CN115697994A

CN115697994A - Fused quinazoline derivative, preparation method and medical application thereof

Info

Publication number: CN115697994A
Application number: CN202180041050.2A
Authority: CN
Inventors: 李心; 董怀德; 曾长根; 钟家鑫; 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: 2020-06-10
Filing date: 2021-06-10
Publication date: 2023-02-03
Anticipated expiration: 2041-06-10
Also published as: CN115697994B; WO2021249475A1; TW202214654A

Abstract

The disclosure relates to fused quinazoline derivatives, preparation methods and medical applications thereof. Specifically, the disclosure relates to a fused quinazoline derivative shown in 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 diseases or symptoms improved by SOS1 inhibition.

Description

Condensed quinazoline derivative, preparation method and medical application thereof

Technical Field

The disclosure belongs to the field of medicine, and relates to a fused quinazoline derivative shown in 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 diseases or symptoms improved by SOS1 inhibition.

Background

RAS is one of the most mutation-frequent 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, the functions of cell proliferation, survival, migration and metabolism are regulated through a plurality of downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM 1-RAc. After mutation of KRAS gene, the protein is continuously activated, resulting in continuous activation of downstream signaling pathways to promote tumorigenesis.

KRAS protein is considered as an unpageable drug target for a long time because of the surface lack of conventional small molecule binding sites and the ultrahigh affinity with guanylic acid, so that the KRAS protein is extremely difficult to inhibit. But based on the importance and prevalence of abnormal KRAS activation 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 aiming at KRAS G12C can irreversibly lock the G12C mutant in an inactivated state, and clinical phase I data of the Ministry and Mirati company show unusual effect 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) Other sites on KRAS were sought that could target more mutants: mainly aiming at the sites binding downstream effector molecules/sites related to the activation of protein molecules, are currently in preclinical phase,IC for inhibition of Activity ₅₀ Commonly in micromolar grades.

3) Inhibition against KRAS downstream signaling protein: for example, in the development of inhibitors such as RAF, MEK, ERK, etc., the effect is not good when used alone clinically.

4) Inhibition of KRAS upstream pathway: such as an inhibitor of SHP2, and the like.

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

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

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 combination of activating molecules for blocking the KRAS and the KRAS, such as a small molecule inhibitor for selectively inhibiting SOS1, namely guanine nucleotide exchange factor (GEF), can block the activation of the KRAS by interfering RAS-SOS1 interaction, and can achieve the aim of inhibiting the activity of the KRAS in a broad spectrum.

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 for 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 the activation of RAS. 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.

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

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:

ring a is aryl or heteroaryl;

ring B is a 5-6 membered heterocyclyl or heteroaryl;

R ⁰ selected from the group consisting of alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, cycloalkylcarbonyl, heterocyclylcarbonyl, -NHC (O) R ¹⁰ Heteroaryl, cycloalkyl and heterocyclyl, wherein said cycloalkyloxy, heterocyclyloxy, cycloalkylcarbonyl, heterocyclylcarbonyl, heteroaryl, cycloalkyl and heterocyclyl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, oxo, carboxy, = NH, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ 、-(CH ₂ ) _t -C(O)R ⁹ And NHC (O) R ¹¹ Substituted with one or more substituents of (a);

wherein R is ⁹ And R ¹¹ Are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, - (CH) ₂ ) _q NR ⁶ R ⁷ Cycloalkyl and heterocyclyl; the alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted by one or more substituents selected from alkyl, alkoxy, cyano, carboxy;

R ¹⁰ selected from hydrogen, alkyl, hydroxyalkyl, hydroxy, - (CH) ₂ ) _q NR ⁶ R ⁷ Cycloalkyl and heterocyclyl; said alkyl, cycloalkyl andeach heterocyclyl is independently optionally substituted by one or more substituents selected from alkyl, alkoxy, cyano, carboxy;

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 each independently 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 each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ 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 each independently optionally 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 the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, - (CH) ₂ ) _q 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 each independently optionally selected from the group consisting of hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, - (CH) ₂ ) _q NR ⁶ R ⁷ 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, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

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

q is 0, 1 or 2

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

t 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 ⁰ Selected from the group consisting of alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, cycloalkyl and heterocyclyl, wherein said cycloalkyloxy, heterocyclyloxy, cycloalkyl and heterocyclyl are each independently optionally substituted with a group selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ and-C (O) R ⁹ Is substituted with one or more substituents of (1);

wherein R is ⁹ Selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, - (CH) ₂ ) _q NR ⁶ R ⁷ Cycloalkyl and heterocyclyl;

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

wherein R is ⁶ 、R ⁷ And q is as defined in formula (I).

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 ring B is a five-or six-membered heterocyclic group, preferably a five-membered heterocyclic group.

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 G ¹ 、G ² And G ³ Are the same or different and are each independently selected fromCarbon atom, oxygen atom, nitrogen atom and sulfur atom, with the proviso that G ¹ 、G ² And G ³ Not carbon atoms at the same time;

r is 0 or 1; preferably, r is 0;

the dotted line represents a single or double bond;

ring A, R ⁰ -R ⁵ 、R ⁸ P and n are as defined in formula (I).

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 the dashed line represents a single bond.

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: g ¹ And G ² Is a carbon atom, G ³ Is an oxygen atom; or G ² And G ³ Is a carbon atom, G ¹ Is an oxygen atom; or G ¹ And G ³ Each independently an oxygen atom or a nitrogen atom, G ² Is a carbon atom.

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

Wherein:

ring A, R ⁰ 、R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁸ P and n are as defined in formulae (I) and (II) (R in formula (VI)) ⁵ Optionally substituted on N).

In some preferred embodiments of the present disclosure, a compound represented by formula (I) and (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-1), formula (IV-1), formula (V-1), formula (VI-1), or formula (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: ring A, R ⁰ 、R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁸ P and n are as defined in the general formulae (I) and (II) (R in the general formula (VI-1)) ⁵ Optionally substituted on N).

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 r is 0.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is C _6-10 Aryl or 5-10 membered heteroaryl.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from phenyl, thienyl, pyrrolyl, dihydrobenzofuranyl, and furanyl; the dihydrobenzofuran group can be dihydrobenzofuran-4-yl, dihydrobenzofuran-5-yl, dihydrobenzofuran-6-yl, and dihydrobenzofuran-7-yl;

preferably, ring a is selected from phenyl, thienyl, pyrrolyl and furanyl.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R ⁰ Selected from the group consisting of alkoxy, heterocyclyloxy and heterocyclyl, wherein said heterocyclyloxy and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ and-C (O) R ⁹ Is substituted with one or more substituents of (1); wherein R is ⁹ Selected from hydrogen, alkyl, haloalkyl, - (CH) ₂ ) _q NR ⁶ R ⁷ And hydroxyalkyl groups; r ⁶ 、R ⁷ And q is as defined in formula (I). In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁰ Selected from the group consisting of alkoxy, heterocyclyloxy and heterocyclyl, said heterocyclyloxy and heterocyclyl being selected from the group consisting of tetrahydrofuryloxy, azetidinyloxy, tetrahydropyrrolyloxy, cyclobutyloxy, hydrogenatedThiopyranyloxy, morpholinylcarbonyl, C _1-6 Alkoxy, hydropyridinyl, azetidinyl, piperazinyl, cyclohexyl, hydropyranyl, and hydropyranyl; wherein said heterocyclyloxy and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ and-C (O) R ⁹ Is substituted with one or more substituents of (1); wherein R is ⁹ Selected from hydrogen, alkyl, haloalkyl, - (CH) ₂ ) _q NR ⁶ R ⁷ And hydroxyalkyl groups; r ⁶ 、R ⁷ And q is as defined in formula (I);

preferably, R ⁰ Is selected from C _1-6 Alkoxy, a five-membered heterocyclyloxy and a six-membered heterocyclyl, each independently optionally substituted with-C (O) R ⁹ And one or more substituents of hydroxy, wherein R is ⁹ Is C _1-6 Alkyl or- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Identical or different, each independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R ⁰ Selected from tetrahydrofuryloxy, azetidinyloxy, C _1-6 Alkoxy, hydropyridinyl, and hydropyranyl, each independently optionally substituted with-C (O) R ⁹ And/or one or more substituents of hydroxy, wherein R is ⁹ Is C _1-6 Alkyl or- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Identical or different, each independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2;

Preferably, R ⁰ Selected from tetrahydrofuryloxy, C _1-6 Alkoxy, hydropyridyl and hydropyranyl, each independently optionally substituted by-C (O) R ⁹ And/or one or more substituents of hydroxyl, wherein R is ⁹ Is C _1-6 Alkyl or- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Identical or different, each independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R ⁰ Selected from tetrahydrofuryloxy, C _1-6 Alkoxy, piperidinyl, tetrahydropyridinyl, azetidinyloxy, tetrahydropyranyl and dihydropyranyl, each independently optionally substituted by hydroxy and/or-C (O) R ⁹ Wherein R is substituted with one or more substituents of (1) ⁹ Is C _1-6 Alkyl or- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Identical or different, each independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2;

Preferably, R ⁰ Selected from tetrahydrofuryloxy, C _1-6 Alkoxy, piperidinyl, tetrahydropyridinyl, tetrahydropyranyl and dihydropyranyl groups, each independently optionally substituted by hydroxy and/or-C (O) R ⁹ Wherein R is substituted by one or more substituents of (1), wherein R is ⁹ Is C _1-6 Alkyl or- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Identical or different, each independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2;

more preferably, R ⁰ Selected from tetrahydrofuryloxy or tetrahydropyridinyl, said tetrahydropyridinyl being optionally substituted by-C (O) R ⁹ Is substituted in which R ⁹ Is C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R ⁰ Is selected from 3-6 membered cycloalkyl, said 3-6 membered cycloalkyl being optionally substituted by a substituent selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, carboxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano and- (CH) ₂ ) _t -C(O)R ⁹ Is substituted with one or more substituents of (1); wherein R is ⁹ Selected from hydroxy, - (CH) ₂ ) _q NR ⁶ R ⁷ Cycloalkyl and heterocyclyl; said cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from alkyl, alkoxy and cyano; r is ⁶ And R ⁷ Each independently selected from alkyl and hydroxyalkyl; r is ⁶ 、R ⁷ And q is as defined in formula (I);

preferably, R ⁰ Selected from 3-6 membered cycloalkyl, said 3-6 membered cycloalkyl being optionally substituted by a substituent selected from halogen, C _1-6 Alkyl and hydroxy substitution.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1) or a tautomer thereofIsomers, meso forms, racemic forms, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁰ Is composed of

Ring C is selected from cycloalkyl and heterocyclyl;

preferably, R ⁰ Is selected from

W is selected from oxygen atom, sulfur atom,

NR ^13a And CR ^13b R ^13c ；

R ¹³ Identical or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyl, oxo, = NH, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ 、-(CH ₂ ) _t C(O)R ⁹ And NHC (O) R ¹¹ ；

R ^13a 、R ^13b And R ^13c Are the same or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ 、-(CH ₂ ) _t C(O)R ⁹ And NHC (O) R ¹¹ ；

j is 0, 1 or 2;

k is 1 or 2;

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

v is 0, 1, 2 or 3;

t、R ⁹ and R ¹¹ As defined in the general formulae (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1).

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R ⁰ Is selected from

R ¹³ Are identical or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyl, oxo, = NH, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ 、-(CH ₂ ) _t C(O)R ⁹ And NHC (O) R ¹¹ ；

v is 0, 1, 2 or 3;

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R ^13a Is C _1-6 Alkyl, -S (O) ₂ R ⁹ And- (CH) ₂ ) _t -C(O)R ⁹ ；R ⁹ Is selected from C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, hydroxy, - (CH) ₂ ) _q NR ⁶ R ⁷ 3-6 membered cycloalkyl and 3-6 membered heterocyclyl, said C _1-6 The alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocyclyl group may optionally be substituted by C _1-6 Alkoxy and cyano substitution; r ⁶ And R ⁷ Same or different, each independently selected from hydrogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; t is 0, 1 or 2; q is 0, 1 or 2;

preferably, R ^13a Is- (CH) ₂ ) _t -C(O)R ⁹ ；R ⁹ Is selected from C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, hydroxy and- (CH) ₂ ) _q NR ⁶ R ⁷ Said C is _1-6 Alkyl is optionally substituted by C _1-6 Alkoxy and cyano substitution; r is ⁶ And R ⁷ Same or different, each independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A hydroxyalkyl group; t is 0 or 1; q is 0 or 1;

more preferably, R ^13a Is- (CH) ₂ ) _t -C(O)R ⁹ ；R ⁹ Is selected from C _1-6 An alkyl group; t is 0.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ¹³ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R ^13b Is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R ^13c Is hydroxy or- (CH) ₂ ) _t -C(O)R ⁹ ；R ⁹ Selected from hydroxy, - (CH) ₂ ) _q NR ⁶ R ⁷ And 3-6 membered heterocyclyl; said 3-6 membered heterocyclyl is optionally substituted by C _1-6 Alkyl substitution; r is ⁶ And R ⁷ The same or different, each independently selected from hydrogen and C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; t is 0, 1 or 2; q is 0, 1 or 2;

preferably, R ^13c Is- (CH) ₂ ) _t -C(O)R ⁹ ；R ⁹ Selected from hydroxy, - (CH) ₂ ) _q NR ⁶ R ⁷ And 3-6 membered heterocyclyl; the 3-to 6-membered heterocyclic groupOptionally is covered with C _1-6 Alkyl substitution; r is ⁶ And R ⁷ Are the same or different and are each independently selected from C _1-6 Alkyl and C _1-6 A hydroxyalkyl group; t is 0; q is 0.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein u is 0 or 1.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein j is 0 or 1.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-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), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein V is 0.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-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 independentlyIs selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, - (CH) ₂ ) _q NR ⁶ R ⁷ Nitro, hydroxy, hydroxyalkyl, -S (O) ₂ Alkyl and aryl, wherein said alkyl, haloalkyl, hydroxyalkyl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl and- (CH) ₂ ) _q NR ⁶ R ⁷ Q is 0, 1 or 2; r ⁶ And R ⁷ The same or different, each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and hydroxyalkyl;

preferably, R ⁸ Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, - (CH) ₂ ) _q NR ⁶ R ⁷ 、C _1-6 Hydroxyalkyl and C _6-10 Aryl, wherein said C _1-6 Haloalkyl is optionally substituted with one or more hydroxy, said C _6-10 Aryl is optionally substituted by one or more- (CH) ₂ ) _q NR ⁶ R ⁷ Substitution; r ⁶ And R ⁷ Selected from hydrogen or C _1-6 Alkyl, q is 0, 1 or 2.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ¹ Selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl;

preferably, R ¹ Selected from hydrogen, C _1-6 Alkyl and halogen.

More preferably, R ¹ Is a methyl group.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ² Selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl, wherein said alkyl and cycloalkyl are each independently optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy, and amino;

Preferably, R ² Selected from hydrogen and C _1-6 An alkyl group.

More preferably, R ² Is a methyl group.

In some preferred embodiments of the present disclosure, a compound of formula (I) and (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ³ Selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl, wherein said alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, and hydroxyalkyl;

preferably, R ³ 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), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁴ Selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, and hydroxyalkyl;

preferably, R ⁴ Is hydrogen.

In some preferred embodiments of the present disclosure A compound of the general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1) and (VII-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R ⁵ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, -NR ⁶ R ⁷ And cyano, wherein said alkyl and cycloalkyl are each independently optionally substituted with a group selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen and-NR ⁶ R ⁷ Is substituted with one or more substituents of (1); r is ⁶ And R ⁷ The same or different, each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and hydroxyalkyl;

preferably, R ⁵ Hydrogen or methyl, more preferably hydrogen.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁶ And R ⁷ Are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and hydroxyalkyl;

preferably, R ⁶ And R ⁷ Are the same or different and are each independently 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), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ¹⁰ Is- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Are the same or different and are each independently hydrogen or C _1-6 Alkyl, q is 1 or 2.

Preferably, R ¹⁰ Is- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Identical or different, each independently is methyl and q is 1.

In some preferred embodiments of the present disclosure, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), and (VII-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ¹¹ Is cycloalkyl or- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Are the same or different and are each independently hydrogen or C _1-6 Alkyl, q is 1 or 2.

Preferably, R ¹¹ Is cyclopropyl or- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Identical or different and are each independently methyl, q is 1.

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

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-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein:

R ¹ selected from halogen, alkyl, haloalkyl, alkylOxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;

ring B, R ⁰ 、R ⁴ 、R ⁵ And p is as defined in formula (I) as defined herein.

Another aspect of the present disclosure relates to a compound of formula (IA-2) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

Wherein:

G ¹ is an oxygen atom or a sulfur atom;

ring A, R ⁰ -R ⁵ 、R ⁸ P and n are as defined in formula (I) as defined in the description.

Another aspect of the present disclosure relates to a compound represented by general formula (IA-3) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein:

x is halogen;

ring A, ring B, R ¹ -R ⁵ 、R ⁸ P and n are as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by formula (IIA-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein:

dotted line, G ¹ -G ³ 、R ⁰ -R ¹ 、R ⁴ -R ⁵ P, and r are as defined in formula (II).

Another aspect of the present disclosure relates to a compound of formula (IIA-3) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein X is halogen;

dotted line, rings A, G ¹ -G ³ 、R ¹ -R ⁵ 、R ⁸ P, r and n are as defined in formula (II).

Another aspect of the present disclosure relates to a compound of formula (IIIA-1), (IVA-1), (VA-1), (VIA-1) or (VIIA-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

Wherein R is ⁰ -R ¹ 、R ⁴ -R ⁵ And p is as defined in formula (III), (IV), (V), (VI) or (VII).

Another aspect of the disclosure relates to a compound of formula (IIIA-2) or (IVA-2) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein the rings A and R ⁰ -R ² 、R ⁴ -R ⁵ 、R ⁸ P and n are as defined in formula (III) or (IV).

Another aspect of the present disclosure relates to a compound of formula (IIIA-3), (IVA-3), (VA-3), (VIA-3) or (VIIA-3) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein X is halogen;

ring A, R ¹ -R ² 、R ⁴ -R ⁵ 、R ⁸ P and n are as defined in formula (III), (IV), (V), (VI) or (VII).

Another aspect of the present disclosure relates to a compound of formula (IIIA-4), (IVA-4), (VA-4), (VIA-4) or (VIIA-4) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein R is ⁰ -R ¹ 、R ⁴ -R ⁵ And p is as defined in the general formula (III-1), (IV-1), (V-1), (VI-1) or (VII-1).

Another aspect of the present disclosure relates to a compound of formula (IIIA-5) or (IVA-5) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

Wherein the ring A, R ⁰ -R ² 、R ⁴ -R ⁵ 、R ⁸ P and n are as defined in the general formula (III-1) or (IV-1).

Another aspect of the present disclosure relates to a compound of formula (IIIA-6), (IVA-6), (VA-6), (VIA-6) or (VIIA-6) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein X is halogen;

ring A, R ¹ -R ² 、R ⁴ -R ⁵ 、R ⁸ P and n are as defined in the general formula (III-1), (IV-1), (V-1), (VI-1) or (VII-1).

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

wherein Q is ¹ 、Q ² And Q ³ Are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom;

R ¹² identical or different and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, oxo, carboxy, = NH, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ 、-(CH ₂ ) _t -C(O)R ⁹ And NHC (O) R ¹¹ ；

j is 0 or 1;

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

dotted line, R ¹ -R ⁵ 、G ¹ -G ³ 、R ⁸ 、R ⁹ 、R ¹¹ P, r, n and t are as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by formula (IIIaA) or (III-1 aA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

Wherein Q ¹ 、Q ² And Q ³ Are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom;

j is 0 or 1;

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

R ¹ -R ² 、R ⁴ -R ⁵ 、R ⁸ 、R ⁹ 、R ¹¹ p, n and t are as defined in formula (III).

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

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

reacting a compound of formula (IA-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IB) or a salt thereof, preferably the hydrochloride salt, to give a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein Ring A, ring B, and Ring R ⁰ -R ⁵ 、R ⁸ P and n are as defined in formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (I-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (I-1) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer, the mixture or the salt thereof is prepared by taking the compound of the general formula (IA-2) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer, the mixture or the salt thereof as a raw material and carrying out reduction reaction,

wherein G is ¹ Is an oxygen atom or a sulfur atom;

ring A, R ⁰ -R ⁵ 、R ⁸ P and n are as defined in formula (I).

preparing a compound of the general formula (I) or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture form or a salt form thereof by taking a compound of the general formula (IA-3) or the tautomer, the meso form, the racemate, the enantiomer, the diastereomer or the mixture form or the salt form thereof as a raw material and carrying out reaction; the reaction can be carried out by introducing R into the reaction mixture by using transition metal catalytic cross coupling such as Suzuki or Herck coupling, metal halide addition such as Grignard addition, nucleophilic substitution, ullmann reaction and the like ⁰ Preferably by Ullmann reaction, suzuki reaction orThe process of the Grignard reaction is carried out,

wherein X is halogen;

ring A, ring B, R ⁰ -R ⁵ 、R ⁸ P and n are as defined in formula (I).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and table a of the present disclosure, 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.

The present disclosure further relates to the use of compounds of general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and table a, or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for the manufacture of a medicament for inhibiting SOS 1.

The present disclosure further relates to the use of compounds of general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and table a, or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for the manufacture of a medicament for the treatment and/or prevention of SOS1 mediated diseases.

The present disclosure further relates to the use of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and 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-face-skin syndrome (CFC), legore syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably cancer; the cancer is preferably melanoma, skin cancer, liver cancer, hepatocellular carcinoma, kidney cancer, lung cancer, nasopharyngeal carcinoma, stomach 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.

The present disclosure also relates to a method of inhibiting SOS1 comprising administering to a patient in need thereof an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and shown in Table A or a tautomer, meso, 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 SOS 1-mediated diseases comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1), and 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 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), louses syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1), and 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, hepatocellular carcinoma, kidney cancer, lung cancer, nasopharyngeal carcinoma, 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 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.

The present disclosure further relates to a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and table a or a tautomer, meso, 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), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and table a, or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are useful as SOS1 inhibitors.

The present disclosure also relates to compounds of general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and table a or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of SOS1 mediated diseases.

The present disclosure also relates to compounds of general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and table a or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions 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), cardio-facial-skin syndrome (CFC), lebers 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, hepatocellular carcinoma, 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 tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck squamous cell carcinoma, uterine cancer, endometrial cancer, thyroid cancer, lymphoma, sarcoma, 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.

The SOS 1-mediated disease described in the present disclosure is selected from cancer, inflammation, RAS disease, noonan Syndrome (NS), noonan syndrome with multiple plaques (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), costerlo Syndrome (CS), heart-face-skin syndrome (CFC), louses syndrome, hereditary gingival fibromatosis, or other proliferative disease; preferably cancer; preferably, the cancer is selected from the group consisting of melanoma, skin cancer, liver cancer, hepatocellular 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.

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 compounds of the present disclosure are preferably administered in unit doses, or in such a way 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. A suitable unit dose 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, which may be 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 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 and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of 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 an oil phase, the injection or microemulsion being injectable into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion 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 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 prepared into 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.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. 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 a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the severity of the disease, 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, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of the 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 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 (e.g., 1,2, 3, 4, 5, or 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- ,2,2- , ,3,3- ,2,2- , </xnotran> And various branched chain 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. The alkyl group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues 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 group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably an alkylene group containing 1 to 6 (e.g., 1,2, 3, 4, 5 or 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. Alkylene groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of 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 at least one 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 at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted and when substituted, the substituents are preferably one or more 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, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. 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 cyclic 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). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls 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 into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. 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

Etc.; preference is given to

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and 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 mono-or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen or sulfur, which may be optionally substituted by oxo or = NH (i.e. forming a sulfoxide, sulfone or = NH)

) But not comprising-O-O-) -a ring moiety of-O-S-or-S-S-, the remaining ring atoms being carbon. 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 ring atoms (e.g. 3, 4, 5, 6, 7 and 8), 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 sharing one atom (referred to as the spiro atom) between single rings, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen or sulfur, which may be optionally substituted by oxo or = NH (i.e., forming a sulfoxide, sulfone or ether group)

) And 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 groups are classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group, according to the number of spiro atoms shared between ringsHeterocyclic groups and double spiro heterocyclic groups. 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 mono spiroheterocyclyl. 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, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or sulfur, which may be optionally substituted by oxo or = NH (i.e. to form a sulfoxide, sulfone or = NH)

) And 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 a 5 to 14 membered polycyclic heterocyclic group in which 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 a heteroatom selected from nitrogen, oxygen or sulfur, which may be optionally substituted by oxo or = NH (i.e., forming a sulfoxide, sulfone or = NH)

) And 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 a 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 a heterocyclyl, non-limiting examples of which include:

And the like.

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

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (e.g., 1, 2, 3, or 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10 membered), 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 that is attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

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

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived from the parent ring atom by the removal of one hydrogen atom, or those derived from the parent ring atom by the 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 the heterocyclyl-O-, wherein heterocyclyl is as defined above.

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

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

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

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group 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 the group-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 "cycloalkylcarbonyl" refers to cycloalkyl-C (O) -, wherein cycloalkyl is as defined above.

The term "heterocyclylcarbonyl" refers to a heterocyclyl-C (O) -, where the heterocyclyl is as defined above.

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 term "hydrogenated" refers to a compound which, depending on the number of double bonds in the ring, may be dihydro, tetrahydro, hexahydro, and the like, such as for hydrogenated pyridyl, including dihydropyridinyl, tetrahydropyridinyl, and hexahydropyridinyl (i.e., piperidinyl), and such as for hydrogenated pyranyl, including dihydropyranyl and tetrahydropyranyl.

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, having the structure of the disclosure except for replacing hydrogen with "deuterium" or "tritium", or with ¹⁸ F-fluorine labeling: ( ¹⁸ Isotope of F) instead of fluorine, or with ¹¹ C-、 ¹³ C-, or ¹⁴ C-enrichment carbon (C) of (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 may be used as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The present disclosure also includes various deuterated forms of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1), and Table A. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize deuterated forms of the compounds of the formulae (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and Table A with reference to the relevant literature. In preparing deuterated forms of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and Table A, commercially available deuterated starting materials can be used or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterium Borane, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterations can generally retain activity comparable 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" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in a 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 physiologically/pharmaceutically acceptable salts or prodrugs thereof, in admixture with 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.

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in the body of a mammal and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, 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 but 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 a case may be determined by a person skilled in the art in the light of routine tests.

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

By "prodrug" is meant a compound that can be converted in vivo under physiological conditions, e.g., by hydrolysis in blood, to yield the active prodrug compound.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and 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 parameters are not critical, numbers are generally given for illustrative purposes only, and not for limitation.

Synthesis of the Compounds of the disclosure

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

scheme one

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

reacting a compound of formula (IA-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IB) or a salt thereof, preferably the hydrochloride, in the presence of a base and a condensing agent to give a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

Scheme two

The invention discloses a method for preparing a compound shown as a general formula (I-1) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

the compound of the general formula (I-1) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof or the pharmaceutically acceptable salt thereof is prepared by taking the compound of the general formula (IA-2) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof or the salt thereof as a raw material and carrying out reduction reaction under the action of a catalyst,

wherein G is ¹ Is an oxygen atom or a sulfur atom; preferably an oxygen atom;

ring A, R ⁰ -R ⁵ 、R ⁸ P and n are as defined in formula (I).

Scheme three

the compound of the general formula (I) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the salt thereof is prepared by taking the compound of the general formula (IA-3) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof as a raw material and reacting; the reaction can be carried out by introducing R into the reaction mixture by using transition metal catalytic cross coupling such as Suzuki or Herck coupling, metal halide addition such as Grignard addition, nucleophilic substitution, ullmann reaction and the like ⁰ ，

Wherein X is halogen;

ring A, ring B, R ⁰ -R ⁵ 、R ⁸ P and n are as defined in formula (I).

Scheme four

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

reacting a compound of formula (IIA-1) or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IB) or a salt thereof, preferably the hydrochloride, in the presence of a base and a condensing agent to give a compound of formula (II) or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein the dotted line, rings A, G ¹ -G ³ 、R ⁰ -R ⁵ 、R ⁸ P, r and n are as defined in formula (II).

Scheme five

the compound of the general formula (II) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form or the salt form thereof is prepared by taking the compound of the general formula (IIA-3) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form or the pharmaceutically acceptable salt form thereof as a raw material and reacting; the reaction can be performed by introducing R through transition metal catalysis cross coupling (such as Suzuki or Herck coupling, and the like, metal halide addition such as Grignard addition, nucleophilic substitution, ullmann reaction, and the like ⁰ ，

Wherein X is halogen;

dotted line, ring A, R ⁰ -R ⁵ 、R ⁸ P, r and n are as defined in formula (II).

Scheme six

The invention discloses a method for preparing a compound shown in a general formula (III), a general formula (IV), a general formula (V), a general formula (VI) or a general formula (VII) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof or a pharmaceutically acceptable salt form thereof, which comprises the following steps:

reacting a compound of formula (IIIA-1), (IVA-1), (VA-1), (VIA-1) or (VIIA-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IB-1) or a salt thereof, preferably the hydrochloride, in the presence of a base and a condensing agent to give a compound of formula (III), (IV), (V), (VI) or (VII) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein the rings A and R ⁰ -R ² 、R ⁴ -R ⁵ 、R ⁸ P and n are as defined in formula (III), (IV), (V), (VI) or (VII).

Scheme seven

The invention discloses a method for preparing a compound shown in a general formula (III) or (IV) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, which comprises the following steps:

The compound of the general formula (III) or (IV) or the tautomer, the meso form, the enantiomer, the diastereomer, the mixture form or the salt form thereof is prepared by taking the compound of the general formula (IIIA-2) or (IVA-2) or the tautomer, the meso form, the diastereomer, the mixture form or the pharmaceutically acceptable salt form thereof as a raw material and carrying out reduction reaction under the action of a catalyst,

wherein the ring A, R ⁰ -R ² 、R ⁴ -R ⁵ 、R ⁸ P and n are as defined in formula (III) or (IV).

Scheme eight

preparing a compound of general formula (III), (IV), (V), (VI) or (VII) or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, from a compound of general formula (IIIA-3), (IVA-3), (VA-3), (VIA-3) or (VIIA-3) or a tautomer, meso, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, by reacting; the reaction can be carried out by introducing R into the reaction by transition metal catalyzed cross coupling such as Suzuki or Herck coupling, metal halide addition such as Grignard addition, nucleophilic substitution, ullmann reaction, etc ⁰ ，

Wherein X is halogen;

ring A, R ⁰ -R ² 、R ⁴ -R ⁵ 、R ⁸ P and n are as defined in formula (III), (IV), (V), (VI) or (VII).

Scheme nine

Disclosed is a method for producing a compound represented by the general formula (III-1), the general formula (IV-1), the general formula (V-1), the general formula (VI-1) or the general formula (VII-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the steps of:

reacting a compound of formula (IIIA-4), (IVA-4), (VA-4), (VIA-4) or (VIIA-4) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IB-2) or a salt thereof, preferably the hydrochloride, in the presence of a base and a condensing agent to give a compound of formula (III-1), (IV-1), (V-1), (VI-1) or (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein the rings A and R ⁰ -R ² 、R ⁴ -R ⁵ 、R ⁸ P and n are as defined in the general formula (III-1), (IV-1), (V-1), (VI-1) or (VII-1).

Scheme ten

A process for preparing a compound of the general formula (III-1) or (IV-1) of the present disclosure, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Preparing a compound of a general formula (III-1) or (IV-1) or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof or a salt thereof of a compound of a general formula (IIIA-5) or (IVA-5) or a pharmaceutically acceptable salt thereof by a reduction reaction of the compound of the general formula (IIIA-5) or (IVA-5) or the tautomer, the meso form, the racemate, the enantiomer or the diastereomer or the mixture thereof or the pharmaceutically acceptable salt thereof,

wherein the rings A and R ⁰ -R ² 、R ⁴ -R ⁵ 、R ⁸ P and n are as defined in the general formula (III-1) or (IV-1).

Scheme eleven

Disclosed is a method for producing a compound represented by the general formula (III-1), the general formula (IV-1), the general formula (V-1), the general formula (VI-1) or the general formula (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the steps of:

preparing a compound of formula (III-1), (IV-1), (V-1), (VI-1) or (VII-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, by reacting a compound of formula (IIIA-6), (IVA-6), (VA-6), (VIA-6) or (VIIA-6) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a salt thereof; the reaction can be carried out by introducing R through transition metal catalyzed cross coupling such as Suzuki or Herck coupling, etc.), metal halide addition such as Grignard addition, nucleophilic substitution, ullmann reaction, etc ⁰ ；

Wherein X is halogen;

ring A, R ⁰ -R ² 、R ⁴ -R ⁵ 、R ⁸ P and n are as in formula (III)(IV) -1), (IV-1), (V-1), (VI-1) or (VII-1).

Scheme twelve

For the above general formulae (I), (I-1), (II), (III-1), (IV-1), (V-1), (VI-1), (VII) and (VII-1), when the radical R ⁰ Is composed of

These general formulas can be prepared by the following oxidation reaction (since the groups not involved in the reaction site are unchanged before and after the reaction, only the change of the groups at the reaction site is listed):

R ¹² identical or different and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, oxo, carboxy, = NH, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ 、-(CH ₂ ) _t -C(O)R ⁹ And NHC (O) R ¹¹ Is substituted with one or more substituents of (1);

j is 0 or 1;

k is 0, 1, 2, 3, 4 or 5; wherein R is ⁹ -R ¹¹ And t is as defined in formula (I).

For example, for formula (II), when R ⁰ Is composed of

When it is of formula (IIa):

the preparation method comprises the following steps:

the general formula (IIaA) is prepared by oxidation reaction to obtain the general formula (IIa),

j is 0 or 1;

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

dotted line, R ¹ -R ⁵ 、G ¹ -G ³ 、R ⁸ -R ⁹ 、R ¹¹ P, r, n and t are as defined in formula (II).

As another example, for general formulae (III) and (III-1), when R ⁰ Is composed of

When it is of the formulae (IIIa) and (III-1 a):

the preparation method comprises the following steps:

the general formula (IIIa) or (III-1 a) is prepared by oxidation reaction,

j is 0 or 1;

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

R ¹ -R ² 、R ⁴ -R ⁵ 、R ⁸ -R ⁹ 、R ¹¹ p, n and t are as defined in formula (III).

Scheme thirteen

These general formulas can be prepared by the following reduction reaction (since the groups not involved in the reaction site are unchanged before and after the reaction, only the change of the groups at the reaction site is listed):

j is 0 or 1;

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

wherein R is ⁹ -R ¹¹ And t is as defined in formula (I).

For example, for formula (II), when R ⁰ Is composed of

When it is of formula (IIb):

the preparation method comprises the following steps:

the general formula (IIaA) is prepared into the general formula (IIb) through reduction reaction,

wherein Q is ¹ 、Q ² And Q ³ Are the same or different and are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom anda sulfur atom;

j is 0 or 1;

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

The condensing agent used in the above reaction includes, but is not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N ' -dicyclohexylcarbodiimide, N ' -diisopropylcarbodiimide, O-benzotriazol-N, N ' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N ', N ' -tetramethyluronium hexafluorophosphate, 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate, 2- (7-benzotriazol oxide) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate, benzotriazole-1-tris (trimethylamino) -trifluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphates hexafluorophosphate.

The Ullmann reaction may be carried out in the presence of a metal catalyst/ligand/base, including, but not limited to, cuprous iodide, cuprous chloride, cuprous bromide, cu (OTf) ₂ PhH、Cu、CuO、Cu ₂ O、Cu(OAc) ₂ Preferably cuprous iodide; ligands include, but are not limited to, 1, 10-phenanthroline, 4, 7-dichlorophenanthroline, 4, 7-dimethoxyphenanthroline, tetramethylphenanthroline, TEMDA (CAS registry number 110-18-9), N '-dimethyl-1, 2-ethylenediamine, TMHD (CAS registry number 1118-71-4), cyclohexyl-1, 2-diamine, N' -dimethylcyclo-diamine Hexyl-1, 2-diamine, salicylaldoxime, N-diethylsalicylamide, 8-hydroxyquinoline and the like, preferably 1, 10-phenanthroline; the base is defined below and is preferably cesium carbonate.

The base in the above reaction includes 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-diazacyclo [5,4,0] undec-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-diazacyclo [5,4,0] undec-7-ene is preferred.

The catalyst used in the above reduction reaction includes, but is not limited to, palladium on carbon, iron powder, raney nickel, zinc powder, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1' -bis (dibenzylphosphine) dichloropenta-palladium, tris (dibenzylideneacetone) dipalladium, etc., preferably palladium on carbon. Reducing agents used include, but are not limited to, hydrogen, dilute hydrochloric acid, acetic acid or dilute sulfuric acid, preferably hydrogen.

Catalyst systems used in the above oxidation reactions include, but are not limited to, phSiH/Mn (dpm) ₂ (or Mn (dpm) ₃ Or Mn (acac) ₂ Or Co (sdmg) ₃ ) Tetraphenylporphyrinmanganese (III) complex/NaBH ₄ (or Pt-H) ₂ ) Cobalt (II) tetraphenylporphyrin complex/NaBH ₄ (or EtNBH) ₄ ) Cobalt (II)/Primary alcohol, co (acac) ₂ 、Co(salen)、Co(acacen)、BH ₃ Etc.; the oxidant used includes, but is not limited to, oxygen, air, hydrogen peroxide, etc., wherein Mn (dpm) ₂ Is bis (2, 6-tetramethyl-3, 5-heptanedionato) manganese, mn (dpm) ₃ Tris (2, 6-tetramethyl-3, 5-heptanedionato) manganese (CAS registry number 14324-99-3, also known as tris (2, 6-tetramethyl-3, 5-heptenoic acid) manganese), mn (acac) ₂ Manganese (II) bis (acetylacetonate) (CAS registry number 14024-58-9), co (acac) ₂ Is cobalt (II) bis (acetylacetonate) (CAS registry number 193620-63-2), co(salen) N, N '-bis (salicyl) ethylenediamine cobalt (II) (CAS registry number 14167-18-1), co (acacen) N, N' -bis (acetylacetonato) ethylenediamine cobalt (II), co (sdmg) ₃ Is sodium bis (N-salicylidene-2-aminoisobutyrone) cobaltate (CAS registry number 704900-51-6); a preferred catalyst system is PhSiH/Mn (dpm) ₃ Or PhSiH/Mn (acac) ₂ Preferably, the oxidant is oxygen.

The above reaction is preferably carried out in a solvent including, but not limited to: acetic acid, methanol, ethanol, isopropanol, 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 mixtures thereof.

Detailed Description

The following examples are presented to further illustrate the present disclosure, but are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured using Bruker AVANCE-400 NMR spectrometer or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid chromatograph-Mass spectrometer (manufacturer: agilent, MS model: 6110/6120 Quadrupole MS). Waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis was performed using 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 preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson GX-281.

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

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

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

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Litsea crassirhizomes 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 can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shao Yuan Chemical technology (Accela ChemBio Inc), darril 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 clear blue 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 unless otherwise specified.

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

The progress of the reaction in examples was monitored by Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of an eluent for silica gel column chromatography for purifying a compound, 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

N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 1

First step of

2-amino-4-hydroxy-5-methoxybenzoic acid methyl ester 1b

The compound methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate 1a (10.0 g,31.5mmol, shanghai Bingyao pharmaceutical Co., ltd.) was dissolved in tetrahydrofuran (100 mL), 10% Pd/C (1.6 g,1.5 mmol) was added, hydrogen substitution was performed three times, and the reaction was stirred for 16 hours. Filtration through celite and concentration of the filtrate under reduced pressure to dryness afforded the title compound 1b (6.0 g), yield: 96.5 percent.

MS m/z(ESI)：198.0[M+1]。

Second step of

2-amino-4- (2, 2-dimethoxyethoxy) -5-methoxybenzoic acid methyl ester 1c

Compound 1b (2.7g, 13.7mmol) was dissolved in acetonitrile (50 mL), and cesium carbonate (9.0g, 27.6mmol) and 2-bromo-1, 1-dimethoxyethane (3.5g, 20.7mmol) were added, and the mixture was heated to reflux for 16 hours. Cooling and filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 1c (3.5 g), yield: 89.7 percent.

MS m/z(ESI)：286.2[M+1]。

The third step

4-amino-7-methoxybenzofuran-5-carboxylic acid methyl ester 1d

Compound 1c (150mg, 0.5 mmol) was dissolved in chlorobenzene (10 mL), AMBERLYST (R) 15 (20 mg) was added, and the mixture was heated to 120 ℃ for reaction for 14 hours. Cooling and filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 1d (40 mg), yield: 34.4 percent.

MS m/z(ESI)：222.0[M+1]。

The fourth step

6-methoxy-2-methylfuro [2,3-h ] quinazolin-4-ol 1e

Compound 1d (40mg, 0.2mmol) was dissolved in acetonitrile (3.0 mL), methanesulfonic acid (35mg, 0.4 mmol) was added, and the mixture was heated to 100 ℃ with a sealed tube and reacted for 12 hours. After cooling, it was neutralized with a 2N aqueous solution of sodium hydroxide, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1e (30 mg) in yield: 72.0 percent.

MS m/z(ESI)：231.1[M+1]。

The fifth step

2-Methylfuro [2,3-h ] quinazoline-4, 6-diol 1f

Compound 1e (460mg, 2.0 mmol) was dissolved in chloroform (50 mL), boron tribromide (4.0 mL,1M dichloromethane solution) was added, and the mixture was heated to reflux for 16 hours. Cooling, neutralisation with 1N aqueous sodium bicarbonate, filtration and washing the solid with water to dryness gave the title compound 1f (350 mg), yield: 81.7 percent.

MS m/z(ESI)：217.0[M+1]。

The sixth step

(S) -2-methyl-6- ((tetrahydrofuran-3-yl) oxy) furo [2,3-h ] quinazolin-4-ol 1h

Compound 1f (250mg, 1.2mmol) was dissolved in N, N-dimethylformamide (5 mL), and cesium carbonate (753mg, 2.3mmol) and 1g (420mg, 1.7mmol, journal of Medicinal chemistry,2011,54, 4092-4108) were added and heated to 60 ℃ for reaction for 1 hour. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 1h (200 mg), yield: 60.4 percent.

MS m/z(ESI):287.0[M+1]。

Seventh step

(S) -2-methyl-6- ((tetrahydrofuran-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-ol 1i

The compound (1 h) (300mg, 1.0 mmol) was dissolved in methanol (10 mL), 10% palladium on carbon catalyst (50 mg) was added, the mixture was replaced with hydrogen three times, and the reaction was stirred for 16 hours. Filtration through celite and concentration of the filtrate under reduced pressure gave the title compound 1i (75 mg), yield: 24.8 percent.

MS m/z(ESI):289.0[M+1]。

Eighth step

Compound 1i (150mg, 0.5 mmol) was dissolved in N, N-dimethylformamide (5 mL), and compound (R) -1- (3-1-aminoethyl-5- (trifluoromethyl) aniline hydrochloride 1j (233mg, 0.96mmol), prepared by the method disclosed in example B-6N on page 106 of the specification in patent application "WO 2018/115380"), N-diisopropylethylamine (200mg, 1.6 mmol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (345mg, 0.8mmoL) and 1, 8-diazacyclo [5,4,0] undec-7-ene (158mg, 1.0 mmol) were sequentially added, replaced with nitrogen gas three times, heated to 80 ℃ for 14 hours, cooled, filtered, concentrated under reduced pressure in filtrate, and the residue was purified by silica gel column chromatography using silica gel column chromatography as eluent system B to give the title compound 1 (45 mg) in 18.2% yield.

MS m/z(ESI)：475.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.48(s,1H),6.88(d,2H),6.70(d,1H),5.52(q,1H),5.13(dt,1H),4.68(t,2H),3.94-3.86(m,3H),3.81(td,1H),3.39(t,2H),2.36(s,3H),2.22-2.04(m,2H),1.53(d,3H)。

Example 2

N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 2

First step of

N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) furo [2,3-h ] quinazolin-4-amine 2b

Compound 1h (30mg, 0.1 mmol) was dissolved in N, N-dimethylformamide (3 mL), and compound (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine hydrochloride 2a (30mg, 0.13mmol), prepared using the method disclosed in example B-5 on page 141 of the specification in patent application "EP2018086197", benzotriazole-1-tris (trimethylamino) -trifluorophosphate (60mg, 0.14mmoL), and 1, 8-diazacyclo [5,4,0] undec-7-ene (32mg, 0.2mmol) were added sequentially, replaced with nitrogen three times, and heated to 80 ℃ for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 2B (20 mg), yield: 41.7 percent.

MS m/z(ESI):458.1[M+1]。

Second step of

N- ((R) -1- (3- (difluoromethyl) -2-fluorobenzene) ethyl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 2

Compound 2b (20mg, 0.04mmol) was dissolved in methanol (10 mL), and 10% palladium on carbon catalyst (10 mg) was added thereto, and the mixture was replaced with hydrogen gas three times, followed by stirring to conduct the reaction for 16 hours. Filtration through celite, and concentration of the filtrate under reduced pressure gave the title compound 2 (4.0 mg), yield: 20 percent.

MS m/z(ESI):460.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.63(s,1H),7.58(t,1H),7.46(t,1H),7.21(t,1H),7.01(t,1H),5.84(q,1H),5.25(d,1H),4.78(t,3H),4.01(d,2H),3.93(dt,1H),3.49(t,2H),2.40(s,3H),2.28(p,1H),2.19(t,1H),1.67(d,3H)。

Example 3

2, 2-difluoro-2- (2-fluoro-3- ((R) -1- ((2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-yl) amino) ethyl) phenyl) ethan-1-ol 3

First step of

2, 2-difluoro-2- (2-fluoro-3- ((R) -1- ((2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) furo [2,3-h ] quinazolin-4-yl) amino) ethyl) phenyl) ethan-1-ol 3b

Compound 1h (50mg, 0.17mmol) was dissolved in N, N-dimethylformamide (5 mL), and the compound (R) -2- (3- (1-aminoethyl) -2-fluorophenyl) -2, 2-difluoroethanolate hydrochloride 3a (58mg, 0.23mmol, prepared using the method disclosed in example B-5 on page 105 of the specification in the patent application "U.S. Pat. No. 2019194192"), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (100mg, 0.23mmoL), and 1, 8-diazacyclo [5,4,0] undec-7-ene (53mg, 0.35mmol) were added sequentially, replaced with nitrogen three times, and heated to 80 ℃ for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 3B (60 mg), yield: 70.4 percent.

MS m/z(ESI):488.0[M+1]。

Second step of

2, 2-difluoro-2- (2-fluoro-3- ((R) -1- ((2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-yl) amino) ethyl) phenyl) -ethan-1-ol 3

Compound 3b (60mg, 0.12mmol) was dissolved in methanol (10 mL), 10% palladium on carbon catalyst (20 mg) was added, the mixture was replaced with hydrogen gas three times, and the reaction was stirred for 16 hours. Filtration through celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 3 (14.7 mg), yield: 24.4 percent.

MS m/z(ESI):490.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.62(s,1H),7.56(t,1H),7.44(t,1H),7.18(t,1H),5.85(q,1H),5.25(dq,1H),4.77(t,2H),4.10-4.01(m,2H),4.00(d,3H),3.92(td,1H),3.48(t,2H),2.41(s,3H),2.33-2.16(m,2H),1.66(d,3H)。

Example 4

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-methoxy-2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 4

First step of

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-methoxy-2-methylfuro [2,3-h ] quinazolin-4-amine 4a

Compound 1e (30mg, 0.13mmol) was dissolved in N, N-dimethylformamide (2 mL), and compound 1j (40mg, 0.116mmol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (37mg, 0.16mmoL) and 1, 8-diazacyclo [5,4,0] undec-7-ene (30mg, 0.2mmol) were added in this order, and the mixture was reacted with nitrogen three times, heated to 80 ℃ and reacted for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 4a (10 mg), yield: 18.4 percent.

MS m/z(ESI):417.1[M+1]。

Second step of

Compound 4a (10 mg, 0.02mmol) was dissolved in methanol (5 mL), 10% Pd/C (20 mg) was added, hydrogen gas was substituted three times, and the reaction was stirred for 16 hours. Filtration through celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 4 (2.0 mg), yield: 20.0 percent.

MS m/z(ESI):419.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.58(s,1H),7.00(s,1H),6.97(s,1H),6.80(t,1H),5.62(q,1H),4.82-4.74(m,2H),3.97(s,3H),3.49(t,2H),2.46(s,3H),1.63(d,3H)。

Example 5

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 5

First step of

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylfuro [2,3-h ] quinazolin-4-amine 5a

Compound 1e (200mg, 0.87mmol) was dissolved in N, N-dimethylformamide (20 mL), followed by addition of compound 2a (196mg, 0.87mmol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (576 mg, 1.30mmoL) and 1, 8-diazacyclo [5,4,0] undec-7-ene (198.4 mg,1.3 mmol), nitrogen substitution three times, and heating to 80 ℃ for 5 hours. Cooled, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 5a (80 mg), yield: 22.9 percent.

MS m/z(ESI):401.9[M+1]。

Second step of

Dissolving compound 5a (30mg, 0.075mmol) in methanol (5 mL), adding 10% Pd/C (10 mg), replacing with hydrogen gas three times, and stirring for reaction for 36 hours. Filtration through celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 5 (5 mg), yield: 16.6 percent.

MS m/z(ESI):404.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.66(s,1H),7.62-7.59(m,1H),7.49-7.46(m,1H),7.25-7.22(m,2H),7.03(t,1H),4.82-4.78(m,3H),4.01(s,3H),3.52-3.48(m,2H),3.42(s,3H),1.70(d,3H)。

Example 6

2-methyl-N- ((R) -1- (4- (2- ((methylamino) methyl) phenyl) thiophen-2-yl) ethyl) -6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 6

First step of

N- ((R) -1- (4-bromothien-2-yl) ethyl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 6b

Compound 1i (50mg, 0.17mmol) was dissolved in N, N-dimethylformamide (2 mL), and (R) -1- (4-bromothiophen-2-yl) ethylamine hydrochloride 6a (125mg, 0.52mmol, prepared by the method disclosed in example INT-29 on page 117 of the specification in patent application "WO 2018/172250"), N-diisopropylethylamine (67mg, 0.52mmol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (115mg, 0.26mmol) and 1, 8-diazacyclo [5,4,0] undec-7-ene (53mg, 0.35mmol) were added sequentially, replaced with nitrogen three times, and heated to 80 ℃ for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 6B (50 mg), yield: 60.5 percent.

MS m/z(ESI):476.0[M+1]。

Second step of

Compound 6b (50mg, 0.11mmol) was dissolved in 1, 4-dioxane (4 mL), water (1 mL) was added, and the mixture was stirred at room temperature for 10 minutes, followed by addition of palladium tetratriphenylphosphine (60mg, 0.05mmol), potassium carbonate (30mg, 0.21mmol) and pinacol ester of 2- (N-methylaminomethyl) phenylboronic acid (40mg, 0.116mmol) in this order, nitrogen substitution was carried out three times, and the reaction was stirred while heating to 100 ℃ for 16 hours. Cooling, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 6 (7.2 mg), yield: 13.2 percent.

MS m/z(ESI):517.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.53(s,1H),7.41(d,1H),7.32(d,1H),7.30(s,2H),7.18(s,1H),7.13(s,1H),6.05(q,1H),5.20(dq,1H),4.79(t,2H),4.03-3.96(m,3H),3.90(td,1H),3.72(s,2H),3.51(t,2H),2.54(s,3H),2.28-2.21(m,4H),2.21–2.13(m,1H),1.78(d,3H)。

Example 7

N- (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -7, 8-dihydrofuro [3,2-h ] quinazolin-4-amine 7

First step of

3, 5-dimethoxy-2-nitrobenzoic acid methyl ester 7b

The compound methyl 3, 5-dimethoxybenzoate 7a (9 g,45.9mmol, shanghai Biao medicine Co., ltd.) was dissolved in acetic anhydride (60 mL), and nitric acid (2 g,45.9 mmol) was added dropwise under ice-water bath. After stirring for 10 minutes, ice water was added to the reaction system to precipitate a pale green solid, which was filtered, and the filter cake was collected to obtain the title compound 7b (7.6 g), yield: 68.7 percent.

MS m/z(ESI):242.0[M+1]。

Second step of

3-hydroxy-5-methoxy-2-nitrobenzoic acid methyl ester 7c

Compound 7b (0.71g, 3.0 mmol) was dissolved in methylene chloride (10 mL), and aluminum trichloride (1.58g, 11.8mmol) was added thereto in an ice-water bath, followed by stirring and reacting for 3 hours. The reaction system was quenched by pouring into ice diluted hydrochloric acid, extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride solution (10 mL) with water, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 7c (673 mg), yield: 92.5 percent.

MS m/z(ESI):228.0[M+1]。

The third step

2-amino-3-hydroxy-5-methoxybenzoic acid methyl ester 7d

Compound 7c (3.32g, 14.6 mmol) was dissolved in methanol (25 mL), 10% palladium on carbon catalyst (0.3 g) was added, and the reaction was replaced with hydrogen 3 times, stirred for 16 hours, filtered and concentrated under reduced pressure to give the title compound 7d (2.88 g), yield: 99.8 percent.

MS m/z(ESI):198.0[M+1]。

The fourth step

2-amino-3- (2, 2-dimethoxyethoxy) -5-methoxybenzoic acid methyl ester 7e

Compound 7d (0.53g, 2.7 mmol) was dissolved in acetonitrile (15 mL), bromoacetaldehyde dimethanol (0.7 g,4.1 mmol) and cesium carbonate (1.8g, 5.5 mmol) were added in this order, and the mixture was refluxed for 16 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 7e (767 mg), yield: and (3.2).

MS m/z(ESI):286.0[M+1]。

The fifth step

7-amino-4-methoxybenzofuran-6-carboxylic acid methyl ester 7f

Compound 7e (2.0 g,7.0 mmol) was dissolved in polyphosphoric acid (20 mL), and stirred at 100 ℃ for 2 hours. The heating was stopped, the pH was adjusted to about 7 with saturated sodium bicarbonate solution under ice bath, ethyl acetate was extracted (30 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 7f (800 mg), yield: 51.6 percent.

MS m/z(ESI):222.0[M+1]。

The sixth step

7g of 6-methoxy-2-methylfuro [3,2-h ] quinazolin-4-ol

Compound 7f (0.41g, 1.9 mmol) was dissolved in acetonitrile (20 mL), methanesulfonic acid (0.2 g,2.1 mmol) was added dropwise, and the mixture was stirred at 100 ℃ for 16 hours with tube sealing. The reaction solution was concentrated under reduced pressure, and the pH was neutralized to about 7 with a saturated sodium bicarbonate solution to obtain 7g (427 mg) of the title compound, yield: 93.7 percent.

MS m/z(ESI):231.0[M+1]。

Seventh step

2-methylfuro [3,2-h ] quinazoline-4, 6-diol 7h

7g (0.6 g, 2.60mmol) of the compound was dissolved in chloroform (20 mL), boron tribromide (1M dichloromethane solution, 5.21 mL) was added dropwise, and the reaction was stirred at 80 ℃ for 16 hours. Cooled, concentrated under reduced pressure, neutralized with saturated sodium bicarbonate and filtered, and the solid collected was the title compound 7h (563 mg), yield: 88.7 percent.

MS m/z(ESI):217.0[M+1]。

Eighth step

(S) -2-methyl-6- (tetrahydrofuran-3-yl) oxy) furo [3,2-h ] quinazolin-4-ol 7i

Compound 7h (0.06g, 277.53. Mu. Mol) was dissolved in N, N-dimethylformamide (5 mL), and compound 1g (0.07g, 288.90. Mu. Mol) and cesium carbonate (0.18g, 552.45. Mu. Mol) were added in this order and stirred at 60 ℃ for 1 hour. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 7i (79 mg), yield: 50.3 percent.

MS m/z(ESI):287.0[M+1]。

The ninth step

(S) -2-methyl-6- ((tetrahydrofuran-3-yl) oxy) -7, 8-dihydrofuro [3,2-h ] quinazolin-4-ol 7j

Compound 7i (0.04g, 139.72 μmol) was dissolved in methanol (5 mL), 10% palladium on carbon catalyst (0.01g, 27.94 μmol) was added, and replaced with hydrogen gas 3 times, and the reaction was stirred for 16 hours, and the reaction solution was filtered and concentrated under reduced pressure to obtain crude product 7j (32 mg), yield: 79.4%, and the product is used in the next reaction without purification.

MS m/z(ESI):289.0[M+1]。

The tenth step

Compound 7j (0.04g, 138.7454. Mu. Mol) was dissolved in N, N-dimethylformamide (5 mL), and compound (R) -1- (3-amino-5- (trifluoromethyl) phenethylamine hydrochloride 1j (0.057g, 279.15. Mu. Mol), N-diisopropylethylamine (0.053g, 410.08. Mu. Mol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (0.122g, 275.84. Mu. Mol), and 1, 8-diazacyclo [5,4,0] undec-7-ene (0.053g, 348.14. Mu. Mol) were sequentially added, and the mixture was replaced with nitrogen, heated to 80 ℃ for 14 hours, cooled, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 7 (10 mg) in 15% yield.

MS m/z(ESI):475.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.14(s,1H),6.99(d,2H),6.81(s,1H),5.64(q,1H),5.37-5.19(m,1H),4.77(t,2H),3.99(dddd,4H),3.39-3.24(m,5H),2.33(qd,1H),2.19(dt,1H),1.64(d,3H)。

Example 8

2, 2-difluoro-2- (2-fluoro-3- ((R) -1- ((2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -7, 8-dihydrofuro [3,2-h ] quinazolin-4-yl) amino) ethyl) phenyl) ethan-1-ol 8

Using the synthetic route described in example 7, substituting compound 1j as the starting material for compound 3a in the tenth step, compound 8 (10 mg) was obtained, in yield: 11.8 percent.

MS m/z(ESI)：490.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.58(t,1H),7.45(t,1H),7.20(d,2H),5.86(q,1H),5.26(t,1H),4.78(t,2H),4.18-3.84(m,6H),3.28-3.30(m,2H),2.45-2.31(m,4H),2.21(dt,1H),1.69(d,3H)。

Example 9

(R) -1- (4- (6- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -8-methyl- [1,3] dioxolano [4,5-h ] quinazolin-4-yl) piperidin-1-yl) ethan-1-one 9

First step of

(E) -N- (benzo [ d ] [1,3] dioxan-4-yl) -2- (hydroxyaminoylidene) acetamide 9c

Chloral hydrate 9b (5.60g, 33.0mmol, shanghai Tantake Tech Co., ltd.) and anhydrous sodium sulfate (27.76g, 195.4mmol) were dissolved in 50mL of water, and the compounds benzo [ d ] [1,3] dioxolan-4-amine 9a (4g, 29.2mmol, shanghai Shaoshan Yu Co., ltd.), hydroxylamine sulfate (24.9g, 151.7mmol) and concentrated hydrochloric acid (3.1 mL) were added in this order. The mixture was stirred at room temperature for 10 minutes, then heated to 60 ℃ for 1.5 hours, and finally allowed to react overnight at room temperature. The reaction precipitated a solid, which was filtered after standing, and the filter cake was drained to give the title compound 9c (4.5 g). Yield: 74.1 percent.

MS m/z(ESI):209.0[M+1]。

Second step of

6H- [1,3] dioxolano [4,5-g ] indole-6, 7 (8H) -dione 9d

Compound 9c (4.5g, 21.6 mmol) was dissolved in 70mL of methanesulfonic acid and heated to 45 ℃ to react for 1 hour. After cooling, the mixture was poured into ice water and stirred for 1 hour, the reaction precipitated a solid, which was left to stand and filtered, and the filter cake was drained to give the title compound 9d (3.76 g). Yield: 91.0 percent.

MS m/z(ESI):191.9[M+1]。

The third step

4-aminobenzo [ d ] [1,3] dioxolane-5-carboxylic acid 9e

Compound 9d (3.76g, 19.7 mmol) and sodium hydroxide (6.3g, 157.5 mmol) were dissolved in 45mL of water in this order, and 30% hydrogen peroxide (22.3g, 196.7mmol, 24mL) was slowly added dropwise under ice bath, and stirred for 30 minutes. 2M dilute hydrochloric acid was added to neutralize the reaction solution to pH 7 or so, and a solid was precipitated from the system, which was then filtered after standing, washed with water, and the filter cake was drained to give the title compound 9e (2.33 g). Yield: 65.4 percent.

MS m/z(ESI):182.0[M+1]。

The fourth step

4-amino-7-bromobenzo [ d ] [1,3] dioxolane-5-carboxylic acid 9f

Compound 9e (1.833g, 10.1mmol) was dissolved in 50mL acetonitrile and N-bromosuccinimide (1.8g, 10.1mmol) was added portionwise at room temperature for 2 hours. The reaction precipitated a solid, which was filtered after standing, and the filter cake was drained to give the title compound 9f (2.6 g). Yield: 98.8 percent.

MS m/z(ESI):259.9[M+1]。

The fifth step

4-bromo-8-methyl- [1,3] dioxolano [4,5-H ] quinazolin-6 (7H) -one 9g

Compound 9f (2.6g, 10.0 mmol) was dissolved in 20mL of acetic anhydride and the reaction was refluxed for 8 hours. After completion of the reaction, acetic anhydride was removed by concentration under reduced pressure, 30mL of aqueous ammonia was added, and the mixture was stirred at room temperature for 4 hours. Then, 30mL of a 10% aqueous solution of sodium hydroxide was added, and the mixture was heated to 60 ℃ to react for 30 minutes. The reaction solution was cooled to room temperature, concentrated hydrochloric acid was added dropwise in an ice bath to adjust the pH to about 8, and a large amount of solid was precipitated from the system, which was then allowed to stand and filtered, and the filter cake was drained to obtain 9g (1.8 g) of the title compound. Yield: and (3.6).

MS m/z(ESI):282.8[M+1]。

The sixth step

(R) -4-bromo-8-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) - [1,3] dioxolano [4,5-h ] quinazolin-6-amine 9i

Compound 9g (66mg, 233. Mu. Mol) and compound (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamine hydrochloride 9h (63mg, 233. Mu. Mol, prepared by the method disclosed in example B-6a on page 89 of the specification of patent application "CN 110167928A") were dissolved in 2.5mL of anhydrous N, N-dimethylformamide, and N, N-diisopropylethylamine (30mg, 232. Mu. Mol), 1, 8-diazacyclo [5,4,0] undec-7-ene (53mg, 348. Mu. Mol), and benzotriazole-1-tris (trimethylamino) -trifluorophosphate (134mg, 303. Mu. Mol) were sequentially added, stirred for 10 minutes under argon, and then heated to 80 ℃ for 5 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 9i (116 mg), yield: 99.6 percent.

MS m/z(ESI):498.8[M+1]。

Seventh step

(R) -1- (4- (8-methyl-6- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) - [1,3] dioxolano [4,5-H ] quinazolin-4-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one 9k

Compound 9i (116mg, 232. Mu. Mol), compound 1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 9j (80mg, 319. Mu. Mol, shanghai Shao reagent, ltd.), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (19mg, 23. Mu. Mol) and anhydrous sodium carbonate (50mg, 472. Mu. Mol) were dissolved in 3mL dioxane and 0.4mL water, replaced with argon 3 times, and heated to 80 ℃ for 8 hours. Cooled to room temperature, filtered over celite, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system C to give the title compound 9k (100 mg), yield: 79.2 percent.

MS m/z(ESI):544.0[M+1]。

Eighth step

Compound 9k (100mg, 184. Mu. Mol) was dissolved in 10mL of ethanol, 10% palladium on carbon catalyst (100mg, 94. Mu. Mol) was added thereto, and the mixture was replaced with hydrogen gas 3 times, followed by stirring for 16 hours. The reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 9 (6.4 mg), yield: 7 percent.

MS m/z(ESI)：516.2[M+1]。

¹ H NMR (500 MHz, chloroform-d) < delta > 7.23-7.12 (m, 1H), 7.05 (d, 1H), 6.91 (d, 1H), 6.80 (s, 1H), 6.18 (t, 2H), 5.64 (t, 1H), 4.87-4.70 (m, 1H), 3.92 (d, 1H), 3.18 (q, 1H), 3.08-2.95 (m, 1H), 2.68-2.61 (m, 1H), 2.58 (s, 3H), 2.10 (d, 3H), 2.00-1.86 (m, 2H), 1.75 (qd, 2H), 1.64 (dd, 3H).

Example 10

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -4- (3, 6-dihydro-2H-pyran-4-yl) -8-methyl- [1,3] dioxolan [4,5-H ] quinazolin-6-amine 10

First step of

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -4-bromo-8-methyl- [1,3] dioxolano [4,5-h ] quinazolin-6-amine 10a

Compound 9g (120mg, 424. Mu. Mol) and compound 1j (103mg, 428. Mu. Mol) were dissolved in 3mL of anhydrous N, N-dimethylformamide, and N, N-diisopropylethylamine (55mg, 426. Mu. Mol), 1, 8-diazacyclo [5,4,0] undec-7-ene (129mg, 847. Mu. Mol) and benzotriazole-1-tris (trimethylammonio) -trifluorophosphate (282mg, 638. Mu. Mol) were sequentially added, stirred under argon atmosphere for 10 minutes, and then heated to 80 ℃ for reaction for 5 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 10a (198 mg), yield: 99.5 percent.

MS m/z(ESI)：468.9[M+1]。

Second step of

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -4- (3, 6-dihydro-2H-pyran-4-yl) -8-methyl- [1,3] dioxolano [4,5-H ] quinazolin-6-amine 10

Compound 10a (198mg, 422. Mu. Mol), compound 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane 10b (133mg, 633.1012. Mu. Mol, shanghai Shao Yuan reagent, ltd), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (34mg, 42. Mu. Mol) and anhydrous sodium carbonate (90mg, 849. Mu. Mol) were dissolved in 3mL dioxane and 0.4mL water, replaced with argon 3 times, heated to 80 ℃ and reacted for 8 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by high performance liquid preparative chromatography gave the title compound 10 (20.6 mg), yield: 10.3 percent.

MS m/z(ESI):473.1[M+1]。

¹ H NMR (500 MHz, chloroform-d) < delta > 7.10 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 6.80 (s, 1H), 6.50 (s, 1H), 6.21 (s, 2H), 5.75-5.55 (m, 2H), 4.36 (d, 2H), 3.95 (t, 2H), 3.86 (s, 2H), 2.59 (d, 5H), 1.65 (d, 3H).

Example 11

(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) ethan-1-one 11

First step of

(E) -N- (2, 3-dihydrobenzofuran-4-yl) -2- (hydroxyaminoidene) acetamide 11b

Compound 2, 3-dihydrobenzofuran-4-amine 11a (7 g,51.79mmol, shanghai Biao pharmaceutical Co., ltd.) and hydroxylamine sulfate (43g, 261.97mmol) were dissolved in water (100 mL), and concentrated hydrochloric acid (6.17 mL), 2-trichloroethane-1, 1-diol (9.4g, 56.83mmol) and anhydrous sodium sulfate (51g, 359.04mmol) were added in this order. The reaction mixture was heated to 60 ℃ and stirred for 30 minutes, then cooled to room temperature and stirred for 16 hours, the reaction mixture was filtered, and the filter cake was collected to obtain the title compound 11b (10.7 g), yield: 93.6 percent.

MS m/z(ESI)：207.0[M+1]。

Second step of

7, 8-dihydro-1H-furo [2,3-g ] indole-2, 3-dione 11c

Compound 11b (4.0g, 19.4mmol) was mixed with methanesulfonic acid (9.3g, 96.76mmol), and then heated to 45 ℃ and stirred for 1 hour. The reaction was diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (30 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound 11c (1.5 g), yield: 40.9 percent.

MS m/z(ESI)：190.0[M+1]。

The third step

4-amino-2, 3-dihydrobenzofuran-5-carboxylic acid 11d

Compound 11c (1.5g, 7.93mmol) and solid sodium hydroxide (2.55g, 63.75mmol) were dissolved in water (10 mL), hydrogen peroxide (4.50g, 39.65mmol,30% pure) was added under ice-water bath. After stirring at room temperature for 30 minutes, 2M dilute hydrochloric acid was added to neutralize the reaction mixture to pH 7, and a solid precipitated out, the mixture was left to stand, filtered, washed with water, and the filter cake was drained to give the title compound 11d (0.8 g), yield: and 56.3 percent.

MS m/z(ESI)：180.0[M+1]。

The fourth step

4-amino-2, 3-dihydrobenzofuran-5-carboxylic acid methyl ester 11e

Compound 11d was dissolved in methylene chloride (20 mL) and methanol (2 mL), and trimethylsilylated diazomethane (2M, 11.82mL) was added dropwise and reacted with stirring for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 11e (0.5 g), yield: 54.5 percent.

MS m/z(ESI)：194.1[M+1]。

The fifth step

4-amino-7-iodo-2, 3-dihydrobenzofuran-5-carboxylic acid methyl ester 11f

Compound 11e (0.15g, 776.40. Mu. Mol) was dissolved in acetonitrile (5 mL), and N-iodosuccinimide (0.175g, 777.83. Mu. Mol) was added and stirred in an ice-water bath for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 11f (0.22 g), yield: 88.8 percent.

MS m/z(ESI)：320.0[M+1]。

The sixth step

11g of 6-iodo-2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-4-ol

Compound 11f (0.2g, 626.77. Mu. Mol) was dissolved in acetonitrile (3 mL), methanesulfonic acid (0.07g, 728.36. Mu. Mol) was added, and the mixture was stirred with heating at 100 ℃ for 16 hours while being sealed. The reaction mixture was concentrated under reduced pressure, the pH was neutralized with a saturated sodium bicarbonate solution to about 7, a solid was precipitated, and the solid was collected by filtration to obtain 11g (0.18 g) of the title compound in terms of yield: 87.5 percent.

MS m/z(ESI)：329.0[M+1]

Seventh step

(R) -2, 2-difluoro-2- (2-fluoro-3- (1- ((6-iodo-2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-4-yl) amino) ethyl) phenyl) ethan-1-ol 11h

Compound 11g (0.08g, 243.82. Mu. Mol) was dissolved in N, N-dimethylformamide (5 mL), and compound 3a (74mg, 289.4. Mu. Mol), N-diisopropylethylamine (0.038g, 294.02. Mu. Mol), 1, 8-diazacyclo [5,4,0] undec-7-ene (0.075g, 492.66. Mu. Mol), and benzotriazole-1-tris (trimethylamino) -trifluorophosphate (0.215g, 486.12. Mu. Mol) were added in this order, and the mixture was replaced with nitrogen gas three times, heated to 80 ℃ and reacted for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 11h (60 mg), yield: 46.5 percent.

MS m/z(ESI)：530.0[M+1]。

Eighth step

Compound 11h (0.04g, 75.57. Mu. Mol) and N, N-Dimethylpropylurea (DMPU) (19.37mg, 151.14. Mu. Mol) were dissolved in tetrahydrofuran (2 mL), isopropyl magnesium bromide (1M tetrahydrofuran solution, 377.86. Mu.L) was added dropwise at-20 ℃ and, after stirring for 1 hour while maintaining the temperature, 1-acetylpiperidin-4-one (21.3368mg, 151.14. Mu. Mol) was added and warmed to room temperature and stirred for 10 hours. The reaction was quenched with methanol, filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title compound 11 (2 mg), yield: 4.8 percent.

MS m/z(ESI):545.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.21(s,1H),7.61(t,1H),7.47(t,1H),7.21(t,1H),5.90(q,1H),4.78(t,2H),4.61(s,3H),4.49(d,1H),3.67(t,1H),3.50-3.42(m,2H),3.22-3.12(m,1H),2.45(s,5H),2.18(s,3H),1.79(dd,13.8Hz,2H),1.69(d,3H)。

Example 12

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-4-amine 12

First step of

6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-4-ol 12a

Compound 11g (40mg, 122. Mu. Mol), compound 10b (51mg, 243. Mu. Mol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (20mg, 23. Mu. Mol) and anhydrous sodium carbonate (26mg, 245. Mu. Mol) were dissolved in 4mL of N, N-dimethylformamide and 1mL of water, replaced with nitrogen 3 times, and heated to 100 ℃ for reaction for 3 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system C gave the title compound 12a (30 mg), yield: 86.5 percent.

MS m/z(ESI)：285.0[M+1]。

Second step of

Compound 12a (30mg, 106. Mu. Mol) was dissolved in N, N-dimethylformamide (3 mL), and compound 1j (50mg, 208. Mu. Mol), N-diisopropylethylamine (27mg, 209. Mu. Mol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (93mg, 210. Mu. Mol), and 1, 8-diazacyclo [5,4,0] undec-7-ene (30mg, 210. Mu. Mol) were added in this order, replaced with nitrogen three times, and heated to 80 ℃ for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure, and purification of the resulting title compound 12 (18 mg) from the residue by high performance liquid preparative chromatography, yield: 37 percent.

MS m/z(ESI):471.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ7.34(s,1H),7.07(s,1H),6.89(t,1H),6.80(d,1H),6.43(dt,1H),5.62(dt,2H),4.78(t,2H),4.36(q,2H),3.95(t,2H),3.85(s,2H),3.53(t,2H),2.63-2.57(m,5H),1.65(d,3H)。

Example 13

(R) -1- (4- (4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one 13

Using the synthetic route described in example 12, substituting the first step starting compound 10b for compound 9j gave the title compound 13 (30 mg), in yield: 33.4 percent.

MS m/z(ESI)：512.3[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ8.03(d,1H),7.01-6.95(m,2H),6.80(d,1H),6.41(ddt,1H),5.63(q,1H),4.76(td,2H),4.26-4.20(m,2H),3.81(t,1H),3.75(t,1H),3.46(t,2H),2.76-2.72(m,1H),2.68-2.60(m,1H),2.48(s,3H),2.17(d,3H),1.63(d,3H)。

Example 14

(R) -2- (3- (1- ((6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-4-yl) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroethan-1-ol 14

Compound 11h (60mg, 113. Mu. Mol), compound 10b (48mg, 228. Mu. Mol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (48mg, 56. Mu. Mol) and anhydrous sodium carbonate (24mg, 226. Mu. Mol) were dissolved in 4mL of dioxane and 1mL of water, replaced with nitrogen 3 times, and heated to 100 ℃ for reaction for 3 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system C gave the title compound 14 (12 mg), yield: 21.6 percent.

MS m/z(ESI):486.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ7.54(t,1H),7.51-7.46(m,1H),7.40(s,1H),7.18(t,1H),6.47(tt,1H),5.83(q,2H),4.79(t,2H),4.40(q,2H),4.15(t,2H),3.99(t,2H),3.53(td,2H),2.64(dt,2H),2.54(s,3H),1.71(d,3H)。

Example 15

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydrofuro [2,3-H ] quinazolin-4-amine 15

First step of

7-iodo-2, 3-dihydrobenzofuran-4-amine 15a

Compound 11a (8g, 37mmol) was dissolved in acetonitrile (100 mL), N-iodosuccinimide (9.1g, 40.4mmol) was added under an ice-water bath, and the mixture was stirred for 1 hour while maintaining the temperature, and then allowed to spontaneously warm to room temperature and stirred for reaction for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 15a (8.5 g), yield: 88 percent.

MS m/z(ESI)：261.9[M+1]。

Second step of

7- (3, 6-dihydro-2H-pyran-4-yl) -2, 3-dihydrobenzofuran-4-amine 15b

Compound 15a (2g, 7.6 mmol), compound 10b (2.4g, 11.4 mol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (650mg, 767.7. Mu. Mol) and anhydrous sodium carbonate (1.6g, 15.1mmol) were dissolved in 40mL of 1, 4-dioxane and 10mL of water, replaced with nitrogen 3 times, and heated to 100 ℃ for 2 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system C gave the title compound 15b (1.2 g), yield: 72.1 percent.

MS m/z(ESI)：218.0[M+1]。

The third step

7- (tetrahydro-2H-pyran-4-yl) -2, 3-dihydrobenzofuran-4-amine 15c

Compound 15b (1g, 4.6 mmol) was dissolved in methanol (20 mL), 10% palladium on carbon catalyst (300 mg) was added, hydrogen substitution was carried out three times, and the reaction was stirred for 16 hours. Filtration through celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 15c (730 mg), yield: 72.3 percent.

MS m/z(ESI)：220.0[M+1]。

The fourth step

(E) -2- (hydroxyaminoylidene) -N- (7- (tetrahydro-2H-pyran-4-yl) -2, 3-dihydrobenzofuran-4-yl) acetamide 15d

Compound 15c (0.7g, 3.19mmol), hydroxylamine sulfate (2.6g, 15.84mmol) were dissolved in water (15 mL), concentrated hydrochloric acid (0.32 mL), 2-trichloroethane-1, 1-diol (792mg, 4.79mmol), anhydrous sodium sulfate (3.2g, 22.5 mmol) were added in this order, the mixture was heated to 60 ℃ and stirred for reaction for 1.5 hours, then cooled to room temperature and stirred for reaction for 16 hours, the reaction mixture was filtered, and the filter cake was collected to obtain the title compound 15d (0.8 g), yield: 86.3 percent.

MS m/z(ESI)：291.1[M+1]。

The fifth step

5- (tetrahydro-2H-pyran-4-yl) -7, 8-dihydro-1H-furo [2,3-g ] indole-2, 3-dione 15e

Compound 15d (0.8g, 2.75mmol) and methanesulfonic acid (13g, 135.3mmol) were mixed, and the mixture was heated to 45 ℃ and stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride, and the organic phase was collected, dried over anhydrous sodium sulfate and concentrated to give the title compound 15e (750 mg), yield: 99.5 percent.

MS m/z(ESI)：274.0[M+1]。

The sixth step

4-amino-7- (tetrahydro-2H-pyran-4-yl) -2, 3-dihydrobenzofuran-5-carboxylic acid 15f

Compound 15e (750mg, 2.74mmmol) and solid sodium hydroxide (1.1g, 27.5mmol) were dissolved in water (10 mL), and hydrogen peroxide (1.7g, 26.8mmol,30% pure) was added under an ice-water bath. After stirring at room temperature for 30 minutes, 2M dilute hydrochloric acid was added to neutralize the reaction mixture to pH 7, and the system precipitated a solid, which was filtered after standing, washed with water, and the filter cake was drained to give the title compound 15f (720 mg), yield: 99.6 percent.

MS m/z(ESI)：264.0[M+1]。

Seventh step

4-amino-7- (tetrahydro-2H-pyran-4-yl) -2, 3-dihydrobenzofuran-5-carboxylic acid methyl ester 15g

Compound 15f (700mg, 2.73mmmol) was dissolved in methylene chloride (10 mL) and methanol (1 mL), and trimethylsilylated diazomethane (2M, 4.1 mL) was added dropwise and reacted with stirring for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give 15g (250 mg) of the title compound, yield: 33 percent.

MS m/z(ESI)：278.1[M+1]。

Eighth step

2-methyl-6- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydrofuro [2,3-H ] quinazolin-4 (3H) -one 15H

15g (56mg, 201.9. Mu. Mol) of the compound was dissolved in acetonitrile (2 mL), methanesulfonic acid (39mg, 405.8. Mu. Mol) was added, and the mixture was stirred with heating at 100 ℃ for 16 hours while being sealed. After cooling, it was neutralized with 2N aqueous sodium hydroxide solution, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 15h (50 mg), yield: 86.4 percent.

MS m/z(ESI)：287.1[M+1]。

The ninth step

Compound 15h (30mg, 104.7. Mu. Mol) was dissolved in N, N-dimethylformamide (3 mL), and compound 1j (50mg, 208. Mu. Mol), N-diisopropylethylamine (27mg, 209. Mu. Mol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (93mg, 210. Mu. Mol), and 1, 8-diazacyclo [5,4,0] undec-7-ene (30mg, 210. Mu. Mol) were added in this order, replaced with nitrogen three times, and heated to 80 ℃ for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure, and purification of the resulting title compound 15 (14.2 mg) from the residue by high performance liquid preparative chromatography, yield: 28.6 percent.

MS m/z(ESI)：473.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ7.08(s,1H),6.90(t,1H),6.80(t,1H),5.62(m,2H),4.76(t,2H),4.09(m,2H),3.85(s,2H),3.61-3.51(m,3H),3.06(m,1H),2.57(s,3H),2.03-1.87(m,2H),1.83(m,2H),1.65(d,3H)。

Example 16

(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 16

Using the synthetic route in example 12, substituting the first step starting material compound 10b for compound 9j and the second step starting material compound 1j for compound 3a, the title compound 16 (50 mg) was obtained in terms of yield: 44 percent.

MS m/z(ESI)：527.3[M+1]。

¹ H NMR(500MHz,CDCl3)δ7.56-7.53(m,1H),7.50-7.47(m,1H),7.41-7.40(m,1H),7.20-7.17(m,1H),6.38-6.27(m,1H),5.93-5.81(m,2H),4.81-4.76(m,2H),4.31-4.30(m,1H),4.20-4.12(m,3H),3.88-3.85(m,1H),3.72-3.70(m,1H),3.55-3.51(m,2H),2.71-2.64(m,2H),2.54(s,3H),2.20-2.17(d,3H),1.71-1.70(d,3H)。

Example 17

(R) -1- (4- (4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) piperidin-1-yl) ethan-1-one 17

First step of

6-bromo-7-methoxy-2-methyl-quinazolin-4 (3H) -one 17b

The compound 2-amino-5-bromo-4-methoxybenzoic acid 17a (5 g,23mmol, shanghai Binji pharmaceutical Co., ltd.) was dissolved in 2mL of acetic anhydride, and subjected to reflux reaction for 8 hours, cooling and standing overnight, after slight stirring, a large amount of solid was precipitated, filtered, and the filter cake was washed with a small amount of acetic anhydride. Adding the filter cake into 40mL of ammonia water, stirring for 4 hours at room temperature, adding 60mL of 10% sodium hydroxide solution, stirring for 0.5 hour at 60 ℃, cooling to room temperature, dropwise adding concentrated hydrochloric acid in an ice-water bath, adjusting the pH to about 8 (dissolving firstly and then separating out solid), filtering, washing the filter cake with water, and drying in vacuum to obtain a white solid, namely the title compound 17b (4.5 g), yield: 81.4 percent.

MS m/z(ESI)：269.0[M+1]。

Second step of

6-bromo-7-methoxy-2-methyl-8-nitroquinazolin-4 (3H) -one 17c

Compound 17b (0.6 g, 2.23mmol) was dissolved in 5mL of concentrated sulfuric acid, and 2mL of concentrated nitric acid was slowly added thereto to react at room temperature for 0.5 hour. The reaction was poured slowly into ice water to precipitate a large amount of solid, filtered, and the filter cake was washed with water and dried in vacuo to give crude title compound 17c (700 mg), yield: 99.9 percent.

MS m/z(ESI)：314.0[M+1]。

The third step

8-amino-6-bromo-7-methoxy-2-methyl-quinazolin-4 (3H) -one 17d

Compound 17c (700mg, 2.23mmol) was dissolved in 10mL of methanol, and ammonium chloride (1.12g, 22.28mmol) and iron powder (1.12g, 20.06mmol) were added in this order, followed by heating to 80 ℃ and reacting for 4 hours. After cooling to room temperature, the reaction was filtered through celite, and the filtrate was concentrated under reduced pressure to give crude title compound 17d (633 mg), yield: 99.9 percent.

MS m/z(ESI)：284.1[M+1]。

The fourth step

8-amino-6-bromo-7-hydroxy-2-methyl-quinazolin-4 (3H) -one 17e

Compound 17d (633mg, 2.23mmol) was reacted with 10mL of hydrobromic acid solution at 100 ℃ for 16 hours. After cooling to room temperature a solid precipitated, filtered, and the filter cake was washed with water and dried in vacuo to give the crude title compound 17e (600 mg), yield: 99.7 percent.

MS m/z(ESI)：270.0[M+1]。

The fifth step

6-bromo-2-methyl-3, 8,9, 10-tetrahydro-4H- [1,4] oxazino [2,3-H ] quinazolin-4-one 17f

Compound 17e (1.1g, 4.07mmol) was dissolved in N, N-dimethylformamide (50 mL), 1, 2-dibromoethane (385mg, 2mmol) and anhydrous potassium carbonate (1.69g, 12.2mmol) were added, and the mixture was heated to 90 ℃ and stirred for reaction for 1 hour, and 1, 2-dibromoethane (385mg, 2mmol) was further added and stirred for reaction for 1 hour at 90 ℃. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 17f (0.2 g), yield: 16.5 percent.

MS m/z(ESI)：296.1[M+1]。

The sixth step

(R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-4-amine 17g

Compound 17f (100mg, 0.34mmol), compound 3b (80mg, 0.34mmol), N-diisopropylethylamine (44mg, 0.34mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (194mg, 0.44mmol), 1, 8-diazabicycloundecen-7-ene (77mg, 0.51mmol) were dissolved in 5mL of N, N-dimethylformamide, stirred for 10 minutes, and then stirred at 60 ℃ for 2 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 17g (146 mg), yield: 84.4 percent.

MS m/z(ESI)：512.2[M+1]。

Seventh step

(R) -1- (4- (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one 17H

Compound 17g (146mg, 285.0 μmol) and compound 9i (93mg, 370.5 μmol) were dissolved in 5mL1, 4-dioxane and 1mL water, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (23.2mg, 28.5 μmol) and sodium carbonate (60.4 mg,570.0 μmol) were added, heated to 80 ℃ under nitrogen atmosphere for 14 hours, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system C to give the title compound 17h (55 mg), yield: 34.6 percent.

MS m/z(ESI)：557.1[M+1]。

Eighth step

Compound 17h (105mg, 197.9 μmol) was dissolved in 5mL of methanol, 50mg of palladium on carbon catalyst (dry) was added, hydrogen gas was substituted 3 times, the reaction was stirred for 16 hours, filtered, the filtrate was concentrated under reduced pressure and concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 17 (1.5 mg), yield: 8.8 percent.

MS m/z(ESI)：529.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.46-7.33(m,1H),6.97(d,2H),6.79(s,1H),5.61(dq,1H),4.70(d,1H),4.34(s,2H),4.07-3.99(m,1H),3.50(s,2H),3.25(td,2H),2.79-2.66(m,1H),2.47(d,3H),2.14(d,3H),1.98-1.84(m,2H),1.75(dddd,2H),1.61(d,3H)。

Example 18

(R) -1- (4- (4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 18

Compound 17h (180mg, 269.5 μmol) was dissolved in 5mL of methanol, iron powder (135.5mg, 2.43mmol) and ammonium chloride (144.2mg, 2.69 μmol) were added, reflux reaction was carried out for 1 hour, the reaction liquid was cooled to room temperature, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 18 (20 mg), yield: 14.1 percent.

MS m/z(ESI)：527.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ7.35(s,1H),7.00(s,1H),6.96(d,1H),6.80(s,1H),5.91(dd,1H),5.59(q,1H),4.31(q,2H),4.21(dq,2H),3.82-3.75(m,1H),3.73(t,1H),3.51(t,2H),2.72-2.61(m,1H),2.57(s,1H),2.47(s,3H),2.18(d,3H),1.61(dd,3H)。

Example 19

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl-8, 9-dihydro- [1,4] dioxa-cyclo [2,3-H ] quinazolin-4-amine 19

First step of

6-bromo-7, 8-dihydroxy-2-methyl-quinazolin-4 (3H) -one 19a

Compound 9g (2g, 7.06mmol) was dissolved in 20mL hydrobromic acid solution and heated to 100 ℃ for 2 days. After cooling to room temperature a solid precipitated, filtered, and the filter cake was washed with water and dried in vacuo to give crude title compound 19a (1.9 g), yield: 99 percent.

MS m/z(ESI)：271.0[M+1]。

Second step of

6-bromo-2-methyl-8, 9-dihydro- [1,4] dioxa-cyclo [2,3-H ] quinazolin-4 (3H) -one 19b

Compound 19a (1.2g, 4.42mmol) was dissolved in N, N-dimethylformamide (20 mL), and 1, 2-dibromoethane (833mg, 4.43mmol) and anhydrous potassium carbonate (1.83g, 13.4 mmol) were added, followed by heating to 80 ℃ and stirring for reaction for 2 hours. The reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 19b (0.17 g), yield: 12.7 percent.

MS m/z(ESI)：297.1[M+1]。

The third step

(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-bromo-2-methyl-8, 9-dihydro [1,4] dioxa-cyclo [2,3-h ] quinazolin-4-amine 19c

Compound 19b (54mg, 0.18mmol), compound 1j (44mg, 0.18mmol), N-diisopropylethylamine (23.5mg, 0.18mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (120.6 mg, 0.28mmol), and 1, 8-diazabicycloundecen-7-ene (55.3mg, 0.36mmol) were dissolved in 5mL of N, N-dimethylformamide, stirred for 10 minutes, and then stirred at 80 ℃ for 2 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 19C (80 mg), yield: 90.9 percent.

MS m/z(ESI)：483.2[M+1]。

The fourth step

Compound 19c (80mg, 165.6 μmol) and compound 10b (58mg, 276 μmol) were dissolved in 5ml1, 4-dioxane and 1mL water, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (15mg, 18 μmol) and sodium carbonate (40mg, 377.0 μmol) were added, heated to 80 ℃ under nitrogen atmosphere for 14 hours, the reaction was concentrated under reduced pressure, and the residue was purified by hplc to give the title compound 19 (6.1 mg), yield: 6.8 percent.

MS m/z(ESI)：487.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ7.06(s,1H),7.01(s,1H),6.90(s,1H),6.80(s,1H),5.94(s,1H),5.75-5.51(m,2H),4.46(dd,2H),4.34(dt,4H),3.92(t,2H),3.90-3.72(m,2H),2.62(s,3H),2.59-2.49(m,2H),1.64(d,3H)。

Example 20

N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydro- [1,4] dioxa-cyclo [2,3-h ] quinazolin-4-amine 20

First step of

8-hydroxy-2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-carboxylic acid methyl ester 20b

Compound 3,4, 5-Trihydroxybenzoic acid methyl ester 20a (3 g,16.3mmol, shanghai Biao medicine Co., ltd.) was dissolved in N, N-dimethylformamide (50 mL), 1, 2-dibromoethane (4.59g, 24.4 mmol) and cesium carbonate (8.49g, 26.0 mmol) were added, and the reaction was stirred for 1.5 hours while heating to 90 ℃. Filtration through celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 20b (1.8 g), yield: 52.5 percent.

MS m/z(ESI)：211.0[M+1]。

Second step of

7-bromo-8-hydroxy-2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-carboxylic acid methyl ester 20c

Compound 20b (1.1g, 5.2mmol) was dissolved in 50mL of chloroform, and dibromohydantoin (655mg, 7.0mmol) was added in portions at room temperature and reacted for 14 hours. The reaction solution was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate (30 mL × 3), saturated sodium chloride solution (30 mL) and washed with water, the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to obtain the title compound 20c (1.3 g), yield: 85.9 percent.

MS m/z(ESI)：289.1[M+1]。

The third step

(S) -7-bromo-8- ((tetrahydrofuran-3-yl) oxy) -2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-carboxylic acid methyl ester 20d

Compound 20c (500mg, 1.73mmol) was dissolved in N, N-dimethylformamide (10 mL), and cesium carbonate (845mg, 2.6mmol) and 1g (461mg, 1.9mmol) were added and heated to 95 ℃ for 1 hour. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 20d (500 mg), yield: 80.4 percent.

MS m/z(ESI)：359.1[M+1]。

The fourth step

(S) -7-bromo-5-nitro-8- ((tetrahydrofuran-3-yl) oxy) -2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-carboxylic acid methyl ester 20e

Compound 20d (500mg, 1.39mmol) was dissolved in concentrated sulfuric acid (5 mL), and potassium nitrate (154mg, 1.53mmol) was added under ice bath to react at the temperature for 1 hour. The reaction solution was diluted with 20mL of ice water, extracted with ethyl acetate (30 mL × 3), washed with saturated sodium chloride solution (30 mL) and water, the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 20e (300 mg) in yield: 53.3 percent.

MS m/z(ESI)：421.0[M+18]。

The fifth step

(S) -5-amino-8- ((tetrahydrofuran-3-yl) oxy) -2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-carboxylic acid methyl ester 20f

Compound 20e (150mg, 0.37mmol) was dissolved in methanol (5 mL), 10% by weight of Pd/C (20 mg) was added, the mixture was replaced with hydrogen gas three times, and the reaction was stirred for 16 hours. Filtration through celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 20f (70 mg), yield: and 63 percent.

MS m/z(ESI)：296.0[M+1]。

The sixth step

(S) -2-methyl-6- ((tetrahydrofuran-3-yl) oxy) -8, 9-dihydro- [1,4] dioxa-cyclo [2,3-h ] quinazolin-4-ol 20g

Compound 20f (70mg, 0.24mmol) was dissolved in acetonitrile (2.0 mL), methanesulfonic acid (45.6 mg, 0.48mmol) was added, and the mixture was heated to 100 ℃ with a sealed tube and reacted for 12 hours. After cooling, it was neutralized with a 2N aqueous solution of sodium hydroxide, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give 20g (60 mg) of the title compound in yield: 83 percent.

MS m/z(ESI)：305.1[M+1]。

Seventh step

Compound 20g (60mg, 0.2mmol) was dissolved in N, N-dimethylformamide (5 mL), and compound 1j (52.2mg, 0.22mmol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (180mg, 0.4 mmoL) and 1, 8-diazacyclo [5,4,0] undec-7-ene (92mg, 0.6 mmol) were added in this order, replaced with nitrogen three times, and heated to 80 ℃ for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure, and purification of the resulting title compound 20 (13 mg) from the residue by high performance liquid preparative chromatography, yield: 13.4 percent.

MS m/z(ESI)：491.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ7.28(s,1H),7.02-6.96(m,2H),6.82(d,1H),5.63(q,1H),5.19(dt,1H),4.41(tp,4H),4.07-3.98(m,3H),3.93(td,1H),2.47(s,3H),2.35-2.17(m,2H),1.64(d,3H)。

Example 21

(R) -1- (4- (4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) ethanone 21

Using the synthetic route in example 11, substituting the starting compound 3a from the seventh step with compound 1j, the title compound 21 (5.3 mg) was obtained in yield: 5 percent.

MS m/z(ESI)：530.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ8.16(s,1H),7.01(d,2H),6.82(d,1H),5.65(d,1H),4.78(t,2H),4.53-4.43(m,1H),3.85(ddd,1H),3.65(tt,1H),3.47(t,2H),3.25-2.98(m,1H),2.50(s,3H),2.48-2.33(m,2H),2.17(s,3H),1.84-1.71(m,2H),1.65(d,3H)。

Example 22

(R) -4- (4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) tetrahydro-2H-pyran-4-ol 22

Using the synthetic route described in example 11, substituting the starting compound 3a from the seventh step with compound 1j and substituting the starting compound 1-acetylpiperidin-4-one from the eighth step with the compound tetrahydropyranone, the title compound 22 (3 mg) was obtained in terms of yield: 10.5 percent.

MS m/z(ESI)：489.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD)δ8.14(s,1H),7.01(d,2H),6.82(s,1H),5.65(q, 1H),4.80(t,2H),3.99(t,2H),3.85(dd,2H),3.48(t,2H),2.58(td,2H),2.50(s,3H),1.75-1.58(m,4H),1.39-1.28(m,1H)。

Example 23

(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one 23

First step of

(R) -2- (3- (1- ((6-bromo-2-methyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-4-yl) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroethan-1-ol 23a

Compound 17f (140mg, 0.47mmol), compound 3a (120mg, 0.34mmol), N-diisopropylethylamine (60.7 mg, 0.47mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (311mg, 0.71mmol), and 1, 8-diazabicycloundecen-7-ene (142.9mg, 0.94mmol) were dissolved in 5mL of N, N-dimethylformamide, stirred for 10 minutes, and then stirred at 80 ℃ for 2 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 23a (220 mg), yield: 94.2 percent.

MS m/z(ESI)：497.2[M+1]。

Second step of

Compound 23a (110mg, 221.9 μmol) and compound 9i (73mg, 290.7 μmol) were dissolved in 5mL1, 4-dioxane and 1mL water, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (18mg, 22 μmol) and sodium carbonate (50mg, 471.0 μmol) were added, and the mixture was heated to 80 ℃ under nitrogen atmosphere for reaction for 14 hours, the reaction liquid was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 23 (55 mg), yield: 34.6 percent.

MS m/z(ESI)：542.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.55(t,1H),7.43(t,1H),7.38(s,1H),7.17(t,1H),5.91(d,1H),5.84(q,1H),4.35-4.25(m,2H),4.21(dq,2H),4.03(td,2H),3.78(td,1H),3.72(t,1H),3.50(s,2H),2.66(s,1H),2.57(s,1H),2.41(s,3H),2.17(d,3H),1.63(dd,3H)。

Example 24

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) piperidin-1-yl) -2- (dimethylamino) ethanone 24

First step of

4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine hydrochloride 24b

Compound 24a (1g, 3.23mmol) was dissolved in 4N,20mL of 1, 4-dioxane hydrochloride solution, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to give crude product 24b (790 mg), yield: 99.4%, the product was used in the next reaction without purification.

MS m/z(ESI)：210.1[M+1]。

Second step of

2- (dimethylamino) -1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 24c

Compound 24b (790mg, 3.22mmol) and N, N-dimethylglycine (336mg, 3.25mmol, haohnhong biomedical science and technology Co., ltd., shanghai) were dissolved in 25mL of tetrahydrofuran, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1.86g, 4.89mmol) and N, N-diisopropylethylamine (1.05 g, 8.12mmol) were added thereto, and the reaction was stirred for 14 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 24c (800 mg), yield: and 83.4 percent.

MS m/z(ESI)：295.1[M+1]。

The third step

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-iodo-2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 24d

Compound 11g (90mg, 274.3. Mu. Mol) was dissolved in N, N-dimethylformamide (3 mL), and Compound 2a (124mg, 549.5. Mu. Mol), N-diisopropylethylamine (70mg, 541.6. Mu. Mol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (243mg, 549.4. Mu. Mol) and 1, 8-diazacyclo [5,4,0] undec-7-ene (84mg, 551.8. Mu. Mol) were added in this order, and the mixture was replaced with nitrogen three times, heated to 80 ℃ and reacted for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 24d (90 mg), yield: 65.7 percent.

MS m/z(ESI)：500.1[M+1]。

The fourth step

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) -2- (dimethylamino) ethanone 24e

Compound 24d (90mg, 180.2 μmol) and compound 24c (79.5mg, 270.4 μmol) were dissolved in 5ml1, 4-dioxane and 1mL water, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (15.2mg, 18 μmol) and sodium carbonate (38.2mg, 360.5 μmol) were added, heated to 80 ℃ under nitrogen atmosphere for 5 hours, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 24e (30 mg), yield: 30.8 percent.

MS m/z(ESI)：540.2[M+1]。

The fifth step

Compound 24e (30mg, 55.6. Mu. Mol) was dissolved in methanol (5 mL), 10% palladium on carbon catalyst (10 mg) was added, hydrogen gas was substituted three times, and the reaction was stirred for 16 hours. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 24 (3 mg), yield: 10 percent.

MS m/z(ESI)：542.2[M+1]。

1H NMR(500MHz,CD ₃ OD)δ8.00(s,1H),7.60(s,1H),7.48(t,1H),7.23(t,1H),7.03(t,1H),5.87(d,1H),4.77(t,2H),4.61(s,1H),4.21(s,1H),3.48(m,3H),3.22-3.15(m,2H),2.78(m,1H),2.42(s,3H),2.37(s,6H),2.10-1.94(m,3H),1.85(d,2H),1.69(d,3H)。

Example 25

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) ethanone 25

Using the synthetic route described in example 11, substituting compound 3a as the starting material for compound 2a in the seventh step, compound 25 (10 mg) was obtained in terms of yield: 9.7 percent.

MS m/z(ESI)：515.2[M+1]。

1HNMR(500MHz,CD ₃ OD)δ8.20(s,1H),7.61(t,1H),7.47(t,1H),7.22(t,1H),7.01(t,1H),5.87(q,1H),4.77(t,2H),4.50-4.44(m,1H),3.87-3.81(m,1H),3.65(td,1H),3.44(t,2H),3.17-3.11(m,1H),2.51-2.42(m,1H),2.42(s,3H),2.41-2.34(m,1H),2.16(s,3H),1.82(d,1H),1.81-1.71(m,1H),1.68(d,3H)。

Example 26

(R) -4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) tetrahydro-2H-pyran-4-ol 26

Using the synthetic route described in example 11, substituting the starting compound 1-acetylpiperidin-4-one of the eighth step with the compound tetrahydropyranone, compound 26 (3.5 mg) was prepared in yield: 4.6 percent.

MS m/z(ESI)：504.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.19(s,1H),7.61(t,1H),7.46(t,1H),7.21(t,1H),5.90(q,1H),4.80(t,2H),4.60(s,2H),4.12-3.97(m,4H),3.86(dd,2H),3.47(t,2H),2.59(tt,2H),2.45(s,3H),1.72-1.66(d,3H)。

Example 27

(R) -3- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -3-oxopropanenitrile 27

First step of

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -3, 6-dihydropiperidine-1 (2H) -carbonic acid tert-butyl ester 27a

Compound 24d (300mg, 0.6 mmol) and compound 24a (371mg, 1.19mmol) were dissolved in 5ml1, 4-dioxane and 1mL water, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (76mg, 0.09mmol) and sodium carbonate (191mg, 1.8mmol) were added, heated to 90 ℃ under nitrogen atmosphere for reaction for 3 hours, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 27a (300 mg), yield: and 90 percent.

MS m/z(ESI)：555.2[M+1]。

Second step of

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1, 2,3, 6-tetrahydropyridin-4-yl) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine hydrochloride 27b

Compound 27a (180mg, 0.32mmol) was dissolved in 5mL of 4N 1, 4-dioxane hydrochloride solution and reacted with stirring for 14 hours. The reaction solution was concentrated under reduced pressure to give crude product 27b (150 mg), yield: 94%, and the product was used in the next reaction without purification.

MS m/z(ESI)：455.2[M+1]。

The third step

(R) -3- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) -3-oxopropanenitrile 27c

Compound 27b (160mg, 0.35mmol) and 2-cyanoacetic acid (45mg, 0.53mmol, carbofuran) were dissolved in 2mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (200mg, 0.53mmol) and N, N-diisopropylethylamine (183mg, 1.41mmol) were added and reacted with stirring for 4 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 27c (180 mg), yield: 98 percent.

MS m/z(ESI)：522.2[M+1]。

The fourth step

Compound 27c (70mg, 134.2. Mu. Mol) was dissolved in methylene chloride (0.5 mL) and isopropanol (5 mL), and manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (40mg, 66. Mu. Mol) and phenylsilane (28mg, 258. Mu. Mol) were added to replace with oxygen three times, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 27 (8 mg), yield: 11 percent.

MS m/z(ESI)：540.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.21(s,1H),7.61(t,1H),7.47(t,1H),7.22(t,1H),7.01(t,1H),5.86(t,1H),4.78(d,2H),4.50-4.38(m,1H),3.75-3.65(m,2H),3.44(t,2H),3.22-3.16(m,1H),2.48(dq 2H),2.42(s,3H),1.84-1.73(m,2H),1.67(d,3H),1.31(d,2H)。

Example 28

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) piperazin-2-one 28

First step of

Compound 24d (100mg, 200.3. Mu. Mol) was dissolved in 1, 4-dioxane (3 mL), piperazin-2-one (60mg, 599. Mu. Mol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (34mg, 58. Mu. Mol), tris (dibenzylideneacetone) dipalladium (0) (27mg, 29. Mu. Mol), cesium carbonate (130mg, 398. Mu. Mol) were added, and the reaction was stirred at 90 ℃ for 3 hours with nitrogen substitution three times. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 27 (20 mg), yield: 21 percent.

MS m/z(ESI)：472.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.59(t,1H),7.50(s,1H),7.44(t,1H),7.20(t,1H),7.00(t 1H),5.83(q,1H),4.77(d,2H),3.95-3.82(m,2H),3.57-3.39(m,6H),2.39(s,3H),1.67(d,3H)。

Example 29

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) piperidin-1-yl) -3-hydroxy-3-methylbutan-1-one 29

First step of

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) -3-hydroxy-3-methylbutan-1-one 29a

Compound 27b (115mg, 0.25mmol) and β -hydroxyisovaleric acid (50mg, 0.43mmol, haohnhong, shanghai) were dissolved in 2mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (144mg, 0.37mmol) and N, N-diisopropylethylamine (130mg, 1.0mmol) were added and the reaction was stirred for 4 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 29a (100 mg), yield: 71 percent.

MS m/z(ESI)：555.2[M+1]。

Second step of

Compound 29a (50mg, 90. Mu. Mol) was dissolved in methanol (5 mL), 10% palladium on carbon catalyst (20 mg) was added thereto, and the mixture was replaced with hydrogen three times, followed by stirring for 16 hours. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 29 (8 mg), yield: 16 percent.

MS m/z(ESI)：557.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.99(s,1H),7.57(t,1H),7.45(t,1H),7.21(t,1H),7.00(t,1H),5.89-5.81(m,1H),4.77-4.73(m,1H),4.27-4.15(m,1H),3.45(t,2H),3.23(td,1H),3.18-3.08(m,1H),2.76(td,1H),2.70-2.53(m,2H),2.39(s,3H),2.05-1.91(m,2H),1.83(dq,2H),1.66(d,3H),1.32(d,8H)。

Example 30

(1R, 4r) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1-carboxylic acid 30-P1

(1R, 4s) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1-carboxylic acid 30-P2

First step of

4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexyl-3-ene-1-carboxylic acid methyl ester 30b

Compound 24d (200mg, 0.4 mmol), methyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohexyl-3-enecarboxylate 30a (210mg, 0.8mmol, obtained from Shanghai), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (34mg, 40. Mu. Mol) and anhydrous sodium carbonate (85mg, 800. Mu. Mol) were dissolved in 6mL of 1, 4-dioxane and 2mL of water, replaced with nitrogen 3 times, and heated to 100 ℃ for 3 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system C gave the title compound 30b (200 mg), yield: 98.0 percent.

MS m/z(ESI)：512.0[M+1]。

Second step of

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1-carboxylic acid methyl ester 30c

Compound 30b (200mg, 0.4mmol) was dissolved in methanol (15 mL), 10% palladium on carbon catalyst (20mg, 0.4mmol) was added thereto, the mixture was replaced with hydrogen gas three times, and the reaction was stirred at room temperature for 16 hours. Filtration through celite and concentration of the filtrate under reduced pressure gave the title compound 30c (70 mg), yield: 33.2 percent.

MS m/z(ESI)：514.0[M+1]。

The third step

Compound 30c (20mg, 39. Mu. Mol) was dissolved in methanol (5 mL), and a 2N sodium hydroxide solution (1.2 mL) was added thereto, and the mixture was heated to 50 ℃ to react for 2 hours. Cooled to room temperature, neutralized with 6N dilute hydrochloric acid, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compounds 9.3mg and 2.9mg, yield: 47.8 percent and 14.9 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：500.0[M+1]。

HPLC analysis: retention time 10.47 minutes, purity: 98.5% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A23% -42%).

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.11(s,1H),7.63(t,1H),7.51(t,1H),7.27(t,1H),7.03(t,1H),5.94(q,1H),4.82(t,2H),4.61(s,2H),3.48(t,2H),2.88(tt,1H),2.50(d,3H),2.34(tt,1H),2.19-2.08(m,2H),2.01(dd,2H),1.72(d,3H),1.62(qd,2H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：500.0[M+1]。

HPLC analysis: retention time 11.52 minutes, purity: 97.2% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A23% -42%).

Example 31

((1S, 4s) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxycyclohexyl) (morpholino) methanone 31-P1

((1R, 4r) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxycyclohexyl) (morpholino) methanone 31-P2

First step of

4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohex-3-enecarboxylic acid 31a

Compound 30b (120mg, 0.23mmol) and lithium hydroxide (50mg, 2.0 mmol) were dissolved in 5mL of a mixed solvent of methanol/tetrahydrofuran/water =2/2/1, and the reaction was stirred for 15 hours. Concentration under reduced pressure, pH =3 with 1N hydrochloric acid, and concentration under reduced pressure gave the crude title compound 31a (110 mg), yield: 94.2 percent.

MS m/z(ESI)：498.1[M+1]。

Second step of

(4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohex-3-en-1-yl) (morpholinyl) methanone 31b

Compound 31a (110mg, 0.22mmol) and morpholine (58mg, 0.66mmol, carbofuran) were dissolved in 2mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (78mg, 0.33mmol) and N, N-diisopropylethylamine (86mg, 0.66mmol) were added and the reaction was stirred for 3 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 31b (80 mg), yield: and (3.8).

MS m/z(ESI)：567.2[M+1]。

The third step

Compound 31b (80mg, 141. Mu. Mol) was dissolved in methylene chloride (0.5 mL) and isopropanol (5 mL), manganese bis (acetylacetonate) (18mg, 70. Mu. Mol) and phenylsilane (23mg, 211. Mu. Mol) were added, oxygen was replaced three times, and the reaction was stirred for 16 hours. The obtained title compound was purified by high performance liquid preparative chromatography in 20mg and 10mg, yield: 24.2 percent and 12.1 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：585.6[M+1]。

HPLC analysis: retention time 11.28 minutes, purity: 98.5% (column: X-Bridge, prep 30X 150mm, 5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A30% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.16(s,1H),7.62(t,1H),7.48(t,1H),7.24(t,1H),7.03(s,1H),5.90(q,1H),4.79(t,2H),3.78-3.52(m,8H),3.48(t,2H),2.83-2.81(m,3H),2.44(d,3H),1.99(d,3H),1.81-1.79(m,2H),1.70(d,4H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：585.6[M+1]。

HPLC analysis: retention time 13.11 minutes, purity: 99.3% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A30% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.19(s,1H),7.62(t,1H),7.47(t,1H),7.22(t,1H),7.03(s,1H),5.87(q,1H),4.77(t,2H),3.79-3.54(m,8H),3.48(t,2H),2.83-2.80(m,3H),2.43(d,3H),2.09-2.06(m,3H),1.81-1.79(m,2H),1.66(t,4H)。

Example 32

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) tetrahydro-2H-pyran-4-ol 32

Using the synthetic route described in example 11, substituting the seventh starting compound, compound 3a, for compound 2a, and the eighth starting compound, 1-acetylpiperidin-4-one, for the compound tetrahydropyranone, compound 32 (13 mg) was prepared in terms of yield: 5.5 percent.

MS m/z(ESI)：474.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.19(s,1H),7.63(td,1H),7.53-7.43(m,1H),7.23(t,1H),7.02(t,1H),5.89(q,1H),4.80(t,2H),4.06-3.95(m,2H),3.92-3.80(m,2H),3.46(t,2H),2.66-2.52(m,2H),2.44(s,3H),1.77-1.64(m,5H)。

Example 33

(1s, 4S) -1- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1, 4-diol 33-P1

(1r, 4R) -1- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1, 4-diol 33-P2

First step of

4- (4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohex-3-enol 33b

Compound 24d (200mg, 0.4 mmol), compound 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enol 33a (179mg, 0.8mmol, shanghai Biao), complex [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane (32mg, 39. Mu. Mol), and anhydrous sodium carbonate (85mg, 800. Mu. Mol) were dissolved in 6mL of 1, 4-dioxane and 2mL of water, replaced with nitrogen 3 times, and heated to 100 ℃ for 3 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system C gave the title compound 33b (150 mg), yield: 79.7 percent.

MS m/z(ESI)：470.1[M+1]。

Second step of

Compound 33b (150mg, 319.5. Mu. Mol) was dissolved in isopropanol (5 mL) and dichloromethane (0.5 mL), manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (38.6 mg, 63.8. Mu. Mol) was added, and after stirring for 5 minutes, phenylsilane (69.1mg, 638. Mu. Mol) was added, oxygen substitution was conducted 3 times, the reaction was stirred for 20 hours, and after the reaction solution was filtered and concentrated, it was purified by high performance liquid preparative chromatography to give the title compounds 33-P1 (17 mg) and 33-P2 (12 mg), yield: 10.9 percent and 7.7 percent.

Single configuration compound (shorter retention time) 33-P1

MS m/z(ESI)：488.0[M+1]。

HPLC analysis: retention time 10.42 minutes, purity: 98.5% (column: X-Bridge, prep 30X 150mm, 5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.19(s,1H),7.63(t,1H),7.48(t,1H),7.23(t,1H),7.03(t,1H),5.88(q,1H),4.78(t,2H),3.70(tt,1H),3.45(t,2H),2.44(s,3H),2.37(tt,2H),2.01-1.74(m,6H),1.69(d,3H)。

Single configuration compound (longer retention time) 33-P2

MS m/z(ESI)：488.0[M+1]。

HPLC analysis: retention time 12.02 min, purity: 98.5% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.17(s,1H),7.63(t,1H),7.48(t,1H),7.24(t,1H),7.03(t,1H),5.89(q,1H),4.86-4.74(m,2H),4.06(t,1H),3.46(t,2H),2.71-2.59(m,2H),2.44(s,3H),2.09(tt,2H),1.69(d,3H),1.72-1.61(m,4H)。

Example 34

(1R, 4S) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -N- ((S) -2-hydroxypropyl) -N-methylcyclohexane-1-carboxamide 34-P1

(1S, 4R) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorobenzo) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -N- ((S) -2-hydroxypropyl) -N-methylcyclohexane-1-carboxamide 34-P2

First step of

4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuran [2,3-h ] quinazolin-6-yl) cyclohexane-1-carboxylic acid 34a

Compound 30c (50mg, 97. Mu. Mol) was dissolved in methanol (4 mL), and 2N sodium hydroxide solution (1.4 mL) was added and the mixture was heated to 50 ℃ for reaction for 2 hours. Cooled to room temperature, neutralized with 6N dilute hydrochloric acid, and concentrated under reduced pressure to give title compound 34a (48 mg).

MS m/z(ESI)：500.0[M+1]。

Second step of

Compound 34a (48mg, 0.17mmol) and (2S) -1- (methylamino) propan-2-ol (20mg, 0.19mmol, obtained after finishing Shanghai) were dissolved in N, N-dimethylformamide (2 mL), and 2- (7-azobenzotriazol) -N, N, N, N-tetramethyluronium hexafluorophosphate (47mg, 0.2 mmoL) and diisopropylethylamine (25mg, 0.2 mmol) were added in this order, and the reaction was stirred at room temperature for 14 hours. Concentrated under reduced pressure, and the obtained title compound was purified by high performance liquid preparative chromatography (hplc) to yield: 21.9 percent and 20.1 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：571.2[M+1]。

HPLC analysis: retention time 11.39 minutes, purity: 98.5% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A23% -42%)

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.02(s,1H),7.61(t,1H),7.48(t,1H),7.24(t,1H),7.03(t,1H),5.87(q,1H),4.76(t,2H),4.02(td,1H),3.57-3.50(m,1H),3.50-3.44(m,2H),3.25(s,1H),3.00(s,1H),2.91(ddt,2H),2.42(s,3H),2.10-1.90(m,4H),1.90-1.74(m,2H),1.69(d,3H),1.24(d,3H),1.17(d,3H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：571.2[M+1]。

HPLC analysis: retention time 13.47 minutes, purity: 97.2% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A23% -42%)

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.02(s,1H),7.61(t,1H),7.48(t,1H),7.24(t,1H),7.03(t,1H),5.87(q,1H),4.76(t,2H),4.02(td,1H),3.57–3.50(m,1H),3.50–3.44(m,2H),3.25(s,1H),3.00(s,1H),2.91(ddt,2H),2.42(s,3H),2.10–1.90(m,4H),1.90-1.74(m,2H),1.69(d,3H),1.24(d,3H),1.17(d,3H)。

Example 35

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-N, N-dimethylcyclohexanecarboxamide 35

Using the synthetic route in example 11, starting compound 3a from the seventh step was replaced with compound 2a, and starting compound from the eighth step was replaced with N, N-dimethyl-4-oxocyclohexanecarboxamide (prepared using the method disclosed in intercediate 57 on page 123 of the specification in patent application "WO 2013/27001") to give compound 35 (3 mg), yield: 5.5 percent.

MS m/z(ESI)：543.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.24(s,1H),7.64(t,1H),7.49(t,1H),7.25(t,1H),7.03(t,1H),5.90(q,1H),4.80(d,3H),3.46(t,2H),3.19(s,3H),2.98(s,3H),2.80(td,1H),2.45(s,3H),2.40(td,1H),2.12(td,2H),1.81(dt,2H),1.72-1.64(m,5H)。

Example 36

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -2- (dimethylamino) ethanone 36

Compound 24e (50mg, 92.67. Mu. Mol) was dissolved in a mixed solution of methylene chloride (0.4 mL) and isopropyl alcohol (4 mL), manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (15mg, 24.80. Mu. Mol) was added in an ice-water bath, and after stirring for 3 minutes, phenylsilane (30mg, 277.23. Mu. Mol) was added, and the mixture was stirred at room temperature for 16 hours under an oxygen atmosphere. Concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 36 (15 mg), yield: 29.0 percent.

MS m/z(ESI)：558.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.22(s,1H),7.64-7.63(t,1H),7.48(t,1H),7.23(t,1H),7.02(t,1H),5.89(q,1H),4.78-4.75(m,2H),4.63-4.47(m,4H),4.01-3.98(m,1H),3.61(m,1H),3.33(s,6H),3.22-3.19(m,2H),2.51-2.30(m,7H),1.70-1.69(d,3H)。

Example 37

1- ((S) -3- ((4- (((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorobenzene) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) pyrrolidin-1-yl) ethanone 37

First step of

(S) -3- ((4-hydroxy-2-methylfuro [2,3-h ] quinazolin-6-yl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester 37b

Compound 1f (200mg, 0.925mmol) was dissolved in N, N-dimethylformamide (10 mL), and cesium carbonate (603mg, 1.85mmol) and (R) -3- (p-toluenesulfonyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester 37a (310mg, 0.907mmol, prepared by the method disclosed in the example at page 40 of the specification in patent application "WO 2008/133734") were added and heated to 60 ℃ for 1 hour. Cooling, filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography with eluent system B gave the title compound 37B (89 mg), yield: 25.0 percent.

MS m/z(ESI)：386.0[M+1]。

Second step of

(S) -2-methyl-6- (pyrrolidin-3-yloxy) furo [2,3-h ] quinazolin-4-ol 37c

Compound 37b (89mg, 0.231mmol) was dissolved in methanol (5 mL), and a 1, 4-dioxane solution (4.6 mmol,4M, 1.17mL) of hydrochloric acid was added to stir the reaction for 6 hours. Concentration under reduced pressure gave the title compound 37c (65 mg), yield: 98.6 percent.

MS m/z(ESI)：285.9[M+1]。

The third step

e (S) -1- (3- ((4-hydroxy-2-methylfuro [2,3-h ] quinazolin-6-yl) oxy) pyrrolidin-1-yl) ethanone 37d

Compound 37c (65mg, 0.202mmol) was dissolved in methylene chloride (15 mL), and acetic anhydride (30mg, 0.29mmol) and triethylamine (45mg, 0.44mmol) were added in this order to conduct a reaction at room temperature for 1 hour. Concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title compound 37d (50 mg), yield: 75.6 percent.

MS m/z(ESI)：328.0[M+1]。

The fourth step

1- ((S) -3- ((4- (((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylfuro [2,3-h ] quinazolin-6-yl) oxy) pyrrolidin-1-yl) ethanone 37e

Compound 37d (50mg, 0.153mmol) was dissolved in N, N-dimethylformamide (5 mL), and compound 3a (42mg, 0.164mmol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (81mg, 0.183mmol) and 1, 8-diazacyclo [5,4,0] undec-7-ene (47mg, 0.308mmol) were added in this order, replaced with nitrogen three times, and heated to 70 ℃ for 12 hours. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 37e (45 mg), yield: 55.7 percent.

MS m/z(ESI)：529.0[M+1]。

The fifth step

Compound 37e (40mg, 0.076mmol) was dissolved in methanol (10 mL), and 10% palladium on carbon catalyst (30 mg) was added thereto, and the reaction mixture was replaced with hydrogen three times, followed by stirring for 16 hours. Filtration through celite, concentration of the filtrate under reduced pressure, and purification of the residue by high performance liquid preparative chromatography gave the title compound 37 (14 mg), yield: 28.2 percent.

MS m/z(ESI)：531.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.72-7.70(m,1H),7.58(t,1H),7.46(t,1H),7.21(t,1H),5.87(q,1H),5.31-5.25(m,1H),4.91-4.78(m,2H),4.08-4.01(m,2H),3.86-3.59(m,4H),3.53-3.49(m,2H),2.44(s,3H),2.40-2.19(m,2H),2.14-2.09(d,3H),1.69-1.68(d,3H)。

Example 38

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -3-hydroxy-3-methylbutan-1-one 38

Compound 29a (50mg, 91.1. Mu. Mol) was dissolved in 5mL of isopropanol and 0.5mL of dichloromethane, and tris (2, 6-tetramethyl-3, 5-heptenoic acid) manganese (15mg, 24.8. Mu. Mol) was added thereto, followed by stirring for 10 minutes, addition of phenylsilane (20mg, 180.3. Mu. Mol) under ice bath, oxygen substitution was carried out 3 times, and the reaction was stirred for 14 hours while naturally rising to room temperature. The reaction mixture was filtered, concentrated under reduced pressure, and the resulting title compound 38 (5 mg) was purified by high performance liquid preparative chromatography, yield: 9.7 percent.

MS m/z(ESI)：573.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.23(d,1H),7.63(t,1H),7.49(t,1H),7.24(t,1H),7.13-6.91(t,1H),5.90(q,1H),4.78(m,2H),4.54(m,1H),4.02(d,1H),3.64(td,1H),3.46(q,2H),3.23-3.14(m,1H),2.70-2.60(m,2H),2.53-2.39(m,5H),1.85-1.74(m,2H),1.74-1.66(m,3H),1.34(d,6H)。

Example 39

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 39

Using the synthetic route in example 23 substituting compound 3a as the starting material for compound 2a, compound 39 (10 mg) was prepared, yield: 2.2 percent.

MS m/z(ESI)：512.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.58(t,1H),7.47(t,1H),7.40(s,1H),7.22(t,1H),7.02(s,1H),5.93(t,1H),5.84(q,1H),4.60(s,1H),4.31(q,2H),4.23(dq,2H),3.80(td,1H),3.74(t,1H),3.52(t,1H),2.72-2.57(m,2H),2.42(s,3H),2.19(d,3H),1.65(dd,3H)。

Example 40

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) ethanone 40

Compound 39 (50mg, 97.7. Mu. Mol) was dissolved in 4mL of isopropanol and 0.4mL of dichloromethane, and manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (13mg, 21.5. Mu. Mol) was added thereto, followed by stirring for 10 minutes, addition of phenylsilane (21.2mg, 195.5. Mu. Mol) under ice bath, oxygen substitution 3 times, and natural warming to room temperature and stirring for reaction for 14 hours. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 40 (8 mg), yield: 15.4 percent.

MS m/z(ESI)：530.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.77-7.61(m,2H),7.49(d,1H),7.24(d,1H),7.14-6.92(m,1H),5.88-5.84(m,1H),4.64-4.50(m,1H),4.35-4.33(m,2H),3.87-3.84(m,1H),3.71-3.66(m,1H),3.55-3.53(m,2H),3.23-3.16(m,1H),2.49-2.42(m,5H),2.21(s,3H),1.96-1.90(m,2H),1.67(d,3H)。

EXAMPLE 41

(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) piperidin-1-yl) ethanone 41

Compound 23 (725mg, 1.24mmol) was dissolved in methanol 10mL, 10% palladium on carbon catalyst (250 mg) was added, hydrogen gas was substituted 3 times, the reaction was stirred for 16 hours, filtered, the filtrate was concentrated to dryness under reduced pressure, and the obtained title compound 41 (21 mg) was purified by high performance liquid preparative chromatography, yield: 2.9 percent.

MS m/z(ESI)：544.2[M+1]。

¹ H NMR (500 MHz, A)Alcohol-d ₄ ):δ7.57(d,1H),7.50-7.37(m,2H),7.18(t,1H), 5.86(dt,1H),4.73(d,1H),4.35(t,2H),4.13-3.99(m,3H),3.51(t,2H),3.27(dd,2H),2.76(td,1H),2.41(d,3H),2.17(s,3H),1.98(d,1H),1.96-1.88(m,1H),1.79(tq,2H),1.66(d,3H)。

Example 42

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) piperidin-1-yl) ethanone 42

First step of

6-bromo-2, 10-dimethyl-9, 10-dihydro-3H- [1,4] oxazino [2,3-H ] quinazolin-4 (8H) -one 42a

Compound 17f (1.16g, 3.93mmol) was dissolved in 20mL of acetonitrile, glacial acetic acid (1.18g, 19.6 mmol) and aqueous formaldehyde (3.2g, 39.2mmol) were added, after stirring for 1 hour, sodium cyanoborohydride (1.17g, 19.6 mmol) was further added, after 8 hours of reaction, sodium cyanoborohydride (1.17g, 19.6 mmol) was further added, stirring for 14 hours of reaction, the reaction solution was quenched with a saturated sodium bicarbonate solution, dichloromethane was extracted (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 42a (635 mg), yield: 52.1 percent.

MS m/z(ESI)：310.1[M+1]。

Second step of

(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-4-amine 42b

Compound 42a (230mg, 0.74mmol), compound 2a (210mg, 0.93mmol), N-diisopropylethylamine (287.5 mg, 2.22mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (656mg, 1.48mmol), 1, 8-diazabicycloundecen-7-ene (225.8mg, 1.48mmol) were dissolved in 5mL of N, N-dimethylformamide, stirred for 10 minutes, and then stirred at 80 ℃ for reaction for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 42b (261 mg), yield: 73.1 percent.

MS m/z(ESI)：481.1[M+1]。

The third step

(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 42c

Compound 42b (146mg, 0.3mmol), compound 9j (152mg, 0.6 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (24mg, 40. Mu. Mol) and anhydrous sodium carbonate (64mg, 0.6 mmol) were dissolved in 6mL of 1, 4-dioxane and 2mL of water, displaced with nitrogen 3 times, and heated to 80 ℃ for reaction for 3 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 42c (72 mg), yield: 45.1 percent.

MS m/z(ESI)：526.2[M+1]。

The fourth step

Compound 42c (72mg, 137 μmol) was dissolved in 10mL of methanol, 10% palladium on carbon catalyst (70 mg) was added, hydrogen gas was substituted 3 times, the reaction was stirred for 16 hours, filtered, the filtrate was concentrated under reduced pressure and concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 42 (9 mg), yield: 12.4 percent.

MS m/z(ESI)：528.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ ):δ7.54(q,1H),7.47(t,1H),7.18(td,1H),7.06(d,1H),6.93(t,1H),5.81(dt,2H),4.84(d,1H),4.33-4.11(m,2H),3.95(d,1H),3.24(ddd,4H),3.12(s,3H),2.69(dd,1H),2.54(d,3H),2.15(d,3H),2.00(d,1H),1.92(d,1H),1.75(td,1H),1.69(d,4H)。

Example 43

(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydro- [1,4] dioxano [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 43

Using the synthetic route described in example 19, substituting compound 1j as the starting material for compound 3a in the third step and compound 10b as the starting material for compound 9j in the fourth step, compound 43 (10 mg) was obtained in terms of yield: 4.6 percent.

MS m/z(ESI)：543.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.70(s,1H),7.57(t,1H),7.45(t,1H),7.20(t,1H),5.98(q,1H),5.86(q,1H),4.41(t,4H),4.24(dq,2H),4.04(td,2H),3.80(td,1H), 3.75(t,1H),2.68(s,1H),2.59(s,1H),2.43(s,3H),2.19(d,3H),1.66(d,3H)。

Example 44

(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydro- [1,4] dioxa-cyclo [2,3-h ] quinazolin-6-yl) piperidin-1-yl) ethanone 44

Compound 43 (25mg, 46.1. Mu. Mol) was dissolved in 5mL of methanol, 10% palladium on carbon catalyst (15 mg) was added thereto, and the reaction mixture was replaced with hydrogen gas three times, followed by stirring for 16 hours. The filtrate was concentrated under reduced pressure, and the resulting title compound 44 (7 mg) was purified by high performance liquid preparative chromatography, yield: 27.9 percent.

MS m/z(ESI)：545.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.72(s,1H),7.57(q,1H),7.45(t,1H),7.20(t,1H),5.87(qd,1H),4.76-4.71(m,2H)4.49-4.39(m,4H),4.13-4.00(m,3H),3.31-3.25(m,1H),2.77(td,1H),2.43(d,3H),2.18(s,3H),2.04-1.98(m,1H),1.98-1.90(m,1H),1.79(ttd,2H),1.67(d,3H)。

Example 45

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydro- [1,4] dioxa-lo [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) ethanone 45

First step of

(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-8, 9-dihydro- [1,4] dioxa-cyclo [2,3-h ] quinazolin-4-amine 45a

Compound 19b (300mg, 1mmol), compound 2a (229.2mg, 1mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (1.3g, 3mmol), 1, 8-diazabicycloundecen-7-ene (461.2mg, 3mmol) were dissolved in 5mL of N, N-dimethylformamide, stirred for 10 minutes, and then stirred at 80 ℃ for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 45a (300 mg), yield: and (4) 63.4%.

MS m/z(ESI)：468.2[M+1]。

Second step of

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydro- [1,4] dioxa-lo [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 45b

Compound 45a (300mg, 640.7 μmol) and compound 9j (341.3mg, 961 μmol) were dissolved in 5mL1, 4-dioxane and 1mL water, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (51.2mg, 64.1 μmol) and sodium carbonate (135.8mg, 1.28mmol) were added, and the mixture was heated to 80 ℃ under a nitrogen atmosphere for reaction for 14 hours, the reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system a to obtain the title compound 45b (40 mg), yield: 12 percent.

MS m/z(ESI)：513.1[M+1]。

The third step

Compound 45b (40mg, 78. Mu. Mol) was dissolved in 4mL of isopropanol and 0.4mL of dichloromethane, and manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (15mg, 24.8. Mu. Mol, tokyo, douchi, seisaku, ltd.) was added thereto, followed by stirring for 10 minutes, and then phenylsilane (30mg, 277.2. Mu. Mol, tokyo, seisaku, ltd.) was added thereto under ice bath, oxygen substitution was carried out 3 times, and the mixture was naturally warmed to room temperature and stirred for 14 hours. The reaction solution was filtered, concentrated under reduced pressure, and the obtained title compound 45 (8 mg) was purified by high performance liquid preparative chromatography, yield: 19.3 percent.

MS m/z(ESI)：531.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.91(s,1H),7.62(t,1H),7.48(t,1H),7.23(t,1H),7.03(m,1H),5.87(d,1H),4.53-4.47(m,1H),4.43(s,4H),3.90-3.83(m,1H),3.73-3.64(m,1H),3.23-3.14(m,1H),2.54-2.44(m,2H),2.43(s,3H),2.18(s,3H),1.92(d,1H),1.86(d,1H),1.69(d,3H)。

Example 46

2, 2-difluoro-2- (2-fluoro-3- ((R) -1- ((2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydro- [1,4] dioxa-cyclo [2,3-h ] quinazolin-4-yl) amino) ethyl) phenyl) ethanol 46

Using the synthetic route described in example 20, substituting compound 1j as the starting material for compound 3a in the seventh step, compound 46 (20 mg) was prepared, yield: 15.6 percent.

MS m/z(ESI)：506.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ8.01(d,1H),7.60(t,1H),7.41(t,1H),7.37(s,1H),7.24(t,1H),5.80(dd,1H),5.76-5.70(m,1H),5.19(t,1H),4.33(dq,4H),4.03-3.78(m,6H),2.34(dd,1H),2.31(s,3H),2.06(dt,1H),1.60(d,3H)。

Example 47

(R) -4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) oxy) tetrahydro-2H-thiopyran 1, 1-dioxide 47

4-tetrahydro-2H-thiopyran 1, 1-dioxide 47a (60.2mg, 400.6. Mu. Mol, obtained from Shanghai) and compound 24d (100mg, 200.3. Mu. Mol) were dissolved in 2mL1, 4-dioxane, and then cuprous iodide (19mg, 100.2. Mu. Mol), 1, 10-phenanthroline (18mg, 100.2. Mu. Mol) and cesium carbonate (130.5mg, 400.6. Mu. Mol) were sequentially added thereto, and the mixture was replaced with nitrogen, followed by reaction at 120 ℃ for 1 hour. Cooling, filtration, concentration of the filtrate under reduced pressure, and purification of the resulting title compound 47 (20 mg) from the residue by high performance liquid preparative chromatography, yield: 19.1 percent.

MS m/z(ESI)：522.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.85(s,1H),7.59(t,1H),7.48(t,1H),7.23(t,1H),7.03(s,1H),5.84(q,1H),4.82(t,3H),3.50(q,4H),3.05(dt,2H),2.49(dt,2H),2.43-2.31(m,5H),1.68(d,3H)。

Example 48

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) ethanone 48

Compound 42c (32mg, 60.8. Mu. Mol) was dissolved in 4mL of isopropanol and 0.4mL of dichloromethane, tris (2, 6-tetramethyl-3, 5-heptenoic acid) manganese (15mg, 24.8. Mu. Mol, obtained after Heishi) was added, and after stirring for 10 minutes, phenylsilane (20mg, 184.8. Mu. Mol, obtained after Heishi) was added under ice bath, and oxygen substitution was carried out 3 times, and the mixture was naturally warmed to room temperature and stirred for reaction for 14 hours. The reaction solution was concentrated under reduced pressure by filtration, and the residue was purified by high performance liquid preparative chromatography to give the title compound 48 (6 mg), yield: 17.8 percent.

MS m/z(ESI)：544.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.94(d,1H),7.67-7.54(m,1H),7.46(d,1H),7.22(t,1H),7.02(dd,1H),5.94-5.79(m,1H),4.62(s,1H),4.49(d,1H),4.30(s,2H),3.85(d,1H),3.67(d,1H),3.21(s,2H),3.00(d,3H),2.53-2.33(m,5H),2.17(d,3H),1.90(dd,2H),1.68(d,3H)。

Example 49

(R) -4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) oxy) -1-iminotetrahydro-2H-thiopyran 1-oxide 49

First step of

2-methyl-8, 9-dihydrofuro [2,3-h ] quinazoline-4, 6-diol 49a

Compound 1f (100mg, 426.5 μmol) was dissolved in 10mL of methanol, 100mg of palladium on carbon catalyst (dry) was added, hydrogen gas was substituted for 3 times, the reaction was stirred for 16 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 49a (100 mg), yield: 99.%.

MS m/z(ESI)：219.1[M+1]。

Second step of

2, 2-trifluoro-N- (4-hydroxy-1-oxotetrahydro-2H-thiopyran-1-ylidene) acetamide 49c

tetrahydro-2H-thiopyran-4-ol 49b (2g, 16.9mmol, shanghai bigelian) was dissolved in 50mL dichloromethane, trifluoroacetamide (2.87g, 25.4mmol, shanghai bigelian), diacetyloxyiodobenzene (8.18g, 25.4mmol, shanghai shoua), magnesium oxide (2.73g, 67.7mmol), dimeric rhodium acetate (224.4mg, 507.6 μmol, shanghai takoian) were added, the reaction was stirred for 18 hours, the reaction was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system a to afford the title compound 49c (800 mg), yield: 19.2 percent.

MS m/z(ESI)：246.1[M+1]。

The third step

1-Oxo-1- ((2, 2-trifluoroacetyl) imino) tetrahydro-2H-thiopyran-4-yl 4-toluenesulfonate 49d

Compound 49c (400mg, 1.63mmol), p-toluenesulfonyl chloride (466.5mg, 2.44mmol, obtained after finishing Shanghai) and triethylamine (330mg, 3.26mmol) were dissolved in dichloromethane (50 mL), 4-dimethylaminopyridine (20mg, 163. Mu. Mol) was added, and the reaction mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system a to give the title compound 49d (164 mg), yield: 25.1 percent.

MS m/z(ESI)：400.1[M+1]。

The fourth step

4- ((4-hydroxy-2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) oxy) -1-iminotetrahydro-2H-thiopyran-1-oxide 49e

Compound 49a (90mg, 412.4. Mu. Mol) was dissolved in N, N-dimethylformamide (10 mL), and cesium carbonate (268.8mg, 824.9. Mu. Mol) and 49d (164.7 mg, 412.4. Mu. Mol) were added to the solution, and the mixture was heated to 80 ℃ for reaction for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 49e (30 mg), yield: 20.8 percent.

MS m/z(ESI)：350.1[M+1]。

The fifth step

Compound 49e (30mg, 85.8. Mu. Mol), compound 2a (24.4 mg, 128.8. Mu. Mol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (113.9mg, 257.6. Mu. Mol), 1, 8-diazabicycloundecen-7-ene (39.2mg, 257.6. Mu. Mol) were dissolved in 5mL of N, N-dimethylformamide and reacted with stirring at 80 ℃ for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 49 (4 mg), yield: 8.9 percent.

MS m/z(ESI)：521.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.87(s,1H),7.59(q,1H),7.47(q,1H),7.27-7.19(m,1H),7.02(t,1H),5.87-5.79(m,1H),4.85-4.81(m,3H),3.63-3.46(m,4H),3.22-3.10(m,2H),2.47(dd,2H),2.42(s,3H),2.39-2.32(m,2H),1.69(d,3H)。

Example 50

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -2-methoxyethanone 50

First step of

2-methoxy-1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethan-1-one 50a

Compound 24b (1.7g, 6.92mmol) was dissolved in tetrahydrofuran (5 mL), and methoxyacetic acid (805mg, 8.93mmol, shanghai Shaoshan reagent Ltd.), 2- (7-azobenzotriazol) -N, N, N, N-tetramethyluronium hexafluorophosphate (4.63g, 12.17mmol) and N, N-diisopropylethylamine (2.63g, 20.35mmol) were added in this order, and the mixture was stirred and reacted for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 50a (1.2 g), yield: 52.5 percent.

MS m/z(ESI)：282.0[M+1]。

Second step of

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) -2-methoxyethanone 50b

Compound 24d (0.16g, 320.4. Mu. Mol), compound 50a (0.12g, 426.8. Mu. Mol) were dissolved in 1, 4-dioxane (5 mL) and water (1 mL), and potassium phosphate (0.28g, 1.32mmol) and tetratriphenylphosphine palladium (0.05g, 43.27. Mu. Mol) were added in this order, and the mixture was stirred at 90 ℃ for 3 hours. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 50B (120 mg), yield: 71.2 percent.

MS m/z(ESI)：527.2[M+1]。

The third step

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -2-methoxyethan-1-one 50

Compound 50b (50mg, 95.0 μmol) was dissolved in isopropanol (4 mL) and dichloromethane (0.4 mL), manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (5mg, 19.7 μmol) was added, and after stirring for 3 minutes, phenylsilane (0.013g, 120.13 μmol) was added, oxygen substitution was conducted 3 times, the reaction was stirred for 14 hours, and after the reaction solution was filtered and concentrated, the title compound 50 (10 mg) was purified by high performance liquid preparative chromatography to give the title compound: 19.3 percent.

MS m/z(ESI)：545.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.29(s,1H),7.64(t,1H),7.50(t,1H),7.25(t,1H),7.02(t,1H),5.92(q,1H),5.23(s,1H),5.01(s,1H),4.84-4.77(m,2H),4.47(d, 1H),4.30(d,1H),4.18(d,1H),3.81(d,1H),3.59(t,1H),3.46(s,3H),3.20(t,1H),2.56-2.36(m,5H),1.78(t,2H),1.71(d,3H)。

Example 51

(R) -4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -1-methylpyridin-2 (1H) -one 51

Compound 11H (0.23g, 434.54. Mu. Mol) and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (0.2g, 850.75. Mu. Mol, obtained from Shanghai) were dissolved in 1, 4-dioxane (5 mL) and water (1 mL), potassium phosphate (0.28g, 1.32mmol), palladium tetrakistriphenylphosphine (0.05g, 43.2. Mu. Mol) were added, and the reaction was carried out at 90 ℃ for 3 hours. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to give the title compound 51 (35 mg), yield: 15.8 percent.

MS m/z(ESI)：511.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.47(s,1H),7.72(d,1H),7.61(t,1H),7.52-7.37(m,1H),7.22(t,1H),7.15(d,1H),7.00(dd,2.0Hz,1H),5.90(d,1H),4.84(t,2H),4.05(td,2H),3.64(s,3H),3.52(t,2H),2.46(s,3H),1.70(d,3H)。

Example 52

(1S,4s) -4- (4- (((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1-carboxylic acid 52-P1

(1R, 4r) -4- (4- (((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1-carboxylic acid 52-P2

Using the synthetic route from example 30, substituting the first step starting compound 24d for compound 11h gave the title compound 52, which was then purified by high performance liquid preparative chromatography to give the title compounds 3.22mg and 2.8mg, yields: (3.3%, 2.9%).

Single configuration compounds (shorter retention time)

MS m/z(ESI)：530.0[M+1]。

HPLC analysis: retention time 12.4 min, purity: 98.5% (column: X-Bridge, prep 30X 150mm, 5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A30% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.01(s,1H),7.60(t,1H),7.46(t,1H),7.21(t,1H),5.89(q,1H),4.78-4.73(m,2H),4.05(td,2H),3.52-3.44(m,2H),3.19(q,1H),2.87(s,1H),2.43(s,3H),2.31-2.18(m,2H),2.14-2.01(m,2H),2.01-1.94(m,2H),1.78-1.70(m,1H),1.68(d,1H),1.62(dt,3H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：530.0[M+1]。

HPLC analysis: retention time 14.5 min, purity: 98.5% (column: X-Bridge, prep 30X 150mm, 5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A30% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.98(s,1H),7.61(t,1H),7.48-7.41(m,1H),7.20(t,1H),5.90(q,1H),4.75(t,2H),4.05(td,2H),3.47(dd,2H),2.96-2.83(m,1H),2.55(s,1H),2.43(s,3H),2.35(d,2H),1.88(p,2H),1.77(d,2H),1.68(d,3H),1.65-1.57(m,1H),1.40-1.26(m,1H)。

Example 53

(1S,4s) -4- (4- (((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -N, N-dimethylcyclohexane-1-carboxamide 53-P1

(1R, 4r) -4- (4- (((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -N, N-dimethylcyclohexane-1-carboxamide 53-P2

Compound 52 (100mg, 188.8. Mu. Mol) was dissolved in N, N-dimethylformamide (5 mL), and a tetrahydrofuran solution of dimethylamine (1M, 377.6. Mu.L), N, N-diisopropylethylamine (0.04g, 395.3. Mu. Mol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.133g, 378.71. Mu. Mol) were added thereto and reacted with stirring for 2 hours. Concentration under reduced pressure and preparative purification of the residue in liquid phase gave the title compound in 5mg and 8mg, yield: (4.8%, 7.6%).

Single configuration compounds (shorter retention time)

MS m/z(ESI)：557.0[M+1]。

HPLC analysis: retention time 11.2 min, purity: 98.5% (column: X-Bridge, prep 30X 150mm, 5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -45%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.01(s,1H),7.62-7.56(m,1H),7.46(t,1H),7.21(t,1H),5.88(q,1H),4.76(t,2H),4.05(td,2H),3.47(t,2H),3.17(s,3H),2.98(s,3H),2.93-2.85(m,1H),2.79(t,1H),2.43(s,3H),2.07-1.98(m,2H),1.96-1.90(m,2H),1.81(ddd,2H),1.70-1.66(m,5H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：557.0[M+1]。

HPLC analysis: retention time 12.6 minutes, purity: 98.5% (column: X-Bridge, prep 30X 150mm, 5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -45%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.97(s,1H),7.61(td,1H),7.46(td,1H),7.21(t,1H),5.90(q,1H),4.75(t,2H),4.05(td,2H),3.47(t,2H),3.14(s,3H),3.09-3.04(m,1H),2.98(s,3H),2.97-2.91(m,1H),2.43(s,3H),2.19-2.09(m,2H),2.07-2.00(m,2H),1.79(dddt,4H),1.69(d,3H)。

Example 54

(R) -2- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) acetic acid 54

First step of

(R) -tert-butyl 2- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) acetate 54a

After compound 27B (108mg, 220.45 μmol) was dissolved in acetonitrile (5 mL), tert-butyl 2-bromoacetate (0.043 g,220.45 μmol) and potassium carbonate (0.092g, 665.67 μmol) were added in this order, reacted at 70 ℃ for 4 hours, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 54a (100 mg), yield: 79.9 percent.

MS m/z(ESI)：569.0[M+1]。

Second step of

(R) -2- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) acetic acid 54

Compound 54a (0.15g, 263.79 μmol) was dissolved in dichloromethane (3 mL), a dioxane solution of hydrochloric acid (5g, 263.79 μmol) was slowly added dropwise, stirring was performed for 2 hours, and the reaction solution was concentrated under reduced pressure and then purified by high performance liquid preparative chromatography to give the title compound 54 (40 mg), yield: 29.6 percent.

MS m/z(ESI)：513.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.18(s,1H),7.62(t,1H),7.50(t,1H),7.25(t,1H),7.03(t,1H),5.90(d,1H),5.36(t,1H),4.83(t,2H),4.62(s,1H),4.03(s,1H),3.76(s,1H),3.66-3.56(m,2H),3.53-3.46(m,2H),3.06(s,1H),2.47(s,3H),2.21(t,1H),2.10-2.00(m,1H),1.76-1.73(m,1H),1.71(d,3H),1.66-1.58(m,1H)。

Example 55

(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) piperidin-1-yl) ethanone 55

Compound 16 (0.1g, 189.9 μmol) was dissolved in 5mL of methanol, 10% palladium on carbon catalyst (0.01 g) was added, and after stirring for 16 hours, filtration and concentration were carried out to give a crude product, which was purified by high performance liquid preparative chromatography to give the title compound 55 (24.88 mg), yield: 24.8 percent.

MS m/z(ESI)：529.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.01(s,1H),7.58(t,1H),7.46(t,1H),7.20(t,1H),5.89(dt,1H),4.77(t,2H),4.76-4.72(m,1H),4.04(dq,2H),3.48(t,2H),3.28(dd,2H),3.20-3.11(m,1H),2.76(td,1H),2.44(s,3H),2.18(s,3H),2.07-1.99(m,1H),1.96(d,1H),1.84(ddt,2H),1.68(d,3H)。

Example 56

(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7, 8-dihydrofuro [3,2-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 56

First step of

6-bromo-2-methyl-7, 8-dihydrofuro [3,2-h ] quinazolin-4-ol 56b

Using the synthetic route in example 11, substituting the first step compound 2, 3-dihydrobenzofuran-4-amine 11a with the compound 2, 3-dihydrobenzofuran-7-amine 56a gave the title compound 56b (300 mg), yield: 78.5 percent.

MS m/z(ESI)：281.1[M+1]。

Second step of

1- (4- (4-hydroxy-2-methyl-7, 8-dihydrofuro [3,2-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 56c

Compound 56b (0.155g, 551.4. Mu. Mol) and compound 9i (0.277g, 1.1mmol) were dissolved in 4mL of N, N-dimethylformamide and 1mL of water, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.093g, 113.8. Mu. Mol) and sodium carbonate (0.117g, 1.1 mmol) were added in this order and reacted at 100 ℃ for 2 hours under a nitrogen atmosphere. Cooled and concentrated under reduced pressure, and after concentration the crude product was purified by silica gel column chromatography with eluent system B to give the title compound 56c (55 mg), yield: 30.7 percent.

MS m/z(ESI)：326.1[M+1]。

The third step

(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7, 8-dihydrofuro [3,2-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethan-1-one 56

Compound 56c (52mg, 0.159mmol) was dissolved in N, N-dimethylformamide (5 mL), followed by addition of compound 3a (70mg, 0.319mmol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (141mg, 0.318mmol), and 1, 8-diazacyclo [5,4,0] undec-7-ene (49mg, 0.321mmol), replacement with nitrogen three times, and heating to 80 ℃ for 12 hours. The reaction solution was cooled, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 56 (20 mg), yield: 23.8 percent.

MS m/z(ESI)：527.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.73(d,1H),7.59(t,1H),7.46(t,1H),7.21(t,1H),6.03(s,1H),5.88(q,1H),4.76(t,2H),4.26(dt,2H),4.04(td,2H),3.86(td,1H),3.80(t,1H),3.48-3.42(m,2H),2.71(s,1H),2.64(s,1H),2.43(s,3H),2.21(d,3H),1.68(d,3H)。

Example 57

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) propanone 57

First step of

1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridin-1 (2H) -yl) propanone 57a

Compound 24b (0.9g, 4.3mmol) and triethylamine (2.18g, 21.5mmol) were dissolved in 5mL of dichloromethane, and propionyl chloride (0.6g, 6.48mmol) was added dropwise thereto under an ice-water bath, and after 5 minutes, the mixture was allowed to stand at room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 57a (1.14 g), yield: 70.1 percent.

MS m/z(ESI)：266.2[M+1]。

Second step of

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) propan-1-one 57b

Compound 24d (0.12g, 240.3. Mu. Mol) and compound 57a (0.1g, 77.1. Mu. Mol) were dissolved in 4mL dioxane and 1mL water, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.041g, 48.4. Mu. Mol) and sodium carbonate (0.051g, 481.1. Mu. Mol) were added and reacted at 100 ℃ for 3 hours. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 57b (100 mg), yield: 81.5 percent.

MS m/z(ESI)：511.3[M+1]。

The third step

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) propan-1-one 57

The title compound 57 (30 mg) was purified by high performance liquid preparative chromatography by dissolving the compound 57b (80mg, 156.7. Mu. Mol) in methylene chloride (0.5 mL) and isopropanol (5 mL), adding tris (2, 6-tetramethyl-3, 5-heptenoic acid) manganese (20mg, 33.1. Mu. Mol) and phenylsilane (20mg, 462. Mu. Mol), displacing with oxygen three times, stirring the reaction for 16 hours, concentrating the reaction solution under reduced pressure, and purifying the resulting title compound 57 (30 mg) with yield: 24.1 percent.

MS m/z(ESI)：529.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.22(s,1H),7.63(t,1H),7.48(t,1H),7.24(t,1H),7.02(t,1H),5.89(q,1H),4.78(t,2H),4.51(d,1H),3.90(d,1H),3.64(t,1H),3.45(t,2H),3.17(t,1H),2.50(q,2H),2.45(s,3H),1.79(dd,2H),1.69(d,3H),1.33(d,2H),1.19(t,3H)。

Example 58

(1R, 4S) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-N- ((S) -2-hydroxypropyl) -N-methylcyclohexanecarboxamide 58-P1

(1S, 4R) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-N- ((S) -2-hydroxypropyl) -N-methylcyclohexanecarboxamide 58-P2

Using the synthetic route from example 31, the starting compound morpholine was replaced with the compound (S) -1-methylamino-2-propanol to give the title compound 43mg,22mg, yield: 20.8 percent and 10.6 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：587.1[M+1]。

HPLC analysis: retention time 11.4 minutes, purity: 98.5% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -45%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.20(d,1H),7.64(t,1H),7.48(t,1H),7.24(t,1H),7.03(t,1H),5.89(q,1H),4.80(t,2H),4.02(tt,1H),3.61-3.51(m,1H),3.46(t,2H),3.27-3.16(m,2H),3.00(s,1H),2.96-2.75(m,1H),2.44(s,3H),2.42-2.28(m,2H),2.26-2.00(m,2H),1.82(d,2H),1.69(d,3H),1.25(d,3H),1.17(d,3H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：587.1[M+1]。

HPLC analysis: retention time 16.2 minutes, purity: 98.9% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -45%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.20(d,1H),7.64(t,1H),7.48(t,1H),7.24(t,1H),7.03(t,1H),5.89(q,1H),4.80(t,2H),4.02(tt,1H),3.61–3.51(m,1H),3.46(t,2H),3.27–3.16(m,2H),3.00(s,1H),2.96–2.75(m,1H),2.44(s,3H),2.42–2.28(m,2H),2.26–2.00(m,2H),1.82(d,2H),1.69(d,3H),1.25(d,3H),1.17(d,3H)。

Example 59

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -2-hydroxyacetophenone 59

Using the synthetic route in example 27, the starting compound cyanoacetic acid in the third step was replaced with 2-hydroxyacetic acid and purified by high performance liquid preparative chromatography to give the title compound 59 (15 mg), yield: 9.6 percent.

MS m/z(ESI)：531.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.22(s,1H),7.63(t,1H),7.48(t,1H),7.24(t,1H),7.03(t,1H),5.89(q,1H),4.78(t,2H),4.54–4.42(m,1H),4.40–4.24(m,2H),3.67(d,1H),3.58(td,1H),3.45(t,2H),3.24(td,1H),2.44(s,5H),1.87–1.74(m,2H),1.69(d,3H)。

Example 60

(R) -cyclopropyl (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) methanone 60

Using the synthetic route described in example 57, substituting the propionyl chloride, the starting compound for the cyclopropylcarbonyl chloride, gave the title compound 60 (30 mg), yield: 24.1 percent.

MS m/z(ESI)：541.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.23(s,1H),7.63(t,1H),7.48(t,1H),7.24(t,1H),7.03(t,1H),5.89(q,1H),4.78(t,2H),4.47(d,1H),4.28(d,1H),3.71(t,1H),3.46(t,2H),3.21(t,1H),2.57-2.48(m,1H),2.44(s,3H),2.11-2.00(m,1H),1.85(d,1H),1.75(d,1H),1.69(d,3H),1.40-1.26(m,2H),1.00-0.77(m,3H)。

Example 61

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -2-fluoroacetone 61

First step of

2-Fluoroacetic acid 61b

Ethyl 2-fluoroacetate 61a (0.5g, 4.7mmol) was dissolved in methanol (20 mL), and sodium hydroxide (1M, 10mL) was added to stir the reaction for 14 hours. Concentrated under reduced pressure, the residue was dissolved with a small amount of water, neutralized to pH 7-8 with 1M hydrochloric acid, and concentrated under reduced pressure to give the crude title compound 61b (367 mg) which was used in the next step without purification.

MS m/z(ESI)：77.1[M-1]。

Second step of

2-fluoro-1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethanone 61c

Compound 24b (923.8mg, 3.8mmol) and compound 61b (367mg, 4.7mmol) were dissolved in N, N-dimethylformamide (20 mL), and N, N-diisopropylethylamine (1.82g, 14.1mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (2.21g, 9.4mmol) were added in this order and reacted at room temperature under nitrogen for 14 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 61c (600 mg), yield: 47.4 percent.

MS m/z(ESI)：270.2[M+1]。

The third step

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) -2-fluoroacetone 61d

Compound 24d (115mg, 230. Mu. Mol) and compound 61c (93 mg, 346. Mu. Mol) were dissolved in 1, 4-dioxane (2 mL) and water (0.4 mL), followed by addition of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (19mg, 23.3. Mu. Mol) and anhydrous sodium carbonate (49mg, 461. Mu. Mol), nitrogen substitution 3 times, and heating to 90 ℃ for 14 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 61d (100 mg), yield: 84.3 percent.

MS m/z(ESI)：515.2[M+1]。

The fourth step

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -2-fluoroethan-1-one 61

Compound 61d (100mg, 194 μmol) was dissolved in isopropanol (2 mL) and dichloromethane (0.2 mL), manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (24mg, 40 μmol) was added, and after stirring for 3 minutes, phenylsilane (63mg, 582 μmol) was added, oxygen substitution was performed 3 times, reaction was performed at room temperature for 14 hours, and after the reaction solution was filtered and concentrated, it was purified by high performance liquid preparative chromatography to give the title compound 61 (8 mg), yield: 7.7 percent.

MS m/z(ESI)：533.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.24(s,1H),7.62(t,1H),7.48(t,1H),7.23(t,1H),7.01(t,1H),5.89(q,1H),5.29-5.06(m,2H),4.79(t,2H),4.53-4.40(m,1H),3.60(dd,2H),3.45(t,2H),3.28-3.18(m,1H),2.45(s,5H),1.86-1.74(m,2H),1.69(d,3H)。

Example 62

((1R, 4r) -4- (4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxycyclohexyl) (4-methylpiperazin-1-yl) methanone 62-P1

((1S,4s) -4- (4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxycyclohexyl) (4-methylpiperazin-1-yl) methanone 62-P2

First step of

4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylic acid 62a

Compound 30a (1g, 3.76mmol) and lithium hydroxide monohydrate (631mg, 15mmol) were dissolved in a mixed solvent of 10mL of tetrahydrofuran, 2mL of water and 5mL of methanol, stirred at room temperature for 16 hours, 2N hydrochloric acid was added dropwise to adjust the pH to 5-6, and concentrated under reduced pressure to give the title compound 62a (1.8 g), which was directly used in the next step without purification.

MS m/z(ESI)：251.1[M-1]。

Second step of

(4-Methylpiperazin-1-yl) (4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-en-1-yl) methanone 62b

Compound 62a (500mg, 1.98mmol) and 1-methyl-piperazine (238.4mg, 2.38mmol) were dissolved in 10mL of N, N-dimethylformamide, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1.13g, 2.97mmol) and N, N-diisopropylethylamine (512mg, 4.0mmol) were added, the reaction was stirred for 16 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 62b (300 mg) in 45% yield.

MS m/z(ESI)：335.1[M+1]。

The third step

(4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohex-3-en-1-yl) (4-methylpiperazin-1-yl) methanone 62c

Compound 24d (100mg, 200.3. Mu. Mol), compound 62b (133.9mg, 0.4 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (33.92mg, 40. Mu. Mol) and anhydrous sodium carbonate (42.46mg, 0.4 mmol) were dissolved in 10mL of dioxane and 2mL of water, and reacted 3 times with argon at 100 ℃ for 3 hours. Cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to elute compound 62c (100 mg) in 86% yield as eluent system a.

MS m/z(ESI)：580.2[M+1]。

The fourth step

Compound 62d (100mg, 172.5. Mu. Mol) was dissolved in isopropanol (5 mL) and dichloromethane (0.5 mL), manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (60mg, 99.2. Mu. Mol) was added, and after stirring for 5 minutes, phenylsilane (60m g, 554. Mu. Mol) was added, oxygen was replaced 3 times, the reaction was stirred for 20 hours, and after the reaction solution was filtered and concentrated, it was purified by high performance liquid preparative chromatography to give the title compound of 15mg,10mg, yield: 14.5 percent and 9.7 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：598.2[M+1]。

HPLC analysis: retention time 10.12 minutes, purity: 98.5% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A20% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.15(s,1H),7.73(t,1H),7.63(t,1H),7.23(t,1H),7.14(t,1H),5.91(q,1H),4.86-4.77(m,3H),3.65-3.61(m,4H),3.47-3.44(m,2H),2.95-2.93(m,1H),2.93-2.89(m,2H),2.50-2.42(m,4H),2.33(s,3H),2.21(s,3H),1.98-1.97(m,1H),1.85-1.83(m,2H),1.71-1.66(m,5H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：598.2[M+1]。

HPLC analysis: retention time 11.59 min, purity: 99.2% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A20% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.20(s,1H),7.65(t,1H),7.50(t,1H),7.25(t,1H),7.13(t,1H),5.91(q,1H),4.68-4.56(m,3H),3.70-3.66(m,4H),3.48-3.44(m,2H), 2.81-2.77(m,1H),2.53-2.51(m,2H),2.46-2.42(m,4H),2.39(s,3H),2.35(s,3H),2.20-2.09(m,1H),1.82-1.79(m,2H),1.70-1.66(m,5H)。

Example 63

(4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) ((R) -tetrahydrofuran-3-yl) methanone 63

Using the synthetic route for example 27, the starting material compound cyanoacetic acid in the third step was replaced with the compound (R) -tetrahydrofuran-3-carboxylic acid, and purified by high performance liquid preparative chromatography to give the title compound 63 (20 mg), yield: and 19.3 percent.

MS m/z(ESI)：571.3[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.22(s,1H),7.63(t,1H),7.48(t,1H),7.24(t,1H),7.02(t,1H),5.89(q,1H),4.78(t,3H),4.55-4.43(m,2H),4.08-3.97(m,2H),3.92(dt,2H),3.88-3.79(m,1H),3.66(ddt,1H),3.60-3.50(m,1H),3.46(t,2H),3.20(ddd,1H),2.55-2.34(m,4H),2.20(ddt,2H),1.80(ddt,1H),1.70(d,3H)。

Example 64

(1R, 4r) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-N- (2-hydroxy-2-methylpropyl) -N-methylcyclohexanecarboxamide 64-P1

(1S, 4s) -4- (4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-N- (2-hydroxy-2-methylpropyl) -N-methylcyclohexanecarboxamide 64-P2

Using the synthetic route described in example 62, the starting material compound 1-methyl-piperazine was replaced with the compound 2-methyl-1-methylamino-propan-2-ol in the second step to give the title compound as 30mg and 10mg, yields: 29.1 percent and 9.7 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：601.2[M+1]。

HPLC analysis: retention time 10.65 minutes, purity: 98.5% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -45%).

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.19(s,1H),7.62(t,1H),7.48(t,1H),7.24(td,1H),7.03(t,1H),5.90(q,1H)，4.79(t,2H),3.49–3.39(m,2H),3.26(s,3H),3.00-2.91(m,2H),2.44(s,3H),2.06–1.95(m,2H),1.94–1.85(m,1H),1.83-1.74(m,2H),1.69 (d,3H),1.29-1.24(m,2H),1.22-1.18(m,2H),1.17(s,6H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：601.2[M+1]。

HPLC analysis: retention time 12.15 minutes, purity: 98.9% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -45%).

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.23–8.15(m,1H),7.64(t,1H),7.48(t,1H),7.24(t,1H),7.03(t,1H),5.89(q,1H),4.80(t,2H),3.56-3.41(m,4H),3.30(s,3H),3.06(s,1H),2.85(t,1H),2.43(s,3H),2.37-2.28(m,1H),2.19-2.07(m,2H),1.82(d,2H),1.69(d,3H),1.38-1.26(m,2H),1.19(s,6H)。

Example 65

(4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) ((S) -tetrahydrofuran-3-yl) methanone 65

Using the synthetic route for example 27, the starting material compound cyanoacetic acid in the third step was replaced with the compound (S) -tetrahydrofuran-3-carboxylic acid, and purified by high performance liquid preparative chromatography to give the title compound 65 (16 mg), yield: 7.7 percent.

MS m/z(ESI)：571.3[M+1]。

Example 66

1- ((S) -3- ((4- ((((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) pyrrolidin-1-yl) ethanone 66

Compound 24d (100mg, 0.2mmol) and compound (S) -1- (3-hydroxypyrrolidin-1-yl) ethan-1-one (517.3mg, 4 mmol) were dissolved in 1, 4-dioxane, 1, 10-phenanthroline (144mg, 0.8mmol), cesium carbonate (261mg, 8 mmol), cuprous iodide (152mg, 0.8mmol) were added, the mixture was replaced with nitrogen, the reaction was reacted at 120 ℃ for 3 hours with a microwave, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 66 (4.0 mg), yield: 3.9 percent.

MS m/z(ESI)：501.1[M+1]。

¹ H NMR(500MHz,Methanol-d ₄ ):δ7.75(d,1H),7.61(t,1H),7.47(t,1H),7.22(t,1H),7.01(t,1H),5.81(q,1H),5.30-5.25(m,2H),3.88-3.76(m,4H),3.73-3.66(m,1H),3.58-3.48(m,2H),2.41(s,3H),2.40-2.25(m,2H),2.11(d,3H),1.69(d,3H)。

Example 67

1- ((S) -3- ((4- ((((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydro- [1,4] dioxa-cyclo [2,3-h ] quinazolin-6-yl) oxy) pyrrolidin-1-yl) ethanone 67

First step of

(R) -1-acetylpyrrolidin-3-yl 4-methylbenzenesulfonate 67b

(R) -1- (3-hydroxypyrrolidin-1-yl) ethanone 67a (1g, 7.74mmol), 4-dimethylaminopyridine (95mg, 0.77mmol) and triethylamine (1.5g, 14.8mmol) were dissolved in 20mL of dichloromethane, 4-toluenesulfonyl chloride (1.7g, 8.9mmol) was added, the reaction mixture was stirred for 3 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 67b (800 mg) in 36.4% yield.

MS m/z(ESI)：284.0[M+1]。

Second step of

1- ((S) -3- ((4- ((((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydro- [1,4] dioxocyclo [2,3-h ] quinazolin-6-yl) oxy) pyrrolidin-1-yl) ethanone 67

Using the synthetic route described in example 20, substituting the starting material compound 1g for compound 67b and the starting material compound 1j for compound 2a in the third step, compound 67 (20 mg) was obtained in terms of yield: 13.3 percent.

MS m/z(ESI)：517.2[M+1]。

¹ H NMR (400 MHz, methanol-d) ₄ ):7.60-7.58(m,1H),7.49-7.47(m,1H),7.42(d,1H),7.24-7.22(m,1H),7.14-7.03(m,1H)，5.85(q,1H),5.26-5.19(m,1H),4.44-4.41(m,4H),3.83-3.80(m,4H),3.31-2.41(m,5H),2.34(d,3H),1.69(d,3H)。

Example 68

(S) -3- ((4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) -N-methylpyrrolidine-1-carboxamide 68

First step of

(S) -3- ((4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester 68a

Compound 24d (100mg, 0.2mmol) and tert-butyl (3S) -3-hydroxypyrrolidine-1-carboxylate (375mg, 2mmol) were dissolved in 5ml of 1, 4-dioxane, 1, 10-phenanthroline (144mg, 0.8mmol), cesium carbonate (261mg, 0.8mmol), cuprous iodide (152mg, 0.8mmol) were added thereto, the mixture was reacted with nitrogen gas at 120 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography using eluent system C to give the title compound 68a (30 mg) in yield: 26.8 percent.

MS m/z(ESI)：559.2[M+1]。

Second step of

N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (((S) -pyrrolidin-3-yloxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 68b

Compound 68a (30mg, 53.7. Mu. Mol) was dissolved in 2mL of dichloromethane, 1mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 5mL of dichloromethane and 1mL of methanol, a small amount of solid sodium bicarbonate was added, stirred for 20 minutes, the pH was adjusted to be basic, and concentrated by filtration to obtain a crude product 68b (24 mg), yield: 98%, the product was used directly in the next reaction without purification.

MS m/z(ESI)：459.2[M+1]。

The third step

Compound 68b (100mg, 218.1 μmol) and N, N-diisopropylethylamine (66.2mg, 654.3 μmol) were dissolved in 5mL of dichloromethane, N-methyl-1-imidazolecarboxamide (27.3mg, 218.1 μmol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 68 (15 mg), yield: 13.3 percent.

MS m/z(ESI)：516.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.70(s,1H),7.61(t,1H),7.49(t,1H),7.25-7.21(m,1H),7.14(t,1H),5.86(q,1H),5.36-5.25(m,1H),4.81(t,2H),3.70-3.65(m,2H),3.57(t,2H),3.49(t,2H),2.76(s,3H),2.41(s,3H),2.41-2.27(m,2H),1.69(d,3H)。

Example 69

(R) -2- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -N, N-dimethylacetamide 69

First step of

N, N-dimethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridin-1 (2H) -yl) acetamide 69b

Compound 24b (676mg, 3.23mmol), compound 69a (805mg, 4.85mmol) and anhydrous potassium carbonate (894mg, 6.47mmol) were dissolved in N, N-dimethylformamide (10 mL), and the reaction was stirred under a nitrogen atmosphere for 14 hours. The reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to obtain the title compound 69b (457 mg), yield: and 47 percent.

MS m/z(ESI)：295.1[M+1]。

Second step of

(R) -2- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) -N, N-dimethylacetamide 69c

Compound 24d (100mg, 200.3. Mu. Mol) and compound 69b (177mg, 601.6. Mu. Mol) were dissolved in 1, 4-dioxane (2 mL) and water (0.4 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (17mg, 21. Mu. Mol) and anhydrous sodium carbonate (45mg, 425. Mu. Mol) were added in this order, purged with nitrogen 3 times, and heated to 90 ℃ for reaction for 14 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 69c (72 mg), yield: 67%.

MS m/z(ESI)：540.1[M+1]。

The third step

Compound 69c (72mg, 133.4 μmol) was dissolved in isopropanol (3 mL) and dichloromethane (0.3 mL), manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (1695g, 26.7 μmol) was added, and after stirring for 3 minutes, phenylsilane (43mg, 400 μmol) was added, oxygen was substituted 3 times, reaction at room temperature was carried out for 14 hours, and after the reaction solution was filtered and concentrated, it was purified by high performance liquid preparative chromatography to give the title compound 69 (15 mg), yield: 20 percent.

MS m/z(ESI)：558.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ ):δ7.61(s,1H),7.52(t,1H),7.46(d,1H),7.17(t,1H),6.92(t,1H),6.02(d,1H),5.80(t,1H),4.78(t,2H),3.61–3.43(m,2H),3.26(s,2H),3.09(s,3H),2.96(s,3H),2.87(d,2H),2.66(t,2H),2.50(s,3H),2.41(d,2H),1.87(d,3H),1.68(d,3H)。

Example 70

(R) -1- (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) azetidin-1-yl) ethanone 70

First step of

Compound 11g (90mg, 274.3. Mu. Mol) was dissolved in N, N-dimethylformamide (3 mL), and compound 2a (124mg, 549.5. Mu. Mol), N-diisopropylethylamine (70mg, 541.6. Mu. Mol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (243mg, 549.4. Mu. Mol) and 1, 8-diazacyclo [5,4,0] undec-7-ene (84mg, 551.8. Mu. Mol) were added in this order, replaced with nitrogen three times, and heated to 80 ℃ for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 24d (90 mg), yield: 65.7 percent.

MS m/z(ESI)：500.1[M+1]。

Second step of

Compound 24d (500mg, 1.0mmol) and 1- (3-hydroxyazetidin-1-yl) ethanone 70a (400mg, 3.47mmol) were dissolved in 10mL of 1, 4-dioxane, 1, 10-phenanthroline (180mg, 1.0mmol), cesium carbonate (978mg, 3.0mmol), cuprous iodide (95mg, 0.5mmol) were added, the mixture was replaced with nitrogen for 15 minutes, reacted at 125 ℃ for 4.5 hours, the reaction mixture was concentrated under reduced pressure and purified by high performance liquid preparative chromatography to give the title compound 70 (100 mg), yield: 20 percent.

MS m/z(ESI)：487.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.58(t,1H),7.47(d,2H),7.22(t,1H),7.01(t,1H),5.83(t,1H),5.26-5.18(m,1H),4.79(d,2H),4.70-4.64(m,1H),4.51-4.39(m,1H),4.34-4.24(m,1H),4.03(dt,1H),3.49(t,2H),2.40(d,3H),1.93(s,3H),1.67(d,3H)。

Example 71

(1R, 4r) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) -4-hydroxy-N, N-dimethylcyclohexanecarboxamide 71-P1

(1S,4s) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) -4-hydroxy-N, N-dimethylcyclohexanecarboxamide 71-P2

First step of

N, N-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxamide 71a

Compound 62a (150mg, 595. Mu. Mol) and 2M N, N-dimethylamine (595. Mu.L, 1.2 mmol) were dissolved in N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (154mg, 1.2 mmol) and 2- (7-azobenzotriazol) -N, N, N-tetramethylurea hexafluorophosphate (280mg, 1.2 mmol) were sequentially added and reacted at room temperature under nitrogen atmosphere for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 71a (150 mg), yield: 90 percent.

MS m/z(ESI)：280.1[M+1]。

Second step of

4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) -N, N-dimethylcyclohex-3-enecarboxamide 71b

Compound 42a (288mg, 598. Mu. Mol) and compound 71a (360mg, 1.3mmol) were dissolved in 1, 4-dioxane (5 mL) and water (1 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (48mg, 59. Mu. Mol) and anhydrous sodium carbonate (128mg, 1.2mmol) were added in this order, and the mixture was replaced with nitrogen 3 times, heated to 90 ℃ and reacted for 14 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 71b (69 mg), yield: 20.8 percent.

MS m/z(ESI)：554.0[M+1]。

The third step

Compound 71b (69mg, 125 μmol) was dissolved in isopropanol (2 mL) and dichloromethane (0.2 mL), manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (15mg, 25 μmol) was added, and after stirring for 3 minutes, phenylsilane (41mg, 378.88 μmol) was added, oxygen substitution was performed 3 times, reaction was carried out at room temperature for 14 hours, and after the reaction solution was filtered and concentrated, the mixture was purified by high performance liquid preparative chromatography to give the title compounds 3.22mg and 2.8mg, yield: (2.9%, 2.1%).

Single configuration compounds (shorter retention time)

MS m/z(ESI)：572.2[M+1]。

HPLC analysis: retention time 11.2 min, purity: 98% (chromatographic column: X-Bridge, prep 30X 150mm, 5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A30% -55%).

¹ H NMR(500MHz,CDCl ₃ ):δ7.50(dt,7.2Hz,2H),7.40(s,1H),7.18(t,1H),6.92(t,1H),5.80(d,2H),5.34(s,1H),4.36-4.19(m,2H),3.29-3.21(m,2H),3.12(d,6H),2.98(s,3H),2.63(t,1H),2.55(s,3H),2.19(dt,4H),2.03(dd,4H),1.68(d,3H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：572.2[M+1]。

HPLC analysis: retention time 13.1 min, purity: 98% (column: X-Bridge, prep 30 × 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A30% -55%).

¹ H NMR(500MHz,CDCl ₃ ):δ7.57(t,1H),7.47(t,1H),7.37(s,1H),7.18(t,1H),6.95(t,1H),5.88-5.72(m,1H),5.35(t,1H),4.31(dq,2H),4.12(s,1H),3.32-3.19(m, 2H),3.19-3.00(m,6H),2.95(s,3H),2.92-2.85(m,1H),2.53(d,4H),2.26-2.08(m,3H),1.99(dt,4H),1.70(d,3H)。

Example 72

(R) - (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) (1-methylazetidin-3-yl) methanone 72

Using the synthetic route described in example 27, the starting compound cyanoacetic acid in the third step was replaced with the compound 1-methyl-3-azetidinecarboxylic acid to give the title compound 72 (6.0 mg), yield: 11.6 percent.

MS m/z(ESI)：570.3[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ8.21(s,1H),7.63(t,1H),7.48(t,1H),7.23(t,1H),7.02(t,1H),5.92-5.85(m,1H),4.78(t,3H),4.47(d,2H),3.69(s,2H),3.59(dd,2H),3.46(dd,2H),3.24-3.15(m,2H),3.10-2.89(m,1H),2.44(s,3H),2.40(s,3H),1.77(t,2H),1.69(d,3H),1.62(m,1H)。

Example 73

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -4-hydroxy-1-iminotetrahydro-2H-thiopyran-1-oxide 73

First step of

(R) -N- (1- (3- (difluoromethyl) -2-fluorobenzene) ethyl) -6- (3, 6-dihydro-2H-thiopyran-4-yl) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-4-amine 73b

Compound 24d (800mg, 1.6 mmol) and 2- (3, 6-dihydro-2H-thiopyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan 73a (725mg, 3.2mmol, obtained after shanghai) were dissolved in 5mL of 1, 4-dioxane and 1mL of water, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (130mg, 0.16mmol) and sodium carbonate (400mg, 3.2mmol) were added, heated to 90 ℃ under nitrogen atmosphere and reacted for 3 hours, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 73b (660 mg), yield: 87 percent.

MS m/z(ESI)：471.9[M+1]。

Second step of

4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -1-imine-3, 6-dihydro-2H-thiopyran 1-oxide 73c

Compound 73B (660mg, 1.4mmol) was dissolved in 5mL of ethanol, iodobenzene acetate (1.4g, 4.1mmol) and ammonium acetate (430mg, 5.6 mmol) were added, reaction was carried out at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 73c (200 mg), yield: 28 percent.

MS m/z(ESI)：502.8[M+1]。

The third step

Compound 73c (460mg, 915. Mu. Mol) was dissolved in methylene chloride (0.5 mL) and isopropanol (5 mL), manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (110mg, 180. Mu. Mol) and phenylsilane (250mg, 2.3mmol) were added, oxygen was replaced three times, and the reaction was stirred for 16 hours. The obtained title compound 73 (40 mg) was purified by high performance liquid preparative chromatography, yield: 5.4 percent.

MS m/z(ESI)：521.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.29(d,1H),7.63(t,1H),7.49(t,1H),7.24(t,1H),7.02(t,1H),5.90(q,1H),4.81(td,2H),3.64(dtd,2H),3.47(td,2H),3.24-2.94(m,4H),2.45(d,3H),2.10(dt,2H),1.70(d,3H)。

Example 74

(R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -3-hydroxyazetidin-1-yl) ethanone 74

Using the synthetic route described in example 11, substituting compound 11h of the starting material in the eighth step for compound 24d and 1-acetylpiperidin-4-one for 1-acetylazetidin-3-one provided compound 74 (20 mg), yield: 8.5 percent.

MS m/z(ESI)：487.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.26(d,1H),7.61(t,1H),7.48(t,1H),7.23(t,1H),7.02(t,1H),5.88(q,1H),4.87-4.78(m,3H),4.62(d,1H),4.36(dt,1H),4.14(d,1H),3.49(t,2H),2.44(s,3H),1.97(s,3H),1.69(d,3H)。

Example 75

(R) - (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) (tetrahydro-2H-pyran-4-yl) methanone 75

Using the synthetic route from example 50, substituting the starting material methoxyacetic acid in the first step for the compound tetrahydropyran-4-carboxylic acid, compound 75 (40 mg) was prepared in yield: 38.7 percent.

MS m/z(ESI)：585.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.21(s,1H),7.64(t,1H),7.49(t,1H),7.25(t,1H),7.22(t,1H),5.81(q,1H),4.78-7.75(m,2H),4.51(q,1H),4.04-4.01(m,3H),3.66-3.65(m,1H),3.65(t,2H),3.51(t,2H),3.25(q,1H),3.20(q,1H),2.45-2.42(m,5H),1.88-1.74(m,4H),1.69-1.66(m,5H)。

Example 76

(R) -1- (4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) piperidin-1-yl) ethanone 76

Using the synthetic route described in example 70, the starting compound 1-acetyl-3-hydroxyazetidine from the eighth step was replaced with the compound N-acetyl-4-hydroxypiperidine to provide compound 76 (2.0 mg), yield: 7.6 percent.

MS m/z(ESI)：515.3[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.77(s,1H),7.58(t,1H),7.46(t,1H),7.22(t,1H),7.01(t,1H),5.84(q,1H),5.19(s,1H),4.78(s,2H),3.82(ddd,2H),3.64(ddd,1H),3.59-3.42(m,3H),2.41(s,3H),2.15(s,3H),2.06–1.96(m,2H),1.85(dtd,2H),1.68(d,3H)。

Example 77

N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 10-dimethyl-6- (((R) -tetrahydrofuran-3-yl) oxy) -9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-4-amine 77

First step of

4-hydroxy-3-methoxy-5-nitrobenzoic acid methyl ester 77b

The compound methyl 4-hydroxy-3-methoxybenzoate 77a (20.48g, 112.4, mmol) was dissolved in glacial acetic acid (100 mL), and nitric acid (9.4 mL) was slowly added thereto under ice-cooling to return to room temperature for 2 hours. Ice water was added to the reaction solution, and the solid was filtered and drained to obtain compound 77b (20 g) in 78% yield.

MS m/z(ESI)：227.9[M+1]。

Second step of

3-amino-4-hydroxy-5-methoxybenzoic acid methyl ester 77c

Compound 77b (20g, 88.04mmol) was dissolved in methanol (200 mL), and 10% palladium on carbon catalyst (wet) (9.37 g) was added thereto, and the mixture was replaced with hydrogen, and the reaction was stirred overnight. The reaction solution was filtered through celite, and concentrated under reduced pressure to give crude compound 77c (18 g), which was directly used in the next step without purification.

MS m/z(ESI)：198.0[M+1]。

The third step

8-methoxy-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 77d

Compound 77c (18g, 91.3mmol) was dissolved in N, N-dimethylformamide (1000 mL), and anhydrous potassium carbonate (37.87g, 274mmol) and 1, 2-dibromoethane (17.4g, 92.6mmol) were added and reacted at 80 ℃ for 1 hour. The temperature was lowered to room temperature, the reaction solution was filtered through celite, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 77d (20.1g, 90mmol), yield: 98.6 percent.

MS m/z(ESI)：224.0[M+1]。

The fourth step

7-bromo-8-methoxy-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 77e

Compound 77d (10.7g, 47.9mmol) was dissolved in acetonitrile (250 mL), and N-bromosuccinimide (5.12g, 28.8mmol) was added thereto under ice-cooling, and the reaction was stirred for 2 hours. A small amount of the starting material remained, and 350mg of N-bromosuccinimide was added, the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain compound 77e (14.2 g), yield: 98.6 percent.

MS m/z(ESI)：301.9[M+1]。

The fifth step

7-bromo-8-methoxy-4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 77f

Compound 77e (5.84g, 19.36mmol) was dissolved in N, N-dimethylformamide (40 mL), and sodium hydride (890 mg,23.2mmol,60% pure) was added thereto under ice-bath to react for 10 minutes, and methyl iodide (4.12g, 29mmol) was added thereto to react overnight at room temperature. Quenching with saturated ammonium chloride under ice bath, extraction with dichloromethane (50 mL × 3), combining the organic phases, concentrating under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system B gave the title compound 77f (2.75 g), yield: 44.9 percent.

MS m/z(ESI)：315.9[M+1]。

The sixth step

7-bromo-8-hydroxy-4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 77g

Compound 77f (2.75g, 8.7 mmol) was dissolved in dry dichloromethane (40 mL), and boron tribromide (1M, 35mL,35mmol, adamas) was added under ice-bath, and the reaction was stirred for 4 hours. The reaction was complete, quenched with saturated sodium bicarbonate, extracted with dichloromethane (30 mL × 3), the organic phases combined, concentrated under reduced pressure, and the residue purified by silica gel column chromatography with eluent system B to give the title compound 77g (1.56 g), yield: and (5) 59.6%.

MS m/z(ESI)：302.0[M+1]。

Seventh step

7-bromo-8-hydroxy-4-methyl-5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 77H

77g (1.56g, 5.2 mmol) of the compound was dissolved in concentrated sulfuric acid (10 mL), and potassium nitrate (577 mg,5.7 mmol) was added thereto under ice bath, followed by reaction at the temperature for 1 hour. The reaction was slowly added dropwise to ice water, extracted with dichloromethane (30 mL × 3), the organic phases combined and concentrated under reduced pressure to give the title compound 77h (1.7 g), yield: 94.4 percent.

MS m/z(ESI)：347.0[M+1]。

Eighth step

(R) -7-bromo-4-methyl-5-nitro-8- ((tetrahydrofuran-3-yl) oxy) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 77i

Compound 77h (0.9g, 2.5mmol) and compound 1g (942mg, 3.9mmol) were dissolved in N, N-dimethylformamide (10 mL), and cesium carbonate (1.69g, 5.2mmol) was added and reacted at 90 ℃ for 2 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 77i (850 mg), yield: 78.6 percent.

MS m/z(ESI)：417.0[M+1]。

The ninth step

(R) -5-amino-4-methyl-8- ((tetrahydrofuran-3-yl) oxy) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 77j

Compound 77i (850 mg, 2.04mmol) was dissolved in methanol (10 mL), 10% palladium on carbon catalyst (dry) (850 mg, 798.7. Mu. Mol) was added, hydrogen replaced, and the reaction was stirred for 14 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound 77j (300 mg), yield: 47.8 percent.

MS m/z(ESI)：309.2[M+1]。

The tenth step

(R) -5-amino-4-methyl-8- ((tetrahydrofuran-3-yl) oxy) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid 77k

Compound 77j (150mg, 486.5. Mu. Mol) was dissolved in methanol (2 mL), and sodium hydroxide (1M, 1mL) was added to the solution to react at 60 ℃ for 4 hours. After cooling to room temperature and concentrating the reaction solution under reduced pressure, a small amount of water was added to dissolve it, neutralized with 1M hydrochloric acid to pH =7 or so, extracted with dichloromethane (10 mL × 3), the organic phases were combined and concentrated under reduced pressure to obtain the title compound 77k (100 mg), yield: 70 percent.

MS m/z(ESI)：295.2[M+1]。

The eleventh step

(R) -2, 10-dimethyl-6- ((tetrahydrofuran-3-yl) oxy) -9, 10-dihydro-3H- [1,4] oxazino [2,3-H ] quinazolin-4 (8H) -one 77l

Compound 77k (100mg, 340. Mu. Mol) was dissolved in acetic anhydride (4 mL), reacted at 140 ℃ for 8 hours, cooled, and concentrated under reduced pressure to give a solid, which was then added with aqueous ammonia (6 mL), stirred for 4 hours, added with 10% sodium hydroxide solution (6 mL), and reacted at 60 ℃ for 30 minutes. Cooling to room temperature, dripping concentrated hydrochloric acid in ice water bath, and adjusting pH to 7-8. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 77l (51 mg), yield: 47.3 percent.

MS m/z(ESI)：318.1[M+1]。

Example 77

77l (51mg, 161. Mu. Mol) of the compound and 2a (55mg, 244. Mu. Mol) were dissolved in N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (42mg, 321. Mu. Mol), 1, 8-diazabicycloundecen-7-ene (49mg, 321. Mu. Mol) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (142mg, 321. Mu. Mol) were sequentially added and reacted at 90 ℃ for 12 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid preparative chromatography to give the title compound 77 (3 mg) in yield: 3.8 percent.

MS m/z(ESI)：489.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ ):δ7.69(t,1H),7.45(t,1H),7.18(t,1H),6.91(t,2H),5.84(t,1H),5.38(t,1H),4.50-4.35(m,2H),4.19(q,1H),4.09(d,1H),3.88(td,1H),3.77(dd,1H),3.65(d,1H),3.46-3.31(m,2H),3.11(s,3H),2.50(s,3H),2.23(dt,1H),2.00(dd,1H),1.75(d,3H)。

Example 78

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -4-hydroxytetrahydro-2H-thiopyran-1, 1-dioxide 78

Using the synthetic route described in example 11, substituting the seventh starting compound, compound 3a, for 2a, and the eighth starting compound, 1-acetylpiperidin-4-one, for tetrahydro-4H-thiopyran-4-one, 1-dioxide, gave compound 78 (13 mg), yield: 10 percent.

MS m/z(ESI)：522.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.29(s,1H),7.63(t,1H),7.49(t,1H),7.24(t,1H),7.02(t,1H),5.89(q,1H),3.65-3.56(m,2H),3.51-3.44(m,2H),3.10(td,3H),3.03-2.97(m,3H),2.44(s,3H),2.13(dt,2H),1.70(d,3H)。

Example 79

(R) -2- (3- (1- ((6-ethoxy-2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-4-yl) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroethan-1-ol 79

Using the synthetic route described in example 49, substituting compound 49d in the fourth step for the compound ethyl p-toluenesulfonate and substituting compound 2a in the fifth step for compound 3a gave compound 79 (5 mg), yield: 13.7 percent.

MS m/z(ESI)：448.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.64(s,1H),7.61-7.55(m,1H),7.45(td,1H),7.20(t,1H),5.86(q,1H),4.79(t,2H),4.25(q,2H),4.05(td,2H),3.49(t,2H),2.43(s,3H),1.68(d,3H),1.49(t,3H)。

Example 80

rac- (R) -cyclopropyl (3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) azetidin-1-yl) methanone 80

First step of

(R) -3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) azetidine-1-carboxylic acid tert-butyl ester 80b

Dissolving 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester 80a (242mg, 1.39mmol, obtained after Shanghai Biao) and compound 11h (180mg, 340. Mu. Mol) in 2mL1, 4-dioxane, sequentially adding cuprous iodide (259mg, 1.36mmol), 1, 10-phenanthroline (2454mg, 1.36mmol) and cesium carbonate (443mg, 1.36mmol), replacing with nitrogen, and reacting at 120 ℃ for 2 h by microwave. Cooled to room temperature, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 80b (30 mg), yield: 15.3 percent.

MS m/z(ESI)：575.2[M+1]。

Second step of

(R) -2- (3- (1- ((6- (azetidin-3-yloxy) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-4-yl) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroethanol 80c

Compound 80b (50mg, 87. Mu. Mol) was dissolved in 2mL of methylene chloride, and 1mL of trifluoroacetic acid was added to stir the reaction for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 5mL of dichloromethane and 1mL of methanol, followed by addition of solid sodium bicarbonate, stirring for 20 minutes, adjustment of PH to basic, filtration, and concentration to give crude product 80c (30 mg), yield: 72.6%, the product was used directly in the next reaction without purification.

MS m/z(ESI)：475.2[M+1]。

The third step

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- ((1- (methylsulfonyl) azetidin-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 80

Compound 80c (30mg, 63.2 μmol) and N, N-diisopropylethylamine (50mg, 95.7 μmol) were dissolved in 2mL of dichloromethane, cyclopropylcarbonyl chloride (10mg, 61 μmol) was added under ice-bath, the reaction was naturally warmed to room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 80 (3 mg), yield: 8.7 percent.

MS m/z(ESI)：543.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.62-7.57(m,1H),7.49(s,1H),7.48-7.43(m,1H),7.21(td,1H),5.86(q,1H),5.28(s,1H),4.86-4.78(m,3H),4.49(dddt,1H),4.42(ddt,1H),4.12-3.97(m,3H),3.54-3.47(m,2H),2.43(d,3H),1.69(d,3H),1.67-1.62 (m,1H),0.97-0.83(m,4H)。

Example 81

(R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -2-hydroxy-2-methylpropan-1-one 81

Using the synthetic route in example 61, the starting material compound 2-fluoroacetic acid 61b of the second step was replaced with the compound 2-methyl-2-hydroxypropionic acid to give the title compound 81 (7 mg), yield: 8.5 percent.

MS m/z(ESI)：559.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.20(s,1H),7.62(t,1H),7.47(t,1H),7.22(t,1H),7.01(t,1H),5.87(q,1H),4.76(t,2H),4.50(d,2H),3.59(s,1H),3.44(t,2H),3.27-3.09(m,1H),2.43(s,5H),1.80(d,2H),1.68(d,3H),1.49(s,6H)。

Example 82

2, 2-difluoro-2- (2-fluoro-3- ((R) -1- ((8-methyl-4- (((S) -tetrahydrofuran-3-yl) oxy) - [1,3] dioxolano [4,5-h ] quinazolin-6-yl) amino) ethyl) phenyl) ethane-1-ol 82

First step of

(S) -8-methyl-4- ((tetrahydrofuran-3-yl) oxy) - [1,3] dioxolano [4,5-h ] quinazolin-6-ol 82a

The compound 9g (200mg, 0.71mmol) was dissolved in (S) - (+) -3-hydroxytetrahydrofuran (3 mL), 1, 10-phenanthroline (63mg, 0.35mmol), cesium carbonate (690mg, 2.12mmol), cuprous iodide (67mg, 0.35mmol) were added, the reaction was performed under nitrogen substitution at 120 ℃ for 1 hour, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound 82a (40 mg), yield: 19.5 percent.

MS m/z(ESI)：291.0[M+1]。

Second step of

2, 2-difluoro-2- (2-fluoro-3- ((R) -1- ((8-methyl-4- (((S) -tetrahydrofuran-3-yl) oxy) - [1,3] dioxolano [4,5-h ] quinazolin-6-yl) amino) ethyl) phenyl) ethan-1-ol 82

Compound 82a (40mg, 0.14mmol) was dissolved in N, N-dimethylformamide (5 mL), and compound 3a (52mg, 0.21mmol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (122mg, 0.27mmoL) and 1, 8-diazacyclo [5,4,0] undec-7-ene (42mg, 0.28mmol) were added in this order, replaced with nitrogen three times, and heated to 80 ℃ for 14 hours. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by high performance liquid preparative chromatography gave the title compound 82 (10 mg), yield: 14.7 percent.

MS m/z(ESI)：492.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.62-7.60(m,1H),7.49-7.46(m,2H),7.44(t,1H),6.25(s,2H),5.85(q,1H),5.25(dq,1H),4.15-4.0(m,5H),4.0-3.93(m,1H),2.40(s,3H),2.35-2.22(m,2H),1.67(d,3H)。

Example 83

(S) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-2-one 83

First step of

2-oxo-4- (((trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 83b

After dissolving tert-butyl 2, 4-dioxopiperidine-1-carboxylate 83a (1.2g, 5.6 mmol) in dichloromethane (5 mL), adding N, N-diisopropylethylamine (1.7g, 16.8mmol) and 4-dimethylaminopyridine (120mg, 0.98mmol) in this order, dropwise adding trifluoromethanesulfonic anhydride (2.38g, 8.4 mmol) under ice bath, allowing to naturally rise to room temperature for 2 hours, adding water to the reaction mixture, extracting with dichloromethane (30 mL. Times.3), combining the organic phases and concentrating under reduced pressure, the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 83b (1.2 g), yield: 61.7 percent.

MS m/z(ESI)：346.2[M+1]。

Second step of

2-oxo-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 83c

Compound 83b (1.1g, 3.18mmol) was dissolved in 30mL of 1, 4-dioxane, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (233mg, 0.31mmol) and potassium acetate (940mg, 9.57mmol) were added in this order, followed by stirring at 80 ℃ for 14 hours. Cooling, filtration through celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system C gave the title compound 83C (600 mg), yield: 58.2 percent.

MS m/z(ESI)：324.2[M+1]。

The third step

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -6-oxo-5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 83d

Compound 24d (210mg, 0.42mmol) and compound 83c (200mg, 0.618mmol) were dissolved in 5mL of 1, 4-dioxane and 1mL of water, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (68mg, 0.083mmol) and sodium carbonate (88mg, 0.83mmol) were added, the reaction was heated to 100 ℃ for 3 hours under nitrogen protection, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 83d (200 mg), yield: 85.2 percent.

MS m/z(ESI)：569.2[M+1]。

The fourth step

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -5, 6-dihydropyridin-2 (1H) -one 83e

Compound 83d (234mg, 411.5. Mu. Mol) was dissolved in 5mL of dichloromethane, and 1.5mL of trifluoroacetic acid was added thereto, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 83e (150 mg), yield: 77.8 percent.

MS m/z(ESI)：469.2[M+1]。

The fifth step

The compound 83e (150mg, 320.2. Mu. Mol) was dissolved in methylene chloride (0.5 mL) and isopropanol (5 mL), tris (2, 6-tetramethyl-3, 5-heptenoic acid) manganese (39mg, 64.5. Mu. Mol) and phenylsilane (87mg, 804. Mu. Mol) were added, oxygen gas was replaced three times, the reaction was stirred for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 83 (20 mg), yield: 12.8 percent.

MS m/z(ESI)：487.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.27(d,1H),7.63(d,1H),7.49(t,1H),7.24(td,1H),7.03(td,1H),5.89(p,1H),4.81(td,2H),3.70(tdd,1H),3.48(t,2H),3.38-3.35(m,1H),3.21(dd,1H),2.72-2.62(m,1H),2.52-2.46(m,1H),2.45(d,3H),1.98-1.89(m,1H),1.69(d,3H)。

Example 84

(R) -N- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -2- (dimethylamino) acetamide 84

First step of

(R) - (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) carbamic acid tert-butyl ester 84a

Compound 24d (150mg, 300.4. Mu. Mol) was dissolved in 1, 4-dioxane (3 mL), and tert-butyl carbamate (75mg, 640.2. Mu. Mol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (15mg, 31.4. Mu. Mol), tris (dibenzylideneacetone) dipalladium (0) (28mg, 30.5. Mu. Mol) and cesium carbonate (196mg, 601.5. Mu. Mol) were added, and the mixture was replaced with nitrogen three times, and refluxed for 6 hours. The reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 84a (90 mg), yield: 61.3 percent.

MS m/z(ESI)：4891[M+1]。

Second step of

(R)-N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-8, 9-dihydrofuro [2,3-h]Quinazoline-4, 6-diamine 84b

Compound 84a (90mg, 184.2. Mu. Mol) was dissolved in 2mL of dichloromethane, 1mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved with 5mL of dichloromethane and 1mL of methanol under stirring for 20 minutes, solid sodium bicarbonate was added to adjust the pH to be alkaline, and after concentration by filtration, the crude product 84b (70 mg) was obtained in yield: 97.8 percent, and the product is directly used for the next reaction without purification.

MS m/z(ESI)：389.2[M+1]。

The third step

Compound 84b (70mg, 0.18mmol) and N, N-dimethylglycine (25mg, 0.24mmol, shanghai Shao Yuan) were dissolved in 5mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (103mg, 0.27mmol) and N, N-diisopropylethylamine (47mg, 0.36mmol) were added and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid preparative chromatography to give the title compound 84 (25 mg), yield: 29.2 percent.

MS m/z(ESI)：474.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.58(s,1H),7.63(t,1H),7.48(t,1H),7.23(t,1H),7.03(t,1H),5.87(q,1H),4.88-4.84(m,2H),3.54(t,2H),3.24(s,2H),2.45(s,6H),2.43(s,3H),1.68(d,3H)。

Example 85

(R) -1- (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7, 8-dihydrofuro [3,2-h ] quinazolin-6-yl) oxy) azetidin-1-yl) ethanone 85

First step of

(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7, 8-dihydrofuro [3,2-h ] quinazolin-4-amine 85a

Compound 56b (0.3g, 1.07mmol) and compound 3a (0.29g, 1.28mmol) were dissolved in N, N-dimethylformamide (5 mL), N-diisopropylethylamine (0.276 g,2.1 mmol), 1, 8-diazabicycloundecen-7-ene (0.54g, 2.14mmol) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (0.95g, 2.14mmol) were added in this order, and after stirring at room temperature for 10 minutes, the temperature was raised to 80 ℃ and stirring was carried out for 16 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 85a (0.4 g), yield: 82.9 percent.

MS m/z(ESI)：453.1[M+1]。

Second step of

Compound 85a (220mg, 0.486mmol) and compound 70a (224mg, 1, 94mmol) were dissolved in 5mL of 1, 4-dioxane, 1, 10-phenanthroline (350mg, 1.94mmol), cesium carbonate (634mg, 1.94mmol), cuprous iodide (370mg, 1.94mmol) were added, the reaction was performed under nitrogen at 120 ℃ for 3 hours, and the reaction mixture was concentrated under reduced pressure and purified by high performance liquid preparative chromatography to give the title compound 85 (4 mg) in yield: 1.7 percent.

MS m/z(ESI)：487.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.60(s,1H),7.48(t,1H),7.24(t,1H),7.16-6.84(m,2H),5.85(q,1H),5.28-5.24(m,1H),4.86-4.73(m,3H),4.55(t,1H),4.31(dt,1H),4.03(t,1H),3.38(t,2H),2.39(s,3H),1.96(s,3H),1.71(d,3H)。

Example 86

(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- ((1- (methylsulfonyl) azetidin-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 86

First step of

(R) -3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) azetidine-1-carboxylic acid tert-butyl ester 86a

Compound 80a (300mg, 600.9. Mu. Mol, from Shanghai Biao) and compound 24d (312mg, 1.8mmol) were dissolved in 2mL1, 4-dioxane, and cuprous iodide (458mg, 2.4mmol), 1, 10-phenanthroline (433mg, 2.4mmol) and cesium carbonate (783mg, 2.4mmol) were added in this order, and the mixture was reacted under nitrogen at 120 ℃ for 2 hours. Cooling, filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography with eluent system a gave the title compound 86a (120 mg), yield: 36.6 percent.

MS m/z(ESI)：545.2[M+1]。

Second step of

(R) -6- (azetidin-3-yloxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 86b

Compound 86a (30mg, 55.1. Mu. Mol) was dissolved in 2mL of methylene chloride, and 1mL of trifluoroacetic acid was added thereto, followed by stirring for 2 hours. The reaction was concentrated under reduced pressure and the residue was dissolved in 5mL of dichloromethane, solid sodium bicarbonate was added, the PH was adjusted to basic, and after concentration by filtration, the crude 86b (24 mg) was obtained in yield: 98%, the product was used directly in the next reaction without purification.

MS m/z(ESI)：445.2[M+1]。

The third step

Compound 86b (24mg, 54.1 μmol) and N, N-diisopropylethylamine (24.3mg, 166.5 μmol) were dissolved in 2mL of dichloromethane, methanesulfonyl chloride (7mg, 61 μmol) was added under ice-bath, the mixture was allowed to naturally warm to room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 86 (5 mg) in yield: 17.2 percent.

MS m/z(ESI)：523.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.61(t,1H),7.51(s,1H),7.50(t,1H),7.25(t,1H),7.14(t,1H),5.87(q,1H),5.25-5.20(m,1H),4.84-4.60(m,2H),4.44-4.42(m,2H),4.11-4.07(m,2H),3.53-3.50(m,2H),3.04(s,3H),2.42(s,3H),1.69(d,3H)。

Example 87

(R) -cyclopropyl (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) azetidin-1-yl) methanone 87

Using the synthetic route described in example 86, the starting compound, methanesulfonyl chloride, was replaced with the compound cyclopropylcarbonyl chloride in the third step to give the title compound 87 (139 mg), yield: 45 percent.

MS m/z(ESI)：513.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.60(t,1H),7.50(s,1H),7.48(t,1H),7.23(t,1H),7.03(t,1H),5.85(q,1H),5.28(tt,1H),4.82(t,3H),4.48(m,1H),4.42(m,1H),4.09-4.01(m,1H),3.57-3.43(m,2H),2.44-2.40(m,3H),1.69(d,3H),1.64(td,1H),0.91(dd,2H),0.87(dt,2H)。

Example 88

2-methyl-N- ((R) -1- (3- (methylamino) -5- (trifluoromethyl) phenyl) ethyl) -6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 88

Compound 1 (50mg, 105.3 μmol) was dissolved in 3mL of concentrated sulfuric acid, 2mL of an aqueous formaldehyde solution was added at 0 ℃, and naturally warmed to room temperature to react for 14 hours, the reaction solution was adjusted to pH 7 with a saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by high performance liquid preparative chromatography to obtain the title compound 88 (4 mg), yield: 7.7 percent.

MS m/z(ESI)：489.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.59(s,1H),6.98(d,1H),6.90(d,1H),6.68(d,1H),5.66(q,1H),5.27-5.21(m,1H),4.79(t,2H),4.05-3.99(m,3H),3.92(td,1H), 3.50(t,2H),2.79(s,3H),2.48(s,3H),2.33-2.16(m,2H),1.65(d,3H)。

Example 89

(R) - (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) (morpholino) methanone 89

First step of

(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazoline-6-carboxylic acid methyl ester 89a

Compound 24d (100,mg, 200.3 μmol), 1' -bis-diphenylphosphinoferrocene palladium dichloride (33.89mg, 40.05 μmol), triethylamine (55.36mg, 547.1 μmol), methanol (5.0 mL) were mixed, carbon monoxide was substituted three times, and after refluxing at 80 ℃ for 3 hours, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 89a (85 mg), yield: 98 percent.

MS m/z(ESI)：432.4[M+1]。

Second step of

(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazoline-6-carboxylic acid 89b

Compound 89a (100mg, 231.80. Mu. Mol) was dissolved in water (1.0 mL) and acetonitrile (5.0 mL), lithium hydroxide monohydrate (38.94mg, 927.2. Mu. Mol) was added thereto, the reaction mixture was reacted at 40 ℃ for 5 hours, the reaction mixture was concentrated under reduced pressure, most of the solvent was removed, and 1N hydrochloric acid was added thereto to adjust the pH to neutral. After extraction with ethyl acetate (10 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 89b (70.0 mg) in yield: 72 percent.

MS m/z(ESI)：418.4[M+1]。

The third step

Compound 89b (70.0mg, 168. Mu. Mol) was dissolved in N, N-dimethylformamide (3 mL), and morpholine (21.9mg, 251.5. Mu. Mol), 2- (7-azobenzotriazol) -N, N, N, N-tetramethyluronium hexafluorophosphate (95.6mg, 252. Mu. Mol), and N, N-diisopropylethylamine (43.3mg, 335. Mu. Mol) were added. After stirring the reaction for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 89 (30 mg), yield: and 37 percent.

MS m/z(ESI)：487.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.26(s,1H),7.60(t,1H),7.48(t,1H),7.23(t,1H),7.02(t,1H),5.86(q,1H),4.83(t,2H),3.79(dt,4H),3.69(t,2H),3.51(t,2H),3.41(d,2H),2.45(s,3H),1.67(d,3H)。

Example 90

N- ((R) -1- (3- (dimethylamino) -5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 90

Compound 1 (10mg, 21.1. Mu. Mol) was dissolved in 3mL of acetonitrile, glacial acetic acid (6.3mg, 105.4. Mu. Mol) and an aqueous formaldehyde solution (0.5 mL) were added, and after stirring to react for 1 hour, sodium cyanoborohydride (12.6 mg, 210.8mmol) was further added, and after 14 hours of reaction, the reaction solution was concentrated, and the obtained title compound 90 (4 mg) was purified from the residue by high performance liquid preparative chromatography, in a yield: 37.7 percent.

MS m/z(ESI)：503.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.59(s,1H),7.10-7.04(m,2H),6.80(t,1H),5.68(q,1H),5.27-5.22(m,1H),4.79(t,2H),4.06-3.96(m,3H),3.92(td,1H),3.50(t,2H),2.98(s,6H),2.48(s,3H),2.32-2.16(m,2H),1.67(d,3H)。

Example 91

(R) -3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) cyclobutanol 91

Using the synthetic route described in example 70, the starting material compound 70a from the eighth step was replaced with the compound cyclobutane-1, 3-diol to give the title compound 91 (10 mg), yield: 10.8 percent.

MS m/z(ESI)：459.9[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.59(t,1H),7.51-7.47(m,1H),7.46(s,1H),7.23(t,1H),7.03(t,1H),5.86(q,1H),5.11(tt,1H),4.82-4.74(m,3H),4.60-4.53(m,1H), 3.50(t,2H),2.50(m,3H),2.41(s,3H),1.69(d,3H)。

Example 92

(R) -N- (1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) azetidin-3-yl) cyclopropanecarboxamide 92

First step of

(R) - (1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) azetidin-3-yl) carbamic acid tert-butyl ester 92b

Compound 24d (250mg, 500.7. Mu. Mol) was dissolved in 1, 4-dioxane (5 mL), azetidin-3-ylcarbamic acid tert-butyl ester hydrochloride 92a (209mg, 1.0mmol, shanghai Biao, N.O.), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (58.6 mg, 100.1. Mu. Mol), tris (dibenzylideneacetone) dipalladium (0) (45.8mg, 50. Mu. Mol) and cesium carbonate (130mg, 398. Mu. Mol) were added, the reaction was stirred for 14 hours at 100 ℃ with nitrogen substitution three times. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 92b (50 mg), yield: 18.4 percent.

MS m/z(ESI)：544.2[M+1]。

Second step of

(R) -6- (3-Aminoazetidin-1-yl) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 92c

Compound 92b (50mg, 91.9mmol) was dissolved in 2mL of dichloromethane, 1mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 2mL of dichloromethane and 0.5mL of methanol, solid sodium bicarbonate was added, the pH was adjusted to basic by stirring for 10 minutes, and the reaction solution was concentrated by filtration to obtain a crude product 92c (40 mg), yield: 98%, the product was used directly in the next reaction without purification.

MS m/z(ESI)：444.2[M+1]。

The third step

Compound 92c (30mg, 67.6 μmol) and N, N-diisopropylethylamine (17.5 mg,135.3 μmol) were dissolved in 2mL of dichloromethane, cyclopropylcarbonyl chloride (10.6 mg,101.5 μmol) was added under ice-bath, and the reaction mixture was naturally warmed to room temperature for 1 hour, and after the reaction solution was concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography to give the title compound 92 (2 mg), yield: 5.8 percent.

MS m/z(ESI)：512.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.59(t,1H),7.47(t,1H),7.22(t,1H),7.14-6.92(t,1H),7.12(s,1H),5.86(q,1H),4.78-4.68(m,3H),4.60(s,2H),4.37(dt,2H),3.85(dt,2H),3.44(d,2H),2.41(s,3H),1.68(d,3H),1.65-1.60(m,1H),0.95-0.86(m,2H),0.80(dt,2H)。

Example 93

(1S, 4s) -4- (((((((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) cyclohexanol 93-P1

(1R, 4r) -4- ((4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) cyclohexanol 93-P2

Compound 24d (50mg, 100.1. Mu. Mol) and cyclohexane-1, 4-diol 93a (23.3mg, 200.3. Mu. Mol) were dissolved in 5mL of 1, 4-dioxane, 1, 10-phenanthroline (72.2mg, 400.6. Mu. Mol), cesium carbonate (130.5mg, 400.6. Mu. Mol) and cuprous iodide (76.3mg, 400.6. Mu. Mol) were added, replaced with nitrogen, reacted at 120 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure and then purified by high performance liquid preparative chromatography to give the title compound 5mg,35mg, yield: 10.2 percent and 6.1 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：488.1[M+1]。

HPLC analysis: retention time 11.17 min, purity: 98.5% (column: X-Bridge, prep 30X 150mm, 5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -42%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.70(s,1H),7.61(t,1H),7.49(t,1H),7.24(t,1H),7.14(t,1H),5.87(q,1H),4.80(t,2H),4.60-4.55(m,1H),3.77-3.74(m,1H),3.51(t,2H),2.41(s,3H),2.23-2.19(m,2H),2.15-2.03(m,2H),1.69(d,3H),1.64-1.59(m,2H),1.53-1.46(m,2H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：488.1[M+1]。

HPLC analysis: retention time 13.52 minutes, purity: 97.2% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -42%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.73(s,1H),7.60(t,1H),7.49(t,1H),7.24(t,1H),7.14(t,1H),5.88(q,1H),4.80(t,2H),4.69-4.60(m,1H),3.78-3.75(m,1H),3.50(t,2H),2.42(s,3H),2.23-2.20(m,2H),2.09-2.02(m,2H),1.87-1.71(m,4H)1.69(d,3H)。

Example 94

rac- (R) -1- (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) azetidin-1-yl) -2-fluoroacetone 94

Compound 86b (100mg, 0.224mmol) and compound 61b (35.1mg, 0.449mmol) were dissolved in N, N-dimethylformamide (10 mL), N-diisopropylethylamine (58.2mg, 0.449mmol) and 2- (7-azobenzotriazol) -N, N' -tetramethylurea hexafluorophosphate (105.8mg, 0.449mmol) were added in this order, the reaction was stirred under nitrogen for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 94 (20 mg) in yield: 17.6 percent.

MS m/z(ESI)：505.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.60(t,1H),7.49(d,2H),7.24(t,1H),7.14-6.92(t,1H),5.85(q,1H),5.35-5.23(m,2H),4.82(d,4H),4.44(dtd,1H),4.19-4.11(m,1H),3.51(t,2H),2.42(s,3H),1.69(d,3H)。

Example 95

(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -1- (methylsulfonyl) piperidin-4-ol 95

Using the synthetic route in example 57, substituting the starting compound propionyl chloride for the compound methylsulfonyl chloride in the first step, the title compound 95 (70 mg) was prepared in yield: 33.9 percent.

MS m/z(ESI)：551.0[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.22(s,1H),7.63(t,1H),7.48(t,1H),7.23(t,1H),7.02(t,1H),5.89(q,1H),4.81(t,2H),3.67(dt,2H),3.47(t,2H),3.28(t,2H),2.92(s,3H),2.59(tt,2H),2.44(s,3H),1.85(dt,2H),1.69(d,3H)。

Example 96

(S) -1- (4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -2-hydroxypropan-1-one 96

Using the synthetic route for example 27, substituting cyanoacetic acid as the starting compound for L-lactic acid in the third step, the obtained title compound 96 (32 mg) was purified by high performance liquid preparative chromatography in terms of yield: 25.7 percent.

MS m/z(ESI)：545.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.22(s,1H),7.63(t,1H),7.48(t,1H),7.24(t,1H),7.02(t,1H),5.89(q,1H),4.77(t,2H),4.67(q,1H),4.51-4.45(m,1H),3.99-3.93(m,1H),3.46(t,2H),3.27-3.18(m,2H),2.56-2.46(m,1H),2.49-2.45(m,1H),2.44(s,3H),1.81(t,2H),1.69(d,3H),1.38(dd,3H)。

Example 97

(R) -1- (3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) azetidin-1-yl) ethanone 97

Using the synthetic route for example 70, substituting the starting compound 24d for compound 11h, the title compound 97 (6 mg) was prepared in yield: 4.0 percent.

MS m/z(ESI)：517.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ )δ7.58(t,1H),7.50-7.43(m,2H),7.21(t,1H),5.86(q,1H),5.24(t,1H),4.82(t,2H),4.73-4.66(m,1H),4.51-4.44(m,1H),4.32(dd,1H),4.04(ddd,3H),3.51(t,2H),2.43(s,3H),1.95(s,3H),1.69(d,3H)。

Example 98

(R) -4- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) oxy) tetrahydro-2H-thiopyran 1, 1-dioxide 98

Using the synthetic route described in Example 49, substituting compound 49d in the fourth step with the compound 1, 1-dioxotetrahydro-2H-thiopyran-4-yl-4-methylbenzenesulfonic acid (prepared using the method disclosed in patent application "WO2014/170842 A2" at Example 166, example 95) and substituting compound 2a in the fifth step with compound 3a gave compound 98 (21 mg) in yield: 29.6 percent.

MS m/z(ESI)：552.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ ):δ7.52(td,1H),7.47(td,1H),7.17(t,1H),7.07(s,1H),5.79(p,1H),5.67(d,1H),5.34(dd,1H),4.84(tt,1H),4.82-4.74(m,2H),4.19-4.05(m,2H),3.61-3.44(m,4H),2.95(dt,2H),2.51(s,3H),2.47(dq,2H),2.41-2.31(m,2H),1.70(d,3H)。

Example 99

(1s, 4S) -1- (4- (((R) -1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1, 4-diol 99-P1

(1r, 4R) -1- (4- (((R) -1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1, 4-diol 99-P2

First step of

(R) -N- (1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) -6-iodo-2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 99b

11g of the compound (200mg, 609.56. Mu. Mol) was dissolved in N, N-dimethylformamide (5 mL), and the compound (R) -1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethane-1-amine hydrochloride 99a (133mg, 667.68. Mu. Mol, prepared by the method disclosed in example B-5 on page 105 of the specification in the patent application "U.S. Pat. No. 2019194192"), N-diisopropylethylamine (160mg, 1.23mmol), benzotriazole-1-tris (trimethylamino) -trifluorophosphate (540mg, 1.22mmol), and 1, 8-diazacyclo [5,4,0] undec-7-ene (310mg, 1.23mmol) were added in this order, and reacted for 14 hours by nitrogen substitution three times while heating to 80 ℃. Cooling, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 99b (300 mg), yield: 96.6 percent.

MS m/z(ESI)：510.1[M+1]。

Second step of

Using the synthetic route from example 33, substituting the starting compound 24d for compound 99b in the first step, the title compounds 99-P1 (20 mg) and 99-P2 (40 mg) were obtained in yields: 6.8 percent and 13.7 percent.

Single configuration Compound 99-P1 (shorter Retention time)

MS m/z(ESI)：498.2[M+1]。

HPLC analysis: retention time 12.5 minutes, purity: 99.2% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.13(s,1H),7.54(d,1H),7.44(d,1H),7.07(t,1H),5.82(q,1H),4.83-4.70(m,4H),3.71(dp,1H),3.46(t,2H),2.48(s,3H),2.38(td,2H),1.93-1.79(m,4H),1.78-1.72(m,2H),1.67(d,3H)。

Single configuration Compound 99-P2 (longer Retention time)

MS m/z(ESI)：498.2[M+1]。

HPLC analysis: retention time 14.3 minutes, purity: 98.7% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR (500 MHz, methanol-d 4). Delta.8.12 (s, 1H), 7.54 (d, 1H), 7.44 (d, 1H), 7.07 (t, 1H), 5.83 (q, 1H), 4.83-4.73 (m, 4H), 4.06 (t, 1H), 3.47 (t, 2H), 2.65 (ddd, 2H), 2.48 (s, 3H), 2.09 (tt, 2H), 1.73-1.64 (m, 5H), 1.61 (d, 2H).

Example 100

(R) -1- (3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) azetidin-1-yl) -2-fluoroacetone 100

First step of

1- (2-fluoroacetyl) azetidin-3-yl-4-methylbenzenesulfonate 100b

The compound azetidine-3-ol hydrochloride 100a (1g, 9.12mmol, shanghai Shao Yuan) and the compound 61b (712.36mg, 9.12mmol) were dissolved in tetrahydrofuran (20 mL), and N, N-diisopropylethylamine (2.95g, 22.8mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (4.16g, 10.9mmol) were added in this order and reacted with stirring for 14 hours. The reaction mixture was concentrated and dissolved in 50mL of methylene chloride, p-toluenesulfonyl chloride (2.06g, 10.8mmol), triethylamine (1.37g, 13.5 mmol) and 4-dimethylaminopyridine (1.1g, 9mmol) were added, and the reaction mixture was stirred for 16 hours. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 100B (800 mg), yield: 20.8 percent.

MS m/z(ESI)：288.2[M+1]。

Second step of

Using the synthetic route described in example 49, substituting compound 49d as the starting material for compound 100b, substituting compound 2a as the starting material for compound 3a, the title compound was obtained in 100 (5 mg) yield: 8.2 percent.

MS m/z(ESI)：535.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.60(t,1H),7.48-7.44(m,2H),7.22(t,1H),5.88(q,1H),5.29-5.27(m,1H),5.04(s,1H),4.88(s,1H),4.61-4.58(m,4H),4.46-4.42(m,1H),4.17-4.12(m,1H),4.08-4.02(m,2H),3.53-3.49(m,2H),2.43(s,3H),1.69(d,3H)。

Example 101

(R) -1- (3- ((4- ((1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) oxy) azetidin-1-yl) ethanone 101

Using the synthetic route from example 70, substituting compound 2a as starting material for compound 99a in the seventh step, the title compound was obtained in 101 (3 mg) yield: 1.06 percent.

MS m/z(ESI)：497.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.52(d,1H),7.47(s,1H),7.42(dt,1H),7.05(t,1H),5.79(q,1H),5.24(dq,1H),4.80-4.68(m,2H),4.47(s,2H),4.36-4.29(m,2H), 4.05(dd,2H),3.52(t,2H),2.44(s,3H),1.95(s,3H),1.68(d,3H)。

Example 102

(1s, 4S) -1- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) cyclohexane-1, 4-diol 102-P1

(1r, 4R) -1- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) cyclohexane-1, 4-diol 102-P2

First step of

4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) cyclohex-3-enol 102a

Compound 42b (0.2g, 416. Mu. Mol) and compound 33a (140mg, 625. Mu. Mol) were dissolved in 1, 4-dioxane (3 mL) and water (0.6 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (34mg, 42. Mu. Mol) and anhydrous sodium carbonate (90mg, 849. Mu. Mol) were added in this order, replaced with nitrogen 3 times, and heated to 100 ℃ for 14 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography with eluent system a gave the title compound 102a (100 mg), yield: 48.3 percent.

MS m/z(ESI)：498.9[M+1]。

Second step of

Compound 102a (100mg, 200.6 μmol) was dissolved in isopropanol (2 mL) and dichloromethane (0.2 mL), manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (36mg, 60 μmol) was added, and after stirring for 3 minutes, phenylsilane (65mg, 601 μmol) was added, oxygen was substituted 3 times, the reaction was stirred for 14 hours, the reaction solution was filtered and concentrated, and the residue was purified by high performance liquid preparative chromatography to give the title compounds 102-P1 (4.3 mg) and 102-P2 (3.2 mg), yield: (4.2%, 3.1%). .

Single configuration Compound 102-P1 (shorter Retention time)

MS m/z(ESI)：517.2[M+1]。

HPLC analysis: retention time 12.5 min, purity: 98% (chromatographic column: X-Bridge, prep 30X 150mm, 5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A30% -55%)

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.95(s,1H),7.59(d,1H),7.46(s,1H),7.21(t,1H),7.01(t,1H),5.99-5.72(m,1H),5.34(s,1H),4.59(s,1H),4.32(s,2H),3.68(s,1H),3.21(s,2H),2.97(s,3H),2.45(s,3H),2.35(d,2H),1.97(d,4H),1.67(d,3H)。

Single configuration Compound 102-P2 (longer Retention time)

MS m/z(ESI)：517.2[M+1]。

HPLC analysis: retention time 13.8 minutes, purity: 98% (chromatographic column: X-Bridge, prep 30X 150mm, 5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A30% -55%)

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.92(s,1H),7.60(t,1H),7.45(d,1H),7.21(t,1H),7.01(t,1H),5.86(d,1H),5.34(s,1H),4.63-4.51(m,1H),4.33(s,2H),4.06(s,1H),3.21(s,1H),2.99(d,3H),2.84(d,1H),2.61(q,2H),2.44(s,3H),2.13(td,4H),1.67(d,3H)。

Example 103

(R) -1- (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) oxy) azetidin-1-yl) -2-fluoroacetone 103

First step of

(R) -tert-butyl 3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) oxy) azetidine-1-carboxylate 103a

Compound 42b (244mg, 507. Mu. Mol) and 80a (352mg, 2mmol, obtained after Shanghai Biao) were dissolved in 5mL1, 4-dioxane, and cuprous iodide (386mg, 2mmol), 1, 10-phenanthroline (365mg, 2 mmol) and cesium carbonate (661mg, 2mmol) were sequentially added thereto, and the mixture was replaced with nitrogen, followed by reaction at 120 ℃ for 6 hours. Cooled to room temperature, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 103a (50 mg), yield: 17.2 percent.

MS m/z(ESI)：574.1[M+1]。

Second step of

(R) -6- (azetidin-3-yloxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-4-amine 103b

Compound 103a (50mg, 81. Mu. Mol) was dissolved in 2mL of methylene chloride, and 1mL of trifluoroacetic acid was added to stir the reaction for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 5mL of dichloromethane and 1mL of methanol, stirred for 20 minutes by adding solid sodium bicarbonate, adjusted to alkaline, filtered and concentrated to give crude product 103b (41 mg), yield: 99%, and the product is directly used for the next reaction without purification.

MS m/z(ESI)：474.1[M+1]。

The third step

(R) -1- (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) oxy) azetidin-1-yl) -2-fluoroacetone 103b

After compounds 103b (41mg, 86.6. Mu. Mol) and 61b (14mg, 179.3899. Mu. Mol) were dissolved in 2mL of N, N-dimethylformamide, N-diisopropylethylamine (22mg, 170. Mu. Mol) and 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate (41mg, 174. Mu. Mol) were added under ice bath, naturally warmed to room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure, the residue was purified by preparative hplc to obtain the title compound 103 (2 mg) in yield: 4.3 percent.

MS m/z(ESI)：534.1[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.57(t,1H),7.46(t,1H),7.21(t,1H),7.16(d,1H),7.01(t,1H),5.82(q,1H),5.23(dt,1H),5.03(d,1H),4.94-4.92(m,1H),4.58(s,2H),4.50-4.07(m,4H),3.20(t,2H),3.00(d,3H),2.42(d,3H),1.67(dd,3H)。

Example 104

(R) -1- (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 10-dimethyl-9, 10-dihydro-8H- [1,4] oxazino [2,3-H ] quinazolin-6-yl) oxy) azetidin-1-yl) ethanone 104

Compound 42b (200mg, 416 μmol) and 1-acetyl-3-hydroxyazetidine 70a (191mg, 1.66mmol) were dissolved in 5ml of 1, 4-dioxane, 1, 10-phenanthroline (191mg, 1.66mmol), cesium carbonate (541mg, 1.66mmol), cuprous iodide (316 mg, 1.66mmol) were added, the reaction was replaced with nitrogen, reacted at 120 ℃ for 6 hours, the reaction mixture was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give the title compound 104 (9 mg), yield: 4.2 percent.

MS m/z(ESI)：516.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ7.72-7.61(m,1H),7.53(t,1H),7.40(s,1H),7.29(t,1H),7.02(t,1H),5.97(q,1H),5.23(d,1H),4.74(dt,1H),4.51(dd,1H),4.42(t,2H),4.37-4.26(m,1H),4.03(td,1H),3.25(t,2H),2.84(s,3H),2.61(s,3H),1.95(s,3H),1.76(d,3H)。

Example 105

1- ((2R, 4S) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-2-methylpiperidin-1-yl) -2-fluoroethan-1-one 105-P1

1- ((2R, 4R) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-2-methylpiperidin-1-yl) -2-fluoroethan-1-one 105-P2

First step of

(R) -2-methyl-4- (((trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 105b

Compound (R) -2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester 105a (1.0g, 4.7mmol) was dissolved in tetrahydrofuran (20 mL), lithium bistrimethylsilyl amide (1M tetrahydrofuran solution, 5.6mL, 5.6 mmol) was added at-78 ℃, the reaction was stirred for 0.5 hour, N-phenylbis (trifluoromethanesulfonyl) imide (2.0g, 5.6 mmol) was added, after 2 hours of further reaction, 20mL of saturated ammonium chloride was added, ethyl acetate was extracted (50 mL × 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 105b (1.6 g), yield: 97.1 percent

MS m/z(ESI)：346.1[M+1]。

Second step of

(R) -2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 105c

Compound 105b (1.1g, 3.18mmol) was dissolved in 30mL of 1, 4-dioxane, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (350mg, 0.47mmol), potassium acetate (940mg, 9.57mmol) and pinacol diboron ester (0.89g, 3.5 mmol) were added in this order, and the reaction was stirred at 80 ℃ for 14 hours. Cooling, filtration through celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system C gave the title compound 105C (1.01 g), yield: 98.1 percent.

MS m/z(ESI)：324.2[M+1]。

The third step

(R) -6-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine 105d

Compound 105c (500mg, 189 μmol) was dissolved in dichloromethane (3 mL), 4N dioxane hydrochloride solution was added thereto for 1.5mL, and the reaction mixture was concentrated to obtain the title compound 105d (400 mg), yield: 99.1 percent.

MS m/z(ESI)：224.2[M+1]。

The fourth step

(R) -2-fluoro-1- (2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentan-2-yl) -5, 6-dihydropyridin-1 (2H) -yl) ethan-1-one 105e

Compound 61b (350mg, 4.5 mmol) and 105d (400mg, 1.8mmol) were dissolved in N, N-dimethylformamide (3 mL), and N, N-diisopropylethylamine (695mg, 5.38mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (845mg, 3.58mmol) were added in this order and reacted at room temperature under a nitrogen atmosphere for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 105e (600 mg), yield: 49.4 percent.

MS m/z(ESI)：284.1[M+1]。

The fifth step

1- ((R) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-H ] quinazolin-6-yl) -2-methyl-5, 6-dihydropyridin-1 (2H) -yl) -2-fluoroethan-1-one 105f

Compound 24d (100mg, 200. Mu. Mol) and compound 105e (113 mg, 400. Mu. Mol) were dissolved in 1, 4-dioxane (2 mL) and water (0.4 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (25mg, 29.3. Mu. Mol) and anhydrous sodium carbonate (64mg, 590. Mu. Mol) were added in this order, nitrogen was substituted 3 times, and the mixture was heated to 100 ℃ for reaction for 3 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue with silica gel column chromatography using eluent system a gave the title compound 105f (90 mg), yield: 85.0 percent.

MS m/z(ESI)：529.5[M+1]。

The sixth step

After compound 105f (100mg, 189. Mu. Mol) was dissolved in isopropanol (2 mL) and dichloromethane (0.2 mL), manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (34mg, 56. Mu. Mol) was added, and after stirring for 3 minutes, phenylsilane (61mg, 563. Mu. Mol) was added, oxygen was replaced 3 times, the reaction was reacted at room temperature for 14 hours, and after the reaction solution was filtered and concentrated, the residue was purified by high performance liquid preparative chromatography to give the title compounds 105-P1 (20 mg) and 105-P2 (10 mg), yield: 19.3 percent and 9.7 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：547.2[M+1]。

HPLC analysis: retention time 10.2 min, purity: 98.7% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.19(s,1H),7.61(t,1H),7.47(t,1H),7.22(t,1H),7.00(t,1H),5.86(d,1H),5.16(d,1H),4.76(t,2H),3.47–3.34(m,3H),2.56(d,2H),2.42(s,2H),1.81(s,2H),1.77(d,2H),1.67(d,2H),1.59(d,3H),1.48(d,3H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：547.2[M+1]。

HPLC analysis: retention time 11.4 minutes, purity: 98.7% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.19(s,1H),7.63(t,1H),7.44(t,1H),7.22(t,1H),7.01(t,1H),5.86(d,1H),5.19(d,1H),4.76(t,2H),3.45–3.38(m,3H),2.56(d,2H),2.45(s,2H),1.82(s,2H),1.72(d,2H),1.67(d,2H),1.54(d,3H),1.41(d,3H)。

Example 106

(R) -1- (4- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxypiperidin-1-yl) -2-fluoroethan-1-one 106

Using the synthetic route described in example 61, substituting the third step starting compound 24d for compound 11h provided compound 106 (10 mg), yield: 9.6 percent.

MS m/z(ESI)：563.2[M+1]。

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.21(s,1H),7.66-7.53(m,1H),7.45(td,1H),7.19(t,1H),5.89(q,1H),5.26–5.06(m,2H),4.77(t,2H),4.46(d,1H),4.03(td,2H),3.65-3.51(m,2H),3.44(t,2H),3.27-3.15(m,1H),2.44(s,5H),1.85-1.73(m,2H),1.67(d,3H)。

Example 107

(1s, 4S) -1- (4- (((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1, 4-diol 107-P1

(1r, 4R) -1- (4- (((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1, 4-diol 107-P2

Using the synthetic route from example 33, substituting the starting compound 24d for compound 11h in the first step gave the title compounds 107-P1 (7 mg) and 107-P2 (9 mg), in yields: 6.7 percent and 8.6 percent.

Single configuration Compound 107-P1 (shorter Retention time)

MS m/z(ESI)：518.2[M+1]。

HPLC analysis: retention time 11.5 minutes, purity: 99.2% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.20(s,1H),7.62(t,1H),7.50-7.44(m,1H),7.21(t,1H),5.91(q,1H),4.79(t,2H),4.05(td,2H),3.70(tt,1H),3.46(t,2H),2.63(tdd,2H),2.46(s,3H),2.42-2.33(m,2H),1.89-1.78(m,4H),1.69(d,3H)。

Single configuration Compound 107-P2 (longer Retention time)

MS m/z(ESI)：518.2[M+1]。

HPLC analysis: retention time 13.4 minutes, purity: 98.7% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.18(s,1H),7.60(t,1H),7.52-7.40(m,1H),7.20(t,1H),5.91(q,1H),4.79(t,2H),4.09-3.97(m,3H),3.44(t,2H),2.63(tdd,2H),2.46(s,3H),2.14-1.98(m,2H),1.73-1.58(m,7H)。

Example 108

(1S,4s) -4- (4- (((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-N-methylcyclohexane-1-carboxamide 108-P1

(1R, 4r) -4- (4- (((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-N-methylcyclohexane-1-carboxamide 108-P2

Using the synthetic route described in example 62, substituting 1-methyl-piperazine as the starting material compound for methylamine hydrochloride in the second step and substituting compound 24d as the starting material compound for compound 11h in the third step provided the title compounds 108-P1 (17 mg) and 108-P2 (7 mg), in yields: 18.2 percent and 7.5 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：559.2[M+1]。

HPLC analysis: retention time 12.5 min, purity: 99.2% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A15% -45%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.14(s,1H),7.61(t,1H),7.46(t,1H),7.21(t,1H),5.90(q,1H),4.77(t,2H),4.05(td,2H),3.45(t,2H),2.83-2.66(m,5H),2.44-2.50(m,4H),2.03(tt,2H),1.80(d,2H),1.76-1.65(m,5H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：559.2[M+1]。

HPLC analysis: retention time 14.3 minutes, purity: 98.7% (column; X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A15% -45%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.19(d,1H),7.62(t,1H),7.50-7.43(m,1H),7.21(td,1H),5.90(dt,1H),4.78(td,2H),4.05(td,2H),3.46(t,2H),2.76(s,3H),2.45(s,3H),2.35(qd,3H),2.14-2.04(m,2H),1.81(d,2H),1.73(d,2H),1.69(dd,3H)。

Example 109

1- ((2R, 4S) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-2-methylpiperidin-1-yl) ethan-1-one 109-P1

1- ((2R, 4R) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-2-methylpiperidin-1-yl) ethan-1-one 109-P2

Using the synthetic route described in example 105, substituting the starting compound 61b for the compound acetic acid in the third step gave compounds 109-P1 (100 mg) and 109-P2 (45 mg) in yields: 24.1 percent and 10.8 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：529.2[M+1]。

HPLC analysis: retention time 10.6 minutes, purity: 98.2% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A15% -45%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.18(s,1H),7.63(t,1H),7.48(t,1H),7.24(t,1H),7.02(t,1H),5.90-5.85(m,1H),4.61(s,2H),3.48(t,1H),3.33(s,3H),2.58(d,1H),2.44(s,3H),2.39(dd,1H),2.17(s,2H),1.75(d,2H),1.69(d,3H),1.35(d,2H),1.20(d,3H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：529.2[M+1]。

HPLC analysis: retention time 11.3 minutes, purity: 98.7% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A15% -45%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.18(s,1H),7.61(t,1H),7.46(d,1H),7.21(t,1H),7.01(t,1H),5.90–5.83(m,1H),4.75(t,2H),3.78-3.76(m,1H),3.31(s,3H),2.51(d,2H),2.42(s,3H),2.16(s,2H),1.77(d,2H),1.67(d,2H),1.56(d,3H),1.44(d,3H)。

Example 110

(1s, 4S) -1- (2-chloro-4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1, 4-diol 110-P1

(1r, 4R) -1- (2-chloro-4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexane-1, 4-diol 110-P2

First step of

4-amino-7-bromo-2, 3-dihydrobenzofuran-5-carboxylic acid methyl ester 110a

Compound 11e (1.03g, 5.33mmol) was dissolved in acetonitrile (35 mL), N-bromosuccinimide (948.89mg, 5.33mmol) was added, and the mixture was stirred in an ice-water bath for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system a to give the title compound 110a (1.41 g), yield: 97 percent.

MS m/z(ESI)：271.8[M+1]。

Second step of

6-bromo-8, 9-dihydrofuro [2,3-h ] quinazoline-2, 4 (1H, 3H) -dione 110b

Compound 110a (0.30g, 1.1mmol) and urea (662.14mg, 11.02mmol) were combined. Heating to 240 ℃ for open reaction for 15 minutes, finishing the reaction, cooling to room temperature, adding 3N sodium hydroxide solution 2mL, reacting at 100 ℃ for 1 hour, cooling to room temperature, adjusting the pH value to =4 by concentrated hydrochloric acid, separating out a solid, and filtering to obtain a product 110b (0.31 g), wherein the yield is as follows: 99 percent.

MS m/z(ESI)：282.9[M+1]。

The third step

6-bromo-2, 4-dichloro-8, 9-dihydrofuro [2,3-h ] quinazoline 110c

Compound 110b (0.31g, 1.1 mmol) was mixed with phosphorus oxychloride (3.00 mL) and reacted at 100 ℃ for 14 hours with tube sealed. The reaction solution was concentrated under reduced pressure, the residue was diluted with dichloromethane, neutralized with saturated sodium bicarbonate solution under ice bath and extracted with dichloromethane (10 mL × 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 110C (84 mg), yield: and 24 percent.

MS m/z(ESI)：318.9[M+1]。

The fourth step

(R) -6-bromo-2-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -8, 9-dihydrofuro [2,3-h ] quinazolin-4-amine 110d

Compound 110c (104.00mg, 0.33mmol) and compound 2a (80.67mg, 0.36 mmol) were dissolved in tetrahydrofuran (10 mL), followed by dropwise addition of N, N-diisopropylethylamine (126.02mg, 0.98mmol), reaction at room temperature for two days, concentration of the reaction solution under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system A to give the title compound 110d (153.00 mg) in 99% yield.

MS m/z(ESI)：471.8[M+1]。

The fifth step

4- (2-chloro-4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) cyclohexyl-3-en-yl-1-ol 110e

Compound 110d (68.00mg, 0.14mmol), compound 33a (35.46mg, 0.16mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) dichloromethane complex (23.50mg, 0.028mmol) and sodium carbonate (30.49mg, 0.29mmol) were dissolved in water (0.40 mL) and dioxane (1.60 mL) under nitrogen at 100 ℃ for 3 hours, and the reaction was concentrated under reduced pressure and purified by silica gel column chromatography using eluent system A to give the title compound 110e (45.1 mg) in 64% yield.

MS m/z(ESI)：489.9[M+1]。

The sixth step

Compound 110e (45.10mg, 0.092mmol), tris (2, 6-tetramethyl-3, 5-heptenoic acid) manganese (11.13mg, 0.018mmol) and phenylsilane (29.89mg, 0.28mmol) were dissolved in methylene chloride (0.1 mL) and isopropanol (1.00 mL), reacted for two days after oxygen substitution, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to give the title compound 110-P1 (6 mg), 110-P2 (6 mg), yield: 13 percent and 13 percent.

Single configuration Compound 110-P1 (shorter Retention time)

MS m/z(ESI)：508.2[M+1]。

HPLC analysis: retention time 10.1 min, purity: 98.7% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.22(s,1H),7.64(t,1H),7.52(t,1H),7.27(t,1H),7.03(s,1H),5.83(q,1H),4.81(t,2H),4.06(t,1H),3.43(t,2H),2.64(tdd,2H),2.09(tt,2H),1.71(d,3H),1.69-1.45(m,4H)。

Single configuration Compound 110-P2 (longer Retention time)

MS m/z(ESI)：508.2[M+1]。

HPLC analysis: retention time 11.9 minutes, purity: 99.1% (column: X-Bridge, prep 30X 150mm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR (500 MHz, methanol-d) ₄ ):δ8.25(s,1H),7.64(t,1H),7.52(t,1H),7.27(t,1H),7.03(s,1H),5.82(q,1H),4.80(t,2H),3.69(p,1H),3.42(t,2H),2.40-2.28(m,2H),1.98-1.74(m,6H),1.71(d,3H)。

Example 111

1- ((2S, 4S) -4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-2-methylpiperidin-1-yl) ethan-1-one 111-P1

1- ((2S, 4R) -4- (4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [2,3-h ] quinazolin-6-yl) -4-hydroxy-2-methylpiperidin-1-yl) ethan-1-one 111-P2

Using the synthetic route described in example 105, substituting the starting compound 105a for the compound tert-butyl (S) -2-methyl-4-oxopiperidine-1-carboxylate in the first step and the starting compound 61b for the compound acetic acid in the third step gave compounds 111-P1 (25 mg) and 111-P2 (12 mg), in yields: 10.9 percent and 5.2 percent.

Single configuration compounds (shorter retention time)

MS m/z(ESI)：529.2[M+1]。

HPLC analysis: retention time 10.4 minutes, purity: 98.5% (chromatographic column: sharpSil-T, 30X 50mm,5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A15% -45%).

1H NMR(500MHz,CD ₃ OD):δ8.18(s,1H),7.61(t,1H),7.45(d,1H),7.21(t, 1H),7.02(t,1H),5.91-5.85(m,1H),4.75(t,2H),3.79-3.76(m,1H),3.30(s,3H),2.51(d,2H),2.42(s,3H),2.17(s,2H),1.78(d,2H),1.67(d,2H),1.55(d,3H),1.42(d,3H)。

Single configuration compounds (longer retention time)

MS m/z(ESI)：529.2[M+1]。

HPLC analysis: retention time 11.1 min, purity: 98.7% (column: sharpSil-T, 30X 50mm,5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A15% -45%).

1H NMR(500MHz,CD ₃ OD):δ8.18(s,1H),7.63(t,1H),7.46(t,1H),7.23(t,1H),7.01(t,1H),5.92-5.87(m,1H),4.61(s,2H),3.50(t,1H),3.33(s,3H),2.58(d,1H),2.43(s,3H),2.37(dd,1H),2.17(s,2H),1.75(d,2H),1.70(d,3H),1.36(d,2H),1.21(d,3H)。

Example 112

(1s, 4S) -1- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [3',2':4,5] pyrido [3,2-d ] pyrimidin-6-yl) cyclohexane-1, 4-diol 112-P1

(1r, 4R) -1- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [3',2':4,5] pyrido [3,2-d ] pyrimidin-6-yl) cyclohexane-1, 4-diol 112-P2

First step of

(R) -6-chloro-N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrimidine-4, 5-diamine 112b

Compound 112a (0.4g, 2.24mmol), compound 2a (0.51g, 2.24mmol) and N, N-diisopropylethylamine (1g, 7.73mmol) were dissolved in 2mL of N, N-dimethylacetamide and reacted at 160 ℃ for 2 hours. After cooling, water was added to the reaction solution, extraction was performed with dichloromethane (10 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 112b (558 mg), yield: 75.1 percent.

MS m/z(ESI)：331.1[M+1]。

Second step of

3-Bromofuran-2-carboxylic acid methyl ester 112d

The compound, 3-bromofuran-2-carboxylic acid 112c (5 g, 26.2mmol), was dissolved in 50mL of dichloromethane and 5mL of methanol, (trimethylsilyl) diazomethane (20mL, 2M n-hexane solution) was added dropwise in ice bath, and the reaction was allowed to resume at room temperature for 2 hours with stirring. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 112d (4.91 g), yield: 91.4 percent.

MS m/z(ESI)：204.9[M+1]。

The third step

(2- (methoxycarbonyl) furan-3-yl) boronic acid 112e

Compound 112d (788mg, 3.84mmol) was dissolved in 10mL of 1, 4-dioxane, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (280.6 mg, 0.38mmol), potassium acetate (1.13g, 11.5mmol), and pinacol diboron ester (2.93g, 11.5mmol) were added in this order, and the reaction was stirred at 80 ℃ for 14 hours. Cooling, filtration through celite, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography with eluent system a gave the title compound 112e (600 mg), yield: 91.8 percent.

MS m/z(ESI)：171.1[M+1]。

The fourth step

(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylfuro [3',2':4,5] pyrido [3,2-d ] pyrimidin-6 (5H) -one 112f

Compound 112b (300mg, 907.1. Mu. Mol) and compound 112e (462 mg, 2.71 mmol) were dissolved in 1, 4-dioxane (5 mL) and water (1 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (74mg, 90.7. Mu. Mol) and anhydrous potassium carbonate (450mg, 3.25mmol) were added in this order, nitrogen-substituted 3 times, and heated to 110 ℃ for 16 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system a gave the title compound 112f (200 mg), yield: 56.7 percent.

MS m/z(ESI)：389.1[M+1]。

The fifth step

(R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylfuro [3',2, 4,5] pyrido [3,2-d ] pyrimidin-4-amine 112g

Compound 112f (200mg, 515. Mu. Mol) was mixed with phosphorus oxychloride (15 mL), and N, N-diisopropylethylamine (133mg, 1.03mmol) was added to react at 100 ℃ for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with dichloromethane, neutralized with saturated sodium bicarbonate solution under ice bath, extracted with dichloromethane (10 mL × 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system a to give 112g (172 mg) of the title compound, yield: 82.1 percent.

MS m/z(ESI)：407.1[M+1]。

The sixth step

4- (4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylfuro [3',2':4,5] pyrido [3,2-d ] pyrimidin-6-yl) cyclohex-3-en-1-ol 112h

112g of compound (172mg, 422.8. Mu. Mol), 33a (190mg, 847.8. Mu. Mol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (35mg, 42.8. Mu. Mol) and anhydrous sodium carbonate (100mg, 943.5. Mu. Mol) were dissolved in 6mL of 1, 4-dioxane and 2mL of water, purged with nitrogen 3 times, and heated to 110 ℃ for 16 hours. Cooling to room temperature, filtration over celite, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography with eluent system C gave the title compound 112h (190 mg), yield: 95.9 percent.

MS m/z(ESI)：469.2[M+1]。

Step seven

(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylfuro [3',2':4,5] pyrido [3,2-d ] pyrimidin-6-yl) cyclohexane-1, 4-diol 112i

Compound 112h (215mg, 458.9 μmol) was dissolved in isopropanol (5 mL) and dichloromethane (0.5 mL), manganese tris (dipentanoylmethane) (56mg, 92.6 μmol) was added, after stirring for 5 minutes, phenylsilane (124mg, 1.14mmol) was added, oxygen was substituted 3 times, the reaction was stirred for 16 hours, the reaction solution was filtered and concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system a to give the title compound 112i (114 mg), yield: 51 percent.

MS m/z(ESI)：487.2[M+1]。

Eighth step

(R) -1- (4- ((-1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [3',2':4,5] pyrido [3,2-d ] pyrimidin-6-yl) cyclohexane-1, 4-diol 112

(1s, 4S) -1- (4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-8, 9-dihydrofuro [3',2':4,5] pyrido [3,2-d ] pyrimidin-6-yl) cyclohexane-1, 4-diol 112-P1

Compound 112i (114mg, 234.3. Mu. Mol) was dissolved in ethanol (10 mL), 10% palladium on carbon catalyst (100 mg) was added thereto, the mixture was replaced with hydrogen gas three times, and the reaction was stirred for 16 hours. Filtration through celite, concentration of the filtrate under reduced pressure gave the crude title compound 112, which was purified by high performance liquid chromatography (Waters-2545, column: sharp-T, 30 x 50mm,5 μm; mobile phase a: water (containing 10mmol/L ammonium bicarbonate); mobile phase B: acetonitrile; 20 min gradient: 25% -55%, flow rate: 30 mL/min) to afford the title compounds 112-P1 (10.6 mg) and 112-P2 (9.5 mg) in: 9.2 percent and 8.2 percent.

Single conformation compound 112-P1 (shorter retention time)

MS m/z(ESI)：489.0[M+1]。

HPLC analysis: retention time 11.6 minutes, purity: 98.5% (chromatographic column: sharpSil-T, 30X 50mm,5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A25% -55%).

¹ H NMR(500MHz,CD3OD):δ7.66(t,1H),7.49(t,1H),7.24(t,1H),7.02(t,1H),5.85(q,1H),4.86(t,2H),3.70(tt,1H),3.53-3.46(m,2H),2.47(s,3H),2.45-2.35(m,2H),1.88(q,4H),1.69(d,3H),1.67-1.61(m,2H)。

Single configuration Compound 112-P2 (longer Retention time)

MS m/z(ESI)：489.0[M+1]。

HPLC analysis: retention time 13.12 minutes, purity: 98.1% (column: sharpSil-T, 30X 50mm,5 μm; mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: A25% -55%).

¹ H NMR(500MHz,CD3OD):δ7.66(t,1H),7.49(t,1H),7.25(t,1H),7.02(t,1H),5.84(q,1H),4.86(t,2H),4.06(t,1H),3.49(t,2H),2.76(qd,2H),2.47(s,3H),2.10(td,2H),1.70(t,5H),1.52-1.39(m,2H)。

Test example:

biological evaluation

Test example 1, the disclosed compounds inhibit the ability of the KRAS protein to interact with the SOS1 protein by each of its isoforms G12D or G12V.

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

1. experimental materials and instruments

1) Biotin labeling kit (Dojindo, LK 03)

2)GDP(SIGMA，G7127)

3) AlphaLISA Glutathione receptor Beads (Glutathione receptors) (PerkinElmer, AL 109C)

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

5) 384-well microplate (PerkinElmer, 6007290)

6) BSA (Shanghai Sheng Gong, A600332-0100)

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

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

9) KRas G12D, krasG12V (provided by Shanghai Pan Biotech Co., ltd.)

10 Phosphate Buffered Saline (PBS) PH7.4 (Shanghai Yuanpei Biotech Co., ltd., B320)

11 Multifunctional microplate reader (Perkinelmer, envision)

2. Experimental procedure

Preparation of the experiment:

1) The assay buffer was prepared prior to the start of the assay: 1x PBS +0.1% of BSA +0.05% Tween 20.

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

The experimental steps are as follows:

1) Firstly, mixing KRAS G12V or KRAS G12D protein labeled by biotin with SOS1 protein and GDP respectively, and incubating at room temperature for later use.

2) AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads were mixed to 40. Mu.g/ml 1.

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

4) In 384 well microplates, 10. Mu.L of KRAS G12V or KRAS G12D protein mixed with SOS1 and GDP and 5. Mu.L of diluted compound were added per well and incubated for 30 minutes at room temperature in the absence of light.

5) Then 5 μ L of AlphaLISA glutathione acceptor bead and AlphaScreen streptavidin donor bead mixture was added per well and incubated for 60 min at room temperature in the dark.

6) The fluorescence values were read on a multifunctional microplate reader.

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

3. Experimental data

The disclosed compounds inhibit each of the KRAS proteinsAbility of interaction between subtype G12D or G12V and SOS1 protein, IC determined ₅₀ The values are shown in Table 1.

TABLE 1 IC of the disclosed compounds for their ability to inhibit the interaction between the respective subtypes G12D or G12V of KRAS protein and SOS1 protein ₅₀ Value of

And (4) conclusion: the disclosed compound can well inhibit the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein.

Test example 2 biological evaluation of ERK phosphorylation inhibition assay in H358 cells

1. Purpose of testing

This experiment was performed by detecting the inhibitory effect of compounds on cell ERK phosphorylation according to IC ₅₀ Size evaluation of the compounds of the disclosure on the inhibition of KRAS target (containing the G12C mutation).

2. Experimental method

H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH 30809.01) complete medium containing 10% fetal bovine serum. The first day of the experiment, H358 cells were seeded in 96-well plates at a density of 25,000 cells/well using complete medium, 190. Mu.L cell suspension per well, placed at 37 ℃,5% CO ₂ The cell culture box was cultured overnight. The following day, 10. Mu.L of test compound diluted in a gradient prepared with complete medium was added per well, the final concentration of compound was 9 concentration points with 5-fold gradient dilution from 10. Mu.M, a blank containing 0.1% DMSO was set, the well plate was placed at 37 ℃,5% CO ₂ The cell culture chamber of (1) was incubated for 1 hour. After 1 hour, the 96-well cell culture plate was removed, the medium was aspirated off, and 200. Mu.L of PBS (Shanghai culture Biotech Co., ltd., B320) was added to each well and washed once. PBS was aspirated, 50. Mu.L of lysis buffer (lysis buffer, cisbio,64KL1 FDF) containing blocking solution (blocking reagent, cisbio,64KB1 AAC) was added to each well, and the well plates were placed on a shaker and lysed for 40 minutes at room temperature with shaking. After lysis, the mixture was pipetted and mixed well, 16. Mu.L of lysate was transferred to two HTRF 96-well assay plates (Cisbio, 66PL 96100) per well, and then 4. Mu.L of premixed phospho-ERK1/2 antibody solution (Cisbio, 64 AERPEG) or 4. Mu.L of premixed total-ERK1/2 antibody solution (Cisbio, 64 NRKPEG) was added to each plate. The plate was sealed with a sealing membrane, centrifuged for 1 min in a microplate centrifuge and incubated overnight at room temperature in the dark. On the third day, fluorescence values of 337nm wavelength excitation, 665nm and 620nm wavelength emission were read using a PHERAstar multifunctional microplate reader (BMG Labtech, S/N471-0361).

3. Data analysis

IC of inhibitory Activity of Compounds was calculated from Compound concentration and pERK/total ERK ratio using Graphpad Prism software ₅₀ See table 2 below for values, results.

TABLE 2 ERK phosphorylation inhibitory Activity data for H358 cells

And (4) conclusion: the compound disclosed by the invention has a good inhibition effect on ERK phosphorylation of H358 cells.

Test example 3 biological evaluation of H358 cell proliferation inhibition experiment

1. Purpose of testing

The inhibition of the compound of the disclosure on the KRAS target (containing G12C mutation) was evaluated by testing the proliferation inhibition of the compound of the disclosure on H358 cells.

2. Experimental method

H358 cells (ATCC, CRL-5807) were cultured in complete medium, RPMI1640 medium (Hyclone, SH 30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). The first day of the experiment, H358 cells were seeded at a density of 1500 cells/well on a 96-well low adsorption plate (Corning, CLS7007-24 EA) using complete medium, 90. Mu.L of cell suspension was centrifuged at 2000rpm for 5 minutes at room temperature, then placed at 37 ℃ and 5% CO ₂ The cell culture box was incubated overnight. The following day, 10. Mu.L of test compound diluted in a gradient prepared from complete medium was added to each well, the final concentration of compound was 9 concentration points diluted in a 5-fold gradient starting from 10. Mu.M, a blank containing 0.1% DMSO was set, the well plate was placed at 37 ℃ and 5% CO ₂ The cell culture chamber of (2) was cultured for 120 hours. On the seventh day, 96 well cell culture plates were removed and 50. Mu.L of each well was added

After shaking the 3D reagent (Promega, G9682) at room temperature for 25 minutes, the mixture was aspirated and 50. Mu.L of the mixture was transferred to a white, bottom-impermeable 96-well plate (PE, 6005290), and the luminescence signal was read using a multi-functional microplate reader (Perkinelmer, VICTOR 3).

3. Data analysis

IC of compound inhibitory activity was calculated using Graphpad Prism software ₅₀ See table 3 below for values, results.

TABLE 3 H358 cell proliferation inhibitory Activity data

And (4) conclusion: the compound disclosed by the invention has a better inhibiting effect on H358 cell proliferation.

Test example 4 pharmacokinetic evaluation of the Compounds of the disclosure in nude mice

1. Abstract

The drug concentrations in plasma of nude mice at different times after gavage (ig) administration of compound 33-P1 were determined by LC/MS/MS method using nude mice as test animals. The pharmacokinetic behavior of the compounds of the disclosure in nude mice was studied and their pharmacokinetic profile was evaluated.

2. Test protocol

2.1 test drugs

Compound 33-P1

2.2 test animals

The BALB/C nude mice are 18, female, and averagely divided into 2 groups, each group comprises 9 mice, and the mice are purchased from Zhejiang Weitonglihua test animals, inc., and the animal production license number is: SCXK (Zhe) 2019-0001.

2.3 pharmaceutical formulation

A predetermined amount of compound 33-P1 was weighed and added 0.5% of CMCNa to prepare a homogeneous suspension (crushing, administration with stirring).

2.4 administration

The administration is carried out by gastric lavage on nude mice, the administration dosage is respectively 75mg/kg and 150mg/kg, and the administration volume is 0.2mL/10g.

3. Operation of

The compound 33-P1 is administered by gastric gavage to nude mice, blood is collected for 0.1mL at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours before and after administration, the blood is placed in an EDTA-K2 anticoagulation test tube, the blood plasma is separated for 1 minute (4 ℃) at 10000rpm within 1 hour, and the blood plasma is stored for testing at the temperature of 20 ℃ below zero. The blood collection to centrifugation process is operated under ice bath condition.

Determining the content of the compound to be tested in the blood plasma of nude mice after administration of the drugs with different concentrations: mu.L of nude mouse plasma at each time point after administration was taken, 50. Mu.L of internal standard solution (camptothecin 100 ng/ml) and 200. Mu.L of acetonitrile were added, vortex-mixed for 5 minutes, centrifuged for 10 minutes (3700 rpm), and 0.5. Mu.L of supernatant was taken for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

Table 4 pharmacokinetic parameters of the compounds of the present disclosure in nude mice

And (4) conclusion: the compound disclosed by the invention has good drug absorption activity in a nude mouse body and pharmacokinetic advantages.

Test example 5 pharmacokinetic evaluation of Compounds of the disclosure in rats

1. Abstract

Using rats as test animals, the drug concentrations in plasma at various times after gavage (ig) administration of compound 33-P1 in rats were determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the disclosure in rats was studied and their pharmacokinetic profile was evaluated.

2. Test protocol

2.1 test drugs

Compound 33-P1

2.2 test animals

8 SD rats, half male and female, purchased from Zhejiang vitamin Tonglihua laboratory animals GmbH, animal production license number: SCXK (Zhe) 2019-0001, randomly divided into two groups; administration was by gavage after one night fasting.

2.3 pharmaceutical formulation

Weighing an amount of compound 33-P1, adding 1% HPMC K100LV +10% of TPGS to formulate into a homogeneous suspension (crushing, administration with stirring).

2.4 administration

The rats are subjected to intragastric administration, the administration dose is 100.0mg/kg and 200mg/kg respectively, and the administration volume is 10mL/kg.

3. Operation of

Rat gavage was performed with compound 33-P1, 0.1mL of blood was collected from the orbit before and after administration at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours, placed in an EDTA-K2 anticoagulation tube, centrifuged at 10000rpm for 1 minute (4 ℃), plasma was separated within 1 hour, and stored at-20 ℃ for testing. Blood sampling to centrifugation process was performed under ice bath conditions. Food was consumed 2h after dosing.

Determination of the content of the test compound in the plasma of rats after administration of the drugs at different concentrations: mu.L of rat plasma at each time after administration was taken, 50. Mu.L of camptothecin (100 ng/ml) and 200. Mu.L of acetonitrile were added, vortex mixed for 5 minutes, centrifuged for 10 minutes (4000 rpm), and 0.5. Mu.L of supernatant was taken for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

Table 5 pharmacokinetic parameters of Compounds of the disclosure in rats

And (4) conclusion: the compound disclosed by the invention has good pharmacokinetic absorption activity in a rat body and pharmacokinetic advantages.

Test example 6 evaluation of pharmacokinetics of the present disclosure Compounds in dogs

1. Abstract

The drug concentration in plasma of dogs at various times after gavage (ig) administration of compound 33-P1 was determined by LC/MS/MS method using dogs as test animals. The pharmacokinetic behavior of the compounds of the disclosure in dogs was studied and their pharmacokinetic profile evaluated.

2. Test protocol

2.1 test drugs

Compound 33-P1

2.2 test animals

Beagle 4 dogs, male and female half, fasted overnight. Provided by the animal stores of the Mediterranean pharmaceutical technology (Shanghai) Co., ltd. (999M-004). All animals were beagle dogs qualified for physical examination and healthy without abnormalities.

2.3 pharmaceutical formulation

A certain amount of compound 33-P1 was weighed, dissolved by adding 5% by volume of DMSO, 20% by volume of PG, and 20% by volume of PEG400, and then prepared into a clear solution by adding 55% physiological saline.

2.4 administration of drugs

The dose was 2.0mg/kg and the volume was 5.0mL/kg.

3. Operation of

The compound 33-P1 is administered by intragastric administration to dogs, and blood is collected from jugular vein or forelimb vein for 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 24.0 hours before and after administration, and 1.0ml is placed in EDTA-K2 anticoagulation tube, centrifuged at 10000rpm for 5 minutes (4 ℃), plasma is separated within 1 hour, and stored at-80 ℃ for testing. Blood sampling to centrifugation process was performed under ice bath conditions. Food was consumed 3h after dosing.

Determination of the test compound content in the plasma of dogs after administration of different concentrations of the drug: mu.L of canine plasma at each time after administration was taken, 400. Mu.L of acetonitrile (containing camptothecin as an internal standard solution (100 ng/ml)) was added thereto, mixed by vortexing for 1 minute, centrifuged for 7 minutes (18000 rpm), and 1. Mu.L of the supernatant was taken for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

Table 6 pharmacokinetic parameters of the compounds of the present disclosure in dogs

And (4) conclusion: the compound disclosed by the invention has good drug absorption activity in dogs and pharmacokinetic advantages.

Test example 7 inhibition of human liver microsomal CYP450 enzyme by Compounds of the disclosure

The inhibition effect of the disclosed compound on human liver microsome CYP450 enzyme is determined by adopting the following experimental method:

1. experimental materials and instruments

1. Phosphate buffer (20 XPBS, purchased from Biolabs),

2、NADPH(ACROS，A2646-71-1),

3. human liver microsomes (Corning Gentest, cat No,452161, lot No.905002, donor 35),

4. ABI QTrap 4000 liquid dual-purpose instrument (AB Sciex),

5. ZORBAX extended-C18, 3X 50mm,3.5 μm (Agilent, USA),

6. a CYP probe substrate.

2. Experimental procedure

1. Solution preparation

1) Preparation of 100mM Phosphate Buffer Solution (PBS)

Taking 50mL of PBS solution with the concentration of 2000mM, adding 950mL of ultrapure water, diluting to 1000mL, mixing uniformly, adjusting the pH of the solution to 7.4 by using a pH meter to obtain the PBS solution with the pH of 7.4, and storing in a refrigerator at 4 ℃ (the storage life is 6 months).

2) Preparation of NADPH solution

An appropriate amount of NADPH powder is precisely weighed, and PBS buffer solution is added to dissolve the NADPH powder to prepare solution with the concentration of 5mM for later use (the solution is used at present).

3) Preparation of liver microsome solution

Taking appropriate amount of human liver microsome stock solution (concentration of 20 mg/mL), and adding 7.5mM MgCl ₂ The solution was diluted to 0.25mg/mL microsome solution for use (as prepared).

4)MgCl ₂ Preparation of the solution

Weighing MgCl ₂ The appropriate amount of powder was prepared into 300mM stock solution with PBS solution, and stored in a refrigerator at 4 ℃ for further use. And (4) adding a proper amount of the solution, and diluting the solution into 7.5mM working solution by adding 100mM PBS (phosphate buffer solution) to obtain the working solution (which is prepared for use).

5) Preparation of test Compound solutions

a. Accurately weighing a proper amount of test compound standard, adding DMSO to prepare a stock solution with the concentration of 30mM, and storing in a refrigerator at 4 ℃.

b. An appropriate amount of the stock solution is precisely transferred and an appropriate amount of DMSO solution is added to dilute the stock solution into a series of solutions I with the concentrations of 10, 3, 1, 0.3, 0.03 and 0.003 mM. Precisely transferring appropriate amount of the above series solution I, adding appropriate amount of acetonitrile, and diluting to obtain series solution II with concentration of 3, 1, 0.3, 0.1, 0.03, 0.003, 0.0003 mM. Precisely transferring appropriate amount of the above solution II, adding appropriate amount of PBS, and diluting to obtain working solution with concentration of 150, 50, 15, 5, 1.5, 0.15, 0.015 μ M for use.

6) Selection of CYP probe substrates and Selective inhibitors

a. Preparing a probe substrate stock solution: an appropriate amount of each probe substrate was weighed and DMSO was added to prepare a stock solution, the concentration of which is shown in table 7 below.

b. And (3) preparing a probe substrate working solution, namely precisely transferring a proper amount of a probe substrate stock solution, and adding a PBS (phosphate buffer solution) solution to dilute by 200 times to obtain the probe substrate working solution, wherein the concentration of the probe substrate working solution is shown in the following table 7.

TABLE 7

CYP	Probe substrate	Stock solution concentration (mM)	Working solution concentration (μ M)
3A4T	Testosterone	75	375
3A4M	Midazolam	3	15

2. Liver microsome incubation and sample preparation

The protein concentration, substrate and inhibitor concentration in the reaction system are shown in Table 8 below.

TABLE 8

3. Procedure of operation

1) mu.L of human liver microsome solution (0.25 mg/mL), 20. Mu.L of probe substrate solution and 20. Mu.L of test compound solution were precision-pipetted into a 96-well plate and preincubated in a water bath at 37 ℃ for 5 minutes.

2) After a 5-minute preincubation, the reaction was started by adding 20. Mu.L of 5mM NADPH solution and incubated in a 37 ℃ water bath for 30 minutes. Each sample was run in duplicate.

3) After the incubation was completed, 250. Mu.L of acetonitrile solution containing the internal standard was added to terminate the reaction, after shaking at 800rpm for 10 minutes, the reaction was centrifuged at 3700rpm for 10 minutes, 100. Mu.L of the supernatant was removed by precision pipetting, diluted with 80. Mu.L of distilled water and shaken at 800rpm for 10 minutes, and the supernatant was aspirated for LC-MS/MS analysis.

The numerical values are calculated by Graphpad Prism to respectively obtain the IC of the drug for inhibiting the 6 beta-hydroxylation of human liver microsome CYP3A4T testosterone and CYP3A4M midazolam 1-hydroxylation metabolism ₅₀ The values are shown in Table 9.

TABLE 9 IC of the compounds of the disclosure on CYP3A4T Testosterone metabolic site and human liver microsomal CYP3A4M midazolam metabolic site ₅₀ Value of

Example numbering	IC ₅₀ (μM)-CYP3A4T	IC ₅₀ (μM)-CYP3A4M
33-P1	>30	>30

And (4) conclusion: the disclosed compounds do not undergo metabolic drug interactions based on CYP3A4T testosterone 6 β -hydroxylation and CYP3A4M midazolam 1-hydroxylated metabolic sites within a 30 μ M concentration range.

Claims

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

wherein:

ring a is aryl or heteroaryl;

ring B is a 5-6 membered heterocyclyl or heteroaryl;

R ⁰ selected from the group consisting of alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, cycloalkylcarbonyl, heterocyclylcarbonyl, -NHC (O) R ¹⁰ Heteroaryl, cycloalkyl and heterocyclyl, wherein said cycloalkyloxy, heterocyclyloxy, cycloalkylcarbonyl, heterocyclylcarbonyl, heteroaryl, cycloalkyl and heterocyclyl are each independently optionally selected from halogen, alkyl, haloalkane Radical, hydroxyl, oxo, carboxyl, = NH, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ 、-(CH ₂ ) _t -C(O)R ⁹ And NHC (O) R ¹¹ Substituted with one or more substituents of (a);

wherein R is ⁹ And R ¹¹ Are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, - (CH) ₂ ) _q NR ⁶ R ⁷ Cycloalkyl and heterocyclyl; the alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted by one or more substituents selected from alkyl, alkoxy, cyano, carboxy;

R ¹⁰ selected from hydrogen, alkyl, hydroxyalkyl, hydroxy, - (CH) ₂ ) _q NR ⁶ R ⁷ Cycloalkyl and heterocyclyl; the alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted by one or more substituents selected from alkyl, alkoxy, cyano, carboxy;

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 each independently 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 each independently optionally selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, heteroaryl, and mixtures thereof,Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ 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 each independently optionally 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 the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, - (CH) ₂ ) _q 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 each independently optionally selected from hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, - (CH) ₂ ) _q NR ⁶ R ⁷ 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, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

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

q is 0, 1 or 2;

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

t is 0, 1, 2, 3, 4 or 5.
A compound of formula (I) according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: r ⁰ Selected from the group consisting of alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, cycloalkyl and heterocyclyl, wherein said cycloalkyloxy, heterocyclyloxy, cycloalkyl and heterocyclyl are each independently optionally substituted with a group selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S (O) ₂ R ⁹ and-C (O) R ⁹ Is substituted with one or more substituents of (1);

wherein R is ⁹ Selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, - (CH) ₂ ) _q NR ⁶ R ⁷ Cycloalkyl and heterocyclyl;

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

wherein R is ⁶ 、R ⁷ And q is as defined in claim 1.
The compound of formula (I) according to claim 1 or 2, wherein ring B is a five-or six-membered heterocyclic group, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
A compound of general formula (I) according to any one of claims 1 to 3, which is a compound of general formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

Wherein:

G ¹ 、G ² and G ³ Are the same or different and are each independently selected from the group consisting of a carbon atom, an oxygen atom, a nitrogen atom and a sulfur atom, with the proviso that G ¹ 、G ² And G ³ Not carbon atoms at the same time;

r is 0 or 1; preferably, r is 0;

the dotted line represents a double or single bond;

ring A, R ⁰ -R ⁵ 、R ⁸ P and n are as defined in claim 1 or 2.
The compound of general formula (I) according to any one of claims 1 to 4, 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, G ³ Is an oxygen atom; or alternatively

G ² And G ³ Is a carbon atom, G ¹ Is an oxygen atom; or

G ¹ And G ³ Each independently being an oxygen atom or a nitrogen atom, G ² Is a carbon atom.
The compound of formula (I) according to any one of claims 1 to 5, which is a compound of formula (III), formula (IV), formula (V), formula (VI) or formula (VII), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein:

ring A, R ⁰ 、R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁸ P and n are as defined in claim 1 or 2.
The compound represented by the general formula (I) according to any one of claims 1 to 6, which is a compound represented by the general formula (III-1), the general formula (IV-1), the general formula (V-1), the general formula (VI-1) or the general formula (VII-1), or a tautomer, the meso form, the racemic form, the enantiomer, the diastereomer, or the mixture thereof, or a pharmaceutically acceptable salt thereof, or a tautomer, the meso form, the racemic form, the diastereomer, or the mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: ring A, R ⁰ 、R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁸ P and n are as defined in claim 1 or 2.
The compound of general formula (I) according to any one of claims 1 to 7, wherein ring a is C, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof _6-10 Aryl or 5-10 membered heteroaryl.
A compound of general formula (I) according to any one of claims 1 to 8, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring a is selected from phenyl, thienyl, pyrrolyl, dihydrobenzofuranyl, and furanyl; preferably, ring a is selected from phenyl, thienyl, pyrrolyl and furanyl.
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 ⁰ Is selected from C _1-6 Alkoxy, 5-membered heterocyclyloxy and 6-membered heterocyclyl, each of said 5-membered heterocyclyloxy and 6-membered heterocyclyl being independently optionally selected from-C (O) R ⁹ And hydroxy, wherein R is substituted by one or more substituents ⁹ Is C _1-6 Alkyl or- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Identical or different and are each independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2.
The compound of general formula (I) according to any one of claims 1 to 9, wherein R is in the form of its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof ⁰ Selected from tetrahydrofuryloxy, C _1-6 Alkoxy, hydrogenated pyridyl, azetidinyloxy and hydrogenated pyranyl, each independently optionally selected from-C (O) R ⁹ And hydroxy, wherein R is substituted by one or more substituents ⁹ Is C _1-6 Alkyl or- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Are the same or different and are each independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2;

preferably, R ⁰ Selected from tetrahydrofuryloxy, C _1-6 Alkoxy, hydropyridyl and hydropyranyl, each independently optionally substituted with a substituent selected from the group consisting of-C (O) R ⁹ And hydroxy, wherein R is substituted by one or more substituents ⁹ Is C _1-6 Alkyl or- (CH) ₂ ) _q NR ⁶ R ⁷ ，R ⁶ And R ⁷ Identical or different and each independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2.
The compound of general formula (I) according to any one of claims 1 to 11, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof ⁸ Are the same or different and are each independently selected from halogen,C _1-6 Alkyl radical, C _1-6 Haloalkyl, - (CH) ₂ ) _q NR ⁶ R ⁷ 、C _1-6 Hydroxyalkyl and C _6-10 Aryl, wherein said C _1-6 Haloalkyl is optionally substituted with one or more hydroxy, said C _6-10 Aryl is optionally substituted by one or more- (CH) ₂ ) _q NR ⁶ R ⁷ Substitution; r is ⁶ And R ⁷ Selected from hydrogen or C _1-6 Alkyl, q is 0, 1 or 2.
The compound of general formula (I) according to any one of claims 1 to 12, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ¹ Selected from hydrogen, C _1-6 Alkyl and halogen.
The compound of general formula (I) according to any one of claims 1 to 13, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 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 14, wherein R is in the form of its 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 15, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁴ Is hydrogen.
The compound of general formula (I) according to any one of claims 1 to 16, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁵ Hydrogen or methyl, preferably hydrogen.
A compound having the formula:
A compound represented by the general formula (IA-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

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

ring B, R ⁰ 、R ⁴ 、R ⁵ And p is as defined in claim 1 or 2.
A compound of formula (IA-2) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

G ¹ is an oxygen atom or a sulfur atom;

ring A, R ⁰ -R ⁵ 、R ⁸ P and n are as defined in claim 1 or 2.
A compound of formula (IA-3) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

x is halogen;

ring A, ring B, R ¹ -R ⁵ 、R ⁸ P and n are as defined in claim 1 or 2.
A compound of the formula:
a process for the preparation of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Reacting a compound of formula (IA-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IB) or a salt thereof, to give a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein Ring A, ring B, and Ring R ⁰ -R ⁵ 、R ⁸ P and n are as defined in claim 1 or 2.
A process for producing a compound represented by the general formula (I-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the steps of:

the compound of the general formula (I-1) or the tautomer, the mesomer, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof is prepared by taking the compound of the general formula (IA-2) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the salt thereof as a raw material and carrying out reduction reaction,

wherein G is ¹ Is an oxygen atom or a sulfur atom;

ring A, R ⁰ -R ⁵ 、R ⁸ P and n are as defined in claim 1 or 2.
A process for the preparation of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (I) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof or the pharmaceutically acceptable salt thereof is prepared by taking the compound of the general formula (IA-3) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof or the pharmaceutically acceptable salt thereof as raw materials and carrying out Ullmann reaction, suzuki reaction or Grignard reaction,

wherein X is halogen;

ring A, ring B, R ⁰ -R ⁵ 、R ⁸ P and n are as defined in claim 1 or 2.
A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 18 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 18, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, for the preparation of a medicament for the inhibition of SOS 1.
Use of a compound of general formula (I) according to any one of claims 1 to 18 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, 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 syndrome (CM-AVM), costello Syndrome (CS), heart-facial-skin syndrome (CFC), lekes syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably cancer; the cancer is preferably melanoma, skin cancer, liver cancer, hepatocellular cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal 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, 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; the colorectal cancer is preferably colon cancer or rectal cancer; the sarcoma is preferably osteosarcoma.