4.57(d,J＝14.4Hz,2H),4.22(s,3H),3.42(ddd,J＝13.7,10.1,2.6Hz,2H),2.72(d,J＝14.1Hz,2H),2.16(td,J＝9.7,4.8Hz,2H).

Example 25

6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

N, N-diisopropylethylamine (737.60 mg,5.71mmol, 943.22. Mu.L) was added to 3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (491.70 mg,1.90 mmol) and tert-butyl (4- (2-fluorophenyl) piperidin-4-yl) carbamate 25a (560 mg,1.90 mmol) N, N-dimethylacetamide (3 mL), heated to 100℃for 1 hour, after completion of the reaction, water and ethyl acetate were added, the ethyl acetate extracted three times, the organic phases were combined, and the resulting residue was concentrated under reduced pressure to give tert-butyl (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 25b (600 mg) in yield) by further analytical purification via silica gel column chromatography (eluent: A system: 61.08%.

MS m/z(ESI):516.1[M+1]

Second step

(1- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 25b (150 mg,290.49 μmol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (213.40 mg,871.48 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (72.97 mg,87.15 μmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (81.22 mg,174.30 μmol) and potassium phosphate (307.92 mg,1.45 mmol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL). Argon was replaced three times, heated to 130 ℃, and reacted for 4 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 25c (40 mg), yield: 21.63%.

MS m/z(ESI):636.1[M+1]

Third step

6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl (1- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 25c (40 mg, 62.84. Mu. Mol) and trifluoroacetic acid (1 mL) were added to dichloromethane (2 mL), stirred at room temperature for 2 hours, and after completion of the reaction concentrated under reduced pressure to give 6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 25d (33 mg) which was directly subjected to the next reaction without purification. MS m/z (ESI): 519.1[ M-16]

Fourth step

To prepare 6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 25d (33 mg, 61.52. Mu. Mol) was dissolved in methanol (2 mL), sodium hydroxide (24.61 mg, 615.22. Mu. Mol) was added, and then hydrogen peroxide (0.5 mL) was added and stirred at room temperature for 2 hours. After the reaction, pH=7 was adjusted with trifluoroacetic acid, and the mixture was concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazoleAnd [3,4-d ]]Pyrimidine-4-carboxamide 25 (15 mg), yield: 35.34%.

MS m/z(ESI):554.1[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.71(s,1H),7.56(d,J＝8.9Hz,2H),7.30-7.41(m,3H),4.55(d,J＝14.4Hz,2H),4.18(s,3H),3.74(t,J＝11.2Hz,2H),2.79(d,J＝14.6Hz,2H),2.21(t,J＝9.6Hz,2H).

Example 26

6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(1- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 25b (180 mg, 348.59. Mu. Mol), 7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] thiazole 14a (198.24 mg, 871.48. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (58.38 mg, 69.72. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (64.98 mg, 139.44. Mu. Mol) and potassium phosphate (369.51 mg,1.74 mmol) were added to a solution of 1, 4-dioxane (5 mL) and 0.5mL of water. Argon was replaced three times, heated to 130 ℃, and reacted for 4 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 26a (160 mg), yield: 74.14%. MS m/z (ESI): 619.0[ M+1]

Second step

6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl (1- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 26a (160 mg, 258.44. Mu. Mol) and trifluoroacetic acid (1 mL) were added to dichloromethane (2 mL), stirred at room temperature for 1 hour, and after completion of the reaction, concentrated under reduced pressure to give 6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 26b (130 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):502.1[M-16]

Third step

To the end of 6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ]]Thiazol-6-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 26b (130 mg, 250.48. Mu. Mol) was dissolved in methanol (2 mL), sodium hydroxide (100.19 mg,2.50 mmol) was added, hydrogen peroxide (0.6 mL) was added, stirring was performed at room temperature for 2 hours, after the reaction was completed, pH=7 was adjusted with trifluoroacetic acid, and concentrated under reduced pressure to prepare a liquid-phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ]]Thiazol-6-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 26 (46 mg), yield: 27.36%.

MS m/z(ESI):537.2[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.89(d,J＝8.3Hz,1H),7.71(s,1H),7.58(dd,J＝12.8,7.2Hz,2H),7.29-7.44(m,2H),4.55(d,J＝14.3Hz,2H),3.74(t,J＝11.2Hz,2H),2.87(s,3H),2.79(d,J＝14.5Hz,2H),2.21(t,J＝10.2Hz,2H).

Example 27

6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (4-chloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

First step

(1- (3- (4-chloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 25b (150 mg, 290.49. Mu. Mol), (4-chloro-2-methyl-2H-indazol-5-yl) boronic acid 23a (140.07 mg, 665.64. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (44.59 mg, 53.25. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (49.63 mg, 106.50. Mu. Mol) and potassium phosphate (282.23 mg,1.33 mmol) were added to a mixed solution of 1, 4-dioxane (3 mL) and water (0.3 mL). Argon was replaced three times, heated to 110℃and reacted for 4 hours. After the completion of the reaction, the resulting residue was concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (3- (4-chloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 27a (60 mg), yield: 37.43%.

MS m/z(ESI):602.2[M+1]

Second step

(3- (4-chloro-2-methyl-2H-indazol-5-yl) -4-cyano-1H-pyrazolo [3, 4-d)]Pyrimidine-6-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester 27a (20 mg, 33.22. Mu. Mol) and trifluoroacetic acid (1 mL) were added to methylene chloride (3 mL), stirred at room temperature for 1 hour, and after completion of the reaction, concentrated under reduced pressure to prepare a liquid phase for separation (separation column AKZONOBEL Kromasil;250 x 21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% TFA+H ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (4-chloro-2-methyl)1H-pyrazolo [3,4-d ] yl-2H-indazol-5-yl]Pyrimidine-4-carbonitrile 27 (5 mg), yield: 22.24%.

MS m/z(ESI):485.2[M-16]

¹ H NMR(400MHz,Methanol-d ₄ )δ8.45(s,1H),7.70(dd,J＝14.3,8.3Hz,2H),7.57(d,J＝6.6Hz,1H),7.30-7.43(m,3H),4.48(d,J＝14.2Hz,2H),4.29(d,J＝1.5Hz,3H),3.72(t,J＝11.8Hz,2H),2.79(d,J＝14.2Hz,2H),2.16-2.24(m,2H).

Example 28

6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (4-chloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

To prepare 6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (4-chloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 27 (35 mg, 69.73. Mu. Mol) was dissolved in methanol (1.5 mL), sodium hydroxide (27.89 mg, 697.29. Mu. Mol) was added, hydrogen peroxide (0.5 mL) was added, and after completion of the reaction, the reaction was allowed to react at room temperature for 1 hour, pH=7 was adjusted with trifluoroacetic acid, and concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -3- (4-chloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ]]Pyrimidine-4-carboxamide 28 (13 mg), yield: 28.67%.

MS m/z(ESI):520.2[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ8.32(s,1H),7.71(d,J＝1.6Hz,1H),7.58(dd,J＝8.8,0.9Hz,2H),7.30-7.41(m,3H),4.54(d,J＝14.0Hz,2H),4.25(s,3H),3.74(dd,J＝13.2,9.0Hz,2H),2.79(d,J＝14.1Hz,2H),2.21(td,J＝9.5,4.6Hz,2H).

Example 29

2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

(1- (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

5-bromo-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 2c (400 mg,1.55 mmol), N, N-diisopropylethylamine (602.34 mg,4.66mmol,860.49 μl) and tert-butyl (4- (2-fluorophenyl) piperidin-4-yl) carbamate 25a (548.77 mg,1.86 mmol) were added to N-methylpyrrolidone (4 mL), heated to 115℃for 18 hours, after the reaction was completed, water (40 mL) and ethyl acetate (30 mL) were added and stirred, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue which was further purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 29a (300 mg), yield: 22.48%.

MS m/z(ESI):515.1[M+1]

Second step

(1- (5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 29a (100 mg, 194.03. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (118.78 mg, 485.08. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (32.50 mg, 38.81. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (36.17 mg, 77.61. Mu. Mol) and potassium phosphate (205.67 mg, 970.16. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL). Argon was replaced three times, heated to 110℃and reacted for 4 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 29b (20 mg), yield: 16.22%.

MS m/z(ESI):634.9[M+1]

Third step

2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

Tert-butyl (1- (5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 29b (20 mg,31.47 μmol) and trifluoroacetic acid (0.7 mL) were added to dichloromethane (2 mL), heated to 30 ℃, stirred for 1 hour, and after completion of the reaction concentrated under reduced pressure to give 2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 29c (16 mg) which was directly subjected to the next reaction without purification.

MS m/z(ESI):518.1[M-16]

Fourth step

2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 29c (16 mg, 29.88. Mu. Mol) and sodium hydroxide (11.95 mg, 298.84. Mu. Mol) were dissolved in methanol (2 mL), hydrogen peroxide (0.7 mL) was added, and after completion of the reaction, pH=7 was adjusted with trifluoroacetic acid, concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2, 3-d) ]Pyrimidine-4-carboxamide 29 (5 mg), yield: 30%.

MS m/z(ESI):552.8[M+1]

Example 30

2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

(1- (5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 29a (119 mg, 231.16. Mu. Mol), 7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] thiazole 14a (131.46 mg, 577.90. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (38.71 mg, 46.23. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (43.09 mg, 92.46. Mu. Mol) and potassium phosphate (245.03 mg,1.16 mmol) were added to a mixture of 1, 4-dioxane (3.3 mL) and water (0.3 mL). Argon was replaced three times, heated to 100℃and reacted for 6 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 30a (50 mg), yield: 21%.

MS m/z(ESI):618.2[M+1]

Second step

2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

Tert-butyl (1- (5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 30a (100 mg, 97.07. Mu. Mol) and trifluoroacetic acid (0.6 mL) were added to dichloromethane (2 mL), reacted at room temperature for 1 hour, and after completion of the reaction, concentrated under reduced pressure to give 2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 30b (40 mg), which was directly subjected to the next reaction without purification. MS m/z (ESI): 501.0[ M-16]

Third step

2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ]]Thiazol-6-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 30b (40 mg, 77.22. Mu. Mol) and sodium hydroxide (3.09 mg, 77.22. Mu. Mol) were dissolved in methanol (2 mL), hydrogen peroxide (0.7 mL) was added, and after completion of the reaction, pH=7 was adjusted with trifluoroacetic acid, concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ]]Thiazol-6-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carboxamide 30 (5 mg), yield: 12.08%.

MS m/z(ESI):536.0[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.79(d,J＝8.3Hz,1H),7.70(t,J＝8.1Hz,1H),7.53(dd,J＝18.8,7.3Hz,2H),7.28-7.40(m,2H),7.23(s,1H),4.45(d,J＝13.6Hz,2H),3.67(q,J＝8.9,5.3Hz,2H),2.85(s,3H),2.75(d,J＝14.3Hz,2H),2.20(t,J＝10.0Hz,2H).

Example 31

2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

(1- (5- (4-chloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (5-bromo-4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 29a (108 mg, 209.56. Mu. Mol), (4-chloro-2-methyl-2H-indazol-5-yl) boronic acid 23a (110.24 mg, 523.89. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (35.10 mg, 41.91. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (39.06 mg, 83.82. Mu. Mol) and potassium phosphate (222.13 mg,1.05 mmol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL). Argon was replaced three times, heated to 110℃and reacted for 4 hours. After the completion of the reaction, the resulting residue was concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (5- (4-chloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamate 31a (35 mg), yield: 27.79%.

MS m/z(ESI):601.3[M+1]

Second step

2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

(1- (5- (4-chloro-2-methyl-2H-indazol-5-yl) -4-cyano-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2-fluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester 31a (43 mg, 71.54. Mu. Mol) and trifluoroacetic acid (0.7 mL) were added to dichloromethane (2 mL) and reacted at room temperature for 1 hour. After the completion of the reaction, the mixture was concentrated under reduced pressure to give 2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 31b (35 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):501.1[M+1]

Third step

2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-)Nitrile 31b (35 mg, 69.87. Mu. Mol) and sodium hydroxide (11.95 mg, 298.84. Mu. Mol) were dissolved in methanol (2 mL), hydrogen peroxide (0.7 mL) was added, and after the reaction was completed at room temperature for 1 hour, pH=7 was adjusted with trifluoroacetic acid, and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4- (2-fluorophenyl) piperidin-1-yl) -5- (4-chloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2, 3-d)]Pyrimidine-4-carboxamide 31 (5 mg), yield: 13.7%.

MS m/z(ESI):518.9[M+1]

Example 32

6- (4-amino-4-methylpiperidin-1-yl) -3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(1- (4-cyano-3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate 1f (150 mg, 343.80. Mu. Mol), naphthalene-2-ylboronic acid 32a (177.39 mg,1.03 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (57.58 mg, 68.76. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (64.08 mg, 137.52. Mu. Mol) and potassium phosphate (364.42 mg,1.72 mmol) were added to a mixed solution of 1, 4-dioxane (1.5 mL) and water (0.15 mL). Argon was replaced three times, heated to 130 ℃, and reacted for 18 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the resulting residue was further purified by silica gel column chromatography (eluent: a system) to give tert-butyl (1- (4-cyano-3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate 32b (40 mg), yield: 24.03%.

MS m/z(ESI):484.3[M+1]

Second step

6- (4-amino-4-methylpiperidin-1-yl) -3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl (1- (4-cyano-3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate 32b (40 mg, 82.7. Mu. Mol) and trifluoroacetic acid (1 mL) were added to dichloromethane (3 mL) and reacted at room temperature for 1 hour. After the completion of the reaction, the mixture was concentrated under reduced pressure to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 32c (40 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):384.2[M+1]

Third step

To 6- (4-amino-4-methylpiperidin-1-yl) -3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 32c (40 mg, 104.32. Mu. Mol) and sodium hydroxide (41.73 mg,1.04 mmol) were dissolved in methanol (2 mL), hydrogen peroxide (0.8 mL) was added, and after completion of the reaction, pH=7 was adjusted with trifluoroacetic acid, concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ]Pyrimidine-4-carboxamide 32 (15.99 mg), yield: 29.41%.

MS m/z(ESI):402.2[M+1]

Example 33

6- (4-amino-4- (2-methoxyphenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

4-cyano-4- (2-methoxyphenyl) piperidine-1-carboxylic acid tert-butyl ester

2- (2-methoxyphenyl) acetonitrile 33a (1 g,6.79 mmol) and tert-butyl bis (2-chloroethyl) carbamate (1.81 g,7.47 mmol) were dissolved in N, N-dimethylformamide (6 mL), 60% sodium hydride (1.06 g,26.51 mmol) was added in portions, stirred for 40 minutes and then heated to 70℃and reacted overnight. Cooled to room temperature, quenched with water (100 mL) and extracted with ethyl acetate (100 mL. Times.3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: a system) to give 4-cyano-4- (2-methoxyphenyl) piperidine-1-carboxylic acid tert-butyl ester 33b (1.7 g), yield: 79.1%.

MS m/z(ESI):217.0[M-99]

Second step

4-carbamoyl-4- (2-methoxyphenyl) piperidine-1-carboxylic acid tert-butyl ester

Potassium hydroxide (283.75 mg,5.06 mmol) and 4-cyano-4- (2-methoxyphenyl) piperidine-1-carboxylic acid tert-butyl ester 33b (0.8 g,2.53 mmol) were dissolved in dimethyl sulfoxide (5 mL), and hydrogen peroxide (5 mL) was slowly added dropwise. The reaction was carried out at room temperature overnight. A large amount of water (50 mL) was added, and a yellow solid precipitated. Filtration, washing of the filter cake with water and drying gave 4-carbamoyl-4- (2-methoxyphenyl) piperidine-1-carboxylic acid tert-butyl ester 33c (400 mg), yield: 47.3%.

MS m/z(ESI):279.0[M-55]

Third step

4-amino-4- (2-methoxyphenyl) piperidine-1-carboxylic acid tert-butyl ester

Potassium hydroxide (302.02 mg,5.38 mmol) was added to a mixed solution of 4-carbamoyl-4- (2-methoxyphenyl) piperidine-1-carboxylic acid tert-butyl ester 33c (400 mg,1.20 mmol) in acetonitrile (2 mL) and water (3 mL), and 1, 3-dibromo-5, 5-dimethylhydantoin (188.10 mg, 657.88. Mu. Mol) was added in portions and stirred at room temperature for 1 hour. Water (100 mL) and potassium phosphate (279.30 mg,1.32 mmol) were added, stirred for 15 minutes, ethyl acetate (20 mL) and sodium sulfite (15.07 mg, 119.61. Mu. Mol) were added, the solution was separated, the aqueous phase was extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined and washed with saturated sodium chloride solution (20 mL), dried, concentrated under reduced pressure to give 4-amino-4- (2-methoxyphenyl) piperidine-1-carboxylic acid tert-butyl ester 33d (366 mg), yield: 99.6% and the next reaction was carried out without purification.

MS m/z(ESI):234.1[M-72]

Fourth step

4- (2-methoxyphenyl) piperidin-4-amine

4-amino-4- (2-methoxyphenyl) piperidine-1-carboxylic acid tert-butyl ester 33d (365 mg,1.19 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 g,26.31 mmol) was slowly added and stirred overnight at room temperature. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 4- (2-methoxyphenyl) piperidin-4-amine 33e, which was directly subjected to the next reaction without purification.

MS m/z(ESI):190.1[M-16]

Fifth step

6- (4-amino-4- (2-methoxyphenyl) piperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (283.17 mg,1.10 mmol) was added sequentially to N-methylpyrrolidone (3 mL), followed by argon substitution and stirring at 100deg.C for 2 hours, followed by N, N-diisopropylethylamine (566.37 mg,4.38 mmol) of the crude 4- (2-methoxyphenyl) piperidin-4-amine 33 e. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give the product 6- (4-amino-4- (2-methoxyphenyl) piperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 33f (360 mg), yield: 70.8%.

MS m/z(ESI):411.0[M-16]

Sixth step

6- (4-amino-4- (2-methoxyphenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4- (2-methoxyphenyl) piperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 33f (100 mg, 122. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (229 mg, 934. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (39.1 mg, 46.7. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (43.6 mg, 93.4. Mu. Mol) and potassium phosphate (149 mg, 700. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL). Argon was substituted three times and the reaction was heated at 100 ℃ overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give 33g (25 mg) of 6- (4-amino-4- (2-methoxyphenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile, yield: 20%.

MS m/z(ESI):530.8[M-16]

Seventh step

Potassium hydroxide (5.1 mg, 91. Mu. Mol) and 6- (4-amino-4- (2-methoxyphenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]33g (25 mg, 46. Mu. Mol) of pyrimidine-4-carbonitrile was added to a solution of dimethyl sulfoxide (1 mL), hydrogen peroxide (30% at 0.5 mL) was slowly added dropwise to the reaction mixture, stirred for 1 hour after completion of the dropwise addition, and after completion of the reaction, trifluoroacetic acid was added dropwise, pH was adjusted to 3-4, and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4- (2-methoxyphenyl) piperidin-1-yl) -3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 33 (7 mg), yield: 22%.

MS m/z(ESI):566.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.17(s,3H),8.01-8.09(m,1H),7.40-7.66(m,4H),7.29(d,J＝8.8Hz,1H),7.20(d,J＝8.2Hz,1H),7.04-7.12(m,1H),4.23-4.45(m,2H),4.16(s,3H),3.89(s,3H),3.63-3.77(m,2H),2.53-2.63(m,2H),2.05-2.23(m,2H).

Example 34

6- (4-amino-4-phenylpiperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6- (4-amino-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

3-bromo-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 1d (0.7 g,2.71 mmol), 4-phenylpiperidin-4-amine 8a (470 mg,2.67 mmol) and N, N-diisopropylethylamine (1.38 g,10.7mmol,1.77 mL) were added sequentially to N-methylpyrrolidone (6.23 mL). Argon was substituted, heated to 100℃and reacted for 4 hours. After completion of the reaction, the reaction was cooled to room temperature, quenched by addition of aqueous solution (30 mL), ethyl acetate (30 mL), extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 34a (0.8 g), yield: 75%.

MS m/z(ESI):380.9[M-16]

Second step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 34a (100 mg, 251. Mu. Mol), 7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole 14a (155 mg, 502. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (42 mg, 50. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (46.9 mg, 100. Mu. Mol) and potassium phosphate (213 mg,1.00 mmol) were added to a mixed solution of 1, 4-dioxane (3 mL) and water (0.5 mL). Argon was substituted three times and the reaction was heated at 130℃for 24 hours. After completion of the reaction, the reaction was concentrated under reduced pressure, quenched with saturated aqueous ammonium chloride (30 mL), ethyl acetate (30 mL), the aqueous phase extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 34b (40 mg), yield: 32%.

MS m/z(ESI):484.1[M-16]

Third step

To the extent that 6- (4-amino-4-phenylpiperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ]]Thiazol-6-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 34b (40 mg, 80. Mu. Mol) was dissolved in dimethyl sulfoxide (1 mL), potassium hydroxide (8.96 mg, 160. Mu. Mol) was added, and hydrogen peroxide (30%, 0.4 mL) was slowly added and reacted overnight at room temperature. After completion of the reaction, water (100 ml) was added thereto, and the mixture was stirred for 15 minutes to precipitate a solid. Preparation of liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d)]Thiazol-6-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 34 (6 mg), yield: 14.4%.

MS m/z(ESI):519.1[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.88(d,J＝8.2Hz,1H),7.73(d,J＝7.8Hz,2H),7.58(dd,J＝10.2,7.9Hz,3H),7.50(t,J＝7.3Hz,1H),4.69(d,J＝13.9Hz,2H),3.46(t,J＝12.0Hz,2H),2.87(s,3H),2.77(d,J＝13.8Hz,2H),2.16(ddd,J＝14.3,10.7,3.8Hz,2H).

Example 35

2- (4-amino-4-phenylpiperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 8b (200 mg, 503.43. Mu. Mol), 7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] thiazole 14a (468.36 mg,1.51 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (141.17 mg, 302.54. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (126.67 mg, 151.27. Mu. Mol) and potassium phosphate (642.20 mg,3.03 mmol) were added to a mixed solution of 1, 4-dioxane (3 mL) and water (0.5 mL). Argon was substituted three times and the reaction was heated at 130℃for 16 hours. After completion of the reaction, the reaction was concentrated under reduced pressure, quenched with saturated aqueous ammonium chloride (30 mL), ethyl acetate (30 mL), the aqueous phase extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 35a (40 mg), yield: 15.89%.

MS m/z(ESI):483.1[M-16]

Second step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d)]Thiazol-6-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 35a (40 mg, 80.00. Mu. Mol) was dissolved in dimethyl sulfoxide (3 mL), potassium hydroxide (8.98 mg, 159.99. Mu. Mol) was added, and hydrogen peroxide (0.5 mL) was slowly added to react at room temperature for 2 hours. After completion of the reaction, filtration and concentration under reduced pressure were carried out to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05％TFA+H ₂ o, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d)]Thiazol-6-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4-carboxamide 35 (5.0 mg), yield: 8.73%.

MS m/z(ESI):517.9[M+1]

Example 36

6- (4-amino-4-phenylpiperidin-1-yl) -3- (2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 34a (0.2 g, 502.19. Mu. Mol), 2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole 36a (207.08 m g, 753.28. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (70.30 mg, 150.66. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (63.08 mg, 75.33. Mu. Mol) and potassium phosphate (80 mg,1.51 mmol) were added to a mixed solution of 1, 4-dioxane (319 mL) and water (0.5 mL). Argon was substituted three times and the reaction was heated at 130℃for 16 hours. After completion of the reaction, the reaction was concentrated under reduced pressure, quenched with saturated aqueous ammonium chloride (30 mL), ethyl acetate (30 mL), the aqueous phase extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the resulting residue was purified by column chromatography on silica gel (eluent: A system) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 36b (50 mg), yield: 28.45%.

MS m/z(ESI):450.1[M-16]

Second step

To the extent that 6- (4-amino-4-phenylpiperidin-1-yl) -3- (2-methylbenzo [ d ]]Thiazol-6-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 36b (50 mg, 107.17. Mu. Mol) was dissolved in dimethyl sulfoxide (3 mL), potassium hydroxide (12.03 mg, 214.33. Mu. Mol) was added, and hydrogen peroxide (0.5 mL) was slowly added to react at room temperature for 2 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (2-methylbenzo [ d)]Thiazol-6-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 36 (7 mg), yield: 10.86%.

MS m/z(ESI):485.0[M+1]

Example 37

6- (4-amino-4-methylpiperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(1- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester

Tert-butyl (1- (3-bromo-4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate 1f (330 mg, 756.35. Mu. Mol), 7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole 14a (468.36 mg,1.51 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (126.67 mg, 151.27. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (141.17 mg, 302.54. Mu. Mol) and potassium phosphate (642.20 mg,3.03 mmol) were added to a mixed solution of 1, 4-dioxane (3.5 mL) and water (0.5 mL). Argon was substituted three times and the reaction was heated at 130℃for 48 hours. After completion of the reaction, the reaction was concentrated under reduced pressure, quenched with saturated aqueous ammonium chloride (30 mL), ethyl acetate (30 mL), the aqueous phase extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the resulting residue was purified by column chromatography on silica gel (eluent: A system) to give tert-butyl (1- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate 37a (140 mg), yield: 34.34%.

MS m/z(ESI):538.9[M+1]

Second step

6- (4-amino-4-methylpiperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

(1- (3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 37a (140 mg, 259.72. Mu. Mol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 g,26.31 mmol) was slowly added and reacted at room temperature for 3 hours. After completion of the reaction, concentrated under reduced pressure, extracted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution (100 ml×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 37b (100 mg), yield: 87.72%.

MS m/z(ESI):438.9[M+1]

Third step

To 6- (4-amino-4-methylpiperidin-1-yl)) -3- (7-chloro-2-methylbenzo [ d)]Thiazol-6-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 37b (100 mg, 227.82. Mu. Mol) was dissolved in dimethyl sulfoxide (3 mL), potassium hydroxide (25.57 mg, 455.65. Mu. Mol) was added, and hydrogen peroxide (0.5 mL) was slowly added to react at room temperature for 3 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4-methylpiperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d)]Thiazol-6-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carboxamide 37 (22.0 mg), yield: 21.13%.

MS m/z(ESI):456.9[M+1]

Example 38

6- (4-amino-4-phenylpiperidin-1-yl) -3- (2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 34a (100 mg, 251. Mu. Mol), 2-methyl-2H-indazole-5-boronic acid 38a (66.3 mg,0.38 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (42.1 mg, 50. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (46.9 mg, 100. Mu. Mol) and potassium phosphate (159.9 mg,0.75 mmol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL). Argon was substituted three times and heated at 100 ℃ and reacted overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the layers were extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 38b (50 mg), yield: 44.3%.

MS m/z(ESI):433.0[M-16]

Second step

Potassium hydroxide (12.5 mg, 222. Mu. Mol) and 6- (4-amino-4-phenylpiperidin-1-yl) -3- (2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 38B (50 mg, 111. Mu. Mol) were added to a solution of dimethyl sulfoxide (2 mL), hydrogen peroxide (30%, 1 mL) was slowly added dropwise to the reaction solution, stirring was carried out for 1 hour after the dropwise addition was completed, and after completion of the reaction, trifluoroacetic acid was added dropwise to adjust the pH to 3-4 to prepare a liquid phase separation (mobile phase A:0.05% TFA+H2O, mobile phase B: CH3 CN) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (2-methyl-2H-indazol-5-yl) -1H-pyrazolo [3, 4-carboxamide 38 (8 mg), yield: 7.5%. MS m/z (ESI): 468.0[ M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.42(br,3H),8.37(s,1H),8.08(s,1H),7.95(s,1H),7.66-7.78(m,3H),7.56-7.61(m,1H),7.50-7.56(m,3H),7.41-7.49(m,1H),4.27-4.43(m,2H),4.19(s,3H),3.49-3.56(m,2H),2.54-2.55(m,2H),2.04-2.16(m,2H).

Example 39

2- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -5-bromo-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

Diisopropylethylamine (211 mg,1.63 mmol) and 4- (2, 2-difluoroethyl) piperidin-4-amine 13a (112.2 mg,0.68 mmol) were added to 5-bromo-2-chloro-7H-pyrrolo [2,3-d]Pyrimidine-4-carbonitrile 2c (140 mg, 544. Mu. Mol) N-methylpyrrolidine A solution of ketone (3 mL) was heated to 100deg.C and stirred for 1 hour. After completion of the reaction, the reversed phase column was separated (mobile phase A: H ₂ O, mobile phase B: CH (CH) ₃ CN) to give 2- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -5-bromo-7H-pyrrolo [2, 3-d)]Pyrimidine-4-carbonitrile 39a (150 mg), yield: 71.6%.

MS m/z(ESI):384.9[M+1]

Second step

2- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -5-bromo-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 39a (150 mg, 389. Mu. Mol), 7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole 14a (241.1 mg,0.78 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (65.2 mg, 78. Mu. Mol), 2-dicyclohexyl-phosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (72.7 mg, 156. Mu. Mol) and potassium phosphate (248.0 mg,1.17 mmol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL). Argon was substituted three times and heated at 100 ℃ and reacted overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the layers were extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give 2- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 39b (140 mg), yield: 73.7%. MS m/z (ESI): 487.9[ M+1]

Third step

Potassium hydroxide (32.2 mg, 574. Mu. Mol) and 2- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 39B (140 mg, 287. Mu. Mol) were added to a solution of dimethyl sulfoxide (2 mL), hydrogen peroxide (30%, 1 mL) was slowly added dropwise to the reaction mixture, stirred for 1 hour after the dropwise addition was completed, and after the completion of the reaction, trifluoroacetic acid was added dropwise to adjust the pH to 3-4 to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mM I.D.; 5. Mu.m, 20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 2- (4-amino-4- (2, 2-difluoroethyl) piperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2, 3-carboxamide ] yield (39 mg): 2.2%.

MS m/z(ESI):505.8[M+1]

Example 40

6- (4-amino-4- (2, 2-trifluoroethyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

1- (tert-Butoxycarbonyl) -4- (2, 2-trifluoroethyl) piperidine-4-carboxylic acid

Sodium hydroxide (1.23 g,30.65 mmol) was added to a mixed solution of 1- (tert-butyl) -4-ethyl-4- (2, 2-trifluoroethyl) piperidine-1, 4-dicarboxylic acid ester 40a (2.6 g,7.66mmol, obtained by self-preparation according to patent WO 2010106081) in ethanol (10 mL) and water (10 mL), and heated to 60℃for 20 hours. Ethanol was concentrated off, 4N diluted hydrochloric acid was added to adjust the solution ph=1, extracted with ethyl acetate (30 ml×3), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, and concentrated to dryness, and the resulting residue was purified by silica gel column chromatography (eluent: a system) to give 1- (tert-butoxycarbonyl) -4- (2, 2-trifluoroethyl) piperidine-4-carboxylic acid 40b (2.0 g), yield: 83.9%.

MS m/z(ESI):256.0[M-55]

Second step

4-carbamoyl-4- (2, 2-trifluoroethyl) piperidine-1-carboxylic acid tert-butyl ester

Urea N, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (3.66 g,9.64 mmol) was added to a solution of 1- (t-butoxycarbonyl) -4- (2, 2-trifluoroethyl) piperidine-4-carboxylic acid 40b (2.0 g,6.42 mmol) and diisopropylethylamine (124.6 mg,0.96 mmol) in N, N-dimethylformamide (10 mL), heated to 60 ℃, reacted for half an hour, 7M methanolic ammonia (20 mL) was added dropwise, heated to 60 ℃ and reacted for 20 hours. After completion of the reaction, 100mL of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated to dryness, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give tert-butyl 4-carbamoyl-4- (2, 2-trifluoroethyl) piperidine-1-carboxylate 40c (1.7 g), yield: 85.3%.

MS m/z(ESI):255.0[M-55]

Third step

4-amino-4- (2, 2-trifluoroethyl) piperidine-1-carboxylic acid tert-butyl ester

To a mixed solution of 4-carbamoyl-4- (2, 2-trifluoroethyl) piperidine-1-carboxylic acid tert-butyl ester 40c (1.7 g,5.48 mmol) in acetonitrile (15 mL) and water (15 mL) was added [ bis (trifluoroacetoxy) iodo ] benzene (2.59 g,6.03 mmol), and the mixture was heated to 60℃and reacted for 2 hours. After completion of the reaction, saturated sodium hydrogencarbonate solution (40 mL), extraction with ethyl acetate (30 mL. Times.3), washing with saturated sodium chloride solution (30 mL), drying the organic phase over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and further analysis and purification of the resulting residue by silica gel column chromatography (eluent: A system) gave tert-butyl 4-amino-4- (2, 2-trifluoroethyl) piperidine-1-carboxylate 40d (600 mg), yield: 38.8%.

MS m/z(ESI):227.0[M-55]

Fourth step

4- (2, 2-trifluoroethyl) piperidin-4-amine

Trifluoroacetic acid (3 mL) was added dropwise to a solution of 4-amino-4- (2, 2-trifluoroethyl) piperidine-1-carboxylic acid tert-butyl ester 40d (600 mg,2.13 mmol) in dichloromethane (9 mL), stirred at room temperature for 1 hour, concentrated under reduced pressure to give 4- (2, 2-trifluoroethyl) piperidin-4-amine 40e, which was directly fed to the next reaction without purification.

MS m/z(ESI):183.1[M+1]

Fifth step

6- (4-amino-4- (2, 2-trifluoroethyl) piperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Diisopropylethylamine (675.1 mg,5.22 mmol) and the crude 4- (2, 2-trifluoroethyl) piperidin-4-amine 40e above were added to 3-bromo-6-chloro-1H-pyrazolo [3,4-d ]]Pyrimidine-4-carbonitrile 1d (450 mg,1.74 mmol) was heated to 100deg.C in a solution of N-methylpyrrolidone (5 mL) and stirred for 1 hour. After completion of the reaction, the reversed phase column was separated (mobile phase A: H ₂ O, mobile phase B: CH (CH) ₃ CN) to give 6- (4-amino-4- (2, 2-trifluoroethyl) piperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ]]Pyrimidine-4-carbonitrile 40f (600 mg), yield: 85.3%.

MS m/z(ESI):403.9[M+1]

Sixth step

6- (4-amino-4- (2, 2-trifluoroethyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4- (2, 2-trifluoroethyl) piperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 40f (80 mg, 198. Mu. Mol), 7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole 14a (122.6 mg, 396. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (33.2 mg, 40. Mu. Mol), 2-dicyclohexyl-phosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (36.9 mg, 79. Mu. Mol) and potassium phosphate (168.1 mg,0.79 mmol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL). Argon was substituted three times and heated at 100 ℃ and reacted overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the layers were extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to give 40g (50 mg) of 6- (4-amino-4- (2, 2-trifluoroethyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile, yield: 49.8%.

MS m/z(ESI):506.8[M+1]

Seventh step

Potassium hydroxide (11.1 mg, 197. Mu. Mol) and 6- (4-amino-4- (2, 2-trifluoroethyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile (50 mg, 99. Mu. Mol) were added to a solution of dimethyl sulfoxide (1 mL), hydrogen peroxide (30%, 0.5 mL) was slowly added dropwise to the reaction mixture, stirred for 1 hour after the completion of the dropwise addition, and after the completion of the reaction, trifluoroacetic acid was added dropwise to adjust the pH to 3-4 to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5. Mu.m, 20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- (4-amino-4- (2, 2-trifluoroethyl) piperidin-1-yl) -3- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [ 4, 13mg ] amide (13 mg): 20.4%.

MS m/z(ESI):525.1[M+1]

Example 41

2- (4-amino-4-phenylpiperidin-1-yl) -5- (2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 8b (100 mg, 251.72. Mu. Mol), 2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] thiazole 36a (138.53 mg, 503.43. Mu. Mol), potassium phosphate (213.73 mg,1.01 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (46.98 mg, 100.69. Mu. Mol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (42.16 mg, 50.34. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (2 mL) and water (0.4 mL) and the reaction was heated to 130℃for three replacement. The residue was further purified by column chromatography on silica gel (eluent: a system) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 41a (40 mg), yield: 34.13%.

MS m/z(ESI):449.0[M-16]

Second step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 41a (40 mg, 85.92. Mu. Mol) was dissolved in dimethyl sulfoxide (2 mL), potassium hydroxide (9.64 mg, 171.83. Mu. Mol) was added thereto, and hydrogen peroxide (0.4 mL) was slowly added thereto to react at room temperature for 3 hours. After completion of the reaction, filtration, preparation of a liquid phase separation (separation column AKZONOBEL Kromasil;250×21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% tfa+h2o, mobile phase B: CH3 CN) afforded 2- (4-amino-4-phenylpiperidin-1-yl) -5- (2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide 41 (15 mg), yield: 36.15%.

MS m/z(ESI):467.0[M-16]

Example 42

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2- (difluoromethyl) -2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2- (difluoromethyl) -2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 34a (100 mg, 251. Mu. Mol), (4-chloro-2- (difluoromethyl) -2H-indazol-5-yl) boronic acid pinacol ester 42a (123.7 mg,0.38 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (42.1 mg, 50. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (46.9 mg, 100. Mu. Mol) and potassium phosphate (159.9 mg,0.75 mmol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL). Argon was displaced three times, heated to 100 ℃, and reacted overnight. After completion of the reaction, concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2- (difluoromethyl) -2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 42b (40 mg), yield: 30.6%.

MS m/z(ESI):502.9[M-16]

Second step

Potassium hydroxide (8.6 mg, 154. Mu. Mol) and 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2- (difluoromethyl) -2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 42B (40 mg, 77. Mu. Mol) were added to a solution of dimethyl sulfoxide (1 mL), hydrogen peroxide (30%, 0.5 mL) was slowly added dropwise to the reaction mixture, and after completion of the addition, stirring was carried out for 1 hour, and after completion of the reaction, trifluoroacetic acid was added dropwise to adjust the pH to 3-4 to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2- (difluoromethyl) -2H-pyrazolo [3,4-d ] pyrimidine-carboxamide (6.7 mg) yield: 13.1%. MS m/z (ESI): 537.9[ M+1]

Example 43

2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrole [2,3-d ] pyrimidine-4-carboxamide

First step

2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5-bromo-7H-pyrrole [2,3-d ] pyrimidine-4-carbonitrile

To (3R, 4R) -3-fluoropiperidin-4-amine 11a (319 mg,2.19 mmol) in N, N-dimethylformamide (3 mL) was added N, N-diisopropylethylamine (602.34 mg,4.66 mmol), and after stirring at room temperature for 10 minutes, 5-bromo-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 2c (400 mg,1.55 mmol) was added and the reaction was warmed to 110℃and stirred for 9 hours. Concentrated under reduced pressure and the resulting residue purified by silica gel column chromatography (eluent: A system) to give 2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5-bromo-7H-pyrrole [2,3-d ] pyrimidine-4-carbonitrile 43a (200 mg), yield: 37.96%.

MS m/z(ESI):338.9[M+1]

Second step

2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5-bromo-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 43a (200 mg, 589.68. Mu. Mol), (3, 4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (216.59 mg, 884.52. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (98.76 mg, 117.94. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (109.92 mg, 235.87. Mu. Mol) and potassium phosphate (625.06 mg,2.95 mmol) were added to a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL). Argon was replaced three times, heated to 130 ℃, and reacted for 18 hours. After completion of the reaction, the residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: A system) to give 2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 43b (60 mg), yield: 22.15%.

MS m/z(ESI):458.9[M+1]

Third step

To methanol (3 mL) of 2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 43b (60 mg, 130.63. Mu. Mol) was added sodium hydroxide (5M, 130.63. Mu.L), followed by slow dropwise addition of hydrogen peroxide (0.5 mL). The reaction was carried out at room temperature for 1 hour. After the reaction, trifluoroacetic acid was added to adjust the pH to 3-4, and the mixture was concentrated under reduced pressure to give a liquid phase for separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide 43 (2.5 mg), yield: 3.14%.

MS m/z(ESI):476.9[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.48(d,J＝8.8Hz,1H),7.31(d,J＝8.8Hz,1H),7.23(s,1H),5.34(d,J＝13.0Hz,1H),5.01(d,J＝14.8Hz,1H),4.51-4.66(m,1H),4.16(s,3H),3.55-3.63(m,1H),3.04-3.09(m,2H),2.16-2.23(m,1H),1.67-1.76(m,1H).

Example 44

2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5-bromo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5-bromo-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 43a (350 mg,1.03 mmol) was added to tetrahydrofuran (6 mL), sodium hydride (98.42 mg,2.27mmol,60% purity) was added to the above mixed solution at low temperature, stirred at 0deg.C for 30 minutes, and 2- (trisilyl) ethoxymethyl chloride (361.30 mg,2.17 mmol) was added to the above solution, and stirring was continued at room temperature. After the reaction was completed for 1 hour, the reaction mixture was extracted with water, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5-bromo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 44a (70 mg), yield: 14.45%.

MS m/z(ESI):468.9[M+1]

Second step

2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5-bromo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 44a (70 mg, 149.12. Mu. Mol), 7-chloro-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole 14a (115.42 mg, 372.80. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (12.49 mg, 14.91. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (13.90 mg, 29.82. Mu. Mol) and potassium phosphate (158.07 mg, 59. Mu. Mol) were added to N, N-dimethylacetamide at a temperature of three-mL, and the mixture was stirred until the temperature was reached at 80℃for three times. After the reaction was completed, the reaction was cooled to room temperature, ethyl acetate was extracted with water, and the organic phases were combined, and finally the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 44b (40 mg), yield: 46.88%.

MS m/z(ESI):571.9[M+1]

Third step

2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 44b (40 mg, 69.91. Mu. Mol) and trifluoroacetic acid (1 mL) were added to dichloromethane (2 mL), reacted overnight at room temperature, after the end of the reaction, concentrated under reduced pressure, the concentrate was added to an amine methanol solution (2 mL), pH was adjusted to 8-9, reacted at room temperature for 2 hours, concentrated under reduced pressure, the concentrate was added to methanol (2 mL), and 5M sodium hydroxide solution (0.5 mL) was then added dropwise slowly to hydrogen peroxide (0.5 mL), and reacted at room temperature for 1 hour. After completion of the reaction, trifluoroacetic acid was adjusted to pH 3-4 and concentrated under reduced pressure to prepare a liquid phase for separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 2- ((3R, 4R) -4-amino-3-fluoropiperidin-1-yl) -5- (7-chloro-2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide 44 (2 mg), yield: 5.06%.

MS m/z(ESI):460.1[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.80(d,J＝8.3Hz,1H),7.51(d,J＝8.5Hz,1H),7.26(d,J＝1.3Hz,1H),5.34(d,J＝11.4Hz,1H),5.02(d,J＝14.4Hz,1H),4.58(d,J＝50.5Hz,1H),3.59(d,J＝11.0Hz,1H),3.01-3.07(m,2H),2.85(d,J＝1.2Hz,3H),2.20(d,J＝8.3Hz,1H),1.67-1.77(m,1H).

Example 45

2- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -5- (2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

(1- (5-bromo-4-cyano-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2, 4-difluorophenyl) piperidin-4-ylcarbamic acid tert-butyl ester

5-bromo-2-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 45a (248.24 mg, 960.45. Mu. Mol), (4- (2, 4-difluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester 21g (300 mg, 960.45. Mu. Mol) and N, N-diisopropylethylamine (124.13 mg, 960.45. Mu. Mol) were added sequentially to N, N-dimethylacetamide (2 mL) with continuous stirring at 100℃overnight. The reaction was completed, the reaction mixture was cooled to room temperature, extracted with ethyl acetate and water, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl (1- (5-bromo-4-cyano-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2, 4-difluorophenyl) piperidin-4-ylcarbamate 45b (151 mg), yield: 29%.

MS m/z(ESI):663.1[M+1]

Second step

(1- (4-cyano-5- (2-methylbenzo [ d ] thiazol-6-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2, 4-difluorophenyl) piperidin-4-yl) carbamic acid tert-butyl ester

2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] thiazole 36a (158.23 mg, 575.02. Mu. Mol), (1- (5-bromo-4-cyano-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2, 4-difluorophenyl) piperidin-4-ylcarbamic acid tert-butyl ester 45b (318 mg, 479.18. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (80.25 mg, 95.84. Mu. Mol), 2-dicyclohexyl-phosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (89.44 mg, 191.67. Mu. Mol) and potassium phosphate (122.06 mg, 02 ℃ C.) were added to N-dimethylformamide, and the mixture was concentrated to a dry phase by chromatography with a saturated aqueous solution of ethyl sulfate, dried to give a saturated aqueous solution, cooled to 100 mL, and completely cooled to obtain a saturated aqueous solution, and a solution, and the aqueous solution was completely purified by chromatography to obtain a saturated solution, to give tert-butyl (1- (4-cyano-5- (2-methylbenzo [ d ] thiazol-6-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2, 4-difluorophenyl) piperidin-4-yl) carbamate 45c (180 mg), yield: 51.32%.

MS m/z(ESI):732.3[M+1]

Third step

2- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -5- (2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

Tert-butyl (1- (4-cyano-5- (2-methylbenzo [ d ] thiazol-6-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -4- (2, 4-difluorophenyl) piperidin-4-yl) carbamate 45c (50 mg, 68.31. Mu. Mol) was added to a mixed solution of dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL), reacted at room temperature for 1 hour, the reaction was completed, concentrated under reduced pressure, the reaction solution was neutralized by adding saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure. The resulting concentrate was added to an amine methanol solution (1.5 mL), ph=8-9 was adjusted, the reaction was carried out at room temperature for 2 hours, the reaction was complete, and the solution was concentrated under reduced pressure to give 2- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -5- (2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 45d (33 mg), yield: 96.23%, and the next reaction was directly carried out without purification.

MS m/z(ESI):485.1[M-16]

Fourth step

2- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -5- (2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 45d (33 mg, 71.78. Mu. Mol) and potassium hydroxide (8.05 mg, 143.55. Mu. Mol) were added sequentially to dimethyl sulfoxide (1 mL), 30% hydrogen peroxide (0.5 mL) was slowly added, the reaction was completed at 40℃and trifluoroacetic acid was adjusted to pH 3-4, concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5. Mu.m, 20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 2- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -5- (2-methylbenzo [ d ] thiazol-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide (6.45 mg) in a yield of 6.45 mg: 13.33%.

MS m/z(ESI):520.1[M+1]

Example 46

6- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -3- (2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

(1- (3-bromo-4-cyano-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-ylcarbamic acid tert-butyl ester

Tert-butyl (4- (2, 4-difluorophenyl) piperidin-4-yl) carbamate 21g (190 mg, 608.28. Mu. Mol), 3-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-carbonitrile 46a (190 mg, 608.28. Mu. Mol) and N, N-diisopropylethylamine (157.23 mg,1.22 mmol) were added sequentially to N-methylpyrrolidone (2 mL), 100 ^℃ The reaction was allowed to react for 1 hour, was complete, and was cooled to room temperature. Extraction with ethyl acetate and water, combining the organic phases, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying the residue by silica gel column chromatography (eluent: A system) to give (1- (3-bromo-4-cyano-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d)]Pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-ylcarbamic acid tert-butyl ester 46b (310 mg), yield: 82.4%.

MS m/z(ESI):618.1[M+1]

Second step

(1- (3- (2-Methylbenzo [ d ] thiazol-6-yl) -4-cyano-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-ylcarbamic acid tert-butyl ester

2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [ d ] thiazole 36a (133.48 mg, 485.07. Mu. Mol), (1- (3-bromo-4-cyano-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-ylcarbamic acid tert-butyl ester 46b (150 mg, 242.53. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (40.62 mg, 48.51. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (45.27 mg, 97.01. Mu. Mol) and potassium phosphate (102.96 mg, 485.07. Mu. Mol) were sequentially added to N, N-dimethylformamide (2 mL), argon was substituted three times, heated to 100 ℃ and reacted overnight. A system A), to give tert-butyl (1- (3- (2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-ylcarbamate 46c (70 mg), yield 42.03%.

MS m/z(ESI):687.3[M+1]

Third step

6- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -3- (2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl (1- (3- (2-methylbenzo [ d ] thiazol-6-yl) -4-cyano-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -4- (2, 4-difluorophenyl) piperidin-4-ylcarbamate 46c (70 mg, 101.93. Mu. Mol, added to dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL) was added, reacted at room temperature for 1 hour, the reaction was completed, concentrated under reduced pressure, neutralized with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 6- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -3- (2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 46d (51 mg), yield: 99%, and the next reaction was directly carried out without purification.

MS m/z(ESI):502.9[M+1]

Fourth step

6- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -3- (2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 46d (51 mg, 101.48. Mu. Mol) and potassium hydroxide (11.39 mg, 202.97. Mu. Mol) were sequentially added to dimethyl sulfoxide (1.5 mL), 30% hydrogen peroxide (0.5 mL) was slowly added dropwise, heated to 40℃and the reaction was completed under reduced pressure, concentrated to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5. Mu.m, 20mL/min; mobile phase A:0.05% TFA+H2O, mobile phase B: CH3 CN) to give 6- (4-amino-4- (2, 4-difluorophenyl) piperidin-1-yl) -3- (2-methylbenzo [ d ] thiazol-6-yl) -1H-pyrazolo [3, 4-carboxamide-46.32 mg) yield (32 mg): 4.63%.

MS m/z(ESI):521.2[M+1]

Example 47

6- (3-amino-3-methyl-8-azabicyclo [3.2.1] oct-8-yl) -3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

4-chloro-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidine 47a (4.0 g,19.94mmol, prepared according to WO 2019158655), tetrakis triphenylphosphine palladium (2.30 g,1.99 mmol) and zinc cyanide (5.83 g,49.84 mmol) were added to N-methylpyrrolidone (60 mL), replaced three times with argon, heated to 120℃for 0.5 hour, after completion of the reaction, water (40 mL) and ethyl acetate (30 mL) were added, celite filtered, the filtrate organic phase separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 47b (1.1 g), yield: 28.86%.

MS m/z(ESI):192.1[M+1]

Second step

3-iodo-6- (methylsulfanyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 47b (1.2 g,6.28 mmol) and iodosuccinimide (1.55 g,6.90 mmol) were added to N, N-dimethylformamide (15 mL), heated to 90℃for 4 hours, quenched with ice water after completion of the reaction, the filtrate was extracted with ethyl acetate, the organic phase of the filtrate was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 3-iodo-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 47c (1.99 g), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification.

MS m/z(ESI):318.0[M+1]

Third step

3-iodo-6- (methylsulfanyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

3-iodo-6- (methylsulfanyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 47c (1.99 g,6.28 mmol) was added to N, N-dimethylformamide (25.84 mL), cooled to zero degrees Celsius, sodium hydride (326.45 mg,7.53 mmol) was slowly added, reacted for 0.5 hour, 2- (trimethylsilyl) ethoxymethyl chloride (1.57 g,9.41mmol,1.67 mL) was further added, stirred under ice bath for 1 hour, after the reaction was completed, the reaction solution was slowly poured into ice water to quench, extracted with ethyl acetate, the organic phase of the filtrate was separated, dried over anhydrous sodium sulfate, filtered, and the resulting residue was concentrated under reduced pressure, purified by silica gel column chromatography (eluent: A system) to give 3-iodo-6- (methylsulfanyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3, 4-carbonitrile 47d (340 mg), yield: 12.11%.

MS m/z(ESI):448.1[M+1]

Fourth step

3- (naphthalen-2-yl) -6- (methylsulfanyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

3-iodo-6- (methylsulfanyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 47d (190 mg, 424.71. Mu. Mol), naphthalene-2-ylboronic acid 32a (109.57 mg, 637.06. Mu. Mol), bis (triphenylphosphine) palladium chloride (93.14 mg, 127.41. Mu. Mol) and potassium phosphate (135.06 mg, 637.06. Mu. Mol) were added to acetonitrile (3 mL), displaced three times with argon, heated to 80 ℃, the reaction was carried out for 3 hours, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 3- (naphthalen-2-yl) -6- (methylsulfanyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 47e (90 mg), yield: 47.34%.

MS m/z(ESI):448.2[M+1]

Fifth step

3- (naphthalen-2-yl) -6- (methylsulfonyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

3- (naphthalen-2-yl) -6- (methylsulfanyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 47e (90 mg, 201.06. Mu. Mol), m-chloroperoxybenzoic acid (173.48 mg,1.01 mmol) was added sequentially to dichloromethane (2 mL), reacted at room temperature for 4 hours, sodium sulfite was added to the reaction solution, stirred for 20 minutes, extracted with ethyl acetate and water, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 3- (naphthalen-2-yl) -6- (methylsulfonyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 47f (56 mg), yield: 58.07%.

MS m/z(ESI):480.1[M+1]

¹ H NMR(400MHz,Chloroform-d)δ8.45(s,1H),8.06(d,J＝8.8Hz,1H),7.90-8.02(m,3H),7.54-7.65(m,2H),6.03(s,2H),3.82(t,J＝8.2Hz,2H),3.50(s,3H),0.98(t,J＝7.6Hz,2H),0.00(s,9H).

Sixth step

(8- (4-cyano-3- (naphthalen-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-8-azabicyclo [3.2.1] oct-3-yl) carbamic acid tert-butyl ester

Tert-butyl (3-methyl-8-azabicyclo [3.2.1] oct-3-yl) carbamate 20a (28.06 mg, 116.76. Mu. Mol), 3- (naphthalen-2-yl) -6- (methylsulfonyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 47f (56 mg, 116.76. Mu. Mol) and N, N-diisopropylethylamine (30.36 mg, 233.52. Mu. Mol) were added to N-methylpyrrolidone (1.5 mL), heated to 50 ℃, reacted for 2 hours, cooled to room temperature, ethyl acetate was extracted with water, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the resulting residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: A system) to give (8- (4-cyano-3- (naphthalen-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine-3-6-methyl-8-tert-butyl (3.47 mg), the reaction was completed, and the resulting residue was purified by silica gel column chromatography (eluent: A system): 66.93%.

MS m/z(ESI):640.3[M+1]

Seventh step

6- (3-amino-3-methyl-8-azabicyclo [3.2.1] oct-8-yl) -3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

Tert-butyl (8- (4-cyano-3- (naphthalen-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -3-methyl-8-azabicyclo [3.2.1] oct-3-yl) carbamate 47g (50 mg,78.14 μmol) was added to dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL) was added, the reaction was allowed to react at room temperature for 1 hour, the reaction was completed, concentrated under reduced pressure, a small amount of water quench reaction was added, saturated sodium bicarbonate solution was added, ethyl acetate extraction, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting residue was added to an methanolic amine solution (2 mL), reacted at room temperature for 1 hour, and concentrated under reduced pressure to give 6- (3-amino-3-methyl-8-azabicyclo [3.2.1] oct-8-yl) -3- (naphthalen-2-yl) -1H-pyrazolo [3, 4-carbonitrile (31 mg), yield: 97.86%, and the next reaction was directly carried out without purification.

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

Eighth step

6- (3-amino-3-methyl-8-azabicyclo [3.2.1] oct-8-yl) -3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 47H (31 mg, 75.70. Mu. Mol) and potassium hydroxide (8.50 mg, 151.41. Mu. Mol) were sequentially added to dimethyl sulfoxide (1 mL), 30% hydrogen peroxide (0.5 mL) was slowly added to 40 ℃, reacted for 0.5 hours, and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5. Mu.m, 20mL/min; mobile phase A:0.05% TFA+H2O, mobile phase B: CH3 CN) to give 6- (3-amino-3-methyl-8-azabicyclo [3.2.1] oct-8-yl) -3- (naphthalen-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide (47.32 mg), yield: 14.95%.

MS m/z(ESI):411.2[M-16]

Example 48

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

5-bromo-4-chloro-2- (methyl-d 3) -2H-indazole

5-bromo-4-chloro-1H-indazole 3a (5 g,21.60 mmol) was dissolved in tetrahydrofuran (44.62 mL), sodium hydride (1.40 g,32.40 mmol) was added at low temperature, stirred for 30 minutes, deuterated iodomethane (12.52 g,86.40mmol,5.38 mL) was added, and the reaction was allowed to proceed overnight at room temperature, and was complete. Water quenching (10 ml) was added, extraction with ethyl acetate (15 ml. Times.3), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 5-bromo-4-chloro-2- (methyl-d 3) -2H-indazole 48b (1.2 g), yield: 22.35%.

MS m/z(ESI):247.8[M+1]

Second step

4-chloro-2- (methyl-d 3) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2H-indazole

5-bromo-4-chloro-2- (methyl-d 3) -2H-indazole 48b (200.00 mg, 804.76. Mu. Mol) was added to 1, 4-dioxane (6 mL), potassium acetate (236.94 mg,2.41 mmol) was added, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (58.88 mg, 80.48. Mu. Mol) was added, and the reaction was heated to 100℃for 1.5 hours, and the reaction was complete. The reaction solution was cooled to room temperature, filtered through celite, washed with ethyl acetate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: a system) to give 4-chloro-2- (methyl-d 3) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2H-indazole 48c (200 mg), yield: 84.08%.

MS m/z(ESI):296.0[M+1]

Third step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 34a (100 mg, 251.09. Mu. Mol), 4-chloro-2- (methyl-d 3) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2H-indazole 48c (111.33 mg, 376.64. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (42.05 mg, 50.22. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -Diisopropoxy-1, 1' -biphenyl (46.87 mg, 100.44. Mu. Mol) and potassium phosphate (133.25 mg, 627.73. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (3 mL) and water (0.3 mL), after the gas was replaced with argon, the reaction was heated to 130℃for 10 hours, the reaction was completed, cooled to room temperature, ethyl acetate was extracted with water, the organic phase was combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: a system A), to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 48d (60 mg), yield: 49.07%.

MS m/z(ESI):469.9[M-16]

Fourth step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 48d (60.00 mg, 123.21. Mu. Mol) and 5M sodium hydroxide solution (0.5 mL) were added to methanol (3 mL), 30% hydrogen peroxide (0.5 mL) was slowly added, and the reaction was carried out at room temperature for 1 hour. After completion of the reaction, pH=3-4 was adjusted with trifluoroacetic acid and concentrated under reduced pressure to prepare a liquid phase for separation (separation column AKZONOBEL Kromasil;250×21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide 48 (35 mg), yield: 45.23%.

MS m/z(ESI):505.0[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ8.32(s,1H),7.73(dd,J＝7.4,1.6Hz,2H),7.54-7.62(m,3H), 7.47-7.53(m,1H),7.37(dd,J＝8.8,1.4Hz,1H),4.68(d,J＝14.1Hz,2H),3.48(ddd,J＝13.9,10.3,2.5Hz,2H),2.77(d,J＝13.6Hz,2H),2.17(ddd,J＝14.1,10.2,3.9Hz,2H).

Example 49

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

5-bromo-4-chloro-1- (methyl-d 3) -1H-indazole

5-bromo-4-chloro-1H-indazole 3a (5 g,21.60mmol, prepared according to WO 2019167000) was dissolved in tetrahydrofuran (44.62 mL), sodium hydride (1.40 g,32.40 mmol) was added at low temperature, stirred for 30 minutes, deuterated iodomethane (12.52 g,86.40mmol,5.38 mL) was added, and the reaction was carried out overnight at room temperature, and the reaction was complete. Water quenching (10 ml) was added, extraction with ethyl acetate (15 ml. Times.3), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 5-bromo-4-chloro-1- (methyl-d 3) -1H-indazole 49a (2.2 g), yield: 40.98%.

MS m/z(ESI):247.8[M+1]

Second step

4-chloro-1- (methyl-d 3) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indazole

5-bromo-4-chloro-1- (methyl-d 3) -1H-indazole 49a (250 mg,1.01 mmol) was added to 1, 4-dioxane (6 mL), potassium acetate (296.17 mg,3.02 mmol) was added, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (73.61 mg, 100.59. Mu. Mol) was added, and the reaction was heated to 100℃for 1.5 hours, and the reaction was complete. The reaction solution was cooled to room temperature, filtered through celite, washed with ethyl acetate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: a system) to give 4-chloro-1- (methyl-d 3) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indazole 49b (220 mg), yield: 73.99%.

MS m/z(ESI):296.0[M+1]

Third step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 34a (100 mg, 251.09. Mu. Mol), 4-chloro-1- (methyl-d 3) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole 49b (111.33 mg, 376.64. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (42.05 mg, 50.22. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -Diisopropoxy-1, 1' -biphenyl (46.87 mg, 100.44. Mu. Mol) and potassium phosphate (133.25 mg, 627.73. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (3 mL) and water (0.3 mL), after the gas was replaced with argon, the reaction was heated to 130℃for 8 hours, the reaction was completed, cooled to room temperature, ethyl acetate was extracted with water, the organic phase was combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: a system A), to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 49c (50 mg), yield: 40.89%.

MS m/z(ESI):469.9[M-16]

Fourth step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 49c (50.00 mg, 102.68. Mu. Mol) and 5M sodium hydroxide (0.5 mL) were added to methanol (3 mL), 30% hydrogen peroxide (0.5 mL) was slowly added dropwise, the reaction was completed at room temperature, pH=3-4 was adjusted with trifluoroacetic acid, concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O, mobile phase B: CH3 CN) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -1H-pyrazolo [3, 4-carboxamide-4-carboxamide (24 mg) yield (49 mg): 37.10%.

MS m/z(ESI):505.0[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ8.06(s,1H),7.73(dd,J＝7.4,1.6Hz,2H),7.54-7.61(m,3H),7.47-7.53(m,2H),4.68(d,J＝14.1Hz,2H),3.41-3.55(m,2H),2.77(d,J＝13.7Hz,2H),2.18(td,J＝10.0,5.0Hz,2H).

Example 50

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide

First step

5-bromo-4-chloro-2-cyclopropyl-2H-indazole

5-bromo-4-chloro-1H-indazole 3a (2 g,8.64 mmol), cyclopropylboronic acid (1.11 g,12.96 mmol), sodium carbonate (2.29 g,21.60 mmol), copper acetate (2.35 g,12.96 mmol) and 2, 2-bipyridine (2.70 g,17.28 mmol) were added to 1, 2-dichloroethane (30 mL) at low temperature, reacted for 48 hours at room temperature, after completion of the reaction, celite was filtered, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 5-bromo-4-chloro-2-cyclopropyl-2H-indazole 50a (1.27 g), yield: 54.13%.

MS m/z(ESI):271.0[M+1]

Second step

4-chloro-2-cyclopropyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2H-indazole

5-bromo-4-chloro-2-cyclopropyl-2H-indazole 50a (300 mg,1.10 mmol) was added to 1, 4-dioxane (10 mL), potassium acetate (325.28 mg,3.31 mmol) was added, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (80.84 mg, 110.48. Mu. Mol) was added, heated to 100deg.C, the reaction was allowed to cool to room temperature after the completion of the reaction, celite was filtered, washed with ethyl acetate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 4-chloro-2-cyclopropyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2H-indazole 50b (240 mg), yield: 68.18%.

MS m/z(ESI):319.0[M+1]

Third step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile

6- (4-amino-4-phenylpiperidin-1-yl) -3-bromo-1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 34a (100 mg, 251.09. Mu. Mol), 4-chloro-2-cyclopropyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2H-indazole 50b (120.00 mg, 376.64. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (42.05 mg, 50.22. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -Diisopropoxy-1, 1' -biphenyl (46.87 mg, 100.44. Mu. Mol) and potassium phosphate (133.25 mg, 627.73. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (3 mL) and water (0.3 mL), argon was substituted three times, heated to 130℃and reacted for 15 hours, the reaction was completed, cooled to room temperature, extracted with ethyl acetate and water, 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 purified by silica gel column chromatography (eluent: a system A), to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 50c (55 mg), yield: 42.95%.

MS m/z(ESI):492.9[M-16]

Fourth step

6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carbonitrile 50c (55 mg, 107.84. Mu. Mol) and 5M sodium hydroxide solution (0.5 mL) were added to methanol (2 mL) and 30% hydrogen peroxide (0.5 mL) was slowly added dropwise. The reaction was completed at room temperature for 1 hour, pH=3-4 was adjusted with trifluoroacetic acid, and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil;250×21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O, mobile phase B: CH3 CN) to give 6- (4-amino-4-phenylpiperidin-1-yl) -3- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-carboxamide 50 (25 mg), yield: 35.36%.

MS m/z(ESI):527.9[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ8.03(s,1H),7.65-7.77(m,3H),7.54-7.62(m,2H),7.51(dd,J＝8.4,1.5Hz,2H),4.68(dt,J＝14.9,4.4Hz,2H),3.72(td,J＝5.1,1.8Hz,1H),3.48(ddd,J＝13.8,10.4,2.7Hz,2H),2.77(d,J＝13.3Hz,2H),2.18(ddd,J＝14.0,10.1,3.9Hz,2H),1.28-1.14(m,4H).

Example 51

2- (4-amino-4-phenylpiperidin-1-yl) -5- (2- (methyl-d 3) -2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (2- (methyl-d 3) -2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 8b (115 mg, 288.76. Mu. Mol), 2- (methyl-d 3) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2H-indazole 51a (113.11 mg, 433.14. Mu. Mol, prepared according to patent WO 2016180536), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (48.36 mg, 57.75. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -Diisopropoxy-1, 1' -biphenyl (53.90 mg, 115.50. Mu. Mol) and potassium phosphate (153.24 mg, 721.89. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (3 mL) and water (0.3 mL), after the gas was replaced with argon, the reaction was heated to 130℃for 15 hours, the reaction was completed, cooled to room temperature, ethyl acetate was extracted with water, the organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: a system A), to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (2- (methyl-d 3) -2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 51b (33 mg), yield: 25.25%.

MS m/z(ESI):452.0[M+1]

Second step

5M sodium hydroxide solution (0.15 mL) and 2- (4-amino-4-phenylpiperidin-1-yl) -5- (2- (methyl-d 3) -2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 51B (33 mg, 72.92. Mu. Mol) were added to methanol (2 mL), 30% hydrogen peroxide (0.3 mL) was slowly added, stirred at room temperature for 0.5H, the reaction was complete, trifluoroacetic acid was added to adjust the pH to acidity, and concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5. Mu.m, 20mL/min; mobile phase A:0.05% TFA+H2O, mobile phase B: CH3 CN) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (2- (methyl-d 3) -2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide 51 (26 mg), yield: 67.6%.

MS m/z(ESI):470.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ13.39(s,1H),8.35(s,3H),8.09(d,J＝8.2Hz,2H),7.99(s,1H),7.76(s,1H),7.71(d,J＝8.0Hz,2H),7.67(d,J＝2.2Hz,2H),7.55(t,J＝7.6Hz,2H),7.48(d,J＝7.2Hz,1H),4.35(s,2H),3.41-3.54(m,2H),2.57(d,J＝9.7Hz,2H),2.09(dd,J＝12.5,8.2Hz,2H)

Example 52

2- (4-amino-4-phenylpiperidin-1-yl) -5- (1- (methyl-d 3) -1H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (1- (methyl-d 3) -1H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 8b (115 mg, 288.76. Mu. Mol), 1- (methyl-d 3) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indazole 52a (113.11 mg, 433.14. Mu. Mol, prepared according to patent WO 2016180536), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (48.36 mg, 57.75. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -Diisopropoxy-1, 1' -biphenyl (53.90 mg, 115.50. Mu. Mol) and potassium phosphate (153.24 mg, 721.89. Mu. Mol) were added to a mixed solution of 1, 4-dioxane (3 mL) and water (0.3 mL), after the argon gas was replaced, the reaction was heated to 130℃for 15 hours, the reaction was completed, the reaction was cooled to room temperature, ethyl acetate was extracted with water, the organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the resulting residue was purified by silica gel column chromatography (eluent: a system A), to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (1- (methyl-d 3) -1H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 52b (50 mg), yield: 38.26%. MS m/z (ESI): 452.0[ M+1]

Second step

5M sodium hydroxide solution (0.2 mL) and 2- (4-amino-4-phenylpiperidin-1-yl) -5- (1- (methyl-d 3) -1H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 52B (50.00 mg, 110.49. Mu. Mol) were added to methanol (2 mL), 30% hydrogen peroxide (0.4 mL) was slowly added, stirred at room temperature for 3 hours, the reaction was complete, trifluoroacetic acid was added to adjust the pH to acidity, and concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.; 5. Mu.m, 20mL/min; mobile phase A:0.05% TFA+H2O, mobile phase B: CH3 CN) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (1- (methyl-d 3) -1H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide 52 (20 mg), yield: 37.37%.

MS m/z(ESI):470.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ13.37(s,1H),8.38(s,3H),8.09(s,1H),7.96(s,1H),7.67-7.80(m,3H),7.51-7.62(m,4H),7.48(d,J＝6.9Hz,1H),4.35(s,2H),3.52(d,J＝13.9Hz,2H),2.56(d,J＝11.6Hz,2H),2.10(t,J＝9.7Hz,2H).

Example 53

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

5-bromo-2-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 45a (600 mg,1.55 mmol), 4-phenylpiperidin-4-amine 8a (362.09 mg,1.70 mmol) and N, N-diisopropylethylamine (999.96 mg,7.74 mmol) were added to N, N-dimethylacetamide (6 mL). Heating to 110deg.C, reacting for 7 hours, adding 30mL of water, extracting with ethyl acetate (30 mL×3), washing with saturated sodium chloride solution (20 mL), drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying the obtained residue by silica gel column chromatography (eluent: A system) to obtain 2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 53a (700 mg), yield: 85.75%.

MS m/z(ESI):510.0[M-16]

Second step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 53a (100 mg, 189.56. Mu. Mol), 4-chloro-2-cyclopropyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2H-indazole 50b (90.59 mg, 284.34. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (31.75 mg, 37.91. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (35.38 mg, 75.82. Mu. Mol) and potassium phosphate (100.60 mg, 473.91. Mu. Mol) were added to N, N-dimethylamide (3 ℃ C.) and the mixture was stirred at three times at 80℃under stirring. After the completion of the reaction, 20mL of water was added, extracted with ethyl acetate (20 mL. Times.3), and the saturated sodium chloride solution (20 mL) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 53b (110 mg), yield: 90.77%.

MS m/z(ESI):622.3[M-16]

Third step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

Trifluoroacetic acid (1.5 mL) was added to dichloromethane (4.5 mL) of 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 53b (110 mg,172.07 μmol), stirred at room temperature for 2 hours, the reaction was complete, concentrated under reduced pressure, and the resulting residue was added to an methanolic amine solution (3 mL), reacted at room temperature for 2 hours, and the reaction was complete. Concentrating under reduced pressure gave 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 53c (87.8 mg), yield: 99% of the product was used directly in the next reaction without purification.

MS m/z(ESI):492.2[M-16]

Fourth step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 53c (87 mg, 139.64. Mu. Mol) and 5M sodium hydroxide solution (0.5 mL) were added to methanol (3 mL), 30% hydrogen peroxide (0.5 mL) was slowly added, and the reaction was stirred at room temperature for 2 hours and completed. Trifluoroacetic acid was added to adjust ph=6-7, and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil;250×21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% tfa+h2o, mobile phase B: CH3 CN) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2-cyclopropyl-2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide 53 (30 mg), yield: 40.52%.

MS m/z(ESI):527.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.34(s,3H),7.98(s,1H),7.83(s,1H),7.71(d,J＝7.8Hz,2H),7.60(d,J＝8.5Hz,1H),7.54(t,J＝7.6Hz,2H),7.47(t,J＝7.2Hz,1H),7.38(d,J＝8.4Hz,1H), 7.24-7.33(m,2H),4.33(d,J＝14.0Hz,2H),3.82(dt,J＝6.7,3.1Hz,1H),3.45(dd,J＝13.4,8.9Hz,2H),2.54(s,2H),2.10(dd,J＝12.3,8.1Hz,2H),1.07-1.22(m,4H).

Example 54

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 53a (100 mg, 189.56. Mu. Mol), 4-chloro-2- (methyl-d 3) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2H-indazole 48c (120 mg, 406.78. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (31.75 mg, 37.91. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (35.38 mg, 75.82. Mu. Mol) and potassium phosphate (100.60 mg, 473.91. Mu. Mol) were added to N, N-dimethylamide (3 ℃ C.) and the mixture was stirred at three times at 80℃under stirring. After the completion of the reaction, 20mL of water was added, extracted with ethyl acetate (20 mL. Times.3), and the saturated sodium chloride solution (20 mL) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 54a (65 mg), yield: 55.64%. MS m/z (ESI): 599.0[ M-16]

Second step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 54a (61 mg, 98.99. Mu. Mol) and trifluoroacetic acid (1 mL) were added to dichloromethane (2 mL), stirred overnight at room temperature, the reaction was complete, concentrated under reduced pressure, and the resulting residue was added to 7M methanolic amine (2 mL) and reacted at room temperature for 0.5 hours. After completion of the reaction, concentrated under reduced pressure to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 54b (48 mg), yield: 99% of the product was directly subjected to the next reaction without purification.

MS m/z(ESI):468.9[M-16]

Third step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 54b (48 mg, 98.77. Mu. Mol) and 5M sodium hydroxide solution (0.5 mL) were added to methanol (3 mL), 30% hydrogen peroxide (0.5 mL) was slowly added, and the reaction was carried out at room temperature for 1 hour. After completion of the reaction, pH=3-4 was adjusted with trifluoroacetic acid and concentrated under reduced pressure to prepare a liquid phase for separation (separation column AKZONOBEL Kromasil;250×21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H2O; mobile phase B: CH3 CN) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-2- (methyl-d 3) -2H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide 54 (35 mg), yield: 57%.

MS m/z(ESI):504.0[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ8.22(s,1H),7.72(d,J＝7.8Hz,2H),7.57(t,J＝7.6Hz,2H),7.50(dd,J＝8.5,4.7Hz,2H),7.31(dd,J＝8.8,1.9Hz,1H),7.19(d,J＝1.9Hz,1H),4.57(d,J＝14.2Hz,2H),3.44(t,J＝12.2Hz,2H),2.72(d,J＝13.8Hz,2H),2.17(t,J＝11.1Hz,2H).

Example 55

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide

First step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4-phenylpiperidin-1-yl) -5-bromo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 53a (200 mg, 379.12. Mu. Mol), 4-chloro-1- (methyl-d 3) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole 49b (168.10 mg, 568.69. Mu. Mol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (63.49 mg, 75.82. Mu. Mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (70.76 mg, 151.65. Mu. Mol) and potassium phosphate (201.1 mg, 7.81. Mu. Mol) were added to N-dimethylformamide (3 ℃ C.) and the mixture was stirred under stirring until the mixture was replaced with 3mL of three times of argon. After the completion of the reaction, 20mL of water was added, extracted with ethyl acetate (20 mL. Times.3), and the saturated sodium chloride solution (20 mL) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 55a (110 mg), yield: 47.08%.

MS m/z(ESI):599.0[M-16]

Second step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 55a (110 mg, 178.50. Mu. Mol) and trifluoroacetic acid (1 mL) were added to dichloromethane (2 mL), stirred overnight at room temperature, the reaction was complete, concentrated under reduced pressure, and the resulting residue was added to 7M methanolic amine (2 mL) and reacted at room temperature for 0.5 hours. After completion of the reaction, concentrated under reduced pressure to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 55b (75 mg), yield: 99% of the product was directly subjected to the next reaction without purification.

MS m/z(ESI):468.9[M-16]

Third step

2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile 55B (85 g,174.90 mmol) and 5M sodium hydroxide solution (0.5 mL) were added to methanol (3 mL), 30% hydrogen peroxide (0.5 mL) was slowly added dropwise, the reaction was completed at room temperature, ph=3-4 was adjusted with trifluoroacetic acid, and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil;250×21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% tfa+h2o, mobile phase B: CH3 CN) to give 2- (4-amino-4-phenylpiperidin-1-yl) -5- (4-chloro-1- (methyl-d 3) -1H-indazol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-carboxamide (40 mg), yield: 45.29%.

MS m/z(ESI):504.0[M+1]

¹ H NMR(400MHz,Methanol-d ₄ )δ7.99(d,J＝1.5Hz,1H),7.72(dd,J＝7.6,1.7Hz,2H),7.53-7.60(m,2H),7.40-7.52(m,3H),7.17(d,J＝1.6Hz,1H),4.56(dt,J＝14.3,4.4Hz,2H),3.43(ddd,J＝13.8,10.3,2.7Hz,2H),2.72(d,J＝13.7Hz,2H),2.17(ddd,J＝13.8,9.9,3.7Hz,2H).

Biological evaluation

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

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

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

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

Numbering of compounds	SHP2/IC ₅₀ (nM)
SHP-099	128
Example 1	1.05
Example 2	2.50
Example 3	6.96
Example 4	8.79
Example 5	2.80
Example 6	4.19
Example 7	3.84
Example 8	3.43
Example 9	13.43
Example 10	3.31
Example 11	4.57
Example 12	2.39
Example 13	1.59
Example 14	2.98
Example 15	1.28
Example 16	48.38
Example 17	2.02
Example 18	2.97
Example 19	1.44
Example 20	3.56
Example 21	11.15
Example 22	1.28
Example 23	2.26
Example 24	2.68
Example 25	4.15
Example 26	2.92
Example 28	3.82
Example 29	9.82
Example 30	7.41
Example 31	7.15
Example 32	21.29

Example 33	1.79
Example 34	2.05
Example 35	26.04
Example 36	2.70
Example 37	4.925
Example 38	10.96
Example 39	6.57
Example 40	5.42
Example 41	4.89
Example 42	22.86
Example 43	4.59
Example 44	9.87
Example 45	18.88
Example 46	18.37
Example 48	2.84
Example 49	3.72
Example 50	13.43
Example 51	3.11
Example 52	8.15
Example 53	56.03
Example 54	1.76
Example 55	9.98

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

Remarks: the structure of SHP-099 (prepared according to WO 2015107493) is as follows:

test example 2 measurement of NCI-H23 cell proliferation inhibition by Compounds of the invention

The following method was used to determine the effect of the compounds of the invention on NCI-H23 cell proliferation. NCI-H23 (containing KRAS G12C mutation) was purchased from Shanghai institute of life sciences cell resource center, academy of sciences of China and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100. Mu.g/mL streptomycin and 1mM Sodium Pyruvate. Cell viability through CellTiter-

Luminescent Cell Viability Assay kit (Promega, cat# G7573).

The experimental method is operated according to the steps of the instruction book of the kit, and is briefly described as follows: test compounds were first prepared as 10mM stock solutions in DMSO, then diluted with medium to prepare test samples with final concentrations ranging from 10000nM to 1.52nM. Will be inCells in logarithmic growth phase were seeded at a density of 1000 cells per well in 96-well cell culture plates at 37℃with 5% CO ₂ The culture was continued overnight in the incubator, followed by the addition of the test compound and continued for 120 hours. After the incubation was completed, a volume of 50. Mu.L of CellTiter-Glo assay solution was added to each well, and after shaking for 5 minutes, the mixture was allowed to stand for 10 minutes, followed by reading the Luminescence values of each well of the sample on a microplate reader using the Luminescence mode. The percent inhibition of compounds at each concentration point was calculated by comparison with the values of the control group (0.3% dmso), followed by nonlinear regression analysis of the compound concentration log-inhibition in GraphPad Prism 5 software to obtain IC compounds that inhibited cell proliferation ₅₀ The values are shown in Table 2.

TABLE 2 IC of the compounds of the invention for inhibition of NCI-H23 cell proliferation ₅₀ Data

Examples numbering	IC ₅₀ (nM)/NCI-H23
RMC-4550	240
Example 2	87.83
Example 7	34.85
Example 8	12.67
Example 10	97.01
Example 12	47.85
Example 13	80.95
Example 17	83.52
Example 21	82.93
Example 22	8.591
Example 23	71.53
Example 24	75.41
Example 25	60.75
Example 26	57.15
Example 29	39.71
Example 30	46.05
Example 33	12.88
Example 34	4.41
Example 54	50.98
Example 55	68.79

As can be seen from Table 2, the compounds of the present invention have a good inhibitory effect on NCI-H23.

Remarks: the structure of RMC-4550 (prepared according to WO 2018013597) is as follows:

test example 3 inhibition of NCI-H358 cell proliferation assay by Compounds of the invention

The following method was used to determine the effect of the compounds of the invention on NCI-H358 cell proliferation. NCI-H358 cells (containing KRAS G12C mutation) were purchased from Shanghai institute of life sciences, china academy of sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100. Mu.g/mL streptomycin and 1mM Sodium Pyruvate. Cell viability by

Luminescent Cell Viability Assay kit (Promega, cat# G7573).

The experimental method is operated according to the steps of the instruction book of the kit, and is briefly described as follows: test compounds were first prepared as 10mM stock solutions in DMSO, then diluted with medium to prepare test samples with final concentrations ranging from 10000nM to 1.52nM. Cells in the logarithmic growth phase were seeded at a density of 1000 cells per well in 96-well cell culture plates at 37℃with 5% CO ₂ Culturing overnight in incubator, and then adding test compound for continuous culture 1And 20 hours. After the incubation was completed, a volume of 50. Mu.L of CellTiter-Glo assay solution was added to each well, and after shaking for 5 minutes, the mixture was allowed to stand for 10 minutes, followed by reading the Luminescence values of each well of the sample on a microplate reader using the Luminescence mode. The percent inhibition of compounds at each concentration point was calculated by comparison with the values of the control group (0.3% dmso), followed by nonlinear regression analysis of the compound concentration log-inhibition in GraphPad Prism 5 software to obtain IC compounds that inhibited cell proliferation ₅₀ The values are shown in Table 3.

TABLE 3 IC for inhibition of NCI-H358 cell proliferation by the compounds of the present invention ₅₀ Data

Examples numbering	IC ₅₀ (nM)/NCI-H358
RMC-4550	80
Example 7	20.07
Example 12	5.10
Example 21	42.01
Example 22	1.223
Example 23	17.67
Example 24	54.51
Example 25	13.85
Example 26	19.34
Example 29	27.23
Example 34	11.03
Example 54	21.27

As can be seen from Table 3, the compounds of the present invention have a good inhibitory effect on NCI-H358.

Claims

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

wherein:

when Z is selected from-NH-; v is selected from-N-or-CH-; or alternatively; when Z is selected from-O-; v is selected from-N-;

q and T are each independently selected from N or CH; wherein at least one of Q and T is selected from N;

Ring a is selected from naphthyl, bicyclic heteroaryl;

R ¹ the same or different are each independently selected from hydrogen atom, alkyl, alkenyl, alkynyl, cyano, halogen, nitroCycloalkyl, heterocyclyl, -OR ⁵ 、-C(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl OR heterocyclyl is optionally further substituted with one OR more groups selected from deuterium, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Is substituted by a substituent of (2);

R ² selected from cyano, tetrazolyl, -C (O) R ⁵ 、-C(O)OR ⁵ or-C (O) NR ⁶ R ⁷ ；

R ³ And R is ⁴ Together with the N atom to which it is attached form a 4-11 membered heterocyclic group, preferably a 5-11 membered heterocyclic group, wherein said heterocyclic group contains one or more N, O, S or SO ₂ An atom, and optionally further substituted on the heterocyclyl with one or more groups selected from halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CH ₂ R ⁵ 、-CH(OH)R ⁵ 、-CH ₂ OR ⁵ 、＝O、-OR ⁵ 、-SR ⁵ 、-SOR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, amino, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-SO ₂ R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

alternatively, R ³ And R is ⁴ Together with the N atom to which it is attached, form a group:

is a single bond or a double bond;

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

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

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

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

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

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

j is selected from CR ^p R ^q ；

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

r is 0 or 1;

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

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

R ^c And R is ^d Identical OR different, each independently selected from hydrogen, halogen, alkyl OR-OR ⁵ Wherein said alkyl is optionally further substituted with hydroxy, halogen, alkoxy, cycloalkyl or-NR ⁶ R ⁷ Is substituted by a substituent of (2);

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

R ^g The same OR different are each independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR ⁶ R ⁷ Is substituted by a substituent of (2);

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

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

R ^A the same OR different are each independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with hydroxy, halogen, alkyl, alkoxy, cycloalkyl or-NR ⁶ R ⁷ Is substituted by a substituent of (2);

R ^B identical OR different, each independently selected from 3-to 10-membered cycloalkyl OR 3-to 10-membered heterocyclyl, wherein said cycloalkyl OR heterocyclyl is optionally further substituted with one OR more substituents selected from halogen, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-SO ₂ R ⁵ 、-NR ⁶ R ⁷ 、-SO ₂ NR ⁶ R ⁷ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ R ⁵ or-C (O) NR ⁶ R ⁷ Is substituted by a substituent of (2);

R ⁵ 、R ⁶ and R is ⁷ Each independently selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-SO ₂ R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

alternatively, R ⁶ And R is ⁷ Together with the N atom to which it is attached form a 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic ring contains one or more N, O, S or SO ₂ An atom, and optionally further substituted on the 3-to 8-membered heterocyclic ring with one or more substituents selected from hydroxy, halogen, amino, alkyl or alkoxy;

R ⁸ 、R ⁹ and R is ¹⁰ Each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, and carboxylate;

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

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

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

wherein: ring A, m, V, R ¹ ～R ⁴ Is defined as in claim 1.
The compound of claim 2, which is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,

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

R ³ and R is ⁴ Together with the N atom to which it is attached, form a 4-8 membered monocyclic heterocyclic group, preferably a 5-6 membered monocyclic heterocyclic group, more preferably a piperidinyl group, wherein said monocyclic heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, cycloalkyl, phenyl, halophenyl, heteroaryl, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁵ Is substituted by a substituent of (2); wherein said methyl group,Cycloalkyl, phenyl or heteroaryl is optionally further substituted with one or more substituents selected from methanesulfonyl, hydroxy, amino, halogen, haloalkyl, alkoxy, haloalkoxy, pyridinyl or pyrimidinyl; wherein the heteroaryl is preferably pyridyl, pyrimidylmethylpyrazolyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, benzimidazolyl, benzofuryl or benzoxazolyl;

R ⁵ is defined as in claim 1.
A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

R ³ And R is ⁴ Together with the N atom to which it is attached, form a 7-to 11-membered spiroheterocyclyl, wherein said spiroheterocyclyl is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁵ Is substituted by a substituent of (2);

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

R ^a identical or different, each independently selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ OR-OR ⁵ ；

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

t is 1, 2 or 3;

R ⁵ is defined as in claim 1.
A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

R ³ and R is ⁴ Together with the N atom to which it is attached, form a 7-to 11-membered bridged heterocyclic group, wherein said bridged heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁵ Is substituted by a substituent of (2);

R ⁵ is defined as in claim 1.
A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

R ³ And R is ⁴ Together with the N atom to which it is attached, form a 7-to 11-membered fused heterocyclic group, wherein said fused heterocyclic group is optionally further substituted with one or more groups selected from methyl, amino, -CH ₂ NH ₂ 、-CH ₂ OH、-NHC(＝NH)NH ₂ (O) OR-OR ⁵ Is substituted by a substituent of (2);

R ⁵ is defined as in claim 1.
A compound according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (II):

wherein:

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

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

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

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

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

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

R ^p And R is ^q Each independently selected from hydrogen atom, halogen, amino group, C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ Alkyl, amino C ₁ -C ₄ Alkyl OR-OR ⁵ ；

Ring A, V, G, M, m, n, R ¹ ～R ² 、R ⁵ 、R ^k And R is ^g Is defined as in claim 2.
A compound according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (III):

Wherein:

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

j is selected from CR ^p R ^q ；

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

r is 0 or 1;

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

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

R ^p And R is ^q Each independently selected from hydrogen atom, halogen, amino group, C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ Alkyl, amino C ₁ -C ₄ Alkyl OR-OR ⁵ ；

Ring A, V, G, M, m, n, R ¹ ～R ² 、R ⁵ 、R ^k And R is ^g Is defined as in claim 2.
The compound of claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (IV):

wherein:

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

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

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

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

Ring A, V, G, M, m, n, R ¹ ～R ² And R is ^g Is defined as in claim 2.
A compound according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (V):

Wherein:

L ₁ selected from the group consisting of absence, - (c=o) -, - (CR ^w R ^v ) _u -, any one of which- (CR) ^w R ^v ) -optionally further by-N (R ^z )-、-O-、-S-、-SO-、-SO ₂ -replaced;

each R ^w And R is ^v The same or different, each independently selected from hydrogen atom, halogen, hydroxy, alkyl or alkoxy;

each R ^z The same or different are each independently selected from a hydrogen atom or an alkyl group;

ring E is selected from 4-11 membered N-containing monocyclic heterocyclyl, 4-11 membered N-containing fused heterocyclyl OR 4-11 membered N-containing bridged heterocyclyl, wherein said monocyclic heterocyclyl, fused heterocyclyl, bridged heterocyclyl is optionally further substituted with one OR more substituents selected from halogen, alkyl, -OR ⁵ Or = O;

ring K is selected from the group consisting of absent, cycloalkyl, aryl, or heteroaryl, wherein said cycloalkyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-SO ₂ R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

wherein-L ₁ -ring K and- (CH) ₂ ) _W -NH ₂ Attached to the same carbon atom of ring E;

w is 0,1 or 2;

u is 0,1,2 or 3;

ring A, V, m, R ¹ ～R ² 、R ⁵ 、R ⁸ ～R ¹⁰ Is defined as in claim 2.
A compound according to any one of claims 1 to 3, 9 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ¹ Selected from the group consisting of hydrogen atom, F, cl, br, amino, hydroxy, cyano, nitro, methoxy, ethoxy, methyl, ethyl, difluoromethyl, cyclopropyl, d ₃ Methyl, ethynyl, ethyleneRadical, -NHCH ₃ or-N (CH) ₃ ) ₂ 。
A compound according to any one of claims 9 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ² Selected from-C (O) NH ₂ Or cyano.
A compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ⁵ Selected from hydrogen atoms or alkyl groups.
A compound according to any one of claims 1 to 3, 9 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring a is selected from naphthyl, benzopyrazolyl, or benzothiazolyl.
A compound according to any one of claims 9 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring B is selected from:
a compound according to any one of claims 9 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ^g The same or different are each independently selected from hydrogen atom, F, cl, br, amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH ₃ or-N (CH) ₃ ) ₂ ；

Alternatively, two R ^g The same carbon atom as attached may together form c=o.
A compound according to claim 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring E is selected from
A compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
a process for preparing a compound of formula (AII) according to claim 2 or a stereoisomer, tautomer thereof, which process comprises:

compounds of formula (AIIa) and NHR ³ R ⁴ In alkaline conditionsNucleophilic substitution reaction is carried out under the condition to obtain the compound of the formula (AIIb); carrying out Suzuki reaction on a compound shown in a formula (AIIb) and a compound shown in a formula (AIic) under a palladium catalyst and alkaline conditions, and optionally further removing a protecting group from the obtained compound to obtain a compound shown in a formula (AII);

wherein:

M ₁ selected from-B (OH) ₂ Or (b)

X ₁ Selected from leaving groups selected from halogen or-SO ₂ R ^t ；

X ₂ Selected from halogen;

R ^t selected from alkyl groups;

rings A, V, m and R ¹ ～R ⁴ Is defined as in claim 2.
A process for preparing a compound of formula (AII) according to claim 2 or a stereoisomer, tautomer thereof, which process comprises:

Carrying out Suzuki reaction on the compound shown in the formula (AIIa) and the compound shown in the formula (AIic) under palladium catalyst and alkaline condition to obtain the compound shown in the formula (AIId); compounds of formula (AIId) and NHR ³ R ⁴ Carrying out nucleophilic substitution reaction under alkaline condition, and optionally removing protecting group to obtain compound of formula (AII);

wherein:

M ₁ selected from-B (OH) ₂ Or (b)

X ₁ Selected from leaving groups selected from halogen or-SO ₂ R ^t ；

X ₂ Selected from halogen;

R ^t selected from alkyl groups;

rings A, V, m and R ¹ ～R ⁴ Is defined as in claim 2.
A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 20, 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 20, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for the preparation of an inhibitor of SHP2 allosteric.
Use of a compound according to any one of claims 1 to 20, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for the manufacture of a medicament for the treatment of a SHP2 mediated disease, preferably cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or vision disorder.
The use of claim 25, wherein the SHP2 mediated disease is selected from noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.