TW202214608A - Fused pyridazine derivatives, preparation method and medical use thereof - Google Patents

Abstract

The present disclosure relates to fused pyridazine derivatives, preparation method and medical use thereof. Specifically, the present disclosure relates to a fused pyridazine derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a SOS1 inhibitor, as well as its use in the preparation of medicaments for the treatment of conditions or disorders ameliorated by the inhibition of SOS1.

Description

Condensed pyridazine derivative, its preparation method and its application in medicine

The present disclosure belongs to the field of medicine, and relates to a fused pyridazine derivative represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a SOS1 inhibitor and in the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of SOS1.

RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignancies are associated with mutations in the RAS gene. The RAS family includes KRAS, NRAS and HRAS, of which KRAS mutations are the most common, accounting for about 85%. After KRAS is activated, it regulates the functions of cell proliferation, survival, migration and metabolism through numerous downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc. After KRAS gene mutation, the protein is continuously activated, which leads to the continuous activation of downstream signaling pathways and promotes tumorigenesis.

Due to the lack of traditional small molecule binding sites on the surface of KRAS protein, and its high affinity for guanylate, which is extremely difficult to inhibit, it has long been considered as an undruggable drug. object target. However, based on the importance and prevalence of aberrant KRAS activation in cancer progression, KRAS has been and remains a target of great interest in drug development. The current drug development ideas for inhibiting the KRAS pathway mainly include the following aspects:

1) The small-molecule covalent inhibitor developed for KRAS G12C can irreversibly lock the G12C mutant in an inactive state. Currently, the clinical phase I data of Amgen and mirati have shown good results. However, the mutation of KRAS G12C is only one of its many mutations, and other important mutants such as G12V, G12D, G12S, G12A, G13V/D still lack effective drugs.

2) Look for other sites on KRAS that can target more mutants: mainly targeting sites that bind downstream effector molecules/sites related to protein molecule activation, which are currently in the preclinical stage, IC ₅₀ for activity inhibition Usually at the micromolar level.

3) Inhibition of KRAS downstream signaling proteins: For example, the development of inhibitors such as RAF, MEK, ERK, etc., is currently clinically ineffective.

4) Inhibition of the upstream pathway of KRAS: such as inhibitors of SHP2, etc.

5) Modification and localization of KRAS: such as farnesyl transferase, block the membrane localization of KRAS to achieve the effect of inhibiting its effect.

6) KRAS expression was knocked down by RNAi.

Overall, with the exception of KRAS G12C inhibitors, there is still a lack of broad-spectrum KRAS inhibitors that are effective against multiple mutations. Blocking KRAS activating molecules from binding to KRAS, such as selective inhibition of SOS1, a small molecule inhibitor of guanine nucleotide exchange factor (GEF), can block KRAS activation by interfering with the RAS-SOS1 interaction , can achieve the purpose of broad-spectrum inhibition of KRAS activity.

KARS protein is a small GTPase (small GTPase), in cells, KRAS protein is in an inactive state (binding to guanosine diphosphate (GDP)) and an activated state (binding to guanosine diphosphate (GDP)) glycoside triphosphate (GTP) binding). This transition is regulated by guanine nucleotide exchange factor (GEF) and GTPases activating protein (GAP). There are three main types of GEFs in KRAS, namely SOS (sevenless son) 1&2, Ras-GRF and Ras-GRP. The latter two types are only expressed in neurons and leukocytes. Only SOS is widely expressed in various tissues and is considered to be in RAS. play a leading role in the activation. Since the expression level of SOS1 is higher than that of SOS2, and its activity is stronger than that of SOS2, the current research on SOS mainly focuses on SOS1. The specific activation pathway of SOS1 for KRAS protein is as follows: After upstream signals (such as growth factors) activate membrane surface receptors, SOS1 is activated by SHP2-Grb2, SOS1 binds to KRAS, and catalyzes the interaction between KRAS and GDP by causing a series of conformational changes. It dissociates and then combines with GTP to form active KRAS-GTP.

Patent applications that have disclosed compounds as SOS1 inhibitors include WO2018115380A1, WO2019122129A1, WO2018172250A1, and WO2016077793A1, among others.

The purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof:

in,

Ring A is aryl or heteroaryl;

G is CR ⁵ or N atom;

R ⁰ is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , cycloalkane oxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro , cyano, -S(O) ₂ R ⁹ , -C(O)R ¹⁰ , cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with one or more substituents;

R ¹ is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;

R ^is selected from halogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein each of the alkyl, cycloalkyl and heterocyclyl is independently optionally selected Substituted from one or more substituents of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro and cyano;

^R is selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro substituted with one or more substituents of radicals, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and -(CH ₂ ) _p NR ⁶ R ⁷ ;

R and R ⁵ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -(CH ₂ ) _p NR ⁶ R ⁷ , cyano and nitro, wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, substituted with one or more substituents in nitro and -(CH ₂ ) _q NR ¹¹ R ¹² ;

R ⁸ are the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , nitro, hydroxyl, hydroxyalkyl, -S(O) ₂ alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkane group, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, -( CH ₂ ) _q NR ¹¹ R ¹² , substituted with one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁹ and R ¹⁰ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH ₂ ) _q NR ¹¹ R ¹² , a cycloalkyl group and a heterocyclyl group, wherein the alkane , cycloalkyl, and heterocyclyl are each independently optionally selected from hydroxy, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amine, and nitro one or more of the substituents in the substituted;

R ⁶ , R ⁷ , R ¹¹ and R ¹² are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

p and q are the same or different, each independently selected from 0, 1 and 2;

n is selected from 0, 1, 2, 3, 4 and 5.

The purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof:

in,

Ring A is aryl or heteroaryl;

G is CR ⁵ or N atom;

R ⁰ is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , cycloalkane oxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S (O) ₂ R ⁹ , -C(O)R ¹⁰ , one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹ is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;

R ^is selected from halogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein each of the alkyl, cycloalkyl and heterocyclyl is independently optionally selected Substituted from one or more substituents of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro and cyano;

^R is selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro substituted with one or more substituents of radicals, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and -(CH ₂ ) _p NR ⁶ R ⁷ ;

R and R ⁵ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -(CH ₂ ) _p NR ⁶ R ⁷ , cyano and nitro, wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, substituted with one or more substituents in nitro and -(CH ₂ ) _q NR ¹¹ R ¹² ;

R ⁸ are the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , nitro, hydroxyl, hydroxyalkyl, -S(O) ₂ alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkane group, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, -( CH ₂ ) _q NR ¹¹ R ¹² , substituted with one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁹ and R ¹⁰ are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH ₂ ) _q NR ¹¹ R ¹² , a cycloalkyl group and a heterocyclic group;

R ⁶ , R ⁷ , R ¹¹ and R ¹² are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

p and q are the same or different, each independently selected from 0, 1 and 2;

n is selected from 0, 1, 2, 3, 4 and 5.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is CR ⁵ , and R ⁵ is as defined in general formula (I); preferably, G is CH.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

wherein Rings A, R, R ⁰ , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is selected from alkoxy, hydroxyalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocycle aryl, aryl, and heteroaryl, wherein the cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl , one or more of haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ₂ R ⁹ and -C(O)R ¹⁰ wherein, R ⁹ and R ¹⁰ are the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an amino group and a hydroxyalkyl group;

Preferably, R ⁰ is selected from cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyloxy, heterocyclyloxy, ring Alkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from hydroxy and -C(O)R ¹⁰ ; R ¹⁰ is alkyl;

Further preferably, R ⁰ is selected from C _1-6 alkoxy, five-membered heterocyclyloxy and six-membered heterocyclyl, the five-membered heterocyclyloxy and six-membered heterocyclyl are each independently optional is substituted by -C(O)R ¹⁰ and/or hydroxy, wherein R ¹⁰ is C _1-6 alkyl;

More preferably, R ⁰ is selected from tetrahydrofuranyloxy and piperidinyl, each of which is independently optionally substituted by -C(O)R ¹⁰ and/or hydroxy, wherein R ¹⁰ is C _1-6 alkyl.

或

；環B選自環烷基、雜環基、芳基和雜芳基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is

or

; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

、

、

和

；W選自 氧原子、硫原子、

、

、NR^13a和CR^13bR^13c； Preferably, R ⁰ is selected from

,

,

and

; W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j is 0, 1 or 2;

k is 1 or 2;

u is 0, 1, 2, 3, 4, or 5;

v is 0, 1, 2, or 3;

R ⁹ to R ¹⁰ are as defined in the general formula (I).

、

、

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- enantiomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein R ^is selected from

,

,

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

v is 0, 1, 2, or 3;

R ⁹ to R ¹⁰ are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^13a is -C(O)R ¹⁰ ; R ¹⁰ is C _1-6 alkyl or C _1-6 hydroxyalkyl, the C _1-6 alkyl may optionally be substituted with C _1-6 alkoxy and cyano.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹³ and R ^13b are preferably hydrogen atoms.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^13c is -C(O)R ¹⁰ ; R ¹⁰ is _{diC 1-6} alkylamino or 3-6 membered heterocycle Preferably, R ^13c is -C(O)-di-C _1-6 alkylamino group or -C(O)-5- to 6-membered heterocyclic group; more preferably, R ^13c is -C(O )N( _CH3 ) ₂ or -C(O)morpholinyl.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein u is 0 or 1.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein j is 1.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein v is 0.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R, R ⁰ , R ¹ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁸ are the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, Alkoxy, haloalkoxy, cyano, amine, -(CH ₂ ) _p NR ⁶ R ⁷ , nitro, hydroxy, hydroxyalkyl and -S(O) ₂ alkyl, wherein the alkyl, halogen Alkyl and hydroxyalkyl are each independently optionally selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl and -(CH ₂ ) _q NR ¹¹ One or more substituents in R ¹² are substituted; p and q are each independently selected from 0, 1 or 2; R ⁶ , R ⁷ , R ¹¹ and R ¹² are the same or different, each independently selected from hydrogen atom, alkane group, haloalkyl and hydroxyalkyl;

Preferably, R ⁸ is the same or different, each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, amino, -(CH ₂ ) _p NR ⁶ R ⁷ and C _1-6 Hydroxyalkyl, wherein the C _1-6 haloalkyl is optionally substituted with one or more hydroxyl groups; R ⁶ and R ⁷ are hydrogen atoms or C _1-6 alkyl, and p is 0, 1, or 2.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ¹ is selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and hydroxy alkyl;

Preferably, R ¹ is selected from hydrogen atom, C _1-6 alkyl group and halogen.

Further preferably, R ¹ is C _1-6 alkyl.

More preferably, R ¹ is methyl.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^is selected from halogen, alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl, wherein each of the alkyl and cycloalkyl is independently optional is substituted with one or more substituents selected from alkoxy, haloalkoxy and amine;

Preferably, R ² is selected from halogen, alkyl, haloalkyl and hydroxyalkyl;

Further preferably, R ² is a hydrogen atom or a C _1-6 alkyl group.

More preferably, R ² is methyl.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, and a cycloalkyl group, wherein the alkyl group, haloalkyl group , hydroxyalkyl and cycloalkyl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, amino and hydroxyalkyl replace;

Preferably, R ³ is selected from hydrogen atoms, alkyl groups, haloalkyl groups and hydroxyalkyl groups.

Further preferably, R ³ is a hydrogen atom or a C _1-6 alkyl group.

Still further preferably, R ² is C _1-6 alkyl.

More preferably, R ³ is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from hydrogen atom, halogen, alkyl, haloalkyl and hydroxyalkyl; preferably, R ⁴ selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl;

More preferably, R ⁴ is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -( CH ₂ ) _p NR ⁶ R ⁷ , cyano and nitro; R ⁶ and R ⁷ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group and a hydroxyalkyl group; p is 0, 1 or 2 ;

Preferably, R is C _1-6 alkoxy;

More preferably, R is methoxy.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, - (CH ₂ ) _p NR ⁶ R ⁷ and cyano; R ⁶ and R ⁷ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group and a hydroxyalkyl group; p is 0, 1 or 2;

Preferably, R ⁵ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, R ⁵ is hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁶ and R ⁷ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkane base;

Preferably, R ⁶ and R ⁷ are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ¹¹ and R ¹² are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkane base;

Preferably, R ¹¹ and R ¹² are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁹ and R ¹⁰ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkane base;

Preferably, R ⁹ and R ¹⁰ are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1, preferably 0.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer Construct, non-pair An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1, preferably 0.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2 or 3, preferably 2.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (IV) or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

wherein rings A, G, R, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁸ and n are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (IV) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl or 5- to 6-membered heteroaryl.

、

、

、

、

、

、

、

和

；v為0；R^13a為-C(O)R¹⁰；R¹⁰為C_1-6烷基或C_{1- 6}羥烷基，該C_1-6烷基任選可被C_1-6烷氧基和氰基取代；R¹³和R^13b為氫原子；R^13c為-C(O)-二C_1-6烷基胺基或-C(O)-5至6員雜環基；R⁸相同或不同，各自獨立地選自鹵素、C_1-6烷基、C_1-6鹵烷基、胺基、-(CH₂)_pNR⁶R⁷和C_1-6羥烷基，其中該C_1-6鹵烷基任選地被一個或多個羥基取代；R⁶和R⁷為氫原子或C_1-6烷基，p為0、1或2；R¹選自氫原子、C_1-6烷基和鹵素；R³為氫原子或C_1-6烷基；R⁴選自氫原子、鹵素、C_1-6烷基、C_1-6鹵烷基和C_1-6羥烷基；R為C_1-6烷氧基；R⁵選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；n為1、2或3。 In some preferred embodiments of the present disclosure, a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl group or a 5- to 6-membered heteroaryl group; R ⁰ is selected from

,

,

,

,

,

,

,

and

; v is 0; R ^13a is -C(O)R ¹⁰ ; R ¹⁰ is C _1-6 alkyl or C _1-6 hydroxyalkyl, the C _{1-6 alkyl optionally can be replaced by C 1-6 alkane} Oxygen and cyano group substitution; R ¹³ and R ^13b are hydrogen atoms; R ^13c is -C(O) _{-diC 1-6} alkylamino group or -C(O)-5- to 6-membered heterocyclic group; R ⁸ are the same or different, each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, amino, -(CH ₂ ) _p NR ⁶ R ⁷ and C _1-6 hydroxyalkyl, wherein The C _1-6 haloalkyl is optionally substituted by one or more hydroxyl groups; R ⁶ and R ⁷ are hydrogen atoms or C _1-6 alkyl groups, p is 0, 1 or 2; R ¹ is selected from hydrogen atoms, C _1-6 alkyl and halogen; R ³ is hydrogen atom or C _1-6 alkyl; R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; R is C _1-6 alkoxy; R ⁵ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; n is 1, 2 or 3.

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

Another aspect of the present disclosure pertains to compounds of formula (IA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

Wherein, X is halogen, preferably chlorine;

R ⁰ is selected from bromine, iodine, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxyl, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , Heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heterocyclyl The aryl groups are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ₂ Substituted with one or more substituents in R ⁹ , -C(O)R ¹⁰ , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹ is selected from bromine, iodine, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;

R is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycle aryloxy, aryloxy, heteroaryloxy, -(CH ₂ ) _p NR ⁶ R ⁷ , cyano and nitro, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, nitro, and -(CH ₂ ) _q NR ¹¹ R ¹² substituted by one or more of the substituents in;

G, R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , p, q and R ⁴ are as defined in general formula (I).

Another aspect of the present disclosure pertains to compounds of formula (IIA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

Wherein, X is halogen, preferably chlorine;

R, R ⁰ , R ¹ , R ⁴ and R ⁵ are as defined in general formula (II).

Another aspect of the present disclosure pertains to compounds of general formula (IVA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

wherein Rings A, G, R, R ⁰ , R ¹ -R ⁴ , R ⁸ and n are as defined in general formula (I).

Another aspect of the present disclosure pertains to compounds of general formula (IAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

、

、NR^13a和CR^13bR^13c； Wherein, W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j is 0, 1 or 2;

k is 1 or 2;

v is 0, 1, 2, or 3;

Rings ^A , G, R, R1 ^- R4, R8 ^{- R10} and n are as defined in general formula (I).

Another aspect of the present disclosure pertains to compounds of general formula (IIAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

、

、NR^13a和CR^13bR^13c； Wherein, W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j is 0, 1 or 2;

k is 1 or 2;

v is 0, 1, 2, or 3;

Rings ^A , R, R1, R3 ^- R5, ^{R8 - R10} and n are as defined in general formula (II).

Another aspect of the present disclosure pertains to compounds of general formula (IIIAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

、

、NR^13a和CR^13bR^13c； wherein W is selected from oxygen atoms, sulfur atoms,

,

, NR ^13a and CR ^13b R ^13c ;

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j is 0, 1 or 2;

k is 1 or 2;

v is 0, 1, 2, or 3;

R, R ¹ , R ^4- R ⁵ , R ^8- R ¹⁰ and n are as defined in general formula (III).

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

Another aspect of the present disclosure relates to a method for preparing the compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IB) or its salt is reacted to obtain the compound of the general formula (I) or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the reaction is a substitution reaction;

Wherein, X is halogen;

Rings A, G, R, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁸ and n are as defined in general formula (I).

Another aspect of the present disclosure relates to a method for preparing the compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The general formula (IAA) is oxidized to obtain the general formula (I);

； where ^R0 is

;

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j is 0, 1 or 2;

k is 1 or 2;

v is 0, 1, 2, or 3;

Rings A, G, R, R ¹ , R ² , R ³ , R ⁴ , R ⁸ and n are as defined in general formula (I).

Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IIB) or its salt is reacted to obtain the compound of the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;

Wherein, X is halogen;

Rings A, R, R ⁰ , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (II).

Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The general formula (IIAA) is oxidized to obtain the general formula (II);

； where ^R0 is

;

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j is 0, 1 or 2;

k is 1 or 2;

v is 0, 1, 2, or 3;

Rings A, R, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (II).

Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IIIB) or its salt is reacted to obtain the compound of the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;

Wherein, X is halogen;

R, R ⁰ , R ¹ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (III).

Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The general formula (IIIAA) is oxidized to obtain the general formula (III);

； where ^R0 is

;

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j is 0, 1 or 2;

k is 1 or 2;

v is 0, 1, 2, or 3;

R, R ¹ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (III).

Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Compounds of general formula (IVA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof Reduction reaction to obtain the compound of general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt used,

wherein Rings A, G, R, R ⁰ , R ¹ -R ⁴ , R ⁸ and n are as defined in general formula (IV).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula (I), (II), (III), (IV) or Table A of the present disclosure or their interaction Variant, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers , diluent or excipient.

The present disclosure further relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof Use of , diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting SOS1.

The present disclosure further relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof , diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS) , Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Lay Use in the medicament of Guts syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably cancer; the cancer is preferably black melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric oncology, cervical cancer , ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, Neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably Non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably is multiple myeloma; the osteoma is preferably osteochondroma; the liver cancer is preferably hepatocellular carcinoma; the colorectal cancer is preferably colon cancer or rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; The sarcoma is preferably osteosarcoma.

The present disclosure also relates to a method of inhibiting SOS1 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), (II), (III), (IV) or Table A or shown, or a tautomer thereof body, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing SOS1-mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (II), (III), (IV) or shown in Table A the compound or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical containing the same composition.

The present disclosure also relates to a treatment and/or prophylaxis of cancer, inflammation, RAS disease, Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM- AVM), Costello Syndrome (CS), Cardio-Facial-Skin Syndrome (CFC), Leggers Syndrome, Hereditary Gingival Fibromatosis, or other proliferative diseases, preferably for the treatment of cancer A method comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (II), (III), (IV) Or a compound shown in Table A or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophagus cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelium Cancer, Pancreatic Cancer, Polycythemia Vera, Pediatric Oncology, Cervical Cancer, Ovarian Cancer, Breast Cancer, Bladder Cancer, Urothelial Cancer, Ureteral Tumor, Prostate Cancer, Seminoma, Testicular Tumor, Leukemia, Head and Neck Tumor, Uterus Endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably Neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably Preferably diffuse large B cell lymphoma; the myeloma is preferably multiple myeloma; the osteoma is preferably osteochondroma; the liver cancer is preferably hepatocellular carcinoma; the colorectal cancer is preferably colon cancer or Rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma.

The present disclosure further relates to a compound represented by the general formula (I), (II), (III), (IV) or Table A or its tautomer, meso, racemate, enantiomer , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a SOS1 inhibitor.

The present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof , diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment and/or prevention of SOS1-mediated diseases.

The present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof , diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS ), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Leggers syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably for the treatment and/or prevention of cancer; wherein the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, Nasopharyngeal cancer, gastric cancer, esophagus cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, brain tumor, Myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably multiple myeloma; the osteoma is preferably bone chondroma; the liver cancer is preferably hepatocellular carcinoma; the colorectal cancer is preferably colon cancer or rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma.

The active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation. Compounds of the present disclosure The drug can be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injection solutions, dispersible powders or granules, suppositories, lozenges or syrups.

As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form or in a form that the patient can self-administer in a single dose. A unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: filler (diluent), binder, wetting agent, disintegrant or excipient, and the like. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.

Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.

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

Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

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

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.

The compounds of the present disclosure can 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 that is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those of ordinary skill in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the the patient's health status, the patient's behavior, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dose of the compound or the pharmaceutically acceptable The type of salt can be verified according to traditional treatment protocols.

Glossary

Unless stated to the contrary, 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 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-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, 2,2-dimethyhexyl Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-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, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. Better yet Lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3- Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl base, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-Dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from H atoms, D atoms, halogen, alkyl , alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl one or more substituents in the radical, heteroaryl.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 Straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms , more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene ( _-CH2- ), 1,1-ethylene (-CH( _CH3 )-), 1,2-ethylene ( _-CH2) CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylidene (-CH ₂ CH(CH ₃ )-), 1,3-propylidene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), and the like. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkynyl, Alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, One or more substituents of aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and pendant oxy.

The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyls, one of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, or multiple substituents.

The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyls, one of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, or multiple substituents.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms (eg 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl, double-spirocycloalkyl or poly-spirocycloalkyl, preferably mono-spirocycloalkyl and double-spirocycloalkyl . More preferably 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-/5-member or 5-/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, each ring in the system sharing an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more Multiple double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3/4, 3/5, 3/6 Member, 4 Member/4 Member, 4 Member/5 Member, 4 Member/6 Member, 5 Member/4 Member, 5 Member/5 Member, 5 Member/6 Member, 6 Member/3 Member, 6 Member/4 Member, 6-membered/5-membered and 6-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

、

、

等；較佳為

The cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is attached at Rings taken together are cycloalkyl, non-limiting examples include

,

,

etc.; preferably

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, Alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl , aryl, and one or more substituents in heteroaryl.

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

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, The sulfur can be optionally oxidized (ie, to form arsenite or arsenic), but does not include ring moieties of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. It preferably contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are Heteroatoms; more preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (eg 1, 2 and 3); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homo Piperazinyl etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

The term "spiroheterocyclyl" refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur. atom, the sulphur may be optionally oxidized (ie to form arsenic or arsenic), the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 member). According to the number of spiro atoms shared between rings, spiroheterocyclyl groups are classified into mono-spiroheterocyclyl, bis-spiro-heterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiroheterocyclyl and bis-spiro-heterocyclyl . More preferably a 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-/5-member or 5-/6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl 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 other rings in the system, and one or more rings may contain one or more A double bond in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may be optionally oxidized (ie, to form thionite or thionite), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3/4, 3/5, 3/6 Member, 4 Member/4 Member, 4 Member/5 Member, 4 Member/6 Member, 5 Member/4 Member, 5 Member/5 Member, 5 Member/6 Member, 6 Member/3 Member, 6 Member/4 Member, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may be optionally oxidized (i.e. to form thionite or tau), and the rest of the ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocyclic, fused heterocyclic, and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the same as the parent structure The rings linked together are heterocyclyl, non-limiting examples of which include:

和

等。

and

Wait.

Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyls, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, One or more substituents in a heteroaryl group.

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

Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen, halogen, alkyl, alkoxy alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, heterocyclyl One or more substituents in an aryl group.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 members (eg 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked 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 available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, One or more substituents in a heteroaryl group.

The cycloalkyl, heterocyclyl, aryl and heteroaryl groups described above have one residue derived by removing one hydrogen atom from the parent ring atom, or two residues by removing two from the same or two different ring atoms of the parent. Residues derived from a hydrogen atom, namely "divalent cycloalkyl", "divalent heterocyclic group", "aryl extended", "heteroaryl extended".

The term "amine protecting group" is used to protect the amine group with a group that is easy to remove in order to keep the amine group unchanged when the other parts of the molecule are reacted. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxyl protecting group" is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & PGMWuts) for hydroxyl protecting groups. As an example, preferably, the hydroxyl protecting group can be a (C _1-10 alkyl or aryl) ₃ silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silicon, tert-butyldiphenylsilyl, etc.; can be C _1-10 alkyl or substituted alkyl, preferably alkoxy substituted alkyl or aryl substituted alkyl, more preferably C _1-6 Alkoxy substituted C _1-6 alkyl or phenyl substituted C _1-6 alkyl, the best C _1-4 alkoxy substituted C _1-4 alkyl, for example: methyl, tert-butyl , benzyl, methoxymethyl (MOM), ethoxyethyl, etc.; can be (C _1-10 alkyl or aryl) aryl, such as: methyl, acetyl, benzyl can be (C _1-6 alkyl or C _6-10 aryl) sulfonyl; also can be (C _1-6 alkoxy or C _6-10 aryl) oxy) carbonyl.

The term "cycloalkyloxy" refers to cycloalkyl-O-, 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 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 alkoxy 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 hydroxy 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 "thiol" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "pendant oxy" or "pendant oxygen" 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, cycloalkyl are as defined above.

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structures of the compounds described in this disclosure, the bond "

"Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond"

"can be"

"or"

", or both "

"and"

"Two configurations.

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, having the structures of the present disclosure, except replacing hydrogen with "deuterium" or "tritium", or replacing fluorine with ^an18F -fluorine label ( ^18F isotope), or ^using11C- , ^13C- , ^or14C -rich Compounds in which a set of carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) in place of carbon atoms are within the scope of this disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. One of ordinary skill in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "optionally "Alkyl-substituted heterocyclic group" means that an alkyl group may, but need not, be present, and the description includes both the case where the heterocyclic group is substituted with the alkyl group and the case where the heterocyclic group is not substituted with the alkyl group.

"Substituted" means that one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms are independently substituted with the corresponding number of substituents. Those of ordinary skill in the art can determine possible or impossible substitutions without undue effort (either experimentally or theoretically). For example, amine groups or hydroxyl groups with free hydrogens may be unstable when bound to carbon atoms with unsaturated (eg, olefinic) bonds.

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

"Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group with a suitable 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 amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance, and the appropriate effective amount in a case can be determined by one of ordinary knowledge in the art based on routine experiments.

The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonding. In some cases, for example, when incorporated in the crystal lattice of a crystalline solid One or more, preferably 1-3 solvent molecules, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

"Prodrug" means a compound that can be transformed in vivo under physiological conditions, such as by hydrolysis in blood, to yield the active prodrug compound.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications 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 references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is indicated that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by one of ordinary skill in the art, when parameters are not critical, numbers are generally given for illustrative purposes only, and not limitations.

Synthetic methods of compounds of the present disclosure

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

Option One

The compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

The compound of general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IB) or its salt (preferably hydrochloride) is reacted under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (I) or its tautomer, internal elimination A isomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;

Wherein, X is halogen;

Rings A, G, R, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁸ and n are as defined in general formula (I).

Option II

The compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

The general formula (IAA) is oxidized to obtain the general formula (I);

； where ^R0 is

;

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j is 0, 1 or 2;

k is 1 or 2;

v is 0, 1, 2, or 3;

Rings A, G, R, R ¹ , R ² , R ³ , R ⁴ , R ⁸ and n are as defined in general formula (I).

third solution

The compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

The compound of general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IIB) or its salt (preferably hydrochloride) is reacted under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (II) or its tautomer, internal elimination A isomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;

Wherein, X is halogen;

Rings A, R, R ⁰ , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (II).

Option 4

The compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

The general formula (IIAA) is oxidized to obtain the general formula (II);

； where ^R0 is

;

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j is 0, 1 or 2;

k is 1 or 2;

v is 0, 1, 2, or 3;

Rings A, R, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (II).

Option five

The compound represented by the general formula (III) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

The compound of general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IIIB) or its salt (preferably hydrochloride) is reacted under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (III) or its tautomer, internal elimination A isomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;

Wherein, X is halogen;

R, R ⁰ , R ¹ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (III).

Option 6

The compound represented by the general formula (III) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

The general formula (IIIAA) is oxidized to obtain the general formula (III);

； where ^R0 is

;

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j is 0, 1 or 2;

k is 1 or 2;

v is 0, 1, 2, or 3;

R, R ¹ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (III).

Option 7

The compound represented by the general formula (IV) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

The compound of general formula (IVA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof in Through reduction reaction under the action of catalyst, the compound of general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof is obtained, or a pharmaceutically acceptable salt thereof,

wherein Rings A, G, R, R ⁰ , R ¹ -R ⁴ , R ⁸ and n are as defined in general formula (IV).

The reagents that provide the acidic conditions in the above reaction include but are not limited to: ammonium chloride, trifluoroacetic acid, hydrochloric acid, hydrogen chloride in 1,4-dioxane, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid , nitric acid, phosphoric acid and p-toluenesulfonic acid; preferably ammonium chloride.

The reagents that provide the alkaline conditions in the above reaction include organic bases and inorganic bases, and the organic bases include but are not limited to: triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine Lithium propylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazacyclo[5,4,0]undec-7-ene, the inorganic bases including but Not limited to: sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.

The catalyst system used in the above-mentioned oxidation reaction includes but is not limited to: PhSiH/Mn(dpm) ₂ (or Mn(dpm) ₃ or Mn(acac) ₂ or Co(sdmg) ₃ ), tetraphenylporphyrin manganese (III) Complex/NaBH ₄ (or Pt-H ₂ ), Tetraphenylporphyrin cobalt(II) complex/NaBH ₄ (or EtNBH ₄ ), (bis(salicyl-γ-iminopropyl)methylamine ) Cobalt(II)/primary alcohol, Co(acac) ₂ , Co(salen), Co( _acacen ), BH3, etc. The oxidant used includes but is not limited to oxygen, air, hydrogen peroxide, etc., wherein Mn(dpm) ₂ is bis(2,2,6,6-tetramethyl-3,5-heptanedione) manganese, Mn(dpm) ) ₃ is three (2,2,6,6-tetramethyl-3,5-heptanedione) manganese (CAS registration number is 14324-99-3, also known as: three (2,2,6,6- Tetramethyl-3,5-heptenoic acid) manganese), Mn(acac) ₂ is bis(acetylacetone)manganese(II) (CAS Reg. No. 14024-58-9), Co(acac) ₂ is bis(acac) Acetylacetone) cobalt(II) (CAS Reg. No. 193620-63-2), Co(salen) is N,N'-bis(salicyl)ethylenediamine cobalt(II) (CAS Reg. No. 14167-18- 1), Co(acacen) is N,N'-bis(acetylacetone) ethylenediamine cobalt(II), Co(sdmg) ₃ is bis(N-salicylidene-2-aminoisobutanone)cobalt acid Sodium (CAS Reg. No. 704900-51-6); the preferred catalyst system is PhSiH/Mn(dpm) ₃ or PhSiH/Mn(acac) ₂ , and the preferred oxidant is oxygen.

The catalyst used in the above-mentioned reduction reaction includes but is not limited to: palladium carbon, iron powder, Raney nickel, zinc powder, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1,1'-bis(dibenzyl) (phosphorus) dipentyl iron palladium dichloro, tris(dibenzylideneacetone) dipalladium, etc., preferably palladium carbon. The reducing agent used includes but is not limited to hydrogen, dilute hydrochloric acid, acetic acid or dilute sulfuric acid, preferably hydrogen.

The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate Ester, n-hexane, dimethylsulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water, N,N-dimethylacetamide or N,N-dimethylformamide and its mixture.

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

Example

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) , the internal standard is tetramethylsilane (TMS).

For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector) THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)

High Performance Liquid Chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD and a Waters HPLC e2695-2489 high performance liquid chromatograph.

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

High performance liquid preparative chromatography used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

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

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

Known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.

There is no special description in the examples, and the reactions can all be carried out in an argon atmosphere or a nitrogen atmosphere.

Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction used a CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There is no special description in the examples, and the temperature of the reaction is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography method and the developing solvent system of the thin layer chromatography method used for purifying the compound include: : A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethyl ether can also be added Basic or acidic reagents such as amines and acetic acid are used for adjustment.

Example 1

N -(( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-4-methyl-7-((( S )-tetrahydrofuran -3-yl)oxy)phthalazin-1-amine 1

first step

( S )-4-Methoxy-3-((tetrahydrofuran-3-yl)oxy)benzoic acid methyl ester 1b

Methyl 3-hydroxy-4-methoxybenzoate 1a (5.00 g, 27.45 mmol, Shanghai Bide), ( 3R )-tetrahydrofuran-3-ol (2.42 g, 27.45 mmol, Shanghai Bide) and tris Phenylphosphine (8.64 g, 32.94 mmol, Titan) was dissolved in tetrahydrofuran (50 mL), replaced with argon three times, and diisopropyl azodicarboxylate (6.66 g, 32.94 mmol, Shanghai) was slowly added dropwise at 0°C under argon atmosphere. Shaoyuan). The reaction was warmed to room temperature and stirred under an argon atmosphere for 16 hours. The reaction solution was poured into water (100 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system B to give the title compound 1b (4.5 g), yield: 64%.

MS m/z (ESI): 253.1 [M+1].

second step

( S )-Methyl 2-bromo-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)benzoate 1c

Compound 1b (3.30 g, 13.08 mmol) was dissolved in dichloromethane (30 mL), and N -bromosuccinimide (3.03 g, 17.01 mmol, Shanghai Shaoyuan) was added in three batches at 0° C. Hydrobromic acid (1 mL, 50% aqueous solution), the reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography with eluent system B to obtain the title compound 1c (1.6 g), yield: 29%.

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

third step

( S )-Methyl 2-(1-ethoxyvinyl)-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)benzoate 1d

Compound 1c (1.6 g, 4.83 mmol) and bistriphenylphosphine palladium dichloride (339 mg, 0.48 mmol, Bailingwei) were dissolved in 1,4-dioxane (20 mL), replaced with argon for 3 times and slowly added dropwise Tributyl(1-ethoxyethylene)tin (1.92 g, 5.31 mmol, Shanghai Bide). The reaction solution was raised to 100°C and stirred for 16 hours. The reaction solution was cooled, poured into saturated potassium fluoride aqueous solution (50 mL) to quench, and extracted with ethyl acetate (25 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system B to give the title compound 1d (1.3 g), yield: 83%.

MS m/z (ESI): 323.0 [M+1].

the fourth step

( S )-2-Acetyl-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)benzoic acid methyl ester 1e

Compound 1d (1.3 g, 4.0 mmol) was dissolved in tetrahydrofuran (8 mL), concentrated hydrochloric acid (8 mL) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title product 1e (1.1 g), which was used in the next reaction without purification.

MS m/z (ESI): 295.1 [M+1].

the fifth step

( S )-6-Methoxy-4-methyl-7-((tetrahydrofuran-3-yl)oxy)phthalazin-1-ol 1f

Compound 1e (1.1 g, 4.0 mmol), methanol (6 mL) and hydrazine hydrate (3 mL, 80% aqueous solution) were mixed, raised to 80°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by column chromatography using eluent system B to obtain the title compound 1f (620 mg), yield: 55.9%.

MS m/z (ESI): 277.1 [M+1].

Step 6

( S )-1-Chloro-6-methoxy-4-methyl-7-((tetrahydrofuran-3-yl)oxy)phthalazine 1g

Compound 1f (200 mg, 0.724 mmol) was dissolved in phosphorus oxychloride (2 mL), heated to 80°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by column chromatography using eluent system B to obtain 1 g (170 mg) of the title compound, yield: 79%.

MS m/z (ESI): 295.0 [M+1].

Step 7

6-Methoxy-4-methyl- N -(( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7-((( S )-tetrahydrofuran -3-yl)oxy)phthalazin-1-amine 1h

Compound 1g (170mg, 0.577mmol), compound ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine hydrochloride (162mg, 0.692mmol) were prepared using patent application "CN110167928A""prepared by the method disclosed in Example B-6a on page 89 of the manual), ammonium chloride (62 mg, 1.15 mmol) and n-butanol (2 mL). The reaction solution was heated to 110°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by column chromatography using eluent system B to obtain the title compound 1h (190 mg), yield: 66%.

MS m/z (ESI): 493.1 [M+1].

Step 8

N -(( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-4-methyl-7-((( S )-tetrahydrofuran -3-yl)oxy)phthalazin-1-amine 1

Compound 1h (130 mg, 0.26 mmol) was dissolved in methanol (2 mL), 10% palladium on carbon (32 mg, 0.03 mmol) was added, hydrogen was replaced three times, and the mixture was stirred for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain the title compound 1 (20.6 mg, white solid), yield: 13%.

MS m/z (ESI): 463.1 [M+1].

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.77(s,1H), 7.25(s,1H), 7.19(d,1H), 6.84(d,2H), 6.66(s,1H), 5.49( s,2H),5.43-5.39(m,1H),5.36-5.32(m,1H),4.04-4.01(m,1H),3.96(s,3H),3.92-3.81(m,3H),2.60( s, 3H), 2.43-2.32 (m, 1H), 2.09-2.01 (m, 1H), 1.55 (d, 3H).

Example 2

2,2-Difluoro-2-(2-fluoro-3-(( R )-1-((6-methoxy-4-methyl-7-((( S )-tetrahydrofuran-3-yl) Oxy)phthalazin-1-yl)amino)ethyl)phenyl)ethanol 2

Compound 1g (45mg, 0.15mmol), compound ( R )-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride 2a (47mg, 0.18mmol, prepared by the method disclosed in Example B-5 on page 105 of the patent application "US2019194192"), N , N -diisopropylethylamine (60mg, 0.46mmol) was dissolved in 2mL 1,4 -Dioxane, microwave reaction at 120°C for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained title compound 2 (36 mg) was purified by preparative high performance liquid chromatography. Yield: 49.3%.

MS m/z (ESI): 478.1 [M+1].

¹ H NMR (500 MHz, CD ₃ OD): δ 7.80 (s, 1H), 7.57-7.54 (m, 1H), 7.44-7.41 (m, 1H), 7.35 (s, 1H), 7.16-7.13 (m, 1H), 5.76-5.72(m, 1H), 5.40-5.38(m, 1H), 4.13-3.95(m, 9H), 2.67(s, 3H), 2.45-2.37(m, 1H), 2.29-2.23( m, 1H), 1.71-1.70(d, 3H).

Example 3

1-(( S )-3-((4-((( R )-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino )-7-methoxy-1-methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 3

first step

( R )-3-(Tosyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester 3b

Compound ( R )-1-tert-butoxycarbonyl-3-hydroxypyrrolidine 3a (1.5 g, 8 mmol, Shanghai Bide), p-toluenesulfonyl chloride (1.83 g, 9.6 mmol, Shanghai Bide) and triethyl The amine (1.62 g, 16 mmol) was dissolved in dichloromethane (50 mL), 4-dimethylaminopyridine (0.1 g, 0.8 mmol) was added, and the reaction solution was stirred for 2 hours. The reaction solution was poured into water (100 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system B to give the title compound 3b (1.1 g), yield: 40.2%.

MS m/z (ESI): 342.4 [M+1].

second step

Methyl 2-bromo-5-hydroxy-4-methoxybenzoate 3d

The compound 2-bromo-5-hydroxy-4-methoxybenzoic acid 3c (5 g, 20.2 mmol) was dissolved in 30 mL of methanol, concentrated sulfuric acid (1.98 g, 20.2 mmol) was added dropwise under an ice bath, and the reaction was stirred under reflux for 14 hours , the reaction solution was cooled and concentrated under reduced pressure, the residue was poured into ice water, the solid was precipitated, filtered and dried to obtain the title compound 3d (5 g), yield: 94.6%.

MS m/z (ESI): 261.1 [M+1].

third step

Methyl 5-acetoxy-2-bromo-4-methoxybenzoate 3e

Compound 3d (2 g, 7.66 mmol) was dissolved in 20 mL of dichloromethane, N , N -diisopropylethylamine (2.97 g, 22.98 mmol) was added, and acetic anhydride (0.937 g, 9.19 mmol) was added dropwise under an ice bath ), the reaction was naturally raised to room temperature for 14 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography with eluent system B to obtain the title compound 3e (2 g), yield: 86%.

MS m/z (ESI): 303.1 [M+1].

the fourth step

5-Acetyloxy-2-(1-ethoxyvinyl)-4-methoxybenzoic acid methyl ester 3f

Compound 3e (2.3 g, 7.59 mmol) and bistriphenylphosphine palladium dichloride (532 mg, 0.76 mmol, Bailingwei) were dissolved in 1,4-dioxane (20 mL), replaced with argon three times and then slowly added dropwise Tributyl(1-ethoxyethylene)tin (3 g, 8.35 mmol, Shanghai Bide). The reaction solution was raised to 100°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain the title compound 3f (2.3 g), which was used in the next reaction without purification.

MS m/z (ESI): 295.1 [M+1].

the fifth step

5-Acetyloxy-2-acetyl-4-methoxybenzoic acid methyl ester 3g

Compound 3f (2.2 g, 7.45 mmol) was dissolved in tetrahydrofuran (8 mL), concentrated hydrochloric acid (10 mL) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography using eluent system B to obtain the title compound 3 g (2 g), yield: 98%.

MS m/z (ESI): 267.1 [M+1].

Step 6

6-Methoxy-4-methylphthalazine-1,7-diol 3h

Compound 3 g (2 g, 7.51 mmol), methanol (10 mL) and hydrazine hydrate (521 mg, 10.2 mmol) were mixed, and the mixture was heated to 80°C and stirred for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, filtered, and the solid was washed with ice ethanol and dried to obtain the title compound 3h (1.4 g) in a yield of 90.7%.

MS m/z (ESI): 207.1 [M+1].

Step 7

( S )-3-((4-Hydroxy-7-methoxy-1-methylphthalazin-6yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester 3i

Compound 3b (120 mg, 0.38 mmol), 3h (90 mg, 0.41 mmol), and N , N -dimethylformamide (3 mL) were added to the reaction flask, and the mixture was heated to 70° C. and stirred for 5 hours. The reaction solution was cooled, concentrated under reduced pressure, poured into water (20 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 3i (80 mg), yield: 51%.

MS m/z (ESI): 376.4 [M+1].

Step 8

( S )-1-Chloro-6-methoxy-4-methyl-7-(pyrrolidin-3-yloxy)phthalazine hydrochloride 3j

Compound 3i (40 mg, 0.106 mmol) was dissolved in phosphorus oxychloride (2 mL), raised to 70°C and stirred for 3 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain the title compound 3j (50 mg). The product was used in the next reaction without purification.

MS m/z (ESI): 294.1 [M+1].

Step 9

( S )-1-(3-((4-Chloro-7-methoxy-1-methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 3k

Compound 3j (50 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), N , N -diisopropylethylamine (70 mg, 0.51 mmol) and acetyl chloride (20 mg, 0.25 mmol) were added and the reaction was stirred for 2 hours. The resulting residue was purified by column chromatography with eluent system B to give the title compound 3k (50 mg), yield: 87.4%.

MS m/z (ESI): 336.3 [M+1].

Step 10

1-(( S )-3-((4-((( R )-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino )-7-methoxy-1-methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 3

Compound 3k (30 mg, 0.089 mmol), ( R )-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride ( 2a ) (40 mg , 0.178 mmol), ammonium chloride (10 mg, 0.178 mmol) and n-butanol (1 mL) were mixed. The microwave was heated to 110°C and stirred for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain the title compound 3 (3 mg), yield: 6.5%.

MS m/z (ESI): 519.2 [M+1].

¹ H NMR (500MHz, CD3OD): δ 7.73(s,1H), 7.61-7.58(m,1H), 7.50-7.47(m,2H), 7.27-7.25(m,1H), 5.75-5.71(m, 1H), 4.15-4.10(m, 3H), 3.82-3.79(m, 2H), 3.62-3.59(m, 2H), 2.81-2.77(m, 1H), 2.31-2.28(m, 2H), 2.25- 2.22 (m, 3H), 2.15-2.12 (m, 2H), 1.72-1.69 (m, 3H), 1.56-1.54 (d, 3H).

Example 4

( R )-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein oxazin-6-yl)-4-hydroxypiperidin-1-yl)ethanone 4

first step

1,7-Dichloro-6-methoxy-4-methylphthalazine 4a

Compound 3h (2 g, 9.7 mmol) was mixed with phosphorus oxychloride (15 mL), N , N -diisopropylethylamine (3.8 g, 29.1 mmol) was slowly added, and the temperature was raised to 90° C. to react for 14 hours. The reaction solution was concentrated under reduced pressure, poured into ice water, adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography with eluent system B afforded the title compound 4a (1.4 g), yield: 59.4%.

MS m/z (ESI): 243.1 [M+1].

second step

( R )-7-Chloro- N- (1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-4-methylphthalazin-1-amine 4b

Compound 4a (150mg, 0.62mmol), compound ( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride (139mg, 0.62mmol) were prepared using patent application "EP2018086197" prepared by the method disclosed in Example B-5 on page 141 of the specification), ammonium chloride (16.5 mg, 0.31 mmol) and n-butanol (2 mL). Microwave at 120°C for 1 hour. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid preparative chromatography to obtain the title compound 4b (15 mg), yield: 6.15%.

MS m/z (ESI): 396.1 [M+1].

third step

( R )-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein oxazin-6-yl)-5,6-dihydropyridin-1( 2H )-yl)ethanone 4c

Compound 4b (15 mg, 0.038 mmol), compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3 ,6-dihydropyridin-1( 2H )-yl)ethanone (11mg, 0.042mmol, Shanghai Bide), tris(dibenzylideneacetone)dipalladium (10.4mg, 0.011mmol, Bailingwei), 2- Dicyclohexylphosphine-2'-methylbiphenyl (4.4 mg, 0.011 mmol, Shanghai Shaoyuan), anhydrous potassium carbonate (16 mg, 0.011 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL) , microwave reaction at 100 °C for 1 hour, the reaction solution was concentrated under reduced pressure, and purified by thin layer chromatography with eluent system A to obtain the title compound 4c (10 mg), yield: 54.5%.

MS m/z (ESI): 485.2 [M+1].

the fourth step

( R )-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein oxazin-6-yl)-4-hydroxypiperidin-1-yl)ethanone 4

Compound 4c (10 mg, 20.6 μmol), tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (3 mg, 5 μmol, Shanghai Bide), phenylsilane (4.5 mg, 41.2 μmol, Titan) was dissolved in isopropanol (2 mL) and dichloromethane (0.2 mL), oxygen was replaced, and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to obtain the title compound 4 (1.2 mg), yield: 11.5%.

MS m/z (ESI): 503.2 [M+1].

¹ H NMR (500 MHz, CD ₃ OD): δ 8.53 (s, 1H), 7.61-7.58 (m, 1H), 7.46-7.44 (m, 1H), 7.43 (s, 1H), 7.30-7.24 (m, 1H), 7.19-6.90(q, 1H), 5.76-5.55(m, 1H), 4.66-4.49(m, 1H), 4.11(s, 3H), 3.91-3.90(m, 1H), 3.88-3.87( m, 1H), 3.21-3.20(m, 1H), 2.64(s, 3H), 2.62-2.52(m, 2H), 2.20(s, 3H), 1.86-1.76(m, 2H), 1.70(d, 3H).

Example 5

( R )-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein oxazin-6-yl)-4-hydroxypiperidin-1-yl)-2-methoxyethan-1-one 5

first step

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride 5b

Compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-5,6-dihydropyridine-1( 2H ) - 3-butyl carboxylate 5a (1 g, 3.23 mmol, Shanghai Bide) was dissolved in a 4N hydrochloric acid solution in 1,4-dioxane, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 5b (790 mg), yield: 99.4%, and the product was directly used in the next reaction without purification.

MS m/z (ESI): 210.1 [M+1].

second step

2-Methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro Pyridin-1( 2H )-yl)ethan-1-one 5c

Compound 5b (1.7 g, 6.92 mmol), methoxyacetic acid (805 mg, 8.93 mmol, Shanghai Shaoyuan) were dissolved in tetrahydrofuran (5 mL), followed by adding 2-(7-azobenzotriazole) -N , N , N , N -tetramethylurea hexafluorophosphate (4.63 g, 12.17 mmol) and N , N -diisopropylethylamine (2.63 g, 20.35 mmol) were reacted with stirring for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to obtain the title compound 5c (1.2 g), yield: 52.5%.

MS m/z (ESI): 282.0 [M+1].

third step

( R )-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein oxazin-6-yl)-4-hydroxypiperidin-1-yl)-2-methoxyethan-1-one 5

Using the third to fourth steps of the synthetic route in Example 4 , the third step raw material compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Cyclopentan-2-yl)-3,6-dihydropyridin-1( 2H )-yl)ethanone was replaced with compound 5c to obtain compound 5 (15 mg), yield: 22%.

MS m/z (ESI): 533.1 [M+1].

¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.51(s,1H), 7.59(t,1H), 7.43(t,1H), 7.34(s,1H), 7.17(t,1H), 7.00( t, 1H), 5.72(d, 1H), 4.47(s, 1H), 4.31(d, 1H), 4.20(s, 1H), 4.05(s, 3H), 3.83(dd, 1H), 3.63(t , 1H), 3.47(s, 3H), 3.23(t, 1H), 2.67(s, 3H), 2.64-2.50(m, 2H), 1.80(t, 2H), 1.69(d, 3H).

Example 6

( R )-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-4-hydroxy- N , N -dimethylcyclohexane-1-carboxamide 6

first step

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)cyclohex-3-enecarboxylic acid 6b

The compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)cyclohex-3-enecarboxylic acid methyl ester 6a (1 g, 3.76 mmol), lithium hydroxide monohydrate (631 mg, 15 mmol) were dissolved in a mixed solvent of 10 mL of tetrahydrofuran, 2 mL of water and 5 mL of methanol, stirred for 16 hours, added dropwise with 2N hydrochloric acid, adjusted to pH 5-6, and concentrated under reduced pressure to Drying gave the title compound 6b (1.8 g), which was taken to the next step without purification.

MS m/z (ESI): 251.1 [M-1].

second step

N , N -Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)cyclohex-3-enecarboxamide Amine 6c

Compound 6b (150 mg, 595 μmol) and 2M N , N -dimethylamine (595 μL, 1.2 mmol) were dissolved in N , N -dimethylformamide (2 mL), followed by N , N -diiso Propylethylamine (154 mg, 1.2 mmol) and 2-(7-azobenzotriazole) -N , N , N , N -tetramethylurea hexafluorophosphate (280 mg, 1.2 mmol) under nitrogen atmosphere React for 14 hours. The reaction solution was concentrated, and the residue was purified by column chromatography with eluent system A to obtain the title compound 6c (150 mg), yield: 90%.

MS m/z (ESI): 280.1 [M+1].

third step

( R )-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-4-hydroxy- N , N -dimethylcyclohexane-1-carboxamide 6

Using the synthetic route in Example 4 , the raw material compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)-3,6-dihydropyridin-1( 2H) -yl)ethanone was replaced with compound 6c to obtain compound 6 (3 mg), yield: 14.4%.

MS m/z (ESI): 531.1 [M+1].

¹ H NMR (400 MHz, CD ₃ OD): δ 8.41 (s, 1H), 7.60 (t, 1H), 7.46-7.43 (m, 2H), 7.20-7.14 (m, 1H), 7.02-6.92 (m, 1H), 5.74(q, 1H), 4.08(s, 3H), 3.16(s, 3H), 3.02-2.91(m, 6H), 2.69(s, 3H), 2.13-2.07(m, 3H), 1.82 -1.70(m, 6H).

Example 7

( S )-1-(4-(4-((( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1 -Methylphthalazin-6-yl)piperidin-1-yl)-2-hydroxypropan-1-one 7

first step

( R )-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-5,6-dihydropyridine-1( 2H )-carboxylate tert-butyl ester 7a

Compound 4b (35 mg, 0.088 mmol), compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6 - Dihydro- 2H -pyridine-1-carboxylate tert-butyl ester (42 mg, 0.132 mmol, Shanghai Bide), [1,1'-bis(diisopropylphosphine)ferrocene]dichloropalladium ( 10 mg, 0.017 mmol), anhydrous potassium carbonate (37 mg, 0.265 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), reacted at 110 °C for 4 hours, the reaction solution was concentrated under reduced pressure, and thin layer chromatography was used Purification with eluent system A gave the title compound 7a (45 mg), yield: 93.7%.

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

second step

( R )-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)piperidine-1-carboxylic acid tert-butyl ester 7b

Compound 7a (45 mg, 82 μmol) was dissolved in methanol (3 mL), palladium carbon (10%) (13 mg) was added, hydrogen was replaced, and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 7b (40 mg), yield: 88.6%.

MS m/z (ESI): 545.3 [M+1].

third step

( R )-N-(1-(3-(difluoromethyl)-2 - fluorophenyl)ethyl)amino)-6-methoxy-4-methyl-7-(piperidine-4 -yl)phthalazin-1-amine hydrochloride 7c

Compound 7b (40 mg, 0.073 mmol) was dissolved in a 4N hydrochloric acid solution in 1,4-dioxane, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 7c (35 mg), yield: 99.1%, and the product was directly used in the next reaction without purification.

MS m/z (ESI): 445.2 [M+1].

the fourth step

( S )-1-(4-(4-((( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1 -Methylphthalazin-6-yl)piperidin-1-yl)-2-hydroxypropan-1-one 7

Compound 7c (35mg, 0.072mmol), L -lactic acid (13mg, 0.145mmol, Shanghai Shaoyuan Reagent Co., Ltd.) were dissolved in N , N -dimethylformamide (2mL), followed by adding 2-(7- Azobenzotriazole) -N , N , N , N -tetramethylurea hexafluorophosphate (25mg, 0.109mmol) and N , N -diisopropylethylamine (46mg, 0.364mmol), stirred for reaction 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain the title compound 7 (12 mg), yield: 31.9%.

MS m/z (ESI): 517.2 [M+1].

¹ H NMR (500 MHz, CD ₃ OD): δ 8.27 (t, 1H), 7.56 (t, 1H), 7.44 (t, 1H), 7.32 (d, 1H), 7.20-7.10 (m, 1H), 5.74 (q, 1H), 4.77(d, 1H), 4.07(d, 2H), 3.52(d, 2H), 3.29(d, 4H), 2.91-2.83(m, 1H), 2.68(s, 2H), 2.00(d,3H), 1.88(s,2H), 1.69(d,3H), 1.37(d,3H).

Example 8

1-(( S )-3-((4-((( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy- 1-Methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 8

Using the synthetic route in Example 3 , the tenth step raw material compound ( R )-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride Substituted with compound ( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride, the title compound 8 (5 mg) was obtained, yield: 4.3%.

MS m/z (ESI): 489.2 [M+1].

¹ H NMR (500 MHz, CD ₃ OD): δ 7.93 (d, 1H), 7.58 (t, 1H), 7.48-7.40 (m, 2H), 7.18 (t, 1H), 5.71-5.66 (m, 1H) ,4.04-4.04(m,2H),3.89-3.82(m,2H),3.63-3.52(m,2H),2.70(s,1H),2.47-2.29(m,2H),2.24-2.15(m, 3H), 2.13-2.21 (m, 2H), 1.71 (d, 3H), 1.61 (d, 3H).

Example 9

( R )-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine- 6-yl)-4-hydroxycyclohexyl)(morpholinyl)methanone 9

Using the synthetic route in Example 6 , the second-step raw material compound N , N -dimethylamine was replaced with the compound morpholine to obtain compound 9 (10 mg), yield: 48.4%.

MS m/z (ESI): 573.1 [M+1].

¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.40 (s, 1H), 7.60 (t, 1H), 7.44 (t, 1H), 7.36 (s, 1H), 7.17 (t, 1H), 7.01 ( t, 1H), 5.77(q, 1H), 4.09(s, 3H), 3.69-3.61(m, 8H), 3.02-2.98(m, 1H), 2.90-2.81(m, 2H), 2.70(s, 3H), 2.58-2.53 (m, 2H), 2.23-2.17 (m, 2H), 1.76-1.70 (m, 2H), 1.68 (d, 3H).

Example 10

( R )-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein Azin-6-yl)-4-hydroxypiperidin-1-yl)-3-oxopropanenitrile 10

Using the synthetic route in Example 5 , the second step starting material compound methoxyacetic acid was replaced with compound cyanoacetic acid to obtain compound 10 (7 mg), yield: 48.2%.

MS m/z (ESI): 528.2 [M+1].

¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.55(s,1H), 7.62(t,1H), 7.47(t,1H), 7.39(s,1H), 7.20(t,1H), 7.02( t, 1H), 5.76(q, 1H), 4.65(s, 3H), 4.47-4.40(m, 2H), 4.36(s, 2H), 3.76-3.73(m, 2H), 2.69(s, 3H) , 2.29-2.24 (m, 2H), 1.84-1.80 (m, 2H), 1.71 (d, 3H).

Example 11

( R )-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine- 6-yl)oxy)tetrahydro- 2H -thiopyran 1,1-dioxide 11

Using the synthetic route of the first to seventh steps in Example 1 , the first step raw material compound ( 3R )-tetrahydrofuran-3-ol was replaced with the compound 4-hydroxytetrahydro- 2H -thiopyran 1,1 - Dioxide, the seventh step starting compound ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine hydrochloride is replaced by compound ( R )-1-(3 -(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride to obtain compound 11 (10 mg), yield: 5.8%.

MS m/z (ESI): 510.2 [M+1].

¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.01 (s, 1H), 7.57 (t, 1H), 7.44 (t, 1H), 7.39 (s, 1H), 7.17 (t, 1H), 7.01 ( t,1H),5.72(q,1H),5.06(tt,1H),4.08(s,3H),3.48(ddd,2H),3.14-3.05(m,2H),2.68(s,3H),2.62 -2.52(m, 2H), 2.48-2.38(m, 2H), 1.70(d, 3H).

Example 12

( R )-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-4-hydroxy-1-iminotetrahydro- 2H -thiopyran 1-oxide 12

first step

( R )-N-(1-(3-(difluoromethyl)-2 - fluorophenyl)ethyl)-7-(3,6-dihydro- 2H -thiopyran-4-yl )-6-methoxy-4-methylphthalazine-1-amine 12b

Compound 4b (82 mg, 124.3 μmol), compound 2-(3,6-dihydro- 2H -thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane 12a (42.2mg, 186.4μmol, Shanghai Bide), Tris(dibenzylideneacetone)dipalladium (29.6mg, 49.7μmol), Anhydrous potassium carbonate (68.7mg, 497.2μmol) ) was dissolved in 1,4-dioxane (2mL) and water (0.5mL), heated to 110°C for 8 hours, the reaction solution was concentrated under reduced pressure, and purified by column chromatography with eluent system A to obtain The title compound 12b (50 mg), yield: 87.5%.

MS m/z (ESI): 460.2 [M+1].

second step

4-(4-((( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-1-imino-1,2,3,6-tetrahydro-1λ ⁶ -thiopyran 1-oxide 12c

Compound 12b (100 mg, 217.6 μmol) was dissolved in 5 mL of ethanol, iodobenzene acetate (222 mg, 652.8 μmol) and ammonium acetate (67.1 mg, 870.4 μmol) were added, and the reaction was stirred for 3 hours. Purification by chromatography with eluent system A afforded the title compound 12c (37 mg), yield: 34.6%.

MS m/z (ESI): 491.1 [M+1].

third step

( R )-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-4-hydroxy-1-iminotetrahydro- 2H -thiopyran 1-oxide 12

Compound 12c (37 mg, 75.4 μmol), tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (22.8 mg, 37.7 μmol), phenylsilane (16.3 mg, 150.8 μmol) Dissolve in isopropanol (2 mL) and dichloromethane (0.2 mL), replace with oxygen, and stir the reaction for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to obtain the title compound 12 (6 mg), yield: 15.6%.

MS m/z (ESI): 509.2 [M+1].

¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.59(d,1H), 7.61(t,1H), 7.45(t,1H), 7.38(d,1H), 7.18(t,1H), 7.01( t, 1H), 5.75(q, 1H), 4.10(d, 3H), 3.74-3.61(m, 2H), 3.31-3.25(m, 2H), 3.19-3.08(m, 2H), 2.70(d, 3H), 2.05 (dt, 2H), 1.70 (d, 3H).

Example 13

( R )-1-(3-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methyl Phthazin-6-yl)oxy)azetidin-1-yl)ethan-1-one 13

first step

1-Acetylazetidine-3-yl 4-methylbenzenesulfonate 13b

Compound 1-(3-hydroxyazetidin-1-yl)ethanone 13a (10 g, 86.8 mmol, Shanghai Bide), 4-dimethylaminopyridine (534 mg, 4.3 mmol, Shanghai Shaoyuan), Triethylamine (17.5 g, 173 mmol) was dissolved in 200 mL of dichloromethane, 4-toluenesulfonyl chloride (24.8 g, 130.3 mmol) was added, and the reaction was stirred for 14 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to a column layer. Purification by analytical chromatography with eluent system C afforded the title compound 13b (15 g) in 64.1% yield.

MS m/z (ESI): 270.1 [M+1].

second step

( R )-7-(benzyloxy)-N-(1-(3-(difluoromethyl)-2 - fluorophenyl)ethyl)-6-methoxy-4-methylphthalazine- 1-amine 13c

Adopt the seventh step and tenth step of the synthetic route in the embodiment 3 , replace the seventh step raw material compound 3b with compound benzyl bromide, and the tenth step raw material compound ( R )-2-(3-(1-aminoethyl) ( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride , the title compound 13c (120 mg) was obtained, yield: 40.4%.

MS m/z (ESI): 468.2 [M+1].

third step

( R )-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazin-6-ol 13d

Compound 13c (120 mg, 256.7 μmol) was dissolved in methanol (10 mL), 10% palladium-carbon catalyst (wet) (30 mg) was added, hydrogen was replaced, and the reaction was stirred for 14 hours. The reaction solution was filtered through celite, and the crude compound 13d (80 mg) was obtained under reduced pressure. The yield was 82.5%, which was directly used in the next step without purification.

MS m/z (ESI): 378.2 [M+1].

the fourth step

( R )-1-(3-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methyl Phthazin-6-yl)oxy)azetidin-1-yl)ethan-1-one 13

Compound 13b (14.3 mg, 53 μmol), compound 13d (20 mg, 53 μmol), cesium carbonate (34.5 mg, 106 μmol), N , N -dimethylformamide (3 mL) were added to the reaction flask, and the temperature was raised to 70 °C and stirred 5 hours. The reaction solution was cooled, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to obtain the title compound 13 (6 mg), yield: 23.8%.

MS m/z (ESI): 475.2 [M+1].

¹ H NMR (500 MHz, methanol- d ₄ ): δ 7.58(d,2H), 7.44(t,1H), 7.38(s,1H), 7.18(t,1H), 7.01(t,1H), 5.73( q,1H),5.37-5.31(m,1H),4.77-4.61(m,1H),4.55(dd,1H),4.38(ddd,1H),4.16-4.08(m,1H),4.07(s , 3H), 2.68 (s, 3H), 1.97 (s, 3H), 1.71 (d, 3H).

Example 14

( S )-1-(4-(4-((( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1 -Methylphthalazin-6-yl)-4-hydroxypiperidin-1-yl)-2-hydroxypropan-1-one 14

Using the synthetic route in Example 5 , the second-step raw material compound methoxyacetic acid was replaced with compound L -lactic acid to obtain compound 14 (12 mg), yield: 9.6%.

MS m/z (ESI): 533.2 [M+1].

¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.52(d,1H), 7.60(t,1H), 7.44(t,1H), 7.36(s,1H), 7.19(t,1H), 7.06( d, 1H), 5.73(q, 1H), 4.06(d, 3H), 3.99(s, 1H), 3.67(d, 1H), 3.26(t, 2H), 2.69(s, 3H), 2.66-2.43 (m, 2H), 1.82 (q, 2H), 1.70 (d, 3H), 1.41 (dd, 3H), 1.32 (d, 1H).

Example 15

( R )-4-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy -1-Methylphthalazin-6-yl)oxy)tetrahydro- 2H -thiopyran 1,1-dioxide 15

Using the synthetic route in Example 3 , the first step starting compound 3a was replaced with the compound 4-hydroxytetrahydro- 2H -thiopyran 1,1-dioxide to obtain the title compound 15 (15 mg), yielding Rate: 19.3%.

MS m/z (ESI): 540.2 [M+1].

¹ H NMR (400 MHz, CD ₃ OD): δ 8.02 (s, 1H), 7.54 (t, 1H), 7.43-7.40 (m, 1H), 7.14 (t, 1H) 5.73 (q, 1H), 5.07- 5.06(m, 1H), 4.08-4.03(m, 5H), 3.52-3.47(m, 3H), 3.12-3.08(m, 2H), 2.69(s, 3H), 2.59-2.56(m, 2H), 2.44-2.42 (m, 2H), 1.70 (d, 3H).

Example 16

( R )-2,2-difluoro-2-(2-fluoro-3-(1-((15-methyl-2,3,5,6,8,9-hexahydro-[1,4, 7,10] Tetraoxanedodeco[2,3- g ]phthalazin-12-yl)amino)ethyl)phenyl)ethan-1-ol 16

first step

4-Methylphthalazine-1,6,7-triol hydrobromide 16a

Compound 3h (1 g, 4.84 mmol) was dissolved in 30 mL of hydrobromic acid solution, heated to 120° C. and reacted for 16 hours. After cooling to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure and dried in vacuo to obtain the crude title compound 16a (1.1 g). Yield: 83%.

MS m/z (ESI): 274.0 [M+1].

second step

15-Methyl-2,3,5,6,8,9-hexahydro-[1,4,7,10]tetraoxanedodecodo[2,3- g ]phthalazin-12-ol 16b

Compound 16a (130 mg, 476 μmol), compound triethylene glycol bis(p-toluenesulfonate) (261.9 mg, 571.2 μmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.), and anhydrous potassium carbonate (329 mg, 2.38 mmol) were dissolved in 10 mL N , N -dimethylformamide, stirred at 90°C for 2 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 16b (100 mg) as the product Rate: 68.5%.

MS m/z (ESI): 307.1 [M+1].

third step

12-Chloro-15-methyl-2,3,5,6,8,9-hexahydro-[1,4,7,10]tetraoxanedodecano[2,3- g ]phthalazine 16c

Compound 16b (100 mg, 326.4 μmol) was dissolved in 10 mL of phosphorus oxychloride, and the reaction was stirred at 120° C. for 3 hours. The reaction solution was concentrated under reduced pressure, poured into ice water, adjusted to neutral pH with saturated sodium bicarbonate, extracted with ethyl acetate (10 mL×2), combined with the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 16c ( 60 mg), yield: 56.5%.

MS m/z (ESI): 325.1 [M+1].

the fourth step

( R )-2,2-difluoro-2-(2-fluoro-3-(1-((15-methyl-2,3,5,6,8,9-hexahydro-[1,4, 7,10] Tetraoxanedodeco[2,3- g ]phthalazin-12-yl)amino)ethyl)phenyl)ethan-1-ol 16

Compound 16c (30 mg, 92.3 μmol), compound 2a (24.3 mg, 110.8 μmol), ammonium chloride (2.47 mg, 46.2 μmol) and n-butanol (1 mL) were mixed. The microwave was heated to 110°C and stirred for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain the title compound 16 (5 mg), yield: 10.6%.

MS m/z (ESI): 508.2 [M+1].

¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.02 (s, 1H), 7.56-7.53 (m, 2H), 7.44 (t, 1H), 7.16 (t, 1H), 5.74 (q, 1H), 4.43-4.42(m, 2H), 4.38-4.37(m, 2H), 4.17-4.07(m, 2H), 3.95-3.90(m, 4H), 3.80(s, 4H), 2.65(s, 3H), 1.70(d, 3H).

Example 17

( R )-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine- 6-yl)oxy)-1-iminotetrahydro- 2H -thiopyran 1-oxide 17

first step

( R )-N-(1-(3-(difluoromethyl)-2 - fluorophenyl)ethyl)-6-methoxy-4-methyl-7-((tetrahydro- 2H- Thiopyran-4-yl)oxy)phthalazin-1-amine 17b

Using the synthetic route in Example 3 , the first step raw material compound 3a was replaced with compound tetrahydro- 2H -thiopyran-4-ol 17a , and the tenth step raw material compound ( R )-2-(3- (1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride was replaced with compound ( R )-1-(3-(difluoromethyl)-2-fluorophenyl ) ethylamine hydrochloride to obtain the title compound 17b (100 mg), yield: 34%.

MS m/z (ESI): 478.2 [M+1].

second step

( R )-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine- 6-yl)oxy)-1-iminotetrahydro- 2H -thiopyran 1-oxide 17

Compound 17b (100 mg, 209.4 μmol) was dissolved in 5 mL of ethanol, iodobenzene acetate (214 mg, 629.2 μmol) and ammonium acetate (65 mg, 843.2 μmol) were added, and the reaction was carried out at room temperature for 3 hours. The obtained title compound 17 (8 mg) was purified by phase preparative chromatography, yield: 7.5%.

MS m/z (ESI): 509.1 [M+1].

¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.02-8.01(d,1H), 7.59-7.56(q,1H), 7.46-7.43(q,1H), 7.39(d,1H), 7.19-7.16 (q,1H), 7.12-6.90(q,1H), 5.74-5.70(t,1H), 5.08-5.06(m,1H), 4.08-4.07(d,3H), 3.57-3.47(m,2H) , 3.20-3.17(m, 2H), 2.68(s, 3H), 2.55-2.50(m, 2H), 2.45-2.39(m, 2H), 1.71-1.70(d, 3H).

Biological evaluation

Test Example 1 The compound of the present disclosure inhibits the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein

The following methods were used to determine the ability of compounds to inhibit the interaction between the KRAS protein isoforms G12D or G12V and the SOS1 protein. The experimental method is briefly described as follows:

1. Experimental materials and instruments

1) Biotin labeling kit (Dojindo, LK03)

2) GDP (SIGMA, G7127)

3) AlphaLISA Glutathione Acceptor Beads (PerkinElmer, AL109C)

4) AlphaScreen Streptavidin Donor Beads (PerkinElmer, 6760002S)

5) 384-well microplate (PerkinElmer, 6007290)

6) BSA (Shanghai Shenggong, A600332-0100)

7) Tween-20 (Diamond, A100777-0500)

8) GST-TEV-SOS1 (564-1049) (Via Biotechnology, SOS1-191010)

9) KRAS G12D, KRAS G12V (produced by Shanghai Panchao Biotechnology Co., Ltd.)

10) Phosphate Buffered Saline (PBS) PH7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320)

11) Multi-function microplate reader (PerkinElmer, Envision)

2. Experimental steps

Experiment preparation:

1) Prepare the experimental buffer before starting the experiment: 1 x PBS+0.1%BSA+0.05%Tween-20.

2) The KRAS G12D and KRAS-G12V proteins were biotin-labeled with a biotin labeling kit.

Experimental steps:

1) First, the biotin-labeled KRAS G12V or KRAS G12D protein was incubated with SOS1 protein (GST-TEV-SOS1 (564-1049) (Via Biotechnology, SOS1-191010)) and GDP at room temperature for use.

2) Mix AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads 1:1 to 40 μg/mL before use.

3) Compounds were prepared with experimental buffer to an initial concentration of 40 μM, 5-fold gradient dilution, and 10 gradient series concentration points.

4) In a 384-well microplate, add 10 μL of KRAS G12V or KRAS G12D protein, SOS1 and GDP mixture and 5 μL of the diluted compound to each well, and incubate at room temperature for 30 minutes in the dark.

5) Then add 5 μL of AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads mixture to each well, and incubate at room temperature for 60 minutes in the dark.

6) Read the fluorescence value on the multi-function microplate reader.

7) Calculate the _IC50 value of the compound with Graphpad Prism.

3. Experimental data

The compounds of the present disclosure inhibit the interaction ability between each subtype G12D or G12V of KRAS protein and SOS1 protein, and the measured _IC50 values are shown in Table 1.

Table 1 IC ₅₀ values of the compounds of the present disclosure for the ability to inhibit the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein

Conclusion: The disclosed compounds can well inhibit the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein.

Test Example 2 Biological evaluation of ERK phosphorylation inhibition in H358 cells

1. Test purpose

In this experiment, the inhibitory effect of the compounds on cellular ERK phosphorylation was detected, and the inhibitory effect of the disclosed compounds on KRAS targets (containing G12C mutation) was evaluated according to the IC ₅₀ size.

2. Experimental method

H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, H358 cells were seeded in a 96-well plate at a density of 25,000 cells/well in complete medium, with 190 μL of cell suspension per well, and placed in a 37°C, 5% CO ₂ cell incubator overnight. On the second day, 10 μL of the compound to be tested in a serial dilution prepared in complete medium was added to each well. The final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 10 μM, and a blank control containing 0.1% DMSO was set. Place in a 37°C, 5% CO ₂ cell incubator for 1 hour. One hour later, the 96-well cell culture plate was taken out, the medium was aspirated, and 200 μL of PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) was added to each well for washing. PBS was aspirated, 50 μL of lysis buffer (lysis buffer, Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) was added to each well, and the plate was placed on a shaker for 40 minutes at room temperature. After lysis, pipette and mix well, transfer 16 μL of lysate per well to two HTRF 96-well detection plates (Cisbio, 66PL96100), and then add 4 μL of premixed phospho-ERK1/2 antibody solution to the two plates. (Cisbio, 64AERPEG) or 4 μL of premixed total-ERK1/2 antibody solution (Cisbio, 64NRKPEG). The microplate was sealed with sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight at room temperature in the dark. On the third day, use a PHERAstar multi-plate reader (BMG Labtech, S/N 471-0361) to read the fluorescence values for excitation at 337 nm and emission at 665 nm and 620 nm.

3. Data analysis

_IC50 values of compound inhibitory activity were calculated according to compound concentration and pERK/total ERK ratio using Graphpad Prism software, and the results are shown in Table 2 below.

Table 2 ERK phosphorylation inhibitory activity data in H358 cells

Conclusion: The disclosed compounds have a good inhibitory effect on ERK phosphorylation in H358 cells.

Test Example 3 Biological evaluation of H358 cell proliferation inhibition

1. Test purpose

By testing the proliferation inhibitory effect of the disclosed compounds on H358 cells, the inhibitory effect of the disclosed compounds on KRAS targets (containing G12C mutation) was evaluated.

2. Experimental method

H358 cells (ATCC, CRL-5807) were cultured in complete medium ie RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, H358 cells were seeded on 96 low-adsorption plates (Corning, CLS7007-24EA) at a density of 1500 cells/well using complete medium, 90 μL of cell suspension per well, centrifuged at 2000 rpm for 5 minutes at room temperature and placed at 37°C , 5% CO ₂ cell incubator overnight. On the second day, 10 μL of the compound to be tested in a serial dilution prepared in complete medium was added to each well. The final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 10 μM, and a blank control containing 0.1% DMSO was set. Place in a cell incubator at 37°C, 5% CO ₂ for 120 hours. On the seventh day, take out the 96-well cell culture plate, add 50 μL of CellTiter-Glo® 3D Reagent (Promega, G9682) to each well, shake at room temperature for 25 minutes, mix by pipetting, remove 50 μL and transfer to a white impermeable bottom 96-well plate (PE, 6005290), the luminescence signal value was read using a multifunctional microplate reader (PerkinElmer, VICTOR 3).

3. Data analysis

The _IC50 values for the inhibitory activity of the compounds were calculated using Graphpad Prism software, and the results are shown in Table 3 below.

Table 3 H358 cell proliferation inhibitory activity data

Conclusion: The disclosed compounds have a good inhibitory effect on the proliferation of H358 cells.

Pharmacokinetic evaluation

Test Example 4 Pharmacokinetic testing of the compounds of the present disclosure

1. Abstract

Using LC/MS/MS method as a mouse test animal, the drug concentration in the plasma of mice at different times after intravenous injection of the compound of Example 1 was determined. To study the pharmacokinetic behavior of the disclosed compounds in mice, and to evaluate their pharmacokinetic characteristics.

2. Test plan

2.1 Test Drugs

Compound of Example 1.

2.2 Experimental animals

Eighteen healthy adult C57 mice, female, were purchased from Weitong Lihua Laboratory Animal Co., Ltd.

2.3 Drug preparation

Weigh a certain amount of medicine, add 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a liquid.

2.4 Administration

After overnight fasting, the mice were administered intravenously at a dose of 1 mg/kg and an administration volume of 0.1 mL/10 g.

3. Operation

Mice were intravenously injected with the compound of Example 1, and 0.1 mL of blood was collected before administration and at 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24.0 hours after administration, and placed in an EDTA-K2 anticoagulation test tube In the medium, centrifuge at 4°C and 10,000 rpm for 1 minute, separate the plasma within 1 hour, store it at -20°C for testing, and operate under ice bath conditions during the process of blood collection and centrifugation.

Determination of the content of the test compound in mouse plasma after intravenous administration of the drug: take 25 μL of mouse plasma at each time after administration, add 50 μL of internal standard solution (100ng/ml camptothecin), 200 μL of acetonitrile, and vortex for 5 minutes , centrifuged for 15 minutes (3600 rpm), and 0.1 μL of the supernatant was taken from the plasma samples for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

Table 4 Pharmacokinetic parameters of compounds of the present disclosure

Conclusion: The compounds of the present disclosure have good drug metabolism and have obvious pharmacokinetic advantages.

Test Example 5 Inhibitory effect of compounds of the present disclosure on human liver microsomal CYP450 enzymes

The inhibitory effect of the compounds of the present disclosure on human liver microsomal CYP450 enzymes was determined by the following experimental methods:

1. Experimental materials and instruments

1) Phosphate buffer solution (20×PBS, purchased from the manufacturer)

2) NADPH (ACROS, A2646-71-1)

3) Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 905002, Donor35)

4) ABI QTrap 4000 LC/MS (AB Sciex)

5) ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent, USA)

6) CYP probe substrate (phenacetin, diclofenac, (S)-mephenytoin, dextromethorphan, testosterone)

Purchased from Sigma-Aldrich.

2. Experimental steps

2.1. Solution preparation

1) Preparation of 100mM Phosphate Buffered Saline (PBS)

Take 50 mL of PBS solution with a concentration of 2000 mM, add 950 mL of ultrapure water, dilute to 1000 mL, and mix evenly to obtain a PBS solution with pH 7.4, which is stored in a refrigerator at 4°C (the shelf life is 6 months).

2) Preparation of NADPH solution

Precisely weigh an appropriate amount of NADPH powder, add PBS buffer solution to dissolve, and prepare a solution with a concentration of 5 mM, for later use (prepared and used now).

3) Preparation of liver microsome solution

Take an appropriate amount of human liver microsome stock solution (concentration of 20 mg/mL) and dilute it to 0.5 mg/mL microsomal solution with 15 mM MgCl ₂ solution for later use (prepared for current use).

₄ ) Preparation of MgCl solution

Weigh an appropriate amount of MgCl ₂ powder, prepare a 300 mM stock solution with PBS solution, and store it in a 4°C refrigerator for later use. Precisely weigh an appropriate amount of the solution, add 100 mM PBS solution and dilute it into a 15 mM working solution, and that's it (prepared and used now).

5) Preparation of test compound solutions

a. Precisely weigh an appropriate amount of the test compound standard, add DMSO to prepare a stock solution with a concentration of 30 mM, and store in a refrigerator at 4°C.

b. Precisely pipette an appropriate amount of the stock solution, add an appropriate amount of DMSO solution to dilute to a series of solution I with a concentration of 10, 3, 1, 0.3, 0.03 and 0.003 mM. Precisely pipet an appropriate amount of the above series of solution I, add an appropriate amount of acetonitrile to dilute to a series of solution II with a concentration of 3, 1, 0.3, 0.1, 0.03, 0.003, 0.0003 mM. Precisely pipette an appropriate amount of the above-mentioned series of solutions II, add an appropriate amount of PBS to dilute to a working solution with a concentration of 150, 50, 15, 5, 1.5, 0.15, 0.015 μM, and set aside.

6) Selection of CYP probe substrates and selective inhibitors

a. Preparation of probe substrate stock solution: Weigh an appropriate amount of each probe substrate, add DMSO to prepare a stock solution, and its concentration is shown in Table 5 below.

b. Preparation of probe substrate working solution: Precisely pipette an appropriate amount of probe substrate stock solution, add PBS solution and dilute 200 times to obtain probe substrate working solution, the concentration of which is shown in Table 5 below.

table 5

2.2. Incubation of liver microsomes and sample preparation

The protein concentration, substrate and inhibitor concentration in the reaction system are shown in Table 6-1 and Table 6-2 below.

Table 6-1

Table 6-2

2.3. Operation process

1) Precisely pipette 40 μL of human liver microsome solution (0.25 mg/mL), 20 μL of probe substrate solution and 20 μL of test compound solution into a 96-well plate, and pre-incubate in a 37°C water bath for 5 minutes.

2) Take out after 5 minutes of pre-incubation, add 20 μL of NADPH solution with a concentration of 5 mM, start the reaction, and incubate in a 37° C. water bath for 30 minutes. Each sample was replicated in duplicate.

3) After the incubation, add 250 μL of acetonitrile solution containing internal standard to stop the reaction, shake at 800 rpm for 10 minutes, centrifuge at 3700 rpm for 10 minutes, and precisely pipette 100 μL of the supernatant. Add 80 μL of distilled water to dilute, and shake at 800 rpm for 10 minutes, and aspirate the supernatant for LC-MS/MS analysis.

The values were calculated by Graphpad Prism to obtain the drug effects on human liver microsomes CYP1A2 phenacetin O -deethylation, CYP2C9 diclofenac 4'-hydroxylation, CYP2C19 mephentoin 4'-hydroxylation, CYP2D6 dextromethorphan _IC50 values for the metabolic inhibition of Fen O -demethylation and CYP3A4T testosterone 6β-hydroxylation are shown in Table 7.

Table 7 _IC50 values (in μM) of compounds of the present disclosure for inhibition of human liver microsomal CYP1A2 phenacetin, CYP2C9 diclofenac, CYP2C19 mephenytoin, CYP2D6 dextromethorphan and CYP3A4T testosterone metabolic sites

Conclusion: The compounds of the present disclosure do not occur in the concentration range of 30 μM based on CYP1A2 phenacetin O -deethylation, CYP2C9 diclofenac 4'-hydroxylation, CYP2C19 mephentoin 4'-hydroxylation, CYP2D6 dextromethorphan Metabolic drug interactions at the Fen O -demethylation and testosterone 6β-hydroxylation metabolic sites of CYP3A4T.

Test Example 6 Effects of the disclosed compounds on hERG potassium channel

1. Test purpose

The blocking effect of the compounds of the present disclosure on hERG potassium current was tested on stable cell lines transfected with hERG potassium channel using manual patch clamp technique

2. Test method

2.1. Cell culture

The cells used in this experiment were CHO cell lines (provided by Sophion Bioscience, Denmark) transfected with hERG cDNA and stably expressing hERG channels, and the cell passages were P9&P11. Cells were grown in medium (all from Invitrogen) containing the following components: Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 μg/mL hygromycin B, 100 μg/mL Geneticin.

CHO hERG cells were grown in petri dishes containing the above medium and cultured at 37°C in an incubator containing 5% CO ₂ . Twenty-four to 48 hours before electrophysiological experiments, CHO hERG cells were transferred to circular glass slides placed in petri dishes and grown in the same medium and culture conditions as above. The density of CHO hERG cells on each circular slide needs to be such that the vast majority of cells are independent and single.

2.2. Experimental solution

Table 8 Composition of intracellular fluid and extracellular fluid

Table 9 Reagent Details

2.3. Electrophysiological recording system

In this experiment, a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) was used for whole-cell current recording. The round slides with CHO hERG cells grown on the surface were placed in the electrophysiological recording chamber under an inverted microscope. The recording tank was continuously perfused with extracellular fluid (approximately 1 ml per minute). experiment procedure The conventional whole-cell patch-clamp current recording technique was used. Unless otherwise specified, the experiments were carried out at normal room temperature (~25°C). Cells were clamped at -80mV. Cells were depolarized to +20 mV to activate the hERG potassium channel, and then clamped to -50 mV for 5 s to abolish inactivation and generate tail currents. The peak tail current was used as a numerical value for the magnitude of hERG current. After the hERG potassium current recorded in the above steps reaches a stable state under the continuous extracellular fluid perfusion in the recording tank, the drug to be tested can be superimposed and perfused until the inhibitory effect of the drug on the hERG current reaches a stable state. Generally, the recent coincidence of three consecutive current recording lines is used as the criterion for judging whether it is in a stable state. After reaching a steady state, the cells were perfused with extracellular fluid until the hERG current returned to the level before the drug was added. One or more drugs, or multiple concentrations of the same drug, can be tested on a cell, but need to be flushed with extracellular fluid between drugs. Cisapride (cisapride, purchased from Sigma) was used in the experiments as a positive control to ensure that the cells used were of normal quality.

2.4. Test steps

In order to obtain the _IC50 of the compounds, the following concentrations (30, 10, 3, 1, 0.3 and 0.1 [mu]M) were selected for testing. Stock solutions of 10, 3, 1, 0.3 and 0.1 mM were serially diluted with DMSO and the final [mu]M test concentrations were diluted with extracellular fluid prior to the assay. The final concentration of DMSO in each concentration compound solution was 0.1%. The positive control Cisapride (cisapride) was tested at a concentration of 0.1 μM. All compound solutions were routinely sonicated and shaken for 5 to 10 minutes to ensure complete compound dissolution.

The experimental data were analyzed by HEKA Patchmaster (V2x73.2), Microsoft Excel and data analysis software provided by Graphpad Prism 5.0.

2.5. Test results

The blocking effect of the compounds of the present disclosure on hERG potassium current was determined by the above test, and the measured IC ₅₀ values are shown in Table 10.

Table 10 _IC50 of the blocking effect of the compounds of the present disclosure on hERG potassium channel

Conclusion: The disclosed compounds have weak inhibitory effect on hERG and can reduce the side effects caused by the hERG pathway.

Claims (21)

A compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable of salt,

in, Ring A is aryl or heteroaryl; G is CR ⁵ or N atom; R ⁰ is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , cycloalkane oxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro , cyano, -S(O) ₂ R ⁹ , -C(O)R ¹⁰ , cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with one or more substituents; R ¹ is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl; R ^is selected from halogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein each of the alkyl, cycloalkyl and heterocyclyl is independently optionally selected Substituted from one or more substituents of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro and cyano; ^R is selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro substituted with one or more substituents in radical, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ⁴ is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and -(CH ₂ ) _p NR ⁶ R ⁷ ; R and R ⁵ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -(CH ₂ ) _p NR ⁶ R ⁷ , cyano and nitro, wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, substituted with one or more substituents in nitro and -(CH ₂ ) _q NR ¹¹ R ¹² ; R ⁸ are the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , nitro, hydroxyl, hydroxyalkyl, -S(O) ₂ alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkane group, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, -( CH ₂ ) _q NR ¹¹ R ¹² , substituted with one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl; R ⁹ and R ¹⁰ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH ₂ ) _q NR ¹¹ R ¹² , a cycloalkyl group and a heterocyclyl group, wherein the alkane , cycloalkyl, and heterocyclyl are each independently optionally selected from hydroxy, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amine, and nitro one or more of the substituents in the substituted; R ⁶ , R ⁷ , R ¹¹ and R ¹² are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; p and q are the same or different, each independently selected from 0, 1 and 2; n is selected from 0, 1, 2, 3, 4 and 5. The compound represented by the general formula (I) according to claim 1 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof, wherein R ^is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH ₂ ) _pNR6R7 , ^{cycloalkyloxy} , ^{heterocyclyloxy} , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyloxy, heterocyclyloxy , cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine substituted with one or more substituents in group, nitro, cyano, -S(O) ₂ R ⁹ , -C(O)R ¹⁰ , cycloalkyl, heterocyclyl, aryl and heteroaryl; R ⁹ and R ¹⁰ are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH ₂ ) _q NR ¹¹ R ¹² , a cycloalkyl group and a heterocyclic group; R ⁶ , R ⁷ , R ¹¹ , R ¹² , p and q are as defined in claim 1 . The compound represented by the general formula (I) according to claim 1 or 2 or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein G is CR ⁵ , and R ⁵ is as defined in claim 1 or 2; preferably, G is CH. The compound represented by the general formula (I) according to any one of claims 1 to 3 or its tautomer, meso, racemate, enantiomer, and diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, non- an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein rings A, R, R ⁰ , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ and n are as defined in claim 1 or 2. The compound represented by general formula (I) according to any one of claims 1 to 4 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is selected from cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the ring Alkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more selected from hydroxy and -C(O)R ¹⁰ substituted; R ¹⁰ is alkyl. The compound represented by the general formula (I) according to any one of claims 1 to 5 or its tautomer, meso, racemate, enantiomer, and diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is tetrahydrofuranyloxy or piperidinyl, each of which is independently optionally -C(O)R ¹⁰ and/or hydroxy substituted, wherein R ¹⁰ is C _1-6 alkyl. The compound represented by the general formula (I) according to any one of claims 1 to 6 or its tautomer, meso, racemate, enantiomer, and diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, non- an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein R, R ⁰ , R ¹ , R ⁴ , R ⁵ , R ⁸ and n are as defined in claim 1 or 2. The compound represented by the general formula (I) according to any one of claims 1 to 7 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁸ are the same or different, each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, amino, -(CH ₂ ) _p NR ⁶ R ⁷ and C _1-6 hydroxyalkyl, wherein the C _1-6 haloalkyl is optionally substituted by one or more hydroxyl groups; R ⁶ and R ⁷ are hydrogen atoms or C _1-6 alkanes base, p is 0, 1 or 2. The compound represented by the general formula (I) according to any one of claims 1 to 8 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from a hydrogen atom, a C _1-6 alkyl group and a halogen; preferably, R ¹ is a methyl group. The compound represented by the general formula (I) according to any one of claims 1, 2, 3, 5, 6, 8 and 9 or its tautomer, meso, racemate, para Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ² is a hydrogen atom or a C _1-6 alkyl group; preferably, R ² is a methyl group. The compound represented by the general formula (I) according to any one of claims 1 to 6 and 8 to 10 or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom or a C _1-6 alkyl group; preferably, R ³ is a hydrogen atom. The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom. The compound represented by the general formula (I) according to any one of claims 1 to 12 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom. The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is C _1-6 alkoxy. A compound selected from any of the following structures:

A compound represented by general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable of salt,

wherein X is halogen; R ⁰ is selected from bromine, iodine, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxyl, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , Heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently any is optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C ( O) substituted with one or more substituents in R ¹⁰ , cycloalkyl, heterocyclyl, aryl and heteroaryl; R ¹ is selected from bromine, iodine, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl; R is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycle aryloxy, aryloxy, heteroaryloxy, -(CH ₂ ) _p NR ⁶ R ⁷ , cyano and nitro, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, nitro, and -(CH ₂ ) _q NR ¹¹ R ¹² substituted by one or more of the substituents in; G, R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , p, q and R ⁴ are as defined in claim 1 or 2. A compound selected from any of the following structures:

A kind of compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable A method of using the salt, the method comprising the steps of:

The compound of general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IB) or its salt is reacted to obtain the compound of the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its in the form of a mixture, or a pharmaceutically acceptable salt thereof, Wherein, X is halogen; Rings A, G, R, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁸ and n are as defined in claim 1 or 2. A pharmaceutical composition containing a therapeutically effective amount of the compound described in any one of claims 1 to 15 or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. A compound as claimed in any one of claims 1 to 15 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, Use of a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 19 in the preparation of a medicament for inhibiting SOS1. A compound as claimed in any one of claims 1 to 15 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 19 in preparation for the treatment and/or prophylaxis of cancer, inflammation, RAS disease, Noonan syndrome (NS), Noonan syndrome with multiple spots Capillary Malformation-Arteriovenous Malformation Syndrome (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facial-Skin Syndrome (CFC), Leggers Syndrome, Hereditary Gingival Fibrosis The use in the drug of neoplastic disease or other proliferative diseases, preferably cancer; the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, Gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminoma, Testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and Glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or Acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably multiple myeloma; the osteoma is preferably osteochondroma; the liver cancer is preferably hepatocellular carcinoma; the The colorectal cancer is preferably colon cancer or rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma.