WO2022237178A1 - Bicyclic heteroaryl derivative and preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a bicyclic heteroaryl derivative and a preparation method therefor and a use thereof in medicine. Specifically, the present invention relates to a bicyclic heteroaryl derivative represented by formula (AI) and a preparation method therefor and a pharmaceutically acceptable salt thereof, and a use thereof as therapeutic agents, especially SHP2 allosteric inhibitors, wherein substituents in formula (AI) have the same definitions as those in the description.

Description

Bicyclic heteroaryl derivatives and their preparation methods and uses technical field

The present invention relates to a novel bicyclic heteroaryl derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a SHP2 allosteric inhibitor.

Background technique

Src homology domain-2 phosphatase (SHP2) is one of the important members of the protein tyrosine phosphatase (PTP) family, encoded by the protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene, and catalyzes tyrosine in proteins. Amino acid dephosphorylation reaction. The N-terminal of SHP2 contains two SH2 domains, which control the subcellular localization and functional regulation of SHP2, and the C-terminal contains a catalytically active PTP domain and two tyrosine domains related to its activity acid residues. Under normal circumstances, SHP2 is in a state of self-inhibition. When stimulated by growth factors, cytokines or inflammatory factors, such as platelet-derived growth factors PDGF and FGF, the catalytic site is exposed, resulting in the activation of SHP2 enzymes. activation.

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

According to different mechanisms of action, SHP2 inhibitors can be divided into competitive inhibitors (including mutamycin, phenylpyrazole hydrazine sulfonate and NSC-87877), non-competitive inhibitors (including indole salicylic acid and furomosutone) and irreversible inhibitors (including sodium stibogluconate and cryptotanshinone), which have been reported as irreversible inhibitors of SHP2 to inhibit the proliferation of rhabdomyosarcoma, melanoma, colon cancer, and breast cancer in vitro , and in vivo studies have shown that it can inhibit the proliferation of prostate cancer in mice, whether it can further become a clinically effective drug still needs to be verified by many experiments.

At present, the compound RMC-4630 developed by REVOLUTION Medicines Inc has entered the clinical phase II for the treatment of solid tumors. It also includes the preclinical RMC-4550, and there are also three clinical phase I compounds JAB-3068, JAB -3312 and TNO-155, developed by Jacobio Pharmaceuticals Co Ltd and Novartis AG respectively, also including Novartis preclinical drug SHP-099; REVOLUTION Medicines Inc and Novartis AG have disclosed a series of SHP2 inhibition Drug patents, including WO-2019075265, WO-2018136265, WO-2018136264, WO-2017216706 and WO-2018013597, etc. Although the research on SHP2 has made some progress, there is still no effective drug on the market, so it is still There is a need for continued research and development of new SHP2 inhibitors.

Contents of the invention

In view of the above-mentioned technical problems, the present invention provides a new class of bicyclic heteroaryl compounds represented by formula (AI) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

in:

When Z is selected from -NH-; V is selected from -N- or -CH-; or; 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 are the same or different, each independently selected from hydrogen atom, 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 , wherein the alkyl, alkenyl, alkynyl, Cycloalkyl or heterocyclyl is optionally further replaced by one or more 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 - Substituents of C(O)NR ⁶ R ⁷ ;

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

R ³ and R ⁴ form a 4-11-membered heterocyclic group together with the N atom they are connected to, preferably a 5-11-membered heterocyclic group, wherein the heterocyclic group contains one or more N, O, S or SO ₂ atom, and the heterocyclic group is optionally further replaced by one or more selected from halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, 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 is substituted by a substituent, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more groups selected from hydroxyl, amino , halogen, 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 Substituents of ¹⁰ are substituted;

Alternatively, ^R3 and R4 ^together with the N atom to which they are attached form a group:

为单键或双键；

is a single or double bond;

表示单键时，G和M各自独立地选自N或CR ^j； when

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

表示双键时，G和M各自独立地选自C； 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 , p is 1 and q is 1; alternatively, p is 2 and q is 0; when E is selected from NR ^k , O or S, q is 1;

J is selected from CR ^p R ^q ;

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

r is 0 or 1;

R ^m , R ⁿ , R ^p and R ^q are the same or different, each independently selected from ^RA ;

Alternatively, R ^p and R ^q together with the carbon atoms to which they are attached form ^RB ;

R ^c and R ^d are the same or different, each independently selected from hydrogen atom, halogen, alkyl or -OR ⁵ , wherein said alkyl is optionally further replaced by hydroxyl, halogen, alkoxy, cycloalkyl or -NR ⁶ R ⁷ is replaced by a substituent;

Alternatively, ^Rc and ^Rd together with the carbon atoms to which they are attached form ^RB ;

R ^g is the same or different, each independently selected from hydrogen atom, 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further Substituents of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR ⁶ R ⁷ ;

Alternatively, two R ^gs and the same carbon atom to which they are attached may together form C=O;

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

R ^A is the same or different, each independently selected from hydrogen atom, 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further Substituents of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR ⁶ R ⁷ ;

R ^B are the same or different, each independently selected from 3-10 membered cycloalkyl or 3-10 membered heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally further selected from one or more 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 Substituents are substituted;

R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl Or heteroaryl is optionally further replaced by one or more selected from hydroxyl, 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 substituents are substituted;

Alternatively, R ⁶ and R ⁷ form a 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the 3-8 membered heterocyclic ring contains one or more N, O, S or SO ₂ atoms, and The 3- to 8-membered heterocycle is optionally further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy;

R ⁸ , R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group radical or heteroaryl is optionally further replaced by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxyl Substituents of ester groups are substituted;

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 described in formula (AI) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound described in formula (AII) or its stereoisomer isomers, tautomers or pharmaceutically acceptable salts thereof,

Wherein: rings A, m, V, R ¹ -R ⁴ are defined as described in formula (AI).

In a preferred embodiment of the present invention, the compound described in formula (AII) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound described in formula (I) or its stereoisomer isomers, tautomers or pharmaceutically acceptable salts thereof,

Wherein: rings A, V, m, R ¹ , R ³ and R ⁴ are defined as described in formula (AII).

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

R ³ and R ⁴ together form a 4-8 membered monocyclic heterocyclic group, preferably a 5-6 membered monocyclic heterocyclic group, more preferably a piperidinyl group, wherein the monocyclic heterocyclic group The group is optionally further replaced by one or more selected from the group consisting of methyl, amino, cycloalkyl, phenyl, halophenyl, heteroaryl, -CH ₂ NH ₂ , -CH ₂ OH, -NHC(=NH)NH _2. Substituents of =O or -OR ⁵ ; wherein the methyl, cycloalkyl, phenyl or heteroaryl are optionally further selected from one or more methylsulfonyl, hydroxyl, amino, halogen , haloalkyl, alkoxy, haloalkoxy, pyridyl or pyrimidyl substituents; wherein the heteroaryl is preferably pyridyl, pyrimidinylbenzopyrazolyl, pyrrolyl, furyl, Thienyl, pyrazolyl, imidazolyl, thiazolyl, benzimidazolyl, benzofuryl or benzoxazolyl;

R ⁵ is defined as described in formula (AI).

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

R ³ and R ⁴ form a 7- to 11-membered spiroheterocyclyl together with the N atom they are connected to, wherein the spiroheterocyclyl is optionally further replaced by one or more members selected from the group consisting of methyl, amino, -CH ₂ NH ₂ , -CH ₂ OH, -NHC(=NH)NH ₂ , =O or -OR ⁵ are substituted by substituents; the definition of R ⁵ is as described in formula (AI); preferably, the spiroheterocycle described therein Base selected from:

R ^a is the same or different, each independently selected from methyl, amino, -CH ₂ NH ₂ , -CH ₂ OH, -NHC(=NH)NH ₂ or -OR ⁵ ; or, two R ^a are connected with Together with a carbon atom form C=O; t is 1, 2 or 3; R ⁵ is as defined in formula (AI).

In a preferred embodiment of the present invention, the compound described in formula (AI), (AII) or (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ Together with the N atom connected to it, a 7- to 11-member bridged heterocyclic group is formed, wherein the bridged heterocyclic group is optionally further replaced by one or more selected from methyl, amino, -CH ₂ NH ₂ , -CH ₂ OH , -NHC(=NH)NH ₂ , =O or -OR ⁵ substituents; the definition of R ⁵ is as described in formula (AI).

In a preferred embodiment of the present invention, the compound of ^formula (AI), (AII) or (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ^R3 and R4 are connected to it N atoms together form a 7- to 11-membered condensed heterocyclic group, wherein the fused heterocyclic group is optionally further replaced by one or more selected from methyl, amino, -CH ₂ NH ₂ , -CH ₂ OH, -NHC (=NH) Substituted by a substituent of NH ₂ , =O or —OR ⁵ ; R ⁵ is as defined in formula (AI).

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

in:

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

E is selected from NR ^k , (CR ^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 , p is 1 and q is 1; alternatively, p is 2 and q is 0; when E is selected from NR ^k , O or S, q is 1;

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

R ^{n is} selected from a hydrogen atom, methyl or -CH ₂ OH;

R ^p and R ^q are each independently selected from a hydrogen atom, halogen, amino, C ₁ -C ₄ alkyl, hydroxyl C ₁ -C ₄ alkyl, amino C ₁ -C ₄ alkyl or -OR ⁵ ;

环A、V、G、M、m、n、R ¹～R ²、R ⁵、R ^k和R ^g的定义如式(AII)中所述。

Rings A, V, G, M, m, n, R ¹ to R ² , R ⁵ , R ^k and R ^g are as defined in formula (AII).

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

in:

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

J is selected from CR ^p R ^q ;

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

r is 0 or 1;

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

R ^{n is} selected from a hydrogen atom, methyl or -CH ₂ OH;

R ^p and R ^q are each independently selected from a hydrogen atom, halogen, amino, C ₁ -C ₄ alkyl, hydroxyl C ₁ -C ₄ alkyl, amino C ₁ -C ₄ alkyl or -OR ⁵ ;

环A、V、G、M、m、n、R ¹～R ²、R ⁵、R ^k和R ^g的定义如式(AII)中所述。

Rings A, V, G, M, m, n, R ¹ to R ² , R ⁵ , R ^k and R ^g are as defined in formula (AII).

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

in:

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

R ^c and R ^d form a 3-8 membered cycloalkyl group together with the connected atoms;

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

R ^{n is} selected from a hydrogen atom, methyl or -CH ₂ OH;

环A、V、G、M、m、n、R ¹～R ²和R ^g的定义如式(AII)中所述。

Rings A, V, G, M, m, n, R ¹ to R ² and R ^g are defined as described in formula (AII).

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

in:

L ₁ is selected from nonexistent, -(C=O)-, -(CR ^w R ^v ) _u -, wherein any one of -(CR ^w R ^v )- is optionally further replaced by -N(R ^z )-, - O-, -S-, -SO-, -SO ₂ -replaced;

Each ^Rw and ^Rv are the same or different, each independently selected from a hydrogen atom, halogen, hydroxyl, alkyl or alkoxy;

Each ^Rz is the same or different, each independently selected from a hydrogen atom or an alkyl group;

Ring E is selected from 4 to 11 membered N-containing monocyclic heterocyclic groups, 4 to 11 membered N-containing condensed heterocyclic groups, or 4 to 11 membered N-containing bridged heterocyclic groups, wherein the monocyclic heterocyclic group , fused heterocyclic group, and bridged heterocyclic group are optionally further substituted by one or more substituents selected from halogen, alkyl, -OR ⁵ or =O;

Ring K is selected from nonexistent, cycloalkyl, aryl or heteroaryl, wherein said cycloalkyl, aryl or heteroaryl is optionally further replaced by one or more selected from hydroxyl, amino, halogen, nitro , cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O) Substituents of 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 ;

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

w is 0, 1 or 2;

u is 0, 1, 2 or 3;

Rings A, V, Q, T, m, R ¹ to R ² , R ⁵ , R ⁸ to R ¹⁰ are as defined in formula (AII).

In a preferred embodiment of the present invention, the compound described in formula (AI), (AII), (I), (II), (III), (IV) or (V) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R is selected from ^a hydrogen atom, F, Cl, Br, amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, difluoro methyl, cyclopropyl, d ₃ -methyl, ethynyl, vinyl, -NHCH ₃ or -N(CH ₃ ) ₂ .

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

In a preferred embodiment of the present invention, the compound described in formula (AI), (AII), (I), (II), (III), (IV) or (V) or its stereoisomer, tautomer Construct or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from a hydrogen atom or an alkyl group.

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

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

In a preferred embodiment of the present invention, the compound described in formula (II), (III) or (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^g is the same or different , each independently selected from a hydrogen atom, F, Cl, Br, amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH or _- N( _CH3 ) ₂ ;

Alternatively, two ^Rg 's can be taken together to form C=O with the same carbon atom to which they are attached.

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

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

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

Further, the present invention provides a method for preparing the compound of formula (AII) or its stereoisomers and tautomers, the method comprising:

Formula (AIIa) compound and NHR ³ R ⁴ carry out nucleophilic substitution reaction under basic conditions, obtain formula (Ib) compound; Formula (AIIb) compound and formula (AIIc) compound, carry out Suzuki under palladium catalyst and basic condition Reaction, the compound that obtains optionally further removes protecting group, obtains formula (AII) compound;

in:

M ₁ is selected from -B(OH) ₂ or

X ₁ is selected from a leaving group, and the leaving group is selected from halogen or -SO ₂ R ^t ;

X2 is selected from halogen _;

R ^{t is} selected from alkyl;

The definitions of rings A, V, m and R ¹ to R ⁴ are as described in formula (AII).

Further, the present invention provides a method for preparing the compound of formula (AII) or its stereoisomers and tautomers, the method comprising:

Formula (AIIa) compound and formula (AIIc) compound, carry out Suzuki reaction under palladium catalyst and basic condition, obtain formula (AIId) compound; Formula (AIId) compound and NHR ³ R ⁴ carry out nucleophilic substitution under basic condition Reaction, the compound that obtains optionally further removes protecting group, obtains formula (AII) compound;

in:

M ₁ is selected from -B(OH) ₂ or

X ₁ is selected from a leaving group, and the leaving group is selected from halogen or -SO ₂ R ^t ;

X2 is selected from halogen _;

R ^{t is} selected from alkyl;

The definitions of rings A, V, m and R ¹ to R ⁴ are as described in formula (AII).

Furthermore, the present invention provides a pharmaceutical composition containing an effective dose of the formula (AI), (AII), (I), (II), (III), (IV) or (V) The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier, excipient or their combination.

The present invention provides a compound described in formula (AI), (AII), (I), (II), (III), (IV) or (V) or its stereoisomer, tautomer or Use of its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of SHP2 allosteric inhibitors.

The present invention also provides a compound described in formula (AI), (AII), (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicines for the treatment of diseases mediated by SHP2, wherein said diseases mediated by SHP2 are preferably cancer, cancer metastasis, cardiovascular disease, immune Disorder, fibrosis or visual disorder; wherein said disease mediated by SHP2 is preferably selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia , breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.

The present invention further provides a compound described in formula (AI), (AII), (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers Use of the pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for treating cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder.

The present invention provides a compound described in formula (AI), (AII), (I), (II), (III), (IV) or (V) or its stereoisomer, tautomer or Its pharmaceutically acceptable salt, or its pharmaceutical composition is used in the preparation of Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer , lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma and glioblastoma.

The present invention provides a method for inhibiting SHP2 receptors in vitro, comprising combining said SHP2 receptors with formula (AI), (AII), (I), (II), (III), (IV) or (V ) said compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition.

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

Detailed Description of the Invention

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

"Alkyl" when used as a group or a part of a group refers to a C ₁ -C ₂₀ straight chain or branched aliphatic hydrocarbon group. It is preferably C ₁ -C ₁₀ alkyl, more preferably C ₁ -C ₆ alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.

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

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

"Cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged and spiro carbocyclic rings. It is preferably a C ₃ -C ₁₂ cycloalkyl group, more preferably a C ₃ -C ₈ cycloalkyl group, and most preferably a C ₃ -C ₆ cycloalkyl group. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl, cyclohexenyl. Cycloalkyl groups can be optionally substituted or unsubstituted.

"Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one carbon atom (called a spiro atom) shared between the single rings. The ring contains one or more Aromatic systems with double bonds, but none of the rings have fully conjugated π electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the ring and the ring, the spiro cycloalkyl group is divided into single spiro, double spiro or polyspiro cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

"Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more ring structures sharing a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, Aromatic systems where none of the rings have fully conjugated pi-electrons, preferably 6 to 12, more preferably 7 to 10 membered. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthrenyl.

"Bridged cycloalkyl" refers to a 5- to 18-membered, full-carbon polycyclic group that contains two or more ring structures and shares two carbon atoms that are not directly connected to each other. One or more rings may contain one or more Aromatic systems with multiple double bonds but none of the rings having fully conjugated pi electrons are preferably 6 to 12 membered, more preferably 7 to 10 membered. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bis Cycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.

杂环基可以是取代或未取代的。 "Heterocyclyl", "heterocyclic" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclic groups in which one or more atoms forming the ring are heteroatoms, such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, condensed, bridged and spiro rings. Preference is given to 4-11 membered heterocyclic rings which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine Base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl,

A heterocyclyl group can be substituted or unsubstituted.

"Spiroheterocyclic group" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the single rings. The ring contains one or more double bonds, but no Aromatic systems with a ring having fully conjugated π-electrons, in which one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) _n (wherein n is selected from 0, 1 or 2), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is 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[4.4]nonyl, Spiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures that share a pair of atoms with each other. One or more rings may contain one or more double bonds, but none of the rings has a complete Conjugated π-electron aromatic systems in which one or more ring atoms are selected from nitrogen, oxygen or heteroatoms of S(O) _n (where n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably it is 7-11 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. 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]dioxine and

"Bridged heterocyclic group" refers to a polycyclic group with 5 to 14 members, 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, and one or more rings can be Aromatic systems containing one or more double bonds, but none of the rings have fully conjugated π-electrons, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) _n (where n is selected from 0, 1 or 2), the remaining ring atoms are carbon. Preferably it is 7-11 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, cyclo[3.3.2]decyl,

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

杂芳基可以是取代或未取代的。 "Heteroaryl" refers to an aromatic 5 to 6 membered monocyclic ring 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, benzo Dioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzo Isothiazolyl, benzoxazolyl, benzisoxazolyl,

Heteroaryl groups can be substituted or unsubstituted.

"Fused ring" refers to a polycyclic group in which two or more ring structures share 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 complete conjugation At the same time, at least one ring has an aromatic system with fully conjugated π electrons, wherein the ring atoms are selected from 0, one or more ring atoms selected from nitrogen, oxygen or S(O) _n ( wherein n is selected from heteroatoms of 0, 1 or 2), and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:

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

"Hydroxy" means an -OH group.

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

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Benzyl" and "Bn" refer to _-CH2 -phenyl.

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

"Carboxylate group" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein the definitions of alkyl and cycloalkyl are as above.

"DMSO" means dimethylsulfoxide.

"BOC" means t-butoxycarbonyl.

"TFA" means trifluoroacetic acid.

"Hydroxy C ₁ -C ₄ alkyl" refers to hydroxy substituted C ₁ -C ₄ alkyl.

"Amino C ₁ -C ₄ alkyl" refers to amino substituted C ₁ -C ₄ alkyl.

"SEM" means (trimethylsilyl)ethoxymethyl.

"THP" refers to tetrahydropyranyl.

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

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

The "substituted" or "substituted" mentioned in this specification, unless otherwise specified, means that the group can be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, 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 replaced by substituents;

R ⁵ , R ⁶ and R ⁷ are 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 selected from one or more Hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ⁸ , -C(O)OR ⁸ , Substituents of -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 replaced by

Alternatively, R ⁶ and R ⁷ form a 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the 3-8 membered heterocyclic ring contains one or more N, O, S or SO ₂ atoms, and The 3-8 membered heterocycle is further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy;

R ⁸ , R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group radical or heteroaryl is optionally further replaced by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxyl The substituent of the ester group is substituted.

"Pharmaceutically acceptable salt" refers to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use. The pharmaceutically acceptable salt of the compound represented by formula (I) may be a metal salt or an amine salt with a suitable acid.

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

The synthetic method of compound of the present invention

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

The present invention provides a preparation method of a compound of formula (AII) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

Formula (AIIa) compound and NHR ³ R ⁴ carry out nucleophilic substitution reaction under basic conditions, obtain formula (Ib) compound; Formula (AIIb) compound and formula (AIIc) compound, carry out Suzuki under palladium catalyst and basic condition Reaction, the compound that obtains optionally further removes protecting group, obtains formula (AII) compound;

in:

M ₁ is selected from -B(OH) ₂ or

X ₁ is selected from a leaving group, and the leaving group is selected from halogen or -SO ₂ R ^t ;

X2 is selected from halogen _;

R ^{t is} selected from alkyl;

The definitions of rings A, V, m and R ¹ to R ⁴ are as described in formula (AII).

Further, the present invention provides a method for preparing the compound of formula (AII) or its stereoisomers and tautomers, the method comprising:

Formula (AIIa) compound and formula (AIIc) compound, carry out Suzuki reaction under palladium catalyst and basic condition, obtain formula (AIId) compound; Formula (AIId) compound and NHR ³ R ⁴ carry out nucleophilic substitution under basic condition Reaction, the compound that obtains optionally further removes protecting group, obtains formula (AII) compound;

in:

M ₁ is selected from -B(OH) ₂ or

X ₁ is selected from a leaving group, and the leaving group is selected from halogen or -SO ₂ R ^t ;

X2 is selected from halogen _;

R ^{t is} selected from alkyl;

The definitions of rings A, V, m and R ¹ to R ⁴ are as described in formula (AII).

The present invention provides a preparation method of a compound of formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, said method comprising:

Formula (Ia) compound and NHR3R4 carry out nucleophilic substitution reaction under basic conditions, obtain formula (Ib) compound; Formula (Ib) compound and formula (AIIc) compound, carry out Suzuki reaction under palladium catalyst and basic condition, obtain The compound optionally further removes the protecting group to obtain a compound of formula (Ic); the compound of formula (Ic) is hydrolyzed to obtain a compound of formula (I);

in:

M ₁ is selected from -B(OH) ₂ or

X ₁ is selected from a leaving group, and the leaving group is selected from halogen or -SO ₂ R ^t ;

X2 is selected from halogen _;

R ^{t is} selected from alkyl;

Rings A, V, m, R ¹ , R ³ and R ⁴ are as defined in formula (I).

The present invention provides a preparation method of a compound of formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, said method comprising:

Formula (Ia) compound and formula (AIIc) compound, carry out Suzuki reaction under palladium catalyst and basic condition, obtain formula (Id) compound; Formula (Id) compound and NHR ³ R ⁴ carry out nucleophilic substitution under basic condition Reaction, obtain formula (Ic) compound; Formula (Ic) compound hydrolysis, obtain formula (I) compound;

in:

M ₁ is selected from -B(OH) ₂ or

X ₁ is selected from a leaving group, and the leaving group is selected from halogen or -SO ₂ R ^t ;

X2 is selected from halogen _;

R ^{t is} selected from alkyl;

Rings A, V, m, R ¹ , R ³ and R ⁴ are as defined in formula (I).

Detailed ways

The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

Example

The examples give the preparation of representative compounds represented by formula (I) and relevant structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than limit the present invention. The ¹ H NMR spectrum was measured with a Bruker instrument (400 MHz), and the chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. Notation in ¹ H NMR: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, its unit is Hz.

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

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

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

In the following examples, unless otherwise specified, all temperatures are in degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods, and commercially available materials and reagents are not further prepared. Purified and used directly, unless otherwise specified, commercially available manufacturers include but not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd., etc.

Methanol-d ₄ : deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethylsulfoxide.

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

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

The compound was purified by silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: two Chloromethane: ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and can also be adjusted by adding a small amount of acidic or alkaline reagents, 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 (2.81g, 10.48mmol), 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine 1b (1.8g, 9.52mmol) and triethylenediamine ( 213.65mg, 1.90mmol) were successively added into dichloromethane (30mL), and stirring was continued for 2 hours at room temperature. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: B system), and a small amount of triethylamine was added to the system to obtain 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 (200mg, 1.11mmol), N-bromosuccinimide (218.06mg, 1.23mmol) were added to acetonitrile ( 4 mL), heated to 90°C and reacted for 4 hours. After the reaction, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: B system) to obtain 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)carbamate tert-butyl ester

3-Bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (150mg, 580.35μmol), (4-methylpiperidin-4-yl)carbamate tert-butyl Ester 1e (186.56 mg, 870.53 μmol) and diisopropylethylamine (375.03 mg, 2.90 mmol, 506.79 μL) were added to N,N-dimethylacetamide (5 mL), heated to 80° C., and reacted for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (1-(3-bromo-4-cyano-1H-pyrazolo[3 ,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 1f (200 mg), yield: 78.99%.

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

the fourth step

(1-(3-(3,4-Dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidine-6- Base) -4-methylpiperidin-4-yl) tert-butyl carbamate

(1-(3-Bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 1f (200mg, 458.39μmol), (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (336.74mg, 1.38mmol, self-produced according to patent WO2019167000), methanesulfonic acid ( 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (76.77mg , 91.68μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (85.56mg, 183.36μmol) and potassium phosphate (292.05mg, 1.38mmol) were added to In a mixed solution of 1,4-dioxane (2.5mL) and water (0.5mL). Argon was replaced three times, heated to 110°C, and reacted for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (1-(3-(3,4-dichloro-2-methyl-2H -Indazol-5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)tert-butyl carbamate 1h (58 mg), yield: 22.74%.

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

the 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 (1-(3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-1H-pyrazolo[ 3,4-d] pyrimidin-6-yl)-4-methylpiperidin-4-yl) tert-butyl carbamate 1h (58mg, 104.23μmol) in dichloromethane (2.5mL) solution, continue reaction 1 Hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 6-(4-amino-4-methylpiperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazole-5- yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1i (47.56 mg), yield: 100%, without further purification, the next reaction was carried out directly.

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

step six

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

Add 5M sodium hydroxide solution (0.25 mL) to 6-(4-amino-4-methylpiperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazole -5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1i (47.56mg, 104.22μmol) in methanol solution (2mL), followed by adding 30% hydrogen peroxide (0.5mL), Stir at room temperature for 0.5 hours. After the reaction, add trifluoroacetic acid to adjust the pH to acidity, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain 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 (4g, 21.28mmol), tetrakistriphenylphosphine palladium (2.46g, 2.13mmol) and zinc cyanide (5.00g, 42.55 mmol) was added into N,N-dimethylformamide (40 mL), replaced with argon, heated at 110° C., and stirred for 4 hours. After the reaction, add 30mL of water, extract with ethyl acetate (30mL×3), wash with saturated sodium chloride solution (20mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purified by chromatography (eluent: system A) to obtain 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 2b (3.79g), 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 (30mL), heated to 95°C, and reacted for 2 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 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]The third step

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

(4-Methylpiperidin-4-yl) tert-butyl carbamate 1e (262.18mg, 1.22mmol), diisopropylethylamine (451.76mg, 3.50mmol) and 5-bromo-2-chloro-7H -Pyrrolo[2,3-d]pyrimidine-4-carbonitrile 2c (300mg, 1.17mmol) was added to N,N-dimethylacetamide (3mL), heated to 80°C and stirred for 1 hour. After the reaction was completed, ethyl acetate (30 mL) was added, washed successively with saturated sodium chloride solution (30 mL×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 obtain (1-(5-bromo-4-cyano-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-methylpiperidine-4- base) tert-butyl carbamate 2d (120 mg), yield: 23.66%.

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

the 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) tert-butyl carbamate

(1-(5-Bromo-4-cyano-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 2d( 120mg, 275.66μmol), (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (202.50mg, 826.98μmol), methanesulfonic acid (2-dicyclohexylphosphino- 2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (46.17mg, 55.13μmol), 2-bis Cyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (51.45 mg, 110.26 μmol) and potassium phosphate (175.63 mg, 826.98 μmol) were added to 1,4-dioxane (2.5mL) and water (0.5mL) mixed solution. Argon was replaced three times, heated to 110°C, and reacted for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (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)tert-butyl carbamate 2e( 23 mg), yield: 15.02%.

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

the 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 (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) tert-butyl carbamate 2e (23mg, 41.41μmol) in dichloromethane solution (2.5mL), continue to react for 1 hour . After the reaction was completed, it was concentrated under reduced pressure to obtain 2-(4-amino-4-methylpiperidin-1-yl)-5-(3,4-dichloro-2-methyl-2H-indazole-5- Base)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 2f (18 mg), yield: 95.47%, the reaction was not purified, and the next reaction was carried out directly.

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

step six

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

Add 5M sodium hydroxide solution (0.25 mL) to 2-(4-amino-4-methylpiperidin-1-yl)-5-(3,4-dichloro-2-methyl-2H-indazole -5-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 2f (18mg, 39.53μmol) in methanol (2mL) solution, then added 30% hydrogen peroxide (0.5mL), stirred at room temperature for 0.5 Hours, after the reaction, add trifluoroacetic acid to adjust the pH to acidity, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2mm ID; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain 2-(4-amino-4-methylpiperidin-1-yl)-5-(3,4-dichloro-2-methyl-2H-ind Azol-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 (2g, 8.64mmol) was added to sodium hydride (247.20mg, 9.50mmol) in tetrahydrofuran (20mL), after 15 minutes of reaction, iodomethane (1.84 g, 12.96mmol, 806.82μL), the reaction was continued at 0°C for 2 hours. Add 1N dilute hydrochloric acid (6 mL) to the reaction solution, extract with ethyl acetate (30 mL×2), separate the water layer, and wash the combined organic phase with saturated sodium chloride solution (30 mL×2) successively, and dry over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 5-bromo-4-chloro-1-methyl-indazole 3b (850mg), the 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 (980 mg, 3.99 mmol) and chlorosuccinimide (639.63 mg, 4.79 mmol) were added to N,N-dimethylformamide (15 mL), stirred overnight at room temperature. After the reaction was complete, 20 mL of water was added, extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained was further separated and purified by silica gel column chromatography (washing Removal of agent: system A) 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)-1H-indazole

5-bromo-3,4-dichloro-1-methyl-indazole 3c (400mg, 1.43mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolin-2-yl)-1,3,2-dioxaborinane (471.69mg, 1.86mmol), [1,1'-bis(diphenyl Phosphinoyl)ferrocene]palladium dichloride (209.10mg, 285.77μmol) and potassium acetate (420.68mg, 4.29mmol) were dissolved in dioxane (6mL), argon was replaced 3 times, and the temperature was raised to 100°C , reacted for 2 hours. After the reaction, add 10mL of water, extract with ethyl acetate (30mL), separate the water layer, wash the combined organic phase with saturated sodium chloride solution (30mL×2) successively, dry over anhydrous sodium sulfate, filter, and reduce pressure Concentration, the obtained residue was further separated and purified by silica gel column chromatography (eluent: A system) to obtain 3,4-dichloro-1-methyl-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-indazole 3d (400 mg), yield: 85.61%.

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

the fourth step

(1-(4-cyano-3-(3,4-dichloro-1-methyl-1H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Base) -4-methylpiperidin-4-yl) tert-butyl carbamate

(1-(3-Bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 1f (150mg, 343.80μmol), 3,4-dichloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole 3d (337.28mg, 1.03mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2- Amino-1,1'-biphenyl-2-yl)palladium (57.58mg, 68.76μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl ( 64.17mg, 137.52μmol) and potassium phosphate (219.04mg, 1.03mmol) were added to a mixed solution of 1,4-dioxane (6mL) and water (1mL). Argon was replaced three times, heated to 110°C, and reacted for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (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)tert-butyl carbamate 3e (80 mg), yield: 41.82%.

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

the 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 (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 tert-butyl ester 3e (80 mg, 143.77 μmol) in dichloromethane (2.5 mL) and proceed to 1 Hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 6-(4-amino-4-methylpiperidin-1-yl)-3-(3,4-dichloro-1-methyl-1H-indazole-5- Base)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 3f (65.61 mg), yield: 100%, the reaction was not purified, and the next reaction was carried out directly.

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

step six

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

Add 5M sodium hydroxide solution (0.25 mL) to 6-(4-amino-4-methylpiperidin-1-yl)-3-(3,4-dichloro-1-methyl-1H-indazole -5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 3f (65mg, 142.44μmol) in methanol solution (2mL), then added 30% hydrogen peroxide (0.5mL), stirred at room temperature After 0.5 hours, after the reaction, add trifluoroacetic acid to adjust the pH to acidity, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+ H ₂ O, mobile phase B: CH ₃ CN), to obtain 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-methylpropane-2-sulfinamide

3-Bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (150mg, 580.35μmol), (R)-2-methyl-N-((3S,4S )-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)propane-2-sulfinamide 4a (238.89mg, 870.53μmol, self-produced according to patent CN110156786) and two Isopropylethylamine (375.03 mg, 2.90 mmol, 506.79 μL) was added to N,N-dimethylacetamide (5 mL), heated to 80° C., and reacted for 1 hour. After the reaction, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (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 -Methylpropane-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-pyrazole And[3,4-d]pyrimidin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfinamide

(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-methylpropane-2-sulfinamide 4b (100mg, 201.44μmol), (3,4-dichloro-2-methyl -2H-indazol-5-yl)boronic acid 1g (123.32mg, 503.60μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'- Biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (33.74mg, 40.29μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1 , 1'-biphenyl (37.60 mg, 80.58 μmol) and potassium phosphate (128.34 mg, 604.32 μmol) 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°C, and reacted for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (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]decyl4-yl)-2-methylpropane-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

At room temperature, to (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]decane4-yl)-2-methylpropane-2 - To a solution of sulfinamide 4c (36 mg, 58.39 μmol) in dichloromethane (2 mL), slowly add 4M methanolic hydrochloric acid solution (4M, 58.39 μL) dropwise, and react for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 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), yield: 96.93%, The reaction was carried out directly to the next step without purification.

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

the fourth 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-carboxamide

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 (29mg, 56.60μmol) methanol solution (2mL), then add 30% hydrogen peroxide (0.3mL), and stir at room temperature for 0.5 hours. After the reaction, add trifluoroacetic acid to adjust the pH to acidity, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250 ×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain 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-pyrazole Ac[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-indazole -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-nitrogen Heterospiro[4.5]dec-4-yl)-2-methylpropane-2-sulfinamide

3-Bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (150mg, 580.35μmol), (R)-2-methyl-N-((S)- 2-oxa-8-azaspiro[4.5]dec-4-yl)propane-2-sulfinamide 5a (196.46mg, 754.46μmol, self-produced according to patent CN 110156786) and diisopropylethylamine ( 375.03mg, 2.90mmol, 506.79μL) was added to N,N-dimethylacetamide (1.49mL), heated to 80°C, and reacted for 1 hour. After the reaction, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (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-methylpropane-2- Sulfinamide 5b (190 mg), yield: 67.87%.

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

second step

(R)-N-((S)-8-(3-(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-methylpropane-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-methylpropane-2-sulfinamide 5b (190 mg, 393.87 μmol), (3,4-dichloro-2-methyl-2H-indazole- 5-yl)boronic acid 1g (192.89mg, 787.73μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2- Amino-1,1'-biphenyl-2-yl)palladium (65.96mg, 78.77μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl ( 73.52 mg, 157.55 μmol) and potassium phosphate (250.94 mg, 1.18 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°C, and reacted for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (R)-N-((S)-8-(3-(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-methylpropane-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-indazole -5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile

At room temperature, to (R)-N-((S)-8-(3-(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-methylpropane-2-sulfinamide 5c( To a solution of 40 mg, 66.39 μmol) in dichloromethane (2 mL), slowly add methanolic hydrochloric acid solution (4M, 66.39 μL) dropwise, and react for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain (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 (33mg), yield: 99.74%, the reaction was carried out directly without purification Next reaction.

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

the fourth step

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

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 μmol) in methanol (2 mL), Then add 30% hydrogen peroxide (0.3mL), stir at room temperature for 0.5 hours, after the reaction is over, add trifluoroacetic acid to adjust the pH to acidity, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain (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-methylpropane-2-sulfinamide

3-Bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (150mg, 580.35μmol), (R)-2-methyl-N-((R)- 8-azaspiro[4.5]dec-1-yl)propane-2-sulfinamide 6a (209.97mg, 812.50μmol, self-produced according to patent CN 110156786) and diisopropylethylamine (375.03mg, 2.90mmol ) was added to N,N-dimethylacetamide (3 mL), heated to 80° C., and reacted for 1 hour. After the reaction, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (R)-N-((R)-8-(3-bromo-4- Cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-8-azaspiro[4.5]dec-1-yl)-2-methylpropane-2-sulfinamide 6b( 180 mg), yield: 64.56%.

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

second step

(R)-N-((R)-8-(3-(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-methylpropane-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-methylpropane-2-sulfinamide 6b (180 mg, 374.67 μmol), (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (229.36mg, 936.67μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1 '-biphenyl-2-yl)palladium (62.75mg, 74.93μmol), 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl (69.93mg, 149.87μmol ) and potassium phosphate (238.71 mg, 1.12 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°C, and reacted for 16 hours. After the reaction, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (R)-N-((R)-8-(3-(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-methylpropane-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

At room temperature, to (R)-N-((R)-8-(3-(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-methylpropane-2-sulfinamide 6c (70mg, 116.56μmol) To a solution of dichloromethane (2 mL) in a solution of hydrochloric acid in methanol (4M, 116.56 μL) was slowly added dropwise, and reacted for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain (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%, the reaction was directly carried out to the next step without purification.

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

the fourth 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-carboxamide

Add 5M sodium hydroxide (0.25 mL) to (R)-6-(1-amino-8-azaspiro[4.5]dec-8-yl)-3-(3,4-dichloro-2-methyl Base-2H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 6d (57.86mg, 116.56μmol) in methanol (2.5mL) solution, followed by addition of 30% Hydrogen peroxide (0.5mL), stirred at room temperature for 0.5 hours, after the reaction, added trifluoroacetic acid to adjust the pH to acidic, concentrated under reduced pressure, and prepared liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; Mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to obtain (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'-piperidin]-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[ Indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

(R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 7a (301.5 mg, 983.80μmol, self-produced according to patent WO 2020156242), 5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 2c (253.30mg, 983.80μmol) and N,N - Diisopropylethylamine (635.73mg, 4.92mmol) was added to N,N-dimethylacetamide (5mL), heated to 130°C, and reacted overnight. After the reaction, add 20mL of water, extract with ethyl acetate (20mL×3), wash with saturated sodium chloride solution (20mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure, and the obtained residue is passed through a silica gel column Further separation and purification by chromatography (eluent: system A) to obtain (R)-N-((S)-1'-(5-bromo-4-cyano-7H-pyrrolo[2,3-d] Pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-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[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

(R)-N-((S)-1'-(5-bromo-4-cyano-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-1,3-dihydrospiro [Indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 7b (120mg, 227.50μmol), (3,4-dichloro-2-methyl-2H -Indazol-5-yl)boronic acid 1g (139.27mg, 568.74μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl )(2-amino-1,1'-biphenyl-2-yl)palladium (38.10mg, 45.50μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1' - Biphenyl (42.46 mg, 91.00 μmol) and potassium phosphate (144.87 mg, 682.49 μmol) were added to a mixed solution of 1,4-dioxane (3 mL) and water (0.3 mL). Argon was replaced three times, heated to 130°C, and reacted overnight. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: A system) to obtain (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 [Indene-2,4'-piperidin]-1-yl)-2-methylpropane-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 μmol) was added to (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[indene-2,4'-piperidin]-1-yl)-2- A solution of methylpropane-2-sulfinamide 7c (20 mg, 30.88 μmol) in dichloromethane (1 mL) was stirred at room temperature for 2 hours. After the reaction, it was concentrated under reduced pressure to obtain (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 (16.7mg), yield: 99.51%, no reaction After purification, proceed directly to the next reaction.

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

the fourth 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-carboxamide

Add 5M sodium hydroxide solution (0.2 mL) to (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 mg, 29.44 μmol) in methanol (2 mL) Add 30% hydrogen peroxide (0.5mL) to the solution, and stir at room temperature for 1.5 hours. After the reaction, add trifluoroacetic acid to adjust the pH to acidic, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain (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-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 (212mg, 1.20mmol), 5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 2c (309.69mg, 1.20mmol ) and N,N-diisopropylethylamine (777.24mg, 6.01mmol) were added to N,N-dimethylacetamide (6mL), heated to 130°C, and reacted for 2 hours. After the reaction, the pressure was reduced Concentration, C ₁₈ reverse phase chromatography column separation (C ₁₈ separation column 20-45 μm; mobile phase A: H ₂ O, mobile phase B: CH ₃ CN), to obtain 2-(4-amino-4-phenylpiperidine- 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 μmol), (3 , 4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (231.14mg, 943.94μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diiso Propoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (63.23mg, 75.52μmol), 2-dicyclohexylphosphine-2',6 '-Diisopropoxy-1,1'-biphenyl (70.48mg, 151.03μmol) and potassium phosphate (400.93mg, 1.89mmol) were added to 1,4-dioxane (4mL) and water (0.4mL ) in the mixed solution. Argon was replaced three times, heated to 130°C, and reacted for 4 hours. After the reaction, concentrated under reduced pressure, separated by C ₁₈ reverse phase chromatographic column (C ₁₈ separation column 20-45 μm; mobile phase A: H ₂ O, mobile phase B: CH ₃ CN), to obtain 2-(4-amino-4 -Phenylpiperidin-1-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-4 - Nitrile 8c (80mg), 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-carboxamide

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 μmol), 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 the reaction, add trifluoroacetic acid to adjust the pH to acidic, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O , mobile phase B: CH ₃ CN) to give 2-(4-amino-4-phenylpiperidin-1-yl)-5-(3,4-dichloro-2-methyl-2H-indazole- 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 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (219.56 mg, 1.70mmol), after stirring at room temperature for 5 minutes, 3-bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (146.36mg, 566.29μmol) was added, and the reaction was heated to 90°C, stirring for 1 hour. After the reaction, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 6-(4-amino-3-fluoro-4-phenylpiperidine-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 (100mg, 240.24 μmol), (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (176.48mg, 720.72μmol), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (40.23mg, 48.05μmol), 2-dicyclohexylphosphine -2',6'-diisopropoxy-1,1'-biphenyl (44.84 mg, 96.10 μmol) and potassium phosphate (152.98 mg, 720.72 μmol) were added to 1,4-dioxane (5 mL) and water (1 mL). Argon was replaced three times, heated to 130°C, and reacted for 20 hours. After the reaction, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 6-(4-amino-3-fluoro-4-phenylpiperidine-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

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

Sodium hydroxide solution (5M, 0.5mL) 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 (60mg, 124.39μmol) in methanol (2mL), slowly drop 30% hydrogen peroxide (0.5mL ), react at room temperature for 30 minutes. After the reaction, add trifluoroacetic acid to adjust the pH to acidic, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O , mobile phase B: CH ₃ CN), to give 6-(4-amino-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 (400mg, 1.55mmol), 4-cyclopropylpiperidin-4-amine 10a (600mg, 4.28 mmol) and N,N-diisopropylethylamine (600.04mg, 4.64mmol) were added to N,N-dimethylacetamide (2.5mL), raised to 100°C, and reacted for 1 hour. Concentrate under reduced pressure, and the obtained residue is further separated and purified by silica gel column chromatography (eluent: system A) to obtain 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 (70mg, 193.25μmol), (3,4-Dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (189.28mg, 773.00μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (32.36mg, 38.65μmol), 2-dicyclohexylphosphine-2' , 6'-diisopropoxy-1,1'-biphenyl (36.02 mg, 77.30 μmol) and potassium phosphate (204.84 mg, 966.24 μmol) were added to 1,4-dioxane (2 mL) and water ( 0.2mL) in the mixed solution. Argon was replaced three times, heated to 130°C, and reacted for 18 hours. After the reaction, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 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

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

To 5M sodium hydroxide solution (0.5mL) and 6-(4-amino-4-cyclopropylpiperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazole -5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 10c (28mg, 58.05μmol) in methanol (3mL) solution, slowly drop 30% hydrogen peroxide (0.5mL), React at room temperature for 30 minutes. After the reaction, add trifluoroacetic acid to adjust the pH to acidic, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O , mobile phase B: _CH3CN ) to give 6-(4-amino-4-cyclopropylpiperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazole -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 ( 450.04mg, 3.48mmol), after stirring at room temperature for 10 minutes, 3-bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (300mg, 1.16mmol) was added, and the reaction was heated to 90°C, stirring for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 6-((3R,4R)-4-amino-3-fluoropiperidine-1 -yl-3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 11b (390 mg), yield: 98.78%.

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

6-((3R,4R)-4-amino-3-fluoropiperidin-1-yl-3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 11b (200mg, 587.97 μmol), (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (359.94mg, 1.47mmol), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (98.47mg, 117.59μmol), 2-dicyclohexylphosphine -2',6'-diisopropoxy-1,1'-biphenyl (109.60 mg, 235.19 μmol) and potassium phosphate (623.25 mg, 2.94 mmol) were added to 1,4-dioxane (5 mL) and water (1mL) in a mixed solution. Argon was replaced three times, heated to 120 ° C, and reacted for 18 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue obtained 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-(3,4-dichloro-2-methyl-2H-indazol-5-yl )-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 11c (150mg), yield: 55.42%.,

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

third 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-carboxamide

Sodium hydroxide solution (5M, 0.5mL) 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 (150mg, 325.88μmol) in methanol (3mL), slowly dropwise add 30% hydrogen peroxide (1mL ), react at room temperature for 30 minutes. After the reaction, add trifluoroacetic acid to adjust the pH to acidity, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2mm ID; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to give 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 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 [Indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

To (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 7a (306mg ,998.48μmol) in N,N-dimethylacetamide (3mL) solution was added N,N-diisopropylethylamine (107.54mg, 832.07μmol), stirred at room temperature for 10 minutes, then added 3-bromo-6 -Chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (215.06mg, 832.07μmol), the reaction temperature was raised to 90°C and stirred for 1 hour. After the reaction, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain (R)-N-((S)-1'-(3-bromo-4 -Cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methyl Propane-2-sulfinamide 12a (280 mg), yield: 63.68%.

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

second step

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

(R)-N-((S)-1'-(3-bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydro Spiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 12a (280mg, 529.83μmol), (3,4-dichloro-2-methyl- 2H-indazol-5-yl)boronic acid 1g (324.35mg, 1.32mmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (98.90mg, 211.93 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2 -yl) palladium (88.73 mg, 105.97 μmol) and potassium phosphate (337.40 mg, 1.59 mmol) were added to a mixed solution of 1,4-dioxane (10 mL) and water (2 mL). Argon was replaced three times, heated to 130°C, and reacted for 18 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: A system) to obtain (R)-N-((S)-1'-(3-(3, 4-Dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydro Spiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-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-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-1H-pyrazole And[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin-1-yl)-2-methylpropane-2-sulfinamide To 12b (190 mg, 292.94 μmol) in dichloromethane (4 mL), dioxane hydrochloride solution (4M, 366.17 μL) was slowly added dropwise, and reacted for 1 hour. After the reaction, it was concentrated under reduced pressure to obtain (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 (159mg), yield: 99.7%, no reaction After purification, proceed directly to the next reaction.

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

the fourth 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-carboxamide

To sodium hydroxide solution (5M, 292.04μL) and (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 (159mg, 292.04μmol) in methanol (4 mL), slowly added dropwise 30% hydrogen peroxide (1 mL), and reacted at room temperature for 1 hour. After the reaction, add trifluoroacetic acid to adjust the pH to acidic, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O , mobile phase B: CH ₃ CN), to obtain (S)-6-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidinyl]-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] In a solution of pyrimidine-4-carbonitrile 1d (250mg, 967μmol) in N-methylpyrrolidone (3mL), heat to 100°C and stir for 1 hour. After the reaction was complete, C ₁₈ reversed-phase chromatographic column separation (C ₁₈ separation column 20-45 μm; mobile phase A: H ₂ O, mobile phase B: CH ₃ CN) to obtain 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

6-(4-Amino-4-(2,2-difluoroethyl)piperidin-1-yl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 13b (130mg, 337μmol), (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (329.7mg, 1.35mmol), methanesulfonic acid (2-dicyclohexylphosphino- 2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (56.4mg, 67μmol), 2-bicyclo Hexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (62.8 mg, 135 μmol) and potassium phosphate (214.4 mg, 1.01 mmol) were added to 1,4-dioxane (5 mL ) and water (1 mL). Argon was replaced three times, and the reaction was heated at 100°C overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the layers, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, anhydrous Dry over sodium sulfate, concentrate under reduced pressure, and the obtained residue is further purified by silica gel column chromatography (eluent: A system) to obtain 6-(4-amino-4-(2,2-difluoroethyl)piperidine -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

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

Potassium hydroxide (22.2 mg, 395 μmol) 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 (100mg, 198μmol) was added to dimethyl sulfoxide (2mL) solution, slowly drop Add hydrogen peroxide (30%, 1mL) to the reaction solution, stir for 1 hour after the dropwise addition, after the reaction is complete, add trifluoroacetic acid dropwise to adjust the pH to 3-4, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 6-(4-amino-4-(2,2-difluoroethyl)piperidine-1 -yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxamide 13 (30mg ), yield: 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 (120mg, 311μmol), 7-chloro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d ] Thiazole 14a (144.3 mg, 466 μmol, self-produced according to patent WO 2019167000), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl )(2-amino-1,1'-biphenyl-2-yl)palladium (52.0mg, 62μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'- Biphenyl (58.0 mg, 124 μmol) and potassium phosphate (197.9 mg, 0.93 mmol) were added to a mixed solution of 1,4-dioxane (5 mL) and water (1 mL). Argon was replaced three times, and the reaction was heated at 100°C overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the liquids, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, and anhydrous Dry over sodium sulfate, concentrate under reduced pressure, and the obtained residue is further purified by silica gel column chromatography (eluent: A system) to obtain 6-(4-amino-4-(2,2-difluoroethyl)piperidine -1-yl)-3-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 14b (55mg) , Yield: 36.2%.

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

second 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-carboxamide

Potassium hydroxide (12.6 mg, 225 μmol) and 6-(4-amino-4-(2,2-difluoroethyl) piperidin-1-yl)-3-(7-chloro-2-methylbenzene And[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 14b (55mg, 112μmol) was added to dimethyl sulfoxide (1mL) solution, and hydrogen peroxide was slowly added dropwise (30%, 0.5mL) into the reaction solution, stirred for 1 hour after the dropwise addition, after the reaction was complete, added dropwise trifluoroacetic acid to adjust the pH to 3-4, and prepared liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 6-(4-amino-4-(2,2-difluoroethyl)piperidine-1- yl)-3-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxamide 14 (22 mg), yield Rate: 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]thiazole- 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) tert-butyl carbamate

3-Bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (656.82mg, 2.54mmol), ((1R,3r,5S)-8-azabicyclo[ 3.2.1] Oct-3-yl) tert-butyl carbamate 15a (400mg, 1.77mmol) and N,N-diisopropylethylamine (456.85mg, 3.53mmol) were added to N,N-dimethylethyl Amide (3 mL), heated to 100°C, and reacted for 1 hour. After the reaction, extract with ethyl acetate and water, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue is further purified by silica gel column chromatography (eluent: System A), to obtain ((1R,3r,5S)-8-(3-bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-8-azabicyclo [3.2.1] Oct-3-yl) tert-butyl 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)carbamate tert-butyl ester

7-chloro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 14a (207.19 mg, 669.17μmol), ((1R,3r,5S)-8-(3-bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-8-aza Bicyclo[3.2.1]oct-3-yl) tert-butyl carbamate 15b (150 mg, 334.59 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1 ,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (56.03 mg, 66.92 μmol), 2-dicyclohexylphosphine-2',6'-diisopropyl Oxy-1,1'-biphenyl (62.45 mg, 133.83 μmol) and potassium phosphate (142.04 mg, 669.17 μmol) were added to a mixed solution of 1,4-dioxane (2 mL) and water (0.2 mL) . Argon was replaced three times, and the reaction was heated at 110°C overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the liquids, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, and anhydrous Dry over sodium sulfate, concentrate under reduced pressure, and the obtained residue is further purified by silica gel column chromatography (eluent: system A) to obtain ((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]octane- 3-yl) tert-butyl carbamate 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]thiazole- 6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile

((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 tert-butyl ester 15c (138mg, 250.43μmol) in dichloromethane (1.5mL), added three Fluoroacetic acid (0.5 mL) was reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 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), yield: 97.41%, without purification, directly proceed to the next step reaction.

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

the fourth step

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

6-((1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]oct-8-yl)-3-(7-chloro-2-methylbenzo[d]thiazole -6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 15d (110 mg, 243.93 μmol) and sodium hydroxide solution (1M, 975.73 μL) were added to methanol (2 mL) and slowly Add dropwise 30% hydrogen peroxide (1mL), react at room temperature for 1 hour, after the reaction is complete, add dropwise trifluoroacetic acid to adjust the pH to 3-4, and prepare 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: CH3CN), to obtain 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 15 (6.3 mg), yielding Rate: 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

tert-butyl 4-carboxamide-4-(fluoro(phenyl)methyl)piperidine-1-carboxylate

tert-butyl 4-cyano-4-(fluoro(phenyl)methyl)piperidine-1-carboxylate 16a (0.92g, 2.89mmol, self-produced according to patent WO2010068881), potassium hydroxide (324.2mg, 5.78 mmol) were sequentially added to N,N-dimethylsulfoxide (10 mL), hydrogen peroxide (15 mL) was added dropwise in a water bath, and reacted overnight at room temperature. After the reaction was completed, the reaction solution was stirred with a small amount of water, and a white solid precipitated out, which was filtered to obtain tert-butyl 4-formamide-4-(fluoro(phenyl)methyl)piperidine-1-carboxylate 16b (312mg). Yield: 32.1%.

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

second step

tert-butyl 4-amino-4-(fluoro(phenyl)methyl)piperidine-1-carboxylate

4-Carboxamide-4-(fluoro(phenyl)methyl)piperidine-1-carboxylic acid tert-butyl ester 16b (312mg, 927.47μmol), potassium hydroxide (234.18mg, 4.17mmol) were added to acetonitrile (5mL ) and water (5mL), add 1,3-dibromo-5,5-dimethylhydantoin (132.59mg, 463.73μmol), react at room temperature for 3 hours, the reaction is complete, the reaction solution ethyl acetate and Extract with water, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain tert-butyl 4-amine-4-(fluoro(phenyl)methyl)piperidine-1-carboxylate 16c (167 mg). Rate: 58.39%.

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

third step

4-(Fluoro(phenyl)methyl)piperidin-4-amine

4-Amino-4-(fluoro(phenyl)methyl)piperidine-1-carboxylic acid tert-butyl ester 16c (167 mg, 541.52 μmol) and trifluoroacetic acid (0.5 mL) were added to dichloromethane (1.5 mL) , react at room temperature for 1 hour, the reaction is complete, add a small amount of water to quench, add saturated sodium bicarbonate solution, extract with ethyl acetate, combine the organic phases to dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain 4-(fluoro(phenyl) Methyl)piperidin-4-amine 16d (109 mg), yield: 96.64%.

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

the 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 μmol), 4-(fluoro(phenyl)methyl)piperidine-4 -Amine 16d (109mg, 523.35μmol), N,N-diisopropylethylamine (202.91mg, 1.57mmol) were successively added to N,N-dimethylacetamide (2mL), heated to 100°C, and reacted 1 hour. The reaction was complete, extracted with ethyl acetate (30mL) and water, the combined organic phase was washed successively with saturated sodium chloride solution (30mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography Further purification (eluent: A system) gave 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]

the 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

(3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (60.54mg, 247.24μmol), 6-(4-amino-4-(fluoro(phenyl)methyl )piperidin-1-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 16f (59mg, 123.62μmol), methanesulfonic acid (2-dicyclohexylphosphino- 2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (20.70mg, 24.72μmol) and 2-bis Cyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (28.84 mg, 61.81 μmol) and potassium phosphate (52.48 mg, 247.24 μmol) were added to 1,4-dioxane (2mL) and water (0.2mL) mixed solution. The argon gas was replaced three times, and the reaction was heated at 110° C. for 3 hours. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the liquids, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, and anhydrous Dry over sodium sulfate, concentrate under reduced pressure, and the obtained residue is further purified by silica gel column chromatography (eluent: A system) to obtain 6-(4-amino-4-(fluoro(phenyl)methyl)piperidine- 1-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 16g (32mg ), yield: 47.03%.

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

step six

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

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 (64mg, 116.28μmol) and sodium hydroxide (1M, 465.10μL) were sequentially added to methanol (2mL), and 30% hydrogen peroxide was added slowly (1mL), react at room temperature for 0.5 hours, the reaction is complete, drop trifluoroacetic acid to adjust the pH to 3-4, and prepare 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: CH3CN), to obtain 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 16 (9.45 mg), yield: 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]thiazole- 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) tert-butyl carbamate

3-Bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (411.14mg, 1.59mmol), ((1R,3s,5S)-8-azabicyclo[ 3.2.1] Oct-3-yl) tert-butyl carbamate 17a (300mg, 1.33mmol) and N,N-diisopropylethylamine (342.64mg, 2.65mmol) were added to N,N-dimethylethyl Amide (3 mL), heated to 100°C, and reacted for 1 hour. After the reaction, extract with ethyl acetate and water, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue is further purified by silica gel column chromatography (eluent: System A), to obtain ((1R,3s,5S)-8-(3-bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-8-azabicyclo [3.2.1] Oct-3-yl) tert-butyl 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)carbamate tert-butyl ester

7-chloro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 14a (276.25 mg, 892.23μmol), ((1R,3s,5S)-8-(3-bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-8-aza Bicyclo[3.2.1]oct-3-yl) tert-butyl carbamate 17b (150 mg, 334.59 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1 ,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (74.71 mg, 89.22 μmol) and 2-dicyclohexylphosphonium-2',6'-diisopropyl Oxy-1,1'-biphenyl (83.27 mg, 178.45 μmol) and potassium phosphate (189.39 mg, 892.23 μmol) were added to a mixed solution of 1,4-dioxane (2 mL) and water (0.2 mL) . Argon was replaced three times, and the reaction was heated at 110°C overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the liquids, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, and anhydrous Dry over sodium sulfate, concentrate under reduced pressure, and the obtained residue is further purified by silica gel column chromatography (eluent: system A) to obtain ((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]octane- 3-yl) tert-butyl carbamate 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]thiazole- 6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile

((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 tert-butyl ester 17c (120 mg, 217.76 μmol) was added to dichloromethane (1.5 mL), Trifluoroacetic acid (0.5 mL) was added and reacted at room temperature for 1 hour. After the reaction, it was concentrated under reduced pressure to obtain 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), yield: 99.8%, directly carried on to the next step without purification reaction.

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

the fourth step

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

6-((1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]oct-8-yl)-3-(7-chloro-2-methylbenzo[d]thiazole -6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 17d (98mg, 210.67μmol) in sodium hydroxide solution (1M, 842.67μL) was added to methanol (2mL) and slowly added 30% hydrogen peroxide (1mL), react at room temperature for 1 hour, after the reaction is complete, add dropwise trifluoroacetic acid to adjust the pH to 3-4, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5μm, 20mL/min; Mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 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 17 (18.2 mg), yield: 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-ind Azol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxamide

first step

((1R,3s,5S)-8-(3-(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 tert-butyl ester

(3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (218.83mg, 669.17μmol), ((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 tert-butyl ester 17b (150mg, 334.59μmol ), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2- base) palladium (56.03mg, 66.92μmol) and 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (62.45mg, 133.83μmol) and potassium phosphate (142.04mg , 669.17 μmol) was added to a mixed solution of 1,4-dioxane (2 mL) and water (0.2 mL). Argon was replaced three times, and the reaction was heated at 110°C overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the liquids, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, and anhydrous Dry over sodium sulfate, concentrate under reduced pressure, and the obtained residue is further purified by silica gel column chromatography (eluent: A system) to obtain ((1R,3s,5S)-8-(3-(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) tert-butyl carbamate 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-ind Azol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile

((1R,3s,5S)-8-(3-(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 tert-butyl ester 18a (95 mg, 167.12 μmol), was added to dichloroethane (1.5 mL ), added trifluoroacetic acid (0.5 mL), and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 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), yield: 99%, directly carried out without purification Next reaction.

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-ind Azol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxamide

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 μmol) and sodium hydroxide solution (1M, 333.09 μL) were added to methanol (1.5 mL) , slowly added 30% hydrogen peroxide (0.5 mL), and reacted at room temperature for 0.5 hours. After the reaction is complete, add trifluoroacetic acid dropwise to adjust the pH to 3-4, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B: CH3CN), to obtain 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-ind Azol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxamide

first step

((1R,3r,5S)-8-(3-(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 tert-butyl ester

(3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (218.83mg, 669.17μmol), ((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 tert-butyl ester 15b (150mg, 334.59μmol ), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2- base) palladium (56.03mg, 66.92μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (62.45mg, 133.83μmol) and potassium phosphate (142.04mg , 669.17 μmol) was added to a mixed solution of 1,4-dioxane (2 mL) and water (0.2 mL). Argon was replaced three times, and the reaction was heated at 110°C overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the liquids, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, and anhydrous Sodium sulfate was dried, concentrated under reduced pressure, and the obtained residue was further purified by silica gel column chromatography (eluent: A system) to obtain ((1R,3r,5S)-8-(3-(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) tert-butyl carbamate 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-ind Azol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile

((1R,3r,5S)-8-(3-(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 tert-butyl ester 19a (100 mg, 175.91 μmol) was added to dichloromethane (1.5 mL), Add trifluoroacetic acid (0.5mL) and react at room temperature for 1 hour. After the reaction, concentrate under reduced pressure to obtain 6-((1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane- 8-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 19b (82mg ), yield: 99.53%, directly carried out to the next step 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-ind Azol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxamide

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 μmol) in sodium hydroxide solution (1 M, 350.17 μL) was added to methanol (1.5 mL) 30% hydrogen peroxide (0.5 mL) was added, and the reaction time at room temperature was 3 hours. After the reaction is complete, add trifluoroacetic acid dropwise to adjust the pH to 3-4, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B: CH3CN), to obtain 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-indazole-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]octane-3 -yl) tert-butyl carbamate

3-Bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (225.83mg, 873.76μmol), (3-methyl-8-azabicyclo[3.2.1 ]oct-3-yl) tert-butyl carbamate 20a (210mg, 873.76μmol, self-produced according to patent WO 2005042533) and N,N-diisopropylethylamine (225.85mg, 1.75mmol) were added to N, N-dimethylacetamide (2 mL), heated to 100°C, and reacted for 1 hour. After the reaction, extract with ethyl acetate and water, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue is further purified by silica gel column chromatography (eluent: A system), to obtain (8-(3-bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-8-azabicyclo[3.2. 1] tert-butyl (oct-3-yl)carbamate 20b (210 mg), yield: 51.98%.

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

second step

(8-(3-(3,4-Dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidine-6- Base)-3-methyl-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-butyl ester

(3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (222.44mg, 908.42μmol), (8-(3-bromo-4-cyano-1H-pyrazole [3,4-d]pyrimidin-6-yl)-3-methyl-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-butyl ester 20b (210 mg, 454.21 μmol), form Sulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (76.07mg, 90.84μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (84.66mg, 181.68μmol) and potassium phosphate (192.83mg, 908.42μmol ) was added to a mixed solution of 1,4-dioxane (3 mL) and water (0.3 mL). The argon gas was replaced three times, and the reaction was heated at 110° C. for 3 hours. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the liquids, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, and anhydrous Dry over sodium sulfate, concentrate under reduced pressure, and the obtained residue is further purified by silica gel column chromatography (eluent: system A) to obtain (8-(3-(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]octane-3 -yl) tert-butyl 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-indazole-5 -yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile

(8-(3-(3,4-Dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)-3-methyl-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-butyl ester 20c (112 mg, 192.28 μmol), was added to dichloromethane (1.5 mL), and Trifluoroacetic acid (0.5 mL) was reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 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 (92mg), yield: 99%, directly proceed to the next reaction without purification .

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

the fourth step

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

6-(3-amino-3-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-(3,4-dichloro-2-methyl-2H-indazole- 5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 20d (92 mg, 190.73 μmol) in sodium hydroxide solution (1M, 381.45 μL) was added to methanol (1.5 mL), and 30% hydrogen peroxide (1 mL), react at room temperature for 4 hours. After the reaction is complete, add trifluoroacetic acid dropwise to adjust the pH to 3-4, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B: CH3CN), to obtain 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 (3g, 19.59mmol), N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine 21b (5.00g, 21.55mmol) into N,N-dimethylformamide (30mL), stirred at 0°C for 10 minutes, added sodium hydride (5.10g, 127.41mmol, 60% purity), stirred for 1 hour, and the temperature was raised to 60°C, react overnight. After the reaction, the reaction solution was poured into ice water and stirred, solids were precipitated, filtered, the filtrate was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was further purified by silica gel column chromatography (washing Removal of solvent: system A) to obtain 1-benzyl-4-(2,4-difluorophenyl)piperidine-4-carbonitrile 21c (2.2g), 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 (2.2g, 7.04mmol), potassium hydroxide (790.39mg, 14.09mmol) were sequentially added to dimethyl Hydrogen peroxide (15 mL) was slowly added dropwise to sulfone (15 mL), and reacted overnight at room temperature. After the reaction, the reaction solution was poured into ice water and stirred, solids were precipitated, filtered, the filtrate was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was further purified by silica gel column chromatography (washing Removal of solvent: system A) to obtain 1-benzyl-4-(2,4-difluorophenyl)piperidine-4-carboxamide 21d (1g), 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) were added to acetonitrile (3 mL) and To the mixed solution of water (3 mL), 1,3-dibromo-5,5-dimethylhydantoin (476.00 mg, 1.66 mmol) was added. React overnight at room temperature. After the reaction, sodium sulfite (38.15 mg, 302.69 μmol) and potassium phosphate (706.76 mg, 3.33 mmol) were added and stirred for 20 minutes. Extract with ethyl acetate and water, separate the water layer, wash the combined organic phase successively with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1-benzyl-4-(2,4- Difluorophenyl)piperidin-4-amine 21e (500 mg), yield: 54.63%.

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

the fourth step

(1-Benzyl-4-(2,4-difluorophenyl)piperidin-4-yl)carbamate tert-butyl ester

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

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

the fifth step

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

(1-Benzyl-4-(2,4-difluorophenyl)piperidin-4-yl)carbamate tert-butyl ester 21f (430mg, 1.07mmol), palladium on carbon (129.76mg, 1.07mmol) was added to Methanol (20 mL), replaced by hydrogen, reacted at room temperature for 48 hours. After the reaction was complete, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain 21 g (300 mg) of tert-butyl (4-(2,4-difluorophenyl)piperidin-4-yl)carbamate, yield: 89.9 %.

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

step six

(1-(3-Bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-(2,4-difluorophenyl)piperidin-4-yl ) tert-butyl carbamate

3-Bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (248.24mg, 960.45μmol), (4-(2,4-difluorophenyl)piperidine -4-yl) tert-butyl carbamate 21g (300mg, 960.45μmol) and N,N-diisopropylethylamine (124.13mg, 960.45μmol) were sequentially added to N,N-dimethylacetamide (2mL) , heated to 100°C and reacted overnight. After the reaction was complete, extract with ethyl acetate and water, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue was further purified by silica gel column chromatography (eluent: A system) to obtain (1- (3-Bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-(2,4-difluorophenyl)piperidin-4-yl)carbamate tert-butyl ester 21h (151 mg), yield: 29%.

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

step seven

(1-(3-(3,4-Dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidine-6- yl)-4-(2,4-difluorophenyl)piperidin-4-yl)carbamate tert-butyl ester

(3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (91.65mg, 374.28μmol), (1-(3-bromo-4-cyano-1H-pyrazole [3,4-d]pyrimidin-6-yl)-4-(2,4-difluorophenyl)piperidin-4-yl)carbamate tert-butyl ester 21h (100mg, 187.14μmol), 2-di Cyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (34.93mg, 74.86μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-bis Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (31.34 mg, 37.43 μmol) and potassium phosphate (79.45 mg, 374.28 μmol) were added into a mixed solution of 1,4-dioxane (3 mL) and water (0.3 mL). The argon gas was replaced three times, and the reaction was heated at 110° C. for 3 hours. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the liquids, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, and anhydrous Dry over sodium sulfate, concentrate under reduced pressure, and the obtained residue is further purified by silica gel column chromatography (eluent: A system) to obtain (1-(3-(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 ) tert-butyl 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

(1-(3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)-4-(2,4-difluorophenyl)piperidin-4-yl)carbamate tert-butyl ester 21i (60 mg, 91.67 μmol) was added to dichloromethane (1.5 mL) and trifluoroacetic acid was added (0.5 mL), react at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 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-carboxamide

6-(4-amino-4-(2,4-difluorophenyl)piperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazole-5- base)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 21j (66mg, 119.05μmol) and sodium hydroxide (48.0mg, 1.2mmol) were added to methanol (1.5mL), slowly added for 30 % hydrogen peroxide (0.5 mL), react at room temperature for 4 hours. After the reaction is complete, add trifluoroacetic acid dropwise to adjust the pH to 3-4, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B: CH3CN), to obtain 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)carbamate tert-butyl ester

N,N-Diisopropylethylamine (1.27 g, 9.82 mmol, 1.62 mL) was added to 3-iodo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 16e ( 1g, 3.27mmol) and (4-phenylpiperidin-4-yl) tert-butyl carbamate 22a (995mg, 3.6mmol) in N,N-dimethylacetamide (5mL) solution, heated at 100°C, Stir for 1 hour. After the reaction, the mixture was poured into 100 mL 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 obtained residue was further analyzed by silica gel column chromatography Purification (eluent: system A) afforded (1-(4-cyano-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-phenylpiperidine- 4-yl) tert-butyl 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) tert-butyl carbamate

(1-(4-cyano-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-phenylpiperidin-4-yl)carbamate tert-butyl ester 22b (100mg, 183.36μmol), (3,4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (112.25mg, 458.40μmol), methanesulfonic acid (2-dicyclohexylphosphino -2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (30.71mg, 36.67μmol), 2- Dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (34.18mg, 73.34μmol), potassium phosphate (194.36mg, 916.80μmol) was added to 1,4-dioxane Ring (2mL) and water (0.2mL) mixed solution. Argon was replaced three times, heated to 110°C, and reacted for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: system A) to obtain (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)tert-butyl 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]pyrimidine-6- Add tert-butyl)-4-phenylpiperidin-4-yl)carbamate 22c (80 mg, 129.34 μmol) and trifluoroacetic acid (1 mL) into dichloromethane (3 mL), and stir at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 6-(4-amino-4-phenylpiperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazole-5- base)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 22d, without further purification, directly proceeded to the next reaction.

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

the fourth 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-carboxamide

The above crude product 6-(4-amino-4-phenylpiperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyridine Azolo[3,4-d]pyrimidine-4-carbonitrile 22d was dissolved in methanol (3 mL), sodium hydroxide (51.70 mg, 1.29 mmol) and hydrogen peroxide (0.5 mL) were added successively, and stirred at room temperature for another 2 hours. After the reaction, the pH was adjusted to 7 with trifluoroacetic acid, concentrated under reduced pressure, and the preparative liquid phase was separated (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O , mobile phase B: CH ₃ CN), to obtain 6-(4-amino-4-phenylpiperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazole- 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)- tert-butyl 4-phenylpiperidin-4-ylcarbamate

(1-(4-cyano-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-phenylpiperidin-4-yl)carbamate tert-butyl ester 22b (100mg, 183.36μmol), (4-chloro-2-methyl-2H-indazol-5-yl)boronic acid 23a (96.46mg, 458.40μmol), methanesulfonic acid (2-dicyclohexylphosphino-2' ,6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (30.71mg, 36.67μmol), 2-dicyclohexyl Phosphorus-2',6'-diisopropoxy-1,1'-biphenyl (34.18 mg, 73.34 μmol) and potassium phosphate (194.36 mg, 916.80 μmol) were added to 1,4-dioxane (2.5 mL) and water (0.25 mL). Argon was replaced three times, heated to 110°C, and reacted for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(3-(4-chloro-2-methyl-2H-indazole -5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-phenylpiperidin-4-ylcarbamate 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-ylcarbamate tert-butyl ester 23b (100mg, 171.21μmol) was dissolved in trifluoroacetic acid (1mL) and dichloromethane (3mL), and stirred at room temperature for 1.5 hours. After the reaction was completed, the pressure was reduced Concentration gave 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), without purification, was directly used for the next reaction.

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

third step

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

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 (80mg, 165.30μmol), sodium hydroxide (66.12mg, 1.65mmol) was dissolved in methanol (2mL), hydrogen peroxide (0.5mL) was added, stirred at room temperature for 1 hour, after the reaction, Adjust pH=7 with trifluoroacetic acid, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B : CH ₃ CN), to obtain 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)carbamate tert-butyl ester

2-Chloro-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 2b (147mg, 821.09μmol), (4-phenylpiperidin-4-yl)carbamate tert-butyl ester 22a (249.62mg ,903.20μmol), N,N-diisopropylethylamine (529.60mg, 4.11mmol), N,N-dimethylacetamide (3mL), heated to 90°C, reacted for 1.5 hours, after the reaction was completed, add 10 mL of water was extracted with ethyl acetate (20 mL×2), the combined organic phases were concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(4 -Cyano-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-phenylpiperidin-4-yl)carbamate 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)carbamate tert-butyl ester

(1-(4-cyano-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-phenylpiperidin-4-yl)carbamate tert-butyl ester 24a (200mg, 477.91μmol ) was dissolved in N,N-dimethylformamide (1mL), added iodosuccinimide (129.02mg, 573.49μmol), and stirred at room temperature for 2 hours. After the reaction was completed, 10mL of water was added, and ethyl acetate ( 20mL×2) extraction, combined organic phases, concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(4-cyano-5-iodo-7H -pyrrolo[2,3-d]pyrimidin-2-yl)-4-phenylpiperidin-4-yl)carbamate tert-butyl ester 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)carbamate tert-butyl ester

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

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

the 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

(1-(4-cyano-5-(4-chloro-2-methyl-2H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)- 4-Phenylpiperidin-4-yl) tert-butyl carbamate 24c (100 mg, 171.50 μmol) and trifluoroacetic acid (0.5 mL) were added to dichloromethane (1.5 mL), and reacted at room temperature for 2 hours. After the reaction, Concentration under reduced pressure gave 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%, was directly carried out to the next reaction without purification.

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

the 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-carboxamide

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 (80mg, 165.64μmol) and sodium hydroxide (66.26mg, 1.66mmol) were added to methanol (3mL), hydrogen peroxide (1mL) was added, and stirred at room temperature for 2 hours. After the reaction was completed, three Adjust the pH to 7 with fluoroacetic acid, concentrate under reduced pressure, and separate the preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain 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)carbamate tert-butyl ester

N,N-Diisopropylethylamine (737.60 mg, 5.71 mmol, 943.22 μL) was added to 3-bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d ( 491.70 mg, 1.90 mmol) and (4-(2-fluorophenyl)piperidin-4-yl) tert-butyl carbamate 25a (560 mg, 1.90 mmol) in N,N-dimethylacetamide (3 mL), Heat at 100°C and stir for 1 hour. After the reaction is over, add water and ethyl acetate, extract three times with ethyl acetate, combine the organic phases, and concentrate under reduced pressure. The obtained residue is further analyzed and purified by silica gel column chromatography (eluent: System A), to obtain (1-(3-bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-(2-fluorophenyl)piperidine-4 -yl) tert-butyl carbamate 25b (600 mg), yield: 61.08%.

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

second step

(1-(3-(3,4-Dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidine-6- Base)-4-(2-fluorophenyl)piperidin-4-yl)tert-butyl carbamate

(1-(3-bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-(2-fluorophenyl)piperidin-4-yl)amino tert-butyl formate 25b (150mg, 290.49μmol), (3,4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid 1g (213.40mg, 871.48μmol), methanesulfonic acid (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (72.97mg, 87.15 μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (81.22mg, 174.30μmol) and potassium phosphate (307.92mg, 1.45mmol) were added to 1, In a mixed solution of 4-dioxane (5mL) and water (0.5mL). Argon was replaced three times, heated to 130°C, and reacted for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(3-(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)amino tert-Butyl formate 25c (40mg), 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

(1-(3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)-4-(2-fluorophenyl)piperidin-4-yl)carbamate tert-butyl ester 25c (40 mg, 62.84 μmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (2 mL) and stirred at room temperature After 2 hours, after the reaction was completed, it was concentrated under reduced pressure to obtain 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), without purification, was directly used for the next reaction. MS m/z(ESI):519.1[M-16]

the fourth 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-carboxamide

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 (33mg, 61.52μmol) was dissolved in methanol (2mL), sodium hydroxide (24.61mg, 615.22μmol) was added, and hydrogen peroxide (0.5mL ), stirred at room temperature for 2 hours. After the reaction, the pH was adjusted to 7 with trifluoroacetic acid, concentrated under reduced pressure, and the preparative liquid phase was separated (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O , mobile phase B: CH ₃ CN), to obtain 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 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-pyridine Azolo[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)carbamate tert-butyl ester

(1-(3-bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-(2-fluorophenyl)piperidin-4-yl)amino tert-butyl formate 25b (180mg, 348.59μmol), 7-chloro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2- base) benzo[d]thiazole 14a (198.24mg, 871.48μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-Amino-1,1'-biphenyl-2-yl)palladium (58.38mg, 69.72μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'- Biphenyl (64.98 mg, 139.44 μmol) and potassium phosphate (369.51 mg, 1.74 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°C, and reacted for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (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 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-pyridine Azolo[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-(2-fluorophenyl) piperidin-4-yl) tert-butyl carbamate 26a (160 mg, 258.44 μmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (2 mL), stirred at room temperature for 1 Hours, after the reaction was over, concentrated under reduced pressure to obtain 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 (130mg), without further purification, directly proceeded to the next reaction.

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

third step

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

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 (130mg, 250.48μmol) was dissolved in methanol (2mL), added sodium hydroxide (100.19mg, 2.50mmol), added hydrogen peroxide (0.6mL), room temperature Stir for 2 hours, after the reaction is finished, adjust pH=7 with trifluoroacetic acid, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5 μm, 20mL/min; mobile phase A: 0.05% TFA + H ₂ O, mobile phase B: CH ₃ CN), to obtain 6-(4-amino-4-(2-fluorophenyl)piperidin-1-yl)-3-(7-chloro-2-methyl Benzo[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-pyrazole And[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)- tert-butyl 4-(2-fluorophenyl)piperidin-4-yl)carbamate

(1-(3-bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-(2-fluorophenyl)piperidin-4-yl)amino tert-butyl formate 25b (150mg, 290.49μmol), (4-chloro-2-methyl-2H-indazol-5-yl) boronic acid 23a (140.07mg, 665.64μmol), methanesulfonic acid (2-dicyclohexyl Phosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (44.59 mg, 53.25 μmol), 2-Dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (49.63mg, 106.50μmol) and potassium phosphate (282.23mg, 1.33mmol) were added to 1,4-bis In a mixed solution of oxane (3mL) and water (0.3mL). Argon was replaced three times, heated to 110°C, and reacted for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(3-(4-chloro-2-methyl-2H-indazole -5-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-(2-fluorophenyl)piperidin-4-yl)carbamate tert-butyl Ester 27a (60 mg), yield: 37.43%.

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

second step

6-(4-amino-4-(2-fluorophenyl)piperidin-1-yl)-3-(4-chloro-2-methyl-2H-indazol-5-yl)-1H-pyrazole And[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-(2-Fluorophenyl)piperidin-4-yl)carbamate tert-butyl ester 27a (20 mg, 33.22 μmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (3 mL), stirred at room temperature for 1 h , after the reaction, concentrated under reduced pressure, preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2mm ID; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: 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-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-pyrazole And[3,4-d]pyrimidine-4-carboxamide

first step

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

6-(4-amino-4-(2-fluorophenyl)piperidin-1-yl)-3-(4-chloro-2-methyl-2H-indazol-5-yl)-1H-pyridine Azolo[3,4-d]pyrimidine-4-carbonitrile 27 (35mg, 69.73μmol) was dissolved in methanol (1.5mL), added sodium hydroxide (27.89mg, 697.29μmol), added hydrogen peroxide (0.5mL), and reacted at room temperature After 1 hour, after the reaction, adjust pH=7 with trifluoroacetic acid, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+ H ₂ O, mobile phase B: CH ₃ CN), to give 6-(4-amino-4-(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 (400mg, 1.55mmol), N,N-diisopropylethylamine (602.34mg, 4.66mmol, 860.49 μL) and (4-(2-fluorophenyl) piperidin-4-yl) tert-butyl carbamate 25a (548.77 mg, 1.86 mmol) were added to N-methylpyrrolidone (4 mL), heated to 115 ° C, Reacted for 18 hours, after the reaction was finished, add water (40mL) and ethyl acetate (30mL) and stir, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue obtained was further analyzed and purified by silica gel column chromatography (Eluent: A system), to obtain (1-(5-bromo-4-cyano-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-(2-fluorophenyl) tert-butyl 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) tert-butyl carbamate

(1-(5-bromo-4-cyano-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-(2-fluorophenyl)piperidin-4-yl)carbamate Tert-butyl ester 29a (100mg, 194.03μmol), (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (118.78mg, 485.08μmol), methanesulfonic acid (2-di Cyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (32.50mg, 38.81μmol ), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (36.17mg, 77.61μmol) and potassium phosphate (205.67mg, 970.16μmol) were added to 1,4 - in a mixed solution of dioxane (5 mL) and water (0.5 mL). Argon was replaced three times, heated to 110°C, and reacted for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (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 tert-Butyl ester 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

(1-(5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-4-cyano-7H-pyrrolo[2,3-d]pyrimidine-2- yl)-4-(2-fluorophenyl)piperidin-4-yl)carbamate tert-butyl ester 29b (20 mg, 31.47 μmol) and trifluoroacetic acid (0.7 mL) were added to dichloromethane (2 mL) and heated to 30°C, stirred for 1 hour, after the reaction was completed, concentrated under reduced pressure to obtain 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), without purification, was directly used for the next reaction.

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

the 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-carboxamide

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 (16mg, 29.88μmol) and sodium hydroxide (11.95mg, 298.84μmol) were dissolved in methanol (2mL), hydrogen peroxide (0.7mL) was added, and reacted at room temperature After 1 hour, after the reaction, adjust pH=7 with trifluoroacetic acid, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+ H ₂ O, mobile phase B: CH ₃ CN), to give 2-(4-amino-4-(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-pyrrole And[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)- tert-butyl 4-(2-fluorophenyl)piperidin-4-yl)carbamate

(1-(5-bromo-4-cyano-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-(2-fluorophenyl)piperidin-4-yl)carbamate tert-butyl ester 29a (119 mg, 231.16 μmol), 7-chloro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) benzo[d]thiazole 14a (131.46mg, 577.90μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)( 2-Amino-1,1'-biphenyl-2-yl)palladium (38.71mg, 46.23μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-bi Benzene (43.09 mg, 92.46 μmol) and potassium phosphate (245.03 mg, 1.16 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 100°C, and reacted for 6 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (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)tert-butylcarbamate Ester 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-pyrrole And[2,3-d]pyrimidine-4-carbonitrile

(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 tert-butyl ester 30a (100mg, 97.07μmol) and trifluoroacetic acid (0.6mL) were added to dichloromethane (2mL) and reacted at room temperature for 1 hour , after the reaction, concentrated under reduced pressure to obtain 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) was directly carried on 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-pyrrole And[2,3-d]pyrimidine-4-carboxamide

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 (40mg, 77.22μmol) and sodium hydroxide (3.09mg, 77.22μmol) were dissolved in methanol (2mL), hydrogen peroxide (0.7mL) was added, and reacted at room temperature for 1 hour , after the reaction, adjust pH=7 with trifluoroacetic acid, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain 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)carbamate tert-butyl ester

(1-(5-bromo-4-cyano-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-(2-fluorophenyl)piperidin-4-yl)carbamate tert-butyl ester 29a (108mg, 209.56μmol), (4-chloro-2-methyl-2H-indazol-5-yl) boronic acid 23a (110.24mg, 523.89μmol), methanesulfonic acid (2-dicyclohexylphosphine Base-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (35.10mg, 41.91μmol), 2 -Dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (39.06mg, 83.82μmol) and potassium phosphate (222.13mg, 1.05mmol) were added to 1,4-diox Hexacyclic (5mL) and water (0.5mL) mixed solution. Argon was replaced three times, heated to 110°C, and reacted for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(5-(4-chloro-2-methyl-2H-indazole -5-yl)-4-cyano-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-(2-fluorophenyl)piperidin-4-yl)carbamate tert-butyl 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)- tert-Butyl 4-(2-fluorophenyl)piperidin-4-yl)carbamate 31a (43 mg, 71.54 μmol) and trifluoroacetic acid (0.7 mL) were added to dichloromethane (2 mL), and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 2-(4-amino-4-(2-fluorophenyl)piperidin-1-yl)-5-(4-chloro-2-methyl-2H-indazole- 5-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 31b (35 mg), without purification, was directly used for the next reaction.

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-carboxamide

2-(4-amino-4-(2-fluorophenyl)piperidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-7H-pyrrole Dissolve [2,3-d]pyrimidine-4-carbonitrile 31b (35 mg, 69.87 μmol) and sodium hydroxide (11.95 mg, 298.84 μmol) in methanol (2 mL), add hydrogen peroxide (0.7 mL), and react at room temperature for 1 hour , after the reaction, adjust pH=7 with trifluoroacetic acid, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain 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-(naphthalene-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)amino tert-butyl formate

(1-(3-Bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 1f (150mg, 343.80μmol), naphthalen-2-ylboronic acid 32a (177.39mg, 1.03mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1' -biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (57.58 mg, 68.76 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy- 1,1'-Biphenyl (64.08 mg, 137.52 μmol) 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°C, and reacted for 18 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(4-cyano-3-(naphthalene-2-yl)-1H -pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 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

(1-(4-cyano-3-(naphthalene-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl) Tert-butyl carbamate 32b (40 mg, 82.7 μmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (3 mL), and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 6-(4-amino-4-methylpiperidin-1-yl)-3-(naphthalene-2-yl)-1H-pyrazolo[3,4-d] Pyrimidine-4-carbonitrile 32c (40 mg), without purification, was directly carried on to the next reaction.

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

third step

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

6-(4-Amino-4-methylpiperidin-1-yl)-3-(naphthalene-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 32c (40mg , 104.32μmol) and sodium hydroxide (41.73mg, 1.04mmol) were dissolved in methanol (2mL), hydrogen peroxide (0.8mL) was added, and reacted at room temperature for 2 hours. Concentration, preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2mm ID; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain 6-(4 -Amino-4-methylpiperidin-1-yl)-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxamide 32 (15.99 mg), yielding Rate: 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

tert-butyl 4-cyano-4-(2-methoxyphenyl)piperidine-1-carboxylate

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-dimethyl Formamide (6 mL) was added in batches with 60% sodium hydride (1.06 g, 26.51 mmol), stirred for 40 minutes, then heated to 70°C, and reacted overnight. Cool down to room temperature, add water (100 mL) to quench the reaction, and extract with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 4-cyano-4-(2-methoxyphenyl)piperidine-1-carboxylate 33b (1.7g) , Yield: 79.1%.

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

second step

tert-Butyl 4-carbamoyl-4-(2-methoxyphenyl)piperidine-1-carboxylate

Potassium hydroxide (283.75 mg, 5.06 mmol) and tert-butyl 4-cyano-4-(2-methoxyphenyl)piperidine-1-carboxylate 33b (0.8 g, 2.53 mmol) were dissolved in dimethyl To sulfoxide (5 mL), hydrogen peroxide (5 mL) was slowly added dropwise. React overnight at room temperature. A large amount of water (50 mL) was added to precipitate a yellow solid. After filtering, the filter cake was washed with water and dried to obtain tert-butyl 4-carbamoyl-4-(2-methoxyphenyl)piperidine-1-carboxylate 33c (400 mg), yield: 47.3%.

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

third step

tert-butyl 4-amino-4-(2-methoxyphenyl)piperidine-1-carboxylate

Potassium hydroxide (302.02 mg, 5.38 mmol) was added to tert-butyl 4-carbamoyl-4-(2-methoxyphenyl)piperidine-1-carboxylate 33c (400 mg, 1.20 mmol) in acetonitrile (2 mL ) and water (3 mL), 1,3-dibromo-5,5-dimethylhydantoin (188.10 mg, 657.88 μmol) was added in portions, and stirred at room temperature for 1 hour. Add water (100mL) and potassium phosphate (279.30mg, 1.32mmol), stir for 15 minutes, add ethyl acetate (20mL) and sodium sulfite (15.07mg, 119.61μmol), separate the layers, and wash the aqueous phase with ethyl acetate (20mL×2 ) extraction, the organic phases were combined and washed with saturated sodium chloride solution (20 mL), dried, and concentrated under reduced pressure to obtain tert-butyl 4-amino-4-(2-methoxyphenyl)piperidine-1-carboxylate 33d ( 366 mg), yield: 99.6%, directly proceed to the next reaction without purification.

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

the fourth step

4-(2-Methoxyphenyl)piperidin-4-amine

4-Amino-4-(2-methoxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 33d (366 mg, 1.19 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 g, 26.31 mmol), stirred overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure to obtain 4-(2-methoxyphenyl)piperidin-4-amine 33e, which was directly carried out to the next reaction without further purification.

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

the 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 (283.17mg, 1.10mmol), the crude product 4-(2-methoxyphenyl)piperidine -4-Amine 33e and N,N-diisopropylethylamine (566.37mg, 4.38mmol) were sequentially added to N-methylpyrrolidone (3mL), replaced with argon, and stirred at 100°C for 2 hours. Water (30 mL) was added to quench the reaction, and extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to obtain the product 6-(4-amino-4-(2-methoxy phenyl)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]

step six

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( 100mg, 122μmol), (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (229mg, 934μmol), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (39.1mg, 46.7μmol), 2-dicyclohexylphosphine -2',6'-Diisopropoxy-1,1'-biphenyl (43.6 mg, 93.4 μmol) and potassium phosphate (149 mg, 700 μmol) were added to 1,4-dioxane (5 mL) and water (1 mL) of the mixed solution. Argon was replaced three times, and the reaction was heated at 100°C overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10 mL) and water (10 mL), extract the aqueous phase with ethyl acetate (10 mL×2), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and the resulting residue is further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain 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 33g (25mg), yield Rate: 20%.

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

step seven

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

Potassium hydroxide (5.1 mg, 91 μmol) and 6-(4-amino-4-(2-methoxyphenyl) piperidin-1-yl)-3-(3,4-dichloro-2-methyl Base-2H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 33g (25mg, 46μmol) was added to dimethyl sulfoxide (1mL) solution, slowly drop Add hydrogen peroxide (30%, 0.5mL) to the reaction solution, stir for 1 hour after the dropwise addition is complete, after the reaction is complete, add trifluoroacetic acid dropwise, adjust the pH to 3-4, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain 6-(4-amino-4-(2-methanol Oxyphenyl)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 (0.7g, 2.71mmol), 4-phenylpiperidin-4-amine 8a (470mg, 2.67 mmol) and N,N-diisopropylethylamine (1.38 g, 10.7 mmol, 1.77 mL) were sequentially added to N-methylpyrrolidone (6.23 mL). Replaced with argon, heated to 100°C, and reacted for 4 hours. After the reaction was complete, cool down to room temperature, add aqueous solution (30mL) to quench the reaction, add ethyl acetate (30mL), extract the aqueous phase with ethyl acetate (30mL×2), combine the organic phases, wash with saturated brine, anhydrous Dry over sodium sulfate, concentrate under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: A system) to obtain 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 μmol), 7- Chloro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 14a (155mg, 502μmol) , Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl ) palladium (42mg, 50μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (46.9mg, 100μmol) and potassium phosphate (213mg, 1.00mmol) into a mixed solution of 1,4-dioxane (3 mL) and water (0.5 mL). The argon gas was replaced three times, and the reaction was heated at 130° C. for 24 hours. After the reaction was complete, concentrate under reduced pressure, add saturated ammonium chloride aqueous solution (30mL) to quench the reaction, add ethyl acetate (30mL), extract the aqueous phase with ethyl acetate (30mL×2), combine the organic phases, and wash with saturated brine Washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 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

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

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 (40mg, 80μmol) was dissolved in dimethyl sulfoxide (1mL), potassium hydroxide (8.96mg, 160μmol) was added, and hydrogen peroxide (30%, 0.4mL) was slowly added , react overnight at room temperature. After the reaction was completed, water (100ml) was added, stirred for 15 minutes, and a solid was precipitated. Preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to obtain 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 (200mg, 503.43μmol), 7- Chloro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 14a (468.36mg, 1.51 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (141.17mg, 302.54μmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (126.67 mg, 151.27 μmol) and potassium phosphate (642.20 mg, 3.03mmol) was added to a mixed solution of 1,4-dioxane (3mL) and water (0.5mL). The argon gas was replaced three times, and the reaction was heated at 130° C. for 16 hours. After the reaction was complete, concentrate under reduced pressure, add saturated ammonium chloride aqueous solution (30mL) to quench the reaction, add ethyl acetate (30mL), extract the aqueous phase with ethyl acetate (30mL×2), combine the organic phases, and wash with saturated brine Washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 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-carboxamide

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 μmol) was dissolved in dimethylsulfoxide (3 mL), potassium hydroxide (8.98 mg, 159.99 μmol) was added, hydrogen peroxide (0.5 mL) was added slowly, and at room temperature React for 2 hours. After the reaction was completed, filter, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to give 2-(4-amino-4-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 (0.2g, 502.19μmol), 2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 36a (207.08mg, 753.28μmol ), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (70.30mg, 150.66μmol), methanesulfonic acid (2-dicyclohexylphosphino-2' ,6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (63.08mg, 75.33μmol) and potassium phosphate (319.80mg , 1.51mmol) was added to a mixed solution of 1,4-dioxane (3mL) and water (0.5mL). The argon gas was replaced three times, and the reaction was heated at 130° C. for 16 hours. After the reaction was complete, concentrate under reduced pressure, add saturated ammonium chloride aqueous solution (30mL) to quench the reaction, add ethyl acetate (30mL), extract the aqueous phase with ethyl acetate (30mL×2), combine the organic phases, and wash with saturated brine Washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 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

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

6-(4-amino-4-phenylpiperidin-1-yl)-3-(2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d ] Pyrimidine-4-carbonitrile 36b (50mg, 107.17μmol) was dissolved in dimethyl sulfoxide (3mL), potassium hydroxide (12.03mg, 214.33μmol) was added, hydrogen peroxide (0.5mL) was added slowly, and the reaction was carried out at room temperature for 2 Hour. After the reaction was completed, filter, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to obtain 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)carbamate tert-butyl ester

(1-(3-Bromo-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 1f (330mg, 756.35μmol), 7-chloro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[ d] Thiazole 14a (468.36 mg, 1.51 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino- 1,1'-biphenyl-2-yl)palladium (126.67mg, 151.27μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (141.17mg , 302.54μmol) and potassium phosphate (642.20mg, 3.03mmol) were added to a mixed solution of 1,4-dioxane (3mL) and water (0.5mL). The argon gas was replaced three times, and the reaction was heated at 130° C. for 48 hours. After the reaction was complete, concentrate under reduced pressure, add saturated ammonium chloride aqueous solution (30mL) to quench the reaction, add ethyl acetate (30mL), extract the aqueous phase with ethyl acetate (30mL×2), combine the organic phases, and wash with saturated brine Washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain (1-(3-(7-chloro-2-methylbenzo[ d] Thiazol-6-yl)-4-cyano-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)tert-butyl 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)carbamate tert-butyl ester 37a (140mg, 259.72μmol) was dissolved in dichloromethane (5mL), slowly added trifluoroacetic acid (3g, 26.31mmol), at room temperature React for 3 hours. After the reaction was completed, it was 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, and concentrated under reduced pressure to obtain 6-(4-amino -4-methylpiperidin-1-yl)-3-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidine- 4-Nitrile 37b (100 mg), Yield: 87.72%.

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

third step

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

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 μmol) was dissolved in dimethyl sulfoxide (3 mL), potassium hydroxide (25.57 mg, 455.65 μmol) was added, and hydrogen peroxide (0.5 mL) was added slowly , reacted at room temperature for 3 hours. After the reaction was completed, filter, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to give 6-(4-amino-4-methylpiperidin-1-yl)-3-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-1H-pyrazole Ac[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-formamide

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 μmol), 2- Methyl-2H-indazole-5-boronic acid 38a (66.3mg, 0.38mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-bis Phenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (42.1 mg, 50 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1 '-Biphenyl (46.9 mg, 100 μmol) 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 replaced three times, heated at 100°C, and reacted overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the layers, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, anhydrous Drying over sodium sulfate and concentrating under reduced pressure, the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain 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

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

Potassium hydroxide (12.5 mg, 222 μmol) and 6-(4-amino-4-phenylpiperidin-1-yl)-3-(2-methyl-2H-indazol-5-yl)-1H- Pyrazolo[3,4-d]pyrimidine-4-carbonitrile 38b (50mg, 111μmol) was added to dimethyl sulfoxide (2mL) solution, and hydrogen peroxide (30%, 1mL) was slowly added dropwise to the reaction solution, and the Stir for 1 hour after the completion of the reaction. After the reaction is complete, add dropwise trifluoroacetic acid to adjust the pH to 3-4, and prepare liquid phase separation (mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 6-(4- Amino-4-phenylpiperidin-1-yl)-3-(2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-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 - In a solution of 7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 2c (140 mg, 544 μmol) in N-methylpyrrolidone (3 mL), heat to 100° C. and stir for 1 hour. After the reaction is complete, reverse phase chromatography column separation (mobile phase A: H ₂ O, mobile phase B: CH ₃ CN) to obtain 2-(4-amino-4-(2,2-difluoroethyl)piperidine- 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( 150mg, 389μmol), 7-chloro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d] Thiazole 14a (241.1mg, 0.78mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1, 1'-biphenyl-2-yl)palladium (65.2mg, 78μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (72.7mg, 156μmol) And potassium phosphate (248.0mg, 1.17mmol) was added to a mixed solution of 1,4-dioxane (5mL) and water (1mL). Argon was replaced three times, heated at 100°C, and reacted overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the layers, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, anhydrous Drying over sodium sulfate and concentrating under reduced pressure, the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: system A) to obtain 2-(4-amino-4-(2,2-difluoroethyl)piperene Pyridin-1-yl)-5-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 39b (140mg) , Yield: 73.7%. MS m/z(ESI):487.9[M+1]

third 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-carboxamide

Potassium hydroxide (32.2 mg, 574 μmol) and 2-(4-amino-4-(2,2-difluoroethyl) piperidin-1-yl)-5-(7-chloro-2-methylbenzene And[d]thiazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 39b (140mg, 287μmol) was added to dimethyl sulfoxide (2mL) solution, and hydrogen peroxide ( 30%, 1mL) into the reaction solution, stirred for 1 hour after the dropwise addition, after the reaction was complete, added dropwise trifluoroacetic acid to adjust the pH to 3-4, and prepared liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 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 39 (4 mg), yield: 2.2 %.

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

Example 40

6-(4-Amino-4-(2,2,2-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-(2,2,2-trifluoroethyl)piperidine-4-carboxylic acid

Add sodium hydroxide (1.23 g, 30.65 mmol) to 1-(tert-butyl)-4-ethyl-4-(2,2,2-trifluoroethyl)piperidine-1,4-dicarboxylic acid Ester 40a (2.6g, 7.66mmol, self-produced according to patent WO2010106081) in a mixed solution of ethanol (10mL) and water (10mL), heated to 60°C, and reacted for 20 hours. Concentrate to remove ethanol, add 4N dilute hydrochloric acid to adjust the pH of the solution to 1, extract with ethyl acetate (30mL×3), separate the water layer, and wash the combined organic phase with saturated sodium chloride solution (30mL×2) successively, and anhydrous sulfuric acid Na-dried, concentrated to dryness, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to obtain 1-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl) Piperidine-4-carboxylic acid 40b (2.0 g), yield: 83.9%.

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

second step

tert-butyl 4-carbamoyl-4-(2,2,2-trifluoroethyl)piperidine-1-carboxylate

N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (3.66g, 9.64mmol) was added to 1-(tert-butoxy Carbonyl)-4-(2,2,2-trifluoroethyl)piperidine-4-carboxylic acid 40b (2.0g, 6.42mmol) and N,N of diisopropylethylamine (124.6mg, 0.96mmol) - Dimethylformamide (10 mL) solution, heated to 60° C., reacted for half an hour, added dropwise 7M ammonia methanol solution (20 mL), heated to 60° C., reacted for 20 hours. After the reaction is complete, add 100 mL of water, extract with ethyl acetate (50 mL×3), separate the water layer, and wash the combined organic phase with saturated sodium chloride solution (30 mL×2) successively, dry over anhydrous sodium sulfate, and concentrate to dryness , the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: system A) to obtain tert-1-carbamoyl-4-(2,2,2-trifluoroethyl)piperidine-1-carboxylate Butyl ester 40c (1.7 g), yield: 85.3%.

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

third step

tert-butyl 4-amino-4-(2,2,2-trifluoroethyl)piperidine-1-carboxylate

[Bis(trifluoroacetoxy)iodo]benzene (2.59 g, 6.03 mmol) was added to tert-butyl 4-carbamoyl-4-(2,2,2-trifluoroethyl)piperidine-1-carboxylate In a mixed solution of ester 40c (1.7g, 5.48mmol) in acetonitrile (15mL) and water (15mL), heat to 60°C and react for 2 hours. After the reaction was complete, add saturated sodium bicarbonate solution (40mL), extract with ethyl acetate (30mL×3), wash with saturated sodium chloride solution (30mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain The residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 4-amino-4-(2,2,2-trifluoroethyl)piperidine-1-carboxylate 40d ( 600 mg), yield: 38.8%.

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

the fourth step

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

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

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

the fifth step

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

Diisopropylethylamine (675.1 mg, 5.22 mmol) and the above crude 4-(2,2,2-trifluoroethyl)piperidin-4-amine 40e were added to 3-bromo-6-chloro-1H- In a solution of pyrazolo[3,4-d]pyrimidine-4-carbonitrile 1d (450mg, 1.74mmol) in N-methylpyrrolidone (5mL), heat to 100°C and stir for 1 hour. After the reaction was complete, reversed-phase chromatographic column separation (mobile phase A: H ₂ O, mobile phase B: CH ₃ CN) gave 6-(4-amino-4-(2,2,2-trifluoroethyl)piperene Pyridin-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]

step six

6-(4-Amino-4-(2,2,2-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-(2,2,2-trifluoroethyl)piperidin-1-yl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4- Nitrile 40f (80mg, 198μmol), 7-chloro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo [d] Thiazole 14a (122.6 mg, 396 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino -1,1'-biphenyl-2-yl)palladium (33.2mg, 40μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (36.9mg , 79μmol) and potassium phosphate (168.1mg, 0.79mmol) were added to a mixed solution of 1,4-dioxane (5mL) and water (1mL). Argon was replaced three times, heated at 100°C, and reacted overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10mL) and water (10mL), extract and separate the layers, extract the aqueous phase with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine, anhydrous Drying over sodium sulfate and concentrating under reduced pressure, the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain 6-(4-amino-4-(2,2,2-trifluoroethyl )piperidin-1-yl)-3-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 40g (50 mg), yield: 49.8%.

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

step seven

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

Potassium hydroxide (11.1 mg, 197 μmol) and 6-(4-amino-4-(2,2,2-trifluoroethyl)piperidin-1-yl)-3-(7-chloro-2-methyl 40 g (50 mg, 99 μmol) of benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile was added to dimethyl sulfoxide (1 mL) solution, and slowly dropped Add hydrogen peroxide (30%, 0.5mL) to the reaction solution, stir for 1 hour after the dropwise addition is complete, after the reaction is complete, add trifluoroacetic acid dropwise to adjust the pH to 3-4, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250× 21.2mm I.D.; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 6-(4-amino-4-(2,2,2-trifluoroethyl)piperene Pyridin-1-yl)-3-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxamide 40( 13 mg), yield: 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-formamide

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 (100mg, 251.72μmol), 2- Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 36a (138.53mg, 503.43μmol), phosphoric acid Potassium (213.73mg, 1.01mmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (46.98mg, 100.69μmol) and methanesulfonic acid (2-di Cyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (42.16mg, 50.34μmol ) was added to a mixed solution of 1,4-dioxane (2 mL) and water (0.4 mL), argon was replaced three times, heated to 130° C., and reacted for 24 hours. Concentration under reduced pressure, the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain 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-formamide

2-(4-amino-4-phenylpiperidin-1-yl)-5-(2-methylbenzo[d]thiazol-6-yl)-7H-pyrrolo[2,3-d] Pyrimidine-4-carbonitrile 41a (40mg, 85.92μmol) was dissolved in dimethyl sulfoxide (2mL), potassium hydroxide (9.64mg, 171.83μmol) was added, hydrogen peroxide (0.4mL) was added slowly, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, filter and separate the preparative liquid phase (separation column AKZONOBEL Kromasil; 250 × 21.2mm I.D.; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B: CH CN), to obtain 2-(4 -Amino-4-phenylpiperidin-1-yl)-5-(2-methylbenzo[d]thiazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-methyl Amide 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 μmol), (4 -Chloro-2-(difluoromethyl)-2H-indazol-5-yl)boronic acid pinacol ester 42a (123.7mg, 0.38mmol), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (42.1mg, 50μmol), 2-dicyclohexylphosphine- 2',6'-Diisopropoxy-1,1'-biphenyl (46.9 mg, 100 μmol) and potassium phosphate (159.9 mg, 0.75 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL) of the mixed solution. Argon was replaced three times, heated to 100°C, and reacted overnight. After the reaction was complete, concentrate under reduced pressure, add ethyl acetate (10 mL) and water (10 mL), extract the aqueous phase with ethyl acetate (10 mL×2), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: A system) to obtain 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

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

Potassium hydroxide (8.6 mg, 154 μmol) and 6-(4-amino-4-phenylpiperidin-1-yl)-3-(4-chloro-2-(difluoromethyl)-2H-indazole -5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 42b (40mg, 77μmol) was added to dimethyl sulfoxide (1mL) solution, and hydrogen peroxide (30%, 0.5 mL) into the reaction solution, stirred for 1 hour after the dropwise addition, after the reaction was complete, added dropwise trifluoroacetic acid to adjust the pH to 3-4, and prepared 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: CH3CN), to obtain 6-(4-amino-4-phenylpiperidin-1-yl)-3-(4-chloro-2-( Difluoromethyl)-2H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxamide 42 (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 -Pyrrolo[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 (259 mg, 2.19 mmol) in N,N-dimethylformamide (3 mL), was added N,N-diisopropylethylamine (602.34 mg, 4.66mmol), after stirring at room temperature for 10 minutes, 5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 2c (400mg, 1.55mmol) was added, and the reaction was heated to 110°C. Stir for 9 hours. Concentrate under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: system A) to obtain 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-pyrrole[2,3-d]pyrimidine-4-carbonitrile 43a (200mg, 589.68μmol ), (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid 1g (216.59mg, 884.52μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6 '-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (98.76mg, 117.94μmol), 2-dicyclohexylphosphine- 2',6'-Diisopropoxy-1,1'-biphenyl (109.92 mg, 235.87 μmol) and potassium phosphate (625.06 mg, 2.95 mmol) were added to 1,4-dioxane (5 mL) and in a mixed solution of water (1 mL). Argon was replaced three times, heated to 130°C, and reacted for 18 hours. After the reaction was complete, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 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-carbonitrile 43b (60 mg), yield: 22.15%.

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

third 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-carboxamide

To 2-((3R,4R)-4-amino-3-fluoropiperidin-1-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)- Sodium hydroxide (5M, 130.63 μL) was added to 7H-pyrrole[2,3-d]pyrimidine-4-carbonitrile 43b (60 mg, 130.63 μmol) in methanol (3 mL), and then hydrogen peroxide (0.5 mL) was slowly added dropwise. React at room temperature for 1 hour. After the reaction, add trifluoroacetic acid to adjust the pH to 3-4, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H O , mobile phase B: CH3CN), to obtain 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 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-pyrrole And[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-pyrrole[2,3-d]pyrimidine-4-carbonitrile 43a (350mg, 1.03mmol ) into tetrahydrofuran (6mL), sodium hydride (98.42mg, 2.27mmol, 60%purity) was added to the above mixed solution at low temperature, stirred at 0°C for 30 minutes, and 2-(trimethylsilyl)ethoxymethyl Dichloride (361.30 mg, 2.17 mmol) was added to the above solution, and stirring was continued at room temperature. React for 1 hour. After the reaction is complete, extract the reaction solution with ethyl acetate and water, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue is 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 (70mg, 149.12μmol), 7-chloro-2-methyl-6-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)benzo[d]thiazole 14a (115.42 mg, 372.80 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropyl Oxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (12.49 mg, 14.91 μmol), 2-dicyclohexylphosphine-2',6' -Diisopropoxy-1,1'-biphenyl (13.90mg, 29.82μmol) and potassium phosphate (158.07mg, 745.59μmol) were added to N,N-dimethylacetamide (2mL), replaced by argon three times , heated to 80°C, and stirred for 2 hours. After the reaction is complete, the reaction is cooled to room temperature, ethyl acetate and water are extracted, the organic phases are combined, and finally the organic phase is washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue is passed through a silica gel column layer. Analysis and purification (eluent: A system) to obtain 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 (40mg) , 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)-7H-pyrrole And[2,3-d]pyrimidine-4-carboxamide

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 μmol) and trifluoroacetic acid (1 mL) were added into dichloromethane (2 mL), react at room temperature overnight, after the reaction, concentrate under reduced pressure, add the concentrate to amine methanol solution (2 mL), adjust the pH to 8-9, react at room temperature for 2 hours, and concentrate under reduced pressure , the concentrate was added to methanol (2 mL), and then 5M sodium hydroxide solution (0.5 mL) was added, hydrogen peroxide (0.5 mL) was slowly added dropwise, and reacted at room temperature for 1 hour. The reaction was complete, the pH was adjusted to 3-4 with trifluoroacetic acid, concentrated under reduced pressure, and the preparative liquid phase was separated (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H O, flow Phase B: CH3CN) to give 2-((3R,4R)-4-amino-3-fluoropiperidin-1-yl)-5-(7-chloro-2-methylbenzo[d]thiazole-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-ylcarbamate tert-butyl ester

5-Bromo-2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 45a (248.24mg ,960.45μmol), (4-(2,4-difluorophenyl) piperidin-4-yl) tert-butyl carbamate 21g (300mg, 960.45μmol) and N,N-diisopropylethylamine (124.13 mg, 960.45μmol) was added to N,N-dimethylacetamide (2mL) successively, stirred continuously at 100°C, and reacted overnight. After the reaction was complete, the reaction solution 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, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (washing Removal agent: A system), to obtain (1-(5-bromo-4-cyano-7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3 -d] tert-butyl 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)carbamate tert-butyl

2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 36a (158.23mg, 575.02μmol ), (1-(5-bromo-4-cyano-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2 -yl)-4-(2,4-difluorophenyl)piperidin-4-ylcarbamate tert-butyl ester 45b (318mg, 479.18μmol), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (80.25mg, 95.84μmol), 2-dicyclohexylphosphine -2',6'-diisopropoxy-1,1'-biphenyl (89.44mg, 191.67μmol) and potassium phosphate (122.06mg, 575.02μmol) were added to N,N-dimethylformamide ( 3mL), reacted overnight at 100°C. After the reaction was complete, the reaction solution was cooled to room temperature, extracted with ethyl acetate and saturated sodium chloride, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was passed through a silica gel column Chromatographic purification (eluent: A system) to obtain (1-(4-cyano-5-(2-methylbenzo[d]thiazol-6-yl)-7-((2-(trimethyl ylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-(2,4-difluorophenyl)piperidin-4-yl)amino tert-butyl formate 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

(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 tert-butyl ester 45c (50mg, 68.31μmol) was added Add dichloromethane (1.5mL) and trifluoroacetic acid (0.5mL) mixed solution, react at room temperature for 1 hour, the reaction is complete, concentrate under reduced pressure, add saturated sodium bicarbonate to the reaction solution for neutralization, organic phase anhydrous sodium sulfate Dry and distill under reduced pressure. The resulting concentrate was added to amine methanol solution (1.5 mL), adjusted to pH = 8-9, reacted at room temperature for 2 hours, the reaction was complete, and concentrated under reduced pressure to obtain 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%, directly proceed to the next reaction without purification.

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

the 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-carboxamide

2-(4-amino-4-(2,4-difluorophenyl)piperidin-1-yl)-5-(2-methylbenzo[d]thiazol-6-yl)-7H-pyrrole And[2,3-d]pyrimidine-4-carbonitrile 45d (33mg, 71.78μmol) and potassium hydroxide (8.05mg, 143.55μmol) were sequentially added to dimethylsulfoxide (1mL), and 30% hydrogen peroxide (0.5 mL), react at 40°C for 1 hour, the reaction is complete, adjust the pH to 3-4 with trifluoroacetic acid, concentrate under reduced pressure, and prepare 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: CH3CN), to obtain 2-(4-amino-4-(2,4-difluorophenyl)piperidin-1-yl)-5-(2-methyl Benzo[d]thiazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide 45 (6.45 mg), yield: 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-pyrazole And[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-ylcarbamate tert-butyl ester

(4-(2,4-difluorophenyl) piperidin-4-yl) tert-butyl carbamate 21g (190mg, 608.28μmol), 3-bromo-6-chloro-1-(tetrahydro-2H- Pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 46a (190 mg, 608.28 μmol) and N,N-diisopropylethylamine (157.23 mg, 1.22 mmol) Add N-methylpyrrolidone (2 mL) successively, react at 100 ^{° C.} for 1 hour, the reaction is complete, and the reaction is cooled to room temperature. Extract with ethyl acetate and water, combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: system A) to obtain (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-ylcarbamate 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[ tert-butyl 3,4-d]pyrimidin-6-yl)-4-(2,4-difluorophenyl)piperidin-4-ylcarbamate

2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 36a (133.48mg, 485.07μmol ), (1-(3-bromo-4-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)- tert-butyl 4-(2,4-difluorophenyl)piperidin-4-ylcarbamate 46b (150mg, 242.53μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (40.62mg, 48.51μmol), 2-dicyclohexylphosphine-2', 6'-Diisopropoxy-1,1'-biphenyl (45.27mg, 97.01μmol) and potassium phosphate (102.96mg, 485.07μmol) were sequentially added to N,N-dimethylformamide (2mL), argon The gas was replaced three times, heated to 100°C, and reacted overnight. After the reaction was complete, the reaction solution was cooled to room temperature, extracted with ethyl acetate and water, and the organic phases were combined. The organic phase was washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: A system) to obtain (1-(3-(2-methylbenzo[d]thiazol-6-yl)-4-cyano Base-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-(2,4-difluorophenyl)piper tert-Butylpyridin-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-pyrazole And[3,4-d]pyrimidine-4-carbonitrile

(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 tert-butyl ester 46c (70 mg, 101.93 μmol, added to dichloromethane ( 1.5mL), added trifluoroacetic acid (0.5mL), reacted at room temperature for 1 hour, the reaction was complete, concentrated under reduced pressure, neutralized by adding saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 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%, was directly carried out to the next reaction without purification.

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

the fourth step

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

6-(4-amino-4-(2,4-difluorophenyl)piperidin-1-yl)-3-(2-methylbenzo[d]thiazol-6-yl)-1H-pyridine Azolo[3,4-d]pyrimidine-4-carbonitrile 46d (51mg, 101.48μmol) and potassium hydroxide (11.39mg, 202.97μmol) were sequentially added to dimethyl sulfoxide (1.5mL), slowly added dropwise for 30 % hydrogen peroxide (0.5mL), heated to 40°C, reacted for 6 hours, reacted completely, concentrated under reduced pressure, prepared 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: CH3CN), to obtain 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 46 (4.32 mg), yield: 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-(naphthalene-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 (4.0g, 19.94mmol, self-produced according to patent WO2019158655), tetrakistriphenylphosphine palladium (2.30 g, 1.99mmol) and zinc cyanide (5.83g, 49.84mmol) were added to N-methylpyrrolidone (60mL), replaced with argon three times, heated to 120°C, and reacted for 0.5 hours. After the reaction was completed, water (40mL ) and ethyl acetate (30mL), filtered with diatomaceous earth, the organic phase of the filtrate was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: A system) , to obtain 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-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile

6-(Methylthio)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 47b (1.2g, 6.28mmol) and iodosuccinimide (1.55g, 6.90mmol) were added into N,N-dimethylformamide (15mL), heated to 90°C, and reacted for 4 hours. After the reaction, quenched by adding ice water, the filtrate was extracted with ethyl acetate, the organic phase of the filtrate was separated, and anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure to obtain 3-iodo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 47c (1.99g), yield: 100%, Without purification, the next reaction was carried out directly.

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

third step

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

3-Iodo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 47c (1.99 g, 6.28 mmol) was added to N,N-dimethylformamide (25.84mL), cooled to zero degrees Celsius, slowly added sodium hydride (326.45mg, 7.53mmol), reacted for 0.5 hours, then added 2-(trimethylsilyl)ethoxymethyl chloride (1.57g, 9.41mmol, 1.67 mL), stirred in an 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 filtrate was separated from the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, The obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 3-iodo-6-(methylthio)-1-((2-(trimethylsilyl)ethoxy) Methyl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 47d (340 mg), yield: 12.11%.

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

the fourth step

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

3-iodo-6-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4- Nitrile 47d (190 mg, 424.71 μmol), naphthalen-2-ylboronic acid 32a (109.57 mg, 637.06 μmol), bis(triphenylphosphine) palladium chloride (93.14 mg, 127.41 μmol) and potassium phosphate (135.06 mg, 637.06 μmol ) was added to acetonitrile (3mL), replaced by argon three times, heated to 80°C, reacted for 3 hours, concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: A system) to obtain 3-(naphthalene -2-yl)-6-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4 - Nitrile 47e (90 mg), Yield: 47.34%.

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

the fifth step

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

3-(naphthalene-2-yl)-6-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- d] Pyrimidine-4-carbonitrile 47e (90mg, 201.06μmol), m-chloroperoxybenzoic acid (173.48mg, 1.01mmol) were added to dichloromethane (2mL) successively, and reacted at room temperature for 4 hours, the reaction was complete, and added to the reaction solution Add sodium sulfite, stir for 20 minutes, extract with ethyl acetate and water, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the obtained residue is purified by silica gel column chromatography (eluent: system A) to obtain 3-(naphthalene-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).

step six

(8-(4-cyano-3-(naphthalene-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 tert-butyl ester

(3-Methyl-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-butyl ester 20a (28.06 mg, 116.76 μmol), 3-(naphthalene-2-yl)-6-( Methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 47f (56mg, 116.76μmol ) and N,N-diisopropylethylamine (30.36mg, 233.52μmol) were added to N-methylpyrrolidone (1.5mL), heated to 50°C, reacted for 2 hours, the reaction was complete, cooled to room temperature, ethyl acetate Extracted with water, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain (8-(4- Cyano-3-(naphthalen-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-6- 47 g (50 mg) of tert-butyl)-3-methyl-8-azabicyclo[3.2.1]oct-3-yl)carbamate, yield: 66.93%.

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

step seven

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

(8-(4-cyano-3-(naphthalene-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 (50mg, 78.14μmol) was added to dichloromethane (1.5 mL), add trifluoroacetic acid (0.5mL), react at room temperature for 1 hour, the reaction is complete, concentrate under reduced pressure, add a small amount of water to quench the reaction, add saturated sodium bicarbonate solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, reduce Concentrate under reduced pressure, add the obtained residue into amine methanol solution (2 mL), react at room temperature for 1 hour, the reaction is complete, and concentrate under reduced pressure to obtain 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 (31mg), yield: 97.86%, without Purified and proceeded directly to the next reaction.

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

eighth step

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

6-(3-Amino-3-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-(naphthalene-2-yl)-1H-pyrazolo[3,4- d] Pyrimidine-4-carbonitrile 47h (31mg, 75.70μmol) and potassium hydroxide (8.50mg, 151.41μmol) were sequentially added to dimethyl sulfoxide (1mL), and 30% hydrogen peroxide (0.5mL) was slowly added to 40°C, reacted for 0.5 hours, the reaction was complete, concentrated under reduced pressure, and prepared liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 6-(3-amino-3-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-(naphthalene-2-yl)-1H-pyrazolo[3 ,4-d] Pyrimidine-4-carboxamide 47 (6.32 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-d3)-2H-indazol-5-yl)-1H-pyrazolo [3,4-d]pyrimidine-4-carboxamide

first step

5-bromo-4-chloro-2-(methyl-d3)-2H-indazole

Dissolve 5-bromo-4-chloro-1H-indazole 3a (5g, 21.60mmol) in tetrahydrofuran (44.62mL), add sodium hydride (1.40g, 32.40mmol) at low temperature, stir for 30 minutes, add deuteroiodomethane (12.52g, 86.40mmol, 5.38mL), react overnight at room temperature, and the reaction is complete. Add water to quench (10ml), extract with ethyl acetate (15ml×3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, the obtained residue is purified by silica gel column chromatography (eluent: A system), 5-Bromo-4-chloro-2-(methyl-d3)-2H-indazole 48b (1.2 g) was obtained, yield: 22.35%.

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

second step

4-Chloro-2-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)-2H-indazole

5-Bromo-4-chloro-2-(methyl-d3)-2H-indazole 48b (200.00 mg, 804.76 μmol) was added to 1,4-dioxane (6 mL), potassium acetate (236.94 mg , 2.41mmol), added 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (58.88mg, 80.48μmol), heated to 100°C, reacted for 1.5 hours, and the reaction was complete. The reaction solution was cooled to room temperature, filtered with celite, washed with ethyl acetate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 4-chloro-2-(methyl- d3)-5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-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-d3)-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 μmol), 4 -Chloro-2-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)-2H-indazole 48c( 111.33mg, 376.64μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'- Biphenyl-2-yl)palladium (42.05mg, 50.22μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (46.87mg, 100.44μmol) and Potassium phosphate (133.25mg, 627.73μmol) was added to a mixed solution of 1,4-dioxane (3mL) and water (0.3mL). After replacing the gas with argon, heat to 130°C and react for 10 hours. The reaction was complete. , the reaction was cooled to room temperature, ethyl acetate and water were extracted, the organic phase was combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution Reagent: A system) to obtain 6-(4-amino-4-phenylpiperidin-1-yl)-3-(4-chloro-2-(methyl-d3)-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]

the fourth step

6-(4-Amino-4-phenylpiperidin-1-yl)-3-(4-chloro-2-(methyl-d3)-2H-indazol-5-yl)-1H-pyrazolo [3,4-d]pyrimidine-4-carboxamide

6-(4-amino-4-phenylpiperidin-1-yl)-3-(4-chloro-2-(methyl-d3)-2H-indazol-5-yl)-1H-pyrazole And[3,4-d]pyrimidine-4-carbonitrile 48d (60.00mg, 123.21μmol) and 5M sodium hydroxide solution (0.5mL) were added to methanol (3mL), and 30% hydrogen peroxide (0.5mL) was added slowly, React at room temperature for 1 hour. After the reaction is complete, adjust pH=3-4 with trifluoroacetic acid, concentrate under reduced pressure, and prepare 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: CH3CN) to give 6-(4-amino-4-phenylpiperidin-1-yl)-3-(4-chloro-2-(methyl-d3)-2H-indazole-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-d3)-1H-indazol-5-yl)-1H-pyrazolo [3,4-d]pyrimidine-4-carboxamide

first step

5-Bromo-4-chloro-1-(methyl-d3)-1H-indazole

Dissolve 5-bromo-4-chloro-1H-indazole 3a (5g, 21.60mmol, self-produced according to patent WO 2019167000) in tetrahydrofuran (44.62mL), add sodium hydride (1.40g, 32.40mmol) at low temperature, and stir After 30 minutes, deuteroiodomethane (12.52 g, 86.40 mmol, 5.38 mL) was added and reacted at room temperature overnight, and the reaction was complete. Add water to quench (10ml), extract with ethyl acetate (15ml×3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, the obtained residue is purified by silica gel column chromatography (eluent: A system), 5-Bromo-4-chloro-1-(methyl-d3)-1H-indazole 49a (2.2 g) was obtained, yield: 40.98%.

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

second step

4-Chloro-1-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)-1H-indazole

5-Bromo-4-chloro-1-(methyl-d3)-1H-indazole 49a (250 mg, 1.01 mmol) was added to 1,4-dioxane (6 mL), potassium acetate (296.17 mg, 3.02mmol), added 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73.61mg, 100.59μmol), heated to 100°C, reacted for 1.5 hours, and the reaction was complete. The reaction solution was cooled to room temperature, filtered with celite, washed with ethyl acetate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 4-chloro-1-(methyl- d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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-d3)-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 μmol), 4 -Chloro-1-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)-1H-indazole 49b( 111.33mg, 376.64μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'- Biphenyl-2-yl)palladium (42.05mg, 50.22μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (46.87mg, 100.44μmol) and Potassium phosphate (133.25mg, 627.73μmol) was added to a mixed solution of 1,4-dioxane (3mL) and water (0.3mL). After the gas was replaced by argon, it was heated to 130°C and reacted for 8 hours. The reaction was complete. , the reaction was cooled to room temperature, ethyl acetate and water were extracted, the organic phase was combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution Reagent: A system) to obtain 6-(4-amino-4-phenylpiperidin-1-yl)-3-(4-chloro-1-(methyl-d3)-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]

the fourth step

6-(4-Amino-4-phenylpiperidin-1-yl)-3-(4-chloro-1-(methyl-d3)-1H-indazol-5-yl)-1H-pyrazolo [3,4-d]pyrimidine-4-carboxamide

6-(4-amino-4-phenylpiperidin-1-yl)-3-(4-chloro-1-(methyl-d3)-1H-indazol-5-yl)-1H-pyrazole And[3,4-d]pyrimidine-4-carbonitrile 49c (50.00mg, 102.68μmol) and 5M sodium hydroxide (0.5mL) were added to methanol (3mL), and 30% hydrogen peroxide (0.5mL) was slowly added dropwise, React at room temperature for 1 hour, the reaction is complete, adjust pH=3-4 with trifluoroacetic acid, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5μm, 20mL/min; mobile phase A: 0.05 %TFA+H2O, mobile phase B: CH3CN), to obtain 6-(4-amino-4-phenylpiperidin-1-yl)-3-(4-chloro-1-(methyl-d3)-1H- Indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxamide 49 (24 mg), yield: 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 (2g, 8.64mmol), cyclopropylboronic acid (1.11g, 12.96mmol), sodium carbonate (2.29g, 21.60mmol), copper acetate (2.35g , 12.96mmol) and 2,2-bipyridine (2.70g, 17.28mmol) were added to 1,2-dichloroethane (30mL), and reacted at room temperature for 48 hours. After the reaction was completed, the diatomaceous earth was filtered, and the filtrate was concentrated to obtain The residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-bromo-4-chloro-2-cyclopropyl-2H-indazole 50a (1.27g), yield: 54.13%.

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

second step

4-Chloro-2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-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 , add 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (80.84mg, 110.48μmol), heat to 100°C, react for 6 hours, after the reaction, the reaction solution is cooled to room temperature, Pad Celite filter, wash with ethyl acetate, concentrate under reduced pressure, and the obtained residue is purified by silica gel column chromatography (eluent: A system) to obtain 4-chloro-2-cyclopropyl-5-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-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 μmol), 4 -Chloro-2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 50b (120.00mg, 376.64 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl- 2-yl)palladium (42.05mg, 50.22μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (46.87mg, 100.44μmol) and potassium phosphate ( 133.25mg, 627.73μmol) was added to a mixed solution of 1,4-dioxane (3mL) and water (0.3mL), replaced by argon three times, heated to 130°C, and reacted for 15 hours. The reaction was complete, and the reaction was cooled to At room temperature, ethyl acetate and water were extracted, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system), 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]

the 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-indazole-5- base)-1H-pyrazolo[3,4-d]pyrimidine-4-carbonitrile 50c (55mg, 107.84μmol) and 5M sodium hydroxide solution (0.5mL) were added to methanol (2mL), and 30% of hydrogen peroxide (0.5 mL). React at room temperature for 1 hour, the reaction is complete, adjust pH=3-4 with trifluoroacetic acid, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5μm, 20mL/min; mobile phase A: 0.05 %TFA+H2O, mobile phase B: CH3CN), to obtain 6-(4-amino-4-phenylpiperidin-1-yl)-3-(4-chloro-2-cyclopropyl-2H-indazole- 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-d3)-2H-indazol-5-yl)-7H-pyrrolo[2,3- d] pyrimidine-4-carboxamide

first step

2-(4-amino-4-phenylpiperidin-1-yl)-5-(2-(methyl-d3)-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 μmol), 2- (Methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)-2H-indazole 51a (113.11mg, 433.14μmol , self-made according to patent WO 2016180536), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1, 1'-biphenyl-2-yl)palladium (48.36mg, 57.75μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (53.90mg, 115.50 μmol) and potassium phosphate (153.24mg, 721.89μmol) were added to a mixed solution of 1,4-dioxane (3mL) and water (0.3mL), and after replacing the gas with argon, heated to 130°C and reacted for 15 hours , the reaction is complete, the reaction is cooled to room temperature, ethyl acetate and water are extracted, the organic phase is combined, the organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (Eluent: A system) to obtain 2-(4-amino-4-phenylpiperidin-1-yl)-5-(2-(methyl-d3)-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

2-(4-amino-4-phenylpiperidin-1-yl)-5-(2-(methyl-d3)-2H-indazol-5-yl)-7H-pyrrolo[2,3- d] pyrimidine-4-carboxamide

5M sodium hydroxide solution (0.15mL) and 2-(4-amino-4-phenylpiperidin-1-yl)-5-(2-(methyl-d3)-2H-indazole-5- Base)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 51b (33mg, 72.92μmol) was added to methanol (2mL), slowly added 30% hydrogen peroxide (0.3mL), stirred at room temperature for 0.5 hours, and the reaction Completely, add trifluoroacetic acid to adjust the pH to acidity, concentrate under reduced pressure, and prepare 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 : CHCN), to obtain 2-(4-amino-4-phenylpiperidin-1-yl)-5-(2-(methyl-d3)-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-d3)-1H-indazol-5-yl)-7H-pyrrolo[2,3- d] pyrimidine-4-carboxamide

first step

2-(4-amino-4-phenylpiperidin-1-yl)-5-(1-(methyl-d3)-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 μmol), 1- (Methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)-1H-indazole 52a (113.11mg, 433.14μmol , self-made according to patent WO 2016180536), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1, 1'-biphenyl-2-yl)palladium (48.36mg, 57.75μmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (53.90mg, 115.50 μmol) and potassium phosphate (153.24mg, 721.89μmol) were added to a mixed solution of 1,4-dioxane (3mL) and water (0.3mL), and after replacing the gas with argon, heated to 130°C and reacted for 15 hours , the reaction is complete, the reaction is cooled to room temperature, ethyl acetate and water are extracted, the organic phase is combined, the organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (Eluent: A system) to obtain 2-(4-amino-4-phenylpiperidin-1-yl)-5-(1-(methyl-d3)-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

2-(4-amino-4-phenylpiperidin-1-yl)-5-(1-(methyl-d3)-1H-indazol-5-yl)-7H-pyrrolo[2,3- d] pyrimidine-4-carboxamide

5M sodium hydroxide solution (0.2mL) and 2-(4-amino-4-phenylpiperidin-1-yl)-5-(1-(methyl-d3)-1H-indazole-5- Base)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 52b (50.00mg, 110.49μmol) was added to methanol (2mL), slowly added 30% hydrogen peroxide (0.4mL), and stirred at room temperature for 3 hours, After the reaction is complete, add trifluoroacetic acid to adjust the pH to acidity, concentrate under reduced pressure, and prepare liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B: CH3CN) to give 2-(4-amino-4-phenylpiperidin-1-yl)-5-(1-(methyl-d3)-1H-indazol-5-yl)-7H-pyrrole And[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, 1.55mmol), 4-phenylpiperidin-4-amine 8a (362.09mg, 1.70mmol) and N,N-diisopropylethylamine (999.96mg, 7.74mmol) were added to N,N-dimethylethyl Amide (6 mL). Heat to 110°C, react for 7 hours, the reaction is complete, add 30mL of water, extract with ethyl acetate (30mL×3), wash with saturated sodium chloride solution (20mL), dry the organic phase with anhydrous sodium sulfate, filter, and reduce pressure Concentrate, and the obtained residue is purified 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-(tri Methylsilyl)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 (100mg, 189.56μmol), 4-chloro-2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolin-2-yl)-2H-indazole 50b (90.59mg, 284.34μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1, 1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (31.75 mg, 37.91 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy Dimethyl-1,1'-biphenyl (35.38mg, 75.82μmol) and potassium phosphate (100.60mg, 473.91μmol) were added to N,N-dimethylformamide (3mL), replaced with argon three times, and heated to 80°C , and stirred for 2 hours. After the reaction, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was passed through silica gel Purified by column chromatography (eluent: system A) to obtain 2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-2-cyclopropyl-2H-indazole -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 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) in dichloromethane ( 4.5 mL), stirred at room temperature for 2 hours, the reaction was complete, concentrated under reduced pressure, the obtained residue was added to amine methanol solution (3 mL), and reacted at room temperature for 2 hours, the reaction was complete. Concentration under reduced pressure gave 2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-2-cyclopropyl-2H-indazol-5-yl)-7H-pyrrole And[2,3-d]pyrimidine-4-carbonitrile 53c (87.8 mg), yield: 99%, the product was directly used in the next reaction without purification.

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

the 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-carboxamide

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 (87mg, 139.64μmol) and 5M sodium hydroxide solution (0.5mL) were added to methanol (3mL), 30% hydrogen peroxide (0.5mL) was added slowly, and stirred at room temperature for 2 hours , the response is complete. Add trifluoroacetic acid to adjust PH=6-7, concentrate under reduced pressure, and prepare 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 : CHCN), to obtain 2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-2-cyclopropyl-2H-indazol-5-yl)-7H-pyrrole And[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-d3)-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-d3)-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 μmol), 4-chloro-2-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3 ,2-Dioxaborolan-2-yl)-2H-indazole 48c (120mg, 406.78μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (31.75 mg, 37.91 μmol), 2-dicyclohexylphosphine-2',6'-diiso Add propoxy-1,1'-biphenyl (35.38mg, 75.82μmol) and potassium phosphate (100.60mg, 473.91μmol) to N,N-dimethylformamide (3mL), replace with argon three times, and heat to 80°C, stirring for 2 hours. After the reaction, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was passed through silica gel Purified by column chromatography (eluent: system A) to obtain 2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-2-(methyl-d3)-2H -Indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 54a (65mg) , 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-d3)-2H-indazol-5-yl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-carbonitrile

2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-2-(methyl-d3)-2H-indazol-5-yl)-7-(( 2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 54a (61 mg, 98.99 μmol) and trifluoroacetic acid (1 mL) were added to di Chloromethane (2 mL), stirred at room temperature overnight, the reaction was complete, concentrated under reduced pressure, the obtained residue was added to 7M amine methanol solution (2 mL), and reacted at room temperature for 0.5 hours. The reaction was complete and concentrated under reduced pressure to obtain 2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-2-(methyl-d3)-2H-indazole-5- Base)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 54b (48 mg), yield: 99%, the product was directly carried out 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-d3)-2H-indazol-5-yl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-carboxamide

2-(4-Amino-4-phenylpiperidin-1-yl)-5-(4-chloro-2-(methyl-d3)-2H-indazol-5-yl)-7H-pyrrolo [2,3-d]pyrimidine-4-carbonitrile 54b (48mg, 98.77μmol) and 5M sodium hydroxide solution (0.5mL) were added to methanol (3mL), slowly added 30% hydrogen peroxide (0.5mL), and reacted at room temperature 1 hour. After the reaction is complete, adjust pH=3-4 with trifluoroacetic acid, concentrate under reduced pressure, and prepare 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: CH3CN) to give 2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-2-(methyl-d3)-2H-indazole-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-d3)-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-d3)-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 (200mg, 379.12μmol), 4-chloro-1-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-indazole 49b (168.10 mg, 568.69 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy -1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (63.49mg, 75.82μmol), 2-dicyclohexylphosphine-2',6'-di Isopropoxy-1,1'-biphenyl (70.76mg, 151.65μmol) and potassium phosphate (201.19mg, 947.81μmol) were added to N,N-dimethylformamide (3mL), replaced by argon three times, and heated to 80°C and stirred for 2 hours. After the reaction, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was passed through silica gel Purified by column chromatography (eluent: system A) to obtain 2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-1-(methyl-d3)-1H -Indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 55a (110mg) , 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-d3)-1H-indazol-5-yl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-carbonitrile

2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-1-(methyl-d3)-1H-indazol-5-yl)-7-(( 2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 55a (110 mg, 178.50 μmol) and trifluoroacetic acid (1 mL) were added to di Chloromethane (2 mL), stirred at room temperature overnight, the reaction was complete, concentrated under reduced pressure, the obtained residue was added to 7M amine methanol solution (2 mL), and reacted at room temperature for 0.5 hours. The reaction was complete and concentrated under reduced pressure to obtain 2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-1-(methyl-d3)-1H-indazole-5- Base)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile 55b (75 mg), yield: 99%, the product was directly carried out 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-d3)-1H-indazol-5-yl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-carboxamide

2-(4-Amino-4-phenylpiperidin-1-yl)-5-(4-chloro-1-(methyl-d3)-1H-indazol-5-yl)-7H-pyrrolo Add methanol (3mL) to [2,3-d]pyrimidine-4-carbonitrile 55b (85g, 174.90mmol) and 5M sodium hydroxide solution (0.5mL), slowly add 30% hydrogen peroxide (0.5mL) dropwise, and react at room temperature 1 hour, the reaction is complete, adjust the pH=3-4 with trifluoroacetic acid, concentrate under reduced pressure, and prepare 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: CH3CN), to obtain 2-(4-amino-4-phenylpiperidin-1-yl)-5-(4-chloro-1-(methyl-d3)-1H-indazole -5-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide 55 (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, the compound of the present invention is to SHP2 allosteric inhibitory activity determination

The following method is used to determine the degree of inhibition of the compound of the present invention on the activity of recombinant human full-length SHP2 under in vitro conditions. SHP2 is allosterically activated by binding of a bis-tyrosyl-phosphorylated peptide to its Src homology 2 (SH2) domain. The latter activation step results in the release of SHP2 from the inhibitory interface, which subsequently activates the SHP2 protein tyrosine phosphatase (PTP), available for substrate recognition and reaction catalysis.

The experimental procedure is briefly described as follows: the test compound was first dissolved in DMSO to prepare a stock solution. The reaction was carried out in a 384-well Small VolumeTM HiBase microplate (Greiner, 784075). First, SHP2 (signalchem, P38-20G-10ug) and SHP-2 Activating Peptide (IRS1_pY1172(dPEG8)pY1222) (BPS, 79319) were added to the well. -1), the final concentrations were 0.5nM and 0.5uM respectively, then the compound to be tested was added in the concentration range of 0.00004-10uM, and incubated at 25°C for 60 minutes. DiFMUP (Thermo, D6567) was then added to the reaction and incubated at 25°C for 30 minutes. After incubation, read using a microplate reader (BMG) with excitation and emission wavelengths of 340 nm and 450 nm, respectively. By comparing with the fluorescence intensity ratio of the control group (0.1% DMSO), the percent inhibition rate of the compound at each concentration was calculated, and the compound concentration was used for nonlinear regression analysis of the value-inhibition rate by GraphPad Prism 5 software to obtain the compound's See Table 1 for _IC50 values.

Table 1 IC ₅₀ data of compounds of the present invention inhibiting full-length SHP2 enzyme activity

Compound number 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: It can be seen from Table 1 that the compound of the present invention has a good allosteric inhibitory effect on SHP2 enzyme.

Note: The structure of SHP-099 (prepared according to WO2015107493) is as follows:

Test example 2, compound of the present invention is to NCI-H23 cell proliferation inhibitory assay

Luminescent Cell Viability Assay试剂盒(Promega，货号G7573)进行测定。 The following method was used to determine the effect of the compounds of the present invention on the proliferation of NCI-H23 cells. NCI-H23 (containing KRAS G12C mutation) was purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100μg/mL streptomycin and 1mM Sodium Pyruvate . Cell viability via CellTiter-

Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573) was used for determination.

The experimental method is operated according to the steps of the kit instructions, and the brief description is as follows: the test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with the culture medium to prepare a test sample. The final concentration of the compound ranges from 10000nM to 1.52nM . Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well, cultured overnight at 37°C in a 5% _CO2 incubator, and then continued to culture for 120 hours after adding the test compound. After the incubation, add 50 μL of CellTiter-Glo detection solution to each well, shake for 5 minutes and let it stand for 10 minutes, then use the Luminescence mode on the microplate reader to read the luminescence value of each well of the sample. Calculate the percentage inhibition rate of the compound at each concentration point by comparing with the value of the control group (0.3% DMSO), and then perform nonlinear regression analysis with the logarithm of the compound concentration-inhibition rate in the GraphPad Prism 5 software to obtain the compound inhibiting cell proliferation See Table 2 for the _IC50 values.

Table 2 The _IC50 data of the compounds of the present invention on NCI-H23 cell proliferation inhibition

Example number 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

It can be concluded from Table 2 that the compounds of the present invention have a better inhibitory effect on NCI-H23.

Remarks: The structure of RMC-4550 (prepared according to WO2018013597) is as follows:

Test example 3, compound of the present invention is to NCI-H358 cell proliferation inhibitory assay

Luminescent Cell Viability Assay试剂盒(Promega，货号G7573)进行测定。 The following method was used to determine the effect of the compounds of the present invention on the proliferation of NCI-H358 cells. NCI-H358 cells (containing KRAS G12C mutation) were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100μg/mL streptomycin and 1mM Sodium Pyruvate middle. cell viability through

Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573) was used for determination.

The experimental method is operated according to the steps of the kit instructions, and the brief description is as follows: the test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with the culture medium to prepare a test sample. The final concentration of the compound ranges from 10000nM to 1.52nM . Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well, cultured overnight at 37°C in a 5% _CO2 incubator, and then continued to culture for 120 hours after adding the test compound. After the incubation, add 50 μL of CellTiter-Glo detection solution to each well, shake for 5 minutes and let it stand for 10 minutes, then use the Luminescence mode on the microplate reader to read the luminescence value of each well of the sample. Calculate the percentage inhibition rate of the compound at each concentration point by comparing with the value of the control group (0.3% DMSO), and then perform nonlinear regression analysis with the logarithm of the compound concentration-inhibition rate in the GraphPad Prism 5 software to obtain the compound inhibiting cell proliferation See Table 3 for the _IC50 values.

Table 3 The _IC50 data of the compounds of the present invention on NCI-H358 cell proliferation inhibition

Example number 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

It can be concluded from Table 3 that the compounds of the present invention have a better inhibitory effect on NCI-H358.

Claims (26)

A compound represented by formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

in: When Z is selected from -NH-; V is selected from -N- or -CH-; or; 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 are the same or different, each independently selected from hydrogen atom, 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 , wherein the alkyl, alkenyl, alkynyl, Cycloalkyl or heterocyclyl is optionally further replaced by one or more 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 - Substituents of C(O)NR ⁶ R ⁷ ; R ² is selected from cyano, tetrazolyl, -C(O)R ⁵ , -C(O)OR ⁵ or -C(O)NR ⁶ R ⁷ ; R ³ and R ⁴ form a 4-11-membered heterocyclic group together with the N atom they are connected to, preferably a 5-11-membered heterocyclic group, wherein the heterocyclic group contains one or more N, O, S or SO ₂ atom, and the heterocyclic group is optionally further replaced by one or more selected from halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, 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 is substituted by a substituent, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more groups selected from hydroxyl, amino , halogen, 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 Substituents of ¹⁰ are substituted; Alternatively, ^R3 and R4 ^together with the N atom to which they are attached form a group:

is a single or double bond; when

When representing a single bond, G and M are each independently selected from N or CR ^j ; 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 , p is 1 and q is 1; alternatively, p is 2 and q is 0; when E is selected from NR ^k , O or S, q is 1; J is selected from CR ^p R ^q ; K is selected from NR ^k , (CR ^p R ^q ) _r , O or S; r is 0 or 1; R ^m , R ⁿ , R ^p and R ^q are the same or different, each independently selected from ^RA ; Alternatively, R ^p and R ^q together with the carbon atoms to which they are attached form ^RB ; R ^c and R ^d are the same or different, each independently selected from hydrogen atom, halogen, alkyl or -OR ⁵ , wherein said alkyl is optionally further replaced by hydroxyl, halogen, alkoxy, cycloalkyl or -NR ⁶ R ⁷ is replaced by a substituent; Alternatively, ^Rc and ^Rd together with the carbon atoms to which they are attached form ^RB ; R ^g is the same or different, each independently selected from hydrogen atom, 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further Substituents of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR ⁶ R ⁷ ; Alternatively, two R ^gs and the same carbon atom to which they are attached may together form C=O; R ^j and R ^k are the same or different, each independently selected from a hydrogen atom or an alkyl group; R ^A is the same or different, each independently selected from hydrogen atom, 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further Substituents of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR ⁶ R ⁷ ; R ^B are the same or different, each independently selected from 3-10 membered cycloalkyl or 3-10 membered heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally further selected from one or more 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 Substituents are substituted; R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl Or heteroaryl is optionally further replaced by one or more selected from hydroxyl, 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 substituents are substituted; Alternatively, R ⁶ and R ⁷ form a 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the 3-8 membered heterocyclic ring contains one or more N, O, S or SO ₂ atoms, and The 3- to 8-membered heterocycle is optionally further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy; R ⁸ , R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group radical or heteroaryl is optionally further replaced by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxyl Substituents of ester groups are substituted; 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 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is the compound described in formula (AII) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof,

Wherein: rings A, m, V, R ¹ -R ⁴ are as defined in claim 1. The compound according to claim 2 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is the compound described in formula (I) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof,

Wherein: ring A, V, m, R ¹ , R ³ and R ⁴ are as defined in claim 2. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R ³ and R ⁴ together form a 4-8 membered monocyclic heterocyclic group, preferably a 5-6 membered monocyclic heterocyclic group, more preferably a piperidinyl group, wherein the monocyclic heterocyclic group The group is optionally further replaced by one or more selected from the group consisting of methyl, amino, cycloalkyl, phenyl, halophenyl, heteroaryl, -CH ₂ NH ₂ , -CH ₂ OH, -NHC(=NH)NH _2. Substituents of =O or -OR ⁵ ; wherein the methyl, cycloalkyl, phenyl or heteroaryl are optionally further selected from one or more methylsulfonyl, hydroxyl, amino, halogen , haloalkyl, alkoxy, haloalkoxy, pyridyl or pyrimidyl substituents; wherein the heteroaryl is preferably pyridyl, pyrimidinylbenzopyrazolyl, pyrrolyl, furyl, Thienyl, pyrazolyl, imidazolyl, thiazolyl, benzimidazolyl, benzofuryl or benzoxazolyl; R ⁵ is as defined in claim 1. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R ³ and R ⁴ form a 7- to 11-membered spiroheterocyclyl together with the N atom they are connected to, wherein the spiroheterocyclyl is optionally further replaced by one or more members selected from the group consisting of methyl, amino, -CH ₂ NH ₂ , -CH ₂ OH, -NHC(=NH)NH ₂ , =O or -OR ⁵ substituents are substituted; R ⁵ is as defined in claim 1. The compound according to claim 5 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said spiroheterocyclic group is selected from:

R ^a is the same 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 form C=O with the same carbon atom that is connected; t is 1, 2 or 3; R ⁵ is as defined in claim 1. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R ³ and R ⁴ form a 7- to 11-membered bridged heterocyclic group together with the N atom they are connected to, wherein the bridged heterocyclic group is optionally further replaced by one or more members selected from the group consisting of methyl, amino, -CH ₂ NH ₂ , -CH ₂ OH, -NHC(=NH)NH ₂ , =O or -OR ⁵ substituents are substituted; R ⁵ is as defined in claim 1. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R ³ and R ⁴ form a 7- to 11-membered condensed heterocyclic group together with the N atom they are connected to, wherein the condensed heterocyclic group is optionally further replaced by one or more members selected from the group consisting of methyl, amino, -CH ₂ NH ₂ , -CH ₂ OH, -NHC(=NH)NH ₂ , =O or -OR ⁵ substituents are substituted; R ⁵ is as defined in claim 1. The compound according to claim 2 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is the compound described in formula (II) or its stereoisomer, tautomer or its pharmaceutically acceptable salts:

in: Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl; E is selected from NR ^k , (CR ^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 , p is 1 and q is 1; alternatively, p is 2 and q is 0; when E is selected from NR ^k , O or S, q is 1; R ^m is selected from amino, -CH ₂ NH ₂ or -NHC(=NH)NH ₂ ; R ^{n is} selected from a hydrogen atom, methyl or -CH ₂ OH; R ^p and R ^q are each independently selected from a hydrogen atom, halogen, amino, C ₁ -C ₄ alkyl, hydroxyl C ₁ -C ₄ alkyl, amino C ₁ -C ₄ alkyl or -OR ⁵ ;

Rings A, V, G, M, m, n, R ¹ to R ² , R ⁵ , R ^k and R ^g are as defined in claim 2. The compound according to claim 2 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is the compound described in formula (III) or its stereoisomer, tautomer or its pharmaceutically acceptable salts:

in: Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl; J is selected from CR ^p R ^q ; K is selected from NR ^k , (CR ^p R ^q ) _r , O or S; r is 0 or 1; R ^m is selected from amino, -CH ₂ NH ₂ or -NHC(=NH)NH ₂ ; R ^{n is} selected from a hydrogen atom, methyl or -CH ₂ OH; R ^p and R ^q are each independently selected from a hydrogen atom, halogen, amino, C ₁ -C ₄ alkyl, hydroxyl C ₁ -C ₄ alkyl, amino C ₁ -C ₄ alkyl or -OR ⁵ ;

Rings A, V, G, M, m, n, R ¹ to R ² , R ⁵ , R ^k and R ^g are as defined in claim 2. The compound according to claim 2 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is the compound described in formula (IV) or its stereoisomer, tautomer or its pharmaceutically acceptable salts:

in: Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl; R ^c and R ^d form a 3-8 membered cycloalkyl group together with the connected atoms; R ^m is selected from amino, -CH ₂ NH ₂ or -NHC(=NH)NH ₂ ; R ^{n is} selected from a hydrogen atom, methyl or -CH ₂ OH;

Rings A, V, G, M, m, n, R ¹ to R ² and R ^g are as defined in claim 2. The compound according to claim 2 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is the compound described in formula (V) or its stereoisomer, tautomer or its pharmaceutically acceptable salts:

in: L ₁ is selected from nonexistent, -(C=O)-, -(CR ^w R ^v ) _u -, wherein any one of -(CR ^w R ^v )- is optionally further replaced by -N(R ^z )-, - O-, -S-, -SO-, -SO ₂ -replaced; Each ^Rw and ^Rv are the same or different, each independently selected from a hydrogen atom, halogen, hydroxyl, alkyl or alkoxy; Each ^Rz is the same or different, each independently selected from a hydrogen atom or an alkyl group; Ring E is selected from 4 to 11 membered N-containing monocyclic heterocyclic groups, 4 to 11 membered N-containing condensed heterocyclic groups, or 4 to 11 membered N-containing bridged heterocyclic groups, wherein the monocyclic heterocyclic group , fused heterocyclic group, bridged heterocyclic group are optionally further substituted by one or more substituents selected from halogen, alkyl, -OR ⁵ or =O; Ring K is selected from nonexistent, cycloalkyl, aryl or heteroaryl, wherein said cycloalkyl, aryl or heteroaryl is optionally further replaced by one or more selected from hydroxyl, amino, halogen, nitro , cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O) Substituents of 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 ; Wherein -L ₁ -ring K and -(CH ₂ ) _W -NH ₂ are connected 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 are as defined in claim 2. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims ^1-3 , 9-12, wherein R is selected from hydrogen atom, F, Cl, Br , amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, difluoromethyl, cyclopropyl, d ₃ -methyl, ethynyl, vinyl, -NHCH ₃ or -N(CH ₃ ) ₂ . The compound according to any one of claims 9-12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from -C(O)NH ₂ or cyano. The compound according to any one of claims 1-12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from a hydrogen atom or an alkyl group. The compound according to any one of claims 1-3, 9-12 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from naphthyl, benzopyrazolyl or benzothiazolyl. The compound according to any one of claims 9-11 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from:

The compound according to any one of claims 9 to 11 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^g is the same or different, each independently selected from a hydrogen atom, F, Cl, Br, amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH ₃ or -N(CH ₃ ) ₂ ; Alternatively, two ^Rg 's can be taken together to form C=O with the same carbon atom to which they are attached. The compound according to claim 12 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring E is selected from

The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-19, wherein said compound is selected from:

A method for preparing the formula (AII) compound or its stereoisomers and tautomers according to claim 2, the method comprising:

Formula (AIIa) compound and NHR ³ R ⁴ carry out nucleophilic substitution reaction under basic conditions, obtain formula (AIIb) compound; Formula (AIIb) compound and formula (AIIc) compound, carry out Suzuki under palladium catalyst and basic condition Reaction, the compound that obtains optionally further removes protecting group, obtains formula (AII) compound; in: M ₁ is selected from -B(OH) ₂ or

X ₁ is selected from a leaving group, and the leaving group is selected from halogen or -SO ₂ R ^t ; X2 is selected from halogen _; R ^{t is} selected from alkyl; The rings A, V, m and R ¹ -R ⁴ are as defined in claim 2. A method for preparing the formula (AII) compound or its stereoisomers and tautomers according to claim 2, the method comprising:

Formula (AIIa) compound and formula (AIIc) compound, carry out Suzuki reaction under palladium catalyst and basic condition, obtain formula (AIId) compound; Formula (AIId) compound and NHR ³ R ⁴ carry out nucleophilic substitution under basic condition Reaction, the compound that obtains optionally further removes protecting group, obtains formula (AII) compound; in: M ₁ is selected from -B(OH) ₂ or

X ₁ is selected from a leaving group, and the leaving group is selected from halogen or -SO ₂ R ^t ; X2 is selected from halogen _; R ^{t is} selected from alkyl; Ring A, V, m and R ¹ -R ⁴ are as defined in claim 2. A pharmaceutical composition, which contains an effective dose of the compound according to any one of claims 1-20 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, And pharmaceutically acceptable carrier, excipient or their combination. The compound according to any one of claims 1 to 20 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 in the preparation of SHP2 allosteric Use in inhibitors. The compound according to any one of claims 1 to 20 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 in the preparation of treatment by SHP2 Use in medicine for diseases mediated by SHP2, wherein the diseases mediated by SHP2 are preferably cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder. The use according to claim 25, wherein the disease mediated by SHP2 is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia , breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.