WO2021249475A1 - Fused quinazoline derivative, preparation method therefor and application thereof in medicine - Google Patents

Abstract

Disclosed is a fused quinazoline derivative, a preparation method therefor and an application thereof in medicine. Specifically, the present disclosure relates to a fused quinazoline derivative represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative, and a use thereof as a therapeutic agent, especially a use thereof as a SOS1 inhibitor and a use thereof in preparing a drug for treating diseases or conditions that can be improved by inhibiting SOS1.

Description

Condensed quinazoline derivatives, preparation method thereof and application in medicine Technical field

The present disclosure belongs to the field of medicine, and relates to a condensed quinazoline derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as SOS1 The use of the inhibitor and the use in the preparation of a medicament for the treatment of diseases or conditions improved by the inhibition of SOS1.

Background technique

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

Due to the lack of small molecule binding sites on the surface of KRAS protein in the traditional sense, and its super-high affinity with guanylic acid, it is extremely difficult to be inhibited. It has long been considered a drug target that is not druggable. However, based on the importance and ubiquity of abnormal activation of KRAS in cancer progression, KRAS has been and is still a target of great concern for drug development. The current drug development ideas aimed at inhibiting the KRAS pathway mainly include the following aspects:

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

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

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

4) Inhibition of upstream pathways of KRAS: such as inhibitors of SHP2.

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

6) Knock down the expression of KRAS by means of RNAi.

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

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

The patents of compounds that have been published as SOS1 inhibitors include WO2018115380A1, WO2019122129A1, WO2018172250A1 and WO2016077793A1.

Summary of the invention

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

in:

Ring A is aryl or heteroaryl;

Ring B is a 5-6 membered heterocyclic group or heteroaryl group;

R ^{0 is} selected from alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, cycloalkylcarbonyl, heterocyclylcarbonyl, -NHC(O)R ¹⁰ , heteroaryl, cycloalkyl and Heterocyclyl, wherein the 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 are substituted by one or more substituents;

Wherein, R ⁹ and R ^{11 are the} same or different, and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, -(CH ₂ ) _q NR ⁶ R ⁷ , cycloalkyl and heterocyclyl; The alkyl group, cycloalkyl group and heterocyclic group are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, and carboxy;

R ^{10 is} selected from hydrogen, alkyl, hydroxyalkyl, hydroxyl, -(CH ₂ ) _q NR ⁶ R ⁷ , cycloalkyl and heterocyclic group; the alkyl, cycloalkyl and heterocyclic group are each independently Optionally substituted by one or more substituents selected from alkyl, alkoxy, cyano, and carboxy;

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

R ^{2 is} selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are each independently optionally It is substituted by one or more substituents selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro and cyano;

R ^{3 is} selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxy Substituted by one or more substituents of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{4 is} selected from 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 hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , Cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -NR ⁶ R ⁷ , cyano and nitro, wherein the alkyl, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and -NR ⁶ R ⁷ Substituted by one or more substituents;

R ^{8 is the} same or different, and are each independently selected from 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 the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl are each independently optionally selected from hydroxyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, -(CH ₂ ) _q NR ⁶ R ⁷ , cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;

R ⁶ and R ^{7 are the} same or different, and are each independently selected from 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 represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{0 is} selected from the group consisting of alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, cycloalkyl and heterocyclyl, wherein The cycloalkyloxy, heterocyclyloxy, cycloalkyl and heterocyclyl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy Group, amino, nitro, cyano, -S(O) ₂ R ⁹ and -C(O)R ⁹ are substituted by one or more substituents;

Wherein, R ^{9 is} selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, -(CH ₂ ) _q NR ⁶ R ⁷ , cycloalkyl and heterocyclic group;

R ^{8 is the} same or different, and are each independently selected from 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 the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl are each independently optionally selected from hydroxyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, -(CH ₂ ) _q NR ⁶ R ⁷ , one or more substituents in cycloalkyl, heterocyclic, aryl and heteroaryl;

Wherein R ⁶ , R ⁷ and q are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a five-membered or six-membered heterocyclic group, preferably a five-membered heterocyclic group.

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

Wherein G ¹ , G ² and G ^{3 are the} same or different, and are each independently selected from a carbon atom, an oxygen atom, a nitrogen atom and a sulfur atom, provided that G ¹ , G ² and G ^{3 are} not carbon atoms at the same time;

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

Dotted lines indicate single or double bonds;

Ring A, R ⁰ -R ⁵ , R ⁸ , p and n are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a 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 represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: G ¹ and G ² are carbon atoms, G ³ is an oxygen atom; or G ² and G ³ are carbon atoms, and G ¹ is an oxygen atom; or G ¹ and G ³ are each independently an oxygen atom or a nitrogen atom, and G ² is a carbon atom.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) and (II) or its tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are of general formula (III), general formula (IV), general formula (V), general formula (VI) or general formula (VII) The compound shown or its tautomer, mesosome, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

in:

Ring A, R ⁰ , R ¹ , R ² , R ⁴ , R ⁵ , R ⁸ , p and n are as defined in general formula (I) and (II) (R ^{5 in} general formula (VI) can be optionally substituted On N).

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) and (II) or its tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are of general formula (III-1), general formula (IV-1), general formula (V-1), general formula (VI- 1) Or the compound represented by the general formula (VII-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, Or its pharmaceutically acceptable salt:

Wherein: Ring A, R ⁰ , R ¹ , R ² , R ⁴ , R ⁵ , R ⁸ , p and n are as defined in general formulas (I) and (II) (R ^{5 in general formula (VI-1)} Can be optionally substituted on N).

In some preferred embodiments of the present disclosure, a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein r is zero.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is a C _6-10 aryl group or a 5-10 membered heteroaryl group.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is selected from phenyl, thienyl, pyrrolyl, dihydrobenzofuranyl and furanyl; the dihydrobenzofuranyl Furanyl can be dihydrobenzofuran-4-yl, dihydrobenzofuran-5-yl, dihydrobenzofuran-6-yl, dihydrobenzofuran-7-yl;

Preferably, ring A is selected from phenyl, thienyl, pyrrolyl and furyl.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{0 is} selected from the group consisting of alkoxy, heterocyclyloxy and heterocyclyl, wherein the heterocyclyloxy and heterocyclic The groups are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S(O) ₂ R ⁹ and -C (O) One or more substituents in ^{R 9 are substituted; wherein R 9 is} selected from hydrogen, alkyl, haloalkyl, -(CH ₂ ) _q NR ⁶ R ⁷ and hydroxyalkyl; R ⁶ , R ⁷ and q is as defined in general formula (I). In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{0 is} selected from the group consisting of alkoxy, heterocyclyloxy and heterocyclyl, said heterocyclyloxy and heterocyclyl Can be selected from tetrahydrofuranyloxy, azetidinyloxy, tetrahydropyrrolyloxy, cyclobutyloxy, hydrothiopyranyloxy, morpholinylcarbonyl, C _1-6 alkoxy , Hydropyridyl, azetidinyl, piperazinyl, cyclohexyl, hydrothiopyranyl and hydropyranyl; wherein the heterocyclyloxy and heterocyclyl are each independently optionally Selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, -S(O) ₂ R ⁹ and -C(O)R ⁹ One or more substituents are substituted; wherein, R ^{9 is} selected from hydrogen, alkyl, haloalkyl, -(CH ₂ ) _q NR ⁶ R ⁷ and hydroxyalkyl; R ⁶ , R ⁷ and q are as in the general formula (I) As defined in

Preferably, R ^{0 is} selected from C _1-6 alkoxy, five-membered heterocyclyloxy and six-membered heterocyclyl, said five-membered heterocyclyloxy and six-membered heterocyclyl are each independently optionally Ground is substituted by one or more substituents in -C(O)R ^{9 and hydroxyl, wherein R 9} is C _1-6 alkyl or -(CH ₂ ) _q NR ⁶ R ⁷ , R ⁶ and R ^{7 are the} same or Different, each independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{0 is} selected from the group consisting of tetrahydrofuranyloxy, azetidinyloxy, C _1-6 alkoxy, hydropyridyl and Hydropyranyl, said hydropyridyl, azetidinyloxy and hydropyranyl are each independently optionally substituted by one or more of ^{-C(O)R 9 and/or hydroxyl} Group substitution, wherein R 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, and q is 1. Or 2;

Preferably, R ^{0 is} selected from the group consisting of tetrahydrofuranyloxy, C _1-6 alkoxy, hydrogenated pyridyl and hydrogenated pyranyl, and said hydrogenated pyridyl and hydrogenated pyranyl are each independently optionally substituted by -C( O) ^{One or more substituents in R 9} and/or hydroxy, wherein R ⁹ is C _1-6 alkyl or -(CH ₂ ) _q NR ⁶ R ⁷ , R ⁶ and R ^{7 are the} same or different, each Independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{0 is} selected from the group consisting of tetrahydrofuranyloxy, C _1-6 alkoxy, piperidinyl, tetrahydropyridyl, azetidine Alkyloxy, tetrahydropyranyl and dihydropyranyl, the piperidinyl, tetrahydropyridyl, azetidinyloxy, tetrahydropyranyl and dihydropyranyl groups are each independently optionally substituted with the hydroxyl group and / or -C (O) R ⁹ with one or more substituents, wherein R 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, and q is 1 or 2;

Preferably, R ^{0 is} selected from tetrahydrofuranyloxy, C _1-6 alkoxy, piperidinyl, tetrahydropyridinyl, tetrahydropyranyl and dihydropyranyl, the piperidinyl, tetrahydropyranyl Pyridyl, tetrahydropyranyl, and dihydropyranyl are each independently optionally substituted with one or more substituents in ^{hydroxy and/or -C(O)R 9 , wherein R 9} is C _1-6 Alkyl group 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, and q is 1 or 2;

More preferably, R ^{0 is} selected from tetrahydrofuranyloxy or tetrahydropyridyl, and said tetrahydropyridyl is optionally ^{substituted by -C(O)R 9} , wherein R ⁹ is C _1-6 alkyl.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{0 is} selected from 3-6 membered cycloalkyl, and said 3-6 membered cycloalkyl is optionally selected from halogen, alkyl Group, haloalkyl, hydroxy, carboxyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano and -(CH ₂ ) _t -C(O)R ⁹ are substituted with one or more substituents; wherein, R ^{9 is} selected from hydroxyl, -(CH ₂ ) _q NR ⁶ R ⁷ , cycloalkyl and heterocyclyl; each of said cycloalkyl and heterocyclyl is independently optionally selected from alkyl, alkoxy and One or more substituents in the cyano group are substituted; R ⁶ and R ⁷ are each independently selected from alkyl and hydroxyalkyl; R ⁶ , R ⁷ and q are as defined in the general formula (I);

Preferably, R ^{0 is} selected from 3-6 membered cycloalkyl, which is optionally substituted by halogen, C _1-6 alkyl and hydroxy.

环C选自环烷基和杂环基； In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁰ is

Ring C is selected from cycloalkyl and heterocyclyl;

W选自氧原子、硫原子、

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

W is selected from oxygen atom, sulfur atom,

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

R ^{13 are the} same or different, and are each independently selected from 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 a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, a nitro group, a cyano group , -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 are} as general formula (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 general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{0 is} selected from

R ^{13 are the} same or different, and are each independently selected from 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 a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, a nitro group, a cyano group , -S(O) ₂ R ⁹ , -(CH ₂ ) _t C(O)R ⁹ and -NHC(O)R ¹¹ ;

v is 0, 1, 2 or 3;

t, R ⁹ and R ^{11 are} as general formula (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 general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein 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, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, hydroxy, -(CH ₂ ) _q NR ⁶ R ⁷ , 3-6 membered cycloalkyl and 3-6 membered heterocyclic group, the C _1-6 alkyl group, 3-6 membered cycloalkyl group and 3-6 membered heterocyclic group may be optionally _{substituted by C 1-6} alkoxy group and cyano group; R ⁶ Same as or different from R ⁷ and are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; 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, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, hydroxyl and -( CH ₂ ) _q NR ⁶ R ⁷ , the C _1-6 alkyl group may be optionally _{substituted by a C 1-6} alkoxy group and a cyano group; R ⁶ and R ^{7 are the} same or different, and are each independently selected from hydrogen, C _1-6 alkyl and C _1-6 hydroxyalkyl; 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 alkyl; t is zero.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ¹³ is a hydrogen atom.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^13b is a hydrogen atom.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^13c is hydroxyl or -(CH ₂ ) _t -C(O)R ⁹ ; R ^{9 is} selected from hydroxyl, -(CH ₂ ) _q NR ⁶ R ⁷ and a 3-6 membered heterocyclic group; the 3-6 membered heterocyclic group is optionally _{substituted by a C 1-6} alkyl group; R ⁶ and R ^{7 are the} same or different, and are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; 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 is} selected from hydroxyl, -(CH ₂ ) _q NR ⁶ R ⁷ and 3-6 membered heterocyclic groups; the 3-6 The membered heterocyclic group is optionally _{substituted by C 1-6} alkyl; R ⁶ and R ^{7 are the} same or different, and are each independently selected from C _1-6 alkyl and C _1-6 hydroxyalkyl; t is 0; q is 0.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein u is 0 or 1.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein j is 0 or 1.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein k is 1.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( The compounds represented by IV-1), (V-1), (VI-1) and (VII-1) or their tautomers, mesosomes, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein v is zero.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( Compounds represented by IV-1), (V-1), (VI-1) and (VII-1), or tautomers, mesosomes, racemates, and enantiomers thereof , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{8 is the} same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, Halogenated alkoxy, cyano, -(CH ₂ ) _q NR ⁶ R ⁷ , nitro, hydroxy, hydroxyalkyl, -S(O) ₂ alkyl and aryl, wherein the alkyl, halogenated alkyl, hydroxy Alkyl and aryl are each independently optionally selected from hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl and -(CH ₂ ) _q NR ⁶ R ⁷ Is substituted by one or more substituents of, q is 0, 1 or 2; R ⁶ and R ^{7 are the} same or different, and are each independently selected from hydrogen, alkyl, haloalkyl and hydroxyalkyl;

Preferably, R ^{8 are the} same or different, and are each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, -(CH ₂ ) _q NR ⁶ R ⁷ , C _1-6 hydroxyalkyl and C _6-10 aryl group, wherein the C _1-6 haloalkyl group is optionally substituted by one or more hydroxyl groups, and the C _6-10 aryl group is optionally substituted by one or more -(CH ₂ ) _{q is} substituted by NR ⁶ R ^{7 ; R 6} and R ^{7 are} selected from hydrogen or C _1-6 alkyl, and q is 0, 1, or 2.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( Compounds represented by IV-1), (V-1), (VI-1) and (VII-1), or tautomers, mesosomes, racemates, and enantiomers thereof , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{1 is} selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and hydroxyalkyl;

Preferably, R ^{1 is} 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 general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( Compounds represented by IV-1), (V-1), (VI-1) and (VII-1), or tautomers, mesosomes, racemates, and enantiomers thereof , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{2 is} selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl, wherein the alkyl and ring Each of the alkyl groups is independently optionally substituted with one or more substituents selected from the group consisting of alkoxy, haloalkoxy and amino;

Preferably, R ^{2 is} selected from hydrogen and C _1-6 alkyl.

More preferably, R ² is methyl.

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) and (II), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{3 is} selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl, wherein the alkyl, haloalkyl, Each of hydroxyalkyl and cycloalkyl is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, and hydroxyalkyl;

Preferably, R ^{3 is} selected from hydrogen and C _1-6 alkyl.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( Compounds represented by IV-1), (V-1), (VI-1) and (VII-1), or tautomers, mesosomes, racemates, and enantiomers thereof , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{4 is} selected from hydrogen, halogen, alkyl, haloalkyl and hydroxyalkyl;

Preferably, R ⁴ is hydrogen.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( Compounds represented by IV-1), (V-1), (VI-1) and (VII-1), or tautomers, mesosomes, racemates, and enantiomers thereof , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^{5 is the} same or different, and each is independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, Cycloalkyl, -NR ⁶ R ⁷ and cyano, wherein said alkyl and cycloalkyl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen and -NR ⁶ R ⁷ is substituted by one or more substituents; R ⁶ and R ^{7 are the} same or different, and are each independently selected from hydrogen, alkyl, haloalkyl and hydroxyalkyl;

Preferably, R ⁵ is hydrogen or methyl, more preferably hydrogen.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( Compounds represented by IV-1), (V-1), (VI-1) and (VII-1), or tautomers, mesosomes, racemates, and enantiomers thereof , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ⁶ and R ^{7 are the} same or different, and are each independently selected from 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 alkyl.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( Compounds represented by IV-1), (V-1), (VI-1) and (VII-1), or tautomers, mesosomes, racemates, and enantiomers thereof , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ¹⁰ is -(CH ₂ ) _q NR ⁶ R ⁷ , R ⁶ and R ^{7 are the} same or different, and each independently is 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 are the} same or different, and each independently is a methyl group, and q is 1.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( Compounds represented by IV-1), (V-1), (VI-1) and (VII-1), or tautomers, mesosomes, racemates, and enantiomers thereof , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ¹¹ is cycloalkyl or -(CH ₂ ) _q NR ⁶ R ⁷ , R ⁶ and R ^{7 are the} same or different, and are each independent Ground is hydrogen or C _1-6 alkyl, and q is 1 or 2.

Preferably, R ¹¹ is cyclopropyl or -(CH ₂ ) _q NR ⁶ R ⁷ , R ⁶ and R ^{7 are the} same or different, and are each independently a methyl group, and q is 1.

In some preferred embodiments of the present disclosure, a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), ( Compounds represented by IV-1), (V-1), (VI-1) and (VII-1), or tautomers, mesosomes, racemates, and enantiomers thereof , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts 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 the compound represented by the general formula (IA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its salt:

in:

R ^{1 is} selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;

Ring B, R ⁰ , R ⁴ , R ⁵ and p are as defined in the general formula (I).

Another aspect of the present disclosure relates to the compound represented by the general formula (IA-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its salt:

in:

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 the general formula (I).

Another aspect of the present disclosure relates to the compound represented by the general formula (IA-3) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its salt:

in:

X is halogen;

Ring A, ring B, R ¹ -R ⁵ , R ⁸ , p and n are as defined in the general formula (I).

Another aspect of the present disclosure relates to the compound represented by the general formula (IIA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its salt:

in:

The dashed line, G ¹ -G ³ , R ⁰ -R ¹ , R ⁴ -R ⁵ , p, and r are as defined in the general formula (II).

Another aspect of the present disclosure relates to the compound represented by the general formula (IIA-3) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its salt:

Wherein X is halogen;

The dashed line, ring A, G ¹ -G ³ , R ¹ -R ⁵ , R ⁸ , p, r, and n are as defined in the general formula (II).

Another aspect of the present disclosure relates to compounds represented by general formulas (IIIA-1), (IVA-1), (VA-1), (VIA-1) or (VIIA-1) or their tautomers, Meso, racemate, enantiomer, diastereomer, or mixture form or salt thereof:

Wherein R ⁰ -R ¹ , R ⁴ -R ⁵ and p are as defined in the general formula (III), (IV), (V), (VI) or (VII).

Another aspect of the present disclosure relates to compounds represented by general formula (IIIA-2) or (IVA-2) or tautomers, mesosomes, racemates, enantiomers, and non-pairs thereof Enantiomers, or their mixture forms or their salts:

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

Another aspect of the present disclosure relates to compounds represented by general formulas (IIIA-3), (IVA-3), (VA-3), (VIA-3) or (VIIA-3) or their tautomers, Meso, racemate, enantiomer, diastereomer, or mixture form or 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), (IV), (V), (VI) or (VII).

Another aspect of the present disclosure relates to compounds represented by general formulas (IIIA-4), (IVA-4), (VA-4), (VIA-4) or (VIIA-4) or their tautomers, Meso, racemate, enantiomer, diastereomer, or mixture form or salt thereof:

Wherein R ⁰ -R ¹ , R ⁴ -R ⁵ , and p 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 compounds represented by general formula (IIIA-5) or (IVA-5) or tautomers, mesosomes, racemates, enantiomers, and non-pairs thereof Enantiomers, or their mixture forms or their salts:

Wherein, 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 compounds represented by general formulas (IIIA-6), (IVA-6), (VA-6), (VIA-6) or (VIIA-6) or their tautomers, Meso, racemate, enantiomer, diastereomer, or mixture form or salt thereof:

Wherein X is halogen;

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

Another aspect of the present disclosure relates to the compound represented by the general formula (IIaA) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof Form or its salt:

Wherein, Q ¹ , Q ² and Q ^{3 are the} same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;

R ^{12 are the} same or different, and are each independently 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 ;

j is 0 or 1;

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

The dashed line, R ¹ -R ⁵ , G ¹ -G ³ , R ⁸ , R ⁹ , R ¹¹ , p, r, n, and t are as defined in the general formula (II).

Another aspect of the present disclosure relates to compounds represented by general formula (IIIaA) or (III-1aA) or tautomers, mesosomes, racemates, enantiomers, and diastereomers thereof Structure, or its mixture form or its salt:

Wherein, Q ¹ , Q ² and Q ^{3 are the} same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;

R ^{12 are the} same or different, and are each independently 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 ;

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 the general formula (III).

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

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

The compound of general formula (IA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its salt and general formula (IB) The compound or its salt (preferably the hydrochloride) is reacted to obtain the compound of the general formula (I) or its tautomer, meso, racemate, enantiomer, and non-pair Enantiomers, or mixtures thereof or pharmaceutically acceptable salts thereof,

Wherein ring A, ring B, R ⁰ -R ⁵ , R ⁸ , p and n are as defined in the general formula (I).

Another aspect of the present disclosure relates to a preparation of a compound represented by the general formula (I-1) or its tautomer, meso, racemate, enantiomer, diastereomer The method for preparing a phytosome, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method includes the following steps:

Take the compound of the general formula (IA-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its salt as raw material The compound of general formula (I-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof is prepared by reduction reaction or Its medicinal salt,

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 the general formula (I).

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

Take the compound of the general formula (IA-3) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its salt as raw material The compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its medicine is prepared by reaction Use salt; this reaction can be cross-coupling with transition metal catalysis such as Suzuki or Herck coupling, metal halide addition such as Grignard addition, nucleophilic substitution, Ullmann reaction, etc. to introduce R ⁰ , preferably via 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 the general formula (I).

Another aspect of the present disclosure relates to a pharmaceutical composition containing the general formulas (I), (II), (III), (IV), (V), (VI), (VII) of the present disclosure , (III-1), (IV-1), (V-1), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, meso, The racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or its mixture form, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing it, in the preparation of a medicament for inhibiting SOS1.

The present disclosure further relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for the treatment and/or prevention of SOS1 mediated diseases.

The present disclosure further relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS), and multiple spots Noonan Syndrome (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Heart-Facial-Skin Syndrome (CFC), Legus Syndrome, Genetics Use in drugs for gingival fibromatosis or other proliferative diseases, preferably cancer; the cancer is preferably 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, cholangiocarcinoma, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, 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, neuroblast Tumor, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably It is non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; said leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; said 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 for inhibiting SOS1, which comprises administering to a desired patient an effective amount of general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and Table A or the compounds shown in or tautomers, meso, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

The present disclosure also relates to a method for the treatment and/or prevention of SOS1-mediated diseases, which comprises administering to a patient a therapeutically effective amount of general formulas (I), (II), (III), (IV), (V) , (VI), (VII), (III-1), (IV-1), (V-1), (VI-1), (VII-1) and the compounds shown in Table A or their mutual variation Constructs, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

The present disclosure also relates to a treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM -AVM), Costello syndrome (CS), heart-face-skin syndrome (CFC), Legers syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably methods of treating cancer , Which includes the general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV- 1), (V-1), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers , Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them; wherein the cancer is preferably selected from melanoma, skin cancer, liver cancer, hepatocellular carcinoma, renal cancer , Lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, colon cancer, rectal cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric cancer, 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, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably type 1 nerve fiber Neoplasia (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably Diffuse large B-cell lymphoma; the myeloma is preferably multiple myeloma; the osteoma is preferably osteochondroma.

The present disclosure further relates to a general formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V -1), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers Body, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine.

The present disclosure also relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as an SOS1 inhibitor.

The present disclosure also relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or a mixture form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used for the treatment and/or prevention of SOS1 mediated diseases.

The present disclosure also relates to general formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V-1 ), (VI-1), (VII-1) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS), and disease with multiple spots South Syndrome (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Heart-Facial-Skin Syndrome (CFC), Legacy Syndrome, Hereditary Gingival fibromatosis, or other proliferative diseases, are preferably used for the treatment and/or prevention of cancer; wherein the cancer is preferably selected from 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, cholangiocarcinoma, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urine Epithelial 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, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); The lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma The myeloma is preferably multiple myeloma; the osteoma is preferably osteochondroma.

The SOS1-mediated diseases described in the present disclosure are selected from cancer, inflammation, RAS disease, Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), heart-face-skin syndrome (CFC), Legus syndrome, hereditary gingival fibromatosis, or other proliferative diseases; preferably cancer; the Said cancer is preferably selected from 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, cholangiocarcinoma, choriocarcinoma Epithelial 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 tumors, Head and neck squamous cell carcinoma, uterine cancer, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, osteosarcoma, neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glue Plasmoblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; The leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably multiple myeloma; the bone tumor is preferably osteochondroma .

The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (for example, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure can also be formulated into sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

As a general guide, the active compound of the present disclosure is preferably in the form of a unit dose, or a form in which the patient can self-administer in a single dose. The expression mode of the unit dose of the compound or composition of the present disclosure can be tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, regenerating powder or liquid preparation. A suitable unit dose can be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients, which may be selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients剂 etc. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

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

Aqueous suspensions contain the active substance and suitable excipients for mixing to prepare aqueous suspensions. Such excipients are suspending agents, dispersing agents 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 can be formulated by suspending the active ingredients in vegetable oil or mineral oil. The oil suspension may contain thickeners. Sweetening and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil, or mineral oil, or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, and the emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection preparation may be a sterile oil-in-water injection microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

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

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

As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, and the health of the patient. Condition, patient’s behavior, patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best treatment mode, such as the mode of treatment, the daily dosage of the compound, or the type of pharmaceutically acceptable salt It can be verified according to the traditional treatment plan.

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 line containing 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. The chain or branched group is preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 (for example, 1, 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl 2-methylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Base hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available attachment point. The substituents are preferably independently selected from the group consisting of D atom, halogen, alkyl, and alkoxy. Group, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl One or more substituents of.

The term "alkylene" refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbons Atom, more preferably an alkylene group containing 1 to 6 (for example, 1, 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH _{2 -)} CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. The alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from alkenyl, alkynyl, and alkoxy. , Haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in the group, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy One or more substituents among the group, 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 the definition of the alkyl group is as described above. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy One or more substituents among the group, 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 contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 (E.g. 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares one carbon atom (called a spiro atom) between single rings, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" 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 Multiple double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 Five-membered and six-membered/6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl 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 that are not directly connected, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

等；优选

The cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure The ring together is a cycloalkyl group, non-limiting examples include

Etc.; preferably

Cycloalkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available point of attachment. The substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or multiple substituents.

The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of D atom, halogen, alkoxy, halogenated alkyl, and halogenated alkoxy Group, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包 含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3个(例如1、2和3个)是杂原子；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, which contains 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or sulfur, The sulfur can be optionally substituted by oxo or =NH (ie to form sulfoxide, sulfone or

), but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are hetero Atom; more preferably contains 3 to 8 ring atoms (such as 3, 4, 5, 6, 7 and 8), of which 1-3 (such as 1, 2 and 3) are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括： The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, in which one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen or sulfur. Atom, the sulfur may be optionally substituted by oxo or =NH (ie to form sulfoxide, sulfone or

), the remaining ring atoms are carbon. It can contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元双环稠杂环基。稠杂环基的非限制性实例包括： The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or sulfur, and the sulfur may be optionally substituted by oxo or =NH (ie forming sulfoxide, sulfone or

), the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 5-membered 5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括： The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, of which one or more ring atoms It is a heteroatom selected from nitrogen, oxygen or sulfur, and the sulfur may be optionally substituted by oxo or =NH (ie forming sulfoxide, sulfone or

), the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclyl ring includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, wherein it is combined with the parent The structures linked together are heterocyclic groups, non-limiting examples of which include:

等。

Wait.

The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or multiple substituents.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic ring is a ring that shares adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 membered , Such as phenyl and naphthyl. The aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected with the parent structure is an aryl ring, and non-limiting examples thereof include :

Aryl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available attachment point. The substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, haloalkanes Or Multiple substituents.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms (such as 1, 2, 3, or 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10 members (for example, 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkane Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include :

Heteroaryl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available point of attachment. The substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or multiple substituents.

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

The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.

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

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

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

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

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

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

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

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

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

The term "hydroxyl" refers to -OH.

The term "mercapto" refers to -SH.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

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

The term "carbonyl" refers to C=O.

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

The term "cycloalkylcarbonyl" refers to cycloalkyl-C(O)-, where cycloalkyl is as defined above.

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

The term "carboxylate group" 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 the number of double bonds in the ring, which can be dihydro, tetrahydro, hexahydro, etc., such as hydrogenated pyridyl, including dihydropyridyl, tetrahydropyridyl and hexahydropyridyl (ie piper (Pyridyl), as for hydrogenated pyranyl, includes dihydropyranyl and tetrahydropyranyl.

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, in addition to using "deuterium" or "tritium" instead of hydrogen, or using ¹⁸ F-fluorine label ( ¹⁸ F isotope) instead of fluorine, or using ¹¹ C-, ¹³ C-, or ¹⁴ C-rich Compounds in which collective carbons ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) replace carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. The present disclosure also includes formulas (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1) in various deuterated forms , (V-1), (VI-1), (VII-1) and Table A compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize deuterated forms of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV) -1), (V-1), (VI-1), (VII-1) and Table A compounds. In the preparation of deuterated forms of formula (I), (II), (III), (IV), (V), (VI), (VII), (III-1), (IV-1), (V- 1) For (VI-1), (VII-1) and Table A compounds, commercially available deuterated starting materials can be used, or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterium Borane, tri-deuteroborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages.

"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but does not have to be present. The description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (through experiments or theory) without making too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipient. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredients and then exert the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in mammals, and has due biological activity. The salt can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

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

"Prodrug" refers to a compound that can be transformed in the body under physiological conditions, such as by hydrolysis in the blood, to produce an active prodrug compound.

The term "pharmaceutically acceptable" as used herein refers to these compounds, materials, compositions and/or dosage forms, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or Other problems or complications have a reasonable benefit/risk ratio and are effective for the intended use.

As used herein, "a", "an" and "the" in the singular include plural references and vice versa, unless the context clearly dictates otherwise.

When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and is sometimes more preferably within ±5%. As those skilled in the art will understand, when the parameters are not critical, the numbers are usually given for illustrative purposes only, not limitations.

Synthetic method of the compound of the present disclosure

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

Option One

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

The compound of general formula (IA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its salt and general formula (IB) The compound or its salt (preferably hydrochloride) is reacted in the presence of a base and a condensing agent to obtain a compound of the general formula (I) or its tautomer, meso, racemate, and Enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof,

Wherein ring A, ring B, R ⁰ -R ⁵ , R ⁸ , p and n are as defined in the general formula (I).

Option II

The compound represented by the general formula (I-1) of the present disclosure or its tautomers, mesoisomers, racemates, enantiomers, diastereomers, or mixtures thereof, or The preparation method of its pharmaceutically acceptable salt includes the following steps:

In the form of a compound of general formula (IA-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof The raw material is prepared by a reduction reaction under the action of a catalyst to obtain a compound of the general formula (I-1) or its tautomer, meso, racemate, enantiomer, diastereomer, Or its mixture form, or its pharmaceutically acceptable salt,

Wherein G 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 the general formula (I).

third solution

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

In the form of a compound of general formula (IA-3) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof The raw materials are prepared by reaction to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Pharmaceutically acceptable salt; the reaction can be cross-coupling such as Suzuki or Herck coupling catalyzed by transition metals, metal halide addition such as Grignard addition, nucleophilic substitution, Ullmann reaction, etc. to introduce R ⁰ ,

Wherein X is halogen;

Ring A, ring B, R ⁰ -R ⁵ , R ⁸ , p and n are as defined in the general formula (I).

Option Four

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

The compound of general formula (IIA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its salt and general The compound of formula (IB) or its salt (preferably hydrochloride) is reacted in the presence of a base and a condensing agent to obtain a compound of general formula (II) or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

The dotted line, ring A, G ¹ -G ³ , R ⁰ -R ⁵ , R ⁸ , p, r, and n are as defined in the general formula (II).

Option Five

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

In the form of a compound of general formula (IIA-3) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof The raw materials are prepared by reaction to obtain a compound of the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its form or its Pharmaceutical salts; the reaction can be cross-coupling catalyzed by transition metals (such as Suzuki or Herck coupling, etc., metal halide additions such as Grignard addition, nucleophilic substitution, Ullmann reaction, etc., introduce R ⁰ ,

Wherein X is halogen;

The dashed line, ring A, R ⁰ -R ⁵ , R ⁸ , p, r, and n are as defined in the general formula (II).

Option Six

Compounds represented by general formula (III), general formula (IV), general formula (V), general formula (VI) or general formula (VII) of the present disclosure or their tautomers, mesosomes, and exogenous The preparation method of the rotator, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, includes the following steps:

Compounds of general formula (IIIA-1), (IVA-1), (VA-1), (VIA-1) or (VIIA-1) or their tautomers, mesosomes, racemates , Enantiomers, diastereomers, or mixtures thereof, or their salts are reacted with a compound of general formula (IB-1) or a salt thereof (preferably hydrochloride) in the presence of a base and a condensing agent, Obtain the compound of general formula (III), (IV), (V), (VI) or (VII) or its tautomer, meso, racemate, enantiomer, non-pair Enantiomers, or mixtures thereof or pharmaceutically acceptable salts thereof,

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

Option Seven

The compound represented by the general formula (III) or (IV) of the present disclosure or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or its pharmaceutically acceptable salt preparation method, including the following steps:

Compounds of general formula (IIIA-2) or (IVA-2) or tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof The form, or its salt as a raw material, is prepared by a reduction reaction under the action of a catalyst to obtain a compound of the general formula (III) or (IV) or its tautomer, meso, racemate, and enantiomer , Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

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

Option Eight

Compounds represented by general formula (III), general formula (IV), general formula (V), general formula (VI) or general formula (VII) of the present disclosure or their tautomers, mesosomes, and exogenous The preparation method of the rotator, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, includes the following steps:

Compounds of general formula (IIIA-3), (IVA-3), (VA-3), (VIA-3) or (VIIA-3) or their tautomers, mesosomes, racemates The general formula (III), (IV), (V), (VI) or (VII) is prepared by reaction of isomers, enantiomers, diastereomers, or mixtures thereof, or their salts as raw materials. The compound or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts; transition metals can be used for this reaction Catalytic cross-coupling such as Suzuki or Herck coupling, etc., metal halide addition such as Grignard addition, nucleophilic substitution, Ullmann reaction, etc. introduce R ⁰ ,

Wherein X is halogen;

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

Option 9

Compounds represented by general formula (III-1), general formula (IV-1), general formula (V-1), general formula (VI-1) or general formula (VII-1) of the present disclosure or their mutual variation The preparation method of construct, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps:

Compounds of general formula (IIIA-4), (IVA-4), (VA-4), (VIA-4) or (VIIA-4) or their tautomers, mesosomes, racemates , Enantiomers, diastereomers, or mixtures thereof, or their salts are reacted with a compound of general formula (IB-2) or a salt thereof (preferably hydrochloride) in the presence of a base and a condensing agent, Obtain the compound of general formula (III-1), (IV-1), (V-1), (VI-1) or (VII-1) or its tautomer, meso, racemate Isomers, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof,

Wherein ring A, R ⁰ -R ² , R ⁴ -R ⁵ , R ⁸ , p and n are as general formula (III-1), (IV-1), (V-1), (VI-1) or ( As defined in VII-1).

Option ten

The compound represented by the general formula (III-1) or (IV-1) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, Or its mixture form, or its pharmaceutically acceptable salt preparation method, including the following steps:

Compounds of general formula (IIIA-5) or (IVA-5) or tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof Form, or its salt as a raw material, prepared by a reduction reaction under the action of a catalyst to obtain a compound of the general formula (III-1) or (IV-1) or its tautomer, meso, racemate, and Enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof,

Wherein, 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).

Option eleven

Compounds represented by general formula (III-1), general formula (IV-1), general formula (V-1), general formula (VI-1) or general formula (VII-1) of the present disclosure or their mutual variation The preparation method of construct, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps:

Compounds of general formula (IIIA-6), (IVA-6), (VA-6), (VIA-6) or (VIIA-6) or their tautomers, mesosomes, racemates Formula (III-1), (IV-1), (V-1), (III-1), (IV-1), (V-1), ( VI-1) or (VII-1) compound or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form or Pharmaceutical salts; the reaction can be cross-coupling (such as Suzuki or Herck coupling, etc.) catalyzed by transition metals, metal halide additions such as Grignard addition, nucleophilic substitution, Ullmann reaction, etc., to introduce R ⁰ ;

Wherein X is halogen;

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

Scheme 12

时，可通过如下氧化反应制备这些通式(由于不涉及反应位点的基团反应前后不变，因此仅列出反应位点处基团的变化)： For the above general formulas (I), (I-1), (II), (III), (III-1), (IV), (IV-1), (V), (V-1), (VI ), (VI-1), (VII) and (VII-1), when the group R ⁰ is

At the time, these general formulas can be prepared by the following oxidation reaction (because the groups that do not involve the reaction site remain unchanged before and after the reaction, only the changes of the group at the reaction site are listed):

Wherein, Q ¹ , Q ² and Q ^{3 are the} same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;

R ^{12 are the} same or different, and are each independently 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 are substituted by one or more substituents;

j is 0 or 1;

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

时，其为通式(IIa): For example, for the general formula (II), when R ⁰ is

When, it is the general formula (IIa):

The preparation method is:

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

Wherein, Q ¹ , Q ² and Q ^{3 are the} same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;

R ^{12 are the} same or different, and are each independently 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 are substituted by one or more substituents;

j is 0 or 1;

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

The dashed line, R ¹ -R ⁵ , G ¹ -G ³ , R ⁸ -R ⁹ , R ¹¹ , p, r, n, and t are as defined in the general formula (II).

时，其为通式(IIIa)和(III-1a)： For another example, for general formulas (III) and (III-1), when R ⁰ is

When, it is the general formula (IIIa) and (III-1a):

The preparation method is:

The general formula (IIIaA) or (III-1aA) is prepared by oxidation reaction to obtain the general formula (IIIa) or (III-1a),

Wherein, Q ¹ , Q ² and Q ^{3 are the} same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;

R ^{12 are the} same or different, and are each independently 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 are substituted by one or more substituents;

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 the general formula (III).

Scheme 13

时，可通过如下还原反应制备这些通式(由于不涉及反应位点的基团反应前后不变，因此仅列出反应位点处基团的变化)： For the above general formulas (I), (I-1), (II), (III), (III-1), (IV), (IV-1), (V), (V-1), (VI ), (VI-1), (VII) and (VII-1), when the group R ⁰ is

At the time, these general formulas can be prepared by the following reduction reaction (because the groups that do not involve the reaction sites are unchanged before and after the reaction, only the changes of the groups at the reaction sites are listed):

Wherein, Q ¹ , Q ² and Q ^{3 are the} same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;

R ^{12 are the} same or different, and are each independently 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 are substituted by one or more substituents;

j is 0 or 1;

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

Wherein R ^9- R ¹¹ and t are as defined in the general formula (I).

时，其为通式(IIb): For example, for the general formula (II), when R ⁰ is

When, it is the general formula (IIb):

The preparation method is:

General formula (IIaA) is prepared by reduction reaction to obtain general formula (IIb),

Wherein, Q ¹ , Q ² and Q ^{3 are the} same or different, and are each independently selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom;

R ^{12 are the} same or different, and are each independently 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 are substituted by one or more substituents;

j is 0 or 1;

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

The dashed line, R ¹ -R ⁵ , G ¹ -G ³ , R ⁸ -R ⁹ , R ¹¹ , p, r, n, and t are as defined in the general formula (II).

The condensing agent described in the above reaction includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N ,N'-Diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole Nitrozole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate, benzotriazole-1-tris(trimethylamino)-trifluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or hexafluoro Phosphoric acid benzotriazol-1-yl-oxytripyrrolidinyl phosphorus.

The Ullmann reaction can be carried out in the presence of a metal catalyst/ligand/base. The metal catalyst includes but is 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-dichlorophenanthroline Methoxyphenanthroline, tetramethylphenanthroline, TEMDA (CAS registration number 110-18-9), N,N'-dimethyl-1,2-ethylenediamine, TMHD (CAS registration number 1118- 71-4), cyclohexyl-1,2-diamine, N,N'-dimethylcyclohexyl-1,2-diamine, salicylaldoxime, N-diethyl salicylamide, 8-hydroxyquinoline Etc., preferably 1,10-phenanthroline; base is defined as follows, preferably cesium carbonate.

The bases mentioned in the above reaction include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamino. Lithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diaza hetero[5,4,0]undec-7-ene, the inorganic bases include but are not limited to sodium hydride , Potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine or 1,8-dinitrogen Heterocyclic [5,4,0]undec-7-ene.

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, 1,1'-bis(dibenzyl Phosphorus)dichlorodipentyl iron palladium, tris(dibenzylideneacetone)dipalladium, etc., preferably palladium on carbon. The reducing agent used includes but is not limited to hydrogen, dilute hydrochloric acid, acetic acid or dilute sulfuric acid, preferably hydrogen.

The catalyst system used in the above oxidation reaction includes but is not limited to PhSiH/Mn(dpm) ₂ (or Mn(dpm) ₃ or Mn(acac) ₂ or Co(sdmg) ₃ ), tetraphenylporphyrin manganese (III) complex Compound/NaBH ₄ (or Pt-H ₂ ), tetraphenylporphyrin cobalt(II) complex/NaBH ₄ (or EtNBH ₄ ), (bis(salicylic-γ-iminopropyl)methylamine)cobalt (II)/primary alcohol, Co(acac) ₂ , Co(salen), Co(acacen), BH _3, etc.; the oxidants used include but are not limited to oxygen, air, hydrogen peroxide, etc., where Mn(dpm) ₂ is Bis(2,2,6,6-tetramethyl-3,5-heptanedione) manganese, Mn(dpm) ₃ is tris(2,2,6,6-tetramethyl-3,5-heptane Ketone) manganese (CAS registration number 14324-99-3, also known as: tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese), Mn(acac) ₂ is di( Acetylacetone) manganese(II) (CAS registration number 14024-58-9), Co(acac) ₂ is bis(acetylacetone) cobalt(II) (CAS registration number 193620-63-2), Co(salen) is N , N'-bis(salicylic) ethylenediamine cobalt(II) (CAS registration number 14167-18-1), Co(acacen) is N,N'-bis(acetylacetone) ethylenediamine cobalt(II) , Co(sdmg) ₃ is bis(N-salicylidene-2-aminoisobutanone) sodium cobaltate (CAS registration number 704900-51-6); the 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. The solvents used include but are not limited to: acetic acid, methanol, ethanol, isopropanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, Methyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water, N,N-dimethylacetamide or N,N-dimethylformamide and mixtures thereof.

detailed description

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

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} NMR is measured with Bruker AVANCE-400 nuclear magnetometer or Bruker AVANCE NEO 500M, and the solvents are deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) , The internal standard is tetramethylsilane (TMS).

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

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 liquid chromatograph.

Chiral HPLC analysis and determination use Agilent 1260 DAD high performance liquid chromatograph.

HPLC preparative chromatography uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

For chiral preparation, Shimadzu LC-20AP preparative chromatograph was used.

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

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

The silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

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

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

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

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

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

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

The microwave reaction uses CEM Discover-S 908860 microwave reactor.

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

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

The monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of silica gel column chromatography used to purify the compound, and the developing solvent system of thin layer chromatography. Including: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount can also be added Adjust with alkaline or acidic reagents such as triethylamine and acetic acid.

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

Methyl 2-amino-4-hydroxy-5-methoxybenzoate 1b

The compound 4-benzyloxy-5-methoxy-2-nitrobenzoic acid methyl ester 1a (10.0 g, 31.5 mmol, Shanghai Bi De Pharmaceutical Co., Ltd.) was dissolved in tetrahydrofuran (100 mL), and 10% Pd/C was added (1.6g, 1.5mmol), replaced with hydrogen three times, stirred and reacted for 16 hours. It was filtered with celite, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound 1b (6.0 g), yield: 96.5%.

MS m/z(ESI): 198.0[M+1].

Second step

Methyl 2-amino-4-(2,2-dimethoxyethoxy)-5-methoxybenzoate 1c

Compound 1b (2.7g, 13.7mmol) was dissolved in acetonitrile (50mL), cesium carbonate (9.0g, 27.6mmol) and 2-bromo-1,1-dimethoxyethane (3.5g, 20.7mmol) were added, Heat to reflux and react for 16 hours. After cooling and filtering, 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 1c (3.5 g), yield: 89.7%.

MS m/z(ESI): 286.2[M+1].

third step

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

Compound 1c (150 mg, 0.5 mmol) was dissolved in chlorobenzene (10 mL), AMBERLYST (R) 15 (20 mg) was added, and the mixture was heated to 120° C. to react for 14 hours. After cooling and filtering, 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 1d (40 mg), yield: 34.4%.

MS m/z(ESI): 222.0[M+1].

the fourth step

6-Methoxy-2-methylfuro[2,3-h]quinazolin-4-phenol 1e

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

MS m/z(ESI): 231.1[M+1].

the fifth step

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

Compound 1e (460 mg, 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 and reacted for 16 hours. Cooled, neutralized with 1N sodium bicarbonate aqueous solution, filtered, the solid was washed with water and dried to obtain the title compound 1f (350 mg), yield: 81.7%.

MS m/z(ESI): 217.0[M+1].

Sixth step

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

Dissolve compound 1f (250mg, 1.2mmol) in N,N-dimethylformamide (5mL), add cesium carbonate (753mg, 2.3mmol) and 1g (420mg, 1.7mmol, Journal of Medicinal Chemistry, 2011, 54, 4092-4108), heated to 60°C for 1 hour. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1h (200 mg), yield: 60.4%.

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-phenol 1i

Compound 1h (300 mg, 1.0 mmol) was dissolved in methanol (10 mL), 10% palladium-carbon catalyst (50 mg) was added, hydrogen was replaced three times, and the reaction was stirred for 16 hours. It was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound 1i (75 mg), yield: 24.8%.

MS m/z(ESI): 289.0[M+1].

Eighth step

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

Compound 1i (150mg, 0.5mmol) was dissolved in N,N-dimethylformamide (5mL), and compound (R)-1-(3-1-aminoethyl-5-(trifluoromethyl) was added in sequence Aniline hydrochloride 1j (233 mg, 0.96 mmol, prepared by the method disclosed in Example B-6n on page 106 of the specification in the patent application "WO2018/115380"), N,N-diisopropylethylamine ( 200mg, 1.6mmol), benzotriazole-1-tris(trimethylamino)-trifluorophosphate (345mg, 0.8mmoL) and 1,8-diaza heterocycle [5,4,0] undec-7 -Ene (158mg, 1.0mmol), replaced with nitrogen three times, heated to 80°C and reacted for 14 hours. Cooled, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1. (45mg), yield: 18.2%.

MS m/z(ESI): 475.1[M+1].

¹ H NMR(500MHz, 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

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, 0.1mmol) was dissolved in N,N-dimethylformamide (3mL), and compound (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl was added in sequence Amine hydrochloride 2a (30 mg, 0.13 mmol, prepared by the method disclosed in Example B-5 on page 141 of the specification in the patent application "EP2018086197"), benzotriazole-1-tris(trimethylamino)-tri Fluorophosphate (60mg, 0.14mmoL) and 1,8-diaza hetero[5,4,0]undec-7-ene (32mg, 0.2mmol), replaced with nitrogen three times, heated to 80°C for 14 hours . After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2b (20 mg), yield: 41.7%.

MS m/z(ESI): 458.1[M+1].

Second step

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

Compound 2b (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), a 10% palladium-carbon catalyst (10 mg) was added, hydrogen was replaced three times, and the reaction was stirred for 16 hours. It was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound 2 (4.0 mg), yield: 20%.

MS m/z(ESI): 460.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.63 (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

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 (5mL), and compound (R)-2-(3-(1-aminoethyl)-2-fluorophenyl) was added in sequence -2,2-Difluoroethanol hydrochloride 3a (58mg, 0.23mmol, prepared by the method disclosed in Example B-5 on page 105 of the specification in the patent application "US2019194192"), benzotriazole-1- Tris(trimethylamino)-trifluorophosphate (100mg, 0.23mmoL) and 1,8-diaza [5,4,0]undec-7-ene (53mg, 0.35mmol), replaced with nitrogen three times, Heat to 80°C to react for 14 hours. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3b (60 mg), yield: 70.4%.

MS m/z(ESI): 488.0[M+1].

Second step

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 (60 mg, 0.12 mmol) was dissolved in methanol (10 mL), 10% palladium-carbon catalyst (20 mg) was added, hydrogen was replaced three times, and the reaction was stirred for 16 hours. It was filtered with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3 (14.7 mg), yield: 24.4%.

MS m/z(ESI): 490.0[M+1].

¹ H NMR(500MHz, 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

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

Dissolve compound 1e (30mg, 0.13mmol) in N,N-dimethylformamide (2mL), add compound 1j (40mg, 0.16mmol), benzotriazole-1-tris(trimethylamino)-trifluoro Phosphate (37 mg, 0.16 mmoL) and 1,8-diaza heterocyclic [5,4,0] undec-7-ene (30 mg, 0.2 mmol) were replaced with nitrogen three times, and heated to 80° C. to react for 14 hours. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 4a (10 mg), yield: 18.4%.

MS m/z(ESI): 417.1[M+1].

Second step

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

Compound 4a (10 mg, 0.02 mmol) was dissolved in methanol (5 mL), 10% Pd/C (20 mg) was added, hydrogen was replaced three times, and the reaction was stirred for 16 hours. It was filtered with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 4 (2.0 mg), yield: 20.0%.

MS m/z(ESI): 419.0[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.58 (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

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

Dissolve compound 1e (200mg, 0.87mmol) in N,N-dimethylformamide (20mL), add compound 2a (196mg, 0.87mmol), benzotriazole-1-tris(trimethylamino)-trifluoro Phosphate (576mg, 1.30mmoL) and 1,8-diaza hetero[5,4,0]undec-7-ene (198.4mg, 1.3mmol), replaced with nitrogen three times, heated to 80°C for 5 hours . After cooling and concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5a (80 mg), yield: 22.9%.

MS m/z(ESI): 401.9[M+1].

Second step

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

Compound 5a (30 mg, 0.075 mmol) was dissolved in methanol (5 mL), 10% Pd/C (10 mg) was added, hydrogen replacement was performed three times, and the reaction was stirred for 36 hours. It was filtered with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5 (5 mg), yield: 16.6%.

MS m/z(ESI): 404.0[M+1].

¹ H NMR(500MHz, 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

N-((R)-1-(4-Bromothiophen-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 (2mL), and (R)-1-(4-bromothien-2-yl)ethylamine hydrochloride 6a (125mg , 0.52mmol, prepared by the method disclosed in Example INT-29 on page 117 of the specification in the patent application "WO2018/172250"), N,N-diisopropylethylamine (67mg, 0.52mmol), benzene Triazole-1-tris(trimethylamino)-trifluorophosphate (115mg, 0.26mmol) and 1,8-diazahetero[5,4,0]undec-7-ene (53mg, 0.35mmol) ), replaced with nitrogen three times, and heated to 80°C to react for 14 hours. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6b (50 mg), yield: 60.5%.

MS m/z(ESI): 476.0[M+1].

Second step

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

Dissolve compound 6b (50mg, 0.11mmol) in 1,4-dioxane (4mL), add water (1mL), stir at room temperature for 10 minutes, add tetratriphenylphosphine palladium (60mg, 0.05mmol), carbonic acid Potassium (30 mg, 0.21 mmol) and 2-(N-methylaminomethyl) phenylboronic acid pinacol ester (40 mg, 0.16 mmol) were replaced with nitrogen three times, heated to 100°C and stirred for 16 hours. After cooling, filtering with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6 (7.2 mg), yield: 13.2%.

MS m/z(ESI): 517.0[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.53 (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

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

The compound 3,5-dimethoxybenzoic acid methyl ester 7a (9 g, 45.9 mmol, Shanghai Bi De Pharmaceutical Co., Ltd.) was dissolved in acetic anhydride (60 mL), and nitric acid (2 g, 45.9 mmol) was added dropwise under an ice water bath. After stirring for 10 minutes, ice water was added to the reaction system to precipitate a light green solid, filtered, and the filter cake was collected to obtain the title compound 7b (7.6 g), yield: 68.7%.

MS m/z(ESI): 242.0[M+1].

Second step

Methyl 3-hydroxy-5-methoxy-2-nitrobenzoate 7c

Compound 7b (0.71 g, 3.0 mmol) was dissolved in dichloromethane (10 mL), and aluminum trichloride (1.58 g, 11.8 mmol) was added under an ice-water bath, and the reaction was stirred for 3 hours. The reaction system was poured into iced dilute hydrochloric acid for quenching, extracted with ethyl acetate (10mL×3), washed with saturated sodium chloride solution (10mL), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The eluent system A was purified to obtain the title compound 7c (673 mg), yield: 92.5%.

MS m/z(ESI): 228.0[M+1].

third step

Methyl 2-amino-3-hydroxy-5-methoxybenzoate 7d

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

MS m/z(ESI): 198.0[M+1].

the fourth step

Methyl 2-amino-3-(2,2-dimethoxyethoxy)-5-methoxybenzoate 7e

Compound 7d (0.53 g, 2.7 mmol) was dissolved in acetonitrile (15 mL), and bromoacetaldehyde dimethanol (0.7 g, 4.1 mmol) and cesium carbonate (1.8 g, 5.5 mmol) were sequentially added, and heated to reflux for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 7e (767 mg), yield: 63.2%.

MS m/z(ESI): 286.0[M+1].

the fifth step

Methyl 7-amino-4-methoxybenzofuran-6-carboxylate 7f

Compound 7e (2.0 g, 7.0 mmol) was dissolved in polyphosphoric acid (20 mL), and heated and stirred at 100° C. for 2 hours. Stop heating, adjust the pH to about 7 with saturated sodium bicarbonate solution under ice bath, extract with ethyl acetate (30mL×2), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and chromatograph the residue with silica gel column chromatography Purified with eluent system A to obtain the title compound 7f (800mg), yield: 51.6%.

MS m/z(ESI): 222.0[M+1].

Sixth step

6-Methoxy-2-methylfuro[3,2-h]quinazolin-4-phenol 7g

Compound 7f (0.41 g, 1.9 mmol) was dissolved in acetonitrile (20 mL), methanesulfonic acid (0.2 g, 2.1 mmol) was added dropwise, and the tube was sealed and heated at 100°C with stirring for 16 hours. The reaction solution was concentrated under reduced pressure, and the pH was neutralized to about 7 with saturated sodium bicarbonate solution to obtain 7 g (427 mg) of the title compound. Yield: 93.7%.

MS m/z(ESI): 231.0[M+1].

Seventh step

2-Methylfuro[3,2-h]quinazoline-4,6-diphenol 7h

Compound 7g (0.6g, 2.60mmol) was dissolved in chloroform (20mL), boron tribromide (1M dichloromethane solution, 5.21mL) was added dropwise, and the mixture was heated to 80°C and stirred for 16 hours. Cool, concentrate under reduced pressure, add saturated sodium bicarbonate to neutralize, filter, collect the solid to obtain the title compound 7h (563 mg), yield: 88.7%.

MS m/z(ESI): 217.0[M+1].

Eighth step

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

Compound 7h (0.06g, 277.53μmol) was dissolved in N,N-dimethylformamide (5mL), and compound 1g (0.07g, 288.90μmol) and cesium carbonate (0.18g, 552.45μmol) were added in sequence at 60℃. Heat and stir for 1 hour. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 7i (79 mg), yield: 50.3%.

MS m/z(ESI): 287.0[M+1].

Step 9

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

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

MS m/z(ESI): 289.0[M+1].

Tenth step

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

Compound 7j (0.04g, 138.7454μmol) was dissolved in N,N-dimethylformamide (5mL), and compound (R)-1-(3-amino-5-(trifluoromethyl)phenethylamine was added in sequence Hydrochloride 1j (0.057g, 279.15μmol), N,N-diisopropylethylamine (0.053g, 410.08μmol), benzotriazole-1-tris(trimethylamino)-trifluorophosphate (0.122 g, 275.84μmol) and 1,8-diaza hetero[5,4,0]undec-7-ene (0.053g, 348.14μmol), replaced with nitrogen three times, heated to 80°C for 14 hours. Cooled, After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 7 (10 mg), yield: 15%.

MS m/z(ESI): 475.0[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.14 (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)ethane-1-ol 8

Using the synthetic route in Example 7, the raw material compound 1j in the tenth step was replaced with compound 3a to obtain compound compound 8 (10 mg), yield: 11.8%.

MS m/z(ESI): 490.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.58 (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]diox Heteropentyl[4,5-h]quinazolin-4-yl)piperidin-1-yl)ethan-1-one 9

first step

(E)-N-(Benzo[d][1,3]dioxolane-4-yl)-2-(hydroxyaminoimide)acetamide 9c

Chloral hydrate 9b (5.60g, 33.0mmol, Shanghai Titan Technology Co., Ltd.) and anhydrous sodium sulfate (27.76g, 195.4mmol) were dissolved in 50mL of water, followed by the addition of the compound benzo[d][1,3] two Oxolane-4-amine 9a (4g, 29.2mmol, Shanghai Shaoyuan Reagent Co., Ltd.), hydroxylamine sulfate (24.9g, 151.7mmol), concentrated hydrochloric acid (3.1mL). Stir at room temperature for 10 minutes, then heat to 60°C to react for 1.5 hours, and finally return to room temperature to react overnight. A solid precipitated out during the reaction, which was filtered after standing, and the filter cake was sucked dry to obtain the title compound 9c (4.5 g). Yield: 74.1%.

MS m/z(ESI): 209.0[M+1].

Second step

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

Compound 9c (4.5 g, 21.6 mmol) was dissolved in 70 mL of methanesulfonic acid, and heated to 45° C. to react for 1 hour. After cooling, it was poured into ice water and stirred for 1 hour. A solid precipitated out during the reaction. After standing, it was filtered and the filter cake was drained to obtain the title compound 9d (3.76 g). Yield: 91.0%.

MS m/z(ESI): 191.9[M+1].

third step

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

Dissolve compound 9d (3.76g, 19.7mmol) and sodium hydroxide (6.3g, 157.5mmol) in 45mL water in turn, slowly add 30% hydrogen peroxide (22.3g, 196.7mmol, 24mL) in an ice bath, and stir for 30 minutes . 2M diluted hydrochloric acid was added to neutralize the pH to about 7, and the system precipitated solid. After standing, it was filtered and washed with water. The filter cake was drained to obtain the title compound 9e (2.33g). Yield: 65.4%.

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 (1.833 g, 10.1 mmol) was dissolved in 50 mL of acetonitrile, and N-bromosuccinimide (1.8 g, 10.1 mmol) was added in portions at room temperature to react for 2 hours. A solid precipitated out during the reaction, which was filtered after standing, and the filter cake was sucked dry to obtain the title compound 9f (2.6 g). Yield: 98.8%.

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 (2.6 g, 10.0 mmol) was dissolved in 20 mL of acetic anhydride, and the mixture was heated to reflux for 8 hours. After the reaction was completed, acetic anhydride was removed by concentration under reduced pressure, 30 mL of ammonia was added, and the mixture was stirred at room temperature for 4 hours. Then, 30 mL of a 10% sodium hydroxide aqueous solution was added, and the mixture was heated to 60° C. and reacted for 30 minutes. The reaction solution was cooled to room temperature, and concentrated hydrochloric acid was added dropwise to adjust the pH to about 8 under an ice bath. A large amount of solid precipitated out of the system. After standing, it was filtered and the filter cake was drained to obtain 9 g (1.8 g) of the title compound. Yield: 63.6%.

MS m/z(ESI): 282.8[M+1].

Sixth step

(R)-4-Bromo-8-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-[1,3]dioxalano [4,5-h]quinazoline-6-amine 9i

Compound 9g (66mg, 233μmol) and compound (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethylamine hydrochloride 9h (63mg, 233μmol), using patent application "CN110167928A" It was prepared by the method disclosed in Example B-6a on page 89 of the manual) was dissolved in 2.5mL of anhydrous N,N-dimethylformamide, and N,N-diisopropylethylamine (30mg, 232μmol ), 1,8-diaza heterocycle [5,4,0] undec-7-ene (53mg, 348μmol) and benzotriazole-1-tris(trimethylamino)-trifluorophosphate (134mg, 303μmol), stirred for 10 minutes under an argon atmosphere, and then heated to 80°C to react 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 obtain the title compound 9i (116 mg), yield: 99.6%.

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]bis Oxalano[4,5-h]quinazolin-4-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one 9k

Compound 9i (116mg, 232μmol), compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-di Hydropyridine-1(2H)-yl)ethanone 9j (80mg, 319μmol, Shanghai Shaoyuan Reagent Co., Ltd.), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloride Methane complex (19 mg, 23 μmol) and anhydrous sodium carbonate (50 mg, 472 μmol) were dissolved in 3 mL of dioxane and 0.4 mL of water, replaced with argon three times, and heated to 80° C. for reaction for 8 hours. After cooling to room temperature, filtering with Celite, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system C to obtain the title compound 9k (100 mg), yield: 79.2%.

MS m/z(ESI): 544.0[M+1].

Eighth step

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

Compound 9k (100 mg, 184 μmol) was dissolved in 10 mL of ethanol, 10% palladium-carbon catalyst (100 mg, 94 μmol) was added, replaced with hydrogen 3 times, and the reaction was stirred for 16 hours. The reaction solution was filtered with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by HPLC chromatography to obtain the title compound 9 (6.4 mg), yield: 7%.

MS m/z(ESI): 516.2[M+1].

¹ H NMR (500MHz, chloroform-d): δ7.23-7.12(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]dioxolano[4,5-h]quinazolin-6-amine 10

first step

(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-4-bromo-8-methyl-[1,3]dioxalano[ 4,5-h]quinazoline-6-amine 10a

Compound 9g (120mg, 424μmol) and compound 1j (103mg, 428μmol) were dissolved in 3mL of anhydrous N,N-dimethylformamide, and N,N-diisopropylethylamine (55mg, 426μmol), 1 ,8-Diazacyclo[5,4,0]undec-7-ene (129mg, 847μmol) and benzotriazole-1-tris(trimethylamino)-trifluorophosphate (282mg, 638μmol), Stir under argon atmosphere for 10 minutes, and then heat to 80°C 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 obtain the title compound 10a (198 mg), yield: 99.5%.

MS m/z(ESI): 468.9[M+1].

Second step

(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

The compound 10a (198mg, 422μmol), compound 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxide Heteraborane 10b (133mg, 633.1012μmol, Shanghai Shaoyuan Reagent Co., Ltd.), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloride complex (34mg, 42μmol) ) And anhydrous sodium carbonate (90 mg, 849 μmol) were dissolved in 3 mL of dioxane and 0.4 mL of water, replaced with argon three times, and heated to 80°C for 8 hours. Cooled to room temperature, filtered with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound 10 (20.6 mg), yield: 10.3%.

MS m/z(ESI): 473.1[M+1].

¹ H NMR (500MHz, chloroform-d): δ7.10(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

(E)-N-(2,3-Dihydrobenzofuran-4-yl)-2-(hydroxyamino)acetamide 11b

The compound 2,3-dihydrobenzofuran-4-amine 11a (7g, 51.79mmol, Shanghai Beide Pharmaceutical Co., Ltd.) and hydroxylamine sulfate (43g, 261.97mmol) were dissolved in water (100mL), and concentrated hydrochloric acid ( 6.17mL), 2,2,2-trichloroethane-1,1-diol (9.4g, 56.83mmol), anhydrous sodium sulfate (51g, 359.04mmol). The reaction mixture was heated to 60°C and stirred for 30 minutes, and then cooled to room temperature to continue stirring and reacting for 16 hours. The reaction solution was filtered and the filter cake was collected to obtain the title compound 11b (10.7 g). Yield: 93.6%.

MS m/z(ESI): 207.0[M+1].

Second step

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

After mixing compound 11b (4.0 g, 19.4 mmol) and methanesulfonic acid (9.3 g, 96.76 mmol), it was heated to 45° C. and stirred for 1 hour. After the reaction solution was diluted with ethyl acetate (30mL), washed with saturated sodium chloride solution (30mL), the organic phase was collected and dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 11c (1.5g), yield : 40.9%.

MS m/z(ESI): 190.0[M+1].

third step

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

Compound 11c (1.5 g, 7.93 mmol) and solid sodium hydroxide (2.55 g, 63.75 mmol) were dissolved in water (10 mL), and hydrogen peroxide (4.50 g, 39.65 mmol, 30% purity) was added under ice water bath. After stirring for 30 minutes at room temperature, 2M diluted hydrochloric acid was added to neutralize the pH to about 7, and the system precipitated solids. After standing, it was filtered and washed with water. The filter cake was drained to obtain the title compound 11d (0.8g). Yield: 56.3%.

MS m/z(ESI): 180.0[M+1].

the fourth step

Methyl 4-amino-2,3-dihydrobenzofuran-5-carboxylate 11e

Compound 11d was dissolved in dichloromethane (20 mL) and methanol (2 mL), trimethylsilylated diazomethane (2M, 11.82 mL) was added dropwise, and the reaction was stirred 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 obtain the title compound 11e (0.5 g), yield: 54.5%.

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

MS m/z(ESI): 320.0[M+1].

Sixth step

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

Compound 11f (0.2g, 626.77μmol) was dissolved in acetonitrile (3mL), methanesulfonic acid (0.07g, 728.36μmol) was added, and the tube was sealed at 100°C with heating and stirring for 16 hours. The reaction solution was concentrated under reduced pressure, and the pH was neutralized to about 7 with saturated sodium bicarbonate solution, and a solid was precipitated. The solid was collected by filtration to obtain 11 g (0.18 g) of the title compound. Yield: 87.5%.

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]quine (Azolin-4-yl)amino)ethyl)phenyl)ethan-1-ol 11h

Compound 11g (0.08g, 243.82μmol) was dissolved in N,N-dimethylformamide (5mL), and compound 3a (74mg, 289.4μmol), N,N-diisopropylethylamine (0.038 g, 294.02μmol), 1,8-diaza heterocyclic [5,4,0]undec-7-ene (0.075g, 492.66μmol) and benzotriazole-1-tris(trimethylamino)-tri Fluorophosphate (0.215g, 486.12μmol), replaced with nitrogen three times, heated to 80°C and reacted for 14 hours. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 11h (60 mg), yield: 46.5%.

MS m/z(ESI): 530.0[M+1].

Eighth step

(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

Compound 11h (0.04g, 75.57μmol) and N,N-dimethylpropenylurea (DMPU) (19.37mg, 151.14μmol) were dissolved in tetrahydrofuran (2mL), and isopropyl bromide was added dropwise at -20°C Magnesium (1M tetrahydrofuran solution, 377.86 μL), keep the temperature and stir for 1 hour, add 1-acetylpiperidin-4-one (21.3368 mg, 151.14 μmol), and raise to room temperature and stir for 10 hours. The reaction solution was quenched by adding methanol, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title compound 11 (2 mg), yield: 4.8%.

MS m/z(ESI): 545.0[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 8.21 (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, 13.8 Hz, 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

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

Compound 11g (40mg, 122μmol), compound 10b (51mg, 243μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (20mg, 23μmol) And anhydrous sodium carbonate (26mg, 245μmol) were dissolved in 4mL N,N-dimethylformamide and 1mL water, replaced with nitrogen 3 times, and heated to 100℃ to react for 3 hours. After cooling to room temperature, filtering with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 12a (30 mg), yield: 86.5%.

MS m/z(ESI): 285.0[M+1].

Second step

(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

Compound 12a (30mg, 106μmol) was dissolved in N,N-dimethylformamide (3mL), and compound 1j (50mg, 208μmol), N,N-diisopropylethylamine (27mg, 209μmol), Benzotriazole-1-tris(trimethylamino)-trifluorophosphate (93mg, 210μmol) and 1,8-diaza heterocyclic [5,4,0]undec-7-ene (30mg, 210μmol) , Replaced with nitrogen three times, heated to 80°C and reacted for 14 hours. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain title compound 12 (18 mg), yield: 37%.

MS m/z(ESI): 471.1[M+1].

¹ H NMR (500MHz, CDCl ₃ ) δ 7.34 (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-dihydrofuran And[2,3-h]quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one 13

Using the synthetic route in Example 12, the first step starting material compound 10b was replaced with compound 9j to obtain the title compound 13 (30 mg), yield: 33.4%.

MS m/z(ESI): 512.3[M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 8.03 (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-difluoroethane-1-ol 14

Compound 11h (60mg, 113μmol), compound 10b (48mg, 228μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (48mg, 56μmol) And anhydrous sodium carbonate (24mg, 226μmol) were dissolved in 4mL dioxane and 1mL water, replaced with nitrogen 3 times, and heated to 100°C to react for 3 hours. After cooling to room temperature, filtering with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 14 (12 mg), yield: 21.6%.

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

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

Dissolve compound 11a (8g, 37mmol) in acetonitrile (100mL), add N-iodosuccinimide (9.1g, 40.4mmol) under ice-water bath, keep the temperature and stir for 1 hour, then naturally warm to room temperature and stir for reaction 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 obtain the title compound 15a (8.5 g), yield: 88%.

MS m/z(ESI): 261.9[M+1].

Second step

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

Compound 15a (2g, 7.6mmol), compound 10b (2.4g, 11.4mol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (650mg , 767.7μmol) and anhydrous sodium carbonate (1.6g, 15.1mmol) were dissolved in 40mL 1,4-dioxane and 10mL water, replaced with nitrogen 3 times, and heated to 100°C to react for 2 hours. After cooling to room temperature, filtering with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 15b (1.2 g), yield: 72.1%.

MS m/z(ESI): 218.0[M+1].

third step

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

Compound 15b (1 g, 4.6 mmol) was dissolved in methanol (20 mL), 10% palladium-carbon catalyst (300 mg) was added, hydrogen replacement was performed three times, and the reaction was stirred for 16 hours. It 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 15c (730 mg), yield: 72.3%.

MS m/z(ESI): 220.0[M+1].

the fourth step

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

Dissolve compound 15c (0.7g, 3.19mmol), hydroxylamine sulfate (2.6g, 15.84mmol) in water (15mL), add concentrated hydrochloric acid (0.32mL), 2,2,2-trichloroethane-1,1 -Diol (792mg, 4.79mmol), anhydrous sodium sulfate (3.2g, 22.5mmol), first heat to 60°C and stir for 1.5 hours, then cool to room temperature and continue to stir and react for 16 hours. The reaction solution is filtered and the filter cake is collected. The title compound 15d (0.8g) was obtained, and the yield was 86.3%.

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

After mixing compound 15d (0.8 g, 2.75 mmol) and methanesulfonic acid (13 g, 135.3 mmol), it was heated to 45° C. and stirred for 1 hour. After the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride, the organic phase was collected, dried over anhydrous sodium sulfate and concentrated to obtain the title compound 15e (750 mg), yield: 99.5%.

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

Sixth step

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

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

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 dichloromethane (10mL) and methanol (1mL), trimethylsilyldiazomethane (2M, 4.1mL) was added dropwise, and the reaction was stirred 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 obtain 15 g (250 mg) of the title compound. Yield: 33%.

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

15 g (56 mg, 201.9 μmol) of compound was dissolved in acetonitrile (2 mL), methanesulfonic acid (39 mg, 405.8 μmol) was added, and the tube was sealed at 100° C. with heating and stirring for 16 hours. After cooling, it was neutralized with 2N sodium hydroxide aqueous solution, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 15h (50mg), yield: 86.4%.

MS m/z(ESI): 287.1[M+1].

Step 9

(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

Compound 15h (30mg, 104.7μmol) was dissolved in N,N-dimethylformamide (3mL), and compound 1j (50mg, 208μmol) and N,N-diisopropylethylamine (27mg, 209μmol) were added in sequence , Benzotriazole-1-tris(trimethylamino)-trifluorophosphate (93mg, 210μmol) and 1,8-diaza heterocyclic [5,4,0]undec-7-ene (30mg, 210μmol) ), replaced with nitrogen three times, and heated to 80°C to react for 14 hours. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain title compound 15 (14.2 mg), yield: 28.6%.

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-dihydropyridine-1(2H)-yl)ethanone 16

Using the synthetic route in Example 12, the first step raw material compound 10b was replaced with compound 9j, and the second step raw material compound 1j was replaced with compound 3a to obtain the title compound 16 (50 mg), yield: 44%.

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

6-Bromo-7-methoxy-2-methylquinazolin-4(3H)-one 17b

The compound 2-amino-5-bromo-4-methoxybenzoic acid 17a (5g, 23mmol, Shanghai Bi De Pharmaceutical Co., Ltd.) was dissolved in 2 mL of acetic anhydride, and reacted under reflux for 8 hours. After cooling and standing overnight, it precipitated out after a little stirring. A large amount of solids are filtered, and the filter cake is washed with a small amount of acetic anhydride. Add the filter cake to 40mL ammonia water, stir at room temperature for 4 hours, then add 60mL 10% sodium hydroxide solution, stir at 60°C for 0.5 hours, cool to room temperature, add concentrated hydrochloric acid dropwise under an ice water bath to adjust the pH to about 8 (first After dissolving, a solid precipitated out), filtered, the filter cake was washed with water, and dried under vacuum to obtain a white solid, the title compound 17b (4.5g), yield: 81.4%.

MS m/z(ESI): 269.0[M+1].

Second step

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

Compound 17b (0.6g, 2.23mmol) was dissolved in 5mL concentrated sulfuric acid, 2mL concentrated nitric acid was slowly added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was slowly poured into ice water to precipitate a large amount of solids, filtered, the filter cake was washed with water, and dried under vacuum to obtain the crude title compound 17c (700 mg), yield: 99.9%.

MS m/z(ESI): 314.0[M+1].

third step

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

Compound 17c (700 mg, 2.23 mmol) was dissolved in 10 mL of methanol, ammonium chloride (1.12 g, 22.28 mmol) and iron powder (1.12 g, 20.06 mmol) were sequentially added, and the mixture was heated to 80°C for 4 hours. After cooling to room temperature, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 17d (633 mg), yield: 99.9%.

MS m/z(ESI): 284.1[M+1].

the fourth step

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

Compound 17d (633 mg, 2.23 mmol) was heated to 100°C for 16 hours with 10 mL of hydrobromic acid solution. After cooling to room temperature, a solid precipitated out, filtered, the filter cake was washed with water, and dried under vacuum to obtain the crude title compound 17e (600 mg), yield: 99.7%.

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 (50mL), and 1,2-dibromoethane (385mg, 2mmol) and anhydrous potassium carbonate (1.69g, 12.2mmol) were added ), heated to 90°C and stirred for 1 hour, then added 1,2-dibromoethane (385 mg, 2 mmol), and continued to stir and react at 90°C for 1 hour. 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 17f (0.2 g), yield: 16.5%.

MS m/z(ESI): 296.1[M+1].

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,N-diisopropylethylamine (44mg, 0.34mmol), benzotriazol-1-yloxy tris ( Dimethylamino)phosphonium hexafluorophosphate (194mg, 0.44mmol), 1,8-diazabicycloundec-7-ene (77mg, 0.51mmol) dissolved in 5mL N,N-dimethyl In formamide, stir for 10 minutes, and then stir at 60°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain 17 g (146 mg) of the title compound. Yield: 84.4%.

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-dihydropyridine-1(2H)-yl)ethan-1-one 17h

Dissolve compound 17g (146mg, 285.0μmol) and compound 9i (93mg, 370.5μmol) in 5mL 1,4-dioxane and 1mL water, add [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride dichloromethane complex (23.2mg, 28.5μmol) and sodium carbonate (60.4mg, 570.0μmol), under nitrogen atmosphere, heated to 80℃ to react for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was used Purification by silica gel column chromatography using eluent system C to obtain the title compound 17h (55 mg), yield: 34.6%.

MS m/z(ESI): 557.1[M+1].

Eighth step

(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

Compound 17h (105mg, 197.9μmol) was dissolved in methanol 5mL, 50mg of palladium-carbon catalyst (dry) was added, hydrogen replacement 3 times, reaction was stirred for 16 hours, filtered, the filtrate was concentrated under reduced pressure and concentrated under reduced pressure, and the residue was prepared with HPLC The title compound 17 (1.5 mg) was purified by chromatography, yield: 8.8%.

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-dihydropyridine-1(2H)-yl)ethanone 18

Compound 17h (180mg, 269.5μmol) was dissolved in 5mL methanol, iron powder (135.5mg, 2.43mmol) and ammonium chloride (144.2mg, 2.69μmol) were added, and the reaction was refluxed for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain title compound 18 (20 mg), yield: 14.1%.

MS m/z(ESI): 527.1[M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 7.35 (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]dioxacyclo[2,3-h]quinazolin-4-amine 19

first step

6-Bromo-7,8-dihydroxy-2-methylquinazolin-4(3H)-one 19a

Compound 9g (2g, 7.06mmol) was dissolved in 20mL of hydrobromic acid solution, and heated to 100°C to react for 2 days. After cooling to room temperature, a solid precipitated out, filtered, the filter cake was washed with water, and dried under vacuum to obtain the crude title compound 19a (1.9 g), yield: 99%.

MS m/z(ESI): 271.0[M+1].

Second step

6-Bromo-2-methyl-8,9-dihydro-[1,4]dioxacyclo[2,3-h]quinazolin-4(3H)-one 19b

Compound 19a (1.2g, 4.42mmol) was dissolved in N,N-dimethylformamide (20mL), and 1,2-dibromoethane (833mg, 4.43mmol) and anhydrous potassium carbonate (1.83g, 13.4 mmol), heated to 80°C and stirred 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 obtain the title compound 19b (0.17 g), yield: 12.7%.

MS m/z(ESI): 297.1[M+1].

third step

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

The compound 19b (54mg, 0.18mmol), compound 1j (44mg, 0.18mmol), N,N-diisopropylethylamine (23.5mg, 0.18mmol), benzotriazol-1-yloxy three (Dimethylamino)phosphonium hexafluorophosphate (120.6mg, 0.28mmol), 1,8-diazabicycloundec-7-ene (55.3mg, 0.36mmol) were dissolved in 5mL N,N- Stir for 10 minutes in dimethylformamide, then stir and react at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 19c (80 mg), yield: 90.9%.

MS m/z(ESI): 483.2[M+1].

the fourth step

(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-2 -Methyl-8,9-Dihydro-[1,4]dioxacyclo[2,3-h]quinazolin-4-amine 19

Dissolve compound 19c (80 mg, 165.6 μmol) and compound 10b (58 mg, 276 μmol) in 5 mL 1,4-dioxane and 1 mL water, and add [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride dichloromethane complex (15mg, 18μmol) and sodium carbonate (40mg, 377.0μmol), under nitrogen atmosphere, heated to 80℃ to react for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was prepared with HPLC Purification by chromatography gave the title compound 19 (6.1 mg), yield: 6.8%.

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]dioxacyclo[2,3-h]quinazolin-4-amine 20

first step

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

The compound 3,4,5-trihydroxybenzoic acid methyl ester 20a (3g, 16.3mmol, Shanghai Beide Pharmaceutical Co., Ltd.) was dissolved in N,N-dimethylformamide (50mL), and 1,2-dibromo Ethane (4.59g, 24.4mmol) and cesium carbonate (8.49g, 26.0mmol) were heated to 90°C and stirred for 1.5 hours. It 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 20b (1.8 g), yield: 52.5%.

MS m/z(ESI): 211.0[M+1].

Second step

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

Compound 20b (1.1 g, 5.2 mmol) was dissolved in 50 mL of chloroform, and dibromohydantoin (655 mg, 7.0 mmol) was added in portions at room temperature to react for 14 hours. The reaction solution was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate (30mL×3), washed with saturated sodium chloride solution (30mL) and water, the organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant and reduced in pressure After concentration, 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%.

MS m/z(ESI): 289.1 [M+1].

third step

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

Compound 20c (500 mg, 1.73 mmol) was dissolved in N,N-dimethylformamide (10 mL), cesium carbonate (845 mg, 2.6 mmol) and 1 g (461 mg, 1.9 mmol) were added, and the mixture was heated to 95° C. to react for 1 hour. After cooling, filtering, 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 20d (500 mg), yield: 80.4%.

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]dioxane-6 -Methyl carboxylate 20e

Compound 20d (500 mg, 1.39 mmol) was dissolved in concentrated sulfuric acid (5 mL), potassium nitrate (154 mg, 1.53 mmol) was added under ice bath, and the temperature was maintained for 1 hour to react. The reaction solution was diluted with 20mL ice water, extracted with ethyl acetate (30mL×3), washed with saturated sodium chloride solution (30mL) and water, the organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure, the residue Purified by silica gel column chromatography with eluent system A to obtain the title compound 20e (300 mg), yield: 53.3%.

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]dioxane-6-carboxylic acid methyl ester 20f

Compound 20e (150 mg, 0.37 mmol) was dissolved in methanol (5 mL), 10% Pd/C (20 mg) was added, hydrogen was replaced three times, and the reaction was stirred for 16 hours. It 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 20f (70 mg), yield: 63%.

MS m/z(ESI): 296.0[M+1].

Sixth step

(S)-2-Methyl-6-((tetrahydrofuran-3-yl)oxy)-8,9-dihydro-[1,4]dioxacyclo[2,3-h]quinazole Pholin-4-phenol 20g

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

MS m/z(ESI): 305.1[M+1].

Seventh step

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

Compound 20g (60mg, 0.2mmol) was dissolved in N,N-dimethylformamide (5mL), and compound 1j (52.2mg, 0.22mmol), benzotriazole-1-tris(trimethylamino)-tris Fluorophosphate (180mg, 0.4mmoL) and 1,8-diaza hetero[5,4,0]undec-7-ene (92mg, 0.6mmol), replaced with nitrogen three times, heated to 80°C for 14 hours . After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain title compound 20 (13 mg), yield: 13.4%.

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

¹ H NMR (500MHz, CD ₃ OD) δ 7.28 (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-dihydrofuran And [2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)ethanone 21

Using the synthetic route in Example 11, the seventh step raw material compound 3a was replaced with compound 1j to obtain the title compound 21 (5.3 mg), yield: 5%.

MS m/z(ESI): 530.1[M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 8.16 (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 in Example 11, the seventh step raw material compound 3a was replaced by compound 1j and the eighth step raw material compound 1-acetylpiperidin-4-one was replaced by the compound tetrahydropyrone to obtain the title compound 22 (3mg), yield: 10.5%.

MS m/z(ESI): 489.1 [M+1].

¹ H NMR (500MHz, CD ₃ OD) δ 8.14 (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-dihydropyridine-1(2H)-yl)ethyl -1-one 23

first step

(R)-2-(3-(1-((6-Bromo-2-methyl-9,10-dihydro-8H-[1,4]oxazino[2,3-h]quinazoline -4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroethane-1-ol 23a

Compound 17f (140mg, 0.47mmol), compound 3a (120mg, 0.34mmol), N,N-diisopropylethylamine (60.7mg, 0.47mmol), benzotriazol-1-yloxy three (Dimethylamino)phosphonium hexafluorophosphate (311mg, 0.71mmol), 1,8-diazabicycloundec-7-ene (142.9mg, 0.94mmol) dissolved in 5mL N,N-di Stir in methyl formamide for 10 minutes, then stir and react at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 23a (220 mg), yield: 94.2%.

MS m/z(ESI): 497.2[M+1].

Second step

(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-dihydropyridine-1(2H)-yl)ethyl -1-one 23

Dissolve compound 23a (110mg, 221.9μmol) and compound 9i (73mg, 290.7μmol) in 5mL 1,4-dioxane and 1mL water, and add [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride dichloromethane complex (18mg, 22μmol) and sodium carbonate (50mg, 471.0μmol), heated to 80℃ for 14 hours under nitrogen atmosphere, the reaction solution was concentrated under reduced pressure, and the residue was treated with high-performance liquid Purification by preparative chromatography gave the title compound 23 (55 mg), yield: 34.6%.

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-dihydrofuran And [2,3-h]quinazolin-6-yl)piperidin-1-yl)-2-(dimethylamino)ethanone 24

first step

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

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

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

Second step

2-(Dimethylamino)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-di Hydropyridine-1(2H)-yl)ethanone 24c

Dissolve compound 24b (790mg, 3.22mmol) and N,N-dimethylglycine (336mg, 3.25mmol, Shanghai Haohong Biomedical Technology Co., Ltd.) in 25mL of tetrahydrofuran, and add 2-(7-azobenzotriazine) Nitrozole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.86g, 4.89mmol) and N,N-diisopropylethylamine (1.05g, 8.12mmol), stir to react 14 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 24c (800 mg), yield: 83.4%.

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

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, 274.3μmol) was dissolved in N,N-dimethylformamide (3mL), and compound 2a (124mg, 549.5μmol) and N,N-diisopropylethylamine (70mg, 541.6μmol) were added in sequence. ), benzotriazole-1-tris(trimethylamino)-trifluorophosphate (243mg, 549.4μmol) and 1,8-diaza heterocycle[5,4,0]undec-7-ene (84mg , 551.8μmol), replaced with nitrogen three times, heated to 80°C and reacted for 14 hours. After cooling, filtering, 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 24d (90 mg), yield: 65.7%.

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-dihydrofuran And [2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl)-2-(dimethylamino)ethanone 24e

Dissolve compound 24d (90mg, 180.2μmol) and compound 24c (79.5mg, 270.4μmol) in 5mL 1,4-dioxane and 1mL water, add [1,1'-bis(diphenylphosphino) dicene Iron] palladium dichloride dichloromethane complex (15.2mg, 18μmol) and sodium carbonate (38.2mg, 360.5μmol), under nitrogen atmosphere, heated to 80℃ to react for 5 hours, the reaction solution was concentrated under reduced pressure, and the residue was used Purification by silica gel column chromatography using eluent system A to obtain the title compound 24e (30 mg), yield: 30.8%.

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

the fifth step

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

Compound 24e (30 mg, 55.6 μmol) was dissolved in methanol (5 mL), 10% palladium-carbon catalyst (10 mg) was added, hydrogen was replaced three times, and the reaction was stirred for 16 hours. The reaction solution was filtered with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound 24 (3 mg), yield: 10%.

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-dihydrofuran And [2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)ethanone 25

Using the synthetic route in Example 11, the seventh step raw material compound 3a was replaced with compound 2a to obtain compound 25 (10 mg), yield: 9.7%.

MS m/z(ESI): 515.2[M+1].

1HNMR (500MHz, CD ₃ OD) δ 8.20 (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 in Example 11, the raw material compound 1-acetylpiperidin-4-one in the eighth step was replaced with the compound tetrahydropyrone to obtain compound 26 (3.5 mg), yield: 4.6%.

MS m/z(ESI): 504.0[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.19 (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-dihydrofuran And [2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-3-oxopropionitrile 27

first step

(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)-tert-butyl carbonate 27a

Dissolve compound 24d (300mg, 0.6mmol) and compound 24a (371mg, 1.19mmol) in 5mL 1,4-dioxane and 1mL water, add [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride dichloromethane complex (76mg, 0.09mmol) and sodium carbonate (191mg, 1.8mmol), under nitrogen atmosphere, heated to 90℃ to react for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was used on a silica gel column Purification by chromatography with eluent system A to obtain the title compound 27a (300 mg), yield: 90%.

MS m/z(ESI): 555.2[M+1].

Second step

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

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

MS m/z(ESI): 455.2[M+1].

third step

(R)-3-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And [2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl)-3-oxopropionitrile 27c

Dissolve compound 27b (160mg, 0.35mmol) and 2-cyanoacetic acid (45mg, 0.53mmol, Bailingwei) in 2mL N,N-dimethylformamide, add 2-(7-azobenzotriazole) )-N,N,N',N'-tetramethylurea hexafluorophosphate (200mg, 0.53mmol) and N,N-diisopropylethylamine (183mg, 1.41mmol), stirred and reacted for 4 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 27c (180 mg), yield: 98%.

MS m/z(ESI): 522.2[M+1].

the fourth step

(R)-3-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And [2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-3-oxopropionitrile 27

Compound 27c (70mg, 134.2μmol) was dissolved in dichloromethane (0.5mL) and isopropanol (5mL), and manganese tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) was added (40mg, 66μmol) and phenylsilane (28mg, 258μmol), replaced with oxygen three times, and reacted with stirring for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound 27 (8 mg), yield: 11%.

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

¹ H NMR (500MHz, methanol-d ₄ ) δ 8.21 (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

(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

Compound 24d (100mg, 200.3μmol) was dissolved in 1,4-dioxane (3mL), piperazin-2-one (60mg, 599μmol), 4,5-bis(diphenylphosphine)-9, 9-Dimethylxanthene (34mg, 58μmol), tris(dibenzylideneacetone)dipalladium(0) (27mg, 29μmol), cesium carbonate (130mg, 398μmol), replaced with nitrogen three times, stirred at 90℃ for 3 times Hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound 27 (20 mg), yield: 21%.

MS m/z(ESI): 472.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.59 (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-dihydrofuran And [2,3-h]quinazolin-6-yl)piperidin-1-yl)-3-hydroxy-3-methylbutan-1-one 29

first step

(R)-1-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And [2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl)-3-hydroxy-3-methylbutan-1-one 29a

Dissolve compound 27b (115mg, 0.25mmol) and β-hydroxyisovaleric acid (50mg, 0.43mmol, Shanghai Haohong) in 2mL N,N-dimethylformamide, add 2-(7-azobenzo Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (144mg, 0.37mmol) and N,N-diisopropylethylamine (130mg, 1.0mmol), stirred for reaction 4 Hour. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 29a (100 mg), yield: 71%.

MS m/z(ESI): 555.2[M+1].

Second step

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

Compound 29a (50 mg, 90 μmol) was dissolved in methanol (5 mL), 10% palladium-carbon catalyst (20 mg) was added, hydrogen replacement was performed three times, and the reaction was stirred for 16 hours. The reaction solution was filtered with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound 29 (8 mg), yield: 16%.

MS m/z(ESI): 557.2[M+1].

¹ H NMR (500MHz, 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

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, 0.4mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl-3-enecarboxylic acid Methyl ester 30a (210mg, 0.8mmol, Shanghai Bide), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (34mg, 40μmol) and anhydrous Sodium carbonate (85mg, 800μmol) was dissolved in 6mL 1,4-dioxane and 2mL water, replaced with nitrogen three times, and heated to 100°C to react for 3 hours. After cooling to room temperature, filtering with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 30b (200 mg), yield: 98.0%.

MS m/z(ESI): 512.0[M+1].

Second step

(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 (200 mg, 0.4 mmol) was dissolved in methanol (15 mL), 10% palladium-carbon catalyst (20 mg, 0.4 mmol) was added, hydrogen was replaced three times, and the reaction was stirred at room temperature for 16 hours. It was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound 30c (70 mg), yield: 33.2%.

MS m/z(ESI): 514.0[M+1].

third step

(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

Compound 30c (20 mg, 39 μmol) was dissolved in methanol (5 mL), 2N sodium hydroxide solution (1.2 mL) was added, and the reaction was heated to 50° C. for 2 hours. Cooled to room temperature, neutralized with 6N dilute hydrochloric acid, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain 9.3 mg and 2.9 mg of the title compound. Yields: 47.8%, 14.9%.

Single configuration compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 23% -42%).

¹ H NMR (500MHz, methanol-d ₄ ) δ 8.11 (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 compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 23% -42%).

¹ H NMR (500MHz, methanol-d ₄ ) δ 8.11 (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).

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)(morpholinyl)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)(morpholinyl)methanone 31-P2

first step

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

MS m/z(ESI): 498.1[M+1].

Second 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)(morpholinyl)methanone 31b

Dissolve compound 31a (110mg, 0.22mmol) and morpholine (58mg, 0.66mmol, Bailingwei) in 2mL N,N-dimethylformamide, add 2-(7-azobenzotriazole)-N ,N,N',N'-tetramethylurea hexafluorophosphate (78mg, 0.33mmol) and N,N-diisopropylethylamine (86mg, 0.66mmol), stirred and reacted for 3 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 31b (80 mg), yield: 63.8%.

MS m/z(ESI): 567.2[M+1].

third step

((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)(morpholinyl)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)(morpholinyl)methanone 31-P2

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

Single configuration compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30% -55%).

¹ H NMR (500MHz, methanol-d ₄ ) δ 8.16 (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 compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30% -55%).

¹ H NMR (500MHz, methanol-d ₄ ) δ 8.19 (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]quinazoline-6-yl)tetrahydro-2H-pyran-4-ol 32

Using the synthetic route in Example 11, the seventh step raw material compound 3a was replaced with compound 2a, and the eighth step raw material compound 1-acetylpiperidin-4-one was replaced with compound tetrahydropyrone to obtain compound 32 (13 mg ), yield: 5.5%.

MS m/z(ESI): 474.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 8.19 (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

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, 0.4mmol), compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enol 33a (179mg, 0.8mmol, Shanghai Bide), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (32mg, 39μmol) and anhydrous sodium carbonate (85mg, 800μmol) dissolved in 6mL 1,4-dioxane and 2mL water, replaced with nitrogen 3 times, heated to 100°C and reacted for 3 hours. After cooling to room temperature, filtering with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 33b (150 mg), yield: 79.7%.

MS m/z(ESI): 470.1[M+1].

Second step

(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

Compound 33b (150mg, 319.5μmol) was dissolved in isopropanol (5mL) and dichloromethane (0.5mL), and tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) was added Manganese (38.6mg, 63.8μmol), stirred for 5 minutes, added phenylsilane (69.1mg, 638μmol), replaced with oxygen 3 times, stirred and reacted for 20 hours, the reaction solution was filtered and concentrated, and purified by HPLC The title compounds 33-P1 (17 mg) and 33-P2 (12 mg), yields: 10.9%, 7.7%.

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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -55%).

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.19 (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 minutes, purity: 98.5% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -55%).

¹ H NMR (500MHz, 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-bis Hydrofuro[2,3-h]quinazolin-6-yl)-N-((S)-2-hydroxypropyl)-N-methylcyclohexane-1-amide 34-P1

(1S,4R)-4-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-bis Hydrofuro[2,3-h]quinazolin-6-yl)-N-((S)-2-hydroxypropyl)-N-methylcyclohexane-1-amide 34-P2

first step

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 (50 mg, 97 μmol) was dissolved in methanol (4 mL), 2N sodium hydroxide solution (1.4 mL) was added, and the reaction was heated to 50° C. for 2 hours. Cool to room temperature, neutralize with 6N dilute hydrochloric acid, and concentrate under reduced pressure to obtain the title compound 34a (48 mg).

MS m/z(ESI): 500.0[M+1].

Second step

(1R,4S)-4-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-bis Hydrofuro[2,3-h]quinazolin-6-yl)-N-((S)-2-hydroxypropyl)-N-methylcyclohexane-1-amide 34-P1

(1S,4R)-4-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-bis Hydrofuro[2,3-h]quinazolin-6-yl)-N-((S)-2-hydroxypropyl)-N-methylcyclohexane-1-amide 34-P2

Compound 34a (48mg, 0.17mmol) and (2S)-1-(methylamino)propan-2-ol (20mg, 0.19mmol, Shanghai Bide) were dissolved in N,N-dimethylformamide (2mL) , Add 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (47mg, 0.2mmoL) and diisopropylethylamine (25mg, 0.2mmol), the reaction was stirred at room temperature for 14 hours. It was concentrated under reduced pressure, and 12 mg and 11 mg of the title compound were purified by HPLC. Yields: 21.9%, 20.1%.

Single configuration compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 23% -42%)

¹ H NMR(500MHz, 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 compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 23% -42%)

¹ H NMR(500MHz, 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, the seventh step raw material compound 3a was replaced with compound 2a, and the eighth step raw material was replaced with N,N-dimethyl-4-oxocyclohexanecarboxamide (using the patent application " It was prepared by the method disclosed in intermediate 57 on page 123 of the specification in WO2013/27001", and compound 35 (3 mg) was prepared, and the yield was 5.5%.

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

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.24 (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-dihydrofuran And[2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-2-(dimethylamino)ethanone 36

Compound 24e (50mg, 92.67μmol) was dissolved in a mixed solution of dichloromethane (0.4mL) and isopropanol (4mL), and tris(2,2,6,6-tetramethyl-3, 5-heptenoic acid) manganese (15 mg, 24.80 μmol), stirred for 3 minutes, added phenylsilane (30 mg, 277.23 μmol), and stirred at room temperature for 16 hours under an oxygen atmosphere. Concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound 36 (15 mg), yield: 29.0%.

MS m/z(ESI): 558.0[M+1].

¹ H NMR(500MHz, 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-fluorophenyl)ethyl)amino)- 2-Methyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl)oxy)pyrrolidin-1-yl)ethanone 37

first step

(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 (10mL), cesium carbonate (603mg, 1.85mmol) and (R)-3-(p-toluenesulfonyloxy)pyrrolidine were added Tert-butyl-1-carboxylate 37a (310 mg, 0.907 mmol, prepared by the method disclosed in the example on page 40 of the specification in the patent application "WO2008/133734"), heated to 60° C. and reacted for 1 hour. After cooling, filtering, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title compound 37b (89 mg), yield: 25.0%.

MS m/z(ESI): 386.0[M+1].

Second step

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

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

MS m/z(ESI): 285.9[M+1].

third step

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

Compound 37c (65 mg, 0.202 mmol) was dissolved in dichloromethane (15 mL), acetic anhydride (30 mg, 0.29 mmol) and triethylamine (45 mg, 0.44 mmol) were added in sequence, and reacted at room temperature for 1 hour. Concentrated under reduced pressure, purified by silica gel column chromatography with eluent system B to obtain the title compound 37d (50 mg), yield: 75.6%.

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

Dissolve compound 37d (50mg, 0.153mmol) in N,N-dimethylformamide (5mL), add compound 3a (42mg, 0.164mmol), benzotriazole-1-tris(trimethylamino)-trifluoro Phosphate (81mg, 0.183mmol) and 1,8-diaza hetero[5,4,0]undec-7-ene (47mg, 0.308mmol), replaced with nitrogen three times, heated to 70°C for 12 hours. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 37e (45 mg), yield: 55.7%.

MS m/z(ESI): 529.0[M+1].

the fifth step

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

Compound 37e (40 mg, 0.076 mmol) was dissolved in methanol (10 mL), 10% palladium-carbon catalyst (30 mg) was added, hydrogen replacement was performed three times, and the reaction was stirred for 16 hours. It was filtered with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound 37 (14 mg), yield: 28.2%.

MS m/z(ESI): 531.0[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.72-7.70 (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-dihydrofuran And[2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-3-hydroxy-3-methylbutan-1-one 38

Compound 29a (50mg, 91.1μmol) was dissolved in 5mL isopropanol and 0.5mL dichloromethane, and tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (15mg, 24.8 μmol), add phenylsilane (20mg, 180.3μmol) under ice bath after stirring for 10 minutes, replace with oxygen 3 times, and naturally rise to room temperature and stir for 14 hours. The reaction solution was filtered and concentrated under reduced pressure, and the obtained title compound 38 (5 mg) was purified by preparative high performance liquid chromatography, yield: 9.7%.

MS m/z(ESI): 573.2[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ8.23(d,1H), 7.63(t,1H), 7.49(t,1H), 7.24(t,1H), 7.13-691(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-dihydropyridine-1(2H)-yl)ethanone 39

Using the synthetic route in Example 23, the first step starting material compound 3a was replaced with compound 2a to obtain compound 39 (10 mg), yield: 2.2%.

MS m/z(ESI): 512.1[M+1].

¹ H NMR (500MHz, 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)ethane ketone 40

Compound 39 (50mg, 97.7μmol) was dissolved in 4mL isopropanol and 0.4mL dichloromethane, and tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (13mg, 21.5 μmol), add phenylsilane (21.2 mg, 195.5 μmol) under ice bath after stirring for 10 minutes, replace with oxygen 3 times, and naturally rise to room temperature and stir for 14 hours. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain title compound 40 (8 mg), yield: 15.4%.

MS m/z(ESI): 530.0[M+1].

¹ H NMR (500MHz, 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-carbon catalyst (250mg) was added, hydrogen was replaced 3 times, the reaction was stirred for 16 hours, filtered, the filtrate was concentrated under reduced pressure to dryness, and preparative HPLC The title compound 41 (21 mg) was purified, yield: 2.9%.

MS m/z(ESI): 544.2[M+1].

¹ H NMR (500MHz, methanol-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

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, 19.6mmol) and aqueous formaldehyde solution (3.2g, 39.2mmol) were added, and the reaction was stirred for 1 hour, and then sodium cyanoborohydride ( 1.17g, 19.6mmol), after 8 hours of reaction, add sodium cyanoborohydride (1.17g, 19.6mmol), stir the reaction for 14 hours, the reaction solution was quenched with saturated sodium bicarbonate solution, and extracted with dichloromethane (10mL× 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 42a (635 mg), yield: 52.1%.

MS m/z(ESI): 310.1[M+1].

Second step

(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

The compound 42a (230mg, 0.74mmol), compound 2a (210mg, 0.93mmol), N,N-diisopropylethylamine (287.5mg, 2.22mmol), benzotriazol-1-yloxy three (Dimethylamino)phosphonium hexafluorophosphate (656mg, 1.48mmol), 1,8-diazabicycloundec-7-ene (225.8mg, 1.48mmol) were dissolved in 5mL N,N-di In methylformamide, stir for 10 minutes, and then stir at 80°C 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 obtain the title compound 42b (261 mg), yield: 73.1%.

MS m/z(ESI): 481.1[M+1].

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-dihydropyridine-1(2H)-yl)ethanone 42c

Compound 42b (146mg, 0.3mmol), compound 9j (152mg, 0.6mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (24mg, 40μmol) and anhydrous sodium carbonate (64mg, 0.6mmol) were dissolved in 6mL 1,4-dioxane and 2mL water, replaced with nitrogen 3 times, and heated to 80°C for 3 hours. After cooling to room temperature, filtering 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 42c (72 mg), yield: 45.1%.

MS m/z(ESI): 526.2[M+1].

the fourth step

(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

Compound 42c (72mg, 137μmol) was dissolved in methanol 10mL, 10% palladium-carbon catalyst (70mg) was added, hydrogen was replaced 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 prepared with HPLC The obtained title compound 42 (9 mg) was purified by chromatography, yield: 12.4%.

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]dioxacyclo[2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl) Ethyl ketone 43

Using the synthetic route in Example 19, the third step raw material compound 1j was replaced with compound 3a, and the fourth step raw material compound 10b was replaced with compound 9j to obtain compound 43 (10 mg), yield: 4.6%.

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

¹ H NMR (500MHz, 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]dioxacyclo[2,3-h]quinazolin-6-yl)piperidin-1-yl)ethanone 44

Compound 43 (25 mg, 46.1 μmol) was dissolved in 5 mL of methanol, 10% palladium-carbon catalyst (15 mg) was added, hydrogen was replaced three times, and the reaction was stirred for 16 hours. It was filtered with Celite, the filtrate was concentrated under reduced pressure, and the title compound 44 (7 mg) was purified by preparative high performance liquid chromatography. Yield: 27.9%.

MS m/z(ESI): 545.2[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.72 (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]Dioxacyclo[2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)ethanone 45

first step

(R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-8,9-dihydro-[1,4] Dioxacyclo[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-diazabicycloundec-7-ene (461.2mg, 3mmol) was dissolved in 5mL N,N-dimethylformamide, stirred for 10 minutes, and then stirred at 80°C 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 obtain the title compound 45a (300 mg), yield: 63.4%.

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

Second step

(R)-1-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro- [1,4]Dioxacyclo[2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl)ethanone 45b

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

MS m/z(ESI): 513.1[M+1].

third step

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

Compound 45b (40mg, 78μmol) was dissolved in 4mL of isopropanol and 0.4mL of dichloromethane, and tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (15mg, 24.8μmol) was added , Shanghai Bi De), stir for 10 minutes, add phenylsilane (30 mg, 277.2 μmol, Shanghai Bi De) under ice bath, replace with oxygen 3 times, naturally warm to room temperature and stir for 14 hours. The reaction solution was filtered, concentrated under reduced pressure, and the obtained title compound 45 (8 mg) was purified by preparative high performance liquid chromatography. Yield: 19.3%.

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

¹ H NMR (500MHz, 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]dioxacyclo[2,3-h]quinazolin-4-yl)amino)ethyl)phenyl)ethanol 46

Using the synthetic route in Example 20, the seventh step raw material compound 1j was replaced with compound 3a to obtain compound 46 (20 mg), yield: 15.6%.

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

Dissolve 4-tetrahydro-2H-thiopyran 1,1-dioxide 47a (60.2mg, 400.6μmol, Shanghai Bide) and compound 24d (100mg, 200.3μmol) in 2mL 1,4-dioxane In, cuprous iodide (19 mg, 100.2 μmol), 1,10-phenanthroline (18 mg, 100.2 μmol), and cesium carbonate (130.5 mg, 400.6 μmol) were sequentially added, replaced with nitrogen, and reacted in a microwave at 120° C. for 1 hour. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain title compound 47 (20 mg), yield: 19.1%.

MS m/z(ESI): 522.2[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.85 (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, 60.8μmol) was dissolved in 4mL isopropanol and 0.4mL dichloromethane, and tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (15mg, 24.8 μmol, Shanghai Bi De), stir for 10 minutes, add phenylsilane (20 mg, 184.8 μmol, Shanghai Bi De) under ice bath, replace with oxygen 3 times, and naturally rise to room temperature and stir for 14 hours. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain title compound 48 (6 mg), yield: 17.8%.

MS m/z(ESI): 544.2[M+1].

¹ H NMR (500MHz, 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

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

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

MS m/z(ESI): 219.1 [M+1].

Second step

2,2,2-Trifluoro-N-(4-hydroxy-1-oxytetrahydro-2H-thiopyran-1-ylidene)acetamide 49c

Dissolve tetrahydro-2H-thiopyran-4-ol 49b (2g, 16.9mmol, Shanghai Biotech) in 50mL of dichloromethane, add trifluoroacetamide (2.87g, 25.4mmol, Shanghai Biotech), Diacetoxy iodobenzene (8.18g, 25.4mmol, Shanghai Shaoyuan), magnesium oxide (2.73g, 67.7mmol), dimeric rhodium acetate (224.4mg, 507.6μmol, Shanghai Titan), stirred and reacted for 18 hours, the reaction solution After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 49c (800 mg), yield: 19.2%.

MS m/z(ESI): 246.1[M+1].

third step

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

Compound 49c (400mg, 1.63mmol), p-toluenesulfonyl chloride (466.5mg, 2.44mmol, Shanghai Bide) and triethylamine (330mg, 3.26mmol) were dissolved in dichloromethane (50mL), and 4-dimethyl Aminopyridine (20mg, 163μmol), the reaction solution was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 49d (164 mg), yield: 25.1%.

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-sulfur Substituted pyran-1-oxide 49e

Compound 49a (90mg, 412.4μmol) was dissolved in N,N-dimethylformamide (10mL), cesium carbonate (268.8mg, 824.9μmol) and 49d (164.7mg, 412.4μmol) were added, and heated to 80°C to react 14 Hour. After cooling, filtering, 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 49e (30 mg), yield: 20.8%.

MS m/z(ESI): 350.1[M+1].

the fifth step

(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

Compound 49e (30mg, 85.8μmol), compound 2a (24.4mg, 128.8μmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (113.9mg, 257.6μmol) ), 1,8-diazabicycloundec-7-ene (39.2mg, 257.6μmol) was dissolved in 5mL N,N-dimethylformamide, and the reaction was stirred at 80°C for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain title compound 49 (4 mg), yield: 8.9%.

MS m/z(ESI): 521.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 7.87 (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-dihydrofuran And [2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-2-methoxyethanone 50

first step

2-Methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1(2H)-yl)ethane-1-one 50a

Dissolve compound 24b (1.7g, 6.92mmol) in tetrahydrofuran (5mL), add methoxyacetic acid (805mg, 8.93mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 2-(7-azobenzotriazole) in sequence )-N,N,N,N-tetramethylurea hexafluorophosphate (4.63g, 12.17mmol) and N,N-diisopropylethylamine (2.63g, 20.35mmol), 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 obtain the title compound 50a (1.2 g), yield: 52.5%.

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

Second step

(R)-1-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And [2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl)-2-methoxyethanone 50b

Dissolve compound 24d (0.16g, 320.4μmol) and compound 50a (0.12g, 426.8μmol) in 1,4-dioxane (5mL) and water (1mL), add potassium phosphate (0.28g, 1.32mmol) ) And tetrakistriphenylphosphine palladium (0.05g, 43.27μmol), heated and stirred at 90°C for 3 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 B to obtain the title compound 50b (120 mg), yield: 71.2%.

MS m/z(ESI): 527.2[M+1].

third step

(R)-1-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And[2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-2-methoxyethane-1-one 50

Compound 50b (50mg, 95.0μmol) was dissolved in isopropanol (4mL) and dichloromethane (0.4mL), and tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) was added Manganese (5mg, 19.7μmol), stirred for 3 minutes, added phenylsilane (0.013g, 120.13μmol), replaced with oxygen 3 times, stirred and reacted for 14 hours, the reaction solution was filtered and concentrated, and purified by HPLC The title compound 50 (10 mg), yield: 19.3%.

MS m/z(ESI): 545.0[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.29 (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-methylpyridine-2(1H)-one 51

The compound 11h (0.23g, 434.54μmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine- 2(1H)-ketone (0.2g, 850.75μmol, Shanghai Bide) was dissolved in 1,4-dioxane (5mL) and water (1mL), potassium phosphate (0.28g, 1.32mmol) was added, four three Phenylphosphine palladium (0.05g, 43.2μmol), reacted at 90°C for 3 hours. The reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title compound 51 (35 mg), yield: 15.8%.

MS m/z(ESI): 511.0[M+1].

¹ H NMR (500MHz, 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 in Example 30, the first step raw material compound 24d was replaced with compound 11h to obtain the title compound 52, and then 3.22mg and 2.8mg of the title compound were obtained by preparative high performance liquid chromatography. Yield: (3.3%) , 2.9%).

Single configuration compound (shorter retention time)

MS m/z(ESI): 530.0[M+1].

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

¹ H NMR (500MHz, 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 compound (longer retention time)

MS m/z(ESI): 530.0[M+1].

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

¹ H NMR (500MHz, 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, 188.8μmol) was dissolved in N,N-dimethylformamide (5mL), dimethylamine in tetrahydrofuran solution (1M, 377.6μL), N,N-diisopropylethylamine ( 0.04g, 395.3μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.133g, 378.71μmol), stirring reaction 2 Hour. Concentrated under reduced pressure, and the residue was purified by liquid phase preparation to obtain the title compound 5mg and 8mg, yield: (4.8%, 7.6%).

Single configuration compound (shorter retention time)

MS m/z(ESI): 557.0[M+1].

HPLC analysis: retention time 11.2 minutes, purity: 98.5% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -45%).

¹ H NMR (500MHz, 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 compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -45%).

¹ H NMR (500MHz, 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-dihydrofuran And [2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl)acetic acid 54

first step

(R)-2-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And [2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl) tert-butyl acetate 54a

Compound 27b (108mg, 220.45μmol) was dissolved in acetonitrile (5mL), and 2-bromoacetate tert-butyl ester (0.043g, 220.45μmol) and potassium carbonate (0.092g, 665.67μmol) were added successively, and reacted at 70°C for 4 hours , Filtered and concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 54a (100 mg), yield: 79.9%.

MS m/z(ESI): 569.0[M+1].

Second step

(R)-2-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And [2,3-h]quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-yl)acetic acid 54

Compound 54a (0.15g, 263.79μmol) was dissolved in dichloromethane (3mL), and a dioxane solution (5g, 263.79μmol) of hydrochloric acid was slowly added dropwise, and stirred for 2 hours. After the reaction solution was concentrated under reduced pressure, Purification by preparative liquid chromatography gave the title compound 54 (40 mg), yield: 29.6%.

MS m/z(ESI): 513.0[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.18 (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, 189.9μmol) was dissolved in 5mL methanol, 10% palladium-carbon catalyst (0.01g) was added, stirred for 16 hours, filtered and concentrated to obtain the crude product, which was purified by HPLC to obtain the title Compound 55 (24.88 mg), yield: 24.8%.

MS m/z(ESI): 529.0[M+1].

¹ H NMR (500MHz, 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-dihydropyridine-1(2H)-yl)ethanone 56

first step

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

Using the synthetic route in Example 11, the first step compound 2,3-dihydrobenzofuran-4-amine 11a was replaced with compound 2,3-dihydrobenzofuran-7-amine 56a to obtain the title compound 56b (300 mg), yield: 78.5%.

MS m/z(ESI): 281.1[M+1].

Second step

1-(4-(4-Hydroxy-2-methyl-7,8-dihydrofuro[3,2-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H )-Yl) ethyl ketone 56c

Compound 56b (0.155g, 551.4μmol) and compound 9i (0.277g, 1.1mmol) were dissolved in 4mL N,N-dimethylformamide and 1mL water, and then [1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride dichloromethane complex (0.093 g, 113.8 μmol) and sodium carbonate (0.117 g, 1.1 mmol) were reacted at 100° C. for 2 hours under a nitrogen atmosphere. After cooling and concentration under reduced pressure, after concentration, the crude product was purified by silica gel column chromatography with eluent system B to obtain the title compound 56c (55 mg), yield: 30.7%.

MS m/z(ESI): 326.1[M+1].

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-dihydropyridine-1(2H)-yl)ethane-1-one 56

Compound 56c (52mg, 0.159mmol) was dissolved in N,N-dimethylformamide (5mL), and compound 3a (70mg, 0.319mmol), benzotriazole-1-tris(trimethylamino)-trifluoro Phosphate (141mg, 0.318mmol) and 1,8-diazahetero[5,4,0]undec-7-ene (49mg, 0.321mmol) were replaced with nitrogen three times, and heated to 80°C to react for 12 hours. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain the title compound 56 (20 mg). Yield: 23.8%.

MS m/z(ESI): 527.1[M+1].

¹ H NMR (500MHz, 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-dihydrofuran And [2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)acetone 57

first step

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-yl )Acetone 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 under an ice water bath. After 5 minutes, move to Stir at room temperature 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 obtain the title compound 57a (1.14 g), yield: 70.1%.

MS m/z(ESI): 266.2[M+1].

Second step

(R)-1-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And [2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl)propan-1-one 57b

Dissolve compound 24d (0.12g, 240.3μmol) and compound 57a (0.1g, 77.1μmol) in 4mL dioxane and 1mL water, add [1,1'-bis(diphenylphosphine)ferrocene] two Palladium chloride dichloromethane complex (0.041g, 48.4μmol) and sodium carbonate (0.051g, 481.1μmol) were reacted at 100°C 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 obtain the title compound 57b (100 mg), yield: 81.5%.

MS m/z(ESI): 511.3[M+1].

third step

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

Compound 57b (80mg, 156.7μmol) was dissolved in dichloromethane (0.5mL) and isopropanol (5mL), and tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) was added Manganese (20mg, 33.1μmol) and phenylsilane (20mg, 462μmol) were replaced with oxygen three times, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the title compound 57 (30mg) was purified by HPLC. Yield: 24.1%.

MS m/z(ESI): 529.2[M+1].

¹ H NMR(500MHz, 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 in Example 31, the raw material compound morpholine was replaced with the compound (S)-1-methylamino-2-propanol to obtain the title compound 43mg, 22mg, yield: 20.8%, 10.6%.

Single configuration compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -45%).

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.20 (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 compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -45%).

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.20 (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-dihydrofuran And [2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-2-hydroxyethanone 59

Using the synthetic route in Example 27, the raw material compound cyanoacetic acid in the third step was replaced with the compound 2-hydroxyacetic acid, and the title compound 59 (15 mg) was obtained by preparative HPLC purification. The yield: 9.6%.

MS m/z(ESI): 531.0[M+1].

¹ H NMR (500MHz, 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-dihydro Furo[2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)methanone 60

Using the synthetic route in Example 57, the first step raw material compound propionyl chloride was replaced with the compound cyclopropylformyl chloride to obtain the title compound 60 (30 mg), yield: 24.1%.

MS m/z(ESI): 541.2[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.23 (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-dihydrofuran And [2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-2-fluoroethanone 61

first step

2-fluoroacetic acid 61b

The ethyl 2-fluoroacetate 61a (0.5 g, 4.7 mmol) was dissolved in methanol (20 mL), sodium hydroxide (1M, 10 mL) was added, and the reaction was stirred for 14 hours. Concentrate under reduced pressure, add a small amount of water to the residue to dissolve, neutralize the pH to 7-8 with 1M hydrochloric acid, and concentrate under reduced pressure to obtain the title compound 61b (367mg), which is used directly in the next step without purification.

MS m/z(ESI): 77.1 [M-1].

Second step

2-Fluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1( 2H)-yl) ethyl ketone 61c

Compound 24b (923.8mg, 3.8mmol) and compound 61b (367mg, 4.7mmol) were dissolved in N,N-dimethylformamide (20mL), and N,N-diisopropylethylamine (1.82g , 14.1mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.21g, 9.4mmol), react at room temperature under nitrogen atmosphere 14 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 61c (600 mg), yield: 47.4%.

MS m/z(ESI): 270.2[M+1].

third step

(R)-1-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And [2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl)-2-fluoroethanone 61d

Compound 24d (115mg, 230μmol) and compound 61c (93mg,, 346μmol) were dissolved in 1,4-dioxane (2mL) and water (0.4mL), and [1,1'-bis(diphenyl) Phosphinyl)ferrocene]dichloride palladium dichloromethane complex (19mg, 23.3μmol) and anhydrous sodium carbonate (49mg, 461μmol), replaced with nitrogen 3 times, heated to 90°C and reacted for 14 hours. After cooling to room temperature, filtering 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 61d (100 mg), yield: 84.3%.

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-dihydrofuran And [2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-2-fluoroethane-1-one 61

Compound 61d (100mg, 194μmol) was dissolved in isopropanol (2mL) and dichloromethane (0.2mL), and manganese tris(2,2,6,6-tetramethyl-3,5-heptenoate) was added (24mg, 40μmol), stirred for 3 minutes, added phenylsilane (63mg, 582μmol), replaced with oxygen 3 times, reacted at room temperature for 14 hours, the reaction solution was filtered and concentrated, and purified by HPLC to obtain the title compound 61 ( 8mg), yield: 7.7%.

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

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.24 (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

4-(4,4,5,5-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, and 2N hydrochloric acid was added dropwise to adjust the pH to 5 6. Concentrate under reduced pressure to obtain the title compound 62a (1.8g), go to the next step without purification.

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

Second step

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

Dissolve compound 62a (500mg, 1.98mmol) and 1-methyl-piperazine (238.4mg, 2.38mmol) in 10mL N,N-dimethylformamide, add 2-(7-azobenzotriazole) )-N,N,N',N'-Tetramethylurea hexafluorophosphate (1.13g, 2.97mmol) and N,N-diisopropylethylamine (512mg, 4.0mmol), stirred and reacted for 16 hours, Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 62b (300 mg) with a yield of 45%.

MS m/z(ESI): 335.1[M+1].

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, 200.3μmol), compound 62b (133.9mg, 0.4mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (33.92) mg, 40 μmol) and anhydrous sodium carbonate (42.46 mg, 0.4 mmol) were dissolved in 10 mL of dioxane and 2 mL of water, replaced with argon for 3 times, and reacted at 100°C for 3 hours. After cooling to room temperature, filtering with celite, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography with eluent system A to obtain compound 62c (100 mg) with a yield of 86%.

MS m/z(ESI): 580.2[M+1].

the fourth step

((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

Compound 62d (100mg, 172.5μmol) was dissolved in isopropanol (5mL) and dichloromethane (0.5mL), and tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) was added Manganese (60mg, 99.2μmol), after stirring for 5 minutes, add phenylsilane (60mg, 554μmol), replace with oxygen 3 times, stir and react for 20 hours, the reaction solution is filtered and concentrated, and then purified by HPLC to obtain the title Compound 15mg, 10mg, yield: 14.5%, 9.7%.

Single configuration compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 20% -55%).

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.15 (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 compound (longer retention time)

MS m/z(ESI): 598.2[M+1].

HPLC analysis: retention time 11.59 minutes, purity: 99.2% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 20% -55%).

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.20 (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 in Example 27, the third step raw material compound cyanoacetic acid was replaced with compound (R)-tetrahydrofuran-3-carboxylic acid, and purified by HPLC to obtain the title compound 63 (20mg), yield : 19.3%.

MS m/z(ESI): 571.3[M+1].

¹ H NMR (500MHz, 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-bis Hydrofuro[2,3-h]quinazolin-6-yl)-4-hydroxy-N-(2-hydroxy-2-methylpropyl)-N-methylcyclohexanecarboxamide 64-P2

Using the synthetic route in Example 62, the second step raw material compound 1-methyl-piperazine was replaced with the compound 2-methyl-1-methylamino-propan-2-ol to obtain 30 mg and 10 mg of the title compound. Yield: 29.1%, 9.7%.

Single configuration compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -45%).

¹ H NMR (500MHz, methanol-d ₄ ) δ 8.19 (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 compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -45%).

¹ H NMR(500MHz, 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 in Example 27, the third step raw material compound cyanoacetic acid was replaced with compound (S)-tetrahydrofuran-3-carboxylic acid, and purified by HPLC to obtain the title compound 65 (16mg), yield : 7.7%.

MS m/z(ESI): 571.3[M+1].

¹ H NMR (500MHz, 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 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-hydroxypyrrolid-1-yl)ethane-1-one (517.3mg, 4mmol) were dissolved in 1,4-dioxane Add 1,10-phenanthroline (144mg, 0.8mmol), cesium carbonate (261mg, 8mmol), cuprous iodide (152mg, 0.8mmol), replace with nitrogen, react in microwave at 120°C for 3 hours, and reduce the pressure of the reaction solution After concentration, the residue was purified by silica gel column chromatography to obtain the title compound 66 (4.0 mg), yield: 3.9%.

MS m/z(ESI): 501.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 7.75 (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]dioxacyclo[2,3-h]quinazolin-6-yl)oxy)pyrrolidin-1-yl)ethanone 67

first step

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

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

MS m/z(ESI): 284.0[M+1].

Second step

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

Using the synthetic route in Example 20, the third step raw material 1g was replaced with compound 67b, and the seventh step raw material compound 1j was replaced with compound 2a to obtain compound 67 (20 mg), yield: 13.3%.

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

¹ H NMR (400MHz, 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-bis Hydrofuro[2,3-h]quinazolin-6-yl)oxy)-N-methylpyrrolidine-1-carboxamide 68

first step

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

Dissolve compound 24d (100mg, 0.2mmol) and tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (375mg, 2mmol) in 5mL 1,4-dioxane, add 1,10- Phenanthroline (144mg, 0.8mmol), cesium carbonate (261mg, 0.8mmol), cuprous iodide (152mg, 0.8mmol), replaced with nitrogen, reacted in microwave at 120°C for 3 hours, the reaction solution was concentrated under reduced pressure and then layered with silica gel The title compound 68a (30 mg) was obtained by purification with eluent system C by chromatography and yield: 26.8%.

MS m/z(ESI): 559.2[M+1].

Second step

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 (30 mg, 53.7 μmol) was dissolved in 2 mL of dichloromethane, 1 mL 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 in 5 mL of dichloromethane and 1 mL of methanol, added a small amount of solid sodium bicarbonate, stirred for 20 minutes, adjusted the pH to alkaline, filtered and concentrated to obtain the crude product 68b (24 mg), yield: 98 %, the product is directly used in the next reaction without purification.

MS m/z(ESI): 459.2[M+1].

third step

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

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

MS m/z(ESI): 516.2[M+1].

¹ H NMR (500MHz, 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-dihydrofuran And [2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-N,N-dimethylacetamide 69

first step

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

Dissolve compound 24b (676 mg, 3.23 mmol), compound 69a (805 mg, 4.85 mmol) and anhydrous potassium carbonate (894 mg, 6.47 mmol) in N,N-dimethylformamide (10 mL), and stir to react under nitrogen atmosphere 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: 47%.

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

Second step

(R)-2-(4-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And [2,3-h]quinazolin-6-yl)-5,6-dihydropyridine-1(2H)-yl)-N,N-dimethylacetamide 69c

Compound 24d (100mg, 200.3μmol) and compound 69b (177mg, 601.6μmol) were dissolved in 1,4-dioxane (2mL) and water (0.4mL), and [1,1'-bis (two Phenylphosphino)ferrocene]dichloride palladium dichloromethane complex (17mg, 21μmol) and anhydrous sodium carbonate (45mg, 425μmol), replaced with nitrogen 3 times, heated to 90°C and reacted for 14 hours. After cooling to room temperature, filtering 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 69c (72 mg), yield: 67%.

MS m/z(ESI): 540.1[M+1].

third step

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

Compound 69c (72mg, 133.4μmol) was dissolved in isopropanol (3mL) and dichloromethane (0.3mL), and tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) was added Manganese (16mg, 26.7μmol), stirred for 3 minutes, added phenylsilane (43mg, 400μmol), replaced with oxygen 3 times, reacted at room temperature for 14 hours, the reaction solution was filtered and concentrated, and purified by HPLC to obtain the title compound 69 (15 mg), yield: 20%.

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-dihydro Furo[2,3-h]quinazolin-6-yl)oxy)azetidin-1-yl)ethanone 70

first 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, 274.3μmol) was dissolved in N,N-dimethylformamide (3mL), and compound 2a (124mg, 549.5μmol) and N,N-diisopropylethylamine (70mg, 541.6μmol) were added in sequence. ), benzotriazole-1-tris(trimethylamino)-trifluorophosphate (243mg, 549.4μmol) and 1,8-diaza heterocycle[5,4,0]undec-7-ene (84mg , 551.8μmol), replaced with nitrogen three times, heated to 80°C and reacted for 14 hours. After cooling, filtering, 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 24d (90 mg), yield: 65.7%.

MS m/z(ESI): 500.1[M+1].

Second step

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

Dissolve compound 24d (500mg, 1.0mmol) and 1-(3-hydroxyazetidine-1-yl)ethanone 70a (400mg, 3.47mmol) in 1,4-dioxane 10mL, add 1 , 10-phenanthroline (180mg, 1.0mmol), cesium carbonate (978mg, 3.0mmol), cuprous iodide (95mg, 0.5mmol), nitrogen replacement for 15 minutes, microwave reaction at 125°C for 4.5 hours, the reaction solution was concentrated under reduced pressure Then it was purified by HPLC to obtain the title compound 70 (100mg), yield: 20%.

MS m/z(ESI): 487.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.58 (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

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

Dissolve compound 62a (150mg, 595μmol) and 2M N,N-dimethylamine (595μL, 1.2mmol) in N,N-dimethylformamide (2mL), add N,N-diisopropyl Ethylamine (154mg, 1.2mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (280mg, 1.2mmol) under nitrogen atmosphere React at room temperature 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 obtain the title compound 71a (150 mg), yield: 90%.

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

Second step

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-encarboxamide 71b

Compound 42a (288mg, 598μmol) and compound 71a (360mg, 1.3mmol) were dissolved in 1,4-dioxane (5mL) and water (1mL), and [1,1'-bis(diphenyl) Phosphinyl)ferrocene]dichloropalladium dichloride dichloromethane complex (48mg, 59μmol) and anhydrous sodium carbonate (128mg, 1.2mmol), replaced with nitrogen 3 times, heated to 90°C and reacted for 14 hours. After cooling to room temperature, filtering 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 71b (69 mg), yield: 20.8%.

MS m/z(ESI): 554.0[M+1].

third step

(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

Compound 71b (69mg, 125μmol) was dissolved in isopropanol (2mL) and dichloromethane (0.2mL), and manganese tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) was added (15mg, 25μmol), after stirring for 3 minutes, add phenylsilane (41mg, 378.88μmol), replace with oxygen 3 times, react at room temperature for 14 hours, the reaction solution is filtered and concentrated, and purified by HPLC to obtain the title compound 3.22 mg and 2.8 mg, yield: (2.9%, 2.1%).

Single configuration compound (shorter retention time)

MS m/z(ESI): 572.2[M+1].

HPLC analysis: retention time 11.2 minutes, purity: 98% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30% -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 compound (longer retention time)

MS m/z(ESI): 572.2[M+1].

HPLC analysis: retention time 13.1 minutes, purity: 98% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30% -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 in Example 27, the third step raw material compound cyanoacetic acid was replaced with the compound 1-methyl-3-azetidine carboxylic acid to obtain the title compound 72 (6.0 mg), yield: 11.6 %.

MS m/z(ESI): 570.3[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 8.21 (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

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

The compound 24d (800mg, 1.6mmol) and 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- Dioxaborone 73a (725mg, 3.2mmol, Shanghai Bide) dissolved in 5mL 1,4-dioxane and 1mL water, add [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride dichloromethane complex (130mg, 0.16mmol) and sodium carbonate (400mg, 3.2mmol), under nitrogen atmosphere, heated to 90 ℃ to react for 3 hours, the reaction solution was concentrated under reduced pressure, the residue was used silica gel column Purification by chromatography with eluent system A to obtain the title compound 73b (660 mg), yield: 87%.

MS m/z(ESI): 471.9[M+1].

Second step

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 ethanol, iodobenzene acetate (1.4g, 4.1mmol) and ammonium acetate (430mg, 5.6mmol) were added, and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was used Purified by silica gel column chromatography with eluent system B to obtain the title compound 73c (200 mg), yield: 28%.

MS m/z(ESI): 502.8[M+1].

third step

(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

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

MS m/z(ESI): 521.0[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.29 (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-dihydrofuran And [2,3-h]quinazolin-6-yl)-3-hydroxyazetidin-1-yl)ethanone 74

Using the synthetic route in Example 11, the eighth step raw material compound 11h was replaced by compound 24d, and 1-acetylpiperidin-4-one was replaced by 1-acetylazetidine-3-one to obtain the compound compound 74 (20mg), yield: 8.5%.

MS m/z(ESI): 487.1[M+1].

¹ H NMR (500MHz, 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 in Example 50, replacing the starting material methoxyacetic acid in the first step with the compound tetrahydropyran-4-carboxylic acid, the compound 75 (40 mg) was prepared, and the yield was 38.7%.

MS m/z(ESI): 585.2[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 7.21 (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-dihydro Furo[2,3-h]quinazolin-6-yl)oxy)piperidin-1-yl)ethanone 76

Using the synthetic route in Example 70, the raw material compound 1-acetyl-3-hydroxyazetidine in the eighth step was replaced with the compound N-acetyl-4-hydroxypiperidine to obtain compound 76 (2.0 mg) , Yield: 7.6%.

MS m/z(ESI): 515.3[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 7.77 (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

Methyl 4-hydroxy-3-methoxy-5-nitrobenzoate 77b

The compound 4-hydroxy-3-methoxybenzoic acid methyl ester 77a (20.48 g, 112.4, mmol) was dissolved in glacial acetic acid (100 mL), nitric acid (9.4 mL) was slowly added in an ice bath, and the reaction was restored to room temperature for 2 hours. Ice water was added to the reaction solution, and the solid was filtered and sucked dry to obtain compound 77b (20 g) with a yield of 78%.

MS m/z(ESI): 227.9[M+1].

Second step

Methyl 3-amino-4-hydroxy-5-methoxybenzoate 77c

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

MS m/z(ESI): 198.0[M+1].

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 (1000mL), anhydrous potassium carbonate (37.87g, 274mmol) and 1,2-dibromoethane (17.4g, 92.6mmol) were added ), react at 80°C for 1 hour. After cooling to room temperature, the reaction solution was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 77d (20.1 g, 90 mmol), yield: 98.6%.

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

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 (40mL), sodium hydride (890mg, 23.2mmol, 60% pure) was added under ice bath to react for 10 minutes, and methyl iodide (4.12 g, 29 mmol) react overnight at room temperature. It was quenched by adding saturated ammonium chloride under ice bath, extracted with dichloromethane (50mL×3), combined the organic phases, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 77f (2.75g), yield: 44.9%.

MS m/z(ESI): 315.9[M+1].

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

Compound 77g (1.56g, 5.2mmol) was dissolved in concentrated sulfuric acid (10mL), potassium nitrate (577mg, 5.7mmol) was added under ice bath, and the temperature was kept for 1 hour to react. The reaction solution was slowly added dropwise to ice water, dichloromethane was added for extraction (30 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain the title compound 77h (1.7 g), yield: 94.4%.

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

Dissolve compound 77h (0.9g, 2.5mmol) and compound 1g (942mg, 3.9mmol) in N,N-dimethylformamide (10mL), add cesium carbonate (1.69g, 5.2mmol), and react at 90°C for 2 hours . The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 77i (850 mg), yield: 78.6%.

MS m/z(ESI): 417.0[M+1].

Step 9

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

Compound 77i (850 mg, 2.04 mmol) was dissolved in methanol (10 mL), 10% palladium-carbon catalyst (dry) (850 mg, 798.7 μmol) was added, replaced with hydrogen, and the reaction was stirred for 14 hours. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound 77j (300 mg), yield: 47.8%.

MS m/z(ESI): 309.2[M+1].

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 (150 mg, 486.5 μmol) was dissolved in methanol (2 mL), sodium hydroxide (1M, 1 mL) was added, and the reaction was carried out at 60° C. for 4 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, dissolved in a small amount of water, neutralized with 1M hydrochloric acid to pH=7, and extracted with dichloromethane (10mL×3), combined the organic phases, and concentrated under reduced pressure to obtain the title compound 77k( 100mg), yield: 70%.

MS m/z(ESI): 295.2[M+1].

Eleventh step

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

Compound 77k (100mg, 340μmol) was dissolved in acetic anhydride (4mL) and reacted at 140°C for 8 hours. After cooling, it was concentrated under reduced pressure to obtain a solid. Then ammonia water (6mL) was added and the reaction was stirred for 4 hours. 10% sodium hydroxide solution (6mL) was added. ), react at 60°C for 30 minutes. Cool to room temperature, add concentrated hydrochloric acid dropwise under an ice water bath to adjust the pH to 7-8. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 77l (51 mg), yield: 47.3%.

MS m/z(ESI): 318.1[M+1].

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

Compound 77l (51mg, 161μmol) and compound 2a (55mg, 244μmol) were dissolved in N,N-dimethylformamide (2mL), and N,N-diisopropylethylamine (42mg, 321μmol), 1 , 8-Diazabicycloundec-7-ene (49mg, 321μmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (142mg, 321μmol) , React at 90°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC to obtain the title compound 77 (3 mg), yield: 3.8%.

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 in Example 11, the seventh step raw material compound 3a was replaced with 2a, and the eighth step raw material compound 1-acetylpiperidin-4-one was replaced with tetrahydro-4H-thiopyran-4-one 1 ,1-Dioxide, compound 78 (13mg) was prepared, yield: 10%.

MS m/z(ESI): 522.2[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.29 (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-difluoroethane-1-ol 79

Using the synthetic route in Example 49, the fourth step compound 49d was replaced by the compound ethyl p-toluenesulfonate, and the fifth step compound 2a was replaced by compound 3a to obtain compound 79 (5 mg), yield: 13.7%.

MS m/z(ESI): 448.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 7.64 (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

(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

Dissolve tert-butyl 3-hydroxyazetidine-1-carboxylate 80a (242 mg, 1.39 mmol, Shanghai Bi De) and compound 11h (180 mg, 340 μmol) in 2 mL 1,4-dioxane, and add them sequentially Cuprous iodide (259 mg, 1.36 mmol), 1,10-phenanthroline (245 mg, 1.36 mmol), cesium carbonate (443 mg, 1.36 mmol), nitrogen replacement, microwave reaction at 120°C for 2 hours. After cooling to room temperature, filtering and concentrating under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 80b (30 mg), yield: 15.3%.

MS m/z(ESI): 575.2[M+1].

Second step

(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 (50 mg, 87 μmol) was dissolved in 2 mL of dichloromethane, 1 mL 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 in 5 mL of dichloromethane and 1 mL of methanol, solid sodium bicarbonate was added and stirred for 20 minutes, the pH was adjusted to alkaline, filtered, and the crude product 80c (30 mg) was obtained after concentration. Yield: 72.6% , The product is directly used in the next step without purification.

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

third step

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

Dissolve compound 80c (30mg, 63.2μmol) and N,N-diisopropylethylamine (50mg, 95.7μmol) in 2mL of dichloromethane, add cyclopropylformyl chloride (10mg, 61μmol) under ice bath, natural The reaction solution was raised to room temperature and reacted for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was purified by HPLC to obtain the title compound 80 (3 mg). Yield: 8.7%.

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

¹ H NMR (500MHz, 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-dihydrofuran And[2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-1-yl)-2-hydroxy-2-methylpropane-1-one 81

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

MS m/z(ESI): 559.2[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.20 (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]Dioxalano[4,5-h]quinazolin-6-yl)amino)ethyl)phenyl)ethane-1-ol 82

first step

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

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

MS m/z(ESI): 291.0[M+1].

Second step

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

Compound 82a (40mg, 0.14mmol) was dissolved in N,N-dimethylformamide (5mL), and compound 3a (52mg, 0.21mmol), benzotriazole-1-tris(trimethylamino)-trifluoro Phosphate (122mg, 0.27mmoL) and 1,8-diazahetero[5,4,0]undec-7-ene (42mg, 0.28mmol), replaced with nitrogen three times, heated to 80°C and reacted for 14 hours. After cooling, filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound 82 (10 mg), yield: 14.7%.

MS m/z(ESI): 492.0[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 7.62-7.60 (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-dihydro Furo[2,3-h]quinazolin-6-yl)-4-hydroxypiperidin-2-one 83

first step

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

Dissolve 2,4-dioxopiperidine-1-carboxylic acid tert-butyl ester 83a (1.2g, 5.6mmol) in dichloromethane (5mL), add N,N-diisopropylethylamine (1.7g , 16.8mmol) and 4-dimethylaminopyridine (120mg, 0.98mmol). Trifluoromethanesulfonic anhydride (2.38g, 8.4mmol) was added dropwise under an ice bath. After naturally warming to room temperature and reacting for 2 hours, water was added to the reaction solution. , Extracted with dichloromethane (30mL×3), combined the organic phases and concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 83b (1.2g), yield: 61.7% .

MS m/z(ESI): 346.2[M+1].

Second step

2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H) -Tert-butyl carboxylate 83c

Compound 83b (1.1g, 3.18mmol) was dissolved in 30mL 1,4-dioxane, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (233mg, 0.31mmol) and potassium acetate (940mg, 9.57mmol), and the reaction was stirred at 80°C for 14 hours. After cooling, filtering through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 83c (600 mg), yield: 58.2%.

MS m/z(ESI): 324.2[M+1].

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

Dissolve compound 24d (210mg, 0.42mmol) and compound 83c (200mg, 0.618mmol) in 5mL 1,4-dioxane and 1mL water, add [1,1'-bis(diphenylphosphino) dicene Iron] palladium dichloride dichloromethane complex (68mg, 0.083mmol) and sodium carbonate (88mg, 0.83mmol), protected by nitrogen, heated to 100°C for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was used on a silica gel column Purification by chromatography with eluent system A to obtain the title compound 83d (200mg), yield: 85.2%.

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-dihydropyridine-2(1H)-one 83e

Compound 83d (234 mg, 411.5 μmol) was dissolved in 5 mL of dichloromethane, 1.5 mL 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 purified by silica gel column chromatography with eluent system A to obtain the title compound 83e (150 mg), yield: 77.8%.

MS m/z(ESI): 469.2[M+1].

the fifth step

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

Compound 83e (150mg, 320.2μmol) was dissolved in dichloromethane (0.5mL) and isopropanol (5mL), and manganese tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) was added (39mg, 64.5μmol) and phenylsilane (87mg, 804μmol), replaced with oxygen three times, stirred and reacted for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC to obtain the title compound 83 (20mg), yield : 12.8%.

MS m/z(ESI): 487.2[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.27 (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

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

Dissolve compound 24d (150mg, 300.4μmol) in 1,4-dioxane (3mL), add tert-butyl carbamate (75mg, 640.2μmol), 4,5-bis(diphenylphosphine)-9, 9-Dimethylxanthene (15mg, 31.4μmol), tris(dibenzylideneacetone)dipalladium(0) (28mg, 30.5μmol) and cesium carbonate (196mg, 601.5μmol), nitrogen replacement three times, reflux reaction 6 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 84a (90 mg), yield: 61.3%.

MS m/z(ESI): 4891[M+1].

Second step

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

Compound 84a (90 mg, 184.2 μmol) was dissolved in 2 mL of dichloromethane, 1 mL 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 by stirring for 20 minutes, solid sodium bicarbonate was added to adjust the pH to alkaline, filtered and concentrated to obtain the crude product 84b (70mg), yield: 97.8% , The product is directly used in the next reaction without purification.

MS m/z(ESI): 389.2[M+1].

third step

(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

Dissolve compound 84b (70mg, 0.18mmol) and N,N-dimethylglycine (25mg, 0.24mmol, Shanghai Shaoyuan) in 5mL N,N-dimethylformamide, add 2-(7-azo Benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (103mg, 0.27mmol) and N,N-diisopropylethylamine (47mg, 0.36mmol), stir React for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC to obtain the title compound 84 (25 mg), yield: 29.2%.

MS m/z(ESI): 474.2[M+1].

¹ H NMR (500MHz, 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-dihydro Furo[3,2-h]quinazolin-6-yl)oxy)azetidin-1-yl)ethanone 85

first step

(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 (5mL), and N,N-diisopropylethylamine (0.276g , 2.1mmol), 1,8-diazabicycloundec-7-ene (0.54g, 2.14mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium six Fluorophosphate (0.95g, 2.14mmol) was stirred at room temperature for 10 minutes, then heated to 80°C and stirred for 16 hours. The reaction solution 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%.

MS m/z(ESI): 453.1[M+1].

Second step

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

Compound 85a (220mg, 0.486mmol) and compound 70a (224mg, 1,94mmol) were dissolved in 5mL 1,4-dioxane, and 1,10-phenanthroline (350mg, 1.94mmol), cesium carbonate ( 634mg, 1.94mmol), cuprous iodide (370mg, 1.94mmol), replaced with nitrogen, reacted in microwave at 120°C for 3 hours, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain the title compound 85 (4mg). Rate: 1.7%.

MS m/z(ESI): 487.2[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.60 (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 Alk-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine 86

first step

(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

Dissolve compound 80a (300mg, 600.9μmol, Shanghai Bide) and compound 24d (312mg, 1.8mmol) in 2mL 1,4-dioxane, add cuprous iodide (458mg, 2.4mmol), 1,10 -Phenanthroline (433mg, 2.4mmol) and cesium carbonate (783mg, 2.4mmol), replaced with nitrogen, and reacted in microwave at 120°C for 2 hours. After cooling, filtering, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title compound 86a (120 mg), yield: 36.6%.

MS m/z(ESI): 545.2[M+1].

Second step

(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 (30 mg, 55.1 μmol) was dissolved in 2 mL of dichloromethane, 1 mL 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 in 5 mL of dichloromethane, and solid sodium bicarbonate was added to adjust the pH to alkaline. After filtration and concentration, the crude product 86b (24 mg) was obtained. Yield: 98%. The product was directly purified without purification. Used in the next reaction.

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

third step

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

Compound 86b (24mg, 54.1μmol) and N,N-diisopropylethylamine (24.3mg, 166.5μmol) were dissolved in 2mL of dichloromethane, and methylsulfonyl chloride (7mg, 61μmol) was added under ice bath, natural The reaction solution was raised to room temperature and reacted for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was purified by HPLC to obtain the title compound 86 (5 mg), yield: 17.2%.

MS m/z(ESI): 523.2[M+1].

¹ H NMR (500MHz, 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-bis Hydrofuro[2,3-h]quinazolin-6-yl)oxy)azetidin-1-yl)methanone 87

Using the synthetic route in Example 86, the third step raw material compound methanesulfonyl chloride was replaced with the compound cyclopropylformyl chloride to obtain the title compound 87 (139 mg), yield: 45%.

MS m/z(ESI): 513.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.60 (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, 105.3μmol) was dissolved in 3mL concentrated sulfuric acid, 2mL aqueous formaldehyde solution was added at 0°C, and the reaction temperature was raised to room temperature for 14 hours. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution and extracted with dichloromethane ( 10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative high performance liquid chromatography to obtain the title compound 88 (4 mg), yield: 7.7%.

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

¹ H NMR (500MHz, 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

(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), 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (33.89 mg, 40.05 μmol), triethylamine (55.36 mg, 547.1 μmol), methanol ( 5.0mL) was mixed, replaced with carbon monoxide three times, and reacted under reflux at 80°C 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 obtain the title compound 89a( 85mg), yield: 98%.

MS m/z(ESI): 432.4[M+1].

Second step

(R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuro[2,3- h] Quinazoline-6-carboxylic acid 89b

Compound 89a (100 mg, 231.80 μmol) was dissolved in water (1.0 mL) and acetonitrile (5.0 mL), lithium hydroxide monohydrate (38.94 mg, 927.2 μmol) was added, and reacted at 40°C for 5 hours. The reaction solution was concentrated under reduced pressure After removing most of the solvent, add 1N hydrochloric acid 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 obtain the title compound 89b (70.0 mg), yield: 72%.

MS m/z(ESI): 418.4[M+1].

third step

(R)-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuro[2,3 -h]quinazolin-6-yl)(morpholino)methanone 89

Compound 89b (70.0mg, 168μmol) was dissolved in N,N-dimethylformamide (3mL), morpholine (21.9mg, 251.5μmol), 2-(7-azobenzotriazole)-N was added ,N,N,N-tetramethylurea hexafluorophosphate (95.6mg, 252μmol) and N,N-diisopropylethylamine (43.3mg, 335μmol). After stirring and reacting for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain title compound 89 (30 mg), yield: 37%.

MS m/z(ESI): 487.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.26 (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, 21.1μmol) was dissolved in 3mL of acetonitrile, glacial acetic acid (6.3mg, 105.4μmol) and aqueous formaldehyde solution (0.5mL) were added, stirred for 1 hour, and then added sodium cyanoborohydride (12.6mg, 210.8 mmol). After 14 hours of reaction, the reaction solution was concentrated, and the residue was purified by HPLC to obtain the title compound 90 (4 mg). Yield: 37.7%.

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

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.59 (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 in Example 70, the eighth step raw material compound 70a was replaced with the compound cyclobutane-1,3-diol to obtain the title compound 91 (10 mg), yield: 10.8%.

MS m/z(ESI): 459.9[M+1].

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.59 (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-dihydrofuran And [2,3-h]quinazolin-6-yl)azetidin-3-yl)cyclopropanecarboxamide 92

first step

(R)-(1-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuro[ 2,3-h)quinazolin-6-yl)azetidin-3-yl)tert-butyl carbamate 92b

Compound 24d (250mg, 500.7μmol) was dissolved in 1,4-dioxane (5mL), and tert-butyl azetidine-3-ylcarbamate hydrochloride 92a (209mg, 1.0mmol, Shanghai Bi Obtained), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (58.6mg, 100.1μmol), tris(dibenzylideneacetone)dipalladium(0)(45.8mg, 50μmol) and cesium carbonate (130mg, 398μmol) were replaced with nitrogen three times, and the reaction was stirred at 100°C for 14 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 92b (50 mg), yield: 18.4%.

MS m/z(ESI): 544.2[M+1].

Second step

(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 (50 mg, 91.9 mmol) was dissolved in 2 mL of dichloromethane, 1 mL 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 in 2mL of dichloromethane and 0.5mL of methanol, solid sodium bicarbonate was added, stirred for 10 minutes to adjust the pH to alkaline, filtered and concentrated to obtain the crude product 92c (40mg), yield: 98% , The product is directly used in the next reaction without purification.

MS m/z(ESI): 444.2[M+1].

third step

(R)-N-(1-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydrofuran And [2,3-h]quinazolin-6-yl)azetidin-3-yl)cyclopropanecarboxamide 92

Compound 92c (30mg, 67.6μmol) and N,N-diisopropylethylamine (17.5mg, 135.3μmol) were dissolved in 2mL of dichloromethane, and cyclopropylformyl chloride (10.6mg, 101.5μmol) was added under ice bath ), the reaction solution was naturally raised to room temperature and reacted for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was purified by HPLC to obtain the title compound 92 (2 mg). Yield: 5.8%.

MS m/z(ESI): 512.2[M+1].

¹ H NMR (500MHz, 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-bis Hydrofuro[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

Dissolve compound 24d (50mg, 100.1μmol) and cyclohexane-1,4-diol 93a (23.3mg, 200.3μmol) in 5mL 1,4-dioxane, add 1,10-phenanthroline ( 72.2mg, 400.6μmol), cesium carbonate (130.5mg, 400.6μmol) and cuprous iodide (76.3mg, 400.6μmol), replaced with nitrogen, reacted in microwave at 120℃ for 3 hours, the reaction solution was concentrated under reduced pressure and prepared with HPLC Purified by chromatography to obtain the title compound 5mg, 35mg, yield: 10.2%, 6.1%.

Single configuration compound (shorter retention time)

MS m/z(ESI): 488.1[M+1].

HPLC analysis: retention time 11.17 minutes, purity: 98.5% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -42%).

¹ H NMR (500MHz, methanol-d ₄ ): δ 7.70 (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 compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -42%).

¹ H NMR (500MHz, 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-fluoroethanone 94

Compound 86b (100mg, 0.224mmol) and compound 61b (35.1mg, 0.449mmol) were dissolved in N,N-dimethylformamide (10mL), and N,N-diisopropylethylamine (58.2mg , 0.449mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (105.8mg, 0.449mmol), the reaction was stirred under nitrogen atmosphere After 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound 94 (20 mg), yield: 17.6%.

MS m/z(ESI): 505.1[M+1].

¹ H NMR (500MHz, 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, the first step raw material compound propionyl chloride was replaced with the compound methanesulfonyl chloride to obtain the title compound 95 (70 mg), yield: 33.9%.

MS m/z(ESI): 551.0[M+1].

¹ H NMR (500MHz, 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 in Example 27, the third step raw material compound cyanoacetic acid was replaced with compound L-lactic acid, and the obtained title compound 96 (32 mg) was purified by preparative high performance liquid chromatography, yield: 25.7%.

MS m/z(ESI): 545.1[M+1].

¹ H NMR (500MHz, 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 in Example 70, and replacing the starting material compound 24d with compound 11h, the title compound 97 (6 mg) was prepared, yield: 4.0%.

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

¹ H NMR (500MHz, methanol-d ₄ ) δ 7.58 (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 in Example 49, the fourth step compound 49d was replaced with compound 1,1-dioxytetrahydro-2H-thiopyran-4-yl-4-methylbenzenesulfonic acid (using patent application It was prepared by the method disclosed in Example 95 on page 166 of the specification in "WO2014/170842 A2", and compound 98 (21 mg) was prepared by replacing compound 2a in step 5 with compound 3a. Yield: 29.6%.

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 Base-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 Base-8,9-dihydrofuro[2,3-h]quinazolin-6-yl)cyclohexane-1,4-diol 99-P2

first step

(R)-N-(1-(3,3-Difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)-6-iodo-2-methyl-8,9-dihydro Furo[2,3-h]quinazolin-4-amine 99b

Compound 11g (200mg, 609.56μmol) was dissolved in N,N-dimethylformamide (5mL), and compound (R)-1-(3,3-difluoro-2,3-dihydrobenzofuran) was added in sequence -7-yl) ethane-1-amine hydrochloride 99a (133 mg, 667.68 μmol, prepared by the method disclosed in Example B-5 on page 105 of the specification in the patent application "US2019194192"), N,N- Diisopropylethylamine (160mg, 1.23mmol), benzotriazole-1-tris(trimethylamino)-trifluorophosphate (540mg, 1.22mmol) and 1,8-diaza heterocycle [5,4, 0] Undec-7-ene (310 mg, 1.23 mmol), replaced with nitrogen three times, and heated to 80° C. to react for 14 hours. After cooling, filtering, and concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 99b (300 mg), yield: 96.6%.

MS m/z(ESI): 510.1[M+1].

Second step

(1s,4S)-1-(4-(((R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methyl Base-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 Base-8,9-dihydrofuro[2,3-h]quinazolin-6-yl)cyclohexane-1,4-diol 99-P2

Using the synthetic route in Example 33, the first step raw material compound 24d was replaced with compound 99b to obtain title compounds 99-P1 (20 mg) and 99-P2 (40 mg). Yields: 6.8%, 13.7%.

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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -55%).

¹ H NMR (500MHz, 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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -55%).

¹ H NMR (500MHz, methanol-d4): δ 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 Base-8,9-dihydrofuro[2,3-h]quinazolin-6-yl)oxy)azetidin-1-yl)-2-fluoroethanone 100

first step

1-(2-Fluoroacetyl)azetidin-3-yl-4-methylbenzenesulfonate 100b

Compound azetidine-3-ol hydrochloride 100a (1g, 9.12mmol, Shanghai Shaoyuan) and compound 61b (712.36mg, 9.12mmol) were dissolved in tetrahydrofuran (20mL), and N,N-di Isopropylethylamine (2.95g, 22.8mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.16g, 10.9 mmol), the reaction was stirred for 14 hours. The reaction solution was concentrated and dissolved in 50mL of dichloromethane, added p-toluenesulfonyl chloride (2.06g, 10.8mmol), triethylamine (1.37g, 13.5mmol), 4-dimethylaminopyridine (1.1g, 9mmol), the reaction solution After stirring for 16 hours. Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 100b (800 mg), yield: 20.8%.

MS m/z(ESI): 288.2[M+1].

Second step

(R)-1-(3-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl Base-8,9-dihydrofuro[2,3-h]quinazolin-6-yl)oxy)azetidin-1-yl)-2-fluoroethanone 100

Using the synthetic route in Example 49, the fourth step raw material compound 49d was replaced with compound 100b, and the fifth step raw material compound 2a was replaced with compound 3a to obtain the title compound 100 (5 mg). Yield: 8.2%.

MS m/z(ESI): 535.2[M+1].

¹ H NMR (500MHz, 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 in Example 70, the seventh step raw material compound 2a was replaced with compound 99a to obtain the title compound 101 (3 mg). Yield: 1.06%.

MS m/z(ESI): 497.2[M+1].

¹ H NMR (500MHz, 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

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, 416μmol) and compound 33a (140mg, 625μmol) were dissolved in 1,4-dioxane (3mL) and water (0.6mL), and [1,1'-bis(diphenyl) Phosphinyl) ferrocene] dichloride palladium dichloromethane complex (34 mg, 42 μmol) and anhydrous sodium carbonate (90 mg, 849 μmol), replaced with nitrogen 3 times, heated to 100° C. and reacted for 14 hours. After cooling to room temperature, filtering with Celite, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title compound 102a (100 mg), yield: 48.3%.

MS m/z(ESI): 498.9[M+1].

Second step

(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

Compound 102a (100mg, 200.6μmol) was dissolved in isopropanol (2mL) and dichloromethane (0.2mL), and tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) was added Manganese (36mg, 60μmol), stirred for 3 minutes, added phenylsilane (65mg, 601μmol), replaced with oxygen 3 times, stirred and reacted for 14 hours, the reaction solution was filtered and concentrated, and the residue was purified by HPLC to obtain the title Compound 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 minutes, purity: 98% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30% -55%)

¹ H NMR (500MHz, methanol-d ₄ ): δ 7.95 (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% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 30% -55%)

¹ H NMR (500MHz, 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-fluoroethanone 103

first step

(R)-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-carboxylic acid tert-butyl ester 103a

Compound 42b (244mg, 507μmol) and 80a (352mg, 2mmol, Shanghai Bide) were dissolved in 5mL 1,4-dioxane, and cuprous iodide (386mg, 2mmol) and 1,10-phenanthroline were added sequentially (365 mg, 2 mmol), cesium carbonate (661 mg, 2 mmol)), replaced with nitrogen, and reacted in a microwave at 120°C for 6 hours. After cooling to room temperature, filtering and concentrating under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 103a (50 mg), yield: 17.2%.

MS m/z(ESI): 574.1[M+1].

Second step

(R)-6-(azetidin-3-yloxy)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,10-di Methyl-9,10-dihydro-8H-[1,4]oxazino[2,3-h]quinazolin-4-amine 103b

Compound 103a (50 mg, 81 μmol) was dissolved in 2 mL of dichloromethane, 1 mL 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 in 5 mL of dichloromethane and 1 mL of methanol, solid sodium bicarbonate was added and stirred for 20 minutes, the pH was adjusted to alkaline, and the crude product 103b (41 mg) was obtained after filtration and concentration. Yield: 99%. The product was directly used in the next reaction without purification.

MS m/z(ESI): 474.1[M+1].

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-fluoroethanone 103b

Compound 103b (41mg, 86.6μmol) and 61b (14mg, 179.3899μmol) were dissolved in 2mL N,N-dimethylformamide, and N,N-diisopropylethylamine (22mg, 170μmol) was added under ice bath. And 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (41mg, 174μmol), naturally rise to room temperature and react for 1 hour, the reaction solution is reduced After pressure concentration, the residue was purified by preparative high performance liquid chromatography to obtain title compound 103 (2 mg), yield: 4.3%.

MS m/z(ESI): 534.1[M+1].

¹ H NMR (500MHz, methanol-d ₄ ): δ 7.57 (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

Dissolve compound 42b (200mg, 416μmol) and 1-acetyl-3-hydroxyazetidine 70a (191mg, 1.66mmol) in 5mL 1,4-dioxane, add 1,10-phenanthroline (191mg, 1.66mmol), cesium carbonate (541mg, 1.66mmol), cuprous iodide (316mg, 1.66mmol), replaced with nitrogen, reacted in microwave at 120°C for 6 hours, the reaction solution was concentrated under reduced pressure and then subjected to HPLC Purification gave the title compound 104 (9 mg), yield: 4.2%.

MS m/z(ESI): 516.2[M+1].

¹ H NMR (500MHz, 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-fluoroethane-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-fluoroethane-1-one 105- P2

first step

(R)-2-Methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 105b

Dissolve compound (R)-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester 105a (1.0g, 4.7mmol) in tetrahydrofuran (20mL), add bistrimethylsilyl at -78℃ Lithium amide (1M tetrahydrofuran solution, 5.6mL, 5.6mmol), stir and react for 0.5 hours, add N-phenylbis(trifluoromethanesulfonyl)imide (2.0g, 5.6mmol), continue the reaction for 2 hours and add saturated chlorine 20mL of ammonium hydroxide, extraction with ethyl acetate (50mL×3), the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 105b (1.6g), yield: 97.1 %

MS m/z(ESI): 346.1[M+1].

Second step

(R)-2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1(2H)-tert-butyl carboxylate 105c

Compound 105b (1.1g, 3.18mmol) was dissolved in 30mL 1,4-dioxane, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (350mg, 0.47mmol), potassium acetate (940mg, 9.57mmol), pinacol diborate (0.89g, 3.5mmol), and the reaction was stirred at 80°C for 14 hours. After cooling, filtering through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 105c (1.01 g), yield: 98.1%.

MS m/z(ESI): 324.2[M+1].

third step

(R)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6- Tetrahydropyridine 105d

Compound 105c (500 mg, 189 μmol) was dissolved in dichloromethane (3 mL), and 1.5 mL of 4N hydrochloric acid dioxane solution was added, and reacted at room temperature for 1 hour. After the reaction solution was concentrated, the title compound 105d (400 mg) was obtained. Yield: 99.1%.

MS m/z(ESI): 224.2[M+1].

the fourth step

(R)-2-Fluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)-5, 6-Dihydropyridine-1(2H)-yl)ethane-1-one 105e

Compound 61b (350mg, 4.5mmol) and 105d (400mg, 1.8mmol) were dissolved in N,N-dimethylformamide (3mL), and N,N-diisopropylethylamine (695mg, 5.38mmol) was added successively ) And 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (845mg, 3.58mmol), 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 obtain the title compound 105e (600 mg), yield: 49.4%.

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-dihydropyridine-1(2H)-yl)-2-fluoroethane-1- Ketone 105f

Compound 24d (100mg, 200μmol) and compound 105e (113mg, 400μmol) were dissolved in 1,4-dioxane (2mL) and water (0.4mL), and [1,1'-bis(diphenyl) Phosphinyl)ferrocene]dichloropalladium dichloromethane complex (25mg, 29.3μmol) and anhydrous sodium carbonate (64mg, 590μmol), replaced with nitrogen 3 times, heated to 100°C and reacted for 3 hours. After cooling to room temperature, filtering 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 105f (90 mg), yield: 85.0%.

MS m/z(ESI): 529.5[M+1].

Sixth step

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-fluoroethane-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-fluoroethane-1-one 105- P2

Compound 105f (100mg, 189μmol) was dissolved in isopropanol (2mL) and dichloromethane (0.2mL), and manganese tris(2,2,6,6-tetramethyl-3,5-heptenoate) was added (34mg, 56μmol), after stirring for 3 minutes, add phenylsilane (61mg, 563μmol), replace with oxygen 3 times, react at room temperature for 14 hours, after the reaction solution is filtered and concentrated, the residue is purified by HPLC to obtain the title compound 105-P1 (20mg) and 105-P2 (10mg), yields: 19.3%, 9.7%.

Single configuration compound (shorter retention time)

MS m/z(ESI): 547.2[M+1].

HPLC analysis: retention time 10.2 minutes, purity: 98.7% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -55%).

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.19 (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 compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -55%).

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.19 (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-fluoroethane-1-one 106

Using the synthetic route in Example 61, the third step raw material compound 24d was replaced with compound 11h to prepare compound 106 (10 mg), yield: 9.6%.

MS m/z(ESI): 563.2[M+1].

¹ H NMR (500MHz, 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 in Example 33, the first step starting material compound 24d was replaced with compound 11h to obtain title compounds 107-P1 (7 mg) and 107-P2 (9 mg), yield: 6.7%, 8.6%.

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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -55%).

¹ H NMR (500MHz, 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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -55%).

¹ H NMR (500MHz, 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 in Example 62, the second step raw material compound 1-methyl-piperazine was replaced by methylamine hydrochloride, and the third step raw material compound 24d was replaced by compound 11h to obtain the title compound 108-P1 (17 mg) And 108-P2 (7mg), yield: 18.2%, 7.5%.

Single configuration compound (shorter retention time)

MS m/z(ESI): 559.2[M+1].

HPLC analysis: retention time 12.5 minutes, purity: 99.2% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 15% -45%).

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.14 (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 compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 15% -45%).

¹ H NMR (500MHz, 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)ethane-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)ethane-1-one 109-P2

Using the synthetic route in Example 105, the third step raw material compound 61b was replaced with compound acetic acid to prepare compounds 109-P1 (100 mg) and 109-P2 (45 mg), yields: 24.1%, 10.8%.

Single configuration compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 15% -45%).

¹ H NMR (500MHz, 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 compound (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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 15% -45%).

¹ H NMR (500MHz, methanol-d ₄ ): δ 8.18 (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-bis Hydrofuro[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-bis Hydrofuro[2,3-h]quinazolin-6-yl)cyclohexane-1,4-diol 110-P2

first step

Methyl 4-amino-7-bromo-2,3-dihydrobenzofuran-5-carboxylate 110a

Compound 11e (1.03 g, 5.33 mmol) was dissolved in acetonitrile (35 mL), N-bromosuccinimide (948.89 mg, 5.33 mmol) was added, and the mixture was stirred for 1 hour in an ice-water bath. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title compound 110a (1.41 g), yield: 97%.

MS m/z(ESI): 271.8[M+1].

Second step

6-Bromo-8,9-dihydrofuro[2,3-h]quinazoline-2,4(1H,3H)-dione 110b

Compound 110a (0.30 g, 1.1 mmol) and urea (662.14 mg, 11.02 mmol) were mixed. Heat to 240°C for 15 minutes with an open reaction. Cool to room temperature, add 2mL of 3N sodium hydroxide solution, react at 100°C for 1 hour, cool to room temperature, adjust concentrated hydrochloric acid to pH=4, solid precipitate, filter to obtain the product 110b (0.31g), yield: 99%.

MS m/z(ESI): 282.9[M+1].

third step

6-Bromo-2,4-dichloro-8,9-dihydrofuro[2,3-h]quinazoline 110c

Compound 110b (0.31 g, 1.1 mmol) was mixed with phosphorus oxychloride (3.00 mL), and the tube was sealed at 100° C. to react for 14 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with dichloromethane, neutralized with saturated sodium bicarbonate solution in an ice bath, and extracted with dichloromethane (10mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was used on a silica gel column. Purification by chromatography with eluent system C to obtain the title compound 110c (84 mg), yield: 24%.

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) were dissolved in tetrahydrofuran (10mL), and then N,N-diisopropylethylamine (126.02mg, 0.98mmol) was added dropwise at room temperature After two days of reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 110d (153.00 mg) with a yield of 99%.

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-enyl-1-ol 110e

The compound 110d (68.00mg, 0.14mmol), compound 33a (35.46mg, 0.16mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) dichloromethane complex (23.50mg, 0.028mmol) and sodium carbonate (30.49mg, 0.29mmol) were dissolved in water (0.40mL) and dioxane (1.60mL), reacted at 100°C for 3 hours under nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure Then, it was purified by silica gel column chromatography with eluent system A to obtain the title compound 110e (45.1 mg) with a yield of 64%.

MS m/z(ESI): 489.9[M+1].

Sixth step

(1s,4S)-1-(2-chloro-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8,9-bis Hydrofuro[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-bis Hydrofuro[2,3-h]quinazolin-6-yl)cyclohexane-1,4-diol 110-P2

The compound 110e (45.10mg, 0.092mmol), tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (11.13mg, 0.018mmol) and phenylsilane (29.89mg, 0.28mmol) ) Was dissolved in dichloromethane (0.1mL) and isopropanol (1.00mL) and reacted for two days after oxygen replacement. After the reaction solution was concentrated under reduced pressure, the residue was purified by HPLC to obtain the title compound 110-P1 (6mg), 110-P2 (6mg), yield: 13%, 13%.

Single configuration compound 110-P1 (shorter retention time)

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

HPLC analysis: retention time 10.1 minutes, purity: 98.7% (column: X-Bridge, Prep 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -55%).

¹ H NMR (500MHz, 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 30*150mm; 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25% -55%).

¹ H NMR (500MHz, 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 in Example 105, the first step raw material compound 105a was replaced with compound (S)-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester, and the third step raw material compound 61b was replaced Compounds 111-P1 (25mg) and 111-P2 (12mg) were prepared for compound acetic acid, yields: 10.9%, 5.2%.

Single configuration compound (shorter retention time)

MS m/z(ESI): 529.2[M+1].

HPLC analysis: retention time 10.4 minutes, purity: 98.5% (column: SharpSil-T, 30*50mm, 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 15%- 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 compound (longer retention time)

MS m/z(ESI): 529.2[M+1].

HPLC analysis: retention time 11.1 minutes, purity: 98.7% (column: SharpSil-T, 30*50mm, 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 15%- 45%).

1H NMR (500MHz, CD ₃ OD): δ 8.18 (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

(R)-6-chloro-N ⁴ -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrimidine-4,5-diamine 112b

Dissolve compound 112a (0.4g, 2.24mmol), compound 2a (0.51g, 2.24mmol), N,N-diisopropylethylamine (1g, 7.73mmol) in 2mL N,N-dimethylacetamide , Microwave at 160°C for 2 hours. After cooling, water was added to the reaction solution, extracted with dichloromethane (10mL×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 obtain the title compound 112b (558mg ), yield: 75.1%.

MS m/z(ESI): 331.1[M+1].

Second step

Methyl 3-bromofuran-2-carboxylate 112d

The compound 3-bromofuran-2-carboxylic acid 112c (5g, 26.2mmol) was dissolved in 50mL of dichloromethane and 5mL of methanol, and (trimethylsilyl)diazomethane (20mL, 2M n-hexane) was added dropwise under an ice bath. Solution), after the dripping is completed, return to room temperature and stir for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 112d (4.91 g), yield: 91.4%.

MS m/z(ESI): 204.9[M+1].

third step

(2-(Methoxycarbonyl)furan-3-yl)boronic acid 112e

Compound 112d (788mg, 3.84mmol) was dissolved in 10mL 1,4-dioxane, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (280.6mg, 0.38mmol), potassium acetate (1.13g, 11.5mmol), pinacol diborate (2.93g, 11.5mmol), stirred and reacted at 80°C for 14 hours. After cooling, filtering through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title compound 112e (600 mg), yield: 91.8%.

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]pyridine And [3,2-d]pyrimidine-6(5H)-one 112f

Compound 112b (300mg, 907.1μmol) and compound 112e (462mg,, 2.71mmol) were dissolved in 1,4-dioxane (5mL) and water (1mL), followed by adding [1,1'-bis (two Phenylphosphino) ferrocene] dichloropalladium dichloride dichloromethane complex (74 mg, 90.7 μmol) and anhydrous potassium carbonate (450 mg, 3.25 mmol), replaced with nitrogen 3 times, heated to 110° C. and reacted for 16 hours. After cooling to room temperature, filtering 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 112f (200 mg), yield: 56.7%.

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]pyridine And [3,2-d]pyrimidin-4-amine 112g

Compound 112f (200 mg, 515 μmol) and phosphorus oxychloride (15 mL) were mixed, N,N-diisopropylethylamine (133 mg, 1.03 mmol) was added, and the reaction was carried out at 100° C. 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, and extracted with dichloromethane (10mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was used on a silica gel column. Chromatography was purified with eluent system A to obtain 112 g (172 mg) of the title compound, yield: 82.1%.

MS m/z(ESI): 407.1[M+1].

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

Compound 112g (172mg, 422.8μmol), compound 33a (190mg, 847.8μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (35mg, 42.8μmol) and anhydrous sodium carbonate (100mg, 943.5μmol) were dissolved in 6mL 1,4-dioxane and 2mL water, replaced with nitrogen 3 times, and heated to 110℃ to react for 16 hours. After cooling to room temperature, filtering with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 112h (190 mg), yield: 95.9%.

MS m/z(ESI): 469.2[M+1].

Seventh step

(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 (215 mg, 458.9 μmol) was dissolved in isopropanol (5 mL) and dichloromethane (0.5 mL), tris(divalerylmethane) manganese (56 mg, 92.6 μmol) was added, and after stirring for 5 minutes, benzene was added Silane (124mg, 1.14mmol), replaced with oxygen 3 times, stirred and reacted for 16 hours. After the reaction solution was filtered and concentrated under reduced pressure, it was purified by silica gel column chromatography with eluent system A to obtain the title compound 112i (114mg). Yield: 51%.

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-bis Hydrofuro[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

Compound 112i (114 mg, 234.3 μmol) was dissolved in ethanol (10 mL), 10% palladium-carbon catalyst (100 mg) was added, hydrogen replacement was performed three times, and the reaction was stirred for 16 hours. Filtered with celite, and concentrated the filtrate under reduced pressure to obtain the crude title compound 112. The crude product was subjected to high performance liquid chromatography (Waters-2545, column: SharpSil-T, 30*50mm, 5μm; mobile phase A: water (containing 10mmol) /L of ammonium bicarbonate); mobile phase B: acetonitrile; 20 minutes gradient: 25%-55%, flow rate: 30mL/min) preparation and purification to obtain the title compounds 112-P1 (10.6mg) and 112-P2 (9.5mg ), yield: 9.2%, 8.2%.

Single configuration compound 112-P1 (shorter retention time)

MS m/z(ESI): 489.0[M+1].

HPLC analysis: retention time 11.6 minutes, purity: 98.5% (column: SharpSil-T, 30*50mm, 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25%- 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, 30*50mm, 5μm; mobile phase: A-water (10mM ammonium bicarbonate) B-acetonitrile, gradient ratio: A 25%- 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 case:

Biological evaluation

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

The following method is used to determine the compound's ability to inhibit the interaction between the G12D or G12V subtypes of KRAS protein and the SOS1 protein. The experimental method is briefly described as follows:

1. Experimental materials and instruments

1) Biotin labeling kit (Dojindo, LK03)

2) GDP (SIGMA, G7127)

3) AlphaLISA Glutathione Acceptor Beads (PerkinElmer, AL109C)

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

5) 384-well microplate (PerkinElmer, 6007290)

6) BSA (Shanghai Shenggong, A600332-0100)

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

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

9) Kras G12D, KrasG12V (produced by Shanghai Panchao Biotechnology Co., Ltd.)

10) Phosphate buffered saline (PBS) PH7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320)

11) Multifunctional microplate reader (PerkinElmer, Envision)

2. Experimental steps

Experiment preparation:

1) Before the experiment starts, prepare the experiment buffer: 1x PBS+0.1%BSA+0.05% Tween 20.

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

Experimental steps:

1) First, the biotin-labeled KRAS G12V or KRAS G12D protein is mixed with SOS1 protein and GDP and incubated at room temperature for use.

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

3) The compound is formulated with experimental buffer to an initial concentration of 40 μM, a 5-fold gradient dilution, and 10 gradient series concentration points.

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

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

6) Read the fluorescence value on the multifunctional microplate reader.

7) to give compound IC ₅₀ value calculated using Graphpad Prism.

3. Experimental data

The compounds of the present disclosure inhibit the interaction between the G12D or G12V subtypes of KRAS protein and the SOS1 protein. The measured IC ₅₀ values are shown in Table 1.

_{Table 1 The IC 50} value of the compound of the present disclosure inhibiting the interaction between the G12D or G12V subtypes of KRAS protein and the SOS1 protein

Conclusion: The compound of the present disclosure can well inhibit the interaction between the G12D or G12V subtypes of KRAS protein and the SOS1 protein.

Test Example 2. Biological evaluation of ERK phosphorylation inhibition experiment on H358 cells

1. Test purpose

In this experiment a test compound on the inhibition of ERK phosphorylation, inhibition of target KRAS (including G12C mutation) evaluated in accordance with the size of the IC ₅₀ of the disclosed compounds.

2. Experimental method

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

Three, data analysis

_{Graphpad Prism software was used to calculate the IC 50} value of the compound's inhibitory activity based on the compound concentration and the ratio of pERK/total ERK. The results are shown in Table 2 below.

Table 2 ERK phosphorylation inhibitory activity data of H358 cells

Conclusion: The compound of the present disclosure has a good inhibitory effect on ERK phosphorylation of H358 cells.

Test Example 3: Biological Evaluation of H358 Cell Proliferation Inhibition Experiment

1. Test purpose

By testing the inhibitory effect of the compounds of the present disclosure on the proliferation of H358 cells, the inhibitory effects of the compounds of the present disclosure on the KRAS target (containing the G12C mutation) are evaluated.

2. Experimental method

3D试剂(Promega，G9682)，室温震荡25分钟后，吹吸混匀并取出50μL转移至白色不透底的96孔板(PE，6005290)中，使用多功能微孔板酶标仪(PerkinElmer，VICTOR 3)读取发光信号值。 H358 cells (ATCC, CRL-5807) were cultured with complete medium, namely RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal calf serum (Corning, 35-076-CV). On the first day of the experiment, H358 cells were seeded on 96 low-adsorption plates (Corning, CLS7007-24EA) at a density of 1500 cells/well using complete medium, 90 μL of cell suspension per well, centrifuged at 2000 rpm for 5 minutes at room temperature, and placed at 37°C , 5% CO ₂ cell culture incubator overnight. On the second day, add 10 μL of the test compound prepared in complete medium to each well. The final concentration of the compound is 9 concentration points starting from 10 μM in 5-fold dilutions. A blank control containing 0.1% DMSO is set. The plate is placed in a 37°C, 5% CO ₂ cell incubator for 120 hours. On the seventh day, take out the 96-well cell culture plate and add 50μL to each well

3D reagent (Promega, G9682), after shaking at room temperature for 25 minutes, pipetting and mixing, take out 50μL and transfer to a white impermeable 96-well plate (PE, 6005290), use a multi-functional microplate microplate reader (PerkinElmer, VICTOR 3) Read the luminous signal value.

Three, data analysis

Calculated using Graphpad Prism software compound to inhibit the activity of IC ₅₀ values, see Table 3 results.

Table 3 H358 cell proliferation inhibitory activity data

Conclusion: The compound of the present disclosure has a good inhibitory effect on the proliferation of H358 cells.

Test Example 4. Pharmacokinetic evaluation of the compound of the present disclosure in nude mice

1. Summary

Taking nude mice as the test animals, the LC/MS/MS method was used to determine the drug concentration in the plasma of nude mice at different times after intragastric (ig) administration of compound 33-P1. The pharmacokinetic behavior of the compound of the present disclosure in nude mice was studied, and its pharmacokinetic characteristics were evaluated.

2. Test plan

2.1 Experimental drugs

Compound 33-P1

2.2 Experimental animals

18 BALB/C nude mice, females, were equally divided into 2 groups, 9 in each group, purchased from Zhejiang Weitong Lihua Experimental Animal Co., Ltd., animal production license number: SCXK (Zhejiang) 2019-0001.

2.3 Drug preparation

A certain amount of compound 33-P1 is weighed, and 0.5% CMCNa is added to prepare a uniform suspension (crushing, stirring for administration).

2.4 Administration

Nude mice were administered intragastrically, the dosages were 75 mg/kg and 150 mg/kg, and the dosages were both 0.2 mL/10 g.

3. Operation

Nude mice were intragastrically administered compound 33-P1, and 0.1 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after the administration, and placed in an EDTA-K2 anticoagulation test tube. Centrifuge at 10,000 rpm for 1 minute (4°C), separate plasma within 1 hour, and store at -20°C for testing. The process from blood collection to centrifugation was operated under ice bath conditions.

Determine the content of the test compound in the plasma of nude mice after administration of different concentrations of drugs: Take 20μL of nude mouse plasma at each time after administration, add 50μL of internal standard solution (camptothecin 100ng/ml), 200μL of acetonitrile, and vortex to mix Centrifuge for 5 minutes for 10 minutes (3700 rpm), and take 0.5 μL of the supernatant for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

Table 4 Pharmacokinetic parameters of the compounds of the present disclosure in nude mice

Conclusion: The compound of the present disclosure has good pharmacokinetic absorption activity in nude mice, and has pharmacokinetic advantages.

Test Example 5. Pharmacokinetic evaluation of the compound of the present disclosure in rats

1. Summary

Using rats as the test animals, the LC/MS/MS method was used to determine the drug concentration in plasma at different times after the rats were given compound 33-P1 by intragastric administration (ig). To study the pharmacokinetic behavior of the compound of the present disclosure in rats and evaluate its pharmacokinetic characteristics.

2. Test plan

2.1 Experimental drugs

Compound 33-P1

2.2 Experimental animals

8 SD rats, half male and half male, purchased from Zhejiang Weitong Lihua Experimental Animal Co., Ltd., animal production license number: SCXK (Zhe) 2019-0001, randomly divided into two groups; fasted overnight and then given by intragastric administration .

2.3 Drug preparation

Weigh a certain amount of compound 33-P1, add 1% HPMC K100LV + 10% TPGS to prepare a uniform suspension (crushing, stirring for administration).

2.4 Administration

Rats were administered intragastrically, the dosages were 100.0mg/kg, 200mg/kg, and the dosages were both 10mL/kg.

3. Operation

Rats were given compound 33-P1 by intragastric administration, and 0.1 mL of blood was collected from the orbit at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after the administration, and an EDTA-K2 anticoagulation test tube was placed Centrifuge at 10,000 rpm for 1 minute (4°C), separate plasma within 1 hour, and store at -20°C for testing. The process from blood collection to centrifugation was operated under ice bath conditions. Eat 2h after administration.

To determine the content of test compounds in rat plasma after administration of different concentrations of drugs: Take 25 μL of rat plasma at each time after administration, add 50 μL of camptothecin (100ng/ml), 200 μL of acetonitrile, vortex and mix for 5 minutes, Centrifuge for 10 minutes (4000 rpm), and take 0.5 μL of the supernatant for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

Table 5 Pharmacokinetic parameters of the compounds of the present disclosure in rats

Conclusion: The compound of the present disclosure has good pharmacokinetic absorption activity in rats and has pharmacokinetic advantages.

Test Example 6. Pharmacokinetic evaluation of the compound of the present disclosure in dogs

1. Summary

With dogs as the test animals, the LC/MS/MS method was used to determine the drug concentration in the plasma of the dogs at different times after intragastric (ig) administration of compound 33-P1. To study the pharmacokinetic behavior of the compound of the present disclosure in dogs and evaluate its pharmacokinetic characteristics.

2. Test plan

2.1 Experimental drugs

Compound 33-P1

2.2 Experimental animals

Four beagles, half male and half, fasted overnight. Provided by Medicipuya Pharmaceutical Technology (Shanghai) Co., Ltd. Animal Reserve (999M-004). All animals are Beagle dogs that have passed the physical examination and have no abnormal health.

2.3 Drug preparation

Weigh a certain amount of compound 33-P1, add 5% by volume of DMSO, 20% by volume of PG, and 20% by volume of PEG400 to dissolve it, and then add 55% normal saline to prepare a clear solution.

2.4 Administration

The administration dose is 2.0 mg/kg, and the administration volume is 5.0 mL/kg.

3. Operation

Compound 33-P1 was administered to dogs by intragastric administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours before and after administration, 1.0 ml of blood was collected from jugular vein or forelimb vein, and EDTA- In a K2 anticoagulation tube, centrifuge at 10000 rpm for 5 minutes (4°C), separate the plasma within 1 hour, and store it at -80°C for testing. The process from blood collection to centrifugation was operated under ice bath conditions. Eat 3h after administration.

Determine the content of the test compound in the dog plasma after the administration of different concentrations of the drug: Take 10μL of the dog plasma at each time after the administration, add 400μL of acetonitrile (containing the internal standard solution camptothecin (100ng/ml)), vortex to mix 1 After centrifugation for 7 minutes (18000 rpm), 1 μL of the supernatant was taken for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

Table 6 Pharmacokinetic parameters of the compounds of the present disclosure in dogs

Conclusion: The compound of the present disclosure has good pharmacokinetic absorption activity in dogs, and has pharmacokinetic advantages.

Test Example 7. The inhibitory effect of the compound of the present disclosure on the CYP450 enzyme of human liver microsomes

The inhibitory effect of the compounds of the present disclosure on the CYP450 enzyme of human liver microsomes was determined by the following experimental method:

1. Experimental materials and instruments

1. Phosphate buffer (20×PBS, purchased from Zishenggong),

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 and mass dual-purpose instrument (AB Sciex),

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

6. CYP probe substrate.

2. Experimental steps

1. Solution preparation

1) Preparation of 100mM phosphate buffer (PBS)

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

2) Preparation of NADPH solution

Accurately weigh an appropriate amount of NADPH powder, add PBS buffer solution to dissolve it, and prepare a solution with a concentration of 5 mM, ready for use (prepared for current use).

3) Preparation of liver microsome solution

Take an appropriate amount of the human liver microsome storage solution (concentration 20mg/mL), dilute it to 0.25mg/mL microsome solution _{with a concentration of 7.5mM MgCl 2 solution, and use it now.}

4) Preparation of _{MgCl 2 solution}

Weigh an _{appropriate amount of MgCl 2} powder, prepare it into a 300mM stock solution with PBS solution, and store it in a refrigerator at 4°C for later use. Precise the amount of this solution, add 100mM PBS solution and dilute it into a 7.5mM working solution, then (prepared for current use).

5) Preparation of test compound solution

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

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

6) Selection of CYP probe substrate and selective inhibitor

a. Preparation of probe substrate stock solution: Weigh an appropriate amount of each probe substrate and add DMSO to prepare a stock solution, the concentration of which is shown in Table 7 below.

b. Preparation of the probe substrate working solution: accurately pipette an appropriate amount of the probe substrate stock solution, add PBS solution and dilute it 200 times to obtain the probe substrate working solution, the concentration of which is shown in Table 7 below.

Table 7

CYP Probe substrate Concentration of stock solution (mM) Working solution concentration (μM) 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. Operation process

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

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

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

_{The values were calculated by Graphpad Prism to obtain the IC 50} values of the drug for the inhibition of human liver microsomal CYP3A4T testosterone 6β-hydroxylation and CYP3A4M midazolam 1-hydroxylation respectively, shown in Table 9.

_{Table 9 The IC 50} values of the compounds of the present disclosure on the CYP3A4T testosterone metabolism site and the human liver microsome CYP3A4M midazolam metabolism site

Example number IC ₅₀ (μM)-CYP3A4T IC ₅₀ (μM)-CYP3A4M 33-P1 >30 >30

Conclusion: Within the concentration range of 30 μM, there will be no metabolic drug interactions based on CYP3A4T testosterone 6β-hydroxylation and CYP3A4M midazolam 1-hydroxylation metabolic sites.

Claims (28)

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

in: Ring A is aryl or heteroaryl; Ring B is a 5-6 membered heterocyclic group or heteroaryl group; R ^{0 is} selected from alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, cycloalkylcarbonyl, heterocyclylcarbonyl, -NHC(O)R ¹⁰ , heteroaryl, cycloalkyl and Heterocyclyl, wherein the 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 are substituted by one or more substituents; Wherein, R ⁹ and R ^{11 are the} same or different, and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, -(CH ₂ ) _q NR ⁶ R ⁷ , cycloalkyl and heterocyclyl; The alkyl group, cycloalkyl group and heterocyclic group are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, and carboxy; R ^{10 is} selected from hydrogen, alkyl, hydroxyalkyl, hydroxy, -(CH ₂ ) _q NR ⁶ R ⁷ , cycloalkyl and heterocyclic group; said alkyl, cycloalkyl and heterocyclic group are each independently Optionally substituted by one or more substituents selected from alkyl, alkoxy, cyano, and carboxy; R ^{1 is} selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl; R ^{2 is} selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are each independently optionally It is substituted by one or more substituents selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro and cyano; R ^{3 is} selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxy Substituted by one or more substituents of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ^{4 is} selected from 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 hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , Cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -NR ⁶ R ⁷ , cyano and nitro, wherein the alkyl, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro and -NR ⁶ R ⁷ Substituted by one or more substituents; R ^{8 is the} same or different, and are each independently selected from 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 the alkyl, haloalkyl, hydroxyalkyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from hydroxyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, -(CH ₂ ) _q NR ⁶ R ⁷ , cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents; R ⁶ and R ^{7 are the} same or different, and are each independently selected from 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. The compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein: R ^{0 is} selected from alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, cycloalkyl and heterocyclyl, wherein the cycloalkyl Oxy, heterocyclyloxy, cycloalkyl and heterocyclyl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, nitro Substituted by one or more substituents in the group, cyano group, -S(O) ₂ R ⁹ and -C(O)R ^9; Wherein, R ^{9 is} selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, -(CH ₂ ) _q NR ⁶ R ⁷ , cycloalkyl and heterocyclic group; R ^{8 are the} same or different, and are each independently selected from 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 the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl are each independently optionally selected from hydroxyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, -(CH ₂ ) _q NR ⁶ R ⁷ , one or more substituents in cycloalkyl, heterocyclic, aryl and heteroaryl; Wherein R ⁶ , R ⁷ and q are as defined in claim 1. The compound represented by the general formula (I) according to claim 1 or 2 or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, the ring B is a five-membered or six-membered heterocyclic group. The compound represented by the general formula (I) according to any one of claims 1 to 3 or its tautomer, meso, racemate, enantiomer, diastereomer Structure, or its mixture form, or its pharmaceutically acceptable salt, which is a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in: G ¹ , G ² and G ^{3 are the} same or different, and are each independently selected from a carbon atom, an oxygen atom, a nitrogen atom, and a sulfur atom, provided that G ¹ , G ² and G ^{3 are} not carbon atoms at the same time; r is 0 or 1; preferably, r is 0; Dotted lines indicate double bonds or single bonds; Ring A, R ⁰ -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 4 or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: G ¹ and G ² are carbon atoms, and G ³ is an oxygen atom; or G ² and G ³ are carbon atoms, and G ¹ is an oxygen atom; or G ¹ and G ³ are each independently an oxygen atom or a nitrogen atom, and G ² is a carbon atom. The compound represented by the general formula (I) according to any one of claims 1 to 5 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III), the general formula (IV), the general formula (V), the general formula (VI) or the general formula (VII) Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in: 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 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the general formula (III-1), the general formula (IV-1), the general formula (V-1), the general formula (VI-1) or the general formula (VI-1) The compound represented by the formula (VII-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form thereof, or pharmacologically Use salt:

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 7 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is a C _6-10 aryl group or a 5-10 membered heteroaryl group. The compound represented by the general formula (I) according to any one of claims 1 to 8 or its tautomer, meso, racemate, enantiomer, diastereomer Structure, or a 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 furyl. The compound represented by the general formula (I) according to any one of claims 1 to 9 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{0 is} selected from the group consisting of C _1-6 alkoxy, 5-membered heterocyclyloxy and 6-membered heterocyclyl, the 5-membered heterocyclyl The oxy group and the 6-membered heterocyclic group are each independently optionally substituted with one or more substituents ^{selected from -C(O)R 9 and hydroxy, wherein R 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, and q is 1 or 2. The compound represented by the general formula (I) according to any one of claims 1 to 9 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{0 is} selected from the group consisting of tetrahydrofuranyloxy, C _1-6 alkoxy, hydropyridyl, azetidinyloxy and hydropyranyl , The hydropyridyl, azetidinyloxy and hydropyranyl groups are each independently optionally substituted by one or more substituents ^{selected from -C(O)R 9 and hydroxyl, wherein R 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, and q is 1 or 2; Preferably, R ^{0 is} selected from tetrahydrofuranyloxy, C _1-6 alkoxy, hydrogenated pyridyl and hydrogenated pyranyl, and said hydrogenated pyridyl and hydrogenated pyranyl are each independently optionally selected from -C (O) R ⁹ is substituted with one or more substituents of hydroxy, wherein R 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 each Independently selected from hydrogen, alkyl and haloalkyl, q is 1 or 2. The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{8 is the} same or different, and each is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, -(CH ₂ ) _q NR ⁶ R ⁷ , C _1-6 hydroxyalkyl and C _6-10 aryl, wherein the C _1-6 haloalkyl is optionally substituted by one or more hydroxy groups, and the C _6-10 aryl The group is optionally substituted with one or more -(CH ₂ ) _q NR ⁶ R ⁷ ; R ⁶ and R ^{7 are} selected from hydrogen or C _1-6 alkyl, and q is 0, 1, or 2. The compound represented by the general formula (I) according to any one of claims 1 to 12 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from hydrogen, C _1-6 alkyl and halogen. The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from hydrogen and C _1-6 alkyl. The compound represented by the general formula (I) according to any one of claims 1 to 14 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{3 is} selected from hydrogen and C _1-6 alkyl. The compound represented by the general formula (I) according to any one of claims 1 to 15 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen. The compound represented by the general formula (I) according to any one of claims 1 to 16, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁵ is hydrogen or methyl, preferably hydrogen. The compound, its structural formula is as follows:

A compound represented by the general formula (IA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Its medicinal salt:

in: R ^{1 is} selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl; Ring B, R ⁰ , R ⁴ , R ⁵ and p are as defined in claim 1 or 2. A compound represented by general formula (IA-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Its medicinal salt:

in: 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 represented by the general formula (IA-3) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Its medicinal salt:

in: X is halogen; Ring A, ring B, R ¹ -R ⁵ , R ⁸ , p, and n are as defined in claim 1 or 2. The compound, its structural formula is as follows:

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

The compound of general formula (IA-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its salt and general The compound of formula (IB) or its salt is reacted to obtain a compound of formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, Wherein ring A, ring B, R ⁰ -R ⁵ , R ⁸ , p and n are as defined in claim 1 or 2. A kind of compound represented by general formula (I-1) or its tautomer, meso, racemate, enantiomer, diastereomer or its mixture form, Or a method of a pharmaceutically acceptable salt thereof, the method comprises the following steps:

In the form of a compound of general formula (IA-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof The raw material is reduced to obtain the compound of the general formula (I-1) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its pharmaceutically acceptable salt, 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 kind of compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or The method of pharmaceutically acceptable salt, the method includes the following steps:

In the form of a compound of the general formula (IA-3) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a medicine thereof The compound of general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers are prepared by Ullmann reaction, Suzuki reaction or Grignard reaction using salt as raw materials Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, 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 containing the compound represented by the general formula (I) according to any one of claims 1 to 18 or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The compound represented by the general formula (I) according to any one of claims 1 to 18 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26 in the preparation of a medicament for inhibiting SOS1. The compound represented by the general formula (I) according to any one of claims 1 to 18 or its tautomer, meso, racemate, enantiomer, diastereomer The construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26 is prepared for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS), and Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), heart-face-skin syndrome (CFC), Legus 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 cancer, Gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, cholangiocarcinoma, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer , 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, neuroblastoma Tumor, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer , Further preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably multiple Myeloma; the bone tumor is preferably osteochondroma; the colorectal cancer is preferably colon cancer or rectal cancer; the sarcoma is preferably osteosarcoma.