CN111153899B

CN111153899B - Substituted pyridine compound, preparation method and application thereof

Info

Publication number: CN111153899B
Application number: CN201911043519.7A
Authority: CN
Inventors: 易磊; 宋智泉; 田强; 张帅; 王波; 蔡家强; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2018-11-08
Filing date: 2019-10-30
Publication date: 2023-12-01
Anticipated expiration: 2039-10-30
Also published as: CN111153899A

Abstract

The invention relates to a substituted pyridine compound, a preparation method and application thereof. In particular, the present invention relates to compounds of formula I, processes for their preparation, their use in the prevention and/or treatment of SHP2 enzyme-related diseases, and pharmaceutical compositions containing them.

Description

Substituted pyridine compound, preparation method and application thereof

Technical Field

The present invention relates to the field of pharmaceutical chemistry, and in particular to a substituted pyridine compound used as an SHP2 inhibitor, a preparation method thereof, a pharmaceutical composition and use thereof in treating SHP2 enzyme-related diseases.

Background

SHP2 (Src homolog 2 domain containing phosphotyrosine phosphatase 2) is a protein tyrosine phosphatase encoded by the gene PTPN11, structurally comprising two N-terminal SH2 (Src homolog 2) domains, a Protein Tyrosine Phosphatase (PTP) catalytic domain and a C-terminal tail rich in proline groups and tyrosine phosphorylation sites. In the basal state, SHP2 adopts a self-inhibiting configuration, the N-SH2 domain spatially prevents the substrate from contacting the active site. When a ligand containing a phosphorylated tyrosine residue specifically binds to the N-SH2 domain, the configuration of SHP2 is altered, exposing the catalytically active site of the PTP domain, eliminating inhibition of itself, thereby initiating a signaling cascade initiated by tyrosine phosphorylation.

SHP2 is present in the cytoplasm and transduces signals from a variety of receptor-tyrosine kinases in cells and is therefore involved in a cascade of many oncogenic signals (e.g., RAS-ERK, PI3K-AKT, JAK-STAT). It has been reported (Bunda, s., et al, nat. Commun.6, 8859.) that SHP2 is capable of binding to the RAS and undergoing dephosphorylation, enhancing the binding force between RAS-RAF, thereby activating the downstream RAS/ERK/MAPK proliferation signaling pathway. In addition, SHP2 has been reported to be involved in the T cell programmed death/checkpoint pathway (PD-L1/PD-1) in the literature (Li, J., et al cancer Res.75, 508-518.). Activated PD-1 recruits SHP2, dephosphorylates the co-stimulatory receptor CD28, thereby inhibiting T cell function and promoting immune escape. In view of recent success in clinical adoption of anti-PD-L1/PD-1 therapies, there is great interest in the study of SHP2 small molecule inhibitors for cancer immunotherapy.

Some SHP2 inhibitors have been reported (see, for example, WO2015107493 A1), but there is still a need in the art for new SHP2 inhibitors, in particular SHP2 inhibitors with high activity and other excellent properties.

Disclosure of Invention

In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

Wherein:

R ₁ selected from H and NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ Halogen, -CN, -OC _1-6 Alkyl, C _1-6 Alkyl and halogenated C _1-6 An alkyl group;

l is selected from direct bond, -NH-, -CH ₂ -、-CH ₂ CH ₂ -, -ch=ch-, and-C (=ch ₂ )-；

Or L and R ¹ Together with the atoms to which they are attached form a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-10 membered heteroaromatic ring or C _6-10 An aromatic ring, wherein the hydrocarbon ring, the heterocyclic ring, the heteroaromatic ring, and the aromatic ring are each optionally substituted with one or more groups selected from H, -NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ Halogen, -CN, =o, -OH, -OC _1-6 Alkyl, halogenated C _1-6 Alkyl and C _1-6 Substituent substitution of alkyl;

x is selected from direct bond, -S-, -O-, -NR ⁶ -、-C(R ⁶ ) ₂ -and-C (=ch ₂ )-；

W ¹ 、W ² And W is ³ Each independently selected from CH and N;

ring A is selected from 4-10 membered heterocyclic ring and 4-10 membered hydrocarbon ring;

R ² each at each occurrence is independently selected from H, halogen, -OH, -OC _1-6 Alkyl, -CN, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _2-6 Alkenyl, -S (=o) _g -(C _1-6 Alkyl), -NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ 3-10 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, wherein each of said alkyl, cycloalkyl, alkenyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from halogen, =o, -OH, -OC _1-6 Alkyl, -CN, C _1-6 Alkyl, -S (=o) _g -(C _1-6 Alkyl), -NH ₂ 、-NH(C _1-6 Alkyl) and-N (C) _1-6 Alkyl group ₂ Is substituted by a substituent of (a);

alternatively, 2R's in adjacent positions ² Together with the atoms to which they are attached form a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring, or a benzene ring, wherein each of the hydrocarbon ring, heterocyclic ring, heteroaromatic ring, and benzene ring is optionally substituted with one or more groups selected from H, -NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ Halogen, -CN, =o, -OH, -OC _1-6 Alkyl, halogenated C _1-6 Alkyl and C _1-6 Substituent substitution of alkyl;

R ³ selected from H and NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ Halogen, -CN, -OH, -COOH, -C (O) OC _1-6 Alkyl, -C (O) NH ₂ 、-OC _1-6 Alkyl and C _1-6 Alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen, -OH, =o, -OC _1-6 Alkyl, -CN, -S (=o) _g -(C _1-6 Alkyl), -NH ₂ 、-NH(C _1-6 Alkyl) and-N (C) _1-6 Alkyl group ₂ Is substituted by a substituent of (a);

R ⁴ each occurrence is independently selected from H, halogen, =O, -OH, -OC _1-6 Alkyl, -CN, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _2-6 Alkenyl, -S (=o) _g -(C _1-6 Alkyl), -NH ₂ 、-NH(C _1-6 Alkyl) and-N (C) _1-6 Alkyl group ₂ ；

R ^5a And R is ^5b Are substituents on the same carbon atom and are each independently selected from H, halogen, -OH, -OC _1-6 Alkyl, -C _1-6 alkylene-OH, -CN, halo C _1-6 Alkyl, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _2-6 Alkenyl, -S (=o) _g -(C _1-6 Alkyl), -NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ and-C _1-6 alkylene-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ^5a And R is ^5b Together with the atoms to which they are attached, form a 3-8 membered hydrocarbon ring or a 3-8 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted with one or more groups selected from H, halogen, =o, -OH, -OC _1-6 Alkyl, -C _1-6 alkylene-OH, -CN, halo C _1-6 Alkyl, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _2-6 Alkenyl, -S (=o) _g -(C _1-6 Alkyl), -NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ and-C _1-6 alkylene-NH ₂ Is substituted by a substituent of (a);

R ⁶ is H or C _1-6 An alkyl group;

alternatively, any one R ² And one R ⁶ Together with the atoms to which they are attached form a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring, or a benzene ring, wherein each of the hydrocarbon ring, heterocyclic ring, heteroaromatic ring, and benzene ring is optionally substituted with one or more groups selected from H, -NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ Halogen, -CN, =o, -OH, -OC _1-6 Alkyl, halogenated C _1-6 Alkyl and C _1-6 Substituent substitution of alkyl;

g is 0, 1 or 2;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

In a further aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of a SHP2 phosphatase-related disorder.

In a further aspect, the present invention provides a method for preventing or treating SHP2 phosphatase-related diseases, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention.

In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, for use in the prevention or treatment of a SHP2 phosphatase-related disorder.

In one embodiment, the SHP2 phosphatase-related disease is a disease that is sensitive or responsive to SHP2 phosphatase inhibition. In further embodiments, the SHP2 phosphatase-related disease is a neoplastic disorder, including but not limited to solid and hematological malignancies.

In another aspect, the invention further provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, in combination with a further method of treatment for preventing or treating a SHP2 phosphatase-related disease, the further method of treatment comprising, but not limited to: radiation therapy, chemotherapy therapy, immunotherapy or a combination thereof.

Detailed Description

Compounds of the invention

wherein:

W ¹ 、W ² And W is ³ Each independently selected from CH and N;

R ^5a And R is ^5b Is positioned atSubstituents on the same carbon atom and each independently selected from H, halogen, -OH, -OC _1-6 Alkyl, -C _1-6 alkylene-OH, -CN, halo C _1-6 Alkyl, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _2-6 Alkenyl, -S (=o) _g -(C _1-6 Alkyl), -NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ and-C _1-6 alkylene-NH ₂ ；

Or R is ^5a And R is ^5b Together with the atoms to which they are attached, form a 3-8 membered hydrocarbon ring or a 3-8 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted with one or more groups selected from H, halogen, =o, -OH, -OC _1-6 Alkyl, -C _1-6 alkylene-OH, -CN, halo C _1-6 Alkyl, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _2-6 Alkenyl, -S (=o) _g -(C _1-6 Alkyl), -NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ and-C _1-6 alkylene-NH ₂ Is substituted by a substituent of (a);

R ⁶ Is H or C _1-6 An alkyl group;

g is 0, 1 or 2;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4.

In some embodiments, R ¹ Selected from H and NH ₂ 、-OC _1-3 Alkyl, halogenated C _1-3 Alkyl and C _1-3 An alkyl group. In a preferred embodiment, R ¹ Selected from H and NH ₂ and-CH ₃ 。

In some embodiments, L is selected from the group consisting of a direct bond, -NH-, and-CH ₂ -. In a preferred embodiment, L is selected from the group consisting of a direct bond and-CH ₂ -. In a more preferred embodiment, L is selected from direct bonds.

In some embodiments, L and R ¹ Together with the atoms to which they are attached form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein each of the heterocyclic and heteroaromatic rings is optionally substituted with one or more groups selected from H, -NH ₂ F, cl, -CN, =O, -OH, halo C _1-3 Alkyl and C _1-3 Substituent substitution of alkyl; in a preferred embodiment, L and R ¹ Together with the atoms to which they are attached form a 5-6 membered heteroaromatic ring optionally substituted with one or more groups selected from H, -NH ₂ F, cl, -CN, =O, -OH, halo C _1-3 Alkyl and C _1-3 The substituent of the alkyl group is substituted. In another preferred embodiment, L and R ¹ Together with the atoms to which they are attached, form a pyrazole, pyrrole, pyrroline, imidazole, pyrazine or pyridine ring, wherein the rings are each optionally substituted with one or more groups selected from H, -NH ₂ F, cl, -CN, =O, -OH, halo C _1-3 Alkyl and C _1-3 The substituent of the alkyl group is substituted. In a still further preferred embodiment of the present invention,and a moiety selected from the group consisting of: /> In a still further preferred embodiment, +.>And a moiety selected from the group consisting of: /> In a still further preferred embodiment, +.>The moiety is selected from->And->

In some embodiments, X is selected from the group consisting of a direct bond, -S-, -O-, and-C (=ch ₂ ) -; in some embodiments, X is selected from the group consisting of a direct bond, -S-, and-O-; in a preferred embodiment, X is selected from the group consisting of a direct bond and-S-.

In some embodiments, W ¹ Is CH, W ² And W is ³ Each independently selected from CH and N. In a preferred embodiment, W ¹ 、W ² And W is ³ Are all CH.

In some embodiments, ring A is selected from the group consisting of 5-6 membered heterocyclic rings and 5-6 membered hydrocarbon rings; in a preferred embodiment, ring a is selected from the group consisting of 6 membered nitrogen containing heterocycles and 6 membered hydrocarbon rings; in a further preferred embodiment, ring a is selected from the group consisting of piperidine ring and cyclohexene ring; in a further preferred embodiment, ring a is selected from piperidine rings.

In some embodiments, R ² Each at each occurrence is independently selected from H, halogen, -OH, -OC ₁ -6 alkyl, -CN, C ₁ -3 alkyl, halo C ₁ -3 alkyl and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the In a preferred embodiment, R ² Each at each occurrence is independently selected from H, F, cl, br, -OH, -OCH ₃ 、-CH ₃ 、-CH ₂ CH ₃ 、-CF ₃ 、-CHF ₂ and-NH ₂ For example, each independently selected from H, F, cl, -OH, -CH ₃ 、-CH ₂ CH ₃ 、-CF ₃ 、-CHF ₂ and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the In a further preferred embodiment, R ² Each at each occurrence is independently selected from F, cl, br,)OCH ₃ 、-CH ₃ 、-CF ₃ and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the In a further preferred embodiment, R ² Each at each occurrence is independently selected from F, cl, -CH ₃ 、-CF ₃ and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the In a still further preferred embodiment, R ² Each at each occurrence is independently selected from Br, cl and-NH ₂ 。

In some embodiments of the present invention, in some embodiments,a group selected from: 2, 3-dichlorophenyl, 2-chloro-3-aminophenyl, 2- (trifluoromethyl) pyridin-3-yl, 2-amino-3-chloropyridin-4-yl, 2, 3-dichloropyridin-4-yl, 2-bromo-3-chloropyridin-4-yl, 2-bromo-3-fluoropyridin-4-yl, 2, 6-dichloropyridin-4-yl, 2, 3-difluorophenyl, 3, 4-difluorophenyl, 2-methylpyridin-4-yl, 2-chloropyridin-4-yl, 3-chloropyridin-4-yl and 2-methoxy-3-chloropyridin-4-yl. In a preferred embodiment, ∈ >A group selected from: 2, 3-dichlorophenyl, 2-chloro-3-aminophenyl and 2, 3-dichloropyridin-4-yl.

In some embodiments, 2R's in adjacent positions ² Together with the atoms to which they are attached form a 5-7 membered hydrocarbon ring or a 5-7 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted with one or more groups selected from H, -NH ₂ 、F、Cl、-CN、＝O、-OH、-OC _1-3 Alkyl, halogenated C _1-3 Alkyl and C _1-3 Substituent substitution of alkyl; in a preferred embodiment, 2R's are in adjacent positions ² Together with the atoms to which they are attached form a 5-6 membered hydrocarbon ring or a 5-6 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted with one or more groups selected from H, -NH ₂ 、F、Cl、＝O、-OH、-OCH ₃ and-CH ₃ Is substituted by a substituent of (a); in a preferred embodiment, 2R's are in adjacent positions ² Together with the atoms to which they are attached form a ring selected from the group consisting of cyclopentene, dioxole and pyrroline, wherein the rings are each optionallyGround cover one or more selected from H, -NH ₂ 、F、Cl、＝O、-OH、-OCH ₃ and-CH ₃ Is substituted by a substituent of (a); in a more preferred embodiment, the 2R's are relative to the point of attachment to X ² Respectively in the ortho and meta positions. In a more preferred embodiment of the present invention,a group selected from:

in some embodiments, when X is-NR ⁶ -or-C (R) ⁶ ) ₂ When in the ortho position to the X point of attachment ² And one R ⁶ Together with the atoms to which they are attached form a 5-7 membered hydrocarbon ring or a 5-7 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted with one or more groups selected from H, -NH ₂ 、F、Cl、-CN、＝O、-OH、-OC _1-3 Alkyl, halogenated C _1-3 Alkyl and C ₁ - ₃ Substituent substitution of alkyl; in a preferred embodiment, when X is-NR ⁶ -or-C (R) ⁶ ) ₂ When in the ortho position to the X point of attachment ² And one R ⁶ Together with the atoms to which they are attached form a 5-6 membered hydrocarbon ring or a 5-6 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted with one or more groups selected from H, -NH ₂ 、F、Cl、＝O、-OH、-OCH ₃ and-CH ₃ Is substituted by a substituent of (a); in a preferred embodiment, when X is-NR ⁶ -or-C (R) ⁶ ) ₂ When in the ortho position to the X point of attachment ² And one R ⁶ Together with the atoms to which they are attached form a ring selected from cyclohexene and tetrahydropyridine, wherein the rings are each optionally substituted with one or more groups selected from H, -NH ₂ 、F、Cl、-CN、＝O、-OH、-OC _1-3 Alkyl, halogenated C _1-3 Alkyl and C _1-3 The substituent of the alkyl group is substituted. In a more preferred embodiment, when X is-NR ⁶ -or-C (R) ⁶ ) ₂ -at the time of this, the time of the process,selected from the following groups: />

In some embodiments, R ³ Selected from H and NH ₂ Halogen, -CN, -OH, C _1-4 Alkyl, -COOH and-C (O) OC _1-4 Alkyl, wherein the alkyl is optionally substituted with one or more groups selected from halogen, =o, -OH, -S (=o) _g -(C _1-3 Alkyl) and-NH ₂ Is substituted by a substituent of (a); in a preferred embodiment, R ³ Selected from H and NH ₂ 、F、Cl、-CN、-OH、-CH ₃ 、-CF ₃ 、-CH ₂ CH ₃ 、-CH ₂ F、-CHF ₂ 、-CH ₂ OH、-CH ₂ CH ₂ OH、-CH ₂ NH ₂ 、-CH ₂ CH ₂ NH ₂ -COOH and-C (O) OEt; in a further preferred embodiment, R ³ Selected from H, F, -CN, -COOH, -CH ₂ OH、-CH ₂ F、-CHF ₂ and-CH ₂ OH; in a further preferred embodiment, R ³ Selected from H, F and-CH ₂ OH。

In some embodiments, R ⁴ Each at each occurrence is independently selected from H, F, cl, =o, -OH, -OC _1-3 Alkyl, -CN, C _1-3 Alkyl and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the In a preferred embodiment, R ⁴ Each at each occurrence is independently selected from H, F, cl, -OH, -CH ₃ and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the In a further preferred embodiment, R ⁴ Each at each occurrence is independently selected from H and-CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the In a further preferred embodiment, R ⁴ H.

In some embodiments, R ^5a And R is ^5b Each independently selected from H, C _1-3 Alkyl, -NH ₂ 、-C _1-3 Alkylene groups-OH and-C _1-3 alkylene-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ^5a And R is ^5b Together with the atoms to which they are attached form a 5-6 membered hydrocarbon ring or a 5-6 membered heterocyclic ring, wherein theThe hydrocarbon ring and the heterocyclic ring are each optionally substituted with one or more substituents selected from H, F, cl, C _1-3 Alkyl, =o, -NH ₂ 、-OH、-C _1-3 Alkylene groups-OH and-C _1-3 alkylene-NH ₂ Is substituted by a substituent of (a); in a preferred embodiment, R ^5a And R is ^5b Each independently selected from H, -CH ₃ 、-CH ₂ CH ₃ 、-NH ₂ and-CH ₂ NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ^5a And R is ^5b Together with the atoms to which they are attached, form a cyclopentane, an oxacyclopentane or a dihydro-oxazole, each of which is optionally substituted with one or more groups selected from-CH ₃ and-NH ₂ Is substituted by a substituent of (a); in a further preferred embodiment, R ^5a And R is ^5b Each independently selected from-CH ₃ and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ^5a And R is ^5b Together with the atoms to which they are attached, form a cyclopentane, an oxacyclopentane or a dihydro-oxazole, wherein the cyclopentane, the oxacyclopentane or the dihydro-oxazole are each simultaneously bound by-CH ₃ and-NH ₂ Is substituted by a substituent of (a); in a further preferred embodiment, R ^5a is-CH ₃ ，R ^5b is-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ^5a And R is ^5b Together with the atoms to which they are attached form a simultaneously-substituted-CH ₃ and-NH ₂ Substituted oxolanes, preferably R ^5a And R is ^5b Together with the atoms to which they are attached form a group

In some embodiments, g is 0 or 2.

In some embodiments, m is 0, 1, or 2; in a preferred embodiment, m is 0.

In some embodiments, n is 0, 1, or 2; in a preferred embodiment, n is 1 or 2.

In some embodiments, the invention provides a compound of formula (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

Wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ^5a 、R ^5b 、W ¹ 、W ² 、W ³ L, X, A, m and n are as defined above.

In some embodiments, the compounds of formula (I) of the present invention have the structure of formula (III) or formula (IV):

wherein,represents a single bond or a double bond; u is selected from N and C; when->Is a single bond, U is N, when->Is a double bond, U is C; ring B is selected from a 5-6 membered heterocycle or a 5-6 membered heteroaryl ring, wherein the heterocycle and heteroaryl ring are each optionally substituted with one or more substituents selected from H, -NH ₂ F, cl, -CN, =O, -OH, halo C _1-3 Alkyl and C _1-3 Substituent substitution of alkyl; in a preferred embodiment, ring B is selected from 5-6 membered heteroaryl rings. In a preferred embodiment, ring B is selected from a pyrazole ring, a pyrrole ring, a pyrroline ring, an imidazole ring, a pyrazine ring or a pyridine ring; the remaining groups are as defined above. In a preferred embodiment, ∈>Is a single bond, and U is N.

In a preferred embodiment, the compounds of formula (I) according to the invention have the structure of formula (V), formula (VI) or formula (VII):

wherein R is ^2a And R is ^2b Definition is respectively with R ² Identical, R ^2a And R is ^2b May be the same or different; q (Q) ¹ 、Q ² And Q ³ Each independently selected from N, NH, C and CH, and not both C or CH; the remaining groups are as defined above.

Those skilled in the art will appreciate that the present invention encompasses compounds resulting from any combination of the various embodiments. Embodiments resulting from the combination of technical features or preferred technical features of one embodiment with technical features or preferred technical features of another embodiment are also included within the scope of the present invention.

In a preferred embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound is selected from the group consisting of:

in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formulae (I) - (VII) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

In a further aspect, the invention provides the use of a compound of formulae (I) - (VII) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of a SHP2 phosphatase-related disorder.

In a further aspect, the present invention provides a method for preventing or treating SHP2 phosphatase-related diseases, the method comprising administering to a subject in need thereof a compound of formulae (I) - (VII) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention.

In another aspect, the invention provides a compound of formulae (I) - (VII) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, for use in the prevention or treatment of a SHP2 phosphatase-related disorder.

In another aspect, the invention further provides a method of preventing or treating SHP2 phosphatase-related diseases by combining a compound of formulae (I) - (VII) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, with another therapeutic method, including, but not limited to: radiation therapy, chemotherapy therapy, immunotherapy or a combination thereof.

The preparation method of the invention

Still another aspect of the present invention relates to a process for the preparation of a compound of the present invention, said process comprising:

1. reacting a compound of formula S-1 with a compound of formula S-2 to produce a compound of formula IM-1;

2. reacting a compound of formula IM-1 with a compound of formula S-3 to produce a compound of IM-2;

3. removing the protecting group from the compound of formula IM-2 to produce a compound of formula (I);

wherein LG (glass fiber reinforced plastic) ¹ And LG (glass fibre reinforced plastics) ² Each independently represents a halogen leaving group, or C optionally substituted by halogen _1-6 An alkylsulfonate group leaving group (e.g., a trifluoromethanesulfonate group leaving group);

R ^c and R is ^d Each independently represents H or a leaving group;

PG ¹ protecting groups representing hydroxyl groups (e.g., methyl, t-butyldimethylsilyl, triisopropylsilyl, benzyl, and methoxymethyl);

the remaining groups are as defined above.

In a preferred embodiment, LG ¹ And LG (glass fibre reinforced plastics) ² Each independently represents a halogen, such as iodine or chlorine.

In a preferred embodiment, R ^c And R is ^d Independently selected from H, halogenBoric acid groups, boric acid ester groups, substituted silicon groups, substituted metal groups or C optionally substituted by halogen _1-6 Alkyl sulfonate groups. In a more preferred embodiment, R ^c Is boric acid or boric acid ester group, R ^d Is H, boric acid group or boric acid ester group.

In step 1, the reaction may be performed in the presence of a metal catalyst. In a preferred embodiment, the metal catalyst is a metal palladium catalyst such as tetrakis triphenylphosphine palladium, palladium acetate, tris (dibenzylideneacetone) dipalladium, 1' -bis (diphenylphosphine) ferrocene dichloride palladium, 1, 2-bis diphenylphosphine ethane palladium chloride, bis (triphenylphosphine) palladium dichloride, and the like.

In step 2, the reaction may be carried out in the presence of a base and/or a metal catalyst. In a preferred embodiment, the base is an inorganic base, such as potassium phosphate. In another preferred embodiment, the metal catalyst is a metal palladium catalyst such as tetrakis triphenylphosphine palladium, palladium acetate, tris (dibenzylideneacetone) dipalladium, 1' -bis (diphenylphosphine) ferrocene dichloride palladium, 1, 2-bis diphenylphosphine ethane palladium chloride, bis (triphenylphosphine) palladium dichloride, and the like.

In step 3, the reaction may be carried out under acid or catalytic hydrogenolysis conditions. In a preferred embodiment, the acid is an organic acid, preferably trifluoroacetic acid. In another preferred embodiment, the metal catalyst is palladium on carbon.

The starting materials for the preparation process of the present invention may be from commercial sources or may be prepared according to known methods.

It will be appreciated by those skilled in the art that one or more of the steps in the above routes may be omitted, depending on the desired product structure to be obtained. The skilled artisan can also appropriately adjust the order of the reaction steps as desired, as well as add or omit protection/deprotection reaction steps.

The compounds of formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII) and the like of the present invention can be synthesized by similar methods with reference to the above embodiments.

Pharmaceutical compositions, formulations and kits

The invention also provides a pharmaceutical composition comprising a compound of formulae (I) - (VII) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (e.g., hydrate), N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers, and optionally further comprising one or more second therapeutic agents for treating SHP2 enzyme-related diseases.

It is a further object of the present invention to provide a process for preparing a pharmaceutical composition of the present invention, which comprises combining a compound of formulae (I) - (VII), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers. The method may further comprise admixing one or more second therapeutic agents for treating SHP2 enzyme-related diseases.

Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, in particular for injections. Pharmaceutically acceptable carriers include pharmaceutical excipients. Suitable pharmaceutical excipients include, but are not limited to, starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also contain small amounts of wetting agents, emulsifiers, lubricants, stabilizers or pH buffers, etc., as desired. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

The pharmaceutical composition may be administered in any form as long as it achieves prevention, alleviation, prevention or cure of symptoms of a human or animal patient. For example, various suitable dosage forms may be formulated depending on the route of administration.

When administered orally, the pharmaceutical composition may be formulated into any orally acceptable dosage form including, but not limited to, tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, oral emulsions, and the like. Wherein the carrier used for the tablet is, for example, lactose, corn starch, etc., and can optionally be compressed into a tablet in combination with: binding agents, such as acacia or gelatin; disintegrants, for example croscarmellose sodium, crospovidone; lubricants, such as magnesium stearate, and the like. Diluents for capsules such as lactose, dried corn starch and the like. Oral suspensions are typically prepared by mixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweetener, flavoring agent or coloring agent can be added into the oral preparation.

When applied transdermally or topically, the pharmaceutical composition may be formulated as a suitable ointment, lotion or liniment, wherein the active ingredient may be suspended or dissolved in one or more carriers. Carriers that can be used for ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used with lotions or liniments include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, 2-octyldodecanol, benzyl alcohol and water.

The pharmaceutical composition can also be used in the form of injection, including injection, sterile powder for injection and concentrated solution for injection. Among the carriers and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oils may also be used as solvents or suspending media, such as mono-or diglycerides.

In another embodiment, administration of a compound or pharmaceutical composition of the invention may be combined with additional methods of treatment. The additional treatment methods may be selected from, but are not limited to: radiation therapy, chemotherapy, immunotherapy, or a combination thereof. The compound or pharmaceutical composition of the invention may be administered before, during or after the administration of the additional therapeutic method. The additional methods of treatment may be performed simultaneously with the administration of the compounds or pharmaceutical compositions of the present invention, in close succession, or at intervals, the manner and order of administration being selected and adjusted according to the particular treatment.

Another aspect of the invention also relates to a pharmaceutical formulation comprising a compound of formulae (I) - (VII), a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a mixture of same, as an active ingredient, or a pharmaceutical composition of the invention. In some embodiments, the formulation is in the form of a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.

It is a further object of the invention to provide an article of manufacture, for example in the form of a kit. Articles of manufacture as used herein are intended to include, but are not limited to, kits and packages. The article of the invention comprises: (a) a first container; (b) A pharmaceutical composition in a first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of formulae (I) - (VII) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a mixture thereof; and (c) package insert, which illustrates that the pharmaceutical composition may be used for treating a neoplastic condition (as defined hereinabove). In another embodiment, the package insert indicates that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat a neoplastic disorder. The article of manufacture may further comprise: (d) A second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside the second container. Locating within the first and second containers means that each container retains an item within its boundaries.

The first container is a container for containing a pharmaceutical composition. The container may be used for preparation, storage, transportation and/or independent/batch sales. The first container is intended to encompass a bottle, a can, a vial, a flask, a syringe, a tube (e.g., for a cream product), or any other container for preparing, containing, storing, or dispensing a pharmaceutical product.

The second container is a container for holding the first container and optionally packaging instructions. Examples of the second container include, but are not limited to, a box (e.g., a carton or plastic box), a box, a carton, a bag (e.g., a paper or plastic bag), a pouch, and a coarse cloth bag. The package insert may be physically adhered to the exterior of the first container via a tie, glue, staple, or other means of adhesion, or it may be placed inside the second container without any physical means of adhesion to the first container. Alternatively, the package insert is located outside of the second container. When located outside the second container, it is preferred that the package insert is physically adhered via a tie, glue, staple or other means of adhesion. Alternatively, it may abut or contact the exterior of the second container without physical adhesion.

The package insert is a trademark, label, logo, etc. listing information related to the pharmaceutical composition located in the first container. The information listed is typically determined by a regulatory agency (e.g., the U.S. food and drug administration) that governs the area in which the article is to be sold. Preferably, the package insert specifically lists the indication for which the pharmaceutical composition is approved. The package insert may be made of any material from which information contained therein or thereon may be read. Preferably the package insert is a printable material (e.g. paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (e.g. printed or applied).

Therapeutic methods and uses

It is another object of the present invention to provide a method for preventing or treating SHP2 enzyme-related diseases, which comprises administering to a subject in need thereof an effective amount of a compound of formulae (I) - (VII), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, or a mixture of same, or a pharmaceutical composition of the invention.

According to one embodiment of the invention, the SHP2 enzyme-related disease that can be prevented or treated using the compounds of the invention is a disease that is sensitive or responsive to SHP2 enzyme inhibition. In further embodiments, the SHP2 enzyme-related disease is a neoplastic disorder, including but not limited to solid and hematological malignancies. In further embodiments, the oncological disorders include, but are not limited to, breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer) and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulval cancer, as well as leukemias (including Chronic Lymphocytic Leukemia (CLL), acute Lymphocytic Leukemia (ALL) and Chronic Myelogenous Leukemia (CML)), multiple myeloma and lymphoma. In particular embodiments, the neoplastic disease is colon cancer or lung cancer.

In a preferred embodiment, the disease is cancer. In a further preferred embodiment, the compounds of the invention may be used in combination with chemoradiotherapy or immunotherapy for the prevention or treatment of cancer.

The dosing regimen may be adjusted to provide the best desired response. For example, when administered in the form of an injection, a single bolus, bolus and/or continuous infusion, and the like, may be administered. For example, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. Generally, the dosage of treatment will vary depending on considerations such as: age, sex and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; duration of symptoms; as well as other variables that may be adjusted by the respective physician. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions. The amount and regimen of administration of the pharmaceutical composition can be readily determined by one of ordinary skill in the clinical arts. For example, the compositions or compounds of the present invention may be administered in divided doses from 4 times per day to 1 time per 3 days, and the amount administered may be, for example, 0.01 to 1000 mg/time. The required dose may be administered in one or more doses to achieve the desired result. The pharmaceutical composition according to the present invention may also be provided in unit dosage form.

Advantageous effects

The invention provides a novel high-activity SHP2 inhibitor which can realize at least one of the following technical effects:

(1) High inhibitory activity against SHP2 enzyme.

(2) Excellent physicochemical properties (e.g., solubility, physical and/or chemical stability).

(3) Excellent pharmacokinetic properties (e.g. good bioavailability, suitable half-life and duration of action).

(4) Excellent safety (lower toxicity and/or fewer side effects, wider therapeutic window), etc.

General terms and definitions

Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps. Those skilled in the art will appreciate that such terms as "comprising" encompass the meaning of "consisting of …".

The term "about" means within + -10%, preferably within + -5%, more preferably within + -2% of the stated value.

Unless otherwise stated, concentrations are by weight and proportions (including percentages) are by mole.

The term "one or more" or similar expression "at least one" may denote, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

When lower and upper limits of a range of values are disclosed, any number and any range encompassed within the range are specifically disclosed. In particular, each range of values (in the form "about a to b", or equivalently, "about a-b") of values disclosed herein is understood to mean each value and range encompassed within the broader range.

For example, the expression "C ₁ -C ₆ "is understood to cover any subrange therein as well as every point value, e.g. C ₂ -C ₅ 、C ₃ -C ₄ 、C ₁ -C ₂ 、C ₁ -C ₃ 、C ₁ -C ₄ 、C ₁ -C ₅ Etc. and C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ Etc. For example, the expression "C ₃ -C ₁₀ "also should be understood in a similar manner, for example, any subrange and point value contained therein, e.g., C ₃ -C ₉ 、C ₆ -C ₉ 、C ₆ -C ₈ 、C ₆ -C ₇ 、C ₇ -C ₁₀ 、C ₇ -C ₉ 、C ₇ -C ₈ 、C ₈ -C ₉ Etc. and C ₃ 、C ₄ 、C ₅ 、C ₆ 、C ₇ 、C ₈ 、C ₉ 、C ₁₀ Etc. As another example, the expression "3-10 membered" should be understood to cover any subrange therein as well as every point value, e.g., 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5, 4-6, 4-7, 4-8, 5-7, 5-8, 6-7, etc., and 3, 4, 5, 6, 7, 8, 9, 10, etc. Also for example, the expression "5-10 membered" should be understood in a similar manner, e.g. any subrange and point value contained therein, e.g. 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 5-10 membered, 6-7 membered, 6-8 membered, 6-9 membered, 6-10 membered, 7-8 membered etc. and 5, 6, 7, 8, 9, 10 membered etc.

The term "alkyl", when used herein alone or in combination with other groups, refers to a saturated straight or branched hydrocarbon group. As used herein, the term "C _1-6 Alkyl "refers to a saturated straight or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). For example "C _1-6 The alkyl group "may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl or the like.

As used herein, the term "alkylene" refers to a saturated straight or branched divalent hydrocarbon radical. For example, as used herein, the term "C _1-6 Alkylene "refers to a straight or branched chain divalent hydrocarbon radical having 1 to 6 carbon atoms saturated. Such as methylene, ethylene, propylene, butylene, and the like.

The term "cycloalkyl", when used herein, alone or in combination with other groups, refers to a saturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl; or bicyclic, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1)]Amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalin, etc.). Cycloalkyl includes C _3-10 Cycloalkyl, preferably C _3-6 Cycloalkyl groups, more preferably C _5-6 Cycloalkyl groups. For example, the term "C _3-10 Cycloalkyl "refers to cycloalkyl groups having 3 to 10 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, or 10).

The term "hydrocarbon ring", when used herein alone or in combination with other groups, refers to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds within the ring, but not forming an aromatic ring system) mono-or polycyclic hydrocarbon ring having, for example, 3 to 10 (e.g., 4 to 10, 5 to 10, 6 to 10, preferably 5 to 8, more preferably 5 to 6) ring carbon atoms, including, but not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclohexyl rings, cycloheptyl rings, cyclooctyl rings, cyclononyl rings, cyclohexenyl rings, and the like.

The term "halo" or "halogen" group, when used herein alone or in combination with other groups, means F, cl, br or I.

The term "haloalkyl", when used herein alone or in combination with other groups, refers to an alkyl group as described above wherein one or more hydrogen atoms are replaced with a halogen. For example, the term "halo C _1-6 Alkyl "means C optionally substituted with one or more (e.g., 1-3) halogens _1-6 An alkyl group. It will be appreciated by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Examples of haloalkyl groups are, for example, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CCl ₃ 、-C ₂ F ₅ 、-C ₂ Cl ₅ 、-CH ₂ CF ₃ 、-CH ₂ Cl or-CH ₂ CH ₂ CF ₃ Etc.

The term "alkenyl", as used herein alone or in combination with other groups, refers to a straight or branched hydrocarbon group having one or more carbon-carbon double bonds. For example, as used herein, the term "C _2-6 Alkenyl "means a straight or branched hydrocarbon radical having 2 to 6 carbon atoms and one, two or three carbon-carbon double bonds, preferably C containing one carbon-carbon double bond _2-6 Alkenyl groups. Such as ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like.

The term "heterocycle", when used herein alone or in combination with other groups, refers to a monocyclic or bicyclic non-aromatic ring system (i.e., 3-10 membered, 4-10 membered, 5-10 membered, 3-8 membered, 3-6 membered, or 5-6 membered heterocycle) having, for example, 3-10 (e.g., 4-10, 5-10, 6-8, 3-6, or 5-6 membered ring atoms) ring atoms, wherein at least one ring atom (e.g., 1, 2, or 3) is a heteroatom selected from N, O and S, and the remaining ring atoms are C. The ring system may be saturated (which may also be understood as the corresponding "saturated heterocycles") or unsaturated (i.e. having one or more double and/or triple bonds within the ring). The term also covers the case where the C atom may be substituted with (=o) and/or the S atom on the ring may be substituted with 1 or 2 (=o). A heterocyclyl group is a group derived from a heterocycle by removal of one hydrogen atom, examples of which include, but are not limited to: ethylene oxide, an azetidinyl, oxetanyl, thietanyl, thietan tetrahydrofuranyl, tetrahydrothienyl, dioxolyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, 1, 4-thiazalkyl, 1, 4-dioxane, dithianyl, tetrahydropyridinyl, thiomorpholinyl, piperazinyl or trithianyl, and the like.

The term "aromatic ring", when used herein alone or in combination with other groups, refers to an all-carbon monocyclic or fused-ring polycyclic (e.g., bicyclic) aromatic ring having a conjugated pi-electron system. Aryl is a group derived from an aromatic ring by removal of one hydrogen atom. As used herein, the term "C _6-10 Aryl "refers to an aromatic group derived from an aromatic ring containing 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

The term "heteroaryl ring", when used herein alone or in combination with other groups, refers to an aromatic ring in which one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from N, O and S, with the remaining ring atoms being C. Heteroaryl is a group derived from a heteroaromatic ring by removal of one hydrogen atom. Heteroaryl or heteroaromatic rings may be characterized by the number of ring atoms. For example, a 5-10 membered heteroaryl group may contain 5-10 ring atoms (e.g., 5, 6, 7, 8, 9, or 10 ring atoms), particularly 5, 6, 9, 10 ring atoms, and a 5-6 membered heteroaryl group may contain, for example, 5 or 6 ring atoms. And in each case the heteroaryl or heteroaromatic ring may optionally be further benzo-fused. Examples of heteroaryl groups are, for example, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and the benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like, and their benzo derivatives.

The term "hydroxy" means-OH.

The term "cyano" means-CN.

The term "nitro" means-NO ₂ 。

The term "amino" means-NH ₂ 。

The terms "substituted" and "substituted" refer to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally … substituted," the substituent can be (1) unsubstituted or (2) substituted. If an atom or group is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on that atom or group may be replaced with an independently selected, optional substituent. If substituents are described as "independently selected" or "each independently" then each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent. For example, a substituent or substitution position or a different substituent or substitution position has an R group (e.g., without limitation, R) ² 、R ³ 、R ^h 、R ⁱ 、R ^x And/or R ^y ) When R is selected, R may be the same or different. The same is true for the choice of values such as d, g, m, n.

As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.

When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium @ ² H) The tritium is ³ H) A) is provided; isotopes of carbon (e.g ¹³ C, C is a metal alloy ¹⁴ C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g ³⁷ Cl); isotopes of iodine (e.g ¹²⁵ I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g ¹³ N is N ¹⁵ N); isotopes of oxygen (e.g ¹⁷ O and O ¹⁸ O); isotopes of phosphorus (e.g ³² P) is as follows; isotopes of sulfur (e.g ³⁴ S)。

The term "stereoisomer" refers to an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, they can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the present invention encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

Solid (-, solid wedge shaped) may be used hereinOr virtual wedge +.>Depicting the carbon-carbon bonds of the compounds of the present invention. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of a solid or virtual wedge to depict a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, real and imaginary wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, compounds of the present invention may exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.

It will also be appreciated that certain compounds of the invention may exist in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs which, upon administration to a patient in need thereof, are capable of providing the compounds of formulas (I) - (VII) or metabolites thereof directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitate and other similar salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts. For reviews of suitable salts see, e.g., "Remington's Pharmaceutical Sciences", mack Publishing Company, easton, pa., (2005); and "manual of pharmaceutically acceptable salts: properties, selection and application "(Handbook of Pharmaceutical Salts: properties, selection, and Use), stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

As used herein, the term "ester" means an ester derived from a compound described herein, including physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the invention may themselves be esters.

The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires available lone pairs to oxidize to oxides. Those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyl dioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: t.l.gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750 (a.r.katritzky and a.j.boulton, eds., academic Press); and G.W.H.Cheeseman and E.S.G.Werstiuk, advances in Heterocyclic Chemistry, vol.22, pp 390-392 (A.R.Katritzky and A.J.Boulton, eds., academic Press).

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by assay methods. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.

The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, and which, when administered into or onto the body, are converted to the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", vol.14, ACS Symposium Series (T.Higuchi and V.stilla). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g. "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".

The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example those described in t.w. greene & p.g.m. wuts, protective Groups in Organic Synthesis, john Wiley & Sons,2006, which references are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

The invention also encompasses methods of preparing the compounds described herein. It will be appreciated that the compounds of the invention may be synthesized using the methods described herein as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof as would be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction may be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for effecting the conversion.

By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the active ingredient is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio. The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.

The term "effective amount" (e.g., "therapeutically effective amount" or "prophylactically effective amount") as used herein refers to an amount of an active ingredient that, upon administration, will achieve a desired effect to some extent, e.g., to alleviate one or more symptoms of the condition being treated or to prevent the appearance of the condition or symptoms thereof.

As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing a disorder or condition to which the term applies or one or more symptoms of the disorder or condition.

SHP2 phosphatase-related diseases are diseases that are sensitive or responsive to SHP2 phosphatase inhibition, including, but not limited to, solid and hematological malignancies, such as breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer), and prostate cancer, as well as cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, renal cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulval cancer, as well as leukemias (including Chronic Lymphocytic Leukemia (CLL), acute Lymphocytic Leukemia (ALL), and Chronic Myelogenous Leukemia (CML)), multiple myeloma, and lymphoma.

As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Detailed Description

Examples

The present invention will be described in further detail with reference to the following examples and test examples, which do not limit the scope of the present invention and may be modified without departing from the scope of the present invention.

MS was determined using an Agilent (ESI) mass spectrometer, manufacturer: agilent, model: agilent 6120B.

Preparation high performance liquid chromatography A liquid chromatograph (YMC, ODS, 250X 20mm column) was prepared using Shimadzu LC-8A.

Thin layer chromatography purification was performed using a fume bench produced GF 254 (0.4-0.5 nm) silica gel plate.

The reaction is monitored by Thin Layer Chromatography (TLC) or LC-MS using a developing reagent system including but not limited to: the volume ratio of the methylene dichloride and methanol system, the normal hexane and ethyl acetate system and the petroleum ether and ethyl acetate system is adjusted according to the polarity of the compound, or triethylamine and the like are added.

Column chromatography generally uses 200-300 mesh silica gel from Qingdao ocean as stationary phase. The eluent system comprises but is not limited to a methylene dichloride system, a methanol system, a normal hexane system and an ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and the like can be added for adjustment.

Unless otherwise specified in the examples, the reaction temperature was room temperature (20℃to 30 ℃).

Unless otherwise indicated, the reagents used in the examples were purchased from Acros Organics, aldrich Chemical Company, nanjing medical stone technology or Shanghai Summit medicine technology, among others.

Abbreviations used herein have the following meanings:

preparation example

Example a: preparation of 6-chloro-3-iodo-4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridine (A-6)

The first step: preparation of the Compound 2, 6-dichloro-4-methoxypyridine (A-2)

To a 100mL microwave tube were added 2, 6-dichloro-4-nitropyridine (A-1) (10.0 g,51.8 mmol), potassium carbonate (21.5 g,155.8 mmol) and methanol (42 mL), followed by heating to 70℃in a microwave and stirring to react for 0.5 hours. After the reaction was completed, the temperature was lowered to 25℃and then 30mL of ethyl acetate was added for dilution, followed by filtration, and the cake was rinsed with ethyl acetate (30 mL) and the filtrate was concentrated to dryness to give Compound A-2 (9.0 g, yield 98%).

And a second step of: preparation of the Compound 2, 6-dichloro-4-methoxy-pyridine-3-carbaldehyde (A-3)

To a 250mL three-necked flask, 2, 6-dichloro-4-methoxy-pyridine (A-2) (4.5 g,25.42 mmol) and anhydrous THF (100 mL) were added, and the mixture was stirred and dissolved under nitrogen protection, and the temperature was lowered to-78 ℃. Then nBuLi (27.81 mmol,12.85mL,2.5N in THF) was added dropwise to the reaction solution over 20 minutes, and the reaction was continued for 0.5 hours at a constant temperature. DMF (3.70 g,50.56 mmol) was added dropwise to the reaction solution over 15 minutes, and the reaction was allowed to stand for 2 hours after completion of the dropwise addition. The reaction mixture was quenched by slowly adding saturated ammonium chloride (100 mL), extracting twice with ethyl acetate (60 mL), mixing the organic phases, washing 1 with saturated brine (150 mL), drying the organic phase over anhydrous sodium sulfate, and purifying the crude product by silica gel column chromatography to give Compound A-3 (4.5 g, yield 86%).

And a third step of: preparation of 6-chloro-4-methoxy-1H-pyrazolo [3,4-b ] pyridine (A-4)

To a 250mL three-necked flask were added 2, 6-dichloro-4-methoxy-pyridine-3-carbaldehyde (A-3) (4.5 g,21.84 mmol) and THF (50 mL), and 80% hydrazine hydrate (2.5 g,32.76 mmol) was added with stirring. After the addition, the temperature was raised to 50℃for 1 hour, and the solvent was removed by concentration under reduced pressure. Dioxane (40 mL) was added to the residue, which was transferred to a microwave tube and heated to 150 ℃ for 8 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give Compound A-4 (1.0 g, yield 25%).

Fourth step: preparation of 6-chloro-3-iodo-4-methoxy-1H-pyrazolo [3,4-b ] pyridine (A-5)

In a 100mL reaction flask, 6-chloro-4-methoxy-1H-pyrazolo [3,4-b ] pyridine (A-4) (1.0 g,5.4 mmol), NIS (2.5 g,11 mmol) and 1, 2-dichloroethane (30 mL) were added, the temperature was raised to 80℃for 16 hours, the solvent was removed by vacuum concentration, and the crude product was purified by silica gel column chromatography to give compound A-5 (1.5 g, yield 89%).

Fifth step: preparation of 6-chloro-3-iodo-4-methoxy-1- (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridine (A-6)

To a 100mL three-necked flask was added 6-chloro-3-iodo-4-methoxy-1H-pyrazolo [3,4-b ] pyridine (A-5) (1.50 g,4.84 mmol) and anhydrous THF (20 mL), and the mixture was cooled to 0℃under nitrogen. 60% NaH (0.23 g,5.81 mmol) was added to the reaction mixture and stirred for 0.5 h with heat preservation, SEMCl (0.97 g,5.81 mmol) was then added and the reaction was continued for 10 min and then allowed to proceed to room temperature for 20 min. The reaction was quenched by slow addition of saturated ammonium chloride (30 mL), extracted twice with ethyl acetate (20 mL), the organic phases were combined, washed 1 with saturated brine (40 mL), dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography to give Compound A-6 (1.90 g, yield 89%).

EXAMPLE 1 preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 1)

The first step: preparation of 6-chloro-3- (2, 3-dichlorophenyl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridine (1-1)

To a 20mL microwave tube was added 6-chloro-3-iodo-4-methoxy-1- (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridine (A-6) (0.190 g,0.43 mmol), 2, 3-dichlorobenzoboric acid (0.082 g,0.43 mmol), tetrakis triphenylphosphine palladium (50 mg, 43. Mu. Mol), sodium carbonate (0.091 g,0.86 mmol), dioxane (8 mL) and water (1 mL), and the mixture was heated to 100℃in a microwave for 1 hour after nitrogen substitution. After the reaction, the temperature was lowered to 25℃and the mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give Compound 1-1 (0.170 g, yield 86%).

And a second step of: preparation of tert-butyl (1-2) carbamate (1- (3- (2, 3-dichlorophenyl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl)

To a 10mL reaction flask was added tert-butyl 6-chloro-3- (2, 3-dichlorophenyl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridine (1-1) (0.17 g,0.37 mmol), (4-methylpiperidin-4-yl) carbamate (0.16 g,0.74 mmol), potassium phosphate (0.25 g,1.18 mmol) and NMP (8 mL) and the mixture was heated to 120℃for 6 hours. After the reaction was completed, the temperature was lowered to 25℃and water (15 mL) was added. Ethyl acetate (20 mL) was extracted 1 time, saturated brine (20 mL) was washed 1 time, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 1-2 (94 mg, yield 40%).

And a third step of: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 1)

To a 10mL reaction flask was added tert-butyl (1-2) (90 mg,0.14 mmol) of (1- (3- (2, 3-dichlorophenyl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl) carbamate (1-2) (5 mL) and heated to 80℃for 6 hours. Cooling to 25 ℃ after the reaction is finished, and concentrating to dryness under reduced pressure. The residue was added with 40% aqueous hydrobromic acid (15 mL) and heated to 100deg.C for 4 hours. After the reaction was completed, the temperature was lowered to 25 ℃, the pH was adjusted to 9 with 4N NaOH, extraction was performed 2 times with ethyl acetate (10 mL), the organic phases were combined, washed 1 time with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was subjected to reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous trifluoroacetic acid) to prepare trifluoroacetate salt of Compound TM1 (9 mg, yield 13%).

MS m/z(ESI):392.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ12.95(s,1H),10.80(br,1H),7.92(s,3H),7.69(dd,J＝7.4Hz,2.2Hz,1H),7.46-7.39(m,2H),6.04(s,1H),4.00-3.97(m,2H),3.30-3.25(m,2H),1.76-1.66(m,4H),1.38(s.3H).

Example 2: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- ((2, 3-dichlorophenyl) thio) -1H pyrazolo [3,4-b ] pyridin-4-ol (TM 2)

The first step: preparation of 6-chloro-3- ((2, 3-dichlorophenyl) thio) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridine (2-1)

A50 mL reaction flask was charged with 6-chloro-3-iodo-4-methoxy-1- (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridine (A-6) (0.300 g,0.682 mmol), 2, 3-dichlorobenzothiool (0.122 g,0.682 mmol), N-diisopropylethylamine (0.176 g, 1.284 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (39.5 mg, 68.2. Mu. Mol), palladium acetate (15.3 mg, 68.2. Mu. Mol), and dioxane (10 mL). The reaction was carried out at 80℃for 3 hours under nitrogen protection. After the reaction was completed, the temperature was lowered to 25℃and the reaction mixture was extracted twice with water (30 mL) and ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 2-1 (125 mg, yield 37%).

And a second step of: preparation of tert-butyl (2-2) carbamate (1- (3- ((2, 3-dichlorophenyl) thio) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl)

To a 15mL microwave tube was added tert-butyl 6-chloro-3- ((2, 3-dichlorophenyl) thio) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridine (2-1) (125 mg, 254.6. Mu. Mol), (4-methylpiperidin-4-yl) carbamate (218 mg,1.02 mmol), potassium phosphate (162 mg, 763.2. Mu. Mol) and NMP (5 mL). The reaction was carried out at 120℃for 4 hours under microwaves, then the temperature was lowered to 25℃and the reaction mixture was extracted 2 times with water (15 mL) and ethyl acetate (10 mL), and the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give compound 2-2 (98 mg, yield 58%).

And a third step of: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- ((2, 3-dichlorophenyl) thio) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 2)

The trifluoroacetate salt of TM2 was synthesized in a similar manner as described in the third step of example 1, except that 2-2 was used in this step in place of 1-2 in the third step of example 1 (20 mg, yield 25%).

MS m/z(ESI):424.0[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ13.33(s,1H),10.90(br,1H),7.89(s,3H),7.44-7.41(dd,J＝8.0Hz,1.3Hz,1H),7.20-7.16(t,J＝8.0Hz,1H),.6.71-6.68(dd,J＝8.0Hz,1.3Hz,1H),5.99(s,1H),4.00-3.95(m,2H),3.30-3.24(m,2H),1.73-1.67(m,4H),1.37(s.3H).

Example 3: preparation of 6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 3)

The first step: preparation of (3S, 4S) -8- (3-iodo-4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (3-1)

A5 mL reaction flask was charged with A-6 (50 mg,0.11 mmol), (3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (39 mg,0.23 mmol), anhydrous potassium phosphate (72 mg,0.34 mmol) and N-methylpyrrolidone (1 mL) at 25℃and the temperature was raised to 130℃for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted three times with ethyl acetate (10 mL), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, and the crude product was purified by preparative thin layer chromatography to give compound 3-1 (40 mg, yield 61%).

And a second step of: preparation of (3S, 4S) -8- (3- (2, 3-dichlorophenyl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (3-2)

3-1 (10 mg, 0.020mmol) and 2, 3-dichlorobenzoboric acid (4 mg, 0.020mmol) were dissolved in 1, 4-dioxane (1 mL) and water (0.250 mL) at 25℃and tetrakis triphenylphosphine palladium (5 mg, 0.04 mmol) and cesium carbonate (10 mg,0.030 mmol) were added, nitrogen was substituted 3 times, and the temperature was raised to 100℃for reaction for 1 hour. After completion of the reaction, the temperature was lowered to 25℃and diluted with water (20 mL), extracted 3 times with ethyl acetate (20 mL), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 3-2 (10 mg, yield 100%) which was used directly in the next reaction.

And a third step of: preparation of 6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 3)

3-2 (10 mg,0.06 mmol) was dissolved in 40% HBr (1 mL) and reacted at 25℃for 48 hours, after which the reaction was concentrated to dryness. The crude product was prepared by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous trifluoroacetic acid) to give the trifluoroacetate salt of Compound TM3 (4 mg, 40% yield).

MS m/z(ESI):448.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ12.90(s,1H),10.69(s,1H),7.87(s,3H),7.69(d,J＝7.3Hz,1H),7.47-7.38(m,2H),6.02(s,1H),4.22-4.17(m,1H),4.14-4.07(m,1H),4.05-3.98(m,1H),3.89(d,J＝9.2Hz,1H),3.71(d,J＝9.0Hz,1H),3.41-3.34(m,1H),3.15-3.00(m,2H),1.79-1.65(m,3H),1.56-1.48(m,1H),1.21(d,J＝6.5Hz,3H).

Example 4: preparation of 6- ((3S, 4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichloropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 8)

The first step: preparation of (3S, 4S) -8- (3- (2, 3-dichloropyridin-4-yl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -3-methyl-2-oxo-8-pyrazolo [4.5] decan-4-amine (8-1)

8-1 was synthesized (150 mg, yield 48%) by a similar method to that described in the second step of example 3, except that 2, 3-dichloro-pyridine-4-boronic acid pinacol ester was used in this step instead of 2, 3-dichlorobenzoboric acid in the second step of example 3.

And a second step of: preparation of 6- ((3S, 4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichloropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 8)

To a 10mL reaction flask was added 8-1 (90 mg,0.14 mmol) and trifluoroacetic acid (2 mL), and the mixture was heated to 80℃for 6 hours. Cooling to 25 ℃ after the reaction is finished, and concentrating to dryness under reduced pressure. Concentrated hydrochloric acid (15 mL) was added to the residue, and the mixture was heated to 100deg.C to react for 4 hours. After the reaction was completed, the temperature was lowered to 25 ℃, the pH was adjusted to 9 with 4N NaOH, extraction was performed 2 times with ethyl acetate (10 mL), the organic phases were combined, washed 1 time with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was subjected to reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous formic acid solution) to prepare a formate salt of TM8 (26 mg, yield 34%).

MS m/z(ESI):449.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ13.19(s,1H),10.96(s,1H),8.45(d,J＝4.8Hz,1H),7.97(s,3H),7.58(d,J＝4.8Hz,1H),6.09(s,1H),4.21-4.16(m,1H),4.16-4.07(m,1H),4.07-3.98(m,1H),3.93-3.86(m,1H),3.73-3.68(m,1H),3.40-3.34(m,1H),3.09-3.03(m,2H),1.86-1.63(m,3H),1.60-1.50(m,1H),1.22(d,J＝6.5Hz,3H).

Example 5: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichloropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 61)

The first step: preparation of tert-butyl (1- (3-iodo-4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl) carbamate (61-1)

61-1 (500 mg, 71% yield) was synthesized in a similar manner to that described in the first step of example 3, except that tert-butyl (4-methylpiperidin-4-yl) carbamate was used in this step instead of (3 s,4 s) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine in the first step of example 3.

And a second step of: preparation of tert-butyl (1- (3- (2, 3-dichloropyridin-4-yl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl) carbamate (61-2)

61-2 (180 mg, yield 35%) was synthesized in a similar manner to that described in the second step of example 3, except that 2, 3-dichloro-pyridine-4-boronic acid pinacol ester was used in this step instead of 2, 3-dichlorobenzoic acid in the second step of example 3 and 61-1 was used instead of 3-1 in example 3.

And a third step of: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichloropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 61)

Crude TM61 was synthesized in a similar manner to that described in the second step of example 4, except that 61-2 was used in this step instead of 8-1 in the second step of example 4. The crude product was prepared by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous formic acid) to give formate salt of compound TM61 (17 mg, 14% yield).

MS m/z(ESI):393.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ13.21(s,1H),10.97(s,1H),8.44(d,J＝4.9Hz,1H),8.02(s,3H),7.58(d,J＝4.9Hz,1H),6.08(s,1H),3.99(m,2H),3.38-3.20(m,2H),1.79-1.66(m,4H),1.38(s,3H).

Example 6: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2-bromo-3-chloropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 62)

The first step: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2-bromo-3-chloropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 62)

The trifluoroacetate salt of TM62 was synthesized in a similar manner as described in the third step of example 1 except that 61-2 was used in this step instead of 1-2 of example 1 (25 mg, yield 15%).

MS m/z(ESI):437.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ13.20(s,1H),10.95(s,1H),8.41(d,J＝4.8Hz,1H),7.88(s,3H),7.58(d,J＝4.8Hz,1H),6.06(s,1H),4.04-3.95(m,2H),3.32-3.23(m,2H),1.76-1.65(m,4H),1.38(s,3H).

Example 7: preparation of 6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2-bromo-3-chloropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 63)

/>

The first step: preparation of (3S, 4S) -8- (3- (2-bromo-3-chloropyridin-4-yl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (63-1)

63-1 (10 mg, 16% yield) was synthesized in a similar manner to the procedure described in the second step of example 3, except that 2-bromo-3-chloro-pyridine-4-boronic acid was used in this step instead of 2, 3-dichlorobenzoboric acid in the second step of example 3.

And a second step of: preparation of 6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2-bromo-3-chloropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 63)

A crude product of TM63 was synthesized in a similar manner as described in the third step of example 1, except that 63-1 was used in this step instead of 1-2 in example 1. The crude product was prepared by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous formic acid) to give formate salt of compound TM63 (6 mg, 67% yield).

MS m/z(ESI):493.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ13.18(s,1H),10.90(s,1H),8.42(d,J＝4.8Hz,1H),7.86(s,3H),7.58(d,J＝4.8Hz,1H),6.05(s,1H),4.23-4.17(m,1H),4.15-4.10(m,1H),4.06-4.00(m,1H),3.91-3.88(m,1H),3.72-3.70(m,1H),3.41-3.35(m,1H),3.12-3.02(m,2H),1.75-1.66(m,3H),1.54-1.49(m,1H),1.21(d,J＝6.5Hz,3H).

Example 8: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2-bromo-3-fluoropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 64)

The first step: preparation of tert-butyl (64-1) carbamate (1- (3- (2-chloro-3-fluoropyridin-4-yl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl)

Compound 64-1 (90 mg, yield 20%) was synthesized in a similar manner to that described in the second step of example 3, except that 2-chloro-3-fluoro-pyridine-4-boronic acid was used instead of 2, 3-dichlorobenzoic acid in the second step of example 3 and 61-1 was used instead of 3-1 in example 3 in this step.

And a second step of: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2-bromo-3-fluoropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 64)

The trifluoroacetate salt of TM64 was synthesized in a similar manner as described in the third step of example 1, except that 64-1 was used in this step in place of 1-2 of example 1 (17 mg, yield 48%).

MS m/z(ESI):422.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ13.34(s,1H),11.19(brs,1H),8.33(d,J＝4.9Hz,1H),7.93(s,3H),7.76(m,1H),6.12(s,1H),4.01-3.98(m,2H),3.52-3.14(m,2H),1.72(s,4H),1.38(s,3H).

EXAMPLE 9 preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 6-dichloro-4-pyridinyl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 65)

The first step: preparation of tert-butyl (65-1) carbamate (1- (3- (2, 6-dichloro-pyridin-4-yl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl)

Compound 65-1 (90 mg, yield 87%) was synthesized in a similar manner to that described in the second step of example 3, except that 2, 6-dichloro-4-pyridineboronic acid was used instead of 2, 3-dichlorobenzoboric acid in the second step of example 3 and 61-1 was used instead of 3-1 in example 3 in this step.

And a second step of: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 6-dichloro-4-pyridinyl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 65)

Crude TM65 was synthesized in a similar manner as described in the second step of example 4, except that 65-1 was used in this step instead of 8-1 in the second step of example 4. The crude product was prepared by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous formic acid) to give compound TM65 (12 mg, yield 32%).

MS m/z(ESI):393.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ13.26(s,1H),8.60(s,2H),8.36(s,1H),6.02(s,1H),3.95-3.88(m,2H),3.27-3.23(m,2H),1.73-1.52(m,4H),1.33(s,3H).

EXAMPLE 10 preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-difluorophenyl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 66)

The first step: preparation of tert-butyl (66-1) carbamate (1- (3, 4-difluorophenyl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl)

Compound 66-1 (63 mg, yield 62%) was synthesized by a similar method to that described in the second step of example 3, except that 3, 4-difluorophenylboronic acid was used in this step in place of the 2, 3-dichlorobenzoic acid in the second step of example 3 and 61-1 was used in place of 3-1 in example 3.

And a second step of: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-difluorophenyl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 66)

The trifluoroacetate salt of TM66 was synthesized in a similar manner as described in the third step of example 1, except that 66-1 was used in this step in place of 1-2 of example 1 (34 mg, yield 51%).

MS m/z(ESI):360.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ13.00(s,1H),11.32(s,1H),8.14-8.05(m,1H),7.99-7.82(m,4H),7.55-7.44(m,1H),6.16-6.09(m,1H),4.03-3.94(m,2H),3.33-3.23(m,2H),1.78-1.66(m,4H),1.38(s,3H).

EXAMPLE 11 preparation of 6- (4-amino-4-methylpiperidin-1-yl) -5-chloro-3- (2, 3-dichloropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 67)

The first step: preparation of tert-butyl (1- (5-chloro-3- (2, 3-dichloropyridin-4-yl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl) carbamate (67-1)

To a 10mL reaction flask, 61-2 (120 mg, 188.2. Mu. Mol) and acetonitrile (10 mL) were added, and NCS (101 mg, 752.7. Mu. Mol) was further added, followed by reaction at 40℃for 20 hours. After the reaction solution was concentrated, the crude product was purified by preparative thin layer chromatography to give compound 67-1 (72 mg, yield 59%).

And a second step of: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -5-chloro-3- (2, 3-dichloropyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 67)

A crude product of TM67 was synthesized in a similar manner to that described in the third step of example 1, except that 67-1 was used in this step instead of 1-2 in example 1. The crude product was prepared by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous formic acid) to give compound TM67 (25 mg, yield 55%).

MS m/z(ESI):427.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ12.66(s,1H),8.33(d,J＝4.8Hz,1H),8.10-7.85(br,2H),7.75-7.69(m,1H),3.45-3.35(m,2H),3.02-2.88(m,2H),1.95–1.65(m,4H),1.30(s.3H).

EXAMPLE 12 preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 68)

The first step: preparation of tert-butyl (66-1) carbamate (1- (3- (2-methylpyridin-4-yl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl)

Compound 68-1 (90 mg, yield 95%) was synthesized in a similar manner to that described in the second step of example 3, except that 2-methylpyridin-4-yl boric acid was used in the present step instead of 2, 3-dichlorobenzoic acid in the second step of example 3 and 61-1 was used instead of 3-1 in example 3.

And a second step of: preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 68)

Crude TM65 was synthesized in a similar manner as described in the second step of example 4, except that 68-1 was used in this step instead of 8-1 in the second step of example 4. The crude product was prepared by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous trifluoroacetic acid) to give the trifluoroacetate salt of Compound TM68 (20 mg, yield 38%).

MS m/z(ESI):339.2[M+H] ⁺

1H NMR(400MHz,DMSO-d ₆ )δ13.79(s,1H),12.03(brs,1H),8.78(d,J＝6.2Hz,1H),8.64-8.48(m,2H),8.05(s,3H),6.32(s,1H),4.05-3.95(m,2H),3.39-3.24(m,2H),2.75(s,3H),1.75-1.54(m,4H),1.39(s,3H).

Example 13: preparation of 3- (2-amino-3-chloro-pyridin-4-yl) -6- (4-amino-4-methyl-1-piperidinyl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 69)

The first step: preparation of tert-butyl (1- (3- (3-chloro-2- ((2, 4-dimethoxybenzyl) amino) pyridin-4-yl) -4-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl-1H-pyrazolo [3,4-b ] pyridin-6-yl) -4-methylpiperidin-4-yl) carbamate (69-1) 10mL of a microwave tube was charged with 61-2 (80 mg,125.46 mol), 2, 4-dimethoxybenzylamine (105 mg,627.28 mol) and NMP (2 mL) and heated to 150℃in a microwave reactor for 3 hours 10mL of water was added to the reaction solution, ethyl acetate (10 mL) was extracted twice, the organic phases were combined, saturated brine (20 mL) was washed 1 time, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was purified by preparative thin layer chromatography to give compound 69-1 (21 mg, yield 22%).

And a second step of: preparation of 3- (2-amino-3-chloro-pyridin-4-yl) -6- (4-amino-4-methyl-1-piperidinyl) -1H-pyrazolo [3,4-b ] pyridin-4-ol (TM 69)

Crude TM2 was synthesized in a similar manner as described in the third step of example 1, except that 69-1 was used in this step instead of 1-2 in the third step of example 1. The crude product was prepared by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous formic acid) to give compound TM69 (4 mg, 40% yield).

MS m/z(ESI):374.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ:12.79(s,1H),7.89(d,J＝4.8Hz,1H),6.65(d,J＝4.8Hz,1H),6.25(s,2H),5.93(s,1H),3.56-3.54(m,4H),1.49-1.39(m,4H),1.10(s,3H).

Biological examples

Test example 1: in vitro enzyme activity inhibition assay for SHP2 (protein tyrosine phosphatase)

Test system:

kinase: recombinant full-length human PTPN (SHP 2), active (SignalChemCatalog: P38-20G)

A substrate: 6,8-Difluoro-4-methylumbelliferyl phosphate (DiFMUP) (Invitrogen Catalog:D 6567) activator peptide: IRS1_pY1172 (dPEG 8) pY1222 (BPS Bioscience Catalog: 79319-2)

Termination reagent: bpv (phen) (Abcam catalyst: ab 141436)

Test parameters:

SHP2 concentration: 0.5nM; diFMUP concentration: 200. Mu.M; IRS-1 concentration: 0.5. Mu.M; bpv:160 μm buffer system: 60mM Hepes pH7.2;75mM NaCl;75mM KCl;0.05% P-20;1mM EDTA;5mM DTT;

compound incubation and enzyme activation time: room temperature for 60 minutes

Enzyme reaction time with substrate: room temperature for 30 minutes

Parameters of the enzyme-labeled instrument: BMG PHERAstar Fluorescence excitation wavelength 340nm and emission wavelength 450nm

The test steps are as follows:

incubating a mixture of a compound to be tested and phosphatase SHP2 with an activating peptide IRS-1 in a buffer system at room temperature for 60 minutes, adding a substrate DiFMUP to start reaction, incubating at room temperature for 30 minutes, adding bpv to stop reaction, placing a reaction plate in an enzyme-labeled instrument, and reading the fluorescence value of each hole in the plate by adopting an end-point method.

And (3) data processing:

the relative concentrations of the groups were calculated using the vehicle group (containing 0.5nM SHP2, 200. Mu.M DiFMUP, 0.5. Mu.M IRS-1, 160. Mu.M bpv,0.05% DMSO) as negative control and the reaction buffer group (200. Mu.M DiFMUP, 0.5. Mu.M IRS-1, 160. Mu.M bpv,0.05% DMSO) as blank controlInhibition activity = 100% - (test group-blank)/(vehicle group-blank) ×100%. The half maximal Inhibitory Concentration (IC) of the compound was calculated by fitting a curve according to a four parameter model ₅₀ )。

Test results:

inhibition of SHP2 activity by the compounds was determined as described above and the results are shown in table 1.

TABLE 1 results of SHP2 enzyme Activity inhibition test

Numbering of compounds	IC ₅₀ (nM)
		Example 1	36.0
Example 2	90.0
		Example 3	51.0
Example 4	5.3
		Example 5	4.8
Example 6	1.3
		Example 7	8.8
Example 8	2.0
		Example 9	6.3
Example 10	57.5
		Example 11	9.5
Example 12	28.0
		Example 13	59.9

Conclusion:

in the SHP2 enzyme activity inhibition test, the compound of the invention shows stronger inhibition activity.

Test example 2: inhibition assay of KYSE-520 cell proliferation Activity by Compounds

Test system:

cell name/manufacturer: KYSE-520/JCRB Cell Bank

Kit name/manufacturer: cellTiter-Luminescent Cell Viability Assay, promega, test parameters:

cell number: 1500 cells/well

Plating medium: KYSE-520:1640+10% FBS

Dosing medium: KYSE-520:1640+10% FBS

Compound incubation conditions: 37 ℃,5% CO ₂

Incubation time: 5d

Detecting the temperature: RT (reverse transcription) method

Parameters of the enzyme-labeled instrument: BMG PHERAstar FS Luminescent

The test steps are as follows:

culturing cells in a medium containing 10% fetal bovine serum, and standing at 37deg.C with 5% CO ₂ Culturing under culture conditions. Appropriate amount of cells were plated into 96-well plates, and cultured overnight in an incubator to adhere the cells. The following day, the medium was removed, complete medium containing pre-diluted compounds was added and incubated for 5d at 37 ℃. On the fifth day, detection reagent CellTiter-GLo was added to each well and the Relative Luminescence Units (RLU) of each well was detected by chemiluminescence.

And (3) data processing:

background values were obtained using CellTiter-Glo without cell-containing medium.

Cell viability = (sample RLU-background RLU)/(vehicle RLU-background RLU) x 100%,

maximum inhibition = 100% -cell viability _{Maximum concentration of} ，

The half maximal Inhibitory Concentration (IC) of the compound was calculated by fitting a curve according to a four parameter model ₅₀ )。

Test results:

the inhibitory activity of the compounds on KYSE-520 (human esophageal squamous carcinoma cells) proliferation was measured as described above and the results are shown in Table 2.

Results of inhibition of KYSE-520 cell proliferation Activity by Compounds of Table 2

Conclusion:

the compound has stronger cell proliferation inhibition activity on KYSE-520.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

the moiety is selected from->

X is selected from a direct bond and-S-;

W ¹ 、W ² and W is ³ Each independently selected from CH and N;

ring a is selected from piperidine rings;

R ² each at each occurrence is independently selected from H, halogen, C _1-6 Alkyl and-NH ₂ Wherein the alkyl is optionally substituted with one or more substituents selected from halogen;

R ⁴ is H;

R ^5a and R is ^5b Are substituents on the same carbon atom and are each independently selected from H, C _1-6 Alkyl, -NH ₂ and-C _1-6 alkylene-NH ₂ ；

Or R is ^5a And R is ^5b Together with the atoms to which they are attached form a 5-6 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with one or more groups selected from halogen, C _1-6 Alkyl and-NH ₂ Is substituted by a substituent of (a);

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4.

2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein W ¹ Is CH, W ² And W is ³ Each independently selected from CH and N.

3. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein W ¹ 、W ² And W is ³ Are all CH.

4. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ² Each at each occurrence is independently selected from H, halogen, C _1-3 Alkyl and-NH ₂ 。

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein R ² Each at each occurrence is independently selected from H, F, cl, br, -CH ₃ 、-CH ₂ CH ₃ and-NH ₂ 。

6. A compound of formula (I) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R ² Each at each occurrence is independently selected from F, cl, br, -CH ₃ and-NH ₂ 。

7. A compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R ² Each at each occurrence is independently selected from F, cl, -CH ₃ and-NH ₂ 。

8. A compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R ² Each at each occurrence is independently selected from Br, cl and-NH ₂ 。

9. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^5a And R is ^5b Each independently selected from H, C _1-3 Alkyl, -NH ₂ and-C _1-3 alkylene-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ^5a And R is ^5b Together with the atoms to which they are attached form a 5-6 membered heterocyclic ring, wherein each of said heterocyclic rings is optionally substituted with one or more groups selected from C _1-3 Alkyl and-NH ₂ Is substituted by a substituent of (a).

10. A compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein

R ^5a And R is ^5b Each independently selected from H, -CH ₃ 、-CH ₂ CH ₃ 、-NH ₂ and-CH ₂ NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ^5a And R is ^5b Together with the atoms to which they are attached, form an oxacyclopentane, wherein the oxacyclopentane is optionally substituted with one or more groups selected from-CH ₃ and-NH ₂ Is substituted by a substituent of (a).

11. A compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R ^5a And R is ^5b Each independently selected from-CH ₃ and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ^5a And R is ^5b Together with the atoms to which they are attached, form an oxacyclopentane, wherein the oxacyclopentane is simultaneously substituted with-CH ₃ and-NH ₂ Is substituted by a substituent of (a).

12. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

13. A compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt thereof, wherein m is 0.

14. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2.

15. A compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) has the structure of formula (IV),

wherein,represents a single bond, and U is N; />The moiety is selected from->W ₂ 、R ² 、R ⁴ 、X、R ^5a 、R ^5b M and n are as defined in one of claims 1 to 15.

17. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) has the structure of formula (VI),

wherein R is ^2a And R is ^2b Definition of R as defined in one of claims 1 to 15, respectively ² Identical, R ^2a And R is ^2b May be the same or different;the moiety is selected from->And X, R ^5a And R is ^5b As defined in one of claims 1 to 15.

18. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

19. a pharmaceutical composition comprising a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for the prevention or treatment of SHP2 phosphatase-related diseases.

21. The use of claim 20, wherein the SHP2 phosphatase-related disease is a disease that is sensitive or responsive to SHP2 phosphatase inhibition.

22. The use of claim 20, wherein the SHP2 phosphatase-related disease is a oncological disorder.

23. The use of claim 20, wherein the SHP2 phosphatase-related disease is selected from a solid and hematological malignancy.

24. The use of claim 23, wherein the SHP2 phosphatase-related disease is selected from breast cancer, colorectal cancer, colon cancer, lung cancer, prostate cancer, and bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, and vulvar cancer, and leukemia, multiple myeloma, and lymphoma.

25. The use of claim 24, wherein the lung cancer is selected from small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer, and the leukemia is selected from chronic lymphocytic leukemia, acute lymphoblastic leukemia and chronic myelogenous leukemia.

26. A process for the preparation of a compound according to any one of claims 1 to 18, which comprises:

(1) Reacting a compound of formula S-1 with a compound of formula S-2 to produce a compound of formula IM-1;

(2) Reacting a compound of formula IM-1 with a compound of formula S-3 to produce a compound of IM-2; and

(3) Removing the protecting group from the compound of formula IM-2 to produce a compound of formula (I);

wherein LG (glass fiber reinforced plastic) ¹ And LG (glass fibre reinforced plastics) ² Each independently represents halogen, or C optionally substituted by halogen _1-6 An alkylsulfonate group leaving group;

R ^c and R is ^d Each independently represents H or a leaving group; wherein the leaving group is selected from halogen, boric acid group, borate group, substituted silicon group, substituted metal group or C optionally substituted by halogen _1-6 Alkyl sulfonate groups;

PG ¹ selected from methyl, t-butyldimethylsilyl, triisopropylsilyl, benzyl and methoxymethyl;

the remaining groups are as defined in one of claims 1 to 18.

27. The method of claim 26, wherein the C optionally substituted with halo _1-6 The alkyl sulfonate leaving group is a triflate.

28. The production method according to claim 26 or 27, wherein R ^c Is a boric acid group or a boric acid ester group, and R ^d Is H, boric acid group or boric acid ester group.