CN115244058A

CN115244058A - Pyrimidobicyclo derivatives, preparation method thereof and application thereof in medicines

Info

Publication number: CN115244058A
Application number: CN202180019688.6A
Authority: CN
Inventors: 李心; 蔡国栋; 冯斌强; 张喆; 白昌; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-04-08
Filing date: 2021-04-08
Publication date: 2022-10-25
Also published as: WO2021203768A1; TW202144338A

Abstract

The present disclosure relates to pyrimido-bicyclic derivatives, methods for their preparation, and their use in medicine. In particular, the disclosure relates to pyrimido-bicyclic derivatives represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and a use thereof as a therapeutic agent, in particular a use thereof as an SOS1 inhibitor and a use thereof in preparing a medicament for treating a condition or disorder ameliorated by the inhibition of SOS 1.

Description

Pyrimidobicyclo derivatives, preparation method thereof and application thereof in medicines

Technical Field

The disclosure belongs to the field of medicine, and relates to a pyrimido-bicyclic derivative shown as a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and an application of the derivative as a therapeutic agent, in particular to an application of the derivative as an SOS1 inhibitor and an application of the derivative in preparation of a medicament for treating a condition or disorder improved by inhibition of SOS1.

Background

RAS is one of the most mutation-rate oncogenes in tumors, and about 30% of human malignancies are associated with mutations in the RAS gene. The RAS family includes KRAS, NRAS and HRAS, with KRAS mutations being most common, accounting for approximately 85%. After KRAS is activated, it regulates and controls multiple functions such as cell proliferation, survival, migration and metabolism through a plurality of downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM 1-RAc. After KRAS gene mutation, the protein is continuously activated, resulting in continuous activation of downstream signaling pathways to promote tumorigenesis.

KRAS protein is considered as an unforgeable drug target for a long time because the surface of the KRAS protein lacks small molecule binding sites in the traditional sense and has ultrahigh affinity with guanylic acid and is extremely difficult to inhibit. However, based on the importance and prevalence of abnormal activation of KRAS in cancer progression, KRAS has been and remains a very interesting target for drug development. The current drug development thinking aiming at inhibiting the KRAS pathway mainly has the following aspects:

1) The small molecule covalent inhibitor developed for KRAS G12C can irreversibly lock the G12C mutant in an inactivated state, and clinical phase I data of advanced and mirati companies show unusual effects at present. However, the mutation of KRAS G12C is only one of many mutations, and other important mutants such as G12V, G12D, G12S, G12A, G13V/D and the like still lack effective drugs.

2) Finding other sites on KRAS that can target more mutants, mainly for binding to downstream effector molecules/protein molecule activation-related sites, is currently in preclinical stage, IC for activity inhibition ₅₀ Commonly in micromolar grades.

3) For the inhibition of KRAS downstream signal protein, for example, for the development of inhibitors such as RAF, MEK, ERK, etc., the single use and multiple effects are not good clinically at present.

4) And (3) inhibiting KRAS upstream pathway, such as SHP2 inhibitor.

5) Aiming at the modification and positioning of KRAS, the membrane positioning of KRAS is blocked by farnesyl transferase and the like so as to achieve the effect of inhibiting the KRAS.

6) The expression of KRAS was knocked down by the method of RNAi.

In general, there is currently a lack of broad spectrum KRAS inhibitors other than KRAS G12C inhibitors that are effective against a variety of mutations. And the small-molecule inhibitor for selectively inhibiting SOS1, namely guanine nucleotide exchange factor (GEF) can block the activation of KRAS by interfering the RAS-SOS1 interaction, so that the aim of inhibiting the activity of KRAS in a broad spectrum can be fulfilled.

The KARS protein is a small GTPase (small GTPase) that switches intracellularly between an inactive state (bound to Guanosine Diphosphate (GDP)) and an active state (bound to Guanosine Triphosphate (GTP)). This conversion is regulated by guanine nucleotide exchange factor (GEF) and Gtpase Activator Protein (GAP). There are three major groups of GEFs of KRAS, namely SOS (seven less son) 1&2, ras-GRF and Ras-GRP, of which the latter two are expressed only in neurons and leukocytes, and only SOS is widely expressed in various tissues and is considered to play a dominant role in RAS activation. Since SOS1 is expressed in a higher amount than SOS2 and has a higher activity than SOS2, SOS1 is mainly studied at present. The specific activation pathways of SOS1 for KRAS protein are as follows: after upstream signals (such as growth factors) activate membrane surface receptors, SOS1 is activated through SHP2-Grb2, and SOS1 is combined with KRAS, and through causing a series of conformational changes, the KRAS is catalyzed to be dissociated from GDP and then combined with GTP to form active KRAS-GTP.

Relevant patents currently disclosed are WO2003082830A1, WO2018115380A1, WO2019201848A1, WO 20120069660 A1, WO1997003069A1, WO2019052046A1, CN105384745A, WO2019067543A1, US20010031760A1, WO9802434A1 and the like.

Disclosure of Invention

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

wherein:

y is- (OCH) ₂ CH ₂ ) _y -, where O side is attached to Z and C side is attached to O;

z is- (CR) ^m R ⁿ ) _z -or- (CH) ₂ ) _v C(O)NR ⁰ (CH ₂ ) _w -；

T is- (OCH) ₂ CH ₂ ) _t -, where O side is attached to Z and C side is attached to O;

R ^m and R ⁿ The same or different, each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl; or

R ^m 、R ⁿ Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, which may optionally be substituted by one or more R ⁵ Substitution;

ring a is aryl or heteroaryl;

G ¹ and G ² Selected from nitrogen atoms or carbon atoms;

R ⁰ selected from the group consisting of hydrogen, alkyl, haloalkyl or hydroxyalkyl, wherein said alkyl, haloalkyl or hydroxyalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, haloalkoxy, amino, nitro and cyano;

R ¹ selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, and cycloalkyl;

R ² selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl, and heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, and cyano;

R ³ selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ the same or different, each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and-NR ⁶ R ⁷ ；

R ⁵ The same or different, each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -NR ⁶ R ⁷ Cyano and nitro, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and-NR ⁶ R ⁷ Is substituted with one or more substituents of (1);

R ⁸ identical or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, -NR ⁶ R ⁷ Nitro, hydroxy, hydroxyalkyl, -S (O) ₂ Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁶ and R ⁷ The same or different, each independently selected from hydrogen, halogen, alkylAlkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

z is 2,3, 4 or 5;

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

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

t is 0, 1,2,3, 4 or 5; and the sum of y and t is not more than 5;

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

q is 0, 1 or 2;

n is 0, 1,2,3, 4 or 5.

The present disclosure provides a compound represented by general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

z is- (CH) ₂ ) _z -or- (CH) ₂ ) _v C(O)NR ⁰ (CH ₂ ) _w -；

ring a is aryl or heteroaryl;

G ¹ and G ² Selected from nitrogen atoms or carbon atoms;

R ⁰ selected from the group consisting of hydrogen, alkyl, haloalkyl or hydroxyalkyl, wherein said alkyl, haloalkyl or hydroxyalkyl is optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, alkoxy,One or more substituents of haloalkoxy, amino, nitro and cyano;

R ² selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro and cyano;

R ⁵ The same or different, each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -NR ⁶ R ⁷ Cyano and nitro, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and-NR ⁶ R ⁷ Is substituted with one or more substituents of (a);

R ⁸ are the same or different and are each independently selected from halogenElements, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, -NR ⁶ R ⁷ Nitro, hydroxy, hydroxyalkyl, -S (O) ₂ Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁶ and R ⁷ The same or different, each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

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

z is 2,3, 4 or 5;

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

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

t is 0, 1,2,3, 4 or 5; and the sum of y and t is not more than 5;

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

q is 0, 1 or 2;

n is 0, 1,2,3, 4 or 5.

In some preferred embodiments of the present disclosure, a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ^m And R ⁿ Together with the carbon atom to which they are attached form a 3-6 membered heterocyclic group, preferably a 5 membered heterocyclic group.

In some preferred embodiments of the present disclosure, a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is- (CH) ₂ ) _z -or (a)CH ₂ ) _v C(O)NR ⁰ (CH ₂ ) _w -；R ⁰ Z, v and w are as defined in formula (I); preferably, Z is- (CH) ₂ ) ₂ -, and z is 2 or 4.

In some preferred embodiments of the present disclosure, a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Is selected from

Wherein m is 1,2,3, 4 or 5, j is 0, 1,2 or 3, k is 0, 1,2,3 or 4 ⁰ As defined in formula (I).

In some preferred embodiments of the present disclosure, a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein m is 1,2,3, 4 or 5;

rings A, G ¹ 、G ² 、R ¹ -R ⁵ 、R ⁸ P, q and n are as defined in formula (I).

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G ¹ Is a carbon atom.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G ² Is a carbon atom.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G ¹ And G ² Is a carbon atom.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is C _6-10 Aryl, preferably phenyl or

More preferably phenyl.

In some preferred embodiments of the present disclosure, a compound represented by formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein Z is- (CH) ₂ ) _z -；

z is 2 or 4;

y is 0, 1,2 or 3;

t is 0, 1,2 or 3; and the sum of y and t is not more than 3;

R ¹ 、R ² 、R ⁸ and n is as defined in formula (I) or (II).

In some preferred embodiments of the present disclosure, a compound of formula (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Is selected from

Wherein m is 1,2,3, 4 or 5, j is 0, 1,2 or 3, k is 0, 1,2,3 or 4 ⁰ As defined in general formula (III) or (III-1).

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, or derivative thereofIn the form of a isomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁸ Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano, -NR ⁶ R ⁷ Hydroxy and C _1-6 Hydroxyalkyl radical, wherein said C _1-6 Alkyl and C _1-6 Haloalkyl being optionally selected from hydroxy, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano and C _1-6 Substituted by one or more substituents of hydroxyalkyl, R ⁶ And R ⁷ Are the same or different and are each independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group;

preferably, R ⁸ Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, -NR ⁶ R ⁷ And C _1-6 Hydroxyalkyl, wherein said C _1-6 Haloalkyl is optionally substituted with one or more hydroxy groups; r is ⁶ And R ⁷ Selected from hydrogen and C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁸ Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano, -NR ⁶ R ⁷ Hydroxy and C _1-6 Hydroxyalkyl radical, wherein said C _1-6 Alkyl is optionally selected from hydroxy, halogen, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, cyano and C _1-6 One or more substitutions in hydroxyalkylIs substituted by radicals R ⁶ And R ⁷ Are the same or different and are each independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Is composed of

R ⁸ Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, -NR ⁶ R ⁷ And C _1-6 Hydroxyalkyl radical, wherein said C _1-6 Haloalkyl is optionally substituted with one or more hydroxy; r is ⁶ And R ⁷ Selected from hydrogen and C _1-6 An alkyl group; preferably, R ⁸ Are the same or different and are each independently selected from amino, halogen and C _1-6 Haloalkyl, said C _1-6 Haloalkyl may be optionally substituted with hydroxy.

Is composed of

R ⁸ Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, -NR ⁶ R ⁷ And C _1-6 Hydroxyalkyl, wherein said C _1-6 Alkyl optionally substituted with one or more hydroxy and halogen; r ⁶ And R ⁷ Selected from hydrogen and C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, a compound of formula (I), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁰ Selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; hydrogen is preferred.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ¹ Selected from hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl and cyano; preferably, R ¹ Selected from hydrogen, C _1-6 Alkyl and halogen; more preferably methyl.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ² Selected from hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl and cyano; preferably, R ² Selected from hydrogen and C _1-6 An alkyl group; more preferably methyl.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II) or a tautomer, mesoIn the form of a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ Selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ³ Selected from hydrogen and C _1-6 An alkyl group; more preferably hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁴ Are the same or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ⁴ Is hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁵ Are the same or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, amino and cyano; preferably, R ⁵ Are the same or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, R ⁵ Is hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (I), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein y is 0, 1,2 or 3, preferably 1.

In some preferred embodiments of the present disclosure, a compound of formula (I), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein z is 2,4 or 5, preferably 2.

In some preferred embodiments of the present disclosure, a compound of formula (I), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein v is 1.

In some preferred embodiments of the present disclosure, a compound of formula (I), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein w is 2.

In some preferred embodiments of the present disclosure, a compound of formula (I), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t is 0, 1,2 or 3, preferably 1.

In some preferred embodiments of the present disclosure, a compound of formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or 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 of formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or 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 of formula (I), (II), (III), or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 2.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 1,2,3, or 4, preferably 3 or 4, more preferably 3.

In some preferred embodiments of the present disclosure, a compound of formula (I), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein j is 1.

In some preferred embodiments of the present disclosure, a compound of formula (I), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein k is 1.

In some preferred embodiments of the present disclosure, a compound of formula (I), (III) or (III-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is- (CH) ₂ ) _i -(CR ^m R ⁿ )-(CH ₂ ) _r -，R ^m 、R ⁿ Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, which may optionally be substituted by one or more R ⁵ Substitution; i is 0, 1,2 or 3, R is 0, 1,2 or 3, R5 is as defined in formula (I), (III) or (III-1); preferably, R ^m 、R ⁿ Together with the carbon atom to which they are attached form a 3-8 membered heterocyclyl, optionally substituted by halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, -NR ⁶ R ⁷ And one or more radicals of cyano, R ⁶ And R ⁷ Same or different, each independently selected from hydrogen, C _1-6 Alkyl and C _1-6 Haloalkyl, i is 1 or2, r is 1 or 2.

In some preferred embodiments of the present disclosure, a compound of formula (II)Or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is phenyl or

m is 1,2,3 or 4; r ⁸ Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, -NR ⁶ R ⁷ And C _1-6 Hydroxyalkyl radical, wherein said C _1-6 Alkyl optionally substituted with one or more hydroxy and halogen; r is ⁶ And R ⁷ Selected from hydrogen and C _1-6 An alkyl group; r ¹ Selected from hydrogen, C _1-6 Alkyl and halogen; r is ² Selected from hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl and cyano; r ³ Selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; r is ⁴ Are the same or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; r is ⁵ Are the same or different and are each independently selected from hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; g ¹ And G ² Is a carbon atom; p is 0 or 1; q is 0 or I; n is 2.

Is selected from

Wherein m is 1,2,3 or 4, j is 1 or2, k is 0, 1 or 2; r is ⁰ Selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; r ⁸ Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, -NR ⁶ R ⁷ And C _1-6 Hydroxyalkyl, wherein said C _1-6 Alkyl optionally substituted with one or more hydroxy and halogen; r is ⁶ And R ⁷ Selected from hydrogen or C _1-6 An alkyl group; r is ¹ Selected from hydrogen, C _1-6 Alkyl and halogen; r is ² Selected from hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl and cyano; n is 2.

In some preferred embodiments of the present disclosure, a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

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

ring A, Y, Z, T, G ¹ 、G ² 、R ¹ -R ⁵ 、R ⁸ P and q are as defined in formula (I).

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

another aspect of the present disclosure relates to a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ^w is hydroxy or halogen, preferably hydroxy or chloro;

R ¹ selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, and cycloalkyl;

z is- (CH) ₂ ) _z -or- (CH) ₂ ) _v C(O)NR ⁰ (CH ₂ ) _w -；

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

t is 0, 1,2,3, 4 or 5; and the sum of y and t is not 0;

G ¹ 、G ² 、R ⁴ -R ⁵ 、R ⁰ z, v, w, p and q are as defined in formula (I).

Another aspect of the present disclosure relates to a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

R ^w is hydroxy or halogen, preferably hydroxy or chloro;

z is- (CR) ^m R ⁿ ) _z -or- (CH) ₂ ) _v C(O)NR ⁰ (CH ₂ ) _w -；

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

t is 0, 1,2,3, 4 or 5; and the sum of y and t is not 0;

G ¹ 、G ² 、R ⁴ -R ⁵ 、R ⁰ 、R ^m 、R ⁿ z, v, w, p and qAs defined in formula (I).

Another aspect of the present disclosure relates to a compound of formula (IVA) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein;

n is 1,2,3, 4 or 5; rings A, Y, Z, T, G ¹ 、G ² 、R ¹ -R ⁵ 、R ⁸ P and q are as defined in formula (I).

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

another aspect of the present disclosure relates to a process for preparing a compound of formula (I) or (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

reacting the general formula (IA) with the general formula (IB) or a salt thereof (preferably hydrochloride) to obtain a compound of the general formula (I), or subjecting the compound of the general formula (IVA) to a reduction reaction to obtain a compound of the general formula (IV);

wherein:

R ^w is hydroxy or halogen, preferably hydroxy or chlorine; in the general formula (I), n is 0, 1,2,3, 4 or 5;

in the general formula (IV), n is 1,2,3, 4 or 5;

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (II), (III-1) or table a of the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present disclosure further relates to the use of a compound of formula (I), (II), (III-1) or table a, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the inhibition of SOS1.

The present disclosure further relates to the use of a compound of general formula (I), (II), (III-1) or table a or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of SOS 1-mediated diseases, preferably selected from the group consisting of cancer, inflammation, RAS disease, noonan Syndrome (NS), noonan syndrome with erythema (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), costello Syndrome (CS), cardiac-facial-skin syndrome (CFC), louse syndrome, hereditary gingival fibromatosis, or other proliferative diseases.

The present disclosure further relates to the use of a compound of general formula (I), (II), (III-1) or table a or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of cancer, inflammation, RAS disease, noonan Syndrome (NS), noonan syndrome with erythema (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), costello Syndrome (CS), heart-plane-skin syndrome (CFC), lounge syndrome, hereditary gingival fibromatosis, 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, colon cancer, rectal cancer, gallbladder cancer, cholangiocarcinoma, chorioepithelioma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, head and neck squamous cell carcinoma, uterine cancer, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, osteosarcoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF 1); the lung cancer is preferably non-small cell lung cancer, and is further preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myelogenous leukemia; the lymphoma is preferably diffuse large B cell lymphoma; the myeloma is preferably multiple myeloma; the liver cancer is preferably hepatocellular carcinoma; the osteoma is preferably osteochondroma.

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 formula (I), (II), (III-1), or Table A, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or 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 a compound of formula (I), (II), (III-1), or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, preferably selected from the group consisting of cancer, inflammation, RAS disease, noonan Syndrome (NS), noonan syndrome with erythema (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), costello Syndrome (CS), heart-face-skin syndrome (CFC), regis syndrome, hereditary gingival fibromatosis, or other proliferative diseases.

The present disclosure also relates to a method of treating and/or preventing cancer, inflammation, PAS disease, noonan Syndrome (NS), noonan syndrome with erythema (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), costerlos Syndrome (CS), cardiac-facial-skin syndrome (CFC), louses syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III-1) or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein said cancer is preferably selected from the group consisting of melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, colon cancer, rectal cancer, gallbladder cancer, cholangiocarcinoma, chorioepithelioma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, head and neck squamous cell carcinoma, uterine cancer, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, osteosarcoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the PAS disease is preferably neurofibromatosis type 1 (NF 1); the lung cancer is preferably non-small cell lung cancer, and is further preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myelogenous leukemia; the lymphoma is preferably diffuse large B cell lymphoma; the myeloma is preferably multiple myeloma; the liver cancer is preferably hepatocellular carcinoma; the osteoma is preferably osteochondroma.

The present disclosure further relates to a compound of general formula (I), (II), (III-1) or table a or a tautomer, mesomer, racemate, enantiomer, diastereomer, or 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-1) or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an SOS1 inhibitor.

The present disclosure also relates to compounds of general formula (I), (II), (III-1) or table a or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of SOS 1-mediated diseases, preferably selected from the group consisting of cancer, inflammation, RAS disease, noonan Syndrome (NS), noonan syndrome with erythema (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), costello Syndrome (CS), cardiac-facial-skin syndrome (CFC), regus syndrome, hereditary gingival fibromatosis, or other proliferative diseases.

The present disclosure also relates to compounds of general formula (I), (II), (III-1) or table a or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of cancer, inflammation, RAS disease, noonan Syndrome (NS), noonan syndrome with erythema (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), costello Syndrome (CS), heart-plane-skin syndrome (CFC), louses syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably for use in the treatment and/or prevention of cancer; wherein said cancer is preferably selected from the group consisting of melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, colon cancer, rectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, head and neck squamous cell carcinoma, uterine cancer, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, osteosarcoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF 1); the lung cancer is preferably non-small cell lung cancer, and is further preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myelogenous leukemia; the lymphoma is preferably diffuse large B cell lymphoma; the myeloma is preferably multiple myeloma; the liver cancer is preferably hepatocellular carcinoma; the osteoma is preferably osteochondroma.

The cancer described in the present disclosure is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, colon cancer, rectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, head and neck squamous cell cancer, uterine cancer, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma bone tumor, osteosarcoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF 1); the lung cancer is preferably non-small cell lung cancer, and is further preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myelogenous leukemia; the lymphoma is preferably diffuse large B cell lymphoma; the myeloma is preferably multiple myeloma; the liver cancer is preferably hepatocellular carcinoma; the osteoma is preferably osteochondroma.

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

As a general guide, the active compound is preferably administered in a unit dose, or in a manner such that the patient can self-administer the compound in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. Suitable unit doses may be from 0.1 to 1000mg.

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

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

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

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. 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.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifiers 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 colorant and an antioxidant.

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

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to 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 parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and 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 water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

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

Detailed description of the invention

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 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. <xnotran> , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- , ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- , ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- , </xnotran> 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted and when substituted, the substituents may be substituted at any available point of attachment, preferably the substituents are independently optionally one or more substituents selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

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

The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from the group consisting of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing a 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 substituents independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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 (e.g., 3, 4, 5,6, 7, and 8) carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

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

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

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, according to the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the rings attached to the parent structure are cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like; indanyl, tetrahydronaphthyl are preferred.

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

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

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O) ₂ <xnotran> , -O-O-, -O-S- -S-S- , . </xnotran> Preferably 3 to 12 (e.g., 3, 4, 5,6, 7,8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably 3 to 8 (e.g., 3, 4, 5,6, 7 and 8) ring atoms, of which 1-3 (e.g., 1,2 and 3) are heteroatoms; more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group having a single ring atom (S) common between the rings (referred to as spiro atoms), wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O) ₂ The remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group. Non-limiting examples of spiro heterocyclyl groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and one or more of the rings may contain one or more double bonds in which one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O) ₂ The remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to 5 to 14 membered polycyclic heterocyclic group wherein any two rings share two atoms not directly attached, which may contain one or more double bonds wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O) ₂ The remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

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

and so on.

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

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

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

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 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 membered (e.g. 5,6, 7,8, 9 or 10 membered), more preferably 5 or 6 membered, e.g. 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 joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

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

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

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 the alkoxy group is as defined above.

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" or "oxo" means = O.

The term "carbonyl" refers to C = O.

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

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

The compounds of the present disclosure may also comprise isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure,except for replacing hydrogen by "deuterium" or "tritium", or by ¹⁸ F-fluorine labeling: ( ¹⁸ Isotope of F) instead of fluorine, or with ¹¹ C-、 ¹³ C-, or ¹⁴ C-enriched carbon (C) ¹¹ C-、 ¹³ C-, or ¹⁴ C-carbon labeling; ¹¹ C-、 ¹³ c-, or ¹⁴ C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.

The disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. The person skilled in the art is able to synthesize the compounds of formula (I) in deuterated form with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like. Deuterations can generally retain comparable activity to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

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

"substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, of the hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

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

By "pharmaceutically acceptable salt" is meant a salt of a compound of the present disclosure which is safe and effective for use in the body of a mammal and which has the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic and achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "pharmaceutically acceptable" as used herein means that the compounds, materials, compositions, and/or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and 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 meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the following technical solutions are adopted in the present disclosure.

Scheme one

The preparation method of the compound shown in the general formula (I) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form or the pharmaceutically acceptable salt form comprises the following steps:

reacting general formula (IA) with general formula (IB) or a salt thereof (preferably a hydrochloride salt) under basic conditions, optionally in the presence of a condensing agent, to give a compound of general formula (I);

wherein: r ^w Is hydroxy or halogen, preferably hydroxy or chlorine;

rings A, Y, Z, T, G ¹ 、G ² 、R ¹ -R ⁵ 、R ⁸ P, q and n are as defined in formula (I).

Scheme two

The preparation method of the compound shown in the general formula (II) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form thereof, or the pharmaceutically acceptable salt form thereof comprises the following steps:

reacting formula (IIA) with formula (IB) or a salt thereof (preferably the hydrochloride salt) under basic conditions, optionally in the presence of a condensing agent, to give a compound of formula (II);

wherein: r ^w Is hydroxy or halogen, preferably hydroxy or chlorine;

rings A, G ¹ 、G ² 、R ¹ -R ⁵ 、R ⁸ P, q and n are as defined in formula (II).

Scheme three

The preparation method of the compound shown in the general formula (III) or (III-1) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form thereof, or the pharmaceutically acceptable salt form thereof comprises the following steps:

reacting general formula (IIIA) with general formula (IIIB) or a salt thereof (preferably hydrochloride) under basic conditions, optionally in the presence of a condensing agent, to give a compound of general formula (III); or

Reacting the general formula (IIIA-1) with the general formula (IIIB-1) or a salt thereof (preferably hydrochloride) under alkaline conditions, optionally in the presence of a condensing agent, to obtain a compound of the general formula (III-1);

wherein: r is ^w Is hydroxy or halogen, preferably hydroxy or chlorine;

Y、Z、T、R ¹ -R ² 、R ⁸ and n is as defined in formula (III) or (III-1).

Scheme four

The preparation method of the compound shown in the general formula (IV) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof comprises the following steps:

carrying out a reduction reaction on the compound of the general formula (IVA) in the presence of a catalyst to obtain a compound of a general formula (IV);

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

ring A, Y, Z, T, G ¹ 、G ² 、R ¹ -R ⁵ 、R ⁸ P and q are as defined in formula (IV).

The reagents in schemes one through three that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, or 1, 8-diazabicycloundecene-7-ene, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, or cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; n, N-diisopropylethylamine or 1, 8-diazabicycloundecen-7-ene is preferred.

The condensing agent described in the first to third embodiments includes, but is not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N ' -dicyclohexylcarbodiimide, N, N ' -diisopropylcarbodiimide, O-benzotriazol-N, N, N ', N ' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ' -tetramethyluronium hexafluorophosphate, 2- (7-azobenzotriazol) -N, N ' -tetramethyluronium hexafluorophosphate, 2- (7-oxybenzotriazolium) -N, N ' -tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate; benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate is preferred.

Catalysts used in scheme four include, but are not limited to, palladium on carbon, iron powder, raney nickel, zinc powder, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1' -bis (dibenzylphosphine) dichloropentairon palladium, tris (dibenzylideneacetone) dipalladium, and the like, preferably palladium on 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 including, but not limited to: acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, ethylene glycol dimethyl ether, water, N-dimethylacetamide or N, N-dimethylformamide, and a mixture thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

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

MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: thermo, model: finnigan LCQ advantage MAX).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, agilent HPLC 1200VWD and Waters HPLC e2695-2489 liquid chromatographs.

Chiral HPLC analytical determination Agilent 1260 DAD HPLC was used.

High performance liquid preparative chromatography using Waters 2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson-281 preparative chromatographs.

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

CombiFlash flash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).

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

Silica gel column chromatography generally uses 200-300 mesh silica gel from Futai Huanghai silica gel as a carrier.

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

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a Parr 3916EKX type hydrogenator and a Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenator.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

A CEM Discover-S908860 type microwave reactor was used for the microwave reaction.

In the examples, the solution means an aqueous solution without specific indication.

In the examples, the reaction temperature is, unless otherwise specified, room temperature and is 20 ℃ to 30 ℃.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: in the petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7, 8, 10, 11, 13, 14, 16, 17-octahydro- [1,4,7, 10, 13] pentaoxacyclopenta [2,3-g ] quinazolin-4-amine 1

First step of

16-Nitro-2, 3,5,6,8,9, 11, 12-octahydrobenzo [ b ] [1,4,7, 10, 13] pentaoxacyclopentadecane-15-carboxylic acid methyl ester 1b

Methyl 2,3,5,6,8,9, 11, 12-octahydrobenzo [ b ] [1,4,7, 10, 13] pentaoxacyclopentadecano-15-carboxylate 1a (1.2 g,3.67mmol, prepared by the well-known method "Journal of the American Chemical Society,2017, 139, (36), 12338-1234" was dissolved in 4mL of acetic acid, cooled to 0 deg.C, 3mL of concentrated nitric acid and 2mL of concentrated sulfuric acid were added, and the reaction was stirred for 3 hours. The reaction was poured into ice water, filtered, and concentrated under reduced pressure to give the title compound 1b (1 g), yield: 73 percent.

MS m/z(ESI)：372.1[M+1]。

Second step of

16-amino-2, 3,5,6,8,9, 11, 12-octahydrobenzo [ b ] [1,4,7, 10, 13] pentaoxacyclopentadecane-15-carboxylic acid methyl ester 1c

Compound 1b (1g, 2.69mmol) was dissolved in 50mL of methanol, 10% wet palladium on carbon (350 mg) was added, and after the addition, hydrogen was substituted three times, stirred for 14 hours, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to give crude title compound 1c (919 mg), which was used directly in the next reaction.

MS m/z(ESI)：342.1[M+1]。

The third step

2-methyl-7, 8, 10, 11, 13, 14, 16, 17-octahydro- [1,4,7, 10, 13] pentaoxacyclopenta [2,3-g ] quinazolin-4-ol 1d

Compound 1c (500mg, 1.46mmol) was dissolved in 2mL of acetonitrile, 0.5mL of methanesulfonic acid was added, and the reaction was stirred at 100 ℃ for 14 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title compound 1d (130 mg), yield: 25 percent.

MS m/z(ESI)：351.1[M+1]。

The fourth step

4-chloro-2-methyl-7, 8, 10, 11, 13, 14, 16, 17-octahydro- [1,4,7, 10, 13] pentaoxacyclopenta [2,3-g ] quinazoline 1e

The crude compound 1d (200mg, 0.57mmol) was dissolved in 3mL of phosphorus oxychloride and the reaction was stirred at 100 ℃ for 3 hours after the addition. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title compound 1e (130 mg), yield: 61 percent.

MS m/z(ESI)：369.1[M+1]。

The fifth step

Compound 1e (60mg, 0.16mmol), compound (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine hydrochloride 1f (55mg, 0.16mmol, prepared by the method disclosed in example B-5 on page 141 of the specification of patent application "EP 2018086197") was dissolved in 2mL of DMF, N-diisopropylethylamine (84mg, 0.65mmol) was added, and after the addition, the reaction was stirred at 90 ℃ for 14 hours. The reaction solution was concentrated under reduced pressure, and the obtained title compound 1 (1 mg) was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm: mobile phase: water (10 mmol/L ammonium hydrogencarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min), yield: 1 percent.

MS m/z(ESI)：522.2[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.73(s，1H)，7.61(t，1H)，7.48(t，1H)，7.24(t，1H)，7.16-6.89(m，2H)，5.87(q，1H)，4.26(ddd，4H)，3.96(ddd，4H)，3.81-3.71(m，8H)，2.42(s，3H)，1.70(d，3H)。

Example 2

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7, 8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododeca [2,3-g ] quinazolin-4-amine 2

First step of

2-Methylquinazoline-4, 6, 7-trisphenol hydrobromide 2b

6, 7-dimethoxy-2-methylquinazoline-4-ol 2a (700mg, 3.18mmol, jiangsu Aikang biomedical research and development Co., ltd.) was dissolved in 10mL of an aqueous hydrobromic acid solution (40%) and reacted at 120 ℃ with stirring for 14 hours. Cooled to room temperature, aqueous ammonia was added dropwise to the reaction mixture to pH7, filtered, and the filtrate was concentrated under reduced pressure to give the title crude compound 2b (1.1 g).

MS m/z(ESI)：193.2[M+1]。

Second step of

2-methyl-7, 8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododeca [2,3-g ] quinazolin-4-ol 2d

Compound 2b (400mg, 1.13mmol), compound triethylene glycol di (p-toluenesulfonate) 2c (518mg, 1.13mmol, shanghai bei pharma science co., ltd.), anhydrous potassium carbonate (936mg, 6.77mmol) were dissolved in 4ml of n, n-dimethylformamide, stirred at 90 ℃ for 14 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using developer system a to give the title compound 2d (30 mg), yield: 8 percent.

MS m/z(ESI)：307.1[M+1]。

The third step

Compound 2d (30mg, 0.09mmol), compound 1f (26mg, 0.11mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (43mg, 0.09mmol), 1, 8-diazabicycloundec-7-ene (14mg, 0.09mmol) were dissolved in 2mL of N, N-dimethylformamide, stirred at room temperature for 10 minutes, and then stirred at 60 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained title compound 2 (2 mg) was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min), yield: 4 percent.

MS m/z(ESI)：478.2[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.92(s，1H)，7.58(t，1H)，7.46(t，1H)，7.21(t，1H)，7.16-6.86(m，2H)，5.82(q，1H)，4.28(dt，4H)，3.87(dt，4H)，3.77(d，4H)，2.39(s， 3H)，1.66(d，3H)。

Example 3

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7, 8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododeca [2,3-g ] quinazolin-4-amine 3

First step of

(R) -6, 7-dimethoxy-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine 3c

The compound 4-chloro-6,7-dimethoxy-2-methyl quinazoline 3a (50mg, 0.21mmol, shanghaibei pharmaceutical science Co., ltd.) and the compound (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamine hydrochloride 3B (68mg, 0.25mmol, prepared by the method disclosed in example B-6a on page 89 of the specification in patent application "CN 110167928A") were dissolved in 2mL of DMF, N-diisopropylethylamine (63mg, 0.62mmol) was added thereto, and the reaction was stirred at 90 ℃ for 14 hours after completion of the addition. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title compound 3c (50 mg), yield: 50 percent.

MS m/z(ESI)：437.3[M+1]。

Second step of

(R) -2-methyl-4- ((1- (3-nitro-5-trifluoromethyl) phenyl) ethyl) amino) quinazoline-6, 7-diol 3d

Compound 3c (300mg, 0.68mmol) was dissolved in 6mL dichloromethane, boron tribromide (5 mL,17% in dichloromethane, echiei (shanghai) chemical development limited) was added under ice-bath, the reaction was stirred for 14 hours, quenched with methanol, washed with water (3 mL × 2), concentrated under reduced pressure by organic phase, and purified by column chromatography with developer system a to give the title compound 3d (130 mg), yield: 46 percent.

MS m/z(ESI)：409.1[M+1]。

The third step

(R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododeca [2,3-g ] quinazolin-4-amine 3e

Compound 3d (20mg, 0.05mmol), compound 2c (24mg, 0.05mmol, from Shanghai Biao pharmaceutical science Co., ltd.), and anhydrous potassium carbonate (20mg, 0.14mmol) were dissolved in 2mL of N, N-dimethylformamide, and reacted for 14 hours with stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title compound 3e (10 mg), yield: 39 percent.

The fourth step

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7, 8, 10, 11, 13, 14-hexa-oxo- [1,4,7, 10] tetraoxacyclododeca [2,3-g ] quinazolin-4-amine 3

Crude compound 3e (10mg, 0.02mmol) was dissolved in 5mL of methanol, 10% wet palladium on charcoal (10 mg) was added, and after the addition, hydrogen substitution was performed three times, stirring was performed for 14 hours, filtration was performed under reduced pressure, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give title compound 3 (5 mg), yield: and 53 percent.

MS m/z(ESI)：493.2[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.89(d，1H)，7.10(s，1H)，6.97(d，2H)，6.80(s，1H)，5.60(q，1H)，4.27(dt，4H)，4.00-3.81(m，4H)，3.77(s，4H)，2.45(d，3H)，1.62(d，3H)。

Example 4

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7, 8, 10, 11, 13, 14, 16, 17-octahydro- [1,4,7, 10, 13] pentaoxacyclopenta [2,3-g ] quinazolin-4-amine 4

First step of

(R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7,8, 10, 11, 13, 14, 16, 17-octahydro- [1,4,7, 10, 13] pentaoxacyclopenta [2,3-g ] quinazolin-4-amine 4b

Compound 3d (30mg, 0.07mmol), compound tetraethyleneglycol di-p-toluenesulfonate 4a (55 mg,0.11mmol, prepared by a known method "Bioorganic and Medicinal Chemistry,2007, 15 (14), 4841-4856"), and anhydrous potassium carbonate (50mg, 0.36mmol) were dissolved in 4mL of N, N-dimethylformamide and reacted with stirring for 14 hours. The reaction mixture was concentrated under reduced pressure, 2mL of water was added, extraction was performed with ethyl acetate (3 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to give the crude title compound 4b (40 mg) which was used directly in the next reaction.

Second step of

The crude compound 4b (40mg, 0.07mmol) was dissolved in 10mL of methanol, 10% wet palladium on charcoal (40 mg) was added, after which hydrogen was substituted three times, stirred for 14 hours, filtered under reduced pressure, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give the title compound 4 (12 mg), yield: 31%.

MS m/z(ESI)：537.2[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.64(d，1H)，6.98(d，3H)，6.80(d，1H)，5.61(q，1H)，4.22(dt，4H)，3.98-3.88(m，4H)，3.74(dd，8H)，2.45(d，3H)，1.63(dd，3H)。

Example 5

(R) -2, 2-difluoro-2- (2-fluoro-3- (1- ((2-methyl-7, 8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododeca [2,3-g ] quinazolin-4-yl) amino) ethyl) phenyl) ethan-1-ol 5

First step of

(R) -2, 2-difluoro-2- (2-fluoro-3- (1- ((2-methyl-7, 8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododeca [2,3-g ] quinazolin-4-yl) amino) ethyl) phenyl) ethanol 5

Compound 2d (50mg, 0.11mmol), compound (R) -2- (3- (1-ethylamine) -2-fluorophenyl) -2, 2-difluoroethanolate hydrochloride 5a (42mg, 0.14mmol, prepared using the method disclosed in example B-5 on page 105 of the specification in the patent application "US 2019194192"), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (93mg, 0.21mmol), 1, 8-diazabicycloundecan-7-ene (37mg, 0.24mmol) were dissolved in 2mL of N, N-dimethylformamide, stirred at room temperature for 10 minutes, and then stirred at 60 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give title compound 5 (7 mg), yield: 8 percent.

MS m/z(ESI)：508.3[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.95(s，1H)，7.63-7.54(m，1H)，7.49-7.40(m，1H)，7.20(t，1H)，7.09(s，1H)，5.86(q，1H)，4.28(dt，4H)，4.03(td，2H)，3.91(t，2H)，3.87-3.82(m，2H)，3.81-3.73(m，4H)，2.43(s，3H)，1.67(d，3H)。

Example 6

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7, 8, 10, 11, 12, 13, 15, 16-octahydro- [1,4,7, 10] tetraoxacyclotetradeca [5,6-g ] quinazolin-4-amine 6

First step of

(butane-1, 4-diylbis (oxy)) bis (ethane-2, 1-diyl) bis (4-methylbenzenesulfonic acid) 6b

2,2' - (butane-1, 4-diylbis (oxy)) diethanol 6a (2.5 g,14.02mmol, prepared by the well-known method "Angewandte Chemie-International Edition,2015, 54, (12), 3763-3767 Angewaw.chem., 2015, 127 (12), 3834-3838") was dissolved in 50mL of dichloromethane, and potassium hydroxide (8g, 142.58mmol) was added in an ice bath and stirred for 14 hours. Filtration, addition of 20mL of water to the filtrate, concentration of the organic phase under reduced pressure, and purification of the resulting residue by thin layer chromatography using developer system C gave the title compound 6b (2 g), yield: 29 percent.

MS m/z(ESI)：487.0[M+1]。

Second step of

2-methyl-7, 8, 10, 11, 12, 13, 15, 16-octahydro- [1,4,7, 10] tetraoxacyclotetradeco [5,6-g ] quinazolin-4-ol 6c

Compound 2b (150mg, 0.78mmol), compound 6b (455mg, 0.94mmol), anhydrous potassium carbonate (431mg, 3.12mmol) were dissolved in 6ml of n, n-dimethylformamide, stirred at 90 ℃ for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using developer system a to give the title compound 6c (80 mg), yield: 30 percent.

MS m/z(ESI)：335.0[M+1]。

The third step

Compound 6c (50mg, 0.15mmol), compound (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine hydrochloride 1f (40mg, 0.18mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (85mg, 0.19mmol), and 1, 8-diazabicycloundec-7-ene (45mg, 0.29mmol) were dissolved in 2mL of N, N-dimethylformamide, stirred at room temperature for 10 minutes, and then stirred at 60 ℃ for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give title compound 6 (15 mg), yield: 20 percent.

MS m/z(ESI)：506.1[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.70(s，1H)，7.59(t，1H)，7.46(t，1H)，7.21(t，1H)，7.16-6.86(m，2H)，5.83(q，1H)，4.34-4.17(m，4H)，3.94-3.83(m，4H)，3.78(dt，4H)，2.38(s，3H)，1.72(q，4H)，1.68(d，3H)。

Example 7

(R) -2, 2-difluoro-2- (2-fluoro-3- (1- ((2-methyl-7, 8, 10, 11, 13, 14, 16, 17-octahydro- [1,4,7, 10, 13] pentaoxacyclopenta [2,3-g ] quinazolin-4-yl) amino) ethyl) phenyl) ethan-1-ol 7

First step of

Compound 1d (80mg, 0.29mmol), compound 5a (65mg, 0.25mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (161mg, 0.36mmol), 1, 8-diazabicycloundecen-7-ene (69mg, 0.45mmol) were dissolved in 2mL of N, N-dimethylformamide, stirred at room temperature for 10 minutes, and then stirred at 60 ℃ for reaction for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm: mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give title compound 7 (17 mg), yield: 13 percent.

MS m/z(ESI)：552.1[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.67(s，1H)，7.57(t，1H)，7.49-7.39(m，1H)，7.18(t，1H)，6.98(s，1H)，5.84(q，1H)，4.23(ddd，4H)，4.03(td，2H)，3.98-3.87(m，4H)，3.75(dq，8H)，2.39(s，3H)，1.67(d，3H)。

Example 8

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7, 8, 10, 11-tetrahydro- [1,4,7] trioxabicyclo [2,3-g ] quinazolin-4-amine 8

First step of

(R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7,8, 10, 11-tetrahydro- [1,4,7] trioxabicyclo [2,3-g ] quinazolin-4-amine 8b

Compound 3d (65mg, 0.16mmol), compound diethylene glycol bis-p-benzenesulfonate 8a (68mg, 0.16mmol, han hong Kogyo technology and technology Co., ltd., shanghai), and anhydrous potassium carbonate (110mg, 0.8mmol) were dissolved in 4mL of N, N-dimethylformamide and reacted for 14 hours with stirring. The reaction mixture was concentrated under reduced pressure, 2mL of water was added, extracted with ethyl acetate (3 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 8b (70 mg), yield: 91 percent.

MS m/z(ESI)：479.1[M+1]。

Second step of

The crude compound 8b (70mg, 0.15mmol) was dissolved in 10mL of methanol, 10% wet palladium on charcoal (40 mg) was added, after which hydrogen was substituted three times, stirred for 14 hours, filtered under reduced pressure, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give the title compound 8 (5 mg), yield: 7.6 percent.

MS m/z(ESI)：449.1[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.93(d，1H)，7.14(d，1H)，6.99(s，1H)，6.95(s，1H)，6.80(s，1H)，5.58(d，1H)，4.70-4.49(m，2H)，4.36(t，2H)，3.93(d，4H)，2.43(d，3H)，1.61(dd，3H)。

Example 9

((R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7, 8, 10, 11-tetrahydro- [1,4,7] trioxabicyclo [2,3-g ] quinazolin-4-amine 9

First step of

2-methyl-7, 8, 10, 11-tetrahydro- [1,4,7] trioxabicyclo [2,3-g ] quinazolin-4-ol 9a

The compound 2b (100mg, 0.52mmol), the compound diethylene glycol bis-p-benzenesulfonate 8a (259mg, 0.62mmol, han hong Kong Biotechnology medicine, inc., shanghai), and anhydrous potassium carbonate (216mg, 1.6 mmol) were dissolved in 10mL NN-dimethylformamide and stirred at 80 deg.C for 2 hours. The reaction solution was concentrated under reduced pressure, 2mL of water was added, extracted with ethyl acetate (3 mL × 3), concentrated under reduced pressure of the organic phase, and the resulting residue was purified by thin layer chromatography with developer system C to give the title compound 9a (40 mg), yield: 29.3 percent.

MS m/z(ESI)：263.1[M+1]。

Second step of

Compound 9a (40mg, 0.15mmol), compound 1f (40mg, 0.18mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (81mg, 0.18mmol), and 1, 8-diazabicycloundecen-7-ene (35mg, 0.23mmol) were dissolved in 2mL of N, N-dimethylformamide, stirred at room temperature for 10 minutes, and then stirred at 60 ℃ for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give title compound 9 (5 mg), yield: 7.6 percent.

MS m/z(ESI)：434.1[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.96(s，1H)，7.57(t，1H)，7.45(t，1H)，7.21(t，1H)，7，7.19-6.89(m，2H)，5.83-5.79(m，1H)，4.59-4.57(m，2H)，4.38-4.37(m，2H)，3.93(d，4H)，2.36(d，3H)，1.61(dd，3H)。

Example 10

(R) -2, 2-difluoro-2- (2-fluoro-3- (1- ((2-methyl-7, 8, 10, 11-tetrahydro- [1,4,7] trioxabicyclo [2,3-g ] quinazolin-4-yl) amino) ethyl) phenyl) ethan-1-ol 10

First step of

Compound 9a (30mg, 0.11mmol), compound 5a (30mg, 0.12mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (61mg, 0.14mmol), 1, 8-diazabicycloundecen-7-ene (58mg, 0.23mmol) were dissolved in 2mL of N, N-dimethylformamide, stirred at room temperature for 10 minutes, and then stirred at 60 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium hydrogencarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give the title compound 10 (11 mg), yield: 20.7 percent.

MS m/z(ESI)：464.0[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.98(s，1H)，7.59-7.56(m，1H)，7.48-7.45(m， 1H)，7.22-7.19(m，1H)，7.16(s，1H)，5.87(q，1H)，4.88-4.60(m，2H)，4.41-4.39(m，2H)，4.10-3.96(m，3H)，3.94(s，3H)，2.41(s，3H)，1.68(d，3H)。

Example 11

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7, 8-dihydro- [1,4] dioxa-do [2,3-g ] quinazolin-4-amine 11

First step of

(R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7, 8-dihydro- [1,4] dioxa-do [2,3-g ] quinazolin-4-amine 11b

Compound 3d (350mg, 0.86mmol), compound 1, 2-dibromoethane 11a (68mg, 0.16mmol, han hong Kong Biotechnology medicine, inc., shanghai), and cesium carbonate (838mg, 2.57mmol) were dissolved in 10mL of N, N-dimethylformamide and reacted at 80 ℃ with stirring for 16 hours. The reaction mixture was concentrated under reduced pressure, 2mL of water was added, extracted with ethyl acetate (3 mL. Times.3), the organic phase was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography using eluent system A to give the title compound 11b (60 mg) in 16% yield.

MS m/z(ESI)：435.1[M+1]。

Second step of

Compound 11b (60mg, 0.14mmol) was dissolved in 5mL of methanol, 10% palladium on charcoal (10 mg) was added, after addition, hydrogen was replaced three times, stirring was carried out for 16 hours, filtration was carried out under reduced pressure, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm: mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give title compound 11 (55 mg), yield: and 90 percent.

MS m/z(ESI)：405.1[M+1]。

¹ H NMR(400MHz，DMSO-d ₆ )：δ7.90(d，1H)，7.81(s，1H)，6.97(s，1H)，6.87(s，1H)，6.83(s，1H)，6.67(s，1H)，5.53(s，3H)，4.34(s，4H)，2.33(s，3H)，1.51(d，3H)。

Example 12

(R) -4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-10, 11-dihydro-7H- [1,4,7] dioxaazanonacyclo [2,3-g ] quinazolin-8 (9H) -one 12

First step of

(R) - (2- ((6-hydroxy-2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-7-yl) oxy) ethyl) carbamic acid tert-butyl ester 12a

Compound 3d (308mg, 754.3. Mu. Mol), (2-bromoethyl) carbamic acid tert-butyl ester (1699 mg, 754.3. Mu. Mol, shanghai Biao) was dissolved in 2mL of N, N-dimethylformamide, anhydrous potassium carbonate (312.2mg, 2.26mmol) was added, and the reaction was stirred at 50 ℃ for 14 hours with a tube sealed. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system a to give the title compound 12a (80 mg), yield: 19.2 percent.

MS m/z(ESI)：552.3[M+1]。

Second step of

(R) -tert-butyl 2- ((7- (2- ((tert-butoxycarbonyl) amino) ethoxy) -2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) acetate 12b

Compound 12a (200mg, 326.6. Mu. Mol) and t-butyl bromoacetate (63.7 mg, 326.6. Mu. Mol, shanghaitan) were dissolved in 5mL of N, N-dimethylformamide, anhydrous potassium carbonate (180mg, 1.3 mmol) was added, and the reaction was stirred at 35 ℃ for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system a to give the title compound 12b (200 mg), yield: 91.9 percent.

MS m/z(ESI)：666.2[M+1]。

The third step

(R) -2- ((7- (2-aminoethoxy) -2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) acetic acid trifluoroacetate 12c

Compound 12b (20mg, 30. Mu. Mol) was dissolved in 2mL of methylene chloride, and 1mL of trifluoroacetic acid was added to stir the mixture for 1 hour. The reaction solution was concentrated under reduced pressure to give crude product 12c (20 mg), which was used in the next reaction without purification.

MS m/z(ESI)：510.1[M+1]。

The fourth step

(R) -2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -10, 11-dihydro-7H- [1,4,7] dioxaazanonacyclo [2,3-g ] quinazolin-8 (9H) -one 12d

Compound 12c (20mg, 39.2. Mu. Mol) was dissolved in 2mL of N, N-dimethylformamide, and N, N-diisopropylethylamine (15.2mg, 117.7. Mu. Mol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (44.7mg, 117.7. Mu. Mol) were added thereto under ice-cooling, and the mixture was allowed to naturally warm to room temperature and reacted for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give the title compound 12d (19 mg), yield: 98 percent.

MS m/z(ESI)：492.2[M+1]。

The fifth step

Compound 12d (19mg, 38.6.6. Mu. Mol) was dissolved in 5mL of methanol, 10% wet palladium on charcoal (40 mg) was added, and after the addition, hydrogen was substituted three times, stirring was carried out for 14 hours, filtration was carried out under reduced pressure, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm, 5. Mu.m: mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -50%, flow rate: 30 mL/min) to give title compound 12 (2 mg), yield: 1.1 percent.

MS m/z(ESI)：462.1[M+1]。

¹ H NMR(500MHz，DMSO-d ₆ )：δ8.18(d，1H)，7.68(q，1H)，7.28(d，1H)，6.89(s，1H)，6.84(s，1H)，6.70(s，1H)，5.54(s，1H)，5.51(d，1H)，4.91-4.75(m，2H)，4.22-4.09(m，2H)，2.37(s，3H)，1.53(d，3H)。

Example 13

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2' -methyl-7 ',8',10',11' -tetrahydrospiro [ [1,3] dioxolane-2, 9' - [1,4] dioxanonacyclo [2,3-g ] quinazolin-4 ' -amine 13

Using the synthetic route in example 6, the first step starting material compound 6a was replaced with the compound 1, 3-dioxolane-2, 2-diethanol to give the title compound 13 (3.8 mg), yield: 1.4 percent.

MS m/z(ESI)：490.2[M+1]。

¹ H NMR(500MHz，CDCl ₃ )：δ7.50(dq，2H)，7.37(d，2H)，7.20(t，1H)，6.92(t，1H)，5.85-5.71(m，1H)，5.34(s，1H)，4.40(dtd，4H)，3.93(s，4H)，2.53(s，3H)，2.23(d，2H)，2.09(t，2H)，1.69(d，3H)。

Example 14

(R) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -7,8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododeca [2,3-g ] quinazolin-4-amine 14

Using the synthetic route in example 2, the starting compound 1f was replaced with the compound (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (prepared using the method disclosed in example B-6i on page 106 of the specification in the patent application "WO 2018/115380") in the third step to give the title compound 14 (10 mg), yield: 20.1 percent.

MS m/z(ESI)：492.2[M+1]。

¹ H NMR(500MHz，CDCl ₃ )：δ7.61-7.57(m，2H)，7.27-7.19(m，2H)，5.85-5.83(m，1H)，5.47-5.46(m，1H)，4.29-4.25(m，4H)，3.99-3.97(m，2H)，3.88-3.85(m，2H)，3.85-3.82(m，4H)，2.63(s，3H)，2.53(s，3H)，1.68-1.64(d，3H)。

Example 15

(R) -N- (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methyl-7, 8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododeca [2,3-g ] quinazolin-4-amine 15

Using the synthetic route in example 2, the starting compound 1f was replaced with the compound (R) -1- (3- (difluoromethyl) -2-methylphenyl) ethan-1-amine hydrochloride (prepared using the method disclosed in example B-6i on page 106 of the specification in the patent application "WO 2018/115380") in the third step to give the title compound 15 (15 mg), yield: 48.5 percent.

MS m/z(ESI)：474.2[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.92(s，1H)，7.62-7.60(m，1H)，7.40-7.39(m，1H)， 7.28-7.25(m，1H)，7.10(s，1H)，7.08-6.86(t，1H)，5.87-5.83(m，1H)，4.31-4.26(m，4H)，3.93-3.85(m，4H)，3.80-3.77(m，4H)，2.60(s，3H)，2.43(s，3H)，1.63-1.61(d，3H)。

Example 16

(R) -N- (1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) -2-methyl-7, 8, 10, 11, 13, 14-hexahydro- [1,4,7, 10] tetraoxacyclododeca [2,3-g ] quinazolin-4-amine 16

Using the synthetic route in example 2, the third step starting compound 1f was replaced with the compound (R) -I- (3,3-difluoro-2,3-dihydrobenzofuran-7-yl) ethane-1-amine hydrochloride (prepared using the method disclosed in example B-5 on page 105 of the specification in patent application "US 2019194192") to give the title compound 16 (80 mg), yield: 45.6 percent.

MS m/z(ESI)：488.2[M+1]。

¹ H NMR(500MHz，CD ₃ OD)：δ7.94(s，1H)，7.52(d，1H)，7.43(dq，1H)，7.12(s，1H)，7.06(t，1H)，5.79(q，1H)，4.74(t，2H)，4.34-4.30(m，2H)，4.30-4.26(m，2H)，3.96-3.90(m，2H)，3.89-3.84(m，2H)，3.82-3.76(m，4H)，2.43(s，3H)，1.68(d，3H)。

Biological evaluation

Test example 1 ability of Compounds of the present disclosure to inhibit the interaction between each subtype of KRAS protein, G12D, G12C or G12V, and SOS1 protein

The following methods were used to determine the ability of the compounds of the present disclosure to inhibit the interaction between each of the subtypes G12D, G12C or G12V of KRAS protein and SOS1 protein.

The experimental method is as follows:

1. experimental materials and instruments

1. Biotin labeling kit (Dojindo, LK 03)

2、GDP(SIGMA，G7127)

3. AlphaLISA Glutathione Acceptor Beads (AlphaLISA Glutathione acceptors) (PerkinElmer, AL 109C)

4. AlphaScreen Streptavidin Donor beads (AlphaScreen Streptavidin Donor beads) (PerkinElmer, 6760002S)

5. 1/2 AreaPlate-96 well plate (PerkinElmer, 6002290)

6. GST-TEV-SOS1 (564-1049) (Viya Biotechnology, SOS 1-191010)

7. KRasG12D, krasG12C, krasG12V (provided by Shanghai Pan Biotech Co., ltd.)

8. Phosphate Buffered Saline (PBS) PH7.4 (Shanghai Yangbei Biotech, B320)

9. Multifunctional enzyme mark instrument (PerkinElmer, envision)

2. Experimental procedure

Preparation of the experiment:

1. the experiment buffer was prepared prior to the start of the experiment: 1x PBS +0.1% Tween 20 after being subjected to BSA + 0.05%.

2. The KRAS G12D, KRAS-G12C and KRAS-G12V proteins are labeled with biotin using a biotin labeling kit.

The experimental steps are as follows:

1. KRAS G12C or KRAS G12V or KRAS G12D protein is mixed with SOS1 protein and GDP respectively and incubated for later use.

2. AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads were mixed 1: 1 to 40ug/mL before use for future use.

Compounds were formulated in assay buffer at an initial concentration of 40 μ M, 5-fold gradient dilutions, 10 gradient series concentration points.

mu.L of a mixture of KRAS G12C or KRAS G12V or KRAS G12D protein with SOS1 and GDP and 5. Mu.L of the diluted compound were added to each well of a 1/2 area plate-96 well plate, and incubated at room temperature for 30 minutes in the absence of light.

3. Then 5. Mu.L of the bead mixture was added per well and incubated for 60 minutes at room temperature in the absence of light.

4. The fluorescence values were read on a multifunctional microplate reader.

5. The IC of the compound was calculated using Graphpad Prism ₅₀ The value is obtained.

3. Experimental data

The ability of the disclosed compounds to inhibit the interaction between the various subtypes G12D, G12C or G12V of KRAS protein and SOS1 protein, measured as IC ₅₀ The values are shown in Table 1.

TABLE 1 IC inhibiting the ability of compounds of the present disclosure to interact with SOS1 protein and each of the subtypes G12D, G12C or G12V of KRAS protein ₅₀ Value of

And (4) conclusion: the disclosed compound can well inhibit the interaction between various subtypes G12D, G12C or G12V of KRAS protein and SOS1 protein.

Claims

A compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

y is- (OCH) ₂ CH ₂ ) _y -, where O side is attached to Z and C side is attached to O;

z is- (CR) ^m R ⁿ ) _z -or- (CH) ₂ ) _v C(O)NR ⁰ (CH ₂ ) _w -：

T is- (OCH) ₂ CH ₂ ) _t -, where O side is attached to Z and C side is attached to O;

R ^m and R ⁿ The same or different, each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl; or

R ^m 、R ⁿ Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, which may optionally be substituted by one or more R ⁵ Substitution;

ring a is aryl or heteroaryl;

G ¹ and G ² Selected from nitrogen or carbon atoms;

R ⁰ selected from the group consisting of hydrogen, alkyl, haloalkyl or hydroxyalkyl, wherein said alkyl, haloalkyl or hydroxyalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, haloalkoxy, amino, nitro and cyano;

R ¹ selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, and cycloalkyl;

R ² selected from oxygen, halogenAn alkyl, a haloalkyl, a hydroxyalkyl, a hydroxyl, a cyano, a cycloalkyl and a heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro and cyano;

R ³ selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, and-NR ⁶ R ⁷ ；

R ⁵ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -NR ⁶ R ⁷ Cyano and nitro, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and-NR ⁶ R ⁷ Is substituted with one or more substituents of (a);

R ⁸ identical or different and are each independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, -NR ⁶ R ⁷ Nitro, hydroxy, hydroxyalkyl, -S (O) ₂ Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, hydroxyalkylCycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with one or more substituents selected from hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁶ and R ⁷ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

z is 2,3, 4 or 5;

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

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

t is 0, 1,2,3, 4 or 5; and the sum of y and t is not more than 5;

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

q is 0, 1 or 2;

n is 0, 1,2,3, 4 or 5.
The compound of formula (I) according to claim 1, wherein Z is- (CH), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof ₂ ) _z -or- (CH) ₂ ) _v C(O)NR ⁰ (CH ₂ ) _w -；

R ⁰ Z, v and w are as defined in claim 1.
The compound of formula (I) according to claim 1 or2, wherein Z is- (CH) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof ₂ ) _z -, and z is 2 or 4.
A compound of formula (I) according to any one of claims 1 to 3, which is a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein m is 1,2,3, 4 or 5;

rings A, G ¹ 、G ² 、R ¹ -R ⁵ 、R ⁸ P, q and n are as defined in claim 1 or 2.
The compound of formula (I) according to any one of claims 1 to 4, wherein G is G or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof ¹ And G ² Is a carbon atom.
The compound of the general formula (I) according to any one of claims 1 to 5, wherein ring a is C, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof _6-10 Aryl, preferably phenyl or
More preferably phenyl.
The compound of the general formula (I) according to any one of claims 1 to 3,5 to 6, or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (III) or (III-1), or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein Z is- (CH) ₂ ) _z -；

z is 2 or 4; y is 0, 1,2 or 3;

t is 0, 1,2 or 3; and the sum of y and t is not more than 3;

Y、T、R ¹ 、R ² 、R ⁸ and n is as defined in claim 1 or 2.
The compound of formula (I) according to any one of claims 1 to 7, wherein R is R in the form of its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof ⁸ Selected from halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, -NR ⁶ R ⁷ And C _1-6 Hydroxyalkyl of wherein said C _1-6 Haloalkyl is optionally substituted with one or more hydroxy; r is ⁶ And R ⁷ Selected from hydrogen and C _1-6 An alkyl group.
The compound of formula (I) according to any one of claims 1 to 8, wherein R is in the form of its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof ¹ Selected from hydrogen, C _1-6 Alkyl and halogen.
The compound of general formula (I) according to any one of claims 1 to 9, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof ² Selected from hydrogen and C _1-6 An alkyl group.
The compound of general formula (I) according to any one of claims 1 to 6,8 to 10, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof ³ Selected from hydrogen and C _1-6 An alkyl group.
The compound of general formula (I) according to any one of claims 1 to 6,8 to 11, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof ⁴ Is hydrogen.
The compound of formula (I) according to any one of claims 1 to 6,8 to 12, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁵ Is hydrogen.
The compound of the general formula (I) according to any one of claims 1 to 3,5 to 6,8 to 13, or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IV) or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein ring A, Y, Z, T, G ¹ 、G ² 、R ¹ -R ⁵ 、R ⁸ P, q and n are as defined in claim 1 or 2.
A compound of general formula (I) according to any one of claims 1 to 14, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:
a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ^w is hydroxy or halogen, preferably hydroxy or chlorine;

R ¹ selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, and cycloalkyl;

the sum of y and t is not 0;

Y、Z、T、G ¹ 、G ² 、R ⁴ 、R ⁵ p and q are as defined in claim 1 or 2.
A compound of formula (IVA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein:

rings A, Y, Z, T, G ¹ 、G ² 、R ¹ -R ⁵ 、R ⁸ P, q and n are as defined in claim 1 or 2.
The compound of formula (IA) or (IVA) according to claim 16 or 17, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:
a process for preparing a compound of formula (I) or formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

reaction of formula (IA) with formula (IB) or a salt thereof to give a compound of formula (I), or

Carrying out reduction reaction on the compound of the general formula (IVA) to obtain a compound of a general formula (IV);

wherein:

R ^w is hydroxy or halogen, preferably hydroxy or chloro;

ring A, Y, Z, T, G ¹ 、G ² 、R ¹ -R ⁵ 、R ⁸ P, q and n are as defined in claim 1 or 2.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) according to any one of claims 1 to 15, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
Use of a compound of general formula (I) according to any one of claims 1 to 15 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the preparation of a medicament for the inhibition of SOS1.
Use of a compound of general formula (I) according to any one of claims 1 to 15 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the preparation of a medicament for the treatment and/or prevention of cancer, inflammation, RAS disease, noonan Syndrome (NS), noonan syndrome with erythema (NSML), capillary malformation-arteriovenous malformation (CM-AVM), costello Syndrome (CS), heart-plane-skin syndrome (CFC), louses syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably cancer; preferably, the cancer is selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, colon cancer, rectal cancer, gallbladder cancer, cholangiocarcinoma, chorioepithelioma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, head and neck squamous cell carcinoma, uterine cancer, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, osteosarcoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF 1); the lung cancer is preferably non-small cell lung cancer, and is further preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myelogenous leukemia; the lymphoma is preferably diffuse large B cell lymphoma; the myeloma is preferably multiple myeloma; the osteoma is preferably osteochondroma.