CN116981666A

CN116981666A - Fused tetracyclic compounds, their preparation methods and their applications in medicine

Info

Publication number: CN116981666A
Application number: CN202280021238.5A
Authority: CN
Inventors: 李心; 沈峰; 董怀德; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2021-03-26
Filing date: 2022-03-25
Publication date: 2023-10-31
Also published as: WO2022199676A1

Abstract

Relates to a condensed tetracyclic compound, a preparation method and application thereof in medicines. In particular to a condensed tetracyclic compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof as a therapeutic agent, in particular to application thereof in preparing medicines for inhibiting HPK 1. Wherein each group in the general formula (I) is defined in the specification.

Description

Fused tetracyclic compound, preparation method thereof and application thereof in medicines

Technical Field

The present disclosure belongs to the field of medicine, and relates to a fused tetracyclic compound, a preparation method thereof and application thereof in medicine. In particular, the disclosure relates to fused tetracyclic compounds shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds and application thereof in preparing medicines for inhibiting HPK 1.

Background

Anticancer therapy has been advanced from chemotherapy, targeted therapy, to the age of immunotherapy. Targets for tumor immunotherapy mainly include immune checkpoints, immune agonists, tregs, macrophages, tumor microenvironment metabolites such as IDO, the A2AR pathway, and the like. Hematopoietic progenitor kinase1 (Hematopoietic Progenitor Kinase, abbreviated as HPK1; also known as Mitogen-activated protein kinase1 (Mitogen-activated protein kinase kinase kinase kinase 1), abbreviated as MAP4K 1) is a negative regulator in T cells and functions as negative feedback regulator after TCR activation, and is associated with T cell depletion. The signal paths that were studied clearly were: after TCR binding to MHC-peptide, LAT is phosphorylated, recruiting the GADS-SLP76 complex, leading to phosphorylation and pathway activation of downstream PLCs. While at the same time ZAP70 phosphorylates the Y381 site of HPK1, which binds to the SH2 region of SLP76, thereby phosphorylating the S376 site of the latter. SLP76S376 phosphorylates recruitment 14-3-3, resulting in ubiquitination, leading to the disintegration of the entire TCR signal body (signalosome).

HPK1 is currently considered a class of preferred immunotherapeutic targets for the following 3-point reasons: (1) HPK1 expression profile is limited to immune cells, and the safety is good; (2) HPK1 has a variety of negative regulatory effects at different stages of the "cancer-immune cycle", inhibiting HPK1 can regulate the immunosuppressive function of NK cells, DC cells, T cells, and also can regulate B cell activation, with T cell activation being most studied; (3) HPK1 kinase activity is important in inhibiting anti-cancer immune responses.

Studies have shown that HPK1 expression is associated with T cell depletion characteristics (exhaustion signature), including CD3E, PD1, CTLA4, TIM-3, LAG-3 and TIGIT, and that high expression of HPK1 is associated with short survival. TCGA PanCancer database analysis showed a positive correlation between HPK1 (but not other MAP4K family members) expression and PD 1. HPK1 expression was up-regulated in depleted T cells, and expression of HPK1, TIM3 and LAG3 was higher in PD1 high T cells than in PD1 low T cells. In contrast, HPK1 is down-regulated in cd4+ T cells in patients with Systemic Lupus Erythematosus (SLE), and SLEDAI scores are inversely correlated with HPK1mRNA levels. HPK1 expression is also down-regulated in peripheral blood cells of psoriatic arthritis (PsA) patients.

The HPK1 knockout mice were free of any abnormalities in the resting state. Once the TCR is activated, either the HPK1 knock-out, or the HPK1 kinase-inactivated (kinase dead) knock-in, or SLP76S376A knock-in mice, similar results are obtained, which activate the immune response. HPK1 deficient mice are more susceptible to Experimental Autoimmune Encephalomyelitis (EAE). HPK1 kinase activity regulates TCR signaling and cytokine secretion in vitro; inhibition of HPK1 may alleviate PGE2 and adenosine mediated immunosuppression. The HPK1 kinase inactivated mice inhibit tumor growth in vivo, and after removal of CD8+ or CD4+ T cells, the anti-tumor effect of HPK 1-/-mice is almost lost, indicating that T cells mediate most of the immunosuppressive effects of HPK 1.

The above mouse data for HPK1 knockdown and kinase inactivated knockdown indicate that HPK1 is mainly still acting through kinase activity, but some documents report that its scaffold (scaffold) also has a certain function, so the drug development concept for inhibiting HPK1 is mainly kinase inhibitors, and some PROTAC molecules are also available.

Related patents which have been disclosed at present are WO2016205942A1, WO2019238067A1, WO2021013083A1, WO2020103896A1 and WO2021000925A1, etc.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

wherein:

ring a is aryl or heteroaryl;

ring B is phenyl or 5-or 6-membered heteroaryl;

G ¹ is CR (CR) ¹ Or a nitrogen atom;

G ² is CR (CR) ² Or a nitrogen atom;

G ⁶ selected from C (O), CR ^6a R ^6b 、NR ^6c And an oxygen atom;

G ⁷ selected from C (O), CR ^7a R ^7b 、NR ^7c And an oxygen atom;

R ^6a 、R ^6b 、R ^7a and R is ^7b And are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl One or more substituents of heterocyclyl, aryl, and heteroaryl;

R ⁰ 、R ^6c and R is ^7c The same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

each R is ^a Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _r NR ^m R ⁿ 、-OR ^p Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or two R ^a Forming a fused ring with ring B, said fused ring optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R’、R ¹ And R is ² Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR ^d R ^e 、-OR ^g 、-(CO)R ^f 、-(CO)NR ^d R ^e 、-(CO)OR ^g 、-SO ₂ R ^f 、-SO ₂ NR ^d R ^e 、-NR ^h (CO)R ^f 、-NR ^h (CO)NR ^d R ^e 、-NR ^h (CO)OR ^g 、-NR ^h SO ₂ R ^f 、-NR ^h SO ₂ NR ^d R ^e Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR ^d2 R ^e2 、-OR ^g2 、-(CO)R ^f2 、-(CO)NR ^d2 R ^e2 、-(CO)OR ^g2 、-SO ₂ R ^f2 、-SO ₂ NR ^d2 R ^e2 、-NR ^h2 (CO)R ^f2 、-NR ^h2 (CO)NR ^d2 R ^e2 、-NR ^h2 (CO)OR ^g2 、-NR ^h2 SO ₂ R ^f2 、-NR ^h2 SO ₂ NR ^d2 R ^e2 One or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^m 、R ⁿ 、R ^p 、R ^d 、R ^e 、R ^f 、R ^g 、R ^h 、R ^d2 、R ^e2 、R ^f2 、R ^g2 and R is ^h2 Identical or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, which areEach independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Or R is ^m And R is ⁿ 、R ^d And R is ^e 、R ^d2 And R is ^e2 Forming, together with the nitrogen atom to which they are attached, a heterocyclic group optionally substituted with one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

q is 0, 1, 2, 3 or 4; and is also provided with

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

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II) or (III):

wherein the method comprises the steps of

G ³ Is CR (CR) ³ Or a nitrogen atom;

G ⁵ is CR (CR) ⁵ Or a nitrogen atom;

R ³ and R is ⁵ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^4a And R is ^4b Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _r NR ^m R ⁿ 、-OR ^p Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

each R is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or (b)

Two R together form an oxo group;

R ^q selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

n is 0, 1, 2, 3, 4, 5 or 6;

ring A, G ¹ 、G ² 、G ⁶ 、G ⁷ 、R ⁰ 、R ^m 、R ⁿ 、R ^p R', R and q are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is a compound of formula (IV) or (V) or a pharmaceutically acceptable salt thereof:

wherein:

ring A, G ¹ 、G ⁶ 、G ⁷ 、R ⁰ 、R ² 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ^q R', R, q and n are as defined in formula (II) or (III).

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (VI):

wherein the method comprises the steps of

t is 0, 1, 2 or 3;

ring a, ring B, R ^d 、R ^e 、G ¹ 、G ² 、G ⁶ 、G ⁷ 、R ⁰ 、R ^a R' and p are as defined in formula (I)。

In some embodiments of the present disclosure, the compound of formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof, wherein-G ⁷ -G ⁶ -selected from-O-CHR ^6a -、-CHR ^7a -O-、-NR ^7c -CHR ^6a -、-CHR ^7a -NR ^6c -、-C(O)-NR ^6c -and-NR ^7c -C(O)-，R ^6a 、R ^7a 、R ^6c And R is ^7c As defined in formula (I); preferably, -G ⁷ -G ⁶ -selected from-O-CH ₂ -、-CH ₂ -O-、-NH-CH ₂ -、-CH ₂ -NH-, -C (O) -NH-and-NH-C (O) -; more preferably, -G ⁷ -G ⁶ -is-O-CH ₂ -。

In some embodiments of the present disclosure, the compound of formula (I), (II), (III), (IV), (V) or (VI), or a pharmaceutically acceptable salt thereof, wherein ring a is a 6-10 membered aryl or a 5-or 6-membered heteroaryl, preferably phenyl or pyrazolyl.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof, wherein G ¹ Is CR (CR) ¹ ，R ¹ As defined in formula (I);

preferably, R ¹ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group;

further preferably, R ¹ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof, wherein G ¹ Is CR (CR) ¹ ，R ¹ As defined in formula (I); preferably G ¹ Is CR (CR) ¹ ，R ¹ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group; further preferably G ¹ Is CR (CR) ¹ ，R ¹ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably G ¹ CH.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (VI) or a pharmaceutically acceptable salt thereof, wherein G ² Is CR (CR) ² ，R ² As defined in formula (I);

preferably, R ² Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group;

further preferably, R ² Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (VI) or a pharmaceutically acceptable salt thereof, wherein G ² Is CR (CR) ² ，R ² As defined in formula (I); preferably G ² Is CR (CR) ² ，R ² Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group; further preferably G ² Is CR (CR) ² ，R ² Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably G ² CH.

In some embodiments of the present disclosure, the compound of formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G ³ Is CR (CR) ³ ，R ³ As defined in general formula (II) or (III);

preferably, R ³ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group;

further preferably, R ³ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G ³ Is CR (CR) ³ ，R ³ As defined in general formula (II) or (III); preferably G ³ Is CR (CR) ³ ，R ³ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group; further preferably G ³ Is CR (CR) ³ ，R ³ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably G ³ CH.

In some embodiments of the present disclosure, the compound of formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G ⁵ Is CR (CR) ⁵ ，R ⁵ As defined in general formula (II) or (III);

preferably, R ⁵ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group;

further preferably, R ⁵ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably a hydrogen atom or a methyl group.

In some embodiments of the present disclosure, the compound of formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G ⁵ Is CR (CR) ⁵ ，R ⁵ As defined in general formula (II) or (III); preferably G ⁵ Is CR (CR) ⁵ ，R ⁵ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group; further preferably G ⁵ Is CR (CR) ⁵ ，R ⁵ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably G ⁵ Is CR (CR) ⁵ ，R ⁵ Is a hydrogen atom or a methyl group.

In some embodiments of the present disclosure, the compound of formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R ⁵ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 An alkoxy group; preferably, R ⁵ Selected from the group consisting of a hydrogen atom, F, methyl, and methoxy.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof, wherein each R' is the same or different and is independently selected from C _1-6 Alkyl, C _1-6 HaloalkanesRadical or- (CO) NR ^d R ^e ，R ^d And R is ^e As defined in formula (I);

preferably, R ^d And R is ^e Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Hydroxyalkyl, or R ^d And R is ^e Together with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclic group, said 3-to 8-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 One or more groups in the hydroxyalkyl group are substituted;

further preferably, R ^d And R is ^e Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Hydroxyalkyl, or R ^d And R is ^e Together with the nitrogen atom to which they are attached, form an azetidinyl group, which is optionally substituted with a member selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, cyano, hydroxy and C _1-6 One or more groups in the hydroxyalkyl group are substituted.

In some embodiments of the present disclosure, the compounds of formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salts thereof, wherein each R' is the same or different and is independently C _1-6 Alkyl or- (CO) NR ^d R ^e ，R ^d And R is ^e As defined in formula (I);

preferably, each R' is the same or different and is each independently C _1-6 Alkyl or- (CO) NR ^d R ^e ，R ^d And R is ^e Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 Hydroxyalkyl, or R ^d And R is ^e Together with the nitrogen atom to which they are attached, form a 3 to 8 membered heterocyclyl, said 3 to 8 membered heterocyclyl optionally being substituted with one or more hydroxy groups;

More preferably, each R' is the same or different and is each independently C _1-6 Alkyl or- (CO) NR ^d R ^e ，R ^d And R is ^e Identical or different and are each independently selected from C _1-6 Alkyl and C _1-6 Hydroxyalkyl, or R ^d And R is ^e Together with the nitrogen atom to which they are attached, form an azetidinyl group, which is optionally substituted with one or more hydroxyl groups.

In some embodiments of the present disclosure, the compounds of formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salts thereof, wherein each R' is the same or different and is each independentlyEthyl group,

In some embodiments of the present disclosure, the compound of formula (II) or (IV) or a pharmaceutically acceptable salt thereof, wherein R ^4a And R is ^4b Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _r NR ^m R ⁿ Hydroxy and C _1-6 Hydroxyalkyl group wherein said C _1-6 Alkyl and C _1-6 Alkoxy groups are each independently optionally selected from halogen, C _1-6 Alkoxy, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl radicalInstead of R ^m 、R ⁿ And r is as defined in formula (II);

preferably, R ^4a And R is ^4b At least one of them is- (CH) ₂ ) _r NR ^m R ⁿ ，R ^m And R is ⁿ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Hydroxyalkyl group wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, C _1-6 One or more substituents of haloalkoxy, cyano and amino are substituted; or R is ^m And R is ⁿ Together with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclic group, said 3-to 8-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy, oxo and C _1-6 One or more groups in the hydroxyalkyl group are substituted; r is 0, 1 or 2;

further preferably, R ^4a And R is ^4b One of them is- (CH) ₂ ) _r NR ^m R ⁿ The other being a hydrogen atom, R ^m And R is ⁿ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; or R is ^m And R is ⁿ Together with the nitrogen atom to which they are attached, form a piperazine ring, which is optionally substituted with a halogen, C _1-6 Alkyl and C _1-6 One or more groups in the haloalkyl group are substituted; r is 0 or 1.

In some embodiments of the present disclosure, the compound of formula (II) or (IV) or a pharmaceutically acceptable salt thereof, wherein R ^4a And R is ^4b One of them is- (CH) ₂ ) _r NR ^m R ⁿ The other being a hydrogen atom or C _1-6 Alkyl, R ^m And R is ⁿ Identical or different and are each independently C _1-6 An alkyl group; or R is ^m And R is ⁿ Together with the nitrogen atom to which they are attached form a piperazine ring, optionally substituted with one or more C' s _1-6 Alkyl substitution; r is 0 or 1.

In some embodiments of the present disclosure, the compound of formula (II) or (IV) or a pharmaceutically acceptable salt thereof, wherein R ^4a And R is ^4b Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _r NR ^m R ⁿ Hydroxy and C _1-6 Hydroxyalkyl group wherein said C _1-6 Alkyl and C _1-6 Alkoxy groups are each independently optionally selected from halogen, C _1-6 Alkoxy, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 One or more substituents in hydroxyalkyl are substituted, and R ^4a And R is ^4b At least one of them is- (CH) ₂ ) _r NR ^m R ⁿ ，R ^m And R is ⁿ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Hydroxyalkyl group wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, C _1-6 One or more substituents of haloalkoxy, cyano and amino are substituted; or R is ^m And R is ⁿ Together with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclic group, said 3-to 8-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy, oxo and C _1-6 One or more groups in the hydroxyalkyl group are substituted; r is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (II) or (IV) or a pharmaceutically acceptable salt thereof, wherein R ^4a Is piperazinyl, said piperazinyl optionally being C _1-6 Alkyl substitution; and/or R ^4b Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (II) or (IV) or a pharmaceutically acceptable salt thereof, wherein R ^4a 4-methylpiperazin-1-yl or 4-ethylpiperazin-1-yl; and/or R ^4b Is a hydrogen atom or a methyl group.

In some embodiments of the present disclosure, the compound of formula (II) or (IV) or a pharmaceutically acceptable salt thereof, wherein R ^4b is-CH ₂ -N(CH ₃ ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the And/or R ^4a Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (III) or (V) or a pharmaceutically acceptable salt thereof, wherein each R is the same or different and is independently selected from the group consisting of a hydrogen atom, a halogen, and C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group;

preferably, each R is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some embodiments of the present disclosure, the compound of formula (III) or (V) or a pharmaceutically acceptable salt thereof, wherein R ^q Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably C _1-6 Alkyl groups, more preferably methyl groups.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1; preferably q is 1.

In some embodiments of the present disclosure, the compound of formula (III) or (V) or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

In some embodiments of the present disclosure, the compound of formula (I) or (VI) or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; preferably, p is 1.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein-G ⁷ -G ⁶ -selected from-O-CH ₂ -、-CH ₂ -O-、-NH-CH ₂ -、-CH ₂ -NH-, -C (O) -NH-and-NH-C (O) -; ring a is phenyl or pyrazolyl; g ¹ Is CR (CR) ¹ ，R ¹ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; g ² Is CR (CR) ² ，R ² Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; g ³ Is CR (CR) ³ ，R ³ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; g ⁵ Is CR (CR) ⁵ ，R ⁵ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; r is R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R' is the same or different and is independently selected from C _1-6 Alkyl, C _1-6 Haloalkyl or- (CO) NR ^d R ^e ，R ^d And R is ^e Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Hydroxyalkyl, or R ^d And R is ^e Together with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclic group, said 3-to 8-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 One or more of the hydroxyalkyl groupsA plurality of groups; r is R ^4a And R is ^4b Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _r NR ^m R ⁿ Hydroxy and C _1-6 Hydroxyalkyl group wherein said C _1-6 Alkyl and C _1-6 Alkoxy groups are each independently optionally selected from halogen, C _1-6 Alkoxy, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 One or more substituents in hydroxyalkyl are substituted, and R ^4a And R is ^4b At least one of them is- (CH) ₂ ) _r NR ^m R ⁿ ，R ^m And R is ⁿ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Hydroxyalkyl group wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, C _1-6 One or more substituents of haloalkoxy, cyano and amino are substituted; or R is ^m And R is ⁿ Together with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclic group, said 3-to 8-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy, oxo and C _1-6 One or more groups in the hydroxyalkyl group are substituted; r is 0, 1 or 2; and q is 0 or 1.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein-G ⁷ -G ⁶ -is-O-CH ₂ -; ring a is phenyl or pyrazolyl; g ¹ Is CR (CR) ¹ ，R ¹ Is a hydrogen atom; g ² Is CR (CR) ² ， R ² Is a hydrogen atom;G ³ is CR (CR) ³ ，R ³ Is a hydrogen atom; g ⁵ Is CR (CR) ⁵ ，R ⁵ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 An alkoxy group; r is R ⁰ Is a hydrogen atom; q is 1; each R' is C _1-6 Alkyl or- (CO) NR ^d R ^e ，R ^d And R is ^e Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 Hydroxyalkyl, or R ^d And R is ^e Together with the nitrogen atom to which they are attached, form a 3 to 8 membered heterocyclyl, said 3 to 8 membered heterocyclyl optionally being substituted with one or more hydroxy groups; r is R ^4a And R is ^4b One of them is- (CH) ₂ ) _r NR ^m R ⁿ The other being a hydrogen atom or C _1-6 Alkyl, R ^m And R is ⁿ Identical or different and are each independently C _1-6 An alkyl group; or R is ^m And R is ⁿ Together with the nitrogen atom to which they are attached form a piperazine ring, optionally substituted with one or more C' s _1-6 Alkyl substitution; and r is 0 or 1.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound represented by the general formula (IA) or a salt thereof,

wherein: r is R ^w Is an amino protecting group; preferably Ts;

ring a, ring B, G ¹ 、G ² 、G ⁶ 、G ⁷ 、R’、R ^a P and q are as defined in formula (I).

Another aspect of the present disclosure relates to compounds represented by formula (IIA) or (IIIA) or salts thereof,

wherein: r is R ^w Is an amino protecting group; preferably Ts;

ring A, G ¹ 、G ² 、G ³ 、G ⁵ 、G ⁶ 、G ⁷ 、R’、R ^4a 、R ^4b 、R ^q R, n and q are as defined in formula (II) or (III).

Another aspect of the present disclosure relates to a compound represented by the general formula (IVA) or (VA) or a salt thereof,

wherein: r is R ^w Is an amino protecting group; preferably Ts;

ring A, G ¹ 、R ² 、R ³ 、R ⁵ 、G ⁶ 、G ⁷ 、R’、R ^4a 、R ^4b 、R ^q R, n and q are as defined in formula (IV) or (V).

Another aspect of the present disclosure relates to a compound represented by the general formula (VIA) or a salt thereof,

wherein: r is R ^w Is an amino protecting group; preferably Ts;

ring a, ring B, R ^d 、R ^e 、G ¹ 、G ² 、G ⁶ 、G ⁷ 、R ^a R', t and p are as defined in formula (VI).

Typical intermediate compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

deprotection of a compound of formula (IA) or a salt thereof to give a compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein R is ^w Is an amino protecting group; preferably Ts;

R ⁰ is a hydrogen atom;

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or (III), or a pharmaceutically acceptable salt thereof, comprising:

deprotection of a compound of formula (IIA) or a salt thereof to give a compound of formula (II) or a pharmaceutically acceptable salt thereof; or (b)

Deprotection of a compound of formula (IIIA) or a salt thereof to give a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein R is ^w Is an amino protecting group; preferably Ts;

R ⁰ is a hydrogen atom;

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or (V) or a pharmaceutically acceptable salt thereof, the method comprising:

deprotection of a compound of formula (IVA) or a salt thereof to give a compound of formula (IV) or a pharmaceutically acceptable salt thereof; or (b)

Deprotection of a compound of the general formula (VA) or a salt thereof to give a compound of the general formula (V) or a pharmaceutically acceptable salt thereof;

wherein R is ^w Is an amino protecting group; preferably Ts;

R ⁰ is a hydrogen atom;

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:

deprotection of a compound of formula (VIA) or a salt thereof to give a compound of formula (VI) or a pharmaceutically acceptable salt thereof;

wherein R is ^w Is an amino protecting group; preferably Ts;

R ⁰ is a hydrogen atom;

the compound shown in the general formula (VIA') or salt thereof and the general formula (VIB) or salt thereof are subjected to acylation reaction to obtain a compound shown in the general formula (VI) or pharmaceutically acceptable salt thereof;

wherein Q is halogen or hydroxy, preferably hydroxy;

ring a, ring B, R ^d 、R ^e 、G ¹ 、G ² 、G ⁶ 、G ⁷ 、R ^a 、R ⁰ R', t and p are as defined in formula (VI).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI) or table a of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The disclosure further relates to the use of a compound shown in general formula (I), (II), (III), (IV), (V), (VI) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting HPK 1.

The present disclosure further relates to the use of a compound shown in general formula (I), (II), (III), (IV), (V), (VI) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder by inhibiting HPK 1; the use of a disease or condition preferably selected from the group consisting of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders, preferably selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke and Alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibromatosis, glioma, and neuroblastoma.

The present disclosure further relates to the use of a compound of formula (I), (II), (III), (IV), (V), (VI) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders, preferably selected from cancer, allergy, asthma, sepsis, hiv infection, hepatitis b infection, ischemia, atherosclerosis, stroke and alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibromatosis, glioma, and neuroblastoma.

The present disclosure further relates to a method of inhibiting HPK1 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing a disease or disorder by inhibiting HPK1 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the disease or condition is preferably selected from the group consisting of cancer, autoimmune disease, inflammatory disease, infectious disease, cardiovascular disease, neurodegenerative disease, diabetes and reproductive disorders; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibromatosis, glioma, and neuroblastoma.

The present disclosure further relates to a method of treating and/or preventing cancer, autoimmune disease, inflammatory disease, infectious disease, cardiovascular disease, neurodegenerative disease, diabetes and diseases or conditions of reproductive dysfunction comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibromatosis, glioma, and neuroblastoma.

The disclosure further relates to a compound of formula (I), (II), (III), (IV), (V), (VI) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The disclosure further relates to a compound of formula (I), (II), (III), (IV), (V), (VI) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for inhibiting HPK 1.

The present disclosure further relates to a compound of formula (I), (II), (III), (IV), (V), (VI) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of a disease or disorder treated and/or prevented by inhibition of HPK 1; wherein the disease or condition is preferably selected from the group consisting of cancer, autoimmune disease, inflammatory disease, infectious disease, cardiovascular disease, neurodegenerative disease, diabetes and reproductive disorders; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibromatosis, glioma, and neuroblastoma.

The present disclosure further relates to a compound of formula (I), (II), (III), (IV), (V), (VI) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a treatment and/or prophylaxis of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and diseases or disorders of reproduction, preferably selected from cancer, allergy, asthma, sepsis, aids virus infection, hepatitis b virus infection, ischemia, atherosclerosis, stroke and alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibromatosis, glioma, and neuroblastoma.

Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue carcinoma is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyoma, leiomyosarcoma, dedifferentiated liposarcoma, polymorphous liposarcoma, malignant fibrous histiocytoma, round cell sarcoma and synovial sarcoma; lymphomas are selected from hodgkin's disease and non-hodgkin's lymphomas (e.g., mantle cell lymphomas, diffuse large B-cell lymphomas, follicular central lymphomas, marginal zone B-cell lymphomas, lymphoplasmacytic lymphomas, and peripheral T-cell lymphomas); the liver cancer is preferably hepatocellular carcinoma; lung cancer is selected from non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma) and Small Cell Lung Cancer (SCLC); the kidney cancer is selected from the group consisting of renal cell carcinoma, clear cell, and renal eosinophil tumor; leukemia is selected from Chronic Lymphocytic Leukemia (CLL), chronic myelogenous leukemia, acute Lymphoblastic Leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic Myelogenous Leukemia (CML), and Acute Myelogenous Leukemia (AML); the skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; the throat cancer is selected from nasopharyngeal cancer.

Colorectal cancer described in the present disclosure is also known as colorectal cancer, preferably colon cancer or rectal cancer; the glioma is preferably glioblastoma.

The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure may also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, troches or syrups.

As a general guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of the active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

The compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group having from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms _1-12 Alkyl), more preferably alkyl having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-balloono Ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any useful point of attachment, preferably selected from one or more of D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, heteroaryl of aryl.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably having from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C _1-12 Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C _1-6 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ (-), 1-ethylene (-CH (CH) ₃ ) (-), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene(-CH(CH ₂ CH ₃ ) (-), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-), 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkenyl" refers to an alkyl group having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, preferably having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C _2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C _2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C _2-12 Alkynyl), more preferably alkynyl having 2 to 6 carbon atoms (i.e., C _2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted and when substituted the substituents are preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocycle One or more of a acyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms (i.e., 3 to 14 membered cycloalkyl), preferably comprising 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl), more preferably comprising 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered, monocyclic, polycyclic group sharing one carbon atom (referred to as the spiro atom) between the monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spirocycloalkyl group is classified into a single spirocycloalkyl group or a multiple spirocycloalkyl group (e.g., a double spirocycloalkyl group) according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused ring alkyl" refers to 5 to 20 membered, all carbon polycyclic groups in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The condensed ring alkyl group may be classified as a double-ring or multiple-ring (e.g., tricyclic, tetra-ring) according to the number of constituent rings, and is preferably a double-ring or tricyclic, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered condensed ring alkyl group. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly attached, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Cycloalkyl groups which may be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridge are preferred, bicyclic, tricyclic or tetracyclic, more preferred bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples includeEtc.; preferably is

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any useful point of attachment, preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3 to 20 membered heterocyclyl) wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but excluding the ring portions of-O-, -O-S-, or-S-, the remaining ring atoms being carbon. Preferably containing from 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms (i.e., 3 to 14 membered heterocyclyl), of which 1 to 4 (e.g., 1,2,3, and 4) are heteroatoms; more preferably from 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3 to 8 membered heterocyclyl) or from 6 to 14 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14), wherein 1-3 is a heteroatom (e.g., 1,2, and 3); more preferably 3 to 8 ring atoms, of which 1-3 (e.g., 1,2, and 3) are heteroatoms; most preferably contain 5 or 6 ring atoms (i.e., 5-or 6-membered heterocyclyl) of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) therebetween, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered spiroheterocyclyl). The spiroheterocyclyl groups are classified into single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, and are preferably single spiroheterocyclyl groups and double spiroheterocyclyl groups. More preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), and the remaining ring atoms are carbon. Preferably 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered fused heterocyclyl). The number of constituent rings may be classified into a bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered bridged heterocyclyl). Heterocyclic groups which may be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridge according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

the heterocyclyl ring includes heterocyclyl (including monocyclic, spiro, fused and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

etc.

The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (fused polycyclic being a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any useful point of attachment, preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroaryl" refers to heteroaromatic systems containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered) (i.e., 5 to 10 membered heteroaryl), more preferably 5 or 6 membered (i.e., 5 or 6 membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any useful point of attachment, preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived from the removal of one hydrogen atom from the parent ring atom, or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

The term "amino protecting group" is intended to mean an amino group that is protected by an easily removable group in order to keep the amino group unchanged when the reaction is carried out at other positions of the molecule. Non-limiting examples include (trimethylsilicon) ethoxymethyl (SEM), tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-toluenesulfonyl (Ts), p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro; the amino protecting group is preferably Ts.

The term "hydroxy protecting group" refers to a hydroxy derivative that is typically used to block or protect a hydroxy group while the reaction proceeds on other functional groups of the compound. By way of example, preferably, the hydroxyl protecting group may be triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl.

The term "cycloalkyloxy" refers to a cycloalkyl-O-group, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S-, wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" or "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

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

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

Ts refers to p-toluenesulfonyl.

The compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to an isomer that is identical in structure but differs in the arrangement of atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformational isomers and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may present additional asymmetric atoms. All such stereoisomers, and mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is performed by conventional methods well known in the art to give the pure isomer. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr at the same time contain Two configurations. For all carbon-carbonDouble bonds, even if only one configuration is named, both Z and E are included.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization.

As reference to pyrazolyl, it is understood to include mixtures of either or both tautomers of either structure.

All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound wherein at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, e.g., respectively ² H (deuterium, D), ³ H (tritium, T), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³² p、 ³³ p、 ³³ S、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ¹⁸ F、 ³⁶ Cl、 ⁸² Br、 ¹²³ I、 ¹²⁴ I、 ¹²⁵ I、 ¹²⁹ I and ¹³¹ i, etc., deuterium is preferred.

Compared with non-deuterated medicines, deuterated medicines have the advantages of reducing toxic and side effects, increasing medicine stability, enhancing curative effect, prolonging biological half-life of medicines and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein replacement of deuterium may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced by at least one deuterium.

"optionally" or "optionally" is intended to mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "optionally halogen-or cyano-substituted alkyl" means that halogen or cyano may be, but need not be, present, and the description includes both the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

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

"pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect. The determination of a therapeutically effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and the appropriate therapeutically effective amount in an individual case can be determined by one of skill in the art based on routine experimentation.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and are effective for the intended use.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

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

scheme one

The present disclosure provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

deprotection of a compound of formula (IA) or a salt thereof under alkaline or microwave conditions to give a compound of formula (I) or a pharmaceutically acceptable salt thereof;

Wherein R is ^w Is an amino protecting group; preferably Ts;

R ⁰ is a hydrogen atom;

Scheme II

The present disclosure provides a process for producing a compound represented by the general formula (II) or (III) or a pharmaceutically acceptable salt thereof, which comprises:

deprotection of a compound of formula (IIA) or a salt thereof under alkaline or microwave conditions to give a compound of formula (II) or a pharmaceutically acceptable salt thereof; or (b)

Deprotection of a compound of formula (IIIA) or a salt thereof under alkaline or microwave conditions to give a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein R is ^w Is an amino protecting group; preferably Ts;

R ⁰ is a hydrogen atom;

Scheme III

The present disclosure provides a process for producing a compound represented by the general formula (IV) or (V) or a pharmaceutically acceptable salt thereof, which comprises:

deprotection of a compound of formula (IVA) or a salt thereof under alkaline or microwave conditions to give a compound of formula (IV) or a pharmaceutically acceptable salt thereof; or (b)

Deprotection of a compound of formula (VA) or a salt thereof under alkaline or microwave conditions to give a compound of formula (V) or a pharmaceutically acceptable salt thereof;

wherein R is ^w Is an amino protecting group; preferably Ts;

R ⁰ Is a hydrogen atom;

Scheme IV

The present disclosure provides a process for preparing a compound of formula (VI) or a pharmaceutically acceptable salt thereof, which comprises:

deprotection of a compound of formula (VIA) or a salt thereof under alkaline or microwave conditions to give a compound of formula (VI) or a pharmaceutically acceptable salt thereof;

wherein R is ^w Is an amino protecting group; preferably Ts;

R ⁰ is a hydrogen atom;

Scheme five

acylating the compound of formula (VIA') or a salt thereof with formula (VIB) or a salt thereof in the presence of an alkaline condition and a condensing agent to obtain a compound of formula (VI) or a pharmaceutically acceptable salt thereof;

wherein Q is hydroxy;

Scheme six

acylating the compound of formula (VIA') or a salt thereof with formula (VIB) or a salt thereof under alkaline conditions to obtain a compound of formula (VI) or a pharmaceutically acceptable salt thereof;

Wherein Q is halogen;

Reagents providing basic conditions in the above synthetic schemes include organic bases including, but not limited to, triethylamine, pyridine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide in tetrahydrofuran, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, lithium bis (trimethylsilyl) amide in tetrahydrofuran, or 1, 8-diazabicyclo undec-7-ene, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; the reagent for the deprotection reaction to provide alkaline conditions is preferably sodium hydroxide; the reagent providing basic conditions for the acylation reaction is preferably N, N-diisopropylethylamine.

Condensing agents described in the above synthetic schemes include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine; preferably 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU).

The reaction of the above steps is preferably carried out in solvents including, but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.

The reaction temperature of the above-mentioned microwave reaction is 50 to 180℃and preferably 100 ℃.

The reaction time of the microwave reaction is 0.5-4 hours; preferably 2 hours.

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: thermo, model number Finnigan LCQ advantage MAX).

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 liquid chromatograph.

Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.

High performance liquid chromatography was performed using Waters 2767, waters 2767-SQ detector 2, shimadzu LC-20AP and Gilson-281 preparative chromatographs.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

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

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: the volume ratio of the ethyl acetate to the dichloromethane to the n-hexane is adjusted according to the polarity of the compound, and can be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like.

Example 1

N, N-dimethyl-4- (7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide 1

First step

5-bromo-4-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine 1b

The compound 5-bromo-4-fluoro-1H-pyrrolo [2,3-b ] pyridine 1a (5.0 g,23.3mmol, nanjing's medical stone) was dissolved in tetrahydrofuran (60 mL), sodium hydride (1.2 g,30.2mmol, content 60%) was added under ice-bath, and after restoring room temperature reaction for 30 minutes, p-toluenesulfonyl chloride (5.7 g,30.2 mmol) was added. After stirring for 1 hour, water (60 mL) was added to the reaction mixture, the mixture was extracted with methylene chloride (50 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, and then added to a mixed solution of petroleum ether and ethyl acetate (V: V=10:1), stirred for 20 minutes, and after precipitation of a solid, the mixture was filtered and dried to give the title compound 1b (8.2 g, yield: 95%).

MS m/z(ESI):368.9[M+1]。

Second step

4-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine 1c

Compound 1b (4.3 g,11.6 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (1.9 g,2.3 mmol), pinacol biborate (5.9 g,23.3 mmol), potassium acetate (3.4 g,34.9 mmol) was dissolved in 1, 4-dioxane (60 mL). The reaction was carried out at 100℃for 14 hours under nitrogen atmosphere, filtered through celite, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to give the title compound 1c (4.3 g, yield: 88%).

MS m/z(ESI):417.2[M+1]。

Third step

(2-bromo-5- (4-methylpiperazin-1-yl) phenyl) methanol 1f

Compound 1d (10.6 g,36.9 mmol) was dissolved in methanol (200 mL) using well-known method "Journal of Medicinal Chemistry,2005,48,2667-2677") and sodium borohydride (2.4 g,63.7 mmol) was added in portions while ice-bath. After the reaction was continued for 1 hour at room temperature, the reaction mixture was concentrated under reduced pressure, water (60 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and the drying agent was removed by filtration, and then concentrated under reduced pressure, followed by purification by silica gel column chromatography using eluent system A to give the title compound 1f (6.3 g, yield: 60%). MS m/z (ESI): 285.2[ M+1].

Fourth step

1g of (2- (4-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) -5- (4-methylpiperazin-1-yl) phenyl) methanol

Compound 1c (4.0 g,8.7 mmol), compound 1f (2.5 g,8.7 mmol), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (1.4 g,1.7 mmol), sodium carbonate (1.9 g,17.9 mmol) were dissolved in 110mL of a mixed solution of 1, 4-dioxane and water (V: V=10:1). The reaction was carried out at 100℃for 6 hours under nitrogen atmosphere, and the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound (1 g, 3.9g, yield: 90%).

MS m/z(ESI):495.2[M+1]。

Fifth step

7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridine for 1h

Compound 1g (3.9 g,7.8 mmol) was dissolved in dimethyl sulfoxide (40 mL), potassium tert-butoxide (4.5 g,40.1 mmol) was added, and after reaction at 100℃for 1 hour, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 1h (1.5 g, yield: 60%).

MS m/z(ESI):321.2[M+1]。

Sixth step

3-iodo-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridine 1i

Compound 1h (1.3 g,4.0 mmol) was dissolved in tetrahydrofuran (20 mL) and N-iodosuccinimide (960 mg,4.26 mmol) was added under ice-bath. After 1 hour of reaction, methylene chloride (200 mL) was added for dilution, and the mixture was washed with 2M sodium hydroxide solution (100 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to give the title compound 1i (1.5 g, yield: 82%).

MS m/z(ESI):447.1[M+1]。

Seventh step

3-iodo-7- (4-methylpiperazin-1-yl) -1-p-toluenesulfonyl-1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridine 1j

Compound 1i (1.1 g,2.5 mmol) was dissolved in tetrahydrofuran (15 mL) and sodium hydride (152 mg,3.8mmol, 60% content) was added under ice-bath. After reaction at the maintained temperature for 30 minutes, p-toluenesulfonyl chloride (616 mg,3.2 mmol) was added, and after stirring for 1 hour, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 1j (1.3 g, yield: 84%).

MS m/z(ESI):601.2[M+1]。

Eighth step

N, N-dimethyl-4- (7- (4-methylpiperazin-1-yl) -1-p-toluenesulfonyl-1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide 1k

Compound 1j (200 mg,0.33 mmol), compound N, N-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (138 mg,0.50mmol, [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (52 mg,0.06 mmol), sodium carbonate (68 mg,0.66 mmol) was dissolved in a mixed solution of 6ml of 1, 4-dioxane and water (V: v=10:1). The reaction was carried out at 100℃for 12 hours under nitrogen atmosphere, and the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 1k (80 mg, yield: 26%).

MS m/z(ESI):622.2[M+1]。

Ninth step

Compound 1k (80 mg,0.14 mmol) was dissolved in methanol (5 mL), 2M sodium hydroxide solution (0.75 mL) was added, reacted for 1 hour at 50℃and the reaction mixture was concentrated under reduced pressure and then purified by high performance liquid chromatography (Waters-2545, column chromatography: sharpsil-T C, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 25% -50%, flow rate: 30 mL/min) to give the title compound 1 (30 mg, yield: 50%).

MS m/z(ESI):468.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.50(s,1H),7.66(d,2H),7.62(d,1H),7.38-7.33(m,3H),6.94(dd,1H),6.76(d,1H),5.10(s,2H),3.18(t,4H),3.04(s,3H),3.01(s,3H)2.57(t,4H),2.29(s,3H)。

Example 2

3- (1-ethyl-1H-pyrazol-4-yl) -7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridine 2

Compound 1j (30 mg, 49.96. Mu. Mol), compound 1-ethyl-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (17 mg, 76.54. Mu. Mol, shanghai Pichia), bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (7.8 mg, 9.56. Mu. Mol), sodium carbonate (10.8 mg, 101.9. Mu. Mol) was dissolved in 3mL of a mixed solution of 1, 4-dioxane and water (V: V=10:1). The reaction was carried out at 100℃for 2 hours under nitrogen atmosphere with microwaves, and after concentrating the reaction solution under reduced pressure, the title compound 2 (1.1 mg, yield: 5%) was purified by high performance liquid chromatography (Waters-2545, column chromatography: sharpsil-T C, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 25% -50%, flow rate: 30 mL/min).

MS m/z(ESI):415.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.56(s,1H),7.97(s,1H),7.82(s,1H),7.72(d,1H),7.41(s,1H),7.06(dd,1H),6.90(d,1H),5.31(s,2H),4.25(q,2H),3.31-3.28(m,4H),2.67(t,4H),2.39(s,3H),1.53(t,3H)。

Example 3

(3-hydroxyazetidin-1-yl) (4- (7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone 3

First step

4- (7- (4-methylpiperazin-1-yl) -1-p-toluenesulfonyl-1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid methyl ester 3a

Compound 1j (20 mg, 33. Mu. Mol), methyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (13 mg, 49.5. Mu. Mol), shanghai Le Yan, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (5.6 mg, 6.8. Mu. Mol), sodium carbonate (7.2 mg, 67.9. Mu. Mol) were dissolved in 3mL of a mixed solution of 1, 4-dioxane and water (V: V=10:1). The reaction was carried out at 100℃for 12 hours under nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure and purified by column chromatography with eluent system A to give the title compound 3a (20 mg, yield: 98.5%). MS m/z (ESI) 609.2[ M+1].

Second step

4- (7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid 3b

Compound 3a (20 mg, 32.8. Mu. Mol) was dissolved in a mixed solution of 4mL of methanol and tetrahydrofuran (V: V=10:1), and 2M aqueous sodium hydroxide solution (1 mL) was added. After reaction at 50℃for 12 hours, the reaction mixture was cooled to room temperature and then the pH was adjusted to neutrality with 2M hydrochloric acid (1 mL) and concentrated under reduced pressure to give the crude title compound 3b (14 mg), which was used in the next reaction without purification.

MS m/z(ESI):441.2[M+1]。

Third step

Compound 3b (14 mg, 31.78. Mu. Mol) was dissolved in anhydrous N, N-dimethylformamide (2 mL), and 3-hydroxyazetidine (8.4 mg, 114.9. Mu. Mol), 2- (7-azobenzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate (31 mg, 81.5. Mu. Mol), N, N-diisopropylethylamine (32.2 mg, 249. Mu. Mol) was added sequentially. The reaction was stirred for 1 hour, concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: sharpsil-T C, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 25% -50%, flow rate: 30 mL/min) to give the title compound 3 (2 mg, yield: 13%). MS m/z (ESI) 496.1[ M+1].

¹ H NMR(500MHz,CD ₃ OD):δ8.62(s,1H),7.78(d,2H),7.74(d,1H),7.68(d,2H),7.48(s,1H),7.06(dd,1H),6.87(d,1H),5.23(s,2H),4.46(q,1H),4.25(d,2H),4.00(d,2H),3.29(t,4H),2.68(t,4H),2.40(s,3H)。

Example 4

(S) -N- (2-hydroxypropyl) -N-methyl-4- (7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide 4

Compound 3b (15 mg, 34. Mu. Mol) was dissolved in anhydrous N, N-dimethylformamide (2 mL), and (S) -1-methylaminopropan-2-ol (6 mg, 66.6. Mu. Mol), 2- (7-azobenzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate (19 mg, 49.9. Mu. Mol), N, N-diisopropylethylamine (22 mg, 170.2. Mu. Mol) were added sequentially. The reaction was stirred for 1 hour, concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: sharpsil-T C, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 25% -50%, flow rate: 30 mL/min) to give the title compound 4 (2.3 mg, yield: 13%).

MS m/z(ESI):512.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.62(s,1H),7.81-7.72(m,3H),7.54-7.40(m,3H),7.06(dd,1H),6.88(d,1H),5.22(s,2H),4.04(s,1H),3.68(d,2H),3.32-3.26(m,4H),3.19(s,3H),2.68(t,4H),2.40(s,3H),1.28(d,3H)。

Example 5

N, N-dimethyl-4- (6-methyl-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide 5

First step

2- (3-bromo-2-methylphenyl) -1, 3-dioxolane 5b

Compound 3-bromo-2-methylbenzaldehyde 5a (10 g,50.24mmol, shanghai Bide) was dissolved in toluene (200 mL), ethylene glycol (4.68 g,75.36 mmol), p-methylbenzenesulfonic acid (955.6 mg,5.02 mmol) was added, the reaction was heated to 140℃and was separated for 14 hours, the reaction was cooled to room temperature, washed successively with 5% aqueous sodium carbonate (100 mL), saturated brine (100 mL), the organic phase was collected, concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title compound 5B (12 g, yield: 98.2%).

Second step

2-methyl-3- (4-methylpiperazin-1-yl) benzaldehyde 5c

Compound 5b (11 g,45.2 mmol) was dissolved in toluene (100 mL), tris (dibenzylideneacetone) dipalladium (2.07 g,2.26 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (1.97 g,3.16 mmol), potassium tert-butoxide (7.1 g,63.34 mmol), 1-methylpiperazine (5.9 g,58.5 mmol), heated to 100deg.C for 14 hours, cooled to room temperature, 6M hydrochloric acid (100 mL) was added and after stirring the reaction for 2 hours, pH was adjusted to about 13 with 6M aqueous sodium hydroxide solution, ethyl acetate was extracted (100 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered off and concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to give the title compound 5c (5.5 g, yield: 49.8%).

MS m/z(ESI):219.2[M+1]。

Third step

6-bromo-2-methyl-3- (4-methylpiperazin-1-yl) benzaldehyde 5d

Compound 5c (0.5 g,2.29 mmol) was dissolved in dichloromethane (5 mL), potassium bromide (817.7 mg,6.87 mmol) was added under ice-bath, bromine (439.2 mg,2.74 mmol), and the reaction was stirred for 14 hours, quenched by the addition of saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane ester (5 mL. Times.3), the organic phase was collected, concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 5d (500 mg, yield: 73.4%).

MS m/z(ESI):297.9[M+1]。

Fourth step

3-iodo-6-methyl-7- (4-methylpiperazin-1-yl) -1-p-toluenesulfonyl-1, 5-dihydro-isochromano [3,4-d ] pyrrolo [2,3-b ] pyridine 5e

Using the third to seventh steps of the synthetic route in example 1, the starting compound 1d of the third step was replaced with compound 5d to give the title compound 5e (500 mg, yield: 87.7%).

MS m/z(ESI):615.2[M+1]。

Fifth step

N, N-dimethyl-4- (6-methyl-7- (4-methylpiperazin-1-yl) -1-p-toluenesulfonyl-1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide 5f

Compound 5e (50 mg, 81.36. Mu. Mol), compound N, N-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (25 mg, 86.15. Mu. Mol), palladium acetate (1.83 mg, 8.15. Mu. Mol), 1' -bis (di-tert-butylphosphine) ferrocene (4.1 mg, 8.13. Mu. Mol), potassium phosphate (36 mg, 162.16. Mu. Mol) were dissolved in a mixed solution of 2mL of 1, 4-dioxane and water (V: V=10:1). The reaction was carried out at 100℃for 12 hours under nitrogen atmosphere, 5mL of water was added to the reaction mixture to dilute it, the mixture was extracted with methylene chloride (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to give the crude title compound 5f (30 mg) which was used in the next reaction without purification.

MS m/z(ESI):636.2[M+1]。

Sixth step

Compound 5f (50 mg, 78.6. Mu. Mol) was dissolved in methanol (5 mL), 2M sodium hydroxide solution (0.75 mL) was added and reacted at 80℃for 0.5 hours, and after the reaction solution was concentrated under reduced pressure, the reaction solution was purified by high performance liquid chromatography (Waters-2545, column chromatography: sharpsil-T C, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 25% -50%, flow rate: 30 mL/min) to give the title compound 5 (2.1 mg, yield: 5.5%).

MS m/z(ESI):482.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.63(s,1H),7.83-7.76(m,2H),7.69(d,1H),7.48(m,3H),7.17(d,1H),5.33(s,2H),4.61(br,4H),2.61(br,4H),3.16(s,3H),3.13(s,3H),2.40(s,3H),2.28(s,3H)。

Example 6

3- (1-ethyl-1H-pyrazol-4-yl) -6-methyl-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridine 6

The fifth step starting compound N, N-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzamide was replaced with the compound 1-ethyl-4- (tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole using the synthetic route in example 5, to give the title compound 6 (3 mg, yield: 41%).

MS m/z(ESI):429.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ ):δ9.26(s,1H),8.66(s,1H),7.85(s,1H),7.79(s,1H),7.64(d,1H),7.14(d,1H),5.38(s,2H),4.27(q,2H),3.01(t,3H),2.70(m,3H),2.45(m,2H),2.30(s,3H),1.71(m,4H),1.59(t,3H)。

Example 7

1- (3- (1-ethyl-1H-pyrazol-4-yl) -1, 5-dihydroisochromano [3,4-d ] pyrrolo [2,3-b ] pyridin-8-yl) -N, N-dimethylmethylamine 7

First step

3-bromo-4- (hydroxymethyl) -N, N-dimethylbenzamide 7b

A solution of 2M dimethylamine in methanol (2 mL) was dissolved in tetrahydrofuran (5 mL), a solution of 2M trimethylaluminum in toluene (1.5 mL) was added under ice-bath, and the mixture was stirred for 10 minutes, then the compound methyl 3-bromo-4- (hydroxymethyl) benzoate 7a (500 mg,2.0mmol, shanghai bright) was added, and after stirring for 3 hours, the reaction was quenched by the addition of water (10 mL), extracted with methylene chloride (50 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to give the title compound 7b (400 mg, yield: 75%).

MS m/z(ESI):257.9[M+1]。

Second step

(2-bromo-4- ((dimethylamino) methyl) phenyl) methanol 7c

Compound 7b (400 mg,1.55 mmol) was dissolved in tetrahydrofuran (5 mL), borane dimethyl sulfide complex (5.26 mmol,0.5 mL) was added and after reaction for 2 hours at 70℃the reaction was quenched by the addition of methanol (2 mL), the reaction was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 7c (300 mg, yield: 79%).

MS m/z(ESI):244.2[M+1]。

Third step

1- (3-iodo-1-p-toluenesulfonyl-1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-8-yl) -N, N-dimethylmethylamine 7d

Using the fourth to seventh steps of the synthetic route in example 1, the fourth step starting compound 1f was replaced with compound 7c to give the title compound 7d (50 mg, yield: 26%).

MS m/z(ESI):559.9[M+1]。

Fourth step

Compound 7d (100 mg,0.178 mmol), compound 1-ethyl-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (47 mg,0.214 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (15 mg,0.02 mmol), sodium carbonate (38 mg,0.36 mmol) was dissolved in 6ml of a mixed solution of 1, 4-dioxane and water (V: v=10:1). The reaction was carried out at 100℃for 12 hours under nitrogen atmosphere, the reaction solution was concentrated under reduced pressure, the resulting black oily substance was dissolved in methanol (5 mL), 2M sodium hydroxide solution (0.75 mL) was added, and the mixture was reacted at 50℃for 1 hour, after which the reaction solution was concentrated under reduced pressure, it was purified by high performance liquid chromatography (Waters-2545, column chromatography: sharpsil-T C, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 25% -40%, flow rate: 30 mL/min) to give the title compound 7 (2 mg, yield: 3%).

MS m/z(ESI):374.0[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.69(s,1H),7.98(s,1H),7.84(d,2H),7.44(s,1H),7.28(s,2H),5.37(s,2H),4.25(q,2H),3.59(s,2H),2.32(s,6H),1.53(t,3H)。

Example 8

4- (7- (4-ethylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide 8

First step

2- (3-bromophenyl) -1, 3-dioxolan 8b

Compound 3-bromobenzaldehyde 8a (14 g,75.66mmol, shanghai Bifide) was dissolved in toluene (200 mL), ethylene glycol (7.04 g,113.4 mmol), p-toluenesulfonic acid (1.4 g,7.56 mmol) was added, heated to 140℃and reacted with water diversion for 14 hours, the reaction cooled to room temperature, washed successively with 5% aqueous sodium carbonate (100 mL), saturated brine (100 mL), the organic phase collected, concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title compound 8B (17 g, yield: 98%).

Second step

3- (4-ethylpiperazin-1-yl) benzaldehyde 8c

Compound 8b (4 g,17.4 mmol) was dissolved in toluene (60 mL), tris (dibenzylideneacetone) dipalladium (1.59 g,1.73 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (2.17 g,3.48 mmol), potassium tert-butoxide (3.91 g,34.8 mmol), 1-ethylpiperazine (2.99 g,26.2 mmol), heated to 100deg.C for 14 hours, cooled to room temperature, 6M hydrochloric acid (100 mL) was added and after stirring the reaction for 2 hours, pH was adjusted to about 13 with 6M aqueous sodium hydroxide solution, ethyl acetate was extracted (100 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered off and concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to give the title compound 8c (1.9 g, yield: 49.8%).

MS m/z(ESI):219.2[M+1]。

Third step

2-bromo-5- (4-ethylpiperazin-1-yl) benzaldehyde 8d

Compound 8c (1.9 g,8.7 mmol) was dissolved in dichloromethane (30 mL), N-bromosuccinimide (3.09 g,17.36 mmol) was added under ice-bath, the reaction was stirred at room temperature for 1 hour, the reaction solution was adjusted to pH 8 or so with 1M aqueous sodium hydroxide solution, extracted with dichloromethane ester (20 mL. Times.3), the organic phase was collected, concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 8d (1.2 g, yield: 46.3%). MS m/z (ESI): 297.9[ M+1].

The third to ninth steps of the synthetic route in example 1 were followed, substituting the starting compound 1d of the third step with the compound 8d, to give the title compound 8 (5 mg, yield: 18.2%).

MS m/z(ESI):482.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.61(s,1H),7.80-7.75(m,2H),7.73(d,1H),7.50-7.44(m,3H),7.05(dd,1H),6.86(d,1H),5.21(s,2H),3.29(t,4H),3.14(d,6H),2.68(t,4H),2.53(q,2H),1.18(t,3H)。

Example 9

N, N, 2-trimethyl-4- (7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide 9

The title compound 9 (10 mg, yield: 44%) was obtained by substituting N, N, 2-trimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide, which was the eighth step starting compound, N-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide, with the synthetic route in example 1.

MS m/z(ESI):482.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ ):δ9.31(s,1H),8.68(s,1H),7.70(d,1H),7.52(d,2H),7.22(d,1H),7.00(dd,1H),6.73(d,1H),5.18(s,2H),3.28(t,4H),3.20(s,3H),2.96(s,3H),2.62(t,4H),2.39(s,3H),2.37(s,3H)。

Example 10

N, N-dimethyl-4- (8-methyl-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide 10

Using the synthetic route in example 5, the first starting compound 5a was replaced with the compound 3-bromo-4-methylbenzaldehyde to give the title compound 10 (1.2 mg, yield: 4%).

MS m/z(ESI):482.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.65(s,1H),7.77(d,2H),7.69(s,1H),7.50-7.43(m,3H),6.99(s,1H),5.22(s,2H),3.14(d,6H),3.08(s,4H),2.93(s,4H),2.59(s,3H),2.41(s,3H)。

Example 11

4- (6-fluoro-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide 11

Using the synthetic route in example 5, the first starting compound 5a was replaced with the compound 3-bromo-2-fluorobenzaldehyde to give the title compound 11 (3 mg, yield: 13.1%).

MS m/z(ESI):486.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.65(s,1H),7.77(d,2H),7.61(d,1H),7.51-7.46(m,3H),7.12(t,1H),5.36(s,2H),3.24-3.10(m,10H),2.67(t,4H),2.38(s,3H)。

Example 12

4- (6-methoxy-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide 12

Using the synthetic route in example 5, the first starting compound 5a was replaced with the compound 3-bromo-2-methoxybenzaldehyde (Shanghai Biao), affording the title compound 12 (6 mg, yield: 10%).

MS m/z(ESI):498.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.62(s,1H),7.789(d,2H),7.57(d,1H),7.50-7.47(m,3H),7.08(d,1H),5.37(s,2H),3.90(s,3H),3.35-3.21(m,4H),3.21-3.16(m,2H),3.13(d,6H),2.76-2.72(m,2H),2.43(s,3H)。

Example 13

(S) -N- (2-hydroxypropyl) -N-methyl-4- (6-methyl-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide 13

First step

4- (6-methyl-7- (4-methylpiperazin-1-yl) -1-p-toluenesulfonyl-1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid methyl ester 13a

Compound 5e (200 mg,325 μmol), methyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoate (128 mg,488 μmol), the [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (26 mg,32.5 μmol), sodium carbonate (69 mg,650 μmol) were dissolved in 10ml of a mixed solution of 1, 4-dioxane and water (V: v=10:1). The reaction was carried out at 100℃for 12 hours under nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure and purified by column chromatography with eluent system A to give the title compound 13a (150 mg, yield: 74%).

MS m/z(ESI):623.2[M+1]。

Second step

4- (6-methyl-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid 13b

Compound 13a (150 mg, 240. Mu. Mol) was dissolved in a mixed solution of 12mL of methanol and tetrahydrofuran (V: V=10:1), and 2M aqueous sodium hydroxide solution (5 mL) was added. After reacting at 50℃for 12 hours and cooling to room temperature, the reaction mixture was adjusted to pH neutral with 2M hydrochloric acid, and concentrated under reduced pressure to give the crude title compound 13b (100 mg), which was used in the next reaction without purification.

MS m/z(ESI):455.2[M+1]。

Third step

Compound 13b (50 mg, 110. Mu. Mol) was dissolved in anhydrous N, N-dimethylformamide (2 mL), and (S) -1-methylaminopropan-2-ol (40 mg, 444. Mu. Mol), 2- (7-azobenzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate (105 mg, 275. Mu. Mol), N, N-diisopropylethylamine (57 mg, 440. Mu. Mol) was added sequentially. The reaction was stirred for 1 hour, concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: sharpsil-T C, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 25% -50%, flow rate: 30 mL/min) to give the title compound 13 (10 mg, yield: 17.2%).

MS m/z(ESI):526.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.60(s,1H),7.78-7.74(m,3H),7.66(d,1H),7.49(d,1H),7.42(s,1H),7.16(d,1H),5.31(s,2H),4.20-4.03(m,2H),3.69-3.66(m,2H),3.50-3.45(m,2H),3.33(s,3H),3.12(s,3H),2.68-2.60(m,2H),2.40(s,3H),2.22(s,3H),1.34-1.29(m,3H)。

Biological evaluation

Test example 1 HPK1 enzyme Activity assay (ADP-Glo method)

1. Reagents and apparatus

1) ADP-Glo kinase assay kit (comprising ADP-Glo reagent and kinase assay reagent (Kinase Detection Reagent)) (Promega, V9101)

2) 1M Tris-HCl buffer pH=7.5 (Soy pal, T1140)

3)1M MgCl ₂ (Invitrogen,AM9530G)

4)1M DTT(Thermofisher,P2325)

5) 20mg/mL Bovine Serum Albumin (BSA) (TAKARA 2320)

6) ATP solution (10 mM) (Thermofiser PV 3227)

7) Dephosphorylated MBP (Sigma, 13-110) (hereinafter referred to as MBP)

8)HPK1(Signalchem,M23-11G)

9) 96 well small volume whiteboard (Cisbio, 66PL 96100)

10 PHERA star enzyme label instrument (BMG labtech)

2. Experimental method

2.1 preparation of reagents

a. Detection buffer, 40mM Tris-HCl buffer, 7.5;20mM MgCl ₂ ；0.1mg/mL BSA；50μM DTT；

Hpk1 enzyme solution: the detection buffer solution is prepared into HPK1 enzyme solution with the final concentration of 1.5 ng/. Mu.L;

atp and MBP mix substrate: the detection buffer solution is respectively prepared into ATP with the final concentration of 60 mu M and MBP with the final concentration of 0.6 ug/mu L, and the prepared ATP and MBP are mixed in equal volume;

d. a compound: initial concentration 33.3. Mu.M, 3-fold dilution, 9 concentration gradients. All concentrations of compounds were diluted 33.3-fold with assay buffer for use.

2.2 Experimental procedure

a.96 well plate, 2. Mu.L of the prepared HPK1 enzyme solution was added to each well, no enzyme was added to column 1, and 2. Mu.L of detection buffer was added.

b. 2. Mu.L of compound was added per well, no compound was added in columns 1 and 1, DMSO was added as a control, centrifuged, mixed well, shaken for 2 min and incubated at room temperature for 10 min.

c. mu.L of a mixture of ATP and MBP substrate was added to each well, centrifuged, mixed well, shaken for 2 minutes and incubated at room temperature for 60 minutes.

d. 6 mu L of ADP-Glo reagent is added to each well, centrifuged, mixed evenly and shaken for 2 minutes, and incubated for 40 minutes at room temperature.

e. Add 12. Mu.L kinase assay reagent to each well, centrifuge, mix well, shake for 2 min, incubate for 40 min at room temperature.

f. The plate was read with a microplate reader and the RLU (relative luminescence unit (Relative luminescence unit)) values were recorded.

graphpad software mapping, calculation of Compound IC ₅₀ The values are shown in Table 1.

TABLE 1 inhibition of HPK1 enzyme Activity by Compounds of the present disclosure IC ₅₀ Value of

Examples numbering	HPK1/IC ₅₀ (nM)
1	0.7
2	1.5
3	1.3
4	1.5
5	2.8
6	1.3
7	4.9
8	1.7
9	3.6
10	3.0
11	7.0
13	1.5

Conclusion: the compound has obvious inhibiting effect on the activity of HPK1 enzyme.

Test example 2 Jurkat cell SLP76 protein phosphorylation assay (HTRF method)

1. Reagents and apparatus

1) RPMI1640 medium (Gibco, 61870044)

2) Fetal bovine serum (Gibco, 10099141C) (hereinafter referred to as FBS)

3)75cm ² Filter cover cell culture bottle (Corning, 430641)

4)PBS,pH 7.4(Gibco,10010049)

5) CD3Antibody, anti-human, pure functional grade (CD 3 anti-human, pure-functional grade) (Miltenyi Biotec, 130-093-387)

6) Phospho-SLP-76 (Ser 376) cell kit (Cisbio, 63ADK076 PEG)

7) HTRF 96-well small volume whiteboard (Cisbio, 66PL 96100)

8) 96 well plate (Corning, 3788)

9) Micro-pore plate oscillator (Linbell)

10 PHERA star enzyme label instrument (BMG labtech)

11 Automatic cell counter of Countstar BioMed (Shanghai Rui Yu Biotechnology)

12 Ultra-clean bench (Thermo, 1300 ALL)

13)CO ₂ Incubator (Thermo, I160)

2. Cell and culture method

Jurkat E6-1 cells were purchased from American type culture Collection (ATCC, TIB-152) and cultured in RPMI1640 medium (10% FBS). The cell culture density was maintained at 2X 10 ⁵ Up to 2X 10 ⁶ cells/mL, passaged 2-3 times a week.

3. Preparation of Compounds

a. Test compounds were dissolved to 5mM with DMSO.

b. The initial concentration of compound was 5mM, 3-fold diluted, 10 concentration gradients.

c. All concentrations of compounds were diluted 100-fold with culture medium for use.

4. Experimental procedure

Jurkat cell count, cell density was adjusted to 5X 10 with fresh medium ⁶ /mL。

96-well plates, each well was seeded with 20. Mu.L of cells and incubated at 37℃for 4 hours.

c. mu.L of compound (column 1 and column 12 plus 5. Mu.L of 0.5% DMSO) was added to each well and incubated at 37℃for 1 hour.

d. The CD3 antibody was diluted to 20 ng/. Mu.L with the culture solution, 5. Mu.L was added to each well (column 1 plus 5. Mu.L of the culture solution as a control), and incubated at 37℃for half an hour.

e. Cells were lysed by adding 10. Mu.L of lysate per well and shaking at 850rpm at room temperature for half an hour.

f. mu.L of cell lysate was taken into a new HTRF 96-well plate, 4. Mu.L of antibody mixture was added to each well, and left overnight at room temperature.

g. The plate was read with a microplate reader and signal values of 665nm and 620nm were recorded.

Graphpad software mapping, calculation of compound IC ₅₀ The values are shown in Table 2.

TABLE 2 phosphorylation inhibition IC of Jurkat cell SLP76 protein by compounds of the present disclosure ₅₀ Value of

Examples numbering	SLP76 protein phosphorylation/IC 50 (nM)
1	189.0
2	173.0
5	162.6
6	107.6
11	107.5
13	144.1

Conclusion: the compound has obvious inhibition effect on the phosphorylation of the SLP76 protein of Jurkat cells.

Claims

A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

ring a is aryl or heteroaryl;

ring B is phenyl or 5-or 6-membered heteroaryl;

G ¹ is CR (CR) ¹ Or a nitrogen atom;

G ² is CR (CR) ² Or a nitrogen atom;

G ⁶ selected from C (O), CR ^6a R ^6b 、NR ^6c And an oxygen atom;

G ⁷ selected from C (O), CR ^7a R ^7b 、NR ^7c And an oxygen atom;

R ^6a 、R ^6b 、R ^7a and R is ^7b The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁰ 、R ^6c and R is ^7c The same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Each R is ^a Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _r NR ^m R ⁿ 、-OR ^p Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or two R ^a Forming a fused ring with ring B, said fused ring optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R’、R ¹ And R is ² Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR ^d R ^e 、-OR ^g 、-(CO)R ^f 、-(CO)NR ^d R ^e 、-(CO)OR ^g 、-SO ₂ R ^f 、-SO ₂ NR ^d R ^e 、-NR ^h (CO)R ^f 、-NR ^h (CO)NR ^d R ^e 、-NR ^h (CO)OR ^g 、-NR ^h SO ₂ R ^f 、-NR ^h SO ₂ NR ^d R ^e Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR ^d2 R ^e2 、-OR ^g2 、-(CO)R ^f2 、-(CO)NR ^d2 R ^e2 、-(CO)OR ^g2 、-SO ₂ R ^f2 、-SO ₂ NR ^d2 R ^e2 、-NR ^h2 (CO)R ^f2 、-NR ^h2 (CO)NR ^d2 R ^e2 、-NR ^h2 (CO)OR ^g2 、-NR ^h2 SO ₂ R ^f2 、-NR ^h2 SO ₂ NR ^d2 R ^e2 One or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^m 、R ⁿ 、R ^p 、R ^d 、R ^e 、R ^f 、R ^g 、R ^h 、R ^d2 、R ^e2 、R ^f2 、R ^g2 and R is ^h2 The alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently the same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups;

Or R is ^m And R is ⁿ 、R ^d And R is ^e 、R ^d2 And R is ^e2 Forming, together with the nitrogen atom to which they are attached, a heterocyclic group optionally substituted with one or more groups selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

q is 0, 1, 2, 3 or 4; and is also provided with

r is 0, 1, 2, 3 or 4.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II) or (III):

wherein:

G ³ is CR (CR) ³ Or a nitrogen atom;

G ⁵ is CR (CR) ⁵ Or a nitrogen atom;

R ³ and R is ⁵ And are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, and heteroaryl, One or more substituents of alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^4a and R is ^4b Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _r NR ^m R ⁿ 、-OR ^p Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

each R is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Or two R together form oxo;

R ^q selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

n is 0, 1, 2, 3, 4, 5 or 6;

ring A, G ¹ 、G ² 、G ⁶ 、G ⁷ 、R ⁰ 、R ^m 、R ⁿ 、R ^p R', R and q are as defined in claim 1.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein-G ⁷ -G ⁶ -selected from-O-CHR ^6a -、-CHR ^7a -O-、-NR ^7c -CHR ^6a -、-CHR ^7a -NR ^6c -、-C(O)-NR ^6c -and-NR ^7c -C(O)-，R ^6a 、R ^7a 、R ^6c And R is ^7c As defined in claim 1; preferably, -G ⁷ -G ⁶ -selected from-O-CH ₂ -、-CH ₂ -O-、-NH-CH ₂ -、-CH ₂ -NH-, -C (O) -NH-and-NH-C (O) -; more preferably, -G ⁷ -G ⁶ -is-O-CH ₂ -。
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 wherein ring a is a 6-10 membered aryl or a 5-or 6-membered heteroaryl, preferably phenyl or pyrazolyl.
A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein G ¹ Is CR (CR) ¹ ，R ¹ As defined in claim 1; preferably, R ¹ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, R ¹ Is a hydrogen atom.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein G ² Is CR (CR) ² ，R ² As defined in claim 1; preferably ，R ² Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, R ² Is a hydrogen atom.
A compound of the general formula (II) or (III) or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 6, wherein G ³ Is CR (CR) ³ ，R ³ As defined in claim 2; preferably, R ³ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, R ³ Is a hydrogen atom.
A compound of the general formula (II) or (III) or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 7, wherein G ⁵ Is CR (CR) ⁵ ，R ⁵ As defined in claim 2; preferably, R ⁵ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 An alkoxy group.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ⁰ Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably a hydrogen atom.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein each R' is the same or different and is each independently selected from C _1-6 Alkyl, C _1-6 Haloalkyl and- (CO) NR ^d R ^e ，R ^d And R is ^e As defined in claim 1; preferably, R ^d And R is ^e Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Hydroxyalkyl, or R ^d And R is ^e Together with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclic group, said 3-to 8-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 One or more groups in the hydroxyalkyl group are substituted.
A compound of general formula (II) or (III) according to any one of claims 2 to 10, or a pharmaceutically acceptable salt thereof, wherein R ^4a And R is ^4b Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _r NR ^m R ⁿ Hydroxy and C _1-6 Hydroxyalkyl group wherein said C _1-6 Alkyl and C _1-6 Alkoxy groups are each independently optionally selected from halogen, C _1-6 Alkoxy, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 Substituted by one or more substituents in hydroxyalkyl, R ^m 、R ⁿ And r is as defined in claim 1;

preferably, R ^4a And R is ^4b At least one of them is- (CH) ₂ ) _r NR ^m R ⁿ ，R ^m And R is ⁿ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Hydroxyalkyl group wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, C _1-6 One or more substituents of haloalkoxy, cyano and amino are substituted; or R is ^m And R is ⁿ Together with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclic group, said 3-to 8-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy, oxo and C _1-6 One or more groups in the hydroxyalkyl group are substituted; r is 0, 1 or 2.
A compound of general formula (II) or (III) according to any one of claims 2 to 11, or a pharmaceutically acceptable salt thereof, wherein R ^q Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably C _1-6 An alkyl group.
A compound of general formula (I) according to any one of claims 1 to 9 and 11, or a pharmaceutically acceptable salt thereof, selected from the following compounds:
a compound of the general formula (IA):

wherein: r is R ^w Is an amino protecting group; preferably Ts;

ring a, ring B, G ¹ 、G ² 、G ⁶ 、G ⁷ 、R’、R ^a P and q are as defined in claim 1.
A compound of formula (IA) or a salt thereof as claimed in claim 14, which is selected from the following compounds:
a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises:

deprotection of a compound of formula (IA) or a salt thereof to give a compound of formula (I) or a pharmaceutically acceptable salt thereof;

Wherein R is ^w Is an amino protecting group; preferably Ts;

R ⁰ is a hydrogen atom;

ring a, ring B, G ¹ 、G ² 、G ⁶ 、G ⁷ 、R’、R ^a P and q are as defined in claim 1.
A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
Use of a compound of general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 in the manufacture of a medicament for inhibiting HPK 1.
Use of a compound of general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 for the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition selected from cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders.
The use according to claim 19, wherein the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, hiv infection, hepatitis b virus infection, ischemia, atherosclerosis, stroke and alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibromatosis, glioma, and neuroblastoma.