CN115490699A

CN115490699A - Fused ring compound and pharmaceutical composition and application thereof

Info

Publication number: CN115490699A
Application number: CN202210447082.9A
Authority: CN
Inventors: 宋智泉; 易守兵; 张国彪; 房志鹏; 原晨光; 李英富
Original assignee: Shenzhen Haibowei Pharmaceutical Co ltd; Chengdu Haibowei Pharmaceutical Co ltd
Current assignee: Shenzhen Haibowei Pharmaceutical Co ltd; Chengdu Haibowei Pharmaceutical Co ltd
Priority date: 2021-06-19
Filing date: 2022-04-26
Publication date: 2022-12-20
Anticipated expiration: 2042-04-26
Also published as: CN115490699B

Abstract

The invention provides a fused ring compound, a pharmaceutical composition and application thereof, and relates to the technical field of medicines. The fused ring compound is a compound shown in formula I, or a tautomer, or a racemate, or an enantiomer, a diastereoisomer, a mixture form, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable hydrate thereofAn acceptable solvate, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof. The compound has obvious inhibition effect on SOS1 activity, can be used as an SOS1 KRAS inhibitor, has good metabolic stability and has wide application prospect in resisting malignant tumor diseases.

Description

Fused ring compound and pharmaceutical composition and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a fused ring compound, a pharmaceutical composition and application thereof.

Background

RAS proteins are products expressed by RAS genes, and refer to a closely related class of monomeric globulins consisting of 189 amino acids, with a molecular weight of 21KDa. KRAS (Kirsten rat sarcoma virus oncogene homolog) is most common in the RAS family. The KRAS protein is a small gtpase encoded by KRAS gene, and is an important regulatory protein for cell survival and growth, and once KRAS is activated, it can activate multiple signaling pathways to promote cell survival, proliferation and cytokine release. KRAS is activated by binding to GTP, then GTP is cleaved into GDP by KRAS protein, and KRAS is closed by binding to GDP. The conversion of KRAS between inactive and active states is regulated by two factors. One is a guanine nucleotide exchange factor (GEF, such as SOS 1), which catalyzes the binding of KRAS to GTP, promoting the activation of KRAS. The other is GTPase Activating Protein (GAP), which can hydrolyze KRAS-bound GTP into GDP, thereby inhibiting KRAS activity.

There are two SOS homologues hSOS1 and hSOS2 in humans, and although SOS1 and SOS2 are highly similar in structure and sequence, there is some difference in their respective biological functions. Studies have shown that SOS1 is expressed in Drosophila, mouse and humans, hSOS1 has 30% homology with the amino acid sequence of Drosophila SOS, hSOS1 has 65% homology with murine SOS1, and hSOS1 has 70% homology with hSOS 2. SOS1 is a guanine nucleotide exchange factor for Ras and Rac and plays an important role in Ras and Rac signaling pathways by regulating GDP/GTP exchange.

KRAS is one of the most common oncogenes in solid tumors, with KRAS mutations occurring in approximately 30% of tumors, including 90% of pancreatic cancers, 50% of colon cancers, and 25% of lung cancers. The most common sites for gene mutation are codons 12, 13 and 61, with mutations at codon 12 being most common, such as G12C. The KRAS mutation status is not affected by the upstream EGFR gene, only the wild-type KRAS gene is affected by the upstream EGFR gene, and thus patients with mutant KRAS genes are ineffective for treatment with EGFR-targeted drugs.

Several drugs have entered clinical research stages against KRAS G12C mutations, such as AMG510, MRTX-849 and ARS-3248. However, there are still no suitable treatments for tumor diseases caused by mutations in other KRAS genes, including KRAS-G12D and KRAS-G12V, which account for half of all KRAS-driven cancers. Selective inhibition of SOS1 provides one possible treatment: the SOS1 inhibitor inhibits the activation of KRAS by binding to SOS1, and KRAS blocking can be realized regardless of the type of KRAS mutation. Preclinical data suggest that pan KRAS inhibitors may inhibit the growth of multiple G12 and G13 KRAS gene mutant tumors (AACR; mol Cancer Ther 2019 (12 Suppl): abstract PL 06-01). Some SOS1 inhibitors have been reported so far (see, for example, WO 2018115380), but there is still a great need in the art for new SOS1 inhibitors, in particular SOS1 inhibitors with high activity and other excellent properties.

Disclosure of Invention

The invention aims to provide a fused ring compound serving as an SOS1 inhibitor, a composition and application thereof, which can effectively inhibit the interaction of SOS1 and KRAS.

In order to solve the technical problems, the invention provides:

a compound shown in formula I, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystal form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof:

wherein,

ring A is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-14 membered aryl, 5-14 membered heteroaryl;

m1 is 0, 1,2,3,4 or 5;

R ¹ is a substituent of the ring A, each R ¹ When present is independently selected from substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, halogen, amino, hydroxyl, carboxyl, cyano, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, substituted OR unsubstituted 5-to 14-membered aryl, substituted OR unsubstituted 5-to 14-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or any two R ¹ Are connected to form a substituted or unsubstituted 3-to 12-membered cycloalkyl group, a substituted or unsubstituted 3-to 12-membered cycloalkyl groupA membered aryl group, a substituted or unsubstituted 3-to 12-membered heterocyclic group, a substituted or unsubstituted 3-to 12-membered heteroaryl group; or two R on the same atom ¹ Composition = O;

R ² selected from hydrogen, halogen, substituted or unsubstituted C ₁ ～C ₁₀ An alkyl group;

R ¹⁰ selected from hydrogen, halogen, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, hydroxy, amino, carboxy, cyano, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² ；

The ring B is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, 5-14 membered aryl, 5-14 membered heteroaryl;

m2 is 0, 1,2,3,4 or 5;

R ³ is a substituent of the ring B, each R ³ Independently at the occurrence is selected from substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, halogen, amino, hydroxyl, carboxyl, cyano, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, substituted OR unsubstituted 5-to 14-membered aryl, substituted OR unsubstituted 5-to 14-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or any two R ³ Are connected to form a substituted or unsubstituted 3-to 12-membered cycloalkyl group, a substituted or unsubstituted 3-to 12-membered aryl group, a substituted or unsubstituted 3-to 12-membered heterocyclic group, a substituted or unsubstituted 3-to 12-membered heteroaryl group; or two R on the same atom ³ Composition = O;

the substituents are respectively and independently selected from halogen and C ₁ ～C ₁₀ Alkyl radical, C ₂ ～C ₁₀ Alkenyl radical, C ₁ ～C ₁₀ Haloalkyl, C ₁ ～C ₁₀ Alkoxy radical, C ₁ ～C ₁₀ Alkylthio, 2-to 10-membered oxaalkyl, amino, carboxyl, hydroxyl, nitro, 3-to 12-membered cycloalkyl, 3-to 12-membered heterocyclyl, 5-to 14-membered aryl, 5-to 14-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or two substituents on the same atom make up = O;

R ¹² are respectively and independently selected from hydrogen and C ₁ ～C ₁₀ Alkyl, amino, 2-to 10-membered heteroalkyl, 3-to 12-membered cycloalkyl, 3-to 12-membered heterocyclyl, 5-to 14-membered aryl, 5-to 14-membered heteroaryl.

Further, the compound is shown as a formula II-1 or a formula II-2:

wherein,

the ring A is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, 5-14 membered aryl, 5-14 membered heteroaryl;

m1 is 0, 1,2,3,4 or 5;

R ¹ is a substituent of the ring A, each R ¹ When present is independently selected from substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, halogen, amino, hydroxyl, carboxyl, cyano, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, substituted OR unsubstituted 5-to 14-membered aryl, substituted OR unsubstituted 5-to 14-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or any two of R ¹ Are linked to form a substituted or unsubstituted 3-12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered aryl, substituted or unsubstituted 3-to 12-membered heterocyclyl, substituted or unsubstituted 3-to 12-membered heteroaryl; or two R on the same atom ¹ Composition = O;

R ¹⁰ selected from hydrogen, halogen, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, hydroxy, amino, carboxyl, cyano, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² ；

U ¹ 、U ² 、U ³ Are independently selected from-O-, -S-, -NR ⁴ -、-CR ^5a R ^5b -；

V ¹ 、V ² Are respectively and independently selected from-O-, -S (O) (O) -, -NR ⁴ -、-CR ^5a R ^5b -；

R ⁴ Selected from hydrogen, halogen, cyano, hydroxy, carboxy, cyano, amino, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, substituted OR unsubstituted 5-to 10-membered aryl, substituted OR unsubstituted 5-to 12-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² ；

R ^5a 、R ^5b Each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, amino, cyano, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstitutedSubstituted C ₂ ～C ₁₀ Alkenyl, substituted OR unsubstituted 6-to 10-membered aryl, substituted OR unsubstituted 5-to 12-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or R ^5a 、R ^5b Common composition = O; or R ^5a 、R ^5b Are connected to form a substituted or unsubstituted 3-to 12-membered cycloalkyl group, a substituted or unsubstituted 3-to 12-membered aryl group, a substituted or unsubstituted 3-to 12-membered heterocyclic group, a substituted or unsubstituted 3-to 12-membered heteroaryl group;

R ⁶ 、R ⁷ each occurrence is independently selected from halogen, cyano, hydroxy, carboxy, -C (O) R ₁₂ Amino, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstituted C ₂ ～C ₁₀ An alkenyl group; or two R on the same carbon atom ⁶ Linked to form a substituted or unsubstituted 3-to 6-membered cycloalkyl group or composition = O; or two R on the same carbon atom ⁷ Linked to form a substituted or unsubstituted 3-to 6-membered cycloalkyl group or composition = O;

R ¹² are respectively independentSelected from hydrogen, C ₁ ～C ₁₀ Alkyl, amino, 2-to 10-membered heteroalkyl, 3-to 12-membered cycloalkyl, 3-to 12-membered heterocyclyl, 5-to 14-membered aryl, 5-to 14-membered heteroaryl;

n ₁ 、n ₂ each independently selected from 0, 1,2,3,4, 5;

d1, d2, d3 and d4 are respectively and independently selected from 0, 1,2 and 3.

Further, the air conditioner is provided with a fan,

ring A is selected from phenyl;

m1 is 0, 1,2 or 3;

R ¹ is a substituent of the ring A, each R ¹ Independently at the occurrence is selected from substituted or unsubstituted C ₁ ～C ₂ Alkyl, halogen, amino; or any two of R ¹ Are connected to form a substituted or unsubstituted 5-to 6-membered cycloalkyl group, a substituted or unsubstituted 5-to 6-membered heterocyclic group; the substituent groups are respectively and independently selected from hydroxyl, halogen or two substituent groups on the same atom to form = O;

R ² selected from hydrogen, halogen, C ₁ ～C ₄ An alkyl group;

R ¹⁰ selected from hydrogen, halogen, C ₁ ～C ₄ Alkyl, hydroxy, amino, carboxyl, cyano, C ₁ ～C ₄ Alkoxy, dimethylamino, acetyl;

R ¹² are respectively and independently selected from hydrogen and C ₁ ～C ₆ Alkyl, amino, 3-to 6-membered cycloalkyl, pyridyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl.

Further, the air conditioner is provided with a fan,

U ¹ 、U ² 、U ³ is selected from-O-;

V ¹ 、V ² are each independently selected from-O-, -NR ⁴ -、-CR ^5a R ^5b -；

R ⁴ Selected from hydrogen, halogen, cyano, hydroxy, carboxy, amino, substituted or unsubstituted C ₁ ～C ₆ Alkyl, 3-to 6-membered cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, substituted or unsubstituted piperidinyl, C ₂ ～C ₆ Alkenyl, -C (O) R ¹² 、-S(O)(O)R ¹² ；

R ^5a 、R ^5b Each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, amino, substituted or unsubstituted C ₁ ～C ₆ Alkyl, 3-to 6-membered cycloalkyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, substituted or unsubstituted piperidinyl, C ₂ ～C ₆ Alkenyl, -C (O) R ¹² 、-S(O)(O)R ¹² (ii) a Or R ^5a 、R ^5b Common composition = O; or R ^5a 、R ^5b Are connected to form 3-6 membered cycloalkyl;

R ⁶ 、R ⁷ each occurrence is independently selected from halogen, cyano, hydroxy, carboxy, -C (O) R ₁₂ Amino, substituted or unsubstituted C ₁ ～C ₆ Alkyl, 3-to 6-membered cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, substituted or unsubstituted piperidinyl, C ₂ ～C ₆ Alkenyl, -S (O) (O) R ¹² (ii) a Or two R on the same carbon atom ⁶ Are linked to form a 3-to 6-membered cycloalkyl group or composition = O; or two R on the same carbon atom ⁷ Are linked to form a 3-to 6-membered cycloalkyl group or composition = O;

R ⁴ 、R ^5a 、R ^5b 、R ⁶ 、R ⁷ wherein the substituents are respectively and independently selected from halogen and C ₁ ～C ₆ Alkyl radical, C ₂ ～C ₆ Alkenyl radical, C ₁ ～C ₆ Haloalkyl, C ₁ ～C ₆ Alkoxy radical, C ₁ ～C ₆ Alkylthio, amino, carboxyl, hydroxyl, nitro, 3-to 6-membered cycloalkyl, oxetanyl, -S (O) (O) R ¹² ；

R ¹² Are respectively and independently selected from hydrogen and C ₁ ～C ₆ Alkyl, amino, 3-to 6-membered cycloalkyl, pyridyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl;

n ₁ 、n ₂ each independently selected from 0, 1,2,3,4, 5;

Further, the compound is shown in formula IV-1, formula IV-2, formula IV-3 and formula IV-4:

wherein,

R ^1a 、R ^1b 、R ^1c independently selected from hydrogen, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, halogen, amino, hydroxyl, carboxyl, cyano, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, substituted OR unsubstituted 5-to 14-membered aryl, substituted OR unsubstituted 5-to 14-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or R ^1a 、R ^1b 、R ^1c Any two of which are connected to form a substituted or unsubstituted 3-to 12-membered cycloalkyl group, a substituted or unsubstituted 3-to 12-membered aryl group, a substituted or unsubstituted 3-to 12-membered heterocyclic group, a substituted or unsubstituted 3-to 12-membered heteroaryl group;

R ^6a 、R ^6b 、R ^6c 、R ^6d 、R ^7a 、R ^7b Are independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) R ₁₂ Amino, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstituted C ₂ ～C ₁₀ An alkenyl group; or R on the same carbon atom ^6a And R ^6b Linked to form a substituted or unsubstituted 3-to 6-membered cycloalkyl group or composition = O; or R on the same carbon atom ^6c And R ^6d Linked to form a substituted or unsubstituted 3-to 6-membered cycloalkyl group or composition = O; or R on the same carbon atom ^7a And R ^7b Linked to form a substituted or unsubstituted 3-to 6-membered cycloalkyl or composition = O;

Further, the air conditioner is provided with a fan,

R ^1a 、R ^1b 、R ^1c independently selected from hydrogen, substituted or unsubstituted C ₁ ～C ₂ Alkyl, halogen, amino; or any two R ¹ Joined to form a substituted or unsubstituted 5-to 6-membered cycloalkyl, substituted or unsubstitutedA 5-to 6-membered heterocyclic group; the substituent groups are respectively and independently selected from hydroxyl, halogen or two substituent groups on the same atom to form = O.

Further, the air conditioner is provided with a fan,

R ⁴ selected from hydrogen, halogen, cyano, hydroxy, carboxy, amino, substituted or unsubstituted C ₁ ～C ₆ Alkyl, 3-to 6-membered cycloalkyl, oxetanyl, substituted or unsubstituted tetrahydrofuryl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted C ₂ ～C ₆ Alkenyl, -C (O) R ¹² 、-S(O)(O)R ¹² ；

R ^6a 、R ^6b 、R ^6c 、R ^6d 、R ^7a 、R ^7b Are independently selected from hydrogen, halogen, cyano, hydroxy, carboxy, -C (O) R ¹² Amino, substituted or unsubstituted C ₁ ～C ₆ Alkyl, 3-to 6-membered cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, substituted or unsubstituted piperidinyl, C ₂ ～C ₆ Alkenyl, -S (O) (O) R ¹² (ii) a Or R on the same carbon atom ^6a And R ^6b Are linked to form a 3-to 6-membered cycloalkyl group or composition = O; or R on the same carbon atom ^6c And R ^6d Are linked to form a 3-to 6-membered cycloalkyl group or composition = O; or R on the same carbon atom ^7a And R ^7b Are linked to form a 3-to 6-membered cycloalkyl group or composition = O;

R ⁴ 、R ^6a 、R ^6b 、R ^6c 、R ^6d 、R ^7a 、R ^7b wherein the substituents are respectively and independently selected from halogen and C ₁ ～C ₆ Alkyl radical, C ₂ ～C ₆ Alkenyl radical, C ₁ ～C ₆ Haloalkyl, C ₁ ～C ₆ Alkoxy radical, C ₁ ～C ₆ Alkylthio, amino, carboxyl, hydroxyl, nitro, 3-6 membered cycloalkyl, oxetanyl, -S (O) (O) R ¹² ；

R ¹² Are each independently selected from C ₁ ～C ₆ Alkyl, amino, 3-to 6-membered cycloalkyl, pyridyl, oxetanyl, tetrahydrofuranyl, tetrahydrochyseneA pyranyl group.

Further, the compound is one of the following compounds:

the invention also provides application of the compound, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystal form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof in preparing a non-heptakinase homolog 1 inhibitor.

The invention also provides the application of the compound, or the tautomer, or the racemate, or the enantiomer, or the diastereoisomer, or the mixture thereof, or the pharmaceutically acceptable hydrate, or the pharmaceutically acceptable solvate, or the crystal form, or the isotope, or the metabolite, or the prodrug, or the salt thereof in preparing the medicine for treating and/or preventing tumor diseases.

Further, the tumor disease is pancreatic cancer, laryngeal cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, bone cancer, large intestine cancer, colorectal cancer, bile duct epithelial cancer, biliary tract cancer, kidney cancer, hepatocellular cancer, stomach cancer, hairy cell cancer, follicular cancer, nasopharyngeal cancer, pharyngeal cancer, esophageal cancer, bronchial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, cervical cancer, thyroid cancer, breast cancer, ovarian cancer, testicular cancer, prostate cancer, bladder cancer, urothelial cancer, genitourinary tract cancer, head and neck squamous cell cancer, diffuse large B-cell lymphoma, non-hodgkin's lymphoma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, myelogenous leukemia, sarcoma, glioblastoma, central nervous system cancer of the brain.

Further, the tumor diseases are pancreatic cancer, lung cancer, cholangiocarcinoma, colorectal cancer;

preferably, the lung cancer is non-small cell lung cancer.

Further, the disease is selected from G12C, G12V, G12D, G12R-associated KRAS mutated lung adenocarcinoma; G12D, G12V, G12C, G12R, G13D-related KRAS-mutated colorectal adenocarcinoma; G12D, G12V, G12R, G12C, Q61H related KRAS mutated pancreatic adenocarcinomas.

The invention also provides the use of the aforementioned compound, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, in the manufacture of a medicament for the treatment and/or prevention of neurofibromatosis type 1, noonan's syndrome, lentigo multiplex noonan's syndrome, LEOPARD syndrome, capillary malformation-arteriovenous malformation syndrome, costi's syndrome, cardio-facio-cutaneous syndrome, reji's syndrome, or NF 1-like syndrome, hereditary gingival fibromatosis.

The invention also provides a medicament, which is a preparation prepared by taking the compound, or the tautomer, or the racemate, or the enantiomer, or the diastereoisomer, or the stereoisomer, or the mixture form, or the pharmaceutically acceptable hydrate, or the pharmaceutically acceptable solvate, or the crystal form, or the nitrogen oxide, or the isotope, or the metabolite, or the prodrug, or the ester, or the salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

The invention also provides a pharmaceutical composition, the active ingredients of which are selected from the compound, or the tautomer thereof, or the inner racemate thereof, or the enantiomer thereof, or the diastereoisomer thereof, or the mixture form thereof, or the pharmaceutically acceptable hydrate thereof, or the pharmaceutically acceptable solvate thereof, or the crystal form thereof, or the isotope thereof, or the metabolite thereof, or the prodrug thereof, or the combination of more than one of the salts thereof.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, columbus, OH) naming system.

Definitions of terms used in relation to the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be afforded to them by a person skilled in the art, in light of the disclosure and context, should be given.

"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

"alkyl" refers to an aliphatic hydrocarbon group and to a saturated hydrocarbon group. The alkyl moiety may be a straight chain or branched chain alkyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.

C1-Cn used in the invention comprises C1-C2, C1-C3 \8230, 8230, C1-Cn, n is an integer more than one; the prefix as a substituent denotes the minimum and maximum number of carbon atoms in the substituent, for example, "C1-C6 alkyl" means a straight or branched alkyl group containing one to 6 carbon atoms.

"heteroalkyl" refers to an alkyl group containing a heteroatom.

"alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl groups may be straight-chain or branched.

"cycloalkyl" refers to saturated or unsaturated cyclic hydrocarbon substituents e.g., "C3-C6 cycloalkyl" refers to cycloalkyl groups having 3 to 6 carbon atoms.

"Heterocyclyl" refers to a ring containing at least one heteroatom in the ring backbone.

Heteroatoms include, but are not limited to, O, S, N, P, si, and the like.

"Ring" refers to any covalently closed structure, including, for example, carbocycles (e.g., aryl or cycloalkyl), heterocycles (e.g., heteroaryl or heterocycloalkyl), aryls (e.g., aryl or heteroaryl), nonaromatic (e.g., cycloalkyl or heterocycloalkyl). The "ring" in the present invention may be a monocyclic ring or a polycyclic ring, and may be a fused ring, a spiro ring or a bridged ring.

Typical heterocyclic groups include, but are not limited to:

"aryl" means a planar ring with delocalized pi electron systems and containing 4n +2 pi electrons, where n is an integer. The aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms. Aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracyl, fluorenyl, indenyl, and the like.

"heteroaryl" refers to an aryl group in which a carbon atom has been replaced with an atom other than carbon, such as an atom of N, O, S, or the like. Typical heteroaryl groups include, but are not limited to:

"halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

Hereinbefore, unless already indicated, the term "substituted" means that the mentioned groups may be substituted by one or more additional groups each and independently selected from alkyl, cycloalkyl, aryl, carboxy, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, alkylthio, aryloxy, nitro, acyl, halogen, haloalkyl, amino and the like.

As used herein, "pharmaceutically acceptable" is meant to include any material that does not interfere with the effectiveness of the biological activity of the active ingredient and is not toxic to the host to which it is administered.

The pharmaceutically acceptable auxiliary materials are general names of all the additional materials except the main medicine in the medicine, and the auxiliary materials have the following properties: (1) has no toxic or side effect on human body; (2) The chemical property is stable and is not easily influenced by temperature, pH, storage time and the like; (3) Has no incompatibility with the main drug, and does not influence the curative effect and quality inspection of the main drug; (4) do not interact with the packaging material. The auxiliary materials in the invention include, but are not limited to, filling agent (diluting agent), lubricating agent (glidant or anti-adhesion agent), dispersing agent, wetting agent, adhesive, regulator, solubilizer, antioxidant, bacteriostatic agent, emulsifier, disintegrating agent and the like. The binder comprises syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethylcellulose, ethyl cellulose or hydroxypropyl methylcellulose), gelatin slurry, syrup, starch slurry or polyvinylpyrrolidone; the filler comprises lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salt (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; the lubricant comprises superfine silica gel powder, magnesium stearate, talcum powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol and the like; the disintegrating agent comprises starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone or microcrystalline cellulose, etc.; the wetting agent comprises sodium lauryl sulfate, water or alcohol, etc.; the antioxidant comprises sodium sulfite, sodium bisulfite, sodium pyrosulfite, dibutylbenzoic acid, etc.; the bacteriostatic agent comprises 0.5% of phenol, 0.3% of cresol, 0.5% of chlorobutanol and the like; the regulator comprises hydrochloric acid, citric acid, potassium (sodium) hydroxide, sodium citrate, and buffer (including sodium dihydrogen phosphate and disodium hydrogen phosphate); the emulsifier comprises polysorbate-80, sorbitan fatty acid, pluronic F-68, lecithin, soybean lecithin, etc.; the solubilizer comprises Tween-80, bile, glycerol, etc.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. The acid base is a generalized Lewis acid base. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) Disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The compounds of the invention can likewise be used in injectable formulations. Wherein the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (refers to a mold tablet or machine pressed tablet prepared by aseptic operation of medicine, and is dissolved with water for injection for subcutaneous or intramuscular injection when in use).

Wherein the powder for injection contains at least an excipient in addition to the above-mentioned compound. The excipients described in the present invention, which are components intentionally added to a drug, should not have pharmacological properties in the amounts used, however, the excipients may aid in the processing, dissolution or dissolution of the drug, delivery by a targeted route of administration, or stability.

The invention provides a series of compounds capable of inhibiting SOS1 KRAS activity, tests show that the compounds have obvious inhibiting effect on SOS1 KRAS, a new scheme is provided for treating diseases taking SOS1 as a target for treatment, such as malignant tumor diseases, neurofibromatosis type 1, noonan syndrome and the like, the compounds can be used for preparing medicines for treating related diseases, and meanwhile, the compounds have good metabolic stability and wide application prospect.

In a word, the compound has obvious inhibition effect on SOS1 activity, can be used as an SOS1 KRAS inhibitor, has good metabolic stability and has wide application prospect in resisting malignant tumor diseases.

In the invention, SOS1:: KRAS represents the interaction of two proteins, and SOS1:: KRAS inhibitor is an inhibitor for inhibiting the interaction of SOS1 and KRAS. The compounds of the invention bind to the catalytic domain of SOS1, thereby preventing SOS1 and KRAS interaction.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed Description

The technical solutions of the present invention are described clearly and completely below, and it is obvious that the described embodiments are some, not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The reaction was monitored by Thin Layer Chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent system used for purification of silica gel column or thin layer preparative plate includes but is not limited to: dichloromethane/methanol system, n-hexane/ethyl acetate system and petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to different polarities of the compounds, or ammonia water, triethylamine and the like are added for adjustment. The developer systems used for reverse phase preparative purification include, but are not limited to: (a) phase A: water, phase B: acetonitrile; (b) phase A: water, phase B: methanol.

Unless otherwise specified in the examples, the reaction temperature was room temperature (20 ℃ C. To 30 ℃ C.).

Unless otherwise indicated, reagents used in the examples are commercially available.

In the present invention, the structure of the compound is determined by Mass Spectrometry (MS) and/or nuclear magnetic resonance (M) ¹ HNMR) device. The abbreviations have the following meanings:

DMF: n, N-dimethylformamide

THF: tetrahydrofuran (THF)

DIPEA: n, N-diisopropylethylamine

Et ₃ N: triethylamine

Ti(OEt) ₄ : tetraethyltitanate (TET)

Pd(PPh ₃ ) ₂ Cl ₂ : bis (triphenylphosphine) palladium dichloride

1,4-dioxane:1, 4-dioxane

DAST: diethylaminosulfur trifluoride

NaBH ₄ : sodium borohydride

MeOH: methanol

EtOH: ethanol

IPA: isopropyl alcohol

CH ₃ CN: acetonitrile

POCl ₃ : phosphorus oxychloride

BF ₃ ·Et ₂ O: boron trifluoride diethyl etherate

NaH: sodium hydride

Zn(CN) ₂ : zinc cyanide

DCM: methylene dichloride

DCE (DCE): 1, 2-dichloroethane

DMSO (dimethylsulfoxide): dimethyl sulfoxide

Toluene.: toluene

ACE-Cl: 1-chloroethyl chloroformate

NH ₄ Cl: ammonium chloride

K ₂ CO ₃ : potassium carbonate

AcOH: acetic acid

TFA: trifluoroacetic acid

TsCl: p-toluenesulfonyl chloride

MsCl: methane sulfonyl chloride

t-BuONa: sodium tert-butoxide

t-BuOK: potassium tert-butoxide

NaBH ₃ CN: sodium cyanoborohydride

1. Preparation of intermediate A

Preparation of (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine (A)

The first step is as follows: preparation of 1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-one (A-2)

Compound A-1 (25.0 g,104.6 mmol) was added to a dry three-necked flask, dissolved in 1,4-dioxane (250 mL), and Et was added thereto ₃ N (21.1g, 208.5mmol) and tributyl (1-ethoxyethylene) tin (45.3g, 125.4mmol) were added, and Pd (PPh) was substituted for nitrogen ₃ ) ₂ Cl ₂ (3.7g, 5.3mmol) was heated to 80 ℃ under nitrogen and stirred overnight. Cooling the reaction system to room temperature, and concentrating under reduced pressure to removePart of the solvent was removed, and 1N hydrochloric acid was added to the remaining solution, followed by heating and stirring at 45 ℃ for 0.5h. Concentrating under reduced pressure to remove organic solvent, adding water, filtering to remove generated solid, extracting the filtrate with ethyl acetate, washing the organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 16.8g of product a-2, yield: 79 percent.

The second step is that: preparation of (S, E) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethylene) propane-2-sulfinamide (A-3)

Compound A-2 (16.8g, 83.1mmol) was charged to a reaction flask, dissolved in tetrahydrofuran (200 mL), and S-t-butylsulfinamide (15.1g, 124.6 mmol) and tetraethyltitanate (47.4g, 207.8mmol) were added, and the system was heated to 80 ℃ and stirred for reaction overnight. Cooling the reaction system to room temperature, pouring into ice water, filtering to remove the generated solid, extracting the filtrate with ethyl acetate, washing the organic phase with saturated brine, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column to give 15.3g of product a-3, yield: 60 percent.

The third step: preparation of (S) -2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide (A-4)

Compound A-3 (15.3 g, 50.1mmol) was added to the reaction flask, dissolved in tetrahydrofuran (150 mL), the nitrogen was replaced, the system was cooled to-78 deg.C, lithium tri-sec-butylborohydride (1M in THF,75mL,75.0 mmol) was added dropwise at this temperature, and after addition was complete, the system was slowly returned to room temperature and stirred overnight. The reaction system was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 7.1g of product A-4, yield: 46 percent.

The fourth step: preparation of (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine (A)

Compound A-4 (3.0 g,9.8 mmol) was charged into a reaction flask, dissolved in 1,4-dioxane (15 mL), and a 4M HCl/1, 4-dioxane solution (15 mL) was added dropwise thereto, and the system was stirred at room temperature for 3 hours. Concentrating under reduced pressureRemoving the solvent and adding saturated NaHCO ₃ Stirring the aqueous solution, extracting with ethyl acetate, washing the organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure gave 2.0g of product a, yield: 100 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：204.1

2. Preparation of intermediate B

Preparation of (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (B)

The first step is as follows: preparation of 1-bromo-3- (difluoromethyl) -2-fluorobenzene (B-2)

Compound B-1 (10.0 g,49.3 mmol) was added to a reaction flask, dissolved in methylene chloride (120 mL), and DAST (13.6 g,84.4 mmol) was slowly added dropwise under cooling in an ice-water bath, and after completion of the addition, the reaction mixture was stirred at room temperature overnight. The reaction system was poured into saturated NaHCO ₃ Extracting with dichloromethane, washing the organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure, and the resulting crude product is purified by silica gel column to give 10.3g of product B-2, yield: 93 percent.

The second step is that: preparation of 1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-one (B-3)

Compound B-2 (10.3g, 45.8mmol) was charged into a dry three-necked flask, dissolved in 1,4-dioxane (130 mL), and Et was added thereto ₃ N (11.6 g,114.6 mmol) and tributyl (1-ethoxyethylene) tin (19.9 g,55.1 mmol) were added, replacing the nitrogen atmosphere, pd (PPh) ₃ ) ₂ Cl ₂ (1.6g, 2.3mmol), the system was heated to 100 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature, concentrated under reduced pressure to remove a part of the solvent, and 1N hydrochloric acid was added to the remaining solution, followed by heating and stirring at 45 ℃ for 2 hours. Concentrating under reduced pressure to remove organic solvent, adding water, filtering to remove generated solid, extracting the filtrate with ethyl acetate, washing the organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure,the crude product obtained was purified by silica gel column to give 6.1g of product B-3, yield: 71 percent.

The third step: preparation of (R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfinamide (B-4)

Compound B-3 (3.0 g,15.9 mmol) was added to a reaction flask, dissolved in tetrahydrofuran (60 mL), R-tert-butylsulfinamide (2.9 g,23.9 mmol) and tetraethyl titanate (10.9 g,47.8 mmol) were added, and the system was heated to 80 deg.C and stirred overnight. Cooling the reaction system to room temperature, pouring into ice water, filtering to remove the solid, extracting the filtrate with ethyl acetate, washing the organic phase with saturated brine, anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 3.5g of product B-4, yield: and 75 percent.

The fourth step: preparation of (R) -N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide (B-5)

To a reaction flask was added compound B-4 (3.5g, 12.0 mmol), dissolved in tetrahydrofuran (50 mL), the system was cooled to-78 deg.C, and NaBH was added portionwise while maintaining the temperature ₄ (677mg, 17.9mmol), after the addition the system is warmed to-40 ℃ and stirred for 2h. The reaction system was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 1.9g of product B-5, yield: 54 percent.

The fifth step: preparation of (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (B)

Compound B-5 (1.9g, 6.5 mmol) was charged into a reaction flask, dissolved in 1,4-dioxane (20 mL), and a 4M HCl/1, 4-dioxane solution (20 mL) was added dropwise thereto, and the system was stirred at room temperature for 3 hours. Concentrating under reduced pressure to remove solvent, adding saturated NaHCO ₃ Stirring the aqueous solution, extracting with ethyl acetate, washing the organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure gave 1.1g of product B, yield: 89 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：190.1

3. Preparation of intermediate C

Preparation of (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (C)

The first step is as follows: preparation of 1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-one (C-2)

Compound C-1 (5.0 g,18.5 mmol) was added to a three-necked flask, dissolved in 1,4-dioxane (50 mL), and Et was added thereto ₃ N (3.7g, 36.6 mmol) and tributyl (1-ethoxyethylene) tin (8.7g, 24.1 mmol), replacement of nitrogen, addition of Pd (PPh) ₃ ) ₂ Cl ₂ (650 mg, 0.9mmol), the system is heated to 80 deg.C under nitrogen and stirred overnight. The reaction system was cooled to room temperature, concentrated under reduced pressure to remove a part of the solvent, and 1N hydrochloric acid was added to the remaining mixture, heated to 50 ℃ and stirred for 1 hour. Concentrating under reduced pressure to remove solvent, adding water, extracting with ethyl acetate, washing organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 4.1g of product C-2, yield: 95 percent.

The second step is that: preparation of (R, E) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylene) propane-2-sulfinamide (C-3)

Compound C-2 (1.0 g,4.3 mmol) was added to a reaction flask, dissolved in tetrahydrofuran (40 mL), R-tert-butylsulfinamide (779mg, 6.4 mmol) and tetraethyl titanate (2.5g, 11.0 mmol) were added, and the system was heated to 80 ℃ and stirred for reaction overnight. Cooling the reaction system to room temperature, pouring into ice water, filtering to remove solids, extracting the filtrate with ethyl acetate, washing the organic phase with saturated brine, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure, and the resulting crude product purified by silica gel column to yield 460mg of product C-3, yield: 33 percent.

The third step: preparation of (R) -2-methyl-N- ((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide (C-4)

Compound C-3 (460mg, 1.4 mmol) was added to the reaction flask and dissolved in tetrahydrofuran (5)mL), water (0.1 mL) was added, the system was cooled to-78 deg.C, and NaBH was added portionwise ₄ (93mg, 2.5 mmol), after the addition was complete, the system was slowly returned to room temperature and stirred for 30min. The reaction system was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure to dryness, the crude product obtained is purified by silica gel column to give 310mg of product C-4, yield: 66 percent.

The fourth step: preparation of (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine (C-5)

Compound C-4 (310mg, 0.92mmol) was added to a reaction flask, dissolved in 1,4-dioxane (2 mL), and a 4M HCl/1, 4-dioxane solution (2 mL) was added dropwise, and the system was stirred at room temperature for 1h. Concentrating under reduced pressure to remove solvent, adding saturated NaHCO ₃ Adjusting the system to alkalescence with water solution, extracting with ethyl acetate, washing the organic phase with saturated saline solution, and collecting anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure to dryness, the crude product obtained is purified by silica gel column to yield 146mg of product C-5, yield: 67 percent.

The fifth step: preparation of (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (C)

Compound C-5 (146mg, 0.62mmol) was added to a reaction flask, dissolved in methanol (4 mL), pd/C (200 mg) was added, the air in the reaction flask was replaced with hydrogen, and the system was stirred under hydrogen atmosphere for reaction overnight. And (4) carrying out suction filtration, and concentrating the filtrate under reduced pressure to obtain 120mg of a crude product C which is directly used for the next reaction.

LC-MS(ESI)m/z(M+H) ⁺ ：205.2

4. Preparation of intermediate D

Preparation of (R) -2- (3- (1-aminoethyl) phenyl) -2, 2-difluoroethane-1-ol (D)

The first step is as follows: preparation of ethyl 2- (3-bromophenyl) -2, 2-difluoroacetate (D-2)

Compound D-1a (42.9g, 211.4mmol) was added to the reaction flask, and dissolved in DMSO (140 mL)) Copper powder (13.6g, 214.0mmol) was added thereto under stirring at room temperature, and after the addition, the system was stirred at room temperature for 1 hour, and then compound D-1 (24.0g, 84.8mmol) was added thereto, and the system was heated to 80 ℃ and stirred to react for 2 hours. Cooling the reaction system to room temperature, pouring into ice water, filtering to remove the solid, extracting the filtrate with ethyl acetate, washing the organic phase with saturated brine, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column to give 16.0g of product D-2, yield: 68 percent.

The second step is that: preparation of 2- (3-bromophenyl) -2, 2-difluoroethan-1-ol (D-3)

The compound D-2 (12.7g, 45.5mmol) was charged into a reaction flask, dissolved in ethanol (120 mL), and NaBH was added in portions while cooling in an ice salt bath ₄ (3.5g, 92.5mmol), the temperature of the system is kept below 0 ℃ in the feeding process, and the system is slowly recovered to the room temperature after the feeding is finished and stirred for 4h. The reaction system was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 10.1g of product D-3, yield: 94 percent.

The third step: preparation of 1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethan-1-one (D-4)

Compound D-3 (10.1g, 42.6 mmol) was added to a dry three-necked flask, dissolved in 1,4-dioxane (100 mL), and Et was added thereto ₃ N (8.6g, 85.0mmol) and tributyl (1-ethoxyethylene) tin (20.0g, 55.4mmol) were added thereto, and Pd (PPh) was added while substituting nitrogen gas ₃ ) ₂ Cl ₂ (1.5g, 2.1mmol), the system was heated to 80 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature, concentrated under reduced pressure to remove a part of the solvent, and 1N hydrochloric acid was added to the remaining solution, followed by heating and stirring at 45 ℃ for 2 hours. Concentrating under reduced pressure to remove organic solvent, adding appropriate amount of water, filtering to remove generated solid, extracting the filtrate with ethyl acetate, washing the organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 5.9g of product D-4, yield: and 69 percent.

The fourth step: preparation of (R, E) -N- (1- (3- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethylene) -2-methylpropane-2-sulfinamide (D-5)

Compound D-4 (4.0 g,20.0 mmol) was charged into a reaction flask, dissolved in tetrahydrofuran (40 mL), and R-t-butylsulfinamide (3.6 g,29.7 mmol) and tetraethyltitanate (11.4 g,50.0 mmol) were added and the system was heated to 80 ℃ and stirred for reaction overnight. Cooling the reaction system to room temperature, pouring into ice water, filtering to remove the solid, extracting the filtrate with ethyl acetate, washing the organic phase with saturated brine, anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product obtained is purified by means of a silica gel column to give 5.1g of product D-5, yield: 84 percent.

The fifth step: preparation of (R) -N- ((R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide (D-6)

To a reaction flask was added compound D-5 (5.1g, 16.8mmol), dissolved in tetrahydrofuran (50 mL), water (1 mL) was added, the system was cooled to-78 deg.C, and NaBH was added portionwise while maintaining the temperature ₄ (1.1g, 29.1mmol), after addition the system was slowly warmed to room temperature and stirred for 3h. The reaction system was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column to give 3.1g of product D-6, yield: 60 percent.

And a sixth step: preparation of (R) -2- (3- (1-aminoethyl) phenyl) -2, 2-difluoroethane-1-ol (D)

Compound D-6 (2.0 g,6.5 mmol) was added to a reaction flask, dissolved in 1,4-dioxane (20 mL), and 4M HCl/1, 4-dioxane solution (20 mL) was added dropwise and stirred at room temperature for 3h. Concentrating under reduced pressure to remove solvent, adding saturated NaHCO ₃ After stirring well, the aqueous solution was concentrated under reduced pressure to remove the solvent, and was redissolved with a solvent of dichloromethane/methanol =10 (1 (v/v), and anhydrous Na was used ₂ SO ₄ Drying, filtration and concentration under reduced pressure gave 1.1g of product D, yield: 83 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：202.1

5. Preparation of intermediate E

Preparation of (R) -1- (3- (trifluoromethyl) phenyl) ethane-1-amine (E)

The first step is as follows: preparation of (R, E) -N- (1- (3-bromo-5- (trifluoromethyl) phenyl) ethylene) -2-methylpropane-2-sulfinamide (E-2)

Compound E-1 (500mg, 1.87mmol) was added to a reaction flask, dissolved in tetrahydrofuran (15 mL), R-tert-butylsulfinamide (340mg, 2.81mmol) and tetraethyl titanate (1.1g, 4.82mmol) were added, and the system was heated to 80 ℃ and stirred overnight. Cooling the reaction system to room temperature, pouring into ice water, filtering to remove the solid, extracting the filtrate with ethyl acetate, washing the organic phase with saturated brine, anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 610mg of product E-2, yield: 88 percent.

The second step is that: preparation of (R) -N- ((R) -1- (3-bromo-5- (trifluoromethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide (E-3)

Compound E-2 (610mg, 1.65mmol) was added to the reaction flask, dissolved in tetrahydrofuran (15 mL), water (0.3 mL) was added, the system was cooled to-78 deg.C and NaBH was added portionwise while maintaining this temperature ₄ (112mg, 2.97mmol), after the addition the system was warmed to-20 ℃ and stirred for 2h. The reaction system was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure, and the crude product purified through silica gel column to yield 447mg of product E-3, yield: 73 percent.

The third step: preparation of (R) -2-methyl-N- ((R) -1- (3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide (E-4)

Compound E-3 (100mg, 0.27mmol) was added to a reaction flask, and dissolved in absolute ethanol (5 mL), and then sodium acetate (24mg, 0.30mmol) and Pd/C (10 mg) were added thereto, and the air in the reaction flask was replaced with hydrogen gas, and the system was stirred overnight at room temperature under a hydrogen atmosphere. And (3) carrying out suction filtration on the reaction system, carrying out reduced pressure concentration on the filtrate, and purifying the obtained crude product through a silica gel column to obtain a product E-4 of 50mg, wherein the yield is as follows: and 63 percent.

The fourth step: preparation of (R) -1- (3- (trifluoromethyl) phenyl) ethan-1-amine (E)

Compound E-4 (50mg, 0.17mmol) was added to a reaction flask, dissolved in 1,4-dioxane (1 mL), and 4M HCl/1, 4-dioxane solution (1 mL) was added dropwise and stirred at room temperature for 3h. Concentrating under reduced pressure to remove solvent, adding saturated NaHCO ₃ After stirring well, the aqueous solution was concentrated under reduced pressure to remove the solvent, and was redissolved with a solvent of dichloromethane/methanol =10 (1 (v/v), and anhydrous Na was used ₂ SO ₄ Drying, filtration and concentration under reduced pressure gave 30mg of product E, yield: 93 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：190.1

6. Preparation of intermediate F

Preparation of (R) -1- (3-methyl-5- (trifluoromethyl) phenyl) ethan-1-amine (F)

The first step is as follows: preparation of 2-methyl-N- ((R) -1- (3-methyl-5- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide (F-1)

The compound E-3 (100mg, 0.27mmol) was added to the reaction flask, dissolved in 1,4-dioxane (5 mL), and purified water (1 mL), methylboronic acid (80mg, 1.35mmol), anhydrous potassium carbonate (74mg, 0.54mmol), pd (dppf) were added thereto ₂ Cl ₂ (19mg, 0.03mmol) under nitrogen. The system was heated to 90 ℃ and stirred for 2h. And (3) carrying out suction filtration on the reaction system, carrying out reduced pressure concentration on the filtrate, and purifying the obtained crude product through a silica gel column to obtain 70mg of a product F-1, wherein the yield is as follows: 85 percent.

The second step: preparation of (R) -1- (3-methyl-5- (trifluoromethyl) phenyl) ethan-1-amine (F)

Compound F-1 (70mg, 0.23mmol) was added to a reaction flask, dissolved in 1,4-dioxane (1 mL), and 4M HCl/1, 4-dioxane solution (1 mL) was added dropwise and stirred at room temperature for 3h. Concentrating under reduced pressure to remove solvent, adding saturated NaHCO ₃ After the aqueous solution was sufficiently stirred, the solvent was removed by concentration under reduced pressure, redissolved with a dichloromethane/methanol =10 (1 (v/v) solvent, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give 35mg of product E, yield: 76 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：204.1

7. Preparation of intermediate G

Preparation of (R) -1- (3, 5-difluorophenyl) ethan-1-amine (G)

The first step is as follows: preparation of (R, E) -N- (1- (3, 5-difluorophenyl) ethylene) -2-methylpropane-2-sulfinamide (G-2)

Compound G-1 (3.1g, 20.0 mmol) was charged into a reaction flask, dissolved in tetrahydrofuran (40 mL), and R-t-butylsulfinamide (3.6g, 29.7mmol) and tetraethyl titanate (11.4g, 50.0 mmol) were added and the system was heated to 80 ℃ and stirred for reaction overnight. Cooling the reaction system to room temperature, pouring into ice water, filtering to remove the solid, extracting the filtrate with ethyl acetate, washing the organic phase with saturated brine, anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 4.3G of product G-2, yield: 84 percent.

The second step: preparation of (R) -N- ((R) -1- (3, 5-difluorophenyl) ethyl) -2-methylpropane-2-sulfinamide (G-3)

To a reaction flask was added compound G-2 (4.3g, 16.8mmol), dissolved in tetrahydrofuran (50 mL), water (1 mL) was added, the system was cooled to-78 deg.C, and NaBH was added portionwise while maintaining the temperature ₄ (1.1g, 29.1mmol), after addition the system was slowly warmed to room temperature and stirred for 3h. The reaction system was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 2.6G of product G-3, yield: 60 percent.

The third step: preparation of (R) -1- (3, 5-difluorophenyl) ethan-1-amine (G)

Compound G-3 (2.0G, 7.7 mmol) was added to a reaction flask, dissolved in 1,4-dioxane (20 mL), and 4M HCl/1, 4-dioxane solution (20 mL) was added dropwise at room temperatureStirring for 3h. Concentrating under reduced pressure to remove solvent, adding saturated NaHCO ₃ After stirring well, the aqueous solution was concentrated under reduced pressure to remove the solvent, and was redissolved with a solvent of dichloromethane/methanol =10 (1 (v/v), and anhydrous Na was used ₂ SO ₄ Drying, filtration and concentration under reduced pressure gave 1.1g of product D, yield: 92 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：158.1

Example 1

Preparation of (R) -1- (2 '-methyl-4' - (((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -8 'H-spiro [ piperidine-4, 7' - [1,4] dioxine [2,3-g ] quinazolin-1-yl) ethan-1-one (T-1)

The first step is as follows: preparation of 6-benzyl-1-oxa-6-azaspiro [2.5] octane (1-2)

Adding NaH (5.5 g,137.5mmol and 60 percent content) into a reaction bottle, dispersing the NaH into DMSO (120 mL), replacing air in the reaction bottle with nitrogen, cooling the system to 10 ℃ under the protection of nitrogen, adding trimethyl sulfoxide iodide (25.6 g and 116.3 mmol) in batches, returning the system to room temperature, stirring for 1h, then cooling the reaction system to 10 ℃, dropwise adding a DMSO (80 mL) solution of a compound 1-1 (20.0 g and 105.8 mmol), controlling the temperature of the system to be not higher than 15 ℃ in the dropwise adding process, and stirring the reaction system at room temperature for 2h after the dropwise adding is completed. Pouring the reaction system into ice water, extracting with ethyl acetate, backwashing the organic phase with water for three times, then washing with saturated brine, anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product obtained is purified by silica gel column to give 21.0g of the product 1-2, yield: 98 percent.

The second step is that: preparation of (1-benzyl-4- (5-bromo-2-fluorophenoxy) piperidin-4-yl) methanol (1-4)

Compound 1-2 (14.2g, 69.9mmol) and compound 1-3 (16.0g, 83.8mmol) were added to a reaction flask, dissolved in dichloromethane (400 mL), the system was cooled to 0 ℃ and BF was slowly added dropwise to the system under nitrogen protection ₃ .Et ₂ O (39.6g, 279.0 mmol), and the reaction was completed after dropwise additionThe system was allowed to return to room temperature and the reaction was stirred overnight. Concentrating under reduced pressure to remove part of the solvent, and adding saturated Na ₂ CO ₃ The solution was extracted with ethyl acetate, the organic phase was washed successively with water, saturated brine and anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 8.5g of products 1-4, yield: 31 percent.

The third step: preparation of 3- ((1-benzyl-4- (hydroxymethyl) piperidin-4-yl) oxy) -4-fluorobenzonitrile (1-5)

To a reaction flask, compounds 1-4 (2.3g, 5.8mmol) were added, dissolved in DMF (46 mL), and then Zn (CN) was added ₂ (1.4g, 11.9mmol), the nitrogen gas was replaced, and Pd (PPh) was added ₃ ) ₄ (676mg, 0.6 mmol), nitrogen was again replaced, and the system was heated to 100 ℃ and stirred for reaction overnight. Cooling the reaction system to room temperature, suction filtering, washing the solid with ethyl acetate, pouring the filtrate into water, extracting with ethyl acetate, washing the organic phase with water and saturated brine successively, and anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product obtained is purified by silica gel column to give 2.0g of products 1-5, yield: 100 percent.

The fourth step: preparation of 1 '-benzyl-3H-spiro [ benzo [ b ] [1,4] dioxine-2, 4' -piperidine ] -7-carbonitrile (1-6)

To a reaction flask, compounds 1 to 5 (2.0g, 5.8mmol) were added and dissolved in DMF (30 mL), followed by addition of t-BuOK (986 mg, 8.8mmol), and the system was heated to 80 ℃ and stirred for reaction for 2 hours. Cooling the reaction system to room temperature, adding water to quench, extracting with ethyl acetate, washing the organic phase with water and saturated brine successively, and obtaining anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure to dryness gave 1.8g of crude product 1-6, which was used without further purification in the next reaction, yield: 96 percent.

The fifth step: preparation of 1 '-benzyl-6-nitro-3H-spiro [ benzo [ b ] [1,4] dioxine-2, 4' -piperidine ] -7-carbonitrile (1-7)

The compound 1-6 (1.5g, 4.7 mmol) was added to the reaction flask, dissolved in glacial acetic acid (12 mL), concentrated nitric acid (4 mL) was added dropwise to the mixture, and the system was heated to 60 ℃ and stirred for reaction overnight. The reaction was cooled to room temperature, poured into ice water, and washed with Nadjusting pH of the system to 9 with aOH solution, extracting with ethyl acetate, washing the organic phase with saturated brine, and removing anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure, and the resulting crude product purified by silica gel column to give 280mg of products 1-7, yield: 16 percent.

And a sixth step: preparation of 1 '-benzyl-6-nitro-3H-spiro [ benzo [ b ] [1,4] dioxine-2, 4' -piperidine ] -7-carboxamide (1-8)

To a reaction flask, compound 1-7 (280mg, 0.77mmol) was added, dissolved in ethanol (4 mL), water (1 mL) and NaOH (46mg, 1.15mmol) were added, then aqueous hydrogen peroxide (1 mL) was slowly added dropwise, and the system was stirred at room temperature overnight. Diluting with water, adding sodium hydrosulfite to remove hydrogen peroxide, extracting with ethyl acetate, washing organic phase with saturated saline solution, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product on thin layer silica gel plates gives 200mg of product 1-8, yield: 68 percent.

The seventh step: preparation of 6-amino-1 '-benzyl-3H-spiro [ benzo [ b ] [1,4] dioxine-2, 4' -piperidine ] -7-carboxamide (1-9)

To a reaction flask was added compounds 1-8 (200mg, 0.52mmol), dissolved in ethanol (5 mL) and water (1 mL), followed by iron powder (539mg, 2.60mmol) and NH ₄ Cl (140mg, 2.62mmol) and the system was heated to 70 ℃ and the reaction stirred for 2h. After the reaction system was cooled to room temperature, ethyl acetate and Na were added to the system ₂ SO ₄ Stirring uniformly, filtering, washing a filter cake with ethyl acetate, concentrating a filtrate under reduced pressure, and purifying an obtained crude product by using a thin-layer silica gel plate to obtain 78mg of a product 1-9 with the yield: 42 percent.

Eighth step: preparation of 1-benzyl-2 '-methyl-8' H-spiro [ piperidine-4,7 '- [1,4] dioxins [2,3-g ] quinazolin-4' -ol (1-10)

The compound 1-9 (78mg, 0.22mmol) was added to a tubular thick-walled pressure-resistant bottle, dissolved in ethanol (2 mL), and trimethyl orthoacetate (265mg, 2.21mmol) was added thereto, and the system was sealed and heated to 120 ℃ and stirred for reaction for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column to give 79mg of product 1-10, yield: 95 percent.

The ninth step: preparation of 1-benzyl-4 '-chloro-2' -methyl-8 'H-spiro [ piperidine-4, 7' - [1,4] dioxine [2,3-g ] quinazoline ] (1-11)

The compound 1-10 (46mg, 0.12mmol) was added to a reaction flask, dissolved in toluene (2 mL), and POCl was added dropwise ₃ (224mg, 1.46mmol) and DIPEA (79mg, 0.61mmol), the system was heated to 85 ℃ and stirred for 6h. Concentrating under reduced pressure to remove solvent, adding toluene to remove residual solvent, diluting with ethyl acetate and water, layering, separating organic phase, extracting water layer with ethyl acetate, mixing organic phases, washing with saturated saline solution, and removing anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product through a silica gel column gives 47mg of products 1-11, yield: 97 percent.

The tenth step: preparation of (R) -1-benzyl-2 '-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -8' H-spiro [ piperidine-4, 7'- [1,4] dioxine [2,3-g ] quinazoline ] -4' -amine (1-12)

Compound 1-11 (34mg, 0.09mmol) and compound A (26mg, 0.13mmol) were charged into a tubular thick-walled pressure-resistant bottle, dissolved in isopropanol (2 mL), DIPEA (33mg, 0.26mmol) was added, and the system was sealed and heated to 120 ℃ and stirred for reaction for 30 hours. Concentrating under reduced pressure to remove solvent, adding appropriate amount of water, extracting with ethyl acetate, washing organic phase with saturated saline solution, and removing anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product is purified by thin layer silica gel plate to yield 45mg of product 1-12, yield: 93 percent.

The eleventh step: preparation of (R) -2 '-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -8' H-spiro [ piperidine-4,7 '- [1,4] dioxins [2,3-g ] quinazoline ] -4' -amine (1-13)

The compound 1-12 (45mg, 0.08mmol) was added to a reaction flask, dissolved in 1, 2-dichloroethane (1 mL), and 1-chloroethyl chloroformate (23mg, 0.16mmol) was added thereto, and the system was heated to 90 ℃ and stirred for 1 hour, and concentrated under reduced pressure to remove the solvent, then MeOH (1 mL) was added to the system, and the reaction system was heated to 80 ℃ and stirred for 2 hours. Concentrating under reduced pressure to remove solvent, adding ethyl acetate, and adding saturated NaHCO ₃ Adjusting pH of the system to 8, washing the organic phase with saturated brine, and removing anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure to obtain crude productPurification on silica gel plates gives 30mg of product 1-13, yield: 79 percent.

The twelfth step: preparation of (R) -1- (2 '-methyl-4' - (((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -8 'H-spiro [ piperidine-4, 7' - [1,4] dioxine [2,3-g ] quinazolin-1-yl) ethan-1-one (T-1)

The compound 1-13 (7mg, 0.015mmol) was added to the reaction flask, dissolved in dichloromethane (1 mL), and Et was added successively ₃ N (5mg, 0.050mmol) and acetic anhydride (3mg, 0.029mmol) and the system was stirred at room temperature for 20min. Quenching the reaction by adding a proper amount of water, extracting with dichloromethane, washing the organic phase with saturated brine, and removing anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product by thin layer silica gel plate afforded 4mg of product T-1, yield: 52 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：515.2

¹ H NMR(400MHz,DMSO-d ₆ )δ8.26(d,J＝6.8Hz,1H),7.97(s,1H),7.78(d,J＝7.6Hz,1H),7.52(d,J＝7.6Hz,1H),7.36-7.30(m,1H),7.00(s,1H),5.73-5.64(m,1H),4.19-4.10(m,3H),3.77-3.68(m,1H),3.44-3.37(m,1H),3.10-3.00(m,1H),2.62(s,3H),2.27(s,3H),2.04(s,3H),1.79-1.58(m,4H),1.51(d,J＝7.2Hz,3H).

Example 2

Preparation of (R) -2 '-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -1- (methylsulfonyl) -8' H-spiropiperidine-4, 7'- [1,4] dioxine [2,3-g ] quinazoline ] -4' -amine (T-2)

The compound 1-13 (7mg, 0.015mmol) was added to the reaction flask, dissolved in dichloromethane (1 mL), and Et was added successively ₃ N (5mg, 0.050mmol) and methanesulfonyl chloride (3mg, 0.026mmol) were reacted with stirring at room temperature for 20min. Quenching the reaction with appropriate amount of water, extracting with dichloromethane, washing the organic phase with saturated brine, anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product on thin-layer silica gel plates afforded 4mg of product T-2, yield: 49 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：551.2

¹ H NMR(400MHz,DMSO-d ₆ )δ8.28(d,J＝7.2Hz,1H),7.97(s,1H),7.78(d,J＝8.0Hz,1H),7.52(d,J＝7.6Hz,1H),7.36-7.30(m,1H),7.01(s,1H),5.74-5.65(m,1H),4.20-4.16(m,2H),3.55-3.46(m,2H),3.10-3.00(m,2H),2.96(s,3H),2.62(s,3H),2.27(s,3H),1.87-1.80(m,4H),1.51(d,J＝6.8Hz,3H).

Example 3

Preparation of (R) -1,2 '-dimethyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -8' H-spiro [ piperidine-4, 7'- [1,4] dioxine [2,3-g ] quinazoline ] -4' -amine (T-3)

Adding Compound 1-13 (16mg, 0.034mmol) to a reaction flask, dissolving in methanol (1 mL), adding aqueous formaldehyde solution (37% in water,55mg, 0.678mmol), trifluoroacetic acid (4 mg, 0.035mmol) and 100mg anhydrous MgSO ₄ The reaction system is stirred for 1h at room temperature, and then NaBH is added into the reaction system ₃ CN (6 mg, 0.095mmol), and the reaction system was stirred at room temperature for 1 hour. Adding ethyl acetate into the system, filtering, and adding saturated Na into the filtrate ₂ CO ₃ Neutralizing the solution, washing with saturated brine, and washing with anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product on thin-layer silica gel plates afforded 12mg of product T-3, yield: 73 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：487.2

¹ H NMR(400MHz,DMSO-d ₆ )δ8.57-8.35(m,1H),8.01(s,1H),7.79(d,J＝8.0Hz,1H),7.52(d,J＝7.6Hz,1H),7.37-7.31(m,1H),7.04(s,1H),5.75-5.66(m,1H),4.26-4.17(m,2H),3.30-2.92(m,4H),2.71-2.58(m,3H),2.62(s,3H),2.30(s,3H),2.00-1.84(m,4H),1.53(d,J＝6.8Hz,3H).

Example 4

Preparation of 9-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -1,2,4a, 5-tetrahydro-4H- [1,4] oxazine [4',3':4,5] [1,4] oxazine [3,2-g ] quinazolin-11-amine (T-4)

The first step is as follows: preparation of methyl 4-fluoro-5- (3- (hydroxymethyl) morpholino) -2-nitrobenzoate (4-2)

Compound 4-1 (100mg, 0.46mmol) and 3-hydroxymethylmorpholine (54mg, 0.46mmol) were added to a reaction flask, dissolved in DMF (5 mL), and the system was heated to 60 ℃ and stirred for 2 days. Cooling the reaction system to room temperature, pouring into water, extracting with ethyl acetate, washing the organic phase with saturated brine, and anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product obtained is purified by silica gel column to give 100mg of product 4-2, yield: and 69 percent.

The second step is that: preparation of methyl 8-nitro-1, 2,4a, 5-tetrahydro-4H-benzo [ b ] [1,4] oxazinyl [4,3-d ] [1,4] oxazine-9-carboxylate (4-3)

To a reaction flask were added compound 4-2 (100mg, 0.32mmol) and K ₂ CO ₃ (66mg, 0.48mmol), dispersed in DMF (5 mL), and the system was heated to 60 ℃ and stirred for 24h. Cooling the reaction system to room temperature, pouring into water, extracting with ethyl acetate, washing the organic phase with saturated brine, and removing anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product obtained is purified by silica gel column to give 80mg of the product 4-3, yield: 85 percent.

The third step: preparation of 8-nitro-1, 2,4a, 5-tetrahydro-4H-benzo [ b ] [1,4] oxazinyl [4,3-d ] [1,4] oxazine-9-carboxamide (4-4)

To a sealed reaction tube was added compound 4-3 (80mg, 0.27mmol), dispersed in methanol (2 mL), aqueous ammonia (6 mL) was added, and the system was sealed and heated to 80 ℃ and stirred for reaction overnight. Cooling the reaction system to room temperature, pouring into water, extracting with ethyl acetate, washing the organic phase with saturated brine, and anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product obtained is purified by silica gel column to give 40mg of the product 4-4, yield: 53 percent.

The fourth step: preparation of 8-amino-1, 2,4a, 5-tetrahydro-4H-benzo [ b ] [1,4] oxazine [4,3-d ] [1,4] oxazine-9-carboxamide (4-5)

Compound 4-4 (40mg, 0.14mmol) was added to a reaction flask, dissolved in methanol (5 mL), pd/C (20 mg) was added, the air in the reaction flask was replaced with hydrogen gas, and the system was stirred under a hydrogen atmosphere for reaction for 2 hours. Filtration and concentration under reduced pressure gave 25mg of product 6-5, yield: 70 percent.

The fifth step: preparation of 9-methyl-1, 2,4a, 5-tetrahydro-4H- [1,4] oxazine [4',3':4,5] [1,4] oxazine [3,2-g ] quinazolin-11-ol (4-6)

Compound 4-5 (25mg, 0.10mmol) was added to a sealed reaction tube, and dissolved in ethanol (2 mL), trimethyl orthoacetate (121mg, 1.01mmol) was added thereto, and the system was sealed and heated to 120 ℃ to stir the reaction overnight. Cooling the reaction system to room temperature, pouring into water, extracting with ethyl acetate, washing the organic phase with saturated brine, and anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product obtained is purified by silica gel column to give 20mg of the product 4-6, yield: 73 percent.

And a sixth step: preparation of 11-chloro-9-methyl-1, 2,4a, 5-tetrahydro-4H- [1,4] oxazine [4',3':4,5] [1,4] oxazine [3,2-g ] quinazoline (4-7)

To a reaction flask, compound 4-6 (20mg, 0.07mmol) was added, dissolved in toluene (2 mL), and POCl was added ₃ (135mg, 0.88mmol) and DIPEA (43mg, 0.33mmol), the system was heated to 90 ℃ and stirred for 4h. Cooling the reaction system to room temperature, concentrating under reduced pressure to remove the solvent, adding appropriate amount of water, extracting with ethyl acetate, washing the organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure, and the resulting crude product purified by silica gel column to give 15mg of products 4-7, yield: 70 percent.

The seventh step: preparation of 9-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -1,2,4a, 5-tetrahydro-4H- [1,4] oxazine [4',3':4,5] [1,4] oxazine [3,2-g ] quinazolin-11-amine (T-4)

Compound 4-7 (15mg, 0.05mmol) was added to a sealed reaction tube, dissolved in isopropanol (2 mL), compound A (21mg, 0.10mmol) and DIPEA (23mg, 0.18mmol) were added, and the system was sealed and heated to 120 ℃ and stirred for reaction for 2 days. Cooling the reaction system to room temperature, pouring into water, extracting with ethyl acetate, and mixing the organic phase with saturated brineWashing with anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product by thin layer silica gel plate afforded 12mg of product T-4, yield: 51 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：459.2

¹ H NMR(400MHz,DMSO-d ₆ )δ8.15(d,J＝6.4Hz,1H),7.76(d,J＝7.6Hz,1H),7.58(s,1H),7.53(d,J＝7.6Hz,1H),7.39-7.31(m,1H),6.82(s,1H),5.77-5.68(m,1H),4.33-4.27(m,1H),4.12-4.05(m,1H),3.98-3.82(m,3H),3.74-3.66(m,1H),3.25-3.16(m,2H),2.89-2.81(m,1H),2.62(s,3H),2.26(s,3H),1.57-1.54(m,3H).

Example 5

Preparation of 9-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -3- (methylsulfonyl) -1,2,3,4,4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazinyl [3,2-g ] quinazolin-11-amine (T-5)

The first step is as follows: preparation of 4- (2-fluoro-5- (methoxycarbonyl) -4-nitrophenyl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (5-2)

Compound 5-1 (2.9g, 13.4mmol) was added to the reaction flask, dissolved in DMF (40 mL), followed by 5-1a (2.4g, 11.1mmol), and the reaction was heated to 60 ℃ and stirred for 72h. Cooling the reaction system to room temperature, pouring into water, extracting with ethyl acetate, washing the organic phase with saturated brine, and anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product obtained is purified by silica gel column to give 2.9g of product 5-2, yield: and 63 percent.

The second step: preparation of 3- (tert-butyl) 9-methyl 8-nitro-1, 2,4a, 5-tetrahydrobenzo [ b ] pyrazino [1,2-d ] [1,4] oxazine-3, 9 (4H) -dicarboxylate (5-3)

Compound 5-2 (2.9g, 7.0 mmol) was added to the reaction flask, dissolved in DMF (40 mL), and then K was added ₂ CO ₃ (1.5g, 10.9mmol), the reaction system was heated to 60 ℃ and stirred for reaction for 12 hours. Cooling the reaction system to room temperature, pouring into water, extracting with ethyl acetate, and collecting organic matterThe phases were washed with saturated brine and anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, the crude product obtained is purified by silica gel column to give 2.7g of product 5-3, yield: 98 percent.

The third step: preparation of 9-carbamoyl-8-nitro-1, 2,4a, 5-tetrahydrobenzo [ b ] pyrazino [1,2-d ] [1,4] oxazine-3 (4H) -carboxylic acid tert-butyl ester (5-4)

Compound No. 5-3 (2.7g, 6.9mmol) was added to a sealed reaction tube, dissolved in methanol (10 mL), followed by addition of aqueous ammonia (30 mL), and the reaction was heated to 80 ℃ in a sealed condition and stirred overnight. Cooling the reaction system to room temperature, concentrating under reduced pressure to remove the solvent, adding appropriate amount of water, extracting with ethyl acetate, washing the organic phase with saturated saline solution, and collecting anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product obtained is purified by silica gel column to give 1.6g of products 5-4, yield: 61 percent.

The fourth step: preparation of 8-amino-9-carbamoyl-1, 2,4a, 5-tetrahydrobenzo [ b ] pyrazine [1,2-d ] [1,4] oxazine-3 (4H) -carboxylic acid tert-butyl ester (5-5)

Compound 5-4 (1.6 g, 4.2mmol) was added to a reaction flask, dissolved in methanol (50 mL), and then Pd/C (300 mg) was added to replace hydrogen, and the reaction system was stirred at room temperature under a hydrogen atmosphere for reaction for 2 hours. Suction filtration, decompression concentration of the filtrate, purification of the obtained crude product through silica gel column to obtain 1.4g of product 5-5, yield: 95 percent.

The fifth step: preparation of 11-hydroxy-9-methyl-1, 2,4a, 5-tetrahydropyrazino [1',2':4,5] [1,4] oxazine [3,2-g ] quinazoline-3 (4H) -carboxylic acid tert-butyl ester (5-6)

Compound 5-5 (1.4g, 4.0mmol) was added to a sealed reaction tube, dissolved in absolute ethanol (30 mL), and trimethyl orthoacetate (5.0g, 41.3mmol) was added thereto, and the reaction system was sealed and heated to 120 ℃ to stir overnight. Cooling the reaction system to room temperature, concentrating under reduced pressure to remove the solvent, adding appropriate amount of water, extracting with ethyl acetate, washing the organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure, the crude product obtained is purified by silica gel column to give 1.3g of products 5-6, yield: 87 percent.

And a sixth step: preparation of 11-chloro-9-methyl-1, 2,4a, 5-tetrahydropyrazino [1',2':4,5] [1,4] oxazine [3,2-g ] quinazoline-3 (4H) -carboxylic acid tert-butyl ester (5-7)

To a reaction flask was added compound 5-6 (150mg, 0.40mmol), dissolved in toluene (3 mL), followed by the sequential addition of POCl ₃ (740mg, 4.83mmol) and DIPEA (234mg, 1.81mmol), and the reaction system was heated to 90 ℃ and stirred for 6 hours. Cooling the reaction system to room temperature, concentrating under reduced pressure to remove the solvent, adding appropriate amount of water, extracting with ethyl acetate, washing the organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure gave 129mg of product 5-7, yield: 82 percent.

The seventh step: preparation of 9-methyl-11- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -1,2,4a, 5-tetrahydropyrazinyl [1',2':4,5] [1,4] oxazine [3,2-g ] quinazoline-3 (4H) -carboxylic acid tert-butyl ester (5-8)

Compound 5-7 (120mg, 0.31mmol) was added to a sealed reaction tube, dissolved in isopropanol (3 mL), followed by intermediate A (125mg, 0.62mmol) and DIPEA (139mg, 1.08mmol), and the reaction was heated to 120 ℃ in a sealed manner and stirred for 36h. Cooling the reaction system to room temperature, concentrating under reduced pressure to remove the solvent, adding appropriate amount of water, extracting with ethyl acetate, washing the organic phase with saturated saline solution, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product through a silica gel column afforded 115mg of product 5-8, yield: 67%.

Eighth step: preparation of 9-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -3- (methylsulfonyl) -1,2,3,4,4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazinyl [3,2-g ] quinazolin-11-amine (T-5)

The compound 5-8 (30mg, 0.05mmol) is added into a reaction flask, dissolved in 1,4-dioxane (1 mL), 4M HCl/1, 4-dioxane solution (1 mL) is added dropwise, and the reaction system is stirred at room temperature for reaction for 1h. The solvent was removed by concentration under reduced pressure, dispersed in dichloromethane (2 mL), and Et was added successively ₃ N (16mg, 0.15mmol) and methylsulfonyl chloride (8mg, 0.07mmol) were reacted at room temperature with stirring for 0.5h. Concentrating to remove solvent, adding appropriate amount of water, extracting with ethyl acetate, washing organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtering and reducing pressureConcentration, purification of the crude product by thin layer silica gel plate to give 20mg of product T-5, yield: 70 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：536.2

¹ H NMR(400MHz,DMSO-d ₆ )δ8.15(d,J＝6.4Hz,1H),7.69-7.66(m,1H),7.53(d,J＝7.6Hz,1H),7.39-7.31(m,1H),6.84(s,1H),5.76-5.67(m,1H),4.49-4.42(m,1H),4.23-4.16(m,1H),4.06-3.95(m,1H),3.78-3.63(m,3H),3.32-3.25(m,1H),3.0-2.87(m,5H),2.64-2.59(m,4H),2.25(s,3H),1.57-1.52(m,3H).

Examples 6 to 11: preparation of Compounds T-6 to T-11

Compounds T-6 and T-7 were prepared in a similar manner to that described in example 5 using different intermediates (cyclopropanesulfonyl chloride, pyridine-3-sulfonyl chloride instead of methanesulfonyl chloride in the eighth step of example 5, respectively); compounds T-10 and T-11 were prepared in a similar manner to that described in example 5 by substituting (S) -tert-butyl 3- (hydroxymethyl) piperazine-1-carboxylate and (R) -tert-butyl 3- (hydroxymethyl) piperazine-1-carboxylate for compound 5-1a of the first step in example 5, respectively; compounds T-8 and T-9, structures, LC-MS and T-9, were prepared by substituting (S) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester, (R) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester for compound 5-1a of the first step in example 5 and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine for compound A of the seventh step in example 5, respectively, in a similar manner to that described in example 5 ¹ The H NMR data are shown in Table 1.

TABLE 1 structures of the compounds T6 to T11 prepared in examples 6 to 11, LC-MS and ¹ h NMR data

Example 12

Preparation of 2, 2-difluoro-2- (3- ((1R) -1- ((9-methyl-3- (methylsulfonyl) -1,2,3, 4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazinyl [3,2-g ] quinazolin-11-yl) amino) ethyl) phenyl) ethan-1-ol (T-12)

The first step is as follows: preparation of 11-chloro-9-methyl-3- (methylsulfonyl) -1,2,3, 4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazine [3,2-g ] quinazoline (12-1)

To a reaction flask, compound 5-7 (50mg, 0.13mmol) was added, dissolved in 1,4-dioxane (1 mL), 4M HCl/1, 4-dioxane solution (1 mL) was added dropwise, the reaction system was stirred at room temperature for 1h, concentrated under reduced pressure to remove the solvent, dispersed in dichloromethane (2 mL), and Et was sequentially added ₃ N (39mg, 0.30mmol) and methylsulfonyl chloride (18mg, 0.16mmol) were stirred at room temperature for 0.5h. Concentrating to remove solvent, adding appropriate amount of water, extracting with ethyl acetate, washing organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product on thin layer silica gel plates afforded 40mg of product 12-1, yield: 85 percent.

The second step: preparation of 2, 2-difluoro-2- (3- ((1R) -1- ((9-methyl-3- (methylsulfonyl) -1,2,3, 4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazinyl [3,2-g ] quinazolin-11-yl) amino) ethyl) phenyl) ethan-1-ol (T-12)

Compound 12-1 (40mg, 0.11mmol) was added to a sealed reaction tube, dissolved in isopropanol (3 mL), followed by addition of compound D (44mg, 0.22mmol) and DIPEA (50mg, 0.39mmol), and the reaction was sealed and heated to 120 ℃ and stirred for 36h. Cooling the reaction system to room temperature, concentrating under reduced pressure to remove the solvent, adding appropriate amount of water, extracting with ethyl acetate, washing the organic phase with saturated saline solution, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product by thin layer silica gel plate afforded 30mg of product T-12, yield: 52 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：534.2

¹ H NMR(400MHz,DMSO-d ₆ )δ8.14(brs,1H),7.68(s,1H),7.61(s,1H),7.58-7.54(m,1H),7.47-7.41(m,1H),6.40-7.35(m,1H),6.86(d,J＝1.6Hz,1H),5.67(t,J＝7.2Hz,1H),5.62(td,J＝6.4,2.0Hz,1H),4.50-4.44(m,1H),4.21-4.15(m,1H),4.06-3.97(m,1H),3.88-3.77(m,2H),3.75-3.63(m,2H),3.32-3.26(m,1H),3.07-2.97(m,1H),2.97(s,3H),2.95-2.85(m,1H),2.65-2.58(m,1H),2.32(s,3H),1.63-1.58(m,3H).

Example 13

Preparation of (R) -N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-methyl-3- (methylsulfonyl) -1,2,3,4,4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazino [3,2-g ] quinazolin-11-amine (T-13)

Compound T-13 was prepared in a similar manner to that described in example 12 by substituting (R) -11-chloro-9-methyl-3- (methylsulfonyl) -1,2,3, 4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazine [3,2-g ] quinazoline (13-1) and (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (C) for compound (12-1) and compound D, respectively, in the second step in example 12.

LC-MS(ESI)m/z(M+H) ⁺ ：537.2

¹ H NMR(400MHz,DMSO-d ₆ )δ8.23(s,1H),7.69(s,1H),6.88(s,1H),6.86(s,1H),6.84(s,1H),6.70(s,1H),5.62-5.54(m,1H),5.56(s,2H),4.47(dd,J＝10.8,2.8Hz,1H),4.18(d,J＝11.6Hz,1H),4.04(dd,J＝10.8,8.4Hz,1H),3.74-3.64(m,2H),3.04-2.96(m,1.5H),2.96(s,3H),2.96-2.88(m,1.5H),2.63(t,J＝11.2Hz,1H),2.35(s,3H),1.55(d,J＝7.2Hz,3H).

Example 14

Preparation of 9-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -3- (oxetan-3-yl) -1,2,3,4,4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazino [3,2-g ] quinazolin-11-amine (T-14)

The compound 5-8 (30mg, 0.05mmol) was added to the reaction flask, dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was added and the reaction stirred at room temperature for 1h. The solvent was removed by concentration under reduced pressure, 1, 2-dichloroethane (2 mL) and 3-oxetanone (7 mg, 0.09mmol) were added, and NaBH was then added ₃ CN (9mg, 0.15mmol), and the reaction system is stirred and reacted for 2h under the condition of room temperature. Adding appropriate amount of water to quench reaction, adjusting pH to alkaline with saturated sodium carbonate solution, extracting with dichloromethane, washing organic phase with saturated sodium chloride solution, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product by thin layer silica gel plate afforded 10mg of product T-14, yield: 39 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：514.2

¹ H NMR(400MHz,DMSO-d ₆ )δ8.36(brs,1H),7.79-7.74(m,1H),7.64(s,1H),7.56-7.51(m,1H),7.40-7.32(m,1H),6.83(s,1H),5.79-5.70(m,1H),4.64-4.47(m,5H),4.39-4.33(m,1H),4.07-3.94(m,3H),3.53-3.47(m,1H),3.24-3.16(m,1H),3.00-2.93(m,1H),2.90-2.77(m,2H),2.62(s,3H),2.29(s,3H),1.59-1.54(m,3H).

Examples 15 to 19: preparation of Compounds T-15 to T-19

Compounds T-15 and T-16 were prepared by a similar method to that described in the first to seventh steps of example 5, substituting (S) -tert-butyl 3- (hydroxymethyl) piperazine-1-carboxylate and (R) -tert-butyl 3- (hydroxymethyl) piperazine-1-carboxylate for compound 5-1a of the first step of example 5 to give intermediates 15-8 and 16-8, respectively, and then substituting 15-8 and 16-8 for compounds 5-8 of example 14 by a similar method to that described in example 14; compounds T-17 to T-19, structures, LC-MS and LC-MS, were prepared by a similar method to that described in example 14, substituting tetrahydropyranone, 1-ethoxy-1-trimethylsilylcyclopropane and acetone for 3-oxetanone in example 14, respectively ¹ The H NMR data are shown in Table 2.

TABLE 2 structures of the compounds T15 to T19 prepared in examples 15 to 19, LC-MS and ¹ h NMR data

Example 20

Preparation of 9-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -1,2,3,4,4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazinyl [3,2-g ] quinazolin-11-amine (T-20)

Compound 5-8 (40mg, 0.072mmol) was added to the reaction flask, dissolved in 1,4-dioxane (1 mL), and 4M HCl/1, 4-dioxane solution (1 mL) was added dropwise, and the system was stirred at room temperature for 3h. Concentrating under reduced pressure to remove solvent, adding saturated NaHCO ₃ Adjusting the system to alkalescence with water solution, extracting with ethyl acetate, washing the organic phase with saturated saline solution, and collecting anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure to dryness, purifying the crude product by a thin-layer silica gel plate to obtain 30mg of a product T-20, yield: 91 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：458.2

¹ H NMR(400MHz,DMSO-d ₆ )δ8.09(d,J＝7.2Hz,1H),7.79-7.73(m,1H),7.55-7.50(m,2H),7.39-7.31(m,1H),6.78(s,1H),5.76-5.67(m,1H),4.33-4.27(m,1H),3.98-3.85(m,2H),3.15-3.08(m,1H),3.06-2.93(m,2H),2.85-2.76(m,1H),2.69-2.60(m,1H),2.63(s,3H),2.35-2.27(m,1H),2.25(s,3H),1.57-1.52(m,3H).

Example 21

Compound T-20 (15mg, 0.033mmol) was charged into a reaction flask, dissolved in dichloromethane (1 ml), and DIPEA (13mg, 0.101mmol) and acetic anhydride (5mg, 0.049mmol) were sequentially added thereto, and the system was stirred at room temperature for 0.5h. Quenching the reaction with appropriate amount of water, extracting with dichloromethane, washing the organic phase with saturated brine, anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product by thin layer silica gel plate afforded 15mg of product T-21, yield: 92 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：500.2

¹ H NMR(400MHz,DMSO-d ₆ )δ8.48(brs,1H),7.81-7.76(m,1H),7.75-7.70(m,1H),7.58-7.52(m,1H),7.40-7.33(m,1H),6.87(s,1H),5.81-5.72(m,1H),4.62-4.33(m,2H),4.13-3.96(m,3H),3.12-3.04(m,1H),2.97-2.81(m,2H),2.76-2.67(m,1H),2.62(s,3H),2.31(s,3H),2.13-2.07(m,3H),1.61-1.55(m,3H).

Example 22

Preparation of (S) -N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-methyl-3- (oxetan-3-yl) -1,2,3, 4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazino [3,2-g ] quinazolin-11-amine (T-22)

Compounds 8-7 were prepared using a similar procedure to that described in example 5.

The first step is as follows: preparation of (S) -9-methyl-11- (((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -1,2,4a, 5-tetrahydropyrazinyl [1',2':4,5] [1,4] oxazine [3,2-g ] quinazoline-3 (4H) -carboxylic acid tert-butyl ester (22-1)

The compound 8-7 (60mg, 0.15mmol) was added to a reaction flask, dissolved in isopropanol (3 mL), followed by the addition of the compound C-5 (72mg, 0.31mmol) and DIPEA (70mg, 0.54mmol), sealing the system and heating to 120 ℃ for stirring reaction for 36h. Cooling the reaction system to room temperature, concentrating under reduced pressure to remove the solvent, adding appropriate amount of water, extracting with ethyl acetate, washing the organic phase with saturated brine, and collecting anhydrous Na ₂ SO ₄ Drying, filtering andconcentration under reduced pressure and purification of the resulting crude product through a silica gel column gave 20mg of product 22-1, yield: 22 percent.

The second step: preparation of (S) -9-methyl-N- ((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -3- (oxetan-3-yl) -1,2,3, 4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazino [3,2-g ] quinazolin-11-amine (22-2)

Compound 22-1 (20mg, 0.034mmol) was charged into a reaction flask, and dissolved in methylene chloride (2 mL), and trifluoroacetic acid (1 mL) was added thereto, and the reaction was stirred at room temperature for 1 hour. Concentrating under reduced pressure to remove the solvent, adding 1, 2-dichloroethane (2 mL) and 3-oxetanone (7 mg,0.097 mmol), and adding NaBH ₃ CN (6 mg, 0.095mmol), and the reaction system was stirred at room temperature for 2 hours. The reaction was quenched by addition of appropriate amount of water to the system and saturated Na ₂ CO ₃ Adjusting pH of the solution to alkaline, extracting with dichloromethane, washing the organic phase with saturated brine, and removing anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product on thin layer silica gel plates afforded 15mg of product 22-2, yield: 81 percent.

The third step: preparation of (S) -N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-methyl-3- (oxetan-3-yl) -1,2,3,4,4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazino [3,2-g ] quinazolin-11-amine (T-22)

Compound 22-2 (15mg, 0.03mmol) was added to a reaction flask, dissolved in ethanol (2 mL), and then purified water (0.4 mL), NH, was added ₄ Cl (6 mg, 0.12mmol) and reduced iron powder (7 mg, 0.12mmol), and the reaction system was heated to 50 ℃ and stirred for reaction for 3 hours. Cooling the reaction system to room temperature, concentrating under reduced pressure to remove organic solvent, adding appropriate amount of water, extracting with ethyl acetate, washing organic phase with saturated saline solution, and collecting anhydrous Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, purification of the crude product on thin layer silica gel plates afforded 10mg of product T-22, yield: 71 percent.

LC-MS(ESI)m/z(M+H) ⁺ ：515.2

¹ H NMR(400MHz,DMSO-d ₆ )δ7.95(brs,1H),7.58(s,1H),6.90-6.83(m,3H),6.69(s,1H),5.61-5.51(m,3H),4.65-4.56(m,2H),4.56-4.47(m,2H),4.39-4.32(m,1H),4.06-3.92(m,2H),3.54-3.45(m,2H),3.19-3.16(m,1H),2.98-2.83(m,2H),2.83-2.64(m,2H),2.31(s,3H),1.54(d,J＝6.4Hz,3H).

Example 23

Preparation of (R) -N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-methyl-3- (oxetan-3-yl) -1,2,3, 4a, 5-hexahydropyrazino [1',2':4,5] [1,4] oxazino [3,2-g ] quinazolin-11-amine (T-23)

Compound T-23 was prepared using a similar procedure to that described in example 22, using a different intermediate (R) -11-chloro-9-methyl-1, 2,4a, 5-tetrahydropyrazino [1',2':4,5] [1,4] oxazine [3,2-g ] quinazoline-3 (4H) -carboxylic acid tert-butyl ester instead of (S) -11-chloro-9-methyl-1, 2,4a, 5-tetrahydropyrazino [1',2':4,5] [1,4] oxazine [3,2-g ] quinazoline-3 (4H) -carboxylic acid tert-butyl ester (8-7) of the first step in example 22).

LC-MS(ESI)m/z(M+H) ⁺ ：515.2

¹ H NMR(400MHz,DMSO-d ₆ )δ7.92(d,J＝6.4Hz,1H),7.56(s,1H),6.89-6.81(m,3H),6.70(s,1H),5.59-5.53(m,3H),4.62-4.56(m,2H),4.54-4.48(m,2H),4.37-4.32(m,1H),4.02-3.96(m,2H),3.52-3.45(m,2H),3.23-3.15(m,1H),2.96-2.91(m,1H),2.89-2.75(m,3H),2.31(s,3H),1.53(d,J＝7.2Hz,3H).

Examples 24 to 27: preparation of Compounds T-24 to T-27

Compounds T-24 to T-27, structures, LC-MS and LC-MS were prepared in a similar manner to that described for the first and second steps of example 22, using different starting materials (R) - (+) -A-methylbenzylamine, intermediate E, intermediate F, intermediate G instead of compound C-5 in example 22, respectively) ¹ The H NMR data are shown in Table 3.

TABLE 3 structures, LC-MS and ¹ h NMR data

The advantageous effects of the present invention are demonstrated by specific test examples below.

Test of drug efficacy

Test example 1: SOS1 homogeneous time-resolved fluorescence binding assay

Protein-protein interactions were determined by homogeneous time-resolved fluorescence techniques.

To a 384 reaction plate (Corning, CLS 4514), 0.1. Mu.l of the compound was added, and after centrifugation, 5. Mu.l of a mixture of Tag2-KRAS G12D (Cisbio, 63ADK000CB17 PEG) protein and GTP (SIGMA, V900868) at a final concentration of 10. Mu.M was added. A further 5. Mu.l of Tag1-SOS1 (Cisbio, 63ADK000CB17 PEG) protein solution were added and reacted at room temperature for 15 minutes. All protein interactions occurred in Diluent (Cisbio, 62 DLBDDF) buffer solution. Add 10. Mu.l of premixed 100 Xanti-Tag 1-Tb and 25 Xanti-Tag 2-XL665 detection solution and react for 180 minutes at 4 ℃. The Detection reagents take place in Detection Buffer (Cisbio, 62DB2 FDG). The reaction signals were detected by a multifunctional microplate reader and the data were analyzed using GraphPad Prism data analysis software.

The structure of reference compound BI-3406 is:

the compound is a commercially available compound.

SOS1 binding inhibition activity of the compounds on KRAS G12D GTP:, is shown in Table 4.

Table 4: SOS1 binding inhibition Activity of Compounds on KRAS G12D GTP

From the above data it can be seen that: the compound has obvious inhibition effect on SOS1 activity, wherein most of the compounds have similar inhibition effect to that of a reference compound BI-3406; the inhibition effect of the T-3, T-5, T-8, T-9, T-11, T-12, T-15, T-21 and T-22 compounds is even better than that of the reference compound BI-3406; the compound can be used as an SOS1 KRAS inhibitor and has wide application prospect in resisting malignant tumor diseases.

Test example 2: liver microsome stability test

1: adding 10 mu L of a test or control working solution and 80 mu L of a microsome working solution (the concentration of the liver microsome protein is 0.5 mg/mL) into a hole site of a T0, T5, T10, T20, T30, T60 and NCF60 sample, adding only the microsome working solution into the hole site of Blank60, and then placing the samples Blank60, T5, T10, T20, T30 and T60 except for the T0 and NCF60 in a water bath kettle at 37 ℃ for preincubation for about 10 minutes;

2: adding 300 mu L of termination solution (acetonitrile solution of conjugation 200ng/mL tolbutamide and 200ng/mL labetalol) into the T0 sample, and then adding 10ul of NADPH regeneration system working solution;

3: after the preincubation of the incubation plates Blank60, T5, T10, T20, T30 and T60 is finished, 10. Mu.L of NADPH regeneration system working solution is added into each sample well to start the reaction, and 10uL of 100mM potassium phosphate buffer solution is added into the NCF60 sample well;

4: after incubation for a suitable period of time (e.g., 5, 10, 20, 30 and 60 minutes), 300. Mu.L of stop solution was added to each of the test sample wells and the control sample wells of Blank60, T5, T10, T20, T30, T60 and NCF60 plates, respectively, to stop the reaction;

5: all sample plates were shaken up and centrifuged at 4000rpm for 20 minutes, 100. Mu.L of test or control supernatants, respectively, were diluted into 300. Mu.L of pure water for LC-MS/MS analysis;

6: data analysis, calculation of T from first order elimination kinetics _1/2 And CL _int(mic) (μ L/min/mg) value, first order elimination kinetics equation:

the results of the human and rat liver microsome stability tests are shown in table 5.

Table 5: partial compound liver microsome stability test results of the invention

From the patent medicine research data, the compound has better metabolic stability on human liver microsomes.

In conclusion, the compound has obvious inhibition effect on SOS1 activity, can be used as an SOS1 KRAS inhibitor, has good metabolic stability and has wide application prospect in resisting malignant tumor diseases.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. A compound shown in formula I, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystal form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof:

wherein,

m1 is 0, 1,2,3,4 or 5;

R ¹ is a substituent of the ring A, each R ¹ Independently at the occurrence is selected from substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, halogen, amino, hydroxyl, carboxyl, cyano, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, substituted OR unsubstituted 5-to 14-membered aryl, substituted OR unsubstituted 5-to 14-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or any two of R ¹ Are connected to form substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered aryl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted 3-12 membered heteroaryl; or two R on the same atom ¹ Composition = O;

R ¹⁰ selected from hydrogen, halogen, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, hydroxyl, amino, carboxyl, cyano, substituted or unsubstituted 2 to 10Hetero-alkyl, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² ；

Ring B is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-14 membered aryl, 5-14 membered heteroaryl;

m2 is 0, 1,2,3,4 or 5;

the substituents are respectively and independently selected from halogen and C ₁ ～C ₁₀ Alkyl radical, C ₂ ～C ₁₀ Alkenyl radical, C ₁ ～C ₁₀ Haloalkyl, C ₁ ～C ₁₀ Alkoxy radical, C ₁ ～C ₁₀ Alkylthio, 2-to 10-membered oxaalkyl, amino, carboxyl, hydroxyl, nitro, 3-to 12-membered cycloalkyl, 3-to 12-membered heterocyclyl, 5-to 14-membered aryl, 5-to 14-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or two on the same atomSubstituent composition = O;

2. The compound according to claim 1, or a tautomer thereof, or an inner racemate thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, wherein: the compound is shown as a formula II-1 or a formula II-2:

wherein,

m1 is 0, 1,2,3,4 or 5;

R ¹ is a substituent of the ring A, each R ¹ Independently at the occurrence is selected from substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, halogen, amino, hydroxyl, carboxyl, cyano, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, substituted OR unsubstituted 5-to 14-membered aryl, substituted OR unsubstituted 5-to 14-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or any two R ¹ Are linked to form a substituted or unsubstituted 3-to 12-membered cycloalkyl group, a substituted or unsubstituted 3-to 12-membered aryl group, a substituted or unsubstituted 3-to 12-membered E12-membered heterocyclic group, substituted or unsubstituted 3-to 12-membered heteroaryl group; or two R on the same atom ¹ Composition = O;

R ^5a 、R ^5b Each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, amino, cyano, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, substituted or unsubstituted 6-to 10-membered aryl, substitutedOR unsubstituted 5-to 12-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or R ^5a 、R ^5b Common composition = O; or R ^5a 、R ^5b Are connected to form substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered aryl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted 3-12 membered heteroaryl;

R ⁶ 、R ⁷ each occurrence is independently selected from halogen, cyano, hydroxy, carboxy, -C (O) R ₁₂ Amino, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstituted C ₂ ～C ₁₀ An alkenyl group; or two R on the same carbon atom ⁶ Linked to form a substituted or unsubstituted 3-to 6-membered cycloalkyl or composition = O; or two R on the same carbon atom ⁷ Linked to form a substituted or unsubstituted 3-to 6-membered cycloalkyl group or composition = O;

R ¹² are respectively and independently selected from hydrogen and C ₁ ～C ₁₀ Alkyl, amino, 2-to 10-membered heteroalkyl, 3-to 12-membered cycloalkaneA group, a 3-to 12-membered heterocyclic group, a 5-to 14-membered aryl group, a 5-to 14-membered heteroaryl group;

n ₁ 、n ₂ are respectively and independently selected from 0, 1,2,3,4 and 5;

3. The compound according to claim 2, or a tautomer thereof, or an inner racemate thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, wherein:

ring A is selected from phenyl;

m1 is 0, 1,2 or 3;

R ¹ is a substituent of the ring A, each R ¹ Independently at the occurrence is selected from substituted or unsubstituted C ₁ ～C ₂ Alkyl, halogen, amino; or any two R ¹ Are connected to form a substituted or unsubstituted 5-6 membered cycloalkyl group, a substituted or unsubstituted 5-6 membered heterocyclic group; the substituent groups are respectively and independently selected from hydroxyl, halogen or two substituent groups on the same atom to form = O;

R ² selected from hydrogen, halogen, C ₁ ～C ₄ An alkyl group;

4. A compound according to claim 2 or 3, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, characterized in that:

U ¹ 、U ² 、U ³ is selected from-O-;

R ⁴ Selected from hydrogen, halogen, cyano, hydroxy, carboxy, amino, substituted or unsubstituted C ₁ ～C ₆ Alkyl, 3-to 6-membered cycloalkyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, substituted or unsubstituted piperidinyl, C ₂ ～C ₆ Alkenyl, -C (O) R ¹² 、-S(O)(O)R ¹² ；

R ^5a 、R ^5b Each independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, amino, substituted or unsubstituted C ₁ ～C ₆ Alkyl, 3-to 6-membered cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, substituted or unsubstituted piperidinyl, C ₂ ～C ₆ Alkenyl, -C (O) R ¹² 、-S(O)(O)R ¹² (ii) a Or R ^5a 、R ^5b Common composition = O; or R ^5a 、R ^5b Are connected to form 3-6 membered cycloalkyl;

R ⁶ 、R ⁷ independently at each occurrence, is selected from halogen, cyano, hydroxy, carboxy, -C (O) R ₁₂ Amino, substituted or unsubstituted C ₁ ～C ₆ Alkyl, 3-to 6-membered cycloalkyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, substituted or unsubstituted piperidinyl, C ₂ ～C ₆ Alkenyl, -S (O) (O) R ¹² (ii) a Or two R on the same carbon atom ⁶ Are linked to form a 3-to 6-membered cycloalkyl group or composition = O; or two R on the same carbon atom ⁷ Are linked to form a 3-to 6-membered cycloalkyl group or composition = O;

5. The compound according to claim 1, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, wherein: the compound is shown in a formula IV-1, a formula IV-2, a formula IV-3 and a formula IV-4:

wherein,

R ^1a 、R ^1b 、R ^1c independently selected from hydrogen, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, halogen, amino, hydroxyl, carboxyl, cyano, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstituted C ₂ ～C ₁₀ Alkenyl, substituted OR unsubstituted 5-to 14-membered aryl, substituted OR unsubstituted 5-to 14-membered heteroaryl, -C (O) OR ¹² 、-C(O)R ¹² 、-C(O)NHR ¹² 、-NHC(O)R ¹² 、-S(O)R ¹² 、-S(O)(O)R ¹² 、-S(O)(O)NHR ¹² 、-NHS(O)(O)R ¹² 、-S(O)NHR ¹² 、-NHS(O)R ¹² (ii) a Or R ^1a 、R ^1b 、R ^1c Any two of which are connected to form a substituted or unsubstituted 3-to 12-membered cycloalkyl group, a substituted or unsubstituted 3-to 12-membered aryl group, a substituted or unsubstituted 3-to 12-membered heterocyclic group, a substituted or unsubstituted 3-to 12-membered heteroaryl group;

R ^6a 、R ^6b 、R ^6c 、R ^6d 、R ^7a 、R ^7b Are independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) R ₁₂ Amino, substituted or unsubstituted C ₁ ～C ₁₀ Alkyl, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted 3-to 12-membered cycloalkyl, substituted or unsubstituted 3-to 12-membered heterocyclic group, substituted or unsubstituted C ₂ ～C ₁₀ An alkenyl group; or R on the same carbon atom ^6a And R ^6b Linked to form a substituted or unsubstituted 3-to 6-membered cycloalkyl group or composition = O; or R on the same carbon atom ^6c And R ^6d Linked to form a substituted or unsubstituted 3-to 6-membered cycloalkyl or composition = O; or R on the same carbon atom ^7a And R ^7b Linked to form a substituted or unsubstituted 3-to 6-membered cycloalkyl or composition = O;

6. The compound according to claim 5, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, wherein:

R ^1a 、R ^1b 、R ^1c independently selected from hydrogen, substituted or unsubstituted C ₁ ～C ₂ Alkyl, halogen, amino; or any two R ¹ Are connected to form a substituted or unsubstituted 5-to 6-membered cycloalkyl group, a substituted or unsubstituted 5-to 6-membered heterocyclic group; the substituent groups are respectively and independently selected from hydroxyl, halogen or two substituent groups on the same atom to form = O.

7. The compound according to claim 5 or 6, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, wherein:

R ^6a 、R ^6b 、R ^6c 、R ^6d 、R ^7a 、R ^7b Are independently selected from hydrogen, halogen, cyano, hydroxy, carboxy, -C (O) R ¹² Amino, substituted or unsubstituted C ₁ ～C ₆ Alkyl, 3-to 6-membered cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, substituted or unsubstituted piperidinyl, C ₂ ～C ₆ Alkenyl, -S (O) (O) R ¹² (ii) a Or R on the same carbon atom ^6a And R ^6b Are linked to form a 3-to 6-membered cycloalkyl group or composition = O; or R on the same carbon atom ^6c And R ^6d Are linked to form a 3-to 6-membered cycloalkyl group or composition = O; or R on the same carbon atom ^7a And R ^7b Connected to form a 3-6 membered cycloalkyl group or composition = O;

R ¹² Are each independently selected from C ₁ ～C ₆ Alkyl, amino, 3-to 6-membered cycloalkyl, pyridyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl.

8. The compound according to any one of claims 1 to 7, or a tautomer thereof, or an inner racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, wherein: the compound is one of the following compounds:

9. use of a compound according to any one of claims 1 to 8, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, for the preparation of a non-heptakinase homolog 1 inhibitor.

10. Use of a compound according to any one of claims 1 to 8, or a tautomer thereof, or an inner racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystal form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, for the manufacture of a medicament for the treatment and/or prevention of a tumor disease.

11. Use according to claim 10, characterized in that: the tumor disease is pancreatic cancer, laryngeal cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, bone cancer, large intestine cancer, colorectal cancer, cholangiocarcinoma, biliary tract cancer, kidney cancer, hepatocellular cancer, stomach cancer, hairy cell cancer, follicular cancer, nasopharyngeal cancer, pharyngeal cancer, esophageal cancer, bronchial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, cervical cancer, thyroid cancer, breast cancer, ovarian cancer, testicular cancer, prostate cancer, bladder cancer, urothelial cancer, genitourinary tract cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, non-hodgkin's lymphoma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, myelogenous leukemia, sarcoma, glioblastoma, cancer of the central nervous system of the brain.

12. Use according to claim 11, characterized in that: the tumor diseases comprise pancreas cancer, lung cancer, bile duct epithelial cancer and colorectal cancer;

preferably, the lung cancer is non-small cell lung cancer.

13. Use according to claim 12, characterized in that: the disease is selected from G12C, G12V, G12D, G12R-associated KRAS mutated lung adenocarcinoma; G12D, G12V, G12C, G12R, G13D-related KRAS-mutated colorectal adenocarcinoma; G12D, G12V, G12R, G12C, Q61H related KRAS mutated pancreatic adenocarcinomas.

14. Use of a compound according to any one of claims 1 to 8, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystalline form thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, for the manufacture of a medicament for the treatment and/or prevention of neurofibromatosis type 1, noonan's syndrome, labyrinthine nevus syndrome, LEOPARD syndrome, capillary malformation-arteriovenous malformation syndrome, costilus syndrome, cardio-facial-skin syndrome, reji's syndrome, or NF 1-like syndrome, hereditary gingival fibromatosis.

15. A medicament, characterized by: the compound is a preparation prepared by taking the compound, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereoisomer thereof, or a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, or a crystal form thereof, or a nitrogen oxide thereof, or an isotope thereof, or a metabolite thereof, or a prodrug thereof, or an ester thereof, or a salt thereof, as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

16. A pharmaceutical composition characterized by: the active ingredients of the pharmaceutical composition are selected from the compounds of any one of claims 1 to 8, or tautomers thereof, or racemates thereof, or enantiomers thereof, or diastereomers thereof, or mixtures thereof, or pharmaceutically acceptable hydrates thereof, or pharmaceutically acceptable solvates thereof, or crystal forms thereof, or isotopes thereof, or metabolites thereof, or prodrugs thereof, or salts thereof.