CN115490709A

CN115490709A - KRASG12D inhibitor and application thereof in medicine

Info

Publication number: CN115490709A
Application number: CN202210444808.3A
Authority: CN
Inventors: 张晨; 何平; 廖鹏飞; 黄清平; 雷鸣; 魏琦; 叶飞; 李瑶; 倪佳; 严庞科
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Tibet Haisike Pharmaceutical Co ltd
Priority date: 2021-04-30
Filing date: 2022-04-27
Publication date: 2022-12-20

Abstract

KRASG12D inhibitor and its application in medicine are provided. The invention relates to a compound shown in a general formula (I-a) or a stereoisomer, a deuteron, an N-oxide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparing a medicament for treating diseases related to KRASG12D activity or expression quantityThe use of (1).

Description

KRAS G12D inhibitor and application thereof in medicine

Technical Field

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparation of medicines for treating diseases related to KRAS G12D activity or expression quantity.

Background

RAS protein is expressed by RAS gene (Rat Sarcoma viral oncogene), is intracellular guanine nucleotide binding protein, and belongs to gtpase (weak hydrolytic activity). RAS proteins exist in two distinct states: an inactive GDP-bound state and an active GTP-bound state. The RAS protein in the activated state signals through interaction with various downstream effectors, and has effects on growth, differentiation, cytoskeleton, protein transport and secretion, etc. of cells. Activation of RAS signaling is regulated by guanine nucleotide exchange factors (GEF, which can result in GDP-GTP exchange) or gtpase activating proteins (GAP, which can result in the RAS protein changing from an active state to an inactive state), and resistance of mutant RAS proteins to GAP can lead to sustained activation of RAS proteins, causing uncontrolled growth of cells, and ultimately progression to cancerous tissues (Molecular Cancer,2018, 17.

RAS gene mutations are a common type of gene mutation in cancer patients (nat. Rev. Drug discov.2014,13, 828-851), and account for, for example, 97.7%,52.2%,42.6% and 32.2% in pancreatic cancer, colorectal cancer, multiple myeloma and NSCLC, respectively. The KARS gene (Kristen Rat Sarcoma viral oncogene) mutation is the most influential mutation among RAS mutations, accounting for 86% of all RAS mutations. The most common way to activate the KRAS gene is by point mutation, with 95% of KRAS mutations occurring primarily at codon 12 and codon 13 of exon 2, and the common forms of mutation being KRAS G12C (39%), KRAS G12V (18-21%) and KRAS G12D (17-18%) mutations.

KRAS mutein inhibitors have received considerable attention since the discovery of KRAS muteins in cancer and the observation that inhibition of these muteins can inhibit tumor proliferation. KRAS has long been recognized as an "unforgeable target": RAS has a high affinity for GTP/GDP (picomolar), and the entire protein also lacks other "ligand binding pockets" (clin. Cancer res.2015,21, 1810-1818).

The KRAS G12D mutation affects approximately 18 million patients in the european and american countries. KRAS G12D accounts for 36% in patients with pancreatic cancer, 12% in patients with colon cancer, 4% in patients with NSCLC adenocarcinoma, and 6% in patients with endometrial cancer. At present, inhibitors against KRAS G12D mutation are still in the early stages, no compounds are in clinical research, only a few companies have relevant patent publications in this field, e.g. Mirati Therapeutics filed an inhibitor patent for KRAS G12D (WO 2021041671). Therefore, there is a need to develop compounds capable of inhibiting KRAS G12D protein for treating related diseases caused by KRAS G12D mutation.

Disclosure of Invention

The invention aims to provide a compound capable of inhibiting KRAS G12D protein or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic, an intermediate and a preparation method thereof, and application of the compound in preparation of medicines for treating diseases related to KRAS G12D activity or expression.

The invention provides a compound shown in a general formula (I-a) or a stereoisomer, a deuterode, an N-oxide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein

In some embodiments, X ₁ Or X ₂ Each independently selected from N or CR ^b ；

In some embodiments, X ₁ 、X ₂ Is selected from N;

in some embodiments, X ₁ 、X ₂ Selected from the group consisting of CR ^b ；

In some embodiments, X ₁ Is selected from N, X ₂ Selected from the group consisting of CR ^b ；

In some embodiments, X ₁ Selected from the group consisting of CR ^b ，X ₂ Is selected from N;

in some embodiments, ring a is selected from 3-to 12-membered carbocyclyl or 4-to 12-membered heterocyclyl, said carbocyclyl or heterocyclyl optionally further substituted with 0 to 6R ^a Substituted, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) substituents selected from O, S,A heteroatom of N;

in some embodiments, L ₁ 、L ₂ Or L ₃ Each independently selected from the group consisting of a bond, O, -CH ₂ -、-OCH ₂ -、-CH ₂ O-, -C (= O) -, S or NR ^x ；

In some embodiments, R ^x Selected from H, C _1-6 Alkyl or C _3-6 Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、 C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy;

in some embodiments, L is ₃ Is selected from a bond;

in some embodiments of the present invention, the substrate is,

is selected from

In some embodiments of the present invention, the substrate is,

selected from 4-to 12-membered nitrogen-containing heterocycles selected from one of the following saturated or partially saturated groups: monocyclic, fused, bridged or spirocyclic ring, said nitrogen-containing heterocycle, monocyclic, fused, bridged or spirocyclic ring being optionally further substituted with 0 to 4 (e.g. 0, 1,2,3 or 4) R ^a Substituted, ring A ₁ Wherein N-H is unsubstituted;

in some embodiments of the present invention, the substrate is,

selected from one of the following unsubstituted or substituted groups:

when substituted, is optionally further substituted with 0 to 4 (e.g., 0, 1,2,3, or 4) R ^a Substituted by a substituent, ring A ₁ Wherein N-H is unsubstituted;

in some embodiments of the present invention, the substrate is,

selected from unsubstituted or substituted

When substituted, is optionally further substituted with 0 to 4 (e.g., 0, 1,2,3, or 4) R ^a Substituted by substituents, ring A ₁ Wherein N-H is unsubstituted;

in some embodiments of the present invention, the substrate is,

is selected from

In some embodiments, R ^a Each independently selected from H, oxo, halogen, cyano, OH, NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 8-membered cycloalkyl, 4-to 8-membered heterocyclyl, -O-3-to 8-membered cycloalkyl, -O-4-to 8-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocyclyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, wherein the heterocyclic group contains 1 to 4 hetero atoms selected from O, S and N;

in some embodiments, R ^a Each independently selected from H, oxo, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy, 3-to 6-membered cycloalkyl, 4-to 6-membered heterocyclyl, -O-3-to 6-membered cycloalkyl,-O-4 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocyclyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, wherein the heterocyclic group contains 1 to 4 hetero atoms selected from O, S and N;

in some embodiments, R ^a Each independently selected from H, oxo, F, cl, br, I, cyano, OH, NH ₂ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, F, cl, br, I, OH, cyano, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

in some embodiments, R ^a Each independently selected from H, oxo, F, cl, br, I, cyano, OH, NH ₂ Methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, -O-cyclopropyl, said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, F, cl, br, I, OH, cyano, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy or propoxy;

in some embodiments, R ^a Each independently selected from H;

in some embodiments, two R are ^a Taken together with the atoms to which they are attached form a 3-to 12-membered carbocyclic or 4-to 12-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N;

in some embodiments, two R are ^a Together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 4-to 6-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、 NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N;

in some embodiments, ring B ₁ Selected from 3 to 8 membered carbocyclyl, 5 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl or phenyl, optionally further substituted with 0 to 7 (e.g. 0, 1,2,3,4, 5,6, 7) R ^b (iii) substituted, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments of the present invention, the substrate is,

is selected from

Left side and L of it ₂ Is connected, above and to ring A ₁ Connecting;

in some embodiments of the present invention, the substrate is,

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ Connecting;

in some embodiments of the present invention, the substrate is,

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ Connecting;

in some embodiments of the present invention, the substrate is,

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ Connecting;

in some embodiments of the present invention, the substrate is,

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ Connecting;

in some embodiments of the present invention, the substrate is,

is selected from

Left side and L of it ₂ Is connected, above and to ring A ₁ Connecting;

in some embodiments, R ^b Each independently selected from H, oxo, halogen, cyano, OH, NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkylthio radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, 3-to 8-membered cycloalkyl, 4-to 8-membered heterocyclyl, -O-3-to 8-membered cycloalkyl, -O-4-to 8-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl or heterocycloalkyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Alkoxy, 4-7 membered heterocyclyl or C _3-6 Cycloalkyl, said heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, two R are ^b Taken together with the atoms to which they are attached form a 3-to 12-membered carbocyclyl or a 4-to 12-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N;

in some embodiments, R ^b Each independently selected from H, oxo, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkylthio radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, 3-to 6-membered cycloalkyl, 4-to 6-membered heterocyclyl, -O-3-to 6-membered cycloalkyl, -O-4-to 6-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl or heterocycloalkyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halo, OH, cyano, oxo, CF ₃ 、COOH、 NH ₂ 、C _1-4 Alkyl orC _1-4 Alkoxy, said heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, two R are ^b Taken together with the atoms to which they are attached to form a 3-to 6-membered carbocyclyl or a 4-to 6-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N;

in some embodiments, R ^b Each independently selected from H, oxo, F, cl, br, I, cyano, OH, NH ₂ Methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy being optionally further selected from H, F, cl, br, I, OH, cyano, oxo, CF, and 4 (e.g. 0, 1,2,3 or 4) ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

in some embodiments, R ^b Each independently selected from H, oxo, F, cl, br, I, cyano, OH, NH ₂ Methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, -O-cyclopropyl, ethenyl, ethynyl, said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, ethenyl, ethynyl, cyclopropyl being optionally further selected from H, F, cl, br, I, OH, cyano, oxo, CF by 0 to 4 (e.g. 0, 1,2,3 or 4) ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy or propoxy;

in some casesIn embodiments, R ^b Selected from H, F, cl, cyano, OH, NH ₂ Methyl, ethyl, methoxy, ethoxy, cyclopropyl, -O-cyclopropyl;

in some embodiments, L is ₁ Selected from-O-and-O-CH ₂ -；

In some embodiments, R ¹ Selected from halogen, OH, cyano, COOH, NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, NH ₂ 、-(CH ₂ ) _q -C(＝O)C _1-6 Alkyl, - (CH) ₂ ) _q -C (= O) -3-to 12-membered heterocycle, - (CH) ₂ ) _q -C(＝O)-C _3-10 Carbocyclic ring, - (CH) ₂ ) _q -3 to 12 membered heterocycle or- (CH) ₂ ) _q -C _3-10 Carbocyclic ring of said CH ₂ Alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 (e.g., 0, 1,2,3 or 4) R ^1a (ii) substituted, said heterocyclic ring containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N;

in some embodiments, -L ₁ -R ₁ Is selected from

In some embodiments, R ^1a Each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, -C _1-6 alkylene-OH, - (CH) ₂ ) _q -C _3-10 Carbocyclic ring, - (CH) ₂ ) _q -3 to 12 membered heterocycle, -O-C _3-10 Carbocyclic ring, -O-3 to 12 membered heterocyclic ring, C _1-6 Alkoxy, -N (C) _1-6 Alkyl) C (= O) -3-to 12-membered heterocycle, said alkyl, CH ₂ Alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle is optionally further substituted with 0 to 4 (e.g., 0, 1,2,3 or 4) groups selected from H, halo, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycle or heterocycloalkyl containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N;

in some embodiments, R ^1a Each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、 -NH(C _1-4 Alkyl), -N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, -C _1-4 alkylene-OH, - (CH) ₂ ) _q -C _3-8 Carbocyclic ring, - (CH) ₂ ) _q -3 to 8 membered heterocycle, -O-C _3-8 Carbocycle, -O-3 to 8-membered heterocycle, C _1-4 Alkoxy, -N (C) _1-4 Alkyl) C (= O) -3-to 8-membered heterocyclic substituent, said alkyl, CH ₂ Alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle is optionally further substituted with 0 to 4 (e.g., 0, 1,2,3 or 4) groups selected from H, halo, OH, cyano, oxo, CF ₃ 、 COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycle or heterocycloalkyl containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N;

in some embodiments, R ^1a Each independently selected from H, F, cl, br, I, oxo, OH, cyano, CF ₃ 、COOH、 NH ₂ Methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy being optionally further selected by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

in some embodiments, R is ^1a Is selected from F;

in some embodiments, -L ₁ -R ₁ Is selected from

In some embodiments, L is ₂ Selected from a bond, O or-C (= O) -;

in some embodiments, L is ₂ Selected from a bond or-C (= O) -;

in some embodiments, L ₂ Is selected from a bond;

in some embodiments, R ² Is selected from C _1-6 Alkyl radical, C _3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl optionally further substituted with 0 to 7 (e.g. 0, 1,2,3,4, 5,6 or 7) R ^2a (ii) substituted, said heterocyclyl or heteroaryl containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N;

in some embodiments, R ² Is selected from C _3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted with 0 to 5 (e.g. 0, 1,2,3,4 or 5) R ^2a (ii) substituted, said heterocyclyl or heteroaryl group containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N;

in some embodiments, R ² Selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, indazole, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuryl, benzopyrimidinyl, benzopyridyl, or pyridyl, when substituted, optionally substituted with 0 to 5 (e.g., 0, 1,2,3,4, or 5) R ^2a Substitution;

in some embodiments, R ² Selected from one of the following substituted or unsubstituted groups: phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrazolyl, or naphthyl, when substituted, optionally substituted with 0 to 5 (e.g., 0, 1,2,3,4, or 5) R ^2a Substitution;

in some embodiments, R ² Selected from one of the following substituted groups: phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrazolyl, or naphthyl, when substituted, with 1 to 5 (e.g., 1,2,3,4, or 5) R ^2a Substituted, R ^2a Each independently selected from H, F, cl, OH, cyano, NH ₂ 、CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl, provided that at least one R is ^2a Selected from cyclopropyl, cyclobutyl or cyclopentyl;

in some embodiments, R ² Selected from phenyl, benzopyrazolyl, benzofuranyl, pyridyl, said phenyl being substituted with 1 to 4R ^2a Substituted by 0 to 4R ^2a Substitution;

in some embodiments, R ^2a Each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、 -NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylthio radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, -O-C _3-6 Cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 Aryl or 5 to 10 membered heteroaryl, said alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,Heteroaryl is optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、 NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycloalkyl, heterocyclyl or heteroaryl containing 1 to 4 (e.g., 1,2,3 or 4) heteroatoms selected from O, S, N;

in some embodiments, R ^2a Each independently selected from-NHC (O) C _1-6 Alkyl, -NHS (O) ₂ C _1-6 Alkyl, -P (O) (C) _1-6 Alkyl radical) ₂ Said alkyl is optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N;

in some embodiments, two R are ^2a Together with the atoms to which they are directly attached form a 3-to 12-membered carbocyclic or 4-to 12-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N;

in some embodiments, R ^2a Each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、 -NH(C _1-4 Alkyl), -N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Alkylthio radical, C _2-4 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, -O-C _3-6 Cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylthioThe aryl, heteroaryl is optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、 NH ₂ 、C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycloalkyl, heterocyclyl or heteroaryl containing 1 to 4 (e.g., 1,2,3 or 4) heteroatoms selected from O, S, N;

in some embodiments, R ^2a Each independently selected from-NHC (O) C _1-4 Alkyl, -NHS (O) ₂ C _1-4 Alkyl, -P (O) (C) _1-4 Alkyl radical) ₂ Said alkyl group is optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N;

in some embodiments, two R are ^2a Taken together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 4-to 6-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N;

in some embodiments, R ^2a Each independently selected from H, F, cl, br, I, oxo, OH, NH ₂ Cyano, CF ₃ 、 -SCH ₃ Methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclohexylThe group, cyclopentyl, cyclohexyl are optionally further substituted by 0 to 4 (e.g., 0, 1,2,3, or 4) groups selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

in some embodiments, R ^2a Each independently selected from-NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, said-CH ₃ Cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 (e.g., 0, 1,2,3, or 4) groups selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

in some embodiments, two R are ^2a Taken together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 4-to 6-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R ^2a Each independently selected from H, F, cl, OH, cyano, NH ₂ 、CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl;

in some embodiments, R ^2a Each independently selected from propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, said-CH ₃ Propenyl, cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl;

in some embodiments, R ^2a Each independently selected from F, cl, OH, cyano, NH ₂ 、CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl;

in some embodiments, each q is independently selected from 0, 1,2,3, or 4;

in some embodiments, n is selected from 0, 1,2,3, or 4;

in some embodiments, each m is independently selected from 0, 1,2, or 3;

optionally, with the proviso that

Is different from

m1 is selected from 0, 1 or 2;

optionally, with the proviso that the compound is not

Or

As a first embodiment of the present invention, a compound represented by the aforementioned general formula (I-a), or a stereoisomer, a deuterode, an N-oxide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

X ₁ or X ₂ Each independently selected from N or CR ^b ；

Ring A is selected from 3-to 12-membered carbocyclyl or 4-to 12-membered heterocyclyl, said carbocyclyl or heterocyclyl optionally further substituted with 0 to 6R ^a (ii) substituted, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

ring B ₁ Selected from 3 to 8 membered carbocyclyl, 5 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl or phenyl, said carbocyclyl, heterocyclyl, heteroaryl or phenyl optionally further substituted with 0 to 7R ^b (iii) substituted, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

R ^a each independently selected from H, oxo, halogen, cyano, OH, NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 8-membered cycloalkyl, 4-to 8-membered heterocyclyl, -O-3-to 8-membered cycloalkyl, -O-4-to 8-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, wherein the heterocyclic group contains 1 to 4 hetero atoms selected from O, S and N;

R ^b each independently selected from H, oxo, halogen, cyano, OH, NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkylthio radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, 3-to 8-membered cycloalkyl, 4-to 8-membered heterocyclyl, -O-3-to 8-membered cycloalkyl, -O-4-to 8-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl or heterocycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、 C _1-4 Alkyl radical, C _1-4 Alkoxy, 4-7 membered heterocyclyl or C _3-6 Cycloalkyl, said heterocyclyl or heterocycloalkyl containing from 1 to 4 heteroatoms selected from O, S, N;

or two R ^a Or two R ^b Taken together with the atoms to which they are attached form a 3-to 12-membered carbocyclic or 4-to 12-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、 -NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, wherein the heterocyclic group contains 1 to 4 hetero atoms selected from O, S and N;

L ₁ 、L ₂ or L ₃ Each independently selected from the group consisting of a bond, O, -CH ₂ -、-OCH ₂ -、-CH ₂ O-, -C (= O) -, S or NR ^x ；

R ^x Selected from H, C _1-6 Alkyl or C _3-6 Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Substituted with a substituent of alkoxy;

R ¹ selected from halogen, OH, cyano, COOH, NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, NH ₂ 、-(CH ₂ ) _q -C(＝O)C _1-6 Alkyl, - (CH) ₂ ) _q -C (= O) -3-to 12-membered heterocycle, - (CH) ₂ ) _q -C(＝O)-C _3-10 Carbocyclic ring, - (CH) ₂ ) _q -3 to 12 membered heterocycle or- (CH) ₂ ) _q -C _3-10 Carbocyclic ring of said CH ₂ Alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4R ^1a Substituted, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

R ^1a each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, -C _1-6 alkylene-OH, - (CH) ₂ ) _q -C _3-10 Carbocyclic ring, - (CH) ₂ ) _q -3 to 12 membered heterocycle, -O-C _3-10 Carbocyclic ring, -O-3 to 12 membered heterocyclic ring, C _1-6 Alkoxy, -N (C) _1-6 Alkyl) C (= O) -3-to 12-membered heterocyclic substituent, said alkyl, CH ₂ Alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycle or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

R ² is selected from C _1-6 Alkyl radical, C _3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted with 0 to 7R ^2a (iii) substituted, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

R ^2a each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylthio radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, -O-C _3-6 Cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycloalkyl,Heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N; or

R ^2a Each independently selected from-NHC (O) C _1-6 Alkyl, -NHS (O) ₂ C _1-6 Alkyl, -P (O) (C) _1-6 Alkyl radical) ₂ Said alkyl is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl substituted with 1 to 4 heteroatoms selected from O, S, N;

or two R ^2a Together with the atom to which it is directly attached form a 3-to 12-membered carbocyclyl or a 4-to 12-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、 C _1-4 Alkyl or C _1-4 Alkoxy, wherein the heterocyclic group contains 1 to 4 hetero atoms selected from O, S and N;

q is each independently selected from 0, 1,2,3 or 4.

As a second embodiment of the present invention, a compound represented by the following general formula (I-aa) or a stereoisomer, a deuterode, an N-oxide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

selected from 4-to 12-membered nitrogen-containing heterocycles selected from one of the following saturated or partially saturated groups: a monocyclic, fused, bridged or spirocyclic ring, said nitrogen-containing heterocycle, monocyclic, fused, bridged or spirocyclic ring being optionally further substituted with 0 to 4R ^a Substituted, ring A ₁ Wherein N-H is unsubstituted;

n is selected from 0, 1,2,3 or 4;

provided that

Is not that

m1 is selected from 0, 1 or 2;

with the proviso that the compound is not

The remaining definitions are the same as in the first embodiment of the present invention.

As a third embodiment of the present invention, a compound represented by the aforementioned general formula (I-aa) or a stereoisomer, a deuterode, an N-oxide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

selected from one of the following unsubstituted or substituted groups:

when substituted, is optionally further substituted with 0 to 4R ^a Substituted by a substituent, ring A ₁ Wherein N-H is unsubstituted;

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ Connecting;

each m is independently selected from 0, 1,2 or 3;

the remaining definitions are the same as in the first or second embodiment of the present invention.

As a fourth embodiment of the present invention, a compound represented by the aforementioned general formula (I-aa) or a stereoisomer, a deuterode, an N-oxide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

is selected from

Is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ Connecting;

each m is independently selected from 0, 1,2 or 3;

the remaining definitions are the same as in the first, second or third embodiment of the present invention.

As a fifth embodiment of the present invention, a compound represented by the aforementioned general formula (I-aa) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

L ₂ selected from a bond, O or-C (= O) -;

R ² is selected from C _3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C _6-10 Aryl or 5 to 10 membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted with 0 to 5R ^2a (iii) substituted, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

R ^2a each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-4 Alkyl), -N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Alkylthio radical, C _2-4 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, -O-C _3-6 Cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl substituted with 1 to 4 heteroatoms selected from O, S, N; or

R ^2a Each independently selected from-NHC (O) C _1-4 Alkyl, -NHS (O) ₂ C _1-4 Alkyl, -P (O) (C) _1-4 Alkyl radical) ₂ Said alkyl is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl substituted with 1 to 4 heteroatoms selected from O, S, N;

or two R ^2a Together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 4-to 6-membered heterocyclic group, said carbocyclic or heterocyclic group optionallyFurther substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

the remaining definitions are the same as in the first, second, third or fourth embodiment of the present invention.

As a sixth embodiment of the present invention, a compound represented by the aforementioned general formula (I-aa) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

R ^b each independently selected from H, oxo, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkylthio radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, 3-to 6-membered cycloalkyl, 4-to 6-membered heterocyclyl, -O-3-to 6-membered cycloalkyl, -O-4-to 6-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, heterocycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

or two R ^b Together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 4-to 6-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, wherein the heterocyclic group contains 1 to 4 hetero atoms selected from O, S and N;

R ^1a each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-4 Alkyl), -N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, -C _1-4 alkylene-OH, - (CH) ₂ ) _q -C _3-8 Carbocyclic ring, - (CH) ₂ ) _q -3 to 8 membered heterocycle, -O-C _3-8 Carbocyclic ring, -O-3 to 8 membered heterocyclic ring, C _1-4 Alkoxy, -N (C) _1-4 Alkyl) C (= O) -3-to 8-membered heterocycle, said alkyl, CH ₂ Alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycle or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

q is each independently selected from 0, 1,2,3 or 4;

the remaining definitions are the same as for the first, second, third, fourth or fifth embodiment of the present invention.

As a seventh embodiment of the present invention, a compound represented by the aforementioned general formula (I-aa) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

R ² selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, indazole, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuryl, benzopyrimidinyl, benzopyridyl, or pyridyl, when substituted, optionally substituted with 0 to 5R ^2a Substitution;

R ^2a each independently selected from H, F, cl, br, I, oxo, OH, NH ₂ Cyano, CF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl,Cyclohexyl is optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy; or

R ^2a Each independently selected from-NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, said-CH ₃ Cyclopentenyl, phenyl, pyrazolyl optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

or two R ^2a Taken together with the atoms to which they are attached form a 3-to 6-membered carbocyclyl or a 4-to 6-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、 NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R ^b each independently selected from H, oxo, F, cl, br, I, cyano, OH, NH ₂ Methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

R ^1a each independently selected from H, F, cl, br, I, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propylVinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

the remaining definitions are the same as for the first, second, third, fourth, fifth or sixth embodiment of the invention.

As an eighth embodiment of the present invention, a compound represented by the following general formula (I-aaa), or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof,

L ₂ selected from a bond or-C (= O) -;

R ^b each independently selected from H, oxo, F, cl, br, I, cyano, OH, NH ₂ Methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, -O-cyclopropyl, vinyl, ethynyl, said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, ethynyl, cyclopropyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy or propoxy;

R ² selected from one of the following substituted or unsubstituted groups: phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrazolyl, or naphthyl, when substituted, optionally substituted with 0 to 5R ^2a Substitution;

R ^2a each independently selected from H, F, cl, OH, cyano, NH ₂ 、CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted by 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl; or

R ^2a Each independently selected from propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, said-CH ₃ Propenyl, cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl;

the remaining definitions are the same as for the first, second, third, fourth, fifth or sixth embodiment of the present invention.

As a ninth embodiment of the present invention, a compound represented by the following general formula (I-aaaa) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

R ^b selected from H, F, cl, cyano, OH, NH ₂ Methyl, ethyl, methoxy, ethoxy, cyclopropyl, -O-cyclopropyl;

R ^2a each independently selected from H, F, cl, OH, cyano, NH ₂ 、CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl; or

R ^2a Each independently selected from propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, said-CH ₃ Propenyl, cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl.

As a tenth embodiment of the present invention, a compound represented by the following general formula (I-b) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

R ² selected from phenyl, benzopyrazolyl, benzofuranyl, pyridyl, said phenyl being substituted with 1 to 4R ^2a Substituted by 0 to 4R ^2a Substitution;

R ^2a each independently selected from F, cl, OH, cyano, NH ₂ 、CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, propenyl, -NHC (O) CH ₃ 、 -NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、 -P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl.

As an eleventh embodiment of the present invention, a compound represented by the following general formula (I-aaaa) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

R ² selected from one of the following substituted groups: phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrazolyl, or naphthyl, when substituted, with 1 to 5R ^2a Substitution;

R ^2a each independently selected from H, F, cl, OH, cyano, NH ₂ 、CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl;

provided that at least one R is ^2a Selected from cyclopropyl, cyclobutyl or cyclopentyl.

As a twelfth embodiment of the present invention, a compound represented by the following general formula (I-c) or (I-d) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

m is selected from 0, 1,2 or 3. The invention relates to a compound or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein the compound is selected from one of the following structures:

in some embodiments of the general formulae (I-a), (I-aa), (I-aaa), X ₁ Or X ₂ Each independently selected from N or CR ^b 。

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa) ₁ 、X ₂ Is selected from N.

The invention relates to a deviceIn some embodiments of sub-formulae (I-a), (I-aa), (I-aaa) ₁ 、X ₂ Selected from the group consisting of CR ^b 。

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), X ₁ Is selected from N, X ₂ Selected from the group consisting of CR ^b 。

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), X ₁ Selected from the group consisting of CR ^b ，X ₂ Is selected from N.

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), ring A is selected from a 3-to 12-membered carbocyclyl or a 4-to 12-membered heterocyclic group, said carbocyclyl or heterocyclic group optionally further substituted with 0 to 6R ^a And (b) substituted, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N.

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), L ₁ 、L ₂ Or L ₃ Each independently selected from the group consisting of a bond, O, -CH ₂ -、-OCH ₂ -、-CH ₂ O-, -C (= O) -, S or NR ^x 。

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa) ^x Selected from H, C _1-6 Alkyl or C _3-6 Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy.

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), L ₃ Selected from the group consisting of a bond.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa),

is selected from

The invention relates to compounds of the general formulae (I-a), (I-aa), (I-aaa) in some embodiments of the present invention,

selected from 4-to 12-membered nitrogen-containing heterocycles selected from one of the following saturated or partially saturated groups: monocyclic, fused, bridged or spirocyclic ring, said nitrogen-containing heterocycle, monocyclic, fused, bridged or spirocyclic ring being optionally further substituted with 0 to 4 (e.g. 0, 1,2,3 or 4) R ^a Substituted, ring A ₁ Wherein N-H is not substituted.

selected from one of the following unsubstituted or substituted groups:

when substituted, is optionally further substituted with 0 to 4 (e.g., 0, 1,2,3, or 4) R ^a Substituted by a substituent, ring A ₁ Wherein N-H is not substituted.

selected from unsubstituted or substituted

When substituted, is optionally further substituted with 0 to 4 (e.g., 0, 1,2,3, or 4) R ^a Substituted by substituents, ring A ₁ Wherein N-H is unsubstituted.

is selected from

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa) ^a Each independently selected from H, oxo, halogen, cyano, OH, NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 8-membered cycloalkyl, 4-to 8-membered heterocyclyl, -O-3-to 8-membered cycloalkyl, -O-4-to 8-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocyclyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, CF ₃ 、 COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 The substituent of the alkoxy is substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N.

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), R ^a Each independently selected from H, oxo, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy, 3-to 6-membered cycloalkyl, 4-to 6-membered heterocyclyl, -O-3-to 6-membered cycloalkyl, -O-4-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocyclyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 The substituent of the alkoxy is substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N.

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), R ^a Each independently selected from H, oxo, F, cl, br, I, cyano, OH, NH ₂ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy being optionally further substituted by 0 to 4(e.g., 0, 1,2,3, or 4) is selected from H, F, cl, br, I, OH, cyano, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa) ^a Each independently selected from H, oxo, F, cl, br, I, cyano, OH, NH ₂ Methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, -O-cyclopropyl, said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, F, cl, br, I, OH, cyano, CF ₃ 、 COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy or propoxy.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa) ^a Each independently selected from H.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), two R ^a Taken together with the atoms to which they are attached form a 3-to 12-membered carbocyclic or 4-to 12-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa) ^a Together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 4-to 6-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Substituted by alkoxy substituents, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) hetero atoms selected from O, S, NAnd (4) adding the active ingredients.

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), ring B ₁ Selected from 3 to 8 membered carbocyclyl, 5 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl or phenyl, optionally further substituted with 0 to 7 (e.g. 0, 1,2,3,4, 5,6, 7) R ^b And (b) substituted, wherein said heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N.

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ And (4) connecting.

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ And (4) connecting.

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ And (4) connecting.

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ And (4) connecting.

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ Connecting;

is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ And (4) connecting.

is selected from

Left side and L of it ₂ Is connected, above and to ring A ₁ And (4) connecting.

is selected from

Left side and L of it ₂ Is connected, above and to ring A ₁ And (4) connecting. The present invention relates to some embodiments of general formula (I-a), (I-aa), (I-aaa), (I-aaaa), (I-c) wherein R ^b Each independently selected from H, oxo, halogen, cyano, OH, NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkylthio radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, 3-to 8-membered cycloalkyl, 4-to 8-membered heterocyclyl, -O-3-to 8-membered cycloalkyl, -O-4-to 8-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl or heterocycloalkyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Alkoxy, 4-7 membered heterocyclyl or C _3-6 Cycloalkyl, said heterocyclyl or heterocycloalkyl containing from 1 to 4 heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-c) wherein two R ^b Taken together with the atoms to which they are attached form a 3-to 12-membered carbocyclic or 4-to 12-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy and said heterocyclyl contains 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-c)In the table, R ^b Each independently selected from H, oxo, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkylthio radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, 3-to 6-membered cycloalkyl, 4-to 6-membered heterocyclyl, -O-3-to 6-membered cycloalkyl, -O-4-to 6-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl or heterocycloalkyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy.

The present invention relates to some embodiments of general formula (I-a), (I-aa), (I-aaa), (I-aaaa), (I-c) wherein two R ^b Taken together with the atoms to which they are attached to form a 3-to 6-membered carbocyclyl or a 4-to 6-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N, said heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I-a), (I-aa), (I-aaa), (I-aaaa), (I-c) wherein R ^b Each independently selected from H, oxo, F, cl, br, I, cyano, OH, NH ₂ Methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy.

The present invention relates to some embodiments of general formula (I-a), (I-aa), (I-aaa), (I-aaaa), (I-c) wherein R ^b Each independently selected from H, oxo, F, cl, br, I, cyano, OH, NH ₂ Methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, -O-cyclopropyl, vinyl, ethynyl, said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, ethynyl, cyclopropyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy or propoxy.

The present invention relates to some embodiments of general formula (I-a), (I-aa), (I-aaa), (I-aaaa), (I-c) wherein R ^b Selected from H, F, cl, cyano, OH, NH ₂ Methyl, ethyl, methoxy, ethoxy, cyclopropyl, -O-cyclopropyl.

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), L ₁ Selected from-O-and-O-CH ₂ -。

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), R ¹ Selected from halogen, OH, cyano, COOH, NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, NH ₂ 、-(CH ₂ ) _q -C(＝O)C _1-6 Alkyl, - (CH) ₂ ) _q -C (= O) -3-to 12-membered heterocycle, - (CH) ₂ ) _q -C(＝O)-C _3-10 Carbocyclic ring, - (CH) ₂ ) _q -3 to 12 membered heterocycle or- (CH) ₂ ) _q -C _3-10 Carbocyclic ring of said CH ₂ Alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 (e.g., 0, 1,2,3 or 4) R ^1a And (b) substituted, said heterocycle containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa) — L ₁ -R ₁ Is selected from

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), R ^1a Each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, -C _1-6 alkylene-OH, - (CH) ₂ ) _q -C _3-10 Carbocyclic ring, - (CH) ₂ ) _q -3 to 12 membered heterocycle, -O-C _3-10 Carbocyclic ring, -O-3 to 12 membered heterocyclic ring, C _1-6 Alkoxy, -N (C) _1-6 Alkyl) C (= O) -3-to 12-membered heterocycle, said alkyl, CH ₂ Alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle is optionally further optionally substituted by 0 to 4 (e.g., 0, 1,2,3 or 4) groups selected from H, halo, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycle or heterocycloalkyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa) ^1a Each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-4 Alkyl), -N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, -C _1-4 alkylene-OH, - (CH) ₂ ) _q -C _3-8 Carbocyclic ring, - (CH) ₂ ) _q -3 to 8 membered heterocycle, -O-C _3-8 Carbocyclic ring, -O-3 to 8 membered heterocyclic ring, C _1-4 Alkoxy, -N (C) _1-4 Alkyl) C (= O) -3-to 8-membered heterocyclic substituent, said alkyl, CH ₂ Alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle is optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano、oxo、CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycle or heterocycloalkyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N.

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), R ^1a Each independently selected from H, F, cl, br, I, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy being optionally further selected by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), and R ^1a Is selected from F.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), -L ₁ -R ₁ Is selected from

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), L ₂ Selected from a bond, O or-C (= O) -.

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), L ₂ Is selected from a bond or-C (= O) -.

The invention relates to some implementations of the general formulae (I-a), (I-aa), (I-aaa)In scheme, L ₂ Selected from the group consisting of a bond.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) ² Is selected from C _1-6 Alkyl radical, C _3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted with 0 to 4 (e.g. 0, 1,2,3 or 4) R ^2a And substituted, said heterocyclyl or heteroaryl group contains 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-b), (I-c), (I-d) ² Is selected from C _3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted with 0 to 7 (e.g. 0, 1,2,3,4, 5,6 or 7) R ^2a And (b) substituted, said heterocyclyl or heteroaryl group containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-b), (I-c), (I-d) ² Selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, indazole, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuryl, benzopyrimidinyl, benzopyridyl, or pyridyl, when substituted, optionally substituted with 0 to 5 (e.g., 0, 1,2,3,4, or 5) R ^2a And (4) substitution.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) ² Selected from one of the following substituted or unsubstituted groups: phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrazolyl, or naphthyl, when substituted, optionally substituted with 0 to 5 (e.g., 0, 1,2,3,4, or 5) R ^2a And (4) substitution.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) ² Selected from phenyl, benzopyrazolyl, benzofuranyl, pyridyl, said phenyl being substituted with 1 to 4R ^2a Substituted by 0 to 4R ^2a Substitution;

the present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) ² Selected from one of the following substituted groups: phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrazolyl, or naphthyl, when substituted, with 1 to 5R ^2a Substituted, R ^2a Each independently selected from H, F, cl, OH, cyano, NH ₂ 、 CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl, provided that at least one R is ^2a Selected from cyclopropyl, cyclobutyl or cyclopentyl.

The present invention relates to some embodiments of formula (I-a), (I-aa), (I-aaa), (I-b), (I-c), (I-d) wherein R ^2a Each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylthio radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, -O-C _3-6 Cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 Aryl or 5 to 10 membered heteroaryl, said alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) ^2a Each independently selected from-NHC (O) C _1-6 Alkyl, -NHS (O) ₂ C _1-6 Alkyl, -P (O) (C) _1-6 Alkyl radical) ₂ Said alkyl group is optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、 NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) ^2a Each independently selected from F, cl, OH, cyano, NH ₂ 、CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、 -P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) wherein two R ^2a Together with the atom to which they are directly attached form a 3-to 12-membered carbocyclic group or a 4-to 1-membered carbocyclic group2-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、 COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, said heterocyclyl containing 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) ^2a Each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-4 Alkyl), -N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Alkylthio radical, C _2-4 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, -O-C _3-6 Cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 Aryl or 5 to 10 membered heteroaryl, said alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (I-a), (I-aa) ^2a Each independently selected from-NHC (O) C _1-4 Alkyl, -NHS (O) ₂ C _1-4 Alkyl, -P (O) (C) _1-4 Alkyl radical) ₂ Said alkyl group is optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) wherein two R ^2a Taken together with the atoms to which they are attached to form a 3-to 6-membered carbocyclyl or a 4-to 6-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 (e.g. 0, 1,2,3 or 4) substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、 COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy and said heterocyclyl contains 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) ^2a Each independently selected from H, F, cl, br, I, oxo, OH, NH ₂ Cyano, CF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) ^2a Each independently selected from-NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, said-CH ₃ Cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 (e.g., 0, 1,2,3, or 4) groups selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy,Ethoxy, propoxy or isopropoxy.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-b), (I-c), (I-d) ^2a Taken together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 4-to 6-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 (e.g. 0, 1,2,3 or 4) groups selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、 NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-aaaa), (I-b), (I-c), (I-d) ^2a Each independently selected from H, F, cl, OH, cyano, NH ₂ 、CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclopentyl or cyclohexyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl.

The present invention relates to some embodiments of formula (I-a), (I-aa), (I-aaa), (I-b), (I-c), (I-d) wherein R ^2a Each independently selected from propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, said-CH ₃ Propenyl, cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 (e.g., 0, 1,2,3, or 4) substituents selected from H, F, cl, OH, methyl, ethyl, or cyclopropyl.

In some embodiments of the general formulae (I-a), (I-aa), (I-aaa), each q is independently selected from 0, 1,2,3, or 4.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), n is selected from 0, 1,2,3, or 4.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), (I-c) wherein each m is independently selected from 0, 1,2 or 3.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), provided that

Is not that

m1 is selected from 0, 1 or 2.

The present invention relates to some embodiments of the general formulae (I-a), (I-aa), (I-aaa), provided that the compound is not

The invention relates to a pharmaceutical composition, which comprises the compound or stereoisomer, deutero-compound, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, and a pharmaceutically acceptable carrier.

The invention relates to application of a compound or a stereoisomer, a deutero-compound, an N-oxide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof in preparing a medicament for treating diseases related to KRAS activity or expression.

The invention relates to application of a compound or a stereoisomer, a deuteron, an N-oxide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof in preparing a medicament for treating diseases related to KRAS G12D activity or expression quantity, wherein the diseases are selected from tumors.

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

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I involved in the groups and compounds of the invention include isotopes thereof, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the invention are optionally further substituted with one or moreEach of their corresponding isotopes, wherein the carbon isotopes include ¹² C、 ¹³ C and ¹⁴ c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including ¹⁶ O、 ¹⁷ O and ¹⁸ isotopes of O, sulfur including ³² S、 ³³ S、 ³⁴ S and ³⁶ isotopes of S, nitrogen include ¹⁴ N and ¹⁵ isotopes of N, F include ¹⁷ F and ¹⁹ isotopes of F, chlorine including ³⁵ Cl and ³⁷ cl, isotopes of bromine including ⁷⁹ Br and ⁸¹ Br。

"halogen" means F, cl, br or I.

"halo-substituted" means F, cl, br or I-substituted, including but not limited to 1 to 10 substituents selected from F, cl, br or I, 1 to 6 substituents selected from F, cl, br or I, 1 to 4 substituents selected from F, cl, br or I. "halogen-substituted" is simply referred to as "halo".

"alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including, but not limited to, alkyl of 1 to 20 carbon atoms, alkyl of 1 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; alkyl groups, as used herein, are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent or tetravalent.

"heteroalkyl" means that 1 or more (including but not limited to 2,3,4,5, or 6) carbon atoms in a substituted or unsubstituted alkyl group are replaced with a heteroatom (including but not limited to N, O, or S). Non-limiting examples include-X (CH) ₂ )v-X(CH ₂ )v-X(CH ₂ ) v-H (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom including but not limited to N, O or S, and at least 1X is selected from a heteroatom in which N or S may be oxidized to various oxidation states). The heteroalkyl group may be monovalent, divalent, or trivalentValence or tetravalent.

"alkylene" refers to a substituted or unsubstituted, straight and branched chain, divalent saturated hydrocarbon radical, including- (CH) ₂ ) _v - (v is an integer of 1 to 10), examples of the alkylene group include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

"Heteroalkylidene" means a substituted or unsubstituted alkylene group in which 1 or more (including but not limited to 2,3,4,5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O, or S). Non-limiting examples include-X (CH) ₂ )v-X(CH ₂ )v-X(CH ₂ ) v-, v is an integer from 1 to 5, X is independently selected from bond, N, O or S, and at least 1X is selected from N, O or S.

"cycloalkyl" refers to a substituted or unsubstituted, saturated or unsaturated, nonaromatic, carbocyclic hydrocarbon radical, typically of 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cyclohexyl or cycloheptyl, and the like. Cycloalkyl groups, as found herein, are defined as above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

"heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cycloalkyl group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, or S, with the optionally substituted N, S in the heterocycloalkyl ring being oxidizable to various oxidation states. Heterocycloalkyl groups may be attached to a heteroatom or carbon atom, heterocycloalkyl groups may be attached to an aromatic ring or to a non-aromatic ring, heterocycloalkyl groups may be attached to a bridged or spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidyl, piperazinyl. The heterocycloalkyl radical may be monovalent, divalent, trivalent or tetravalent

"alkenyl" refers to substituted or unsubstituted straight and branched chain unsaturated hydrocarbon groups having at least 1, and typically 1,2 or 3 carbon-carbon double bonds, the backbone includes but is not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 1, 4-hexadiene, 1, 4-hexadiene, 1,4, and the like; alkenyl groups are present herein, the definition of which is consistent with the present definition. The alkenyl group may be monovalent, divalent, trivalent or tetravalent.

"alkynyl" refers to substituted or unsubstituted, straight and branched chain, monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1,2 or 3 carbon-carbon triple bonds, and backbones including from 2 to 10 carbon atoms, including but not limited to from 2 to 6 carbon atoms in the backbone and from 2 to 4 carbon atoms in the backbone, and examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-decynyl, 4-decynyl, and the like; alkynyl groups can be monovalent, divalent, trivalent or tetravalent.

"alkoxy" means a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or a non-aromatic ringThe aromatic or non-aromatic ring may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic or 10-to 15-membered tricyclic ring system, the carbocyclic group may be attached to the aromatic or non-aromatic ring, which is optionally monocyclic, bridged or spiro. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, and mixtures thereof,

"carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent, or tetravalent.

"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system and contains 1 or more (including but not limited to 2,3,4, or 5) heteroatoms selected from N, O, or S, the optionally substituted N, S in the ring of the heterocyclyl group being oxidizable to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridge or spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, chromanyl, dihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, phenylBenzothienyl, benzofuranyl, benzopyrryl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [3.2.1]Octyl, azabicyclo [5.2.0 ] groups]Nonyl, oxatricyclo [5.3.1.1]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]A heptylalkyl group,

"Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spiro" or "spirocyclic" refers to a polycyclic group having one atom (referred to as a spiro atom) in common between substituted or unsubstituted single rings, the number of ring atoms in the spiro ring system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, where one or more rings may contain 0 or more (including but not limited to 1,2,3, or 4) double bonds, and optionally may contain 0 to 5 rings selected from N, O, or S (= O) _n The heteroatom of (2).

The "spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.

"fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more of the rings may contain 0 or more (including but not limited to 1,2,3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (= O) _n Or O, nIs 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

the "fused ring" or "fused ring group" may be monovalent, divalent, trivalent or tetravalent.

"bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly connected, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom containing groups (including but not limited to N, S (= O) N, or O, where N is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include

Cubane and adamantane. The "bridge ring" or "bridge ring group" may be monovalent, divalent, trivalent, or tetravalent.

"carbospiro", "spirocarbocyclic" or "carbospiro" refers to "spiro" rings whose ring system consists of only carbon atoms. The definition of "carbospiro", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospirocyclic group" as appearing herein is consistent with the definition of spirocyclic.

"carbocyclic", "fused carbocyclic", or "carbocyclic" refers to "fused rings" in which the ring system consists of only carbon atoms. "carbocyclic ring", "fused carbocyclic ring group", "fused carbocyclic group", or "fused carbocyclic group" as used herein, is defined in accordance with fused rings.

"Carbobridged ring", "bridged carbocyclyl" or "carbocyclyl" refers to a "bridged ring" in which the ring system consists of only carbon atoms. "Carbobridged ring", "bridged carbocyclyl" or "carbobridged ring" as used herein, are defined in accordance with the definition of bridged ring.

"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to "heterocyclyl" or "heterocycle" of a monocyclic ring system, and heterocyclyl, "monocyclic heterocyclyl" or "heteromonocyclic" as found herein, is defined consistent with the definition of heterocycle.

"Heterocyclo", "heterocyclocyclyl" or "heterocyclocyclyl" means a "fused ring" containing heteroatoms. A hetero-cyclic, "hetero-cyclic", "cyclo-heterocyclic" or "hetero-cyclic" group, as used herein, is defined in accordance with the definition of a fused ring.

"Heterospirocyclic", "heterospirocyclic", "spiroheterocyclic" or "heterospirocyclic" refers to "spirocyclic" containing heteroatoms. The definition of heterospiro, "heterospiro ring", "spiro heterocyclic" or "heterospiro ring" as used herein is consistent with spiro rings.

"heterobridged ring," "heterobridged ring group," "bridged heterocyclic group," or "heterobridged ring group" refers to a "bridged ring" containing a heteroatom. The term "heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group", as used herein, is defined in accordance with the bridged ring.

"aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single or fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include a phenyl ring, a naphthyl ring,

The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is located on the aryl ring.

"heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 selected or heteroatom-containing groups (including but not limited to N, O or S (= O) N, N is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include

Heteroaryl groups, as found herein, are defined in accordance with the present definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is on the heteroaryl ring.

The "5-membered and 5-membered heteroaromatic ring" means a 5-and 5-membered fused heteroaromatic ring in which at least 1 ring of 2 fused rings contains 1 or more heteroatoms (including but not limited to O, S or N), and the whole group has aromaticity, and non-limiting examples include a pyrrolopyrrole ring, a pyrazolopyrrole ring, a pyrazolopyrazole ring, a pyrrolofuran ring, a pyrazolofuran ring, a pyrrolothiophene ring, and a pyrazolothiophene ring.

"5 and 6 membered heteroaromatic ring" means a 5 and 6 membered fused heteroaromatic ring wherein at least 1 ring of the 2 fused rings contains more than 1 heteroatom (including but not limited to O, S or N) and the entire group is aromatic, non-limiting examples include benzo 5 membered heteroaryl, 6 membered heteroaromatic ring and 5 membered heteroaromatic ring.

"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2,3,4, or 5) substituents including but not limited to H, F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocycleGroup, bridged ring group, spiro ring group, fused ring group, hydroxyalkyl group, = O, carbonyl group, aldehyde, carboxylic acid, formate, - (CH) ₂ ) _m -C(＝O)-R ^a 、-O-(CH ₂ ) _m -C(＝O)-R ^a 、-(CH ₂ ) _m -C(＝O)-NR ^b R ^c 、 -(CH ₂ ) _m S(＝O) _n R ^a 、-(CH ₂ ) _m -alkenyl-R ^a 、OR ^d Or- (CH) ₂ ) _m -alkynyl-R ^a (wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR ^b R ^c Etc. wherein R is ^b And R ^c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b And R ^c Five or six membered cycloalkyl or heterocyclyl groups may be formed.

"containing 1 to 5 heteroatoms selected from O, S, N" means containing 1,2,3,4 or 5 heteroatoms selected from O, S, N.

"substituted with 0 to X substituents" means substituted with 0, 1,2,3 \8230Xsubstituents, X is selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0, 1,2,3, or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0, 1,2,3,4, or 5 substituents. By "heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the heterobridged ring is optionally further substituted with 0, 1,2,3 or 4 substituents selected from H or F.

The ring of X-Y element (X is selected from integer less than Y and greater than 3, and Y is selected from any integer between 4 and 12) includes X +1, X +2, X +3, X +4 \8230andY element ring. Rings include heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterospirocyclic, or heterobridged rings. For example, "4-7 membered heteromonocyclic" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterobicyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterobicyclic ring.

"optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention which retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid.

"pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, tautomers, deuterons, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.

By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate.

"animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, and conformers.

"tautomer" refers to isomers of functional groups resulting from rapid movement of an atom in two positions in a molecule, such as keto-enol isomers and amide-imino-alcohol isomers, among others.

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

“IC ₅₀ "is the concentration of drug or inhibitor required to inhibit half of a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.).

Detailed Description

The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. Delta.) at 10 ^-6 The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS);

MS was measured using Agilent 6120B (ESI) and Agilent 6120B (APCI);

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X 4.6mm, 3.5. Mu.M);

the thin layer chromatography silica gel plate is prepared from cigarette bench yellow sea HSGF ₂₅₄ Or Qingdao GF ₂₅₄ The silica gel plate used in Thin Layer Chromatography (TLC) adopts the specification of 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;

column chromatography is carried out by using 200-300 mesh silica gel of Litsea crassirhizomes as carrier;

boc: a tert-butoxycarbonyl group;

ts: a p-toluenesulfonyl group;

cbz: a benzyloxycarbonyl group;

TMS: trimethylsilyl;

TIPS: triisopropyl silicon base;

bpin: pinacol borate ester;

MOM: methylene methyl ether;

HATU:2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate;

LiHMDS: bis-trimethylsilyl amido lithium;

EA: ethyl acetate;

MFSDA: fluorosulfonyl difluoroacetic acid methyl ester;

DIPEA: n, N-diisopropylethylamine;

DMF: n, N-dimethylformamide;

PE: petroleum ether;

DCM: dichloromethane;

NIS: n-iodosuccinimide;

Pd(dppf)Cl ₂ :1,1' -bis-diphenylphosphino ferrocene palladium dichloride;

NBS: n-bromosuccinimide;

ACN: acetonitrile;

TFA: trifluoroacetic acid;

THF: and (4) tetrahydrofuran.

Example 1:4- (2- { [ ((2r, 7as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy ] -4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) pyridinyl [2,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound 1);

4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-(3,8-diazabicyclo[3.2.1]o ctan-3-yl)pyrido[2,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.

the first step is as follows: 3- (2, 7-dichloropyrido [2,3-d ] pyrimidin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1 b);

tert-butyl 3-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate.

the compound 2,4, 7-trichloropyrido [2,3-d ] pyrimidine (300mg, 1.279mmol) is dissolved in 10mL dichloromethane, the system is placed in an ice bath and stirred for 5min under the protection of nitrogen, then N, N-diisopropylethylamine (0.42 mL, 2.558mmol) and tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (300mg, 1.41mmol) are added in sequence under the condition, and the mixture is slowly raised to room temperature to react for 2h. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (PE: EA = 3).

Ms m/z(ESI):410.1[M+H] ⁺

The second step is that: 3- (7-chloro-2- ((((2r, 7as) -2-fluorotetrahydro-1H-pyrrolizine 7a (5H) -yl) methoxy) pyridinyl [2,3-d ] pyrimidin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1 e);

tert-butyl 3-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)pyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

compound (1 b) (240mg, 0.585 mmol) and compound ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (1 c-1) (186mg, 1.17mmol) were dissolved in 10mL of a super-dry 1, 4-dioxane solution, followed by addition of N, N-diisopropylethylamine (0.29mL, 1.755mmol) and 4A molecular sieves (300 mg). The reaction was raised to 100 ℃ for 24h under nitrogen protection, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: meOH = 20.

Ms m/z(ESI):533.2[M+H] ⁺

The third step: 3- (7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((((((2r, 7as) -2-fluorotetrahydro-1H-pyrrolizine 7a (5H) -yl) methoxy) pyridinyl [2,3-d ] pyrimidin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1 f);

tert-butyl 3-(7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d]py rimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

compound (1 e) (210mg, 0.394mmol) and compound ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (1 d-1) (404mg, 0.788mmol) were placed in a sealed tube, dissolved by adding 15mL of a 1, 4-dioxane solution, and then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (32mg, 0.04mmol), cesium carbonate (385mg, 1.18mmol) and 1.5mL of water were added in this order. Under nitrogen protection, the mixture was raised to 100 ℃ for reaction for 3h, the solvent was removed under reduced pressure, 15mL of water and 30mL of ethyl acetate were added to dissolve, the aqueous phase was washed with 20mL of × 2 ethyl acetate, the organic phases were combined, the organic phase was washed once with 10mL of saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, spin-dried, and column-chromatographed (DCM: meOH = 15) to give the target compound (1 f) as a yellow solid (230 mg, yield: 66%).

Ms m/z(ESI):442.3[(M+2H)/2] ⁺

The fourth step: 4- (4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ((((((2r, 7as) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (1 g);

4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol.

compound (1 f) (230mg, 0.26mmol) was dissolved in 5mL of acetonitrile, 2mL of 1, 4-dioxane hydrochloride solution was added dropwise at room temperature, the reaction was continued for 3 hours, and excess acid and solvent were removed under reduced pressure to give crude compound (1 g), (240 mg) which was used in the next reaction without purification.

Ms m/z(ESI):739.3[M+H] ⁺

The fifth step: 4- (2- { [ ((2r, 7as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy ] -4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) pyridinyl [2,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound 1);

the crude compound (1 g) (240 mg) in the previous step was dissolved in 2mL of N, N-dimethylformamide, followed by addition of cesium fluoride (200mg, 1.3 mmol) at room temperature. After the addition was completed, the reaction was continued for 12h under a nitrogen blanket, and 30mL of ethyl acetate was added to the system for dilution, and then the organic phase was washed with 10mL of saturated sodium bicarbonate, 10mL of × 3 water, and 10mL of saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated, and the residue was subjected to silica gel column chromatography (DCM: meOH = 5) to obtain the objective compound (compound 1) as a yellow solid (30 mg, two-step yield: 20%).

Ms m/z(ESI):583.3[M+H] ⁺

Example 2: trifluoroacetate salt of 4- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -4- [3, 8-diazabicyclo [3.2.1] octan-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 2)

4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[3,8-diazabicyclo[3.2.1]o ctan-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol；trifluoroacetic acid

The first step is as follows: 2-amino-4-bromo-3-fluorobenzamide (2B)

2-amino-4-bromo-3-fluorobenzamide

2-amino-4-bromo-3-fluorobenzoic acid (2A) (5 g, 21.46mmol) was dissolved in 60mL of N, N-dimethylformamide, HATU (12.24g, 32.18mmol), N, N-diisopropylethylamine (5.53g, 42.92mmol) and ammonium chloride (11.48 g, 214.60mmol) were added, respectively, and the reaction was continued at room temperature for 3h. The reaction solution was slowly poured into 120mL of ice water, and stirred at room temperature for 10min, and the precipitated solid was filtered, dried, and concentrated under reduced pressure to obtain compound (2B) (4.9 g, yield 98.39%).

LCMS m/z＝233.1[M+H] ⁺

The second step is that: 7-bromo-8-fluoro-1, 2,3, 4-tetrahydroquinazoline-2, 4-dione (2C)

7-bromo-8-fluoro-1,2,3,4-tetrahydroquinazoline-2,4-dione

(2B) (4.9g, 21.12mmol) was dissolved in 100mL of tetrahydrofuran, and triphosgene (9.4g, 31.68mmol) was added thereto, followed by completion of the addition, followed by reaction at 65 ℃ for 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give compound (2C) (4.7 g, 86.23% yield)

LCMS m/z＝259.1[M+H] ⁺

The third step: 7-bromo-2, 4-dichloro-8-fluoroquinazoline (2D)

7-bromo-2,4-dichloro-8-fluoroquinazoline

(2C) (1.5g, 5.81mmol) was dissolved in 30mL of toluene, and phosphorus oxychloride (4.45g, 29.07mmol) and N, N-diisopropylethylamine (2.25g, 17.44mmol) were added thereto, followed by reaction at 110 ℃ for 5 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give compound (2D) as a brown liquid which was used directly in the next reaction.

The fourth step:

3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (2E)

tert-butyl

3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(2D) was dissolved in 30mL of dry dichloromethane, N-diisopropylethylamine (2.25g, 17.44 mmol), intermediate 1 (1.23g, 5.81mmol) was slowly added under ice bath, after completion of addition, the reaction was slowly warmed to room temperature for 2h, after concentration under reduced pressure, the residue was subjected to column chromatography on silica gel to give compound (2E) (0.71 g, 26.00% yield in two steps).

LCMS m/z＝471.1[M+H] ⁺

The fifth step:

3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -7-bromo-8-fluoroquinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (2F)

tert-butyl

3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-y l)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Intermediate 2 (0.4g, 2.51mmol) was dissolved in 15mL of N, N-dimethylformamide, cesium carbonate (0.55 g, 1.70 mmol), triethylenediamine (0.03g, 0.26mmol) and cesium carbonate (0.4g, 2.51mmol) were added

Molecular sieves 500mg, reacted at room temperature under nitrogen for 10min, compound 2E (0.4g, 0.85mmol) was dissolved in N, N-dimethylformamide 2mL and slowly added to the reaction mixture, which was reacted at room temperature for 4h after completion of the addition, water 40mL was slowly added, ethyl acetate (40 mL. Times.2) was extracted twice, ethyl acetate layers were combined, washed twice with water (40 mL. Times.2) and once with saturated saline (40 mL. Times.1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to give Compound (2F) (0.36 g, yield 71.42%)

LCMS m/z＝594.1[M+H] ⁺

And a sixth step:

3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -8-fluoro-7- (7-fluoro-3- (methoxymethyl) -8- (2- (tris (propan-2-yl) silyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (2G)

tert-butyl

3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-7-(7-fluoro-3-(methoxy methoxy)-8-(2-(tris(propan-2-yl)silyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2. 1]octane-8-carboxylate

(2F) (0.36g, 0.60mmol) was dissolved in a mixed solution of 15mL of 1, 4-dioxane and 3mL of water, and intermediate 3 (0.62g, 1.20mmol), cesium carbonate (0.39g, 1.20mmol), pd (dppf) Cl and the like were added thereto ₂ The dichloromethane complex (0.10G, 0.12 mmol) of (a) was reacted at 100 ℃ for 5 hours under nitrogen, the reaction was cooled to room temperature, 40mL of ethyl acetate and 25mL of water were added, the aqueous phase was extracted once with ethyl acetate (40 mL. Times.1), the ethyl acetate layer was combined, the ethyl acetate layer was washed once with saturated brine (40 mL. Times.1), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain compound (2G) (0.24G, yield 44.03%)

LCMS m/z＝900.1[M+H] ⁺

The seventh step:

4- (2- { [ (2r, 7as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -4- [3, 8-diazabicyclo [3.2.1] octan-3-yl ] -8-fluoroquinazolin-7-yl) -6-fluoro-5- (2- (tri (propan-2-yl) silyl) ethynyl) naphthalen-2-ol (2H)

4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[3,8-diazabicyclo[3.2.1]o ctan-3-yl]-8-fluoroquinazolin-7-yl)-6-fluoro-5-(2-(tris(propan-2-yl)silyl)ethynyl)naphthalen-2-ol

The compound (2G) (0.15g, 0.16mmol) was dissolved in 10mL of dichloromethane, 0.5mL of trifluoroacetic acid was added, and after completion of the addition, the reaction was carried out at room temperature for 3 hours, and after concentration under reduced pressure, the compound (2H) was directly used in the next reaction.

LCMS m/z＝756.1[M+H] ⁺

The eighth step:

trifluoroacetate salt of 4- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -4- [3, 8-diazabicyclo [3.2.1] octan-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 2)

Compound (2H) was dissolved in 6mL of N, N-dimethylformamide, cesium fluoride (0.25g, 0.16mmol) was added and reacted at room temperature for 16H, the reaction solvent was removed by concentration under reduced pressure, the residue was purified by HPLC preparation, and the preparation was concentrated to give the trifluoroacetate salt of Compound 2 (7 mg, 7.1% yield in two steps).

The HPLC preparation method comprises the following steps:

1. the instrument comprises: waters 2767 preparation of the liquid phase; and (3) chromatographic column: sunFire @ Prep C18 (19mm. 250mm).

2. The sample was dissolved in DMF and filtered through a 0.45. Mu.M filter to prepare a sample solution.

3. Mobile phase A: acetonitrile; b: purified water (1% contained tfa); gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

¹ H NMR(400MHz,CD ₃ OD)δ7.91–7.82(m,2H),7.46–7.39(m,1H),7.36–7.28(m,2H), 7.09(d,1H),5.62–5.44(m,1H),4.77–4.62(m,4H),4.32–4.20(m,2H),4.06–3.75(m,5H), 3.50–3.40(m,1H),3.22(s,1H),2.75–2.56(m,2H),2.50–2.28(m,3H),2.26–2.05(m,5H).

LCMS m/z＝600.1[M+H] ⁺

Example 3:4- (9- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) furan [2,3-f ] quinazolin-4-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 3)

4-(9-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)m ethoxy)furo[2,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

The first step is as follows: 3- (4-bromo-7-chlorofuran [2,3-f ] quinazolin-9-yl) -3,8-diazabicyclo [3.2.1] octan-8-carboxylic acid tert-butyl ester tert-butyl

3-(4-bromo-7-chlorofuro[2,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Starting material 3a (1.2g, 4.27mmol) was dissolved in 25mL of 1,4 dioxane, N-diisopropylethylamine (2.76g, 21.35mmol) was added, and phosphorus oxychloride (6.55g, 42.7 mmol) was then added slowly dropwise at room temperature. After the dropwise addition, the system was heated to 100 ℃ under nitrogen protection for 3 hours. The mixture is cooled to room temperature, excess phosphorus oxychloride and solvent are removed under reduced pressure to obtain a crude product which is brown oily liquid, the residue is dissolved in 10mL dichloromethane, N-diisopropylethylamine (2.76g, 21.35mmol) and tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (0.91 g,4.27 mmol) are sequentially added into the system under the protection of nitrogen, and the mixture is slowly heated to room temperature for reaction for 2 hours. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (PE: EA = 3)

LCMS m/z＝493.0[M+1] ⁺

The second step: 3- (4-bromo-7- ((((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) furan [2,3-f ] quinazolin-9-yl) -3,8-diazabicyclo [3.2.1] octan-8-carboxylic acid tert-butyl ester

tert-butyl

3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)furo[2,3-f]quinazolin -9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

The starting materials 3b (140mg, 0.28mmol), ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (89mg, 0.56mmol), cesium carbonate (270mg, 0.84mmol), and triethylenediamine (6 mg,0.056 mmol) were dissolved in 10mL of DMF, and added

Reacting for 6 hours at room temperature under the protection of nitrogen by using a molecular sieve. After completion of the reaction, 15mL of water was added, extraction was performed 2 times with ethyl acetate, the organic phases were combined, the organic phase was washed once with 10mL of saturated common salt water, and then the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography to give the objective compound 3c (140 mg, yield 81%)

LCMS m/z＝616.2[M+1] ⁺

The third step: 3- (4- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -7- ((((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) furan [2,3-f ] quinazolin-9-yl) -3,8-diazabicyclo [3.2.1] oct-8-carboxylic acid tert-butyl ester tert-butyl

3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fl uorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)furo[2,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate

3c (140mg, 0.23mmol) and the compound ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (240mg, 0.46mmol) were placed in a sealed tube, dissolved by adding 10mL of a 1, 4-dioxane solution, and then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (50 mg, 0.069 mmol), cesium carbonate (220mg, 0.69mmol), and 2mL of water were sequentially added. Under the protection of nitrogen, the mixture is heated to 100 ℃ for reaction for 3h, cooled to room temperature, the solvent is removed under reduced pressure, 15mL of water and 30mL of ethyl acetate are added for dissolution, the aqueous phase is washed with 20mL of × 2 ethyl acetate, the organic phases are combined, the organic phase is washed once with 10mL of saturated common salt, and then the organic phase is dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to obtain the target compound 3d (150 mg, yield 70.7%).

LCMS m/z＝922.60[M+1] ⁺

The fourth step: 4- (9- ((3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (((((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) furan [2,3-f ] quinazolin-4-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol

4-(9-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)m ethoxy)furo[2,3-f]quinazolin-4-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

Dissolving the raw material 3d (150mg, 0.16mmol) in 10mL acetonitrile, then dropwise adding 2mL hydrochloric acid/1, 4-dioxane solution at room temperature, continuing the reaction for 1h, and removing the redundant hydrochloric acid and solvent under reduced pressure to obtain a crude compound 3e which is directly used for the next reaction.

LCMS m/z＝778.3[M+1] ⁺

The fifth step: 4- (9- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) furan [2,3-f ] quinazolin-4-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The starting material 3e (100mg, 0.13mmol) was dissolved in 3mL of DMF, cesium fluoride (103mg, 0.65mmol) was added, and the mixture was stirred at room temperature for 16 hours and directly subjected to reverse phase C18 column chromatography to isolate and purify Compound 3 (40 mg, yield 49.5%).

¹ H NMR(400MHz,CD ₃ OD)δ7.87–7.80(m,2H),7.43(s,1H),7.32–7.25(m,2H),7.14(d, 1H),6.39–6.35(m,1H),5.39–5.21(m,1H),4.33–4.14(m,4H),3.65–3.58(m,2H),3.57–3.46 (m,2H),3.30–3.15(m,3H),3.05–2.96(m,1H),2.95–2.90(m,1H),2.40–2.18(m,2H),2.18– 1.95(m,2H),2.08–1.95(m,3H),1.94–1.82(m,3H).

LCMS m/z＝622.4[M+1] ⁺ .

Example 4:4- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -4- [ (1R, 5S) -3,8-diazabicyclo [3.2.1] octane-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (Compound 4)

4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[(1R,5S)-3,8-diazabicycl o[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

The first step is as follows: (1R, 5S) -3- (2- { [ (2R, 7aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -7- (8-ethynyl-7-fluoro-3- (methoxymethyl) naphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (4B);

tert-butyl

(1R,5S)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3 -(methoxymethoxy)naphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbo xylate

compound 2G (0.35g, 0.39mmol) was dissolved in 8mL of N, N-dimethylformamide, and cesium fluoride (0.295mg, 1.95mmol) was added and stirred at room temperature for 3 hours. Slowly adding 20mL of water, extracting twice with ethyl acetate (20 mL. Times.2), combining ethyl acetate layers, washing the ethyl acetate layer twice with water (20 mL. Times.2), washing once with 20mL of a saturated aqueous solution of sodium chloride, finally drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying the residue with a silica gel column chromatography to obtain compound 4B (230 mg, yield 79.58%)

Ms m/z(ESI):744.3[M+H] ⁺

The second step is that: (1R, 5S) -3- (2- { [ (2R, 7aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (4C);

tert-butyl

(1R,5S)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-( methoxymethoxy)naphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbox ylate

4B (230mg, 0.31mmol) was dissolved in 5mL of methanol, and 230mg of palladium on carbon was added to the solution to react under hydrogen at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 4C (160 mg, yield 69.26%)

Ms m/z(ESI):748.1[M+H] ⁺

The third step: 4- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -4- [ (1R, 5S) -3,8-diazabicyclo [3.2.1] octane-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (Compound 4)

Dissolving 4C (0.16mg, 0.21mmol) in 8mL of dichloromethane, adding 0.5mL of trifluoroacetic acid, stirring at room temperature for 1 hour, concentrating under reduced pressure to remove residual solvent, and collecting the residue to obtain Compound 4 (8 mg, yield 6.2%)

The preparation method comprises the following steps:

the instrument is SHIMADZU LC-20AP;

the preparation column is Phenomenex C18;

mobile phase A is 10mmol/L NH ₄ HCO ₃ An aqueous solution; b is acetonitrile;

elution method B from 32% to 62% gradient elution 12 min;

the flow rate is 25mL/min;

column temperature is room temperature;

the detection wavelength is 220nm;

Ms m/z(ESI):604.1[M+1] ⁺

example 5:5- (4- (1R, 5S) -3, 8-diazoepoxy [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolidone-7 a (5H) -methyl) -quinazoline-7-methyl) -3-fluoro-2- (trifluoromethyl) aniline (Compound 5)

5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-fluoro-2-(trifluoromethyl)aniline

The first step is as follows: 5-bromo-3-fluoro-2- (trifluoromethyl) aniline (5B)

5-bromo-3-fluoro-2-(trifluoromethyl)aniline

5-bromo-1, 3-difluoro-2- (trifluoromethyl) benzene (5A) (2.00g, 7.66mmol) and 7N methanolic ammonia (10 mL) were added sequentially to a 120mL pressure vessel and stirring continued at 80 ℃ for 8h. The reaction was cooled to room temperature. The solvent was removed by concentration under reduced pressure, followed by extraction with water (30 mL)/dichloromethane (40 mL) and liquid separation, and the organic layer was dried over anhydrous sodium sulfate and then filtered. The organic layer was concentrated under reduced pressure to give crude product (5B) (1.80g, 91.04%) which was used in the next reaction without further purification.

Ms m/z(ESI):258.1[M+H] ⁺

The second step is that: 3-fluoro-5- (4, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) aniline (5C)

3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)aniline

Under the protection of nitrogen, 5B (1.80g, 6.98mmol), pinacol diboron (2.66g, 10.46mmol) and Pd (dppf) Cl are sequentially added ₂ (0.51g, 0.70mmol) and KOAc (2.05g, 20.93mmol) were charged in a 50mL round-bottomed flask, and a mixed solvent of 1, 4-dioxane (15 mL) and water (3 mL) was added to stir the reaction at 90 ℃ for 4 hours. After cooling to room temperature, the solvent was removed under reduced pressure, 30mL of water was added, followed by extraction with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the objective compound 5C (1.50g, 70.48%).

Ms m/z(ESI):306.1[M+H] ⁺

The third step: (1R, 5S) -3- (7- (3-amino-5-fluoro-4- (trifluoromethyl) phenyl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (5D)

tert-butyl

(1R,5S)-3-(7-(3-amino-5-fluoro-4-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(5C) (0.5g, 1.64mmol) was dissolved in a mixed solution of 1, 4-dioxane (10 mL) and water (2 mL) under a nitrogen atmosphere, and then intermediate 2F (0.65g, 1.09mmol), cesium carbonate (0.71g, 2.19mmol) and Pd (dppf) Cl were added in this order ₂ (0.12g, 0.11mmol), reaction at 110 ℃ for 5 hours, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, extracting the aqueous phase once with ethyl acetate (40 mL. Times.1), combining the ethyl acetate layers, washing the ethyl acetate layer once with saturated brine (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to silica gel column chromatography to give compound (5E) (0.61g, 79.27%)

Ms m/z(ESI):693.3[M+H] ⁺

The fourth step: 5- (4- (1R, 5S) -3,8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -3-fluoro-2- (trifluoromethyl) aniline (Compound 5)

Compound (5D) (0.60g, 0.87mmol) was dissolved in 10mL of methylene chloride, 0.5mL of trifluoroacetic acid was added, and after completion of the addition, the reaction was allowed to react at room temperature for 3 hours, and then the reaction was directly concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by reverse phase column chromatography to give target compound 5 (0.4 g, 77.93%).

Ms m/z(ESI):593.3[M+H] ⁺

Example 6:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5- (trifluoromethyl) aniline (Compound 6)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrah ydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-(trifluoromethyl)aniline

The first step is as follows: 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (6A)

7-bromo-2,4,6-trichloro-8-fluoroquinazoline

7-bromo-6-chloro-8-fluoroquinolizine-2, 4 (1H, 3H) -dione (2.0 g, 6.85mmol) was dissolved in 30mL of toluene, and phosphorus oxychloride (5.25g, 34.24mmol), N, N-diisopropylethylamine (2.65g, 20.54mmol) and reacted at 110 ℃ for 5 hours, respectively. The reaction was cooled to room temperature, concentrated under reduced pressure to give the crude compound (6A) directly which was used in the next reaction.

The second step: (1R, 5S) -3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (6B)

tert-butyl

(1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxyl ate

Compound 6A was dissolved in dry dichloromethane 30mL, N-diisopropylethylamine (2.65 g,20.54 mmol) and intermediate 1 (1.45g, 6.85mmol) were added slowly under ice-bath and after addition was returned slowly to room temperature for 2h. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography to isolate and purify the compound (6B) (0.88 g, two-step yield 25.50%).

LCMS m/z＝505.1[M+H] ⁺

The third step: (1R, 5S) -3- (2- { [ (2R, 7aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -7-bromo-6-chloro-8-fluoroquinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (6C)

tert-butyl

(1R,5S)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-bromo-6-chloro-8-flu oroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Under the protection of nitrogen, intermediate 2 (0.5g, 3.14mmol) was dissolved in 15mL of N, N-dimethylformamide, cesium carbonate (0.64g, 1.98mmol), triethylene diamine (0.04g, 0.35mmol) and molecular sieves (500 mg) were added, and after stirring at room temperature for 10min, 2mL of N, N-dimethylformamide as compound 6B (0.5g, 0.99mmol) was slowly added to the reaction mixture, and after completion of the addition, the reaction was carried out at room temperature for 4 hours. Slowly adding water 40mL, extracting twice with ethyl acetate (40 mL. Times.2), combining ethyl acetate layers, washing twice with water (40 mL. Times.2) and once with saturated brine (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the residue by silica gel column chromatography to obtain compound (6C) (0.46 g, yield 74.19%)

LCMS m/z＝628.1[M+H] ⁺

The first step is as follows: 3- (4, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -5- (trifluoromethyl) aniline (6E)

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline

Under the protection of nitrogen, 3-bromo-5- (trifluoromethyl) aniline (6D) (2g, 8.33mmol), pinacol diboron ester (3.17 g, 12.50mmol), potassium acetate (3.27g, 33.32mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (680mg, 0.83mmol) was placed in a sealed tube, and 15mL of 1, 4-dioxane was added, and the temperature was raised to 90 ℃ to react for 5 hours. The reaction was cooled to room temperature, then water was added and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound (6E) (2 g, 84% yield).

LCMS m/z＝288.1[M+H] ⁺

The second step is that: (1R, 5S) -3- (7- (3-amino-5- (trifluoromethyl) phenyl) -6-chloro-8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H) -pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (6F)

tert-butyl

(1R,5S)-3-(7-(3-amino-5-(trifluoromethyl)phenyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Intermediate 6C (150mg, 0.24mmol), 6E (76mg, 0.26mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (21mg, 0.024mmol) and cesium carbonate (160mg, 0.48mmol) were placed in a sealed tube under nitrogen and 4.5mL1, 4-dioxane and 1mL of water were added. The temperature was raised to 105 ℃ to react for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to give compound (6F) (118 mg, 69% yield)

LCMS m/z＝709.3[M+H] ⁺

The third step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5- (trifluoromethyl) aniline (Compound 6)

Compound (6F) (118mg, 0.17mmol) was dissolved in dichloromethane 2.5mL, followed by dropwise addition of 0.5mL trifluoroacetic acid, and the reaction was carried out at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, and then dichloromethane was added thereto to dissolve the reaction mixture, 0.5mL of N, N-diisopropylethylamine was added dropwise thereto, followed by concentration under reduced pressure, and the residue was purified by preparative HPLC, and the preparation was concentrated and lyophilized to obtain Compound 6 (55 mg, yield 53%).

The HPLC preparation method comprises the following steps:

1. the instrument comprises the following steps: waters 2767 preparation of the liquid phase; a chromatographic column: sunFire @ Prep C18 (19mm. Times.250mm).

3. Mobile phase A: acetonitrile; b: purified water (containing 1% of NH) ₄ HCO ₃ ) (ii) a Gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

LCMS m/z＝609.2[M+H] ⁺

Example 7:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5- (trifluoromethyl) aniline (Compound 7)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-(trifluoromethyl)aniline

The first step is as follows: (1R, 5S) -3- (7- (3-amino-5- (trifluoromethyl) phenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizine-7A) (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (7A)

tert-butyl

(1R,5S)-3-(7-(3-amino-5-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrr olizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Under the protection of nitrogen, intermediate 2F (110mg, 0.19mmol), compound 6E (107mg, 0.37mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (16mg, 0.019mmol) and cesium carbonate (124mg, 0.38 mmol) were placed in a sealed tube, and 3mL1, 4-dioxane and 0.6mL of water were added, and the temperature was raised to 105 ℃ for reaction for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to give compound (7A) (115 mg, 90% yield)

LCMS m/z＝675.1[M+H] ⁺

The second step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5- (trifluoromethyl) aniline (Compound 7)

Compound 7A (115mg, 0.17mmol) was dissolved in 2.5mL of methylene chloride, and then 0.5mL of trifluoroacetic acid was added dropwise thereto, followed by reaction at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, and after dropping 0.5ml of n, n-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 7 (45 mg, yield 46%) as a white powder.

The HPLC preparation method comprises the following steps:

3. A mobile phase A: acetonitrile; b: purified water (containing 1% of NH) ₄ HCO ₃ ) (ii) a Gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

LCMS m/z＝575.3[M+H] ⁺

Example 8:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4- (trifluoromethyl) aniline (Compound 8)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrah ydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-(trifluoromethyl)aniline

The first step is as follows: (1R, 5S) -3- (7- (5-amino-2- (trifluoromethyl) phenyl) -6-chloro-8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H) -pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (8B)

tert-butyl

(1R,5S)-3-(7-(5-amino-2-(trifluoromethyl)phenyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Under nitrogen protection, compound 6C (246mg, 0.39mmol), compound 5-amino-2- (trifluoromethyl) phenyl) boronic acid (8A) (89mg, 0.43mmol), tris (dibenzylideneacetone) dipalladium (36mg, 0.039mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropoxy-1, 1' -biphenyl (37mg, 0.08mmol), tetrabutylammonium bromide (13mg, 0.039mmol) and sodium carbonate (83 mg,0.78 mmol) were placed in a sealed tube, 4mL of 1, 4-dioxane and 1mL of water were added, and the temperature was raised to 105 ℃ for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to give compound (8B) (76 mg, 27% yield)

LCMS m/z＝709.3[M+H] ⁺

The third step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4- (trifluoromethyl) aniline (Compound 8)

Compound 8B (76mg, 0.11mmol) was dissolved in 2.5mL of methylene chloride, and then 0.5mL of trifluoroacetic acid was added dropwise thereto, followed by reaction at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, and then dichloromethane was added thereto to dissolve the reaction mixture, 0.5mL of N, N-diisopropylethylamine was added dropwise thereto, followed by concentration under reduced pressure, and the residue was purified by HPLC, and the preparation was concentrated and then lyophilized to obtain Compound 8 (12 mg, yield 17.9%).

The HPLC preparation method comprises the following steps:

the instrument is SHIMADZU LC-20AP;

a chromatographic column is Phenomenex C18;

mobile phase A is 10mmol NH ₄ HCO ₃ An aqueous solution; b is acetonitrile;

elution method, 30% to 60% of B gradient elution with A solution for 12 minutes;

the flow rate is 25mL/min;

column temperature, room temperature;

the detection wavelength is 220nm;

LCMS m/z＝609.2[M+H] ⁺

example 9:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2-chloro-5-fluoroaniline (Compound 9)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-chloro-5-fluoroaniline

The first step is as follows: 3-bromo-2-chloro-5-fluoroaniline (9A-1)

3-bromo-2-chloro-5-fluoroaniline

3-bromo-4-chloro-5-fluoroaniline (9A-2)

3-bromo-4-chloro-5-fluoroaniline

Dissolving the raw material 3-fluoro-5-bromoaniline (15g, 78.94mmol) in 200ml of N, N-dimethylformamide, adding N-chlorosuccinimide (11g, 82.89mmol) in portions under ice bath, stirring at room temperature for 16h, adding water to quench the reaction, adding 200ml of ethyl acetate to extract once, washing the organic phase with water 2 times (150 ml. Times.2), washing with 150ml of saturated saline water once, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain the compound 9A-1 (5 g, yield 28%), the compound 9A-2 (8 g, yield 45%)

LCMS m/z＝224.0[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ6.79(dd,1H),6.61(dd,1H),5.99(br,2H).(9A-1)

¹ H NMR(400MHz,DMSO-d ₆ )δ6.78(dd,1H),6.52(dd,1H),5.81(br,2H).(9A-2)

The second step is that: (4- ((1R, 5S) -8- (tert-butoxycarbonyl) -3,8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) boronic acid (9B)

(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2 -fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)boronic acid

(2F) (1.2g, 2.02mmol) was dissolved in a mixed solution of 15mL of 1, 4-dioxane and 3mL of water, and pinacol diboron ester (0.62g, 2.42mmol), potassium acetate (0.4g, 4.04mmol), pd (dppf) Cl were added ₂ (0.15g, 0.2mmol), reaction at 100 ℃ for 3h under nitrogen, cooling to room temperature, filtering with celite, concentrating the filtrate under reduced pressure, and reverse phase column chromatography to give compound 9B (1 g, 88.5% yield)

LCMS m/z＝560.2[M+H] ⁺

The third step: tert-butyl (1R, 5S) -3- (7- (3-amino-2-chloro-5-fluorophenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (9C)

tert-butyl

(1R,5S)-3-(7-(3-amino-2-chloro-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol izin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(9A-1) (0.11g, 0.49mmol) was dissolved in a mixed solution of 5mL of 1, 4-dioxane and 1mL of water, and 9B (0.22g, 0.39mmol), cesium carbonate (0.32g, 0.98mmol), pd (dppf) Cl ₂ (0.036g, 0.049mmol), reaction at 100 ℃ for 2h under nitrogen protection, cooling the reaction to room temperature, adding ethyl acetate 40mL and water 25mL, extracting the aqueous phase once with ethyl acetate (40 mL. Times.1), combining ethyl acetate layers, washing the ethyl acetate layer once with saturated brine (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to silica gel column chromatography to give compound (9C) (0.13 g, 40.25% yield)

LCMS m/z＝659.2[M+H] ⁺

The fourth step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2-chloro-5-fluoroaniline (Compound 9)

Compound (9C) (0.13g, 0.87mmol) was dissolved in 5mL of methylene chloride, and 0.5mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, and after dropping 0.5mL of N, N-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 9 (20 mg, yield 20%) as a white powder.

The HPLC preparation method comprises the following steps:

3. Mobile phase A: acetonitrile; b: purified water(containing 1% of NH) ₄ HCO ₃ ) (ii) a Gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: 18min

Ms m/z(ESI):559.2[M+H] ⁺

Example 10:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4-chloro-5-fluoroaniline (Compound 10)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-chloro-5-fluoroaniline

The first step is as follows: tert-butyl (1R, 5S) -3- (7- (5-amino-2-chloro-3-fluorophenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizine-) 7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (10A)

tert-butyl

(1R,5S)-3-(7-(5-amino-2-chloro-3-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol izin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(9A-2) (0.11g, 0.49mmol) was dissolved in a mixed solution of 5mL of 1, 4-dioxane and 1mL of water, and 9B (0.22g, 0.39mmol), cesium carbonate (0.32g, 0.98mmol), pd (dppf) Cl ₂ (0.036g, 0.049mmol), reacting at 100 ℃ for 2h under the protection of nitrogen, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, stirring, separating, extracting the aqueous phase once with ethyl acetate (40 mL multiplied by 1), combining ethyl acetate layers, washing the ethyl acetate layer once with saturated saline solution (40 mL multiplied by 1), drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing silica gel column chromatography on the residue to obtain the chemical compoundCompound (10A) (0.13 g, yield 40.25%)

LCMS m/z＝659.2[M+H]+

The second step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4-chloro-5-fluoroaniline (Compound 10)

Compound (10A) (0.13g, 0.87mmol) was dissolved in 5mL of methylene chloride, and 0.5mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, and then dichloromethane was added to dissolve it, 0.5ml of n, n-diisopropylethylamine was added dropwise thereto, and then concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 10 (20 mg, yield 20%) as a white powder.

The HPLC preparation method comprises the following steps:

3. Mobile phase A: acetonitrile; b: purified water (containing 1% of NH) ₄ HCO ₃ ) (ii) a Gradient elution, wherein the content of a mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

Ms m/z(ESI):559.2[M+H] ⁺

Example 11:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2-chloro-4, 5, 6-trifluoroaniline (Compound 11)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-chloro-4,5,6-trifluoroaniline

The first step is as follows: 2,3, 4-trifluoro-5-iodoaniline (11A)

2,3,4-trifluoro-5-iodoaniline

The starting material 2,3, 4-trifluoroaniline (1.0g, 6.8mmol) was dissolved in 5ml of trifluoromethanesulfonic acid, NIS (2.3g, 10.2mmol) was added, and the mixture was stirred at room temperature for 5 hours, diluted with 30ml of water, extracted once with 30ml of ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give compound 11A (1.2 g, yield 64.6%).

The second step is that: 2-chloro-4, 5, 6-trifluoro-3-iodoaniline (11B)

2-chloro-4,5,6-trifluoro-3-iodoaniline

Raw material 11A (0.3 g, 1.1mmol) was dissolved in 5ml of acetic acid, NCS (0.16g, 1.21mmol) was added, stirred at room temperature for 5h, diluted with 30ml of water, extracted once with 30ml of ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatographed to give compound 11B (0.16 g, 47.3% yield).

The third step: tert-butyl (1R, 5S) -3- (7- (3-amino-2-chloro-4, 5, 6-trifluorophenyl) -8-fluoro-2- ((((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (11C)

tert-butyl

(1R,5S)-3-(7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(11B) (0.16g, 0.52mmol) was dissolved in a mixed solution of 5mL of 1, 4-dioxane and 1mL of water, and 9B (0.23g, 0.42mmol), cesium carbonate (0.3g, 1.04mmol), pd (dppf) Cl and the like were added ₂ (0.038g, 0.052mmol), reaction at 100 ℃ for 2 hours under nitrogen atmosphere, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, extracting the aqueous phase with ethyl acetate (40 mL. Times.1) once, combining the ethyl acetate layers, washing the ethyl acetate layer with saturated brine (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to silica gel column chromatography to give compound (11C) (0.11 g, yield 30.4%)

LCMS m/z＝695.2[M+H] ⁺

The fourth step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2-chloro-4, 5, 6-trifluoroaniline (Compound 11)

Compound (11C) (0.11g, 0.16mmol) was dissolved in 5mL of dichloromethane, and 0.5mL of trifluoroacetic acid was added thereto, followed by reaction at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dichloromethane was added to dissolve it, 0.5ml of n, n-diisopropylethylamine was added dropwise thereto, then concentration under reduced pressure was carried out, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 11 (20 mg, yield 21%) as a white powder.

The HPLC preparation method comprises the following steps:

Ms m/z(ESI):595.2[M+H] ⁺

Example 12:3- (4- ((1R, 5S) -3, 8-diazacyclo [3.2.1] octyl-3-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -ylmethoxy) quinazolin-7-yl) -4- (trifluoromethyl) aniline (Compound 12)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-(trifluoromethyl)aniline

The first step is as follows: tert-butyl (1R, 5S) -3- (7- (5-amino-2- (trifluoromethyl) phenyl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (12B)

tert-butyl(1R,5S)-3-(7-(5-amino-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetra hydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxyla te

Intermediate 2F (160mg, 0.27mmol), 12A (120mg, 0.41mmol), pd (dppf) Cl ₂ DCM (22 mg,0.03 mmol) and cesium carbonate (260mg, 0.81mmol) were added to a mixed solvent of 1, 4-dioxane (8 mL) and water (2 mL). The reaction was stirred at 105 ℃ for 5 hours under nitrogen. After the reaction was also cooled to room temperature, the solvent was removed under reduced pressure, 100mL of water was added, followed by extraction with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun-dried, and the residue was separated and purified by silica gel column chromatography to give 12B (140 mg, yield: 76.85)％)。

Ms m/z(ESI):675.4[M+H] ⁺

The second step is that: 3- (4- ((1R, 5S) -3, 8-diazacyclo [3.2.1] octyl-3-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -ylmethoxy) quinazolin-7-yl) -4- (trifluoromethyl) aniline (Compound 12)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-(trifluoromethyl)anne

12B (140mg, 0.21mmol) was dissolved in dichloromethane (10 mL), then 3mL TFA was added at room temperature, and the reaction was continued to stir at room temperature for an additional 1 hour. Excess acid and solvent were removed under reduced pressure, and purification by preparative HPLC was carried out to give the objective compound 12 (40 mg, yield: 33.15%).

Ms m/z(ESI):575.2[M+H] ⁺

Example 13:3- (4- ((1R, 5S) -3, 8-diazacyclo [3.2.1] octyl-3-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -4- (trifluoromethoxy) aniline (Compound 13)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-(trifluoromethoxy)aniline

The first step is as follows: tert-butyl (1R, 5S) -3- (7- (5-amino-2- (trifluoromethoxy) phenyl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -ylmethoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (13B)

tert-butyl(1R,5S)-3-(7-(5-amino-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetr ahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxyl ate

Intermediate 2F (150mg, 0.25mmol), 13A (110mg, 0.38mmol), pd (dppf) Cl ₂ DCM (20 mg, 0.025 mmol) and cesium carbonate (240mg, 0.75mmol) were added to a mixed solvent of 1, 4-dioxane (10 mL) and water (2 mL). The reaction was stirred at 105 ℃ for 3 hours under nitrogen. After the reaction was also cooled to room temperature, the solvent was removed under reduced pressure, 100mL of water was added, followed by extraction with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun-dried, and the residue was separated and purified by silica gel column chromatography to give 13B (140 mg, yield: 81.08%).

Ms m/z(ESI):691.3[M+H] ⁺

The second step is that: 3- (4- ((1R, 5S) -3, 8-diazacyclo [3.2.1] octyl-3-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -4- (trifluoromethoxy) aniline (Compound 13)

13b (140mg, 0.20mmol) was dissolved in methylene chloride (8 mL), and then 2mL of TFA was added at room temperature, and the reaction was further stirred at room temperature for 1 hour. Excess acid and solvent were removed under reduced pressure, and purification by preparative HPLC gave the objective compound 13 (20 mg, yield: 16.93%).

Ms m/z(ESI):591.2[M+H] ⁺

Example 14:3- (1R, 5S) -3, 8-diazo-epoxy [3.2.1] -octane-3-yl) -5-fluoro-3- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolidone-7 a (5H) -yl) methoxy) -isoquinolin-6-yl-5-chloro-4-cyclopropylaniline (Compound 14)

3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)isoquinolin-6-yl)-5-chloro-4-cyclopropylaniline

The first step is as follows: 3-bromo-5-chloro-4-iodoaniline (14B)

3-bromo-5-chloro-4-iodoaniline

3-bromo-5-chloro-aniline (14A) (1.00g, 4.84mmol) and NIS (1.31g, 5.81mmol) were added sequentially to a 50mL round bottom flask and stirring continued at ambient temperature for 3h. After completion of the reaction, the reaction mixture was extracted with water (30 mL)/ethyl acetate (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the objective compound (14B) (1.30g, 80.76%).

The second step is that: 3-bromo-5-chloro-4-cyclopropylaniline (14C)

3-bromo-5-chloro-4-cyclopropylaniline

Under the protection of nitrogen, (14B) (1.30g, 3.91mmol), cyclopropylboronic acid (0.40g, 4.69mmol), pd (dppf) Cl were sequentially added ₂ (0.28g, 0.39mmol) and Cs ₂ CO ₃ (2.55g, 7.82mmol) was charged in a 50mL round-bottomed flask, and a mixed solvent of 1, 4-dioxane (15 mL) and water (3 mL) was further added to the flask, followed by stirring at 110 ℃ for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, 30mL of water was added, and acetic acid was addedExtraction with ethyl ester (20 mL × 3), combination of organic phases, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography (PE: EA =10 1) gave the objective compound 14C (0.80g, 82.96% yield).

The third step: 3-chloro-4-cyclopropyl-5- (4, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) aniline (14D)

3-chloro-4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Under the protection of nitrogen, (14C) (0.80g, 3.25mmol), pinacol diboron (0.99g, 3.89mmol), pd (dppf) Cl were sequentially added ₂ (0.23g, 0.33mmol) and KOAc (0.96g, 9.74mmol) were added to a 50mL round-bottomed flask, and a mixed solvent of 1, 4-dioxane (15 mL) and water (3 mL) was added to the flask, and the reaction was stirred at 90 ℃ for 4 hours. After cooling to room temperature, the solvent was removed under reduced pressure, 30mL of water was added, followed by extraction with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the objective compound (14D) (0.8g, 83.97%).

Ms m/z(ESI):294.2[M+H] ⁺

The fourth step: tert-butyl (1R, 5S) -3- (5-amino-3-chloro-2-cyclopropylbenzene) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolidinone-7 a (5H) -yl) methoxy) -quinazolin-4-yl) -3, 8-diazocyclo [3.2.1] octane-8-carboxylate (14E)

tert-butyl(1R,5S)-3-(7-(5-amino-3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorot etrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbo xylate

(14D) (0.12g, 0.40mmol) was dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL) under nitrogen atmosphere, followed byThen, intermediate 2F (0.20g, 0.33mmol), cesium carbonate (0.22g, 0.67mmol) and Pd (dppf) Cl were added in this order ₂ (0.02g, 0.03mmol), reaction at 110 ℃ for 5 hours, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, stirring and separating the liquids, extracting the aqueous phase once with ethyl acetate (40 mL. Times.1), combining the ethyl acetate layers, washing the ethyl acetate layer once with saturated brine (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to silica gel column chromatography to give compound (14E) (0.20g, 87.27%)

Ms m/z(ESI):681.3[M+H] ⁺

The fifth step: 3- (4- ((1R, 5S) -3, 8-diazoepoxy [3.2.1] -octan-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolidone-7 a (5H) -yl) methyl) -5-chloro-4-cyclopropylaniline (Compound 14)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-cyclopropylaniline

Compound (14E) (0.20g, 0.29mmol) was dissolved in 10mL of dichloromethane, and 0.3mL of trifluoroacetic acid was added thereto, and after completion of the addition, the reaction was reacted at room temperature for 3 hours, and then the reaction was directly concentrated under reduced pressure to remove the solvent, and the residue was subjected to separation and purification by reverse phase column chromatography to give the objective compound 14 (0.18g, 90.00%).

Ms m/z(ESI):581.3[M+H] ⁺

¹ H NMR(400MHz,CDCl ₃ )δ7.57(d,1H),7.09–6.99(m,1H),6.78(d,1H),6.50(d,1H),5.38 –5.17(m,1H),4.48–4.33(m,2H),4.26(d,1H),4.13(d,1H),3.80-3.59(m,4H),3.58–3.46(m, 2H),3.31–3.11(m,3H),3.03–2.92(dm,1H),2.35–2.14(m,3H),2.07–1.72(m,11H),0.68– 0.49(m,2H).

Example 15:3- (4- (1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolidinone-7 a (5H) -yl) methyl) quinazolin-7-yl) -5-chloro-4- (trifluoromethyl) aniline (Compound 15)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

The first step is as follows: (3-bromo-5-chloro-4-iodophenyl) carbamic acid tert-butyl ester (15A)

tert-butyl(3-bromo-5-chloro-4-iodophenyl)carbamate

In N ₂ Under the protection of (1), dissolving the compound 14B (0.5g, 1.5mmol) and di-tert-butyl dicarbonate (0.36g, 1.65mmol) in 2mL THF, then slowly dripping LiHMDS (0.55g, 3.30mL) under the condition of ice bath, after dripping, transferring the reaction solution to the normal temperature condition for reaction for 3H, and after the reaction is completely finished, EA/H ₂ O (150 mL/100 mL) was extracted and washed, and the organic layer was concentrated and purified by column chromatography to give Compound 15A (0.45 g, yield: 69.37%).

Ms m/z(ESI):431.9[M-H] ⁺

The second step: (3-bromo-5-chloro-4- (trifluoromethyl) phenyl) carbamic acid tert-butyl ester (15B)

tert-butyl(3-bromo-5-chloro-4-(trifluoromethyl)phenyl)carbamate

In N ₂ Under the protection of (1), compound 15A (0.1g, 0.23mmol), MFSDA (0.31g, 1.61mmol) and CuI (53.0mg, 0.28mmol) were sequentially added to a reaction tube, and then DIPEA (0.21g, 1.61mmol) was dissolved in 5mL of DMF and slowly added dropwise to the reaction tube. Continuously reacting for 16H in an oil bath at 75 ℃, and after the reaction is finished, EA/H ₂ O (200 mL/150ml × 2) was subjected to extraction washing. The organic layer was finally concentrated and purified by a chromatography column (PE: EA =10 1) to obtain compound 15B (80.0 mg, yield: 92.86% yield.

Ms m/z(ESI):373.9[M-H] ⁺

The third step: tert-butyl (1r, 5s) -3- (7- (5- ((tert-butoxycarbonyl) amino) -3-chloro-2- (trifluoromethyl) phenyl) -8-fluoro-2- ((2r, 7as) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -methoxy) quinazolin-4-yl) -3, 8-diazacyclo [3.2.1] octane-8-carboxylate (15C). tert-butyl (1R, 5S) -3- (7- (5- ((tert-butoxycarbonyl) amino) -3-chloro-2- (trifluoromethylphenyl) -8-fluoro-2- (((2R, 7aS) -2-fluoroetrtrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo o [3.2.1]

Intermediate 9B (200mg, 0.36mmol) and compound 15B (0.16mg, 0.43mmol) were placed in a sealed tube, and 5mL of 1, 4-dioxane solution was added to dissolve, followed by the sequential addition of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (26.0 mg,0.036 mmol), cesium carbonate (230.0mg, 0.72mmol). Under nitrogen protection, the mixture was raised to 110 ℃ for 5h, the solvent was removed under reduced pressure, 50mL of water and 100mL of ethyl acetate were added to dissolve, the aqueous phase was washed with 50mL of × 2 ethyl acetate, the organic phases were combined, the organic phase was washed once with 40mL of saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, spin-dried, and column chromatography (DCM: meOH = 15) gave compound 15C (270.0 mg, yield: 92.68%).

Ms m/z(ESI):809.3[M+H] ⁺

The fourth step: 3- (4- (1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolidinone-7 a (5H) -yl) methyl) quinazolin-7-yl) -5-chloro-4- (trifluoromethyl) aniline (Compound 15)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro lizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

Compound 15C (270mg, 0.33mmol) was dissolved in 10mL of DCM, then 1mL of trifluoroacetic acid was added dropwise at room temperature, the system was reacted for 3 hours, the reaction was concentrated under reduced pressure, the residue was purified by preparative HPLC, and the preparation was concentrated and lyophilized to give the objective compound 15 (150 mg, yield: 74.63%).

The HPLC preparation method comprises the following steps:

1. the instrument comprises: waters 2767 preparation of the liquid phase; a chromatographic column: sunFire @ Prep C18 (19mm. Times.250mm).

3. A mobile phase A: acetonitrile; b: purified water (containing 1% of NH) ₄ HCO ₃ ) (ii) a Gradient elution, wherein the content of a mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

Ms m/z(ESI):609.2[M+H] ⁺

Example 16:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolidone-7 a (5H) -yl) methoxy) quinazolin-7-yl) -5-fluoro-4-cyclopropylaniline (Compound 16)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-cyclopropyl-5-fluoroaniline

The first step is as follows: 3-bromo-5-fluoro-4-iodoaniline (16B)

3-bromo-5-fluoro-4-iodoaniline

3-bromo-5-fluoro-aniline (16A) (2.00g, 10.53mmol) and NIS (2.61g, 11.58mmol) were added sequentially to a 100mL round bottom flask and stirring continued at ambient temperature for 3h. After the reaction was completed, extraction was performed with water (100 mL)/ethyl acetate (150 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the objective compound (16B) (3.10 g, yield: 97.19%).

The second step: 3-bromo-5-fluoro-4-cyclopropylaniline (16C)

3-bromo-5-fluoro-4-cyclopropylaniline

Under nitrogen protection, (16B) (3.0 g, 9.50mmol), cyclopropylboronic acid (0.98g, 11.40mmol), pd (dppf) Cl were added in this order ₂ (0.70g, 0.95mmol) and Cs ₂ CO ₃ (6.19g, 19.00mmol) was added to a 100mL round-bottomed flask, and a mixed solvent of 1, 4-dioxane (15 mL) and water (3 mL) was added thereto, and the reaction was stirred at 110 ℃ for 4 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed under reduced pressure, 100mL of water was added, followed by extraction with ethyl acetate (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE: EA = 10) to obtain the objective compound 16C (1.40 g, yield: 64.05%).

The third step: 3-fluoro-4-cyclopropyl-5- (4, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) aniline (16D)

3-fluoro-4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Under the protection of nitrogen, (16C) (1.40g, 6.08mmol), pinacol diboron (1.85g, 7.30mmol) and Pd (dppf) Cl were sequentially added ₂ (0.45g, 0.61mmol) and KOAc (1.79g, 18.24mmol) were charged in a 50mL round-bottomed flask, and a mixed solvent of 1, 4-dioxane (15 mL) and water (3 mL) was added to stir the reaction at 90 ℃ for 4h. Cooling to room temperature, removing the solvent under reduced pressure, and adding 30mL of water was extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the objective compound (16D) (1.4 g, yield: 83.09%).

Ms m/z(ESI):278.3[M+H] ⁺

The fourth step: tert-butyl (1R, 5S) -3- (5-amino-3-fluoro-2-cyclopropylbenzene) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolidinone-7 a (5H) -yl) methoxy) -quinazolin-4-yl) -3, 8-diazocyclo [3.2.1] octane-8-carboxylate (16E)

tert-butyl(1R,5S)-3-(7-(5-amino-3-fluoro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrah ydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e

(16D) (0.11g, 0.41mmol) was dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL) under nitrogen, and then intermediate 2F (0.20g, 0.34mmol), cesium carbonate (0.10g, 1.02mmol) and Pd (dppf) Cl were added in this order ₂ (25.0 mg, 0.03mmol), reaction at 110 ℃ for 5 hours, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, stirring and separating the layers, extracting the aqueous phase once more with ethyl acetate (40 mL × 1), combining the ethyl acetate layers, washing the ethyl acetate layer once with saturated brine (40 mL × 1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to silica gel column chromatography to give compound 16E) (0.18 g, yield: 79.64%)

Ms m/z(ESI):665.3[M+H] ⁺

The fifth step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolidone-7 a (5H) -yl) methyl) -5-fluoro-4-cyclopropylaniline (Compound 16)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-fluoro-4-cyclopropylaniline

Compound (14E) (0.18g, 0.27mmol) was dissolved in dichloromethane (2.0 mL), and after 0.2mL of trifluoroacetic acid was added, the reaction was allowed to react at room temperature for 3 hours, and after the reaction was directly concentrated under reduced pressure to remove the solvent, the residue was isolated and purified by reverse phase column chromatography to give target compound 16 (0.10 g, yield: 65.59%).

Ms m/z(ESI):565.3[M+H] ⁺

Example 17:4- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydrofuran-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -6-aminobenzofuran-7-carbonitrile (compound 17).

4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro lizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-aminobenzofuran-7-carbonitrile

The first step is as follows: 6-amino-4- (4, 5-tetramethyl-1,3, 2-dioxabenzaldehyde-2-yl) benzofuran-7-carbonitrile 6-amino-4- (4, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) benzofuran-7-carbanitrile

Under the protection of nitrogen, (17A) (0.2g, 0.84mmol), pinacol diboron (10.26g, 1.01mmol), pd (dppf) Cl ₂ (0.06g, 0.084 mmol) and KOAc (0.16g, 1.68mmol) were added to a 50mL round-bottomed flask, 1, 4-dioxane (3 mL) solvent was added, and the reaction was stirred at 90 ℃ for 6h. Cooling to room temperature, removing solvent under reduced pressure, adding 30mL of water, extracting with ethyl acetate (300 mL. Times.3), combining organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressureThe filtrate, the residue was purified by silica gel column chromatography to obtain the objective compound 17B (0.2 g, yield: 83.8%).

Ms m/z(ESI):285.1[M+H] ⁺

The second step is that: tert-butyl (1R, 5S) -3- (7- (6-amino-7-cyanobenzofuran-4-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazacyclo [3.2.1] octane-8-carboxylate (17C).

tert-butyl(1R,5S)-3-(7-(6-amino-7-cyanobenzofuran-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Intermediate 2F (130.0mg, 0.22mmol) and compound 17B (75.0mg, 0.26mmol) were placed in a sealed tube, and dissolved by adding 2mL of a 1, 4-dioxane solution, followed by sequentially adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (16.0 mg, 0.022mmol) and cesium carbonate (140.0mg, 0.44mmol). Under nitrogen protection, the mixture was raised to 110 ℃ for 6h, the solvent was removed under reduced pressure, 30mL of water and 60mL of ethyl acetate were added to dissolve, the aqueous phase was washed with 100mL of × 2 ethyl acetate, the organic phases were combined, the organic phase was washed once with 80mL of saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, spin-dried, and column chromatography (DCM: meOH = 15) gave the target compound (100.0 mg, yield: 67.67%).

Ms m/z(ESI):672.3[M+H] ⁺

The third step: 4- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydrofuran-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -6-aminobenzofuran-7-carbonitrile (compound 17).

Compound 17C (100mg, 0.15mmol) was dissolved in 1mL of LPCM, then 0.1mL of trifluoroacetic acid was added dropwise at room temperature, the system was allowed to continue to react for 3 hours, the reaction was concentrated under reduced pressure, the residue was purified by preparative HPLC, and the preparation was concentrated and lyophilized to give the objective compound 17 (50.0 mg, yield: 58.31%).

The HPLC preparation method comprises the following steps:

1. the instrument comprises the following steps: waters 2767 preparation of the liquid phase; and (3) chromatographic column: sunFire @ Prep C18 (19mm. Times.250mm).

Ms m/z(ESI):572.3[M+H] ⁺

Example 18:2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -3,4,5, 6-tetrafluoroaniline (Compound 18).

2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro lizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3,4,5,6-tetrafluoroaniline

The first step is as follows: 2,3,4, 5-tetrafluoro-6- (4, 5-tetramethyl-1,3, 2-dioxabenzaldehyde-2-yl) aniline (18B)

2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Under the protection of nitrogen, sequentially reacting(18A) (2.28g, 9.35mmol), pinacol diboron (3.97g, 15.61mmol), pd (dppf) Cl ₂ (1.37g, 1.87mmol) and KOAc (1.84g, 18.7 mmol) were charged in a 100mL round-bottomed flask, 1, 4-dioxane (30 mL) solvent was added, and the reaction was stirred at 90 ℃ for 6h. After cooling to room temperature, the solvent was removed under reduced pressure, 100mL of water was added, followed by extraction with ethyl acetate (300 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the objective compound 18B (1.4 g, yield: 83.6%).

Ms m/z(ESI):292.1[M+H] ⁺

The second step is that: tert-butyl (1R, 5S) -3- (7- (2-amino-3, 4,5, 6-tetrafluorophenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazacyclo [3.2.1] octane-8-carboxylate (18C).

tert-butyl(1R,5S)-3-(7-(2-amino-3,4,5,6-tetrafluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Under nitrogen protection, intermediate 2F (0.12g, 0.40mmol) was dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (1 mL), followed by the addition of 18B (0.20g, 0.33mmol), cesium carbonate (0.22g, 0.67mmol), and Pd (dppf) Cl ₂ (0.02g, 0.03mmol), a reaction at 110 ℃ for 5 hours, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, extracting the aqueous phase once more with ethyl acetate (40 mL. Times.1), combining the ethyl acetate layers, washing the ethyl acetate layer once with saturated brine (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to column chromatography on silica gel to give Compound 18C (0.20 g, yield: 86.67%).

Ms m/z(ESI):679.3[M+H] ⁺

The third step: 2- (4- ((1R, 5S) -3, 8-diazacyclo [3.2.1] octyl-3-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -3,4,5, 6-tetrafluoroaniline (Compound 18).

Compound 18C (0.20g, 0.29mmol) was dissolved in 2.0mL of methylene chloride, and 0.2mL of trifluoroacetic acid was added thereto, and after completion of the addition, the reaction was reacted at room temperature for 3 hours, and then the reaction was directly concentrated under reduced pressure to remove the solvent, and after which the target compound 18 (0.1 g, yield: 59.6%) was isolated and purified by reverse phase column chromatography.

Example 19:2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -4-amino-6-fluorobenzonitrile 2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluoroanhydro-1H-pyrro-lizin-7 a (5H) -yl) metho-ne) quinazolin-7-yl) -4-amino-6-fluoro-nitrile

The first step is as follows: 4-bromo-3-chloro-5-fluoroaniline

4-bromo-3-chloro-5-fluoroaniline

Dissolve 19a (1g, 6.87mmol) in acetic acid (12 mL) and add NBS (1.34g, 7.56mmol) at RT and continue stirring at RT for 4h. The excess acid agent was removed under reduced pressure, and subjected to 40g of normal phase column purification (PE: EA = 50.

Ms m/z(ESI):224.1[M+H] ⁺

The second step is that: 4-amino-2-chloro-6-fluorobenzonitrile

4-amino-2-chloro-6-fluorobenzonitrile

19b (0.5g, 2.23mmol) and CuCN (0.4g, 4.46mmol) were dissolved in DMF (5 mL) and the reaction was stirred for 1 hour at 190 ℃ with a microwave. 100mL of water was added, followed by extraction with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried, and the residue was subjected to silica gel column chromatography (PE: EA =50, 1. About.5) to give 19c (156 mg, yield: 41.01%).

Ms m/z(ESI):169.1[M-H]-

The third step: tert-butyl (1R, 5S) -3- (7- (5-amino-2-cyano-3-fluorophenyl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazacyclo [3.2.1] octane-8-carboxylate tert-butyl (1R, 5S) -3- (7- (5-amino-2-cyclo-3-fluorophenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydroxy-1H-pyrolin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] -acetate-8-carboxalinyl-4-yl) -3,8-diazabicyclo [3.2.1]

Intermediate 9B (150mg, 0.28mmol), 19c (72mg, 0.42mmol), pdCl2 (PPh 3) 2 (20mg, 0.028 mmol) and KF (49mg, 0.84mmol) were added to a mixed solvent of ACN (8 mL) and water (2 mL). The reaction was stirred in a sealed tube at 100 ℃ for 12 hours under nitrogen. After the reaction was also cooled to room temperature, the solvent was removed under reduced pressure, 100mL of water was added, followed by extraction with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun-dried, and the residue was purified by silica gel column chromatography to give 19d (81 mg, yield: 44.53%).

Ms m/z(ESI):650.3[M+H] ⁺

The fourth step: 2- (4- ((1R, 5S) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -4-amino-6-fluorobenzonitrile 2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluoroethoxyhydro-1H-pyro-lizin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -4-amino-6-fluorobenzonitril

19d (80mg, 0.12mmol) was dissolved in dichloromethane (8 mL) and then 2mL TFA was added at room temperature and the reaction was allowed to continue stirring at room temperature for an additional 1 hour. Excess acid and solvent were removed under reduced pressure, and purification by preparative HPLC was carried out to give the objective compound 19 (18 mg, yield: 27.29%).

The HPLC preparation method comprises the following steps:

Ms m/z(ESI):550.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ7.83(d,1H),7.24–7.18(m,1H),6.73(s,2H),6.59–6.49 (m,2H),5.38–5.16(m,1H),4.26(d,2H),4.06(dd,2H),3.55–3.42(m,4H),3.16–2.98(m,4H), 2.86–2.78(m,1H),2.20–1.98(m,3H),1.88–1.73(m,3H),1.68–1.58(m,4H).

Example 20:6- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5- (trifluoromethyl) pyridin-2-amine (Compound 20)

6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-(trifluoromethyl)pyridin-2-amine.

The first step is as follows: tert-butyl (1R, 5S) -3- (7- (6-amino-3- (trifluoromethyl) pyridin-2-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H) -pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (20B)

tert-butyl(1R,5S)-3-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbo xylate.

(20A) (0.132g, 0.672mmol) was dissolved in a mixed solution of acetonitrile 10mL and water 1mL, and 9B (0.188 g, 0.336mmol), potassium fluoride (0.073g, 1.257mmol), pd (PPh) were added ₂ Cl ₂ ( 0.023g,0.034 mmol), reacting at 100 ℃ for 12h under nitrogen protection, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, stirring, separating the liquid, extracting the aqueous phase once with ethyl acetate (40 mL × 1), combining the ethyl acetate layers, washing the ethyl acetate layer once with saturated saline (40 mL × 1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography on the residue with silica gel (DCM: meOH = 24) to give compound (20B) (0.15 g, 66.07% yield) )

LCMS m/z＝676.3[M+H] ⁺

The second step is that: 6- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5- (trifluoromethyl) pyridin-2-amine (Compound 20)

Compound (20B) (0.15g, 0.22mmol) was dissolved in 5mL of methylene chloride, and 0.5mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dichloromethane was added to dissolve it, 0.5ml of n, n-diisopropylethylamine was added dropwise thereto, concentration under reduced pressure was performed, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to obtain compound 20 (40 mg, yield 31.3%) as a white powder.

The HPLC preparation method comprises the following steps:

1. the instrument comprises: waters 2767 preparation of the liquid phase; and (3) chromatographic column: sunFire @ Prep C18 (19mm. Times.250mm).

3. A mobile phase A: acetonitrile; b: purifying water (containing 1% of NH) ₄ HCO ₃ ) (ii) a Gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

Ms m/z(ESI):576.2[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.79(d,2H),7.19–7.11(m,1H),6.69(d,1H),5.41–5.21(m, 1H),4.47(t,2H),4.24(dd,2H),3.66–3.53(m,4H),3.36–3.32(m,1H),3.26–3.15(m,2H),3.06 –2.96(m,1H),2.41–2.10(m,3H),2.05–1.87(m,3H),1.86–1.77(m,4H).

Example 21:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2,4, 6-trifluoroaniline (Compound 21)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2,4,6-trifluoroaniline.

The first step is as follows: 2-bromo-1, 3, 5-trifluoro-4-nitrobenzene (21B)

2-bromo-1,3,5-trifluoro-4-nitrobenzene.

(21A) (5.0 g,23.7 mmol) was dissolved in 5mL of concentrated sulfuric acid, and the resulting solution was placed in an ice bath for 10min. Then slowly adding a mixed solvent of 5mL of concentrated nitric acid and 15mL of concentrated sulfuric acid dropwise, and automatically raising the system to room temperature for reacting for 3h after the dropwise addition is finished. After the reaction of the raw materials was completed, the system was poured into 100mL of ice water to quench the reaction, 100mL of ethyl acetate was added, followed by stirring and liquid separation, the aqueous phase was extracted once with ethyl acetate (40 mL. Times.2), the ethyl acetate layers were combined, the ethyl acetate layer was washed once with a saturated sodium bicarbonate solution (40 mL. Times.1) and a saturated saline solution (40 mL. Times.1), respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give compound (21B) (5.7 g, yield 94%)

The second step: 3-bromo-2, 4, 6-trifluoroaniline (21C)

3-bromo-2,4,6-trifluoroaniline.

Compound (21B) (5.7g, 22.23mmol) was dissolved in a mixed solvent of 50mL ethanol and 10mL water, ammonium chloride (5.9g, 111mmol) and iron powder (12.4g, 222mmol) were added, and the mixture was heated to 85 ℃ under nitrogen protection and reacted for 1 hour. After the reaction of the raw materials was completed, the system was cooled to room temperature, insoluble materials were filtered off with celite, the filtrate was concentrated under reduced pressure, then 100mL of ethyl acetate was added to dissolve the organic phase, the organic phase was washed once with (50 mL × 1) water and saturated brine (40 mL × 1), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain compound 21C (3.7 g, 73.5% yield).

The third step: tert-butyl (1R, 5S) -3- (7- (3-amino-2, 4, 6-trifluorophenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H) -pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (21D)

tert-butyl(1R,5S)-3-(7-(3-amino-2,4,6-trifluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydr o-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

(21C) (0.072g, 0.32mmol) was dissolved in a mixed solution of acetonitrile 10mL and water 1mL, and 9B (0.09 g,0.16 mmol), potassium fluoride (0.035g, 0.6 mmol), pd (PPh) were added ₂ Cl ₂ ( 0.011g, 0.016mmol), reacting at 100 ℃ for 12 hours under nitrogen protection, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, stirring, separating the liquid, extracting the aqueous phase once with ethyl acetate (40 mL. Times.1), combining the ethyl acetate layers, washing the ethyl acetate layer once with saturated saline (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and performing silica gel column chromatography (DCM: meOH = 24) to give compound (21D) (0.063 g, 59% yield) )

LCMS m/z＝661.2[M+H] ⁺

The fourth step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2,4, 6-trifluoroaniline (Compound 21)

Compound (21D) (0.063g, 0.095 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added to conduct a reaction at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, and after dropping 0.5ml of n, n-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 21 (13 mg, yield 24.3%) as a white powder.

The HPLC preparation method comprises the following steps:

3. Mobile phase A: acetonitrile; b: purifying water (containing 1% of NH) ₄ HCO ₃ ) (ii) a Gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

Ms m/z(ESI):561.2[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.80(d,1H),7.25–7.18(m,1H),6.96–6.87(m,1H),5.43– 5.19(m,1H),4.52–4.44(m,2H),4.24(dd,2H),3.65–3.53(m,4H),3.27–3.11(m,3H),3.06– 2.96(m,1H),2.42–2.09(m,3H),2.06–1.89(m,3H),1.87–1.75(m,4H).

Example 22:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) aniline (Compound 22)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)aniline.

The first step is as follows: 3-bromo-4-methyl-5- (trifluoromethyl) benzoic acid (22B)

3-bromo-4-methyl-5-(trifluoromethyl)benzoic acid.

(22A) (5.0 g, 24.49mmol) was dissolved in 50mL of concentrated sulfuric acid, and N-bromosuccinimide (4.36 g, 24.49mmol) was added thereto at room temperature, followed by reaction at room temperature for 3 hours. After the reaction of the raw materials was completed, the system was poured into 100mL of ice water to quench the reaction, 100mL of ethyl acetate was added, followed by stirring and liquid separation, the aqueous phase was extracted once with ethyl acetate (40 mL. Times.2), the ethyl acetate layers were combined, the ethyl acetate layer was washed once with a saturated sodium bicarbonate solution (40 mL. Times.1) and a saturated saline solution (40 mL. Times.1), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give compound (22B) (7.1 g, yield 99%)

LCMS m/z＝283.1[M+H] ⁺

The second step is that: (3-bromo-4-methyl-5- (trifluoromethyl) phenyl) carbamic acid tert-butyl ester (22C)

tert-butyl(3-bromo-4-methyl-5-(trifluoromethyl)phenyl)carbamate.

(22B) (7.1g, 24.49mmol) was dissolved in toluene (70 mL), and triethylamine (10.5 mL, 73.47mmol) and azido diphenyl phosphate (8.16mL, 36.7 mmol) were added to the solution, and the mixture was stirred at room temperature for 30 minutes, tert-butanol (70 mL) was added, then under nitrogen, and the reaction was stirred at 110 ℃ for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, added with water (50 mL), extracted with ethyl acetate (70 mL. Times.3), the organic phases were combined and washed once with saturated brine (40 mL. Times.1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give compound (22C) (7.9 g, 89% yield)

LCMS m/z＝354.1[M+H] ⁺

The third step: (4-methyl-3- (4, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -5- (trifluoromethyl) phenyl) carbamic acid tert-butyl ester (22D)

tert-butyl(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)c arbamate.

Under the protection of nitrogen, tert-butyl (3-bromo-4-methyl-5- (trifluoromethyl) phenyl) carbamate (22C) (2g, 5.65mmol), pinacol diboron (1.6 g, 6.21mmol), potassium acetate (1.1g, 11.3mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (461mg, 0.57mmol) were placed in a sealed tube, 30mL of 1, 4-dioxane was added, the temperature was raised to 90 ℃ and the reaction was carried out for 5 hours. The reaction was cooled to room temperature, then water was added and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound (22D) (1.8 g, 78% yield).

Ms m/z(ESI):402.2[M+H] ⁺

The fourth step: tert-butyl (1R, 5S) -3- (7- (5- ((tert-butoxycarbonyl) amino) -2-methyl-3- (trifluoromethyl) phenyl) -8-fluoro-2- (((2R, 7aS)) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (22E)

tert-butyl(1R,5S)-3-(7-(5-((tert-butoxycarbonyl)amino)-2-methyl-3-(trifluoromethyl)phenyl)-8-f luoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazab icyclo[3.2.1]octane-8-carboxylate.

Under nitrogen protection, intermediate 22D (270mg, 0.674mmol), 2F (200mg, 0.337mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (55mg, 0.067mmol) and cesium carbonate (220mg, 0.67mmol) were placed in a sealed tube and 1.5mL of water and 15ml of 1, 4-dioxane were added. The temperature was raised to 105 ℃ to react for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to give compound (22E) (170 mg, 64% yield)

LCMS m/z＝789.3[M+H] ⁺

The fifth step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) aniline (Compound 22)

Compound (22E) (0.17g, 0.216mmol) was dissolved in 10mL of methylene chloride, and 1mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, and after dropping 1mL of N, N-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 22 (96 mg, yield 75.6%) as a white powder.

The HPLC preparation method comprises the following steps:

Ms m/z(ESI):589.3[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.80(d,1H),7.14–7.06(m,2H),6.78(d,1H),5.40–5.21(m,1H), 4.58–4.39(m,2H),4.24(dd,2H),3.67–3.53(m,4H),3.36–3.32(m,1H),3.27–3.17(m,2H), 3.06–2.96(m,1H),2.41–2.13(m,3H),2.10(s,3H),2.06–1.88(m,3H),1.87–1.76(m,4H).

Example 23:4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (5-methyl-1H-indazol-6-yl) quinazoline (compound 23)

4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyr rolizin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-6-yl)quinazoline

The first step is as follows: tert-butyl (1R, 5S) -3- (8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H) -pyrrolizine-7 a (5H) -yl) methoxy) -7- (5-methyl-1H-indazol-6-yl) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (23B)

tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methox y)-7-(5-methyl-1H-indazol-6-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Under the protection of nitrogen, 6-bromo-5-methyl-1H-indazole 23A (113mg, 0.537mmol), 9B (150mg, 0.268mmol),

[1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (22mg, 0.027mmol) and cesium carbonate (175 mg,0.537 mmol) were placed in a sealed tube, and 15mL1, 4-dioxane and 1.5mL of water were added. The temperature was raised to 105 ℃ to react for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to give compound (23B) (150 mg, 90% yield)

LCMS m/z＝646.3[M+H] ⁺

The second step is that: 4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (5-methyl-1H-indazol-6-yl) quinazoline (compound 23)

Compound (23B) (0.15g, 0.23mmol) was dissolved in 10mL of methylene chloride, and 1mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, and after dropping 1mL of N, N-diisopropylethylamine, concentration under reduced pressure was performed, the residue was purified by HPLC preparation, and the preparation solution was concentrated and lyophilized to give compound 23 (73 mg, yield 58.2%) as a white powder.

The HPLC preparation method comprises the following steps:

3. A mobile phase A: acetonitrile; b: purifying water (containing 1% CF ₃ COOH); gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

Ms m/z(ESI):546.3[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ8.05(s,1H),7.93(d,1H),7.75(s,1H),7.43(s,1H),7.38(dd, 1H),5.67–5.48(m,1H),4.78–4.67(m,4H),4.25(s,2H),4.09–3.83(m,5H),3.53–3.44(m,1H), 2.77–2.54(m,2H),2.49–2.31(m,3H),2.26(s,3H),2.23–2.10(m,5H).

Example 24:2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -6-chloro-2 ',4' -difluoro- [1,1' -biphenyl ] -4-amine (Compound 24)

2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-chloro-2',4'-difluoro-[1,1'-biphenyl]-4-amine.

The first step is as follows: 2-bromo-6-chloro-2 ',4' -difluoro- [1,1' -biphenyl ] -4-amine (24B)

2-bromo-6-chloro-2',4'-difluoro-[1,1'-biphenyl]-4-amine.

Intermediate 14B (500mg, 1.5 mmol), (2, 4-difluorophenyl) boronic acid 24A (285mg, 1.8 mmol), tetrakistriphenylphosphine palladium (173mg, 0.15mmol) and potassium carbonate (414.6 mg, 3.0mmol) were placed in a sealed tube under nitrogen protection, and 30mL1, 4-dioxane and 6mL of water were added. The temperature is raised to 100 ℃ for reaction for 12 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography to give compound (24B) (507 mg, 88% yield)

LCMS m/z＝317.9[M+H] ⁺

The second step: tert-butyl (1R, 5S) -3- (7- (4-amino-6-chloro-2 ',4' -difluoro- [1,1' -biphenyl ] -2-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (24C)

tert-butyl(1R,5S)-3-(7-(4-amino-6-chloro-2',4'-difluoro-[1,1'-biphenyl]-2-yl)-8-fluoro-2-(((2R,7 aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]oc tane-8-carboxylate.

(24B) (0.145g, 0.456 mmol) was dissolved in a mixed solution of acetonitrile 10mL and water 1mL, 9B (0.17 g, 0.304mmol), potassium fluoride (0.066 g, 1.14mmol), pd (PPh) 2Cl2 (0.025g, 0.03mmol) were added and reacted at 100 ℃ under nitrogen protection for 12 hours, the reaction was cooled to room temperature, 40mL of ethyl acetate and 25mL of water were added and stirred to separate the solution, the aqueous phase was extracted once with ethyl acetate (40 mL. Times.1), the ethyl acetate layers were combined, the ethyl acetate layer was washed once with saturated saline (40 mL. Times.1), dried over anhydrous sodium sulfate was added, and after concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography to give compound (24C) (0.13 g, yield 74%)

LCMS m/z＝753.2[M+H] ⁺

The third step: 2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -6-chloro-2 ',4' -difluoro- [1,1' -biphenyl ] -4-amine (Compound 24)

Compound (24C) (0.13g, 0.17mmol) was dissolved in 10mL of methylene chloride, and 1mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, and after dropping 1mL of n, n-diisopropylethylamine, it was concentrated under reduced pressure, the residue was purified by HPLC, and the preparation solution was concentrated and lyophilized to give compound 24 (30 mg, yield 27%) as a white powder.

The HPLC preparation method comprises the following steps:

3. A mobile phase A: acetonitrile; b: purified water (1% CF3COOH); gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

Ms m/z(ESI):653.2[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.69(d,1H),7.20–7.14(m,1H),7.11–7.01(m,1H),6.96(d, 1H),6.79–6.69(m,2H),6.67(d,1H),5.65–5.46(m,1H),4.68–4.53(m,4H),4.20(s,2H),4.05– 3.71(m,5H),3.52–3.43(m,1H),2.75–2.51(m,2H),2.46–2.28(m,3H),2.20–2.06(m,5H).

Example 25:5- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2-methyl-4- (trifluoromethyl) aniline (Compound 25)

5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-methyl-4-(trifluoromethyl)aniline

The first step is as follows: 5-bromo-2-iodo-4- (trifluoromethyl) aniline (25B)

5-bromo-2-iodo-4-(trifluoromethyl)aniline

3-bromo-4- (trifluoromethyl) aniline (25A) (4 g, 16.67mmol) was dissolved in 25mL of acetic acid, N-iodosuccinimide (4.12g, 18.33mmol) was added, and the reaction was stirred at room temperature for 3 hours. Then, saturated aqueous sodium bicarbonate was added to adjust the pH to 7, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound (25B) as a reddish brown solid (5.77 g, 95% yield)

LCMS m/z＝365.9[M+H] ⁺

The second step is that: 5-bromo-2-methyl-4- (trifluoromethyl) aniline (25C)

5-bromo-2-methyl-4-(trifluoromethyl)aniline

Compound 25B (3g, 8.22mmol), methylboronic acid (541mg, 9.04mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (671mg, 0.82mmol) and cesium carbonate (5.36g, 16.44mmol) were placed in a sealed tube, and 20mL1, 4-dioxane and 5mL of water were added to replace nitrogen protection. The temperature is raised to 60 ℃ for reaction for 18 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound (25C) as a tan solid (611 mg, 29% yield)

LCMS m/z＝254.0[M+H] ⁺

The third step: 2-methyl-5- (4, 5-tetramethyl-1,3, 2-dioxaboro-2-yl) -4- (trifluoromethyl) phenylamine (25D)

2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

Compound 25C (345mg, 1.36mmol), pinacol diborate diboronate (517mg, 2.03mmol), potassium acetate (400 mg, 4.08mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (114mg, 0.14mmol) were placed in a sealed tube, 5mL of 1, 4-dioxane was added, nitrogen blanket was replaced, and the reaction was allowed to proceed at 90 ℃ for 6 hours. The reaction was cooled to room temperature, then water was added and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound (25D) as a brown solid (232 mg, 56% yield).

LCMS m/z＝302.1[M+H] ⁺

The fourth step: tert-butyl (1R, 5S) -3- (7- (5-amino-4-methyl-2- (trifluoromethyl) phenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (25E) tert-butyl (1R, 5S) -3- (7- (5-amino-4-methyl-2- (trifluoromethyl) phenyl) -8-fluoro-2- (((2R, 7aS) -2-fluoro-1H-pyrolizin-7 a (5H) -yl) methoxy) quinazol-4-yl) -3, 8-diazacyclo [3.2.1] -8-carboxalin-4-yl) -3, 8-diazacyclo [3.2.1] m-8-carboxalin-4-yl ] carboxylate

Intermediate 2F (120mg, 0.20mmol), compound 25D (117mg, 0.39mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (17mg, 0.02mmol) and cesium carbonate (127mg, 0.39mmol) were placed in a sealed tube, and 2mL1, 4-dioxane and 0.5mL of water were added to replace nitrogen for protection. The temperature was raised to 105 ℃ to react for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound (25E) as a tan solid (123 mg, 90% yield)

LCMS m/z＝689.3[M+H] ⁺

The fifth step: 5- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2-methyl-4- (trifluoromethyl) aniline (Compound 25)

After compound 25E (123mg, 0.18mmol) was dissolved in dichloromethane 2.5mL, 0.5mL of trifluoroacetic acid was added dropwise thereto, and the reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, dropwise added to 0.5ml of n, n-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 25 (45 mg, yield 42%) as a white powder.

The HPLC preparation method comprises the following steps:

1. the instrument comprises the following steps: waters 2767 preparation of the liquid phase; and (3) chromatographic column: sunFire @ Prep C18 (19mm. 250mm).

LCMS m/z＝589.3[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.73(d,1H),7.38(s,1H),7.10(dd,1H),6.59(s,1H),5.40– 5.22(m,1H),4.55–4.40(m,2H),4.24(dd,2H),3.66–3.52(m,4H),3.26–3.13(m,3H),3.05– 2.96(m,1H),2.40–2.26(m,1H),2.23(s,3H),2.21–2.09(m,2H),2.05–1.94(m,2H),1.94– 1.75(m,5H).

Example 26:4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (5- (trifluoromethyl) -1H-indazol-6-yl) quinazoline (compound 26)

4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizi n-7a(5H)-yl)methoxy)-7-(5-(trifluoromethyl)-1H-indazol-6-yl)quinazoline

The first step is as follows: 6-bromo-5- (trifluoromethyl) -1H-indazole (26A)

6-bromo-5-(trifluoromethyl)-1H-indazole

Compound 25C (616mg, 2.44mmol) was dissolved in 6mL of acetic acid, purged with nitrogen, placed in an ice bath, and an aqueous solution (1 mL) of sodium nitrite (1699 mg, 2.44mmol) was added slowly, followed by stirring at room temperature for 12 hours. Adjusting pH to 7 with saturated sodium bicarbonate, extracting with ethyl acetate for three times, mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound 26A as brown solid (292 mg, 45% yield)

LCMS m/z＝265.0[M+H] ⁺

The second step is that: tert-butyl (1R, 5S) -3- (8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (5- (trifluoromethyl) -1H-indazol-6-yl) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (26B)

tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methox y)-7-(5-(trifluoromethyl)-1H-indazol-6-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxyl ate

Intermediate 9B (190mg, 0.37mmol), compound 26A (95mg, 0.36mmol), tris (dibenzylidene-BASE acetone) dipalladium (37mg, 0.04mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-I-propyl-11' -biphenyl (43 mg,0.08 mmol) and sodium carbonate (76mg, 0.72mmol) were placed in a sealed tube, and 2mL1, 4-dioxane and 0.5mL of water were added, with nitrogen substitution. The temperature is raised to 120 ℃ for reaction for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound 26B as a tan solid (58 mg, 23% yield)

LCMS m/z＝700.3[M+H] ⁺

The third step: 4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (5- (trifluoromethyl) -1H-indazol-6-yl) quinazoline (compound 26)

4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyr rolizin-7a(5H)-yl)methoxy)-7-(5-(trifluoromethyl)-1H-indazol-6-yl)quinazoline

Compound 26B (58mg, 0.083mmol) was dissolved in dichloromethane (2.5 mL), and then 0.5mL of trifluoroacetic acid was added dropwise thereto, followed by reaction at room temperature for 60 minutes. The reaction mixture was concentrated under reduced pressure, and then dichloromethane was added thereto to dissolve the reaction mixture, 0.5mL of N, N-diisopropylethylamine was added dropwise thereto, followed by concentration under reduced pressure, and the residue was purified by HPLC, and the preparation was concentrated and then lyophilized to obtain Compound 26 (20 mg, yield 40%).

The HPLC preparation method comprises the following steps:

3. Mobile phase A: acetonitrile; b: purified water (containing 1% NH4HCO3); gradient elution, wherein the content of a mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

LCMS m/z＝600.2[M+H] ⁺

Example 27:6- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4- (trifluoromethyl) pyridin-2-amine (Compound 27)

6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-(trifluoromethyl)pyridin-2-amine

The first step is as follows: 6-chloro-4- (trifluoromethyl) pyridin-2-amine (27B)

6-chloro-4-(trifluoromethyl)pyridin-2-amine

Compound 27A (2.5g, 11.58mmol) was placed in an autoclave, 70mL of aqueous ammonia was added, and the temperature was raised to 100 ℃ to react for 24 hours. Cooling the reaction to room temperature, diluting with water, extracting with dichloromethane three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound (27A) as colorless oil (585 mg, 26% yield)

LCMS m/z＝197.1[M+H] ⁺

The second step is that: tert-butyl (1R, 5S) -3- (7- (6-amino-4- (trifluoromethyl) pyridin-2-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (27C)

tert-butyl(1R,5S)-3-(7-(6-amino-4-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbo xylate

Intermediate 9B (160mg, 0.29mmol), compound 27B (69mg, 0.35mmol), bis-triphenylphosphine palladium dichloride (21mg, 0.03mmol), and potassium fluoride (63mg, 1.08mmol) were placed in a sealed tube, 2mL acetonitrile and 0.5mL water were added, and nitrogen blanket was replaced. The temperature is raised to 100 ℃ for reaction for 18 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound 27C as a yellow solid (92 mg, 48% yield)

LCMS m/z＝676.3[M+H] ⁺

The third step: 6- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4- (trifluoromethyl) pyridin-2-amine (Compound 27)

Compound 27C (92mg, 0.136mmol) was dissolved in dichloromethane 2.5mL, followed by dropwise addition of 0.5mL trifluoroacetic acid and reaction at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, and after dropping 0.5ml of n, n-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 27 (17 mg, yield 22%) as a white powder.

The HPLC preparation method comprises the following steps:

LCMS m/z＝576.3[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.83–7.73(m,2H),7.29(s,1H),6.82(s,1H),5.40–5.21(m,1H), 4.52–4.42(m,2H),4.24(dd,2H),3.63–3.54(m,4H),3.27–3.12(m,3H),3.05–2.96(m,1H), 2.40–2.12(m,3H),2.05–1.94(m,2H),1.94–1.75(m,5H).

Example 28:2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4-aminobenzonitrile (Compound 28)

2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-aminobenzonitrile

The first step is as follows: 4-amino-2- (4, 5-tetramethyl-1,3, 2-dioxaboro-2-yl) benzonitrile (28B)

4-amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

4-amino-2-bromobenzylnitrile (28A) (1.65g, 8.33mmol), pinacol diboron (3.17g, 12.50mmol), potassium acetate (3.27g, 33.32mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (680 mg,0.83 mmol) was placed in a sealed tube, 1, 4-dioxane (15mL) was added, nitrogen was replaced, and the mixture was heated to 90 ℃ for 5 hours. The reaction was cooled to room temperature, then water was added and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound 28B as a yellow oil (1.6 g, 79% yield).

LCMS m/z＝245.2[M+H] ⁺

The second step: tert-butyl (1R, 5S) -3- (7- (5-amino-2-cyanophenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H) -pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (28C)

tert-butyl(1R,5S)-3-(7-(5-amino-2-cyanophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol izin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Intermediate 2F (120mg, 0.20mmol), compound 28B (98mg, 0.40mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (1695g, 0.02mmol) and cesium carbonate (130mg, 0.40mmol) were placed in a sealed tube, and 2.5mL1, 4-dioxane and 0.5mL of water were added thereto, and nitrogen gas was replaced. The temperature was raised to 105 ℃ to react for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to give compound 28C as a brown solid (116 mg, 92% yield)

LCMS m/z＝632.3[M+H] ⁺

The third step: 2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4-aminobenzonitrile (Compound 28)

Compound 28C (116mg, 0.18mmol) was dissolved in 2.5mL of methylene chloride, and then 0.5mL of trifluoroacetic acid was added dropwise thereto, followed by reaction at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then dichloromethane was added to dissolve it, 0.5ml of n, n-diisopropylethylamine was added dropwise thereto, followed by concentration under reduced pressure, and the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 28 (39 mg, yield 41%) as a white powder.

The HPLC preparation method comprises the following steps:

LCMS m/z＝532.3[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.81(d,1H),7.50(d,1H),7.22(dd,1H),6.78–6.70(m,2H), 5.40–5.22(m,1H),4.53–4.44(m,2H),4.24(dd,2H),3.64–3.52(m,4H),3.27–3.11(m,3H), 3.06–2.96(m,1H),2.40–2.10(m,3H),2.05–1.94(m,2H),1.93–1.76(m,5H).

Example 29:5- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2-cyclopropyl-4- (trifluoromethyl) aniline (Compound 29)

5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-cyclopropyl-4-(trifluoromethyl)aniline

The first step is as follows: 5-bromo-2-cyclopropyl-4- (trifluoromethyl) aniline (29A)

5-bromo-2-cyclopropyl-4-(trifluoromethyl)aniline

Compound 25B (1g, 2.73mmol), cyclopropylboronic acid (352mg, 4.10mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (221mg, 0.27mmol) and cesium carbonate (1.34g, 4.10mmol) were placed in a sealed tube, and 15mL1, 4-dioxane and 4mL of water were added to replace nitrogen protection. The temperature is raised to 80 ℃ for reaction for 18 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to give compound 29A as a yellow solid (181 mg, 24% yield)

LCMS m/z＝280.0[M+H] ⁺

The second step is that: tert-butyl (1R, 5S) -3- (7- (5-amino-4-cyclopropyl-2- (trifluoromethyl) phenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (29B)

tert-butyl(1R,5S)-3-(7-(5-amino-4-cyclopropyl-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octa ne-8-carboxylate

Intermediate 9B (185mg, 0.33mmol), compound 29A (62mg, 0.22mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (16mg, 0.02mmol) and cesium carbonate (143mg, 0.44mmol) were placed in a sealed tube, and 2mL1, 4-dioxane and 0.5mL of water were added, replacing the nitrogen blanket. The temperature is raised to 110 ℃ for reaction for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound 29B as a tan solid (133 mg, 83% yield)

LCMS m/z＝715.3[M+H] ⁺

The third step: 5- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2-cyclopropyl-4- (trifluoromethyl) aniline (Compound 29)

Compound 29B (133mg, 0.19mmol) was dissolved in dichloromethane 2.5mL, and then 0.5mL of trifluoroacetic acid was added dropwise thereto, followed by reaction at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, and after dropping 0.5ml of n, n-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 29 (48 mg, yield 41%) as a white powder.

The HPLC preparation method comprises the following steps:

3. A mobile phase A: acetonitrile; b: purified water (containing 1% NH4HCO3); gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

LCMS m/z＝615.2[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.84(d,1H),7.33–7.25(m,2H),6.61(s,1H),5.65–5.47(m, 1H),4.75–4.63(m,4H),4.24(s,2H),4.08–3.81(m,5H),3.52–3.43(m,1H),2.78–2.53(m,2H), 2.48–2.30(m,3H),2.23–2.10(m,5H),1.82–1.72(m,1H),1.05–0.95(m,2H),0.68–0.58(m, 2H).

Example 30:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4- (cyclopent-1-en-1-yl) aniline (Compound 30)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-(cyclopent-1-en-1-yl)aniline

The first step is as follows: 3-bromo-5-chloro-4-iodoaniline (30B)

3-bromo-5-chloro-4-iodoaniline

3-bromo-5-chloroaniline (30A) (5 g, 24.22mmol) was dissolved in 25mL of N, N-dimethylformamide, and N-iodosuccinimide (5.99g, 26.64mmol) was added, and the reaction was stirred at room temperature for 3 hours. Then, saturated sodium thiosulfate solution was added, and extraction was performed three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound (30B) as a reddish brown solid (7.49 g, 93% yield)

LCMS m/z＝331.8[M+H] ⁺

The second step: 3-bromo-5-chloro-4- (cyclopent-1-en-1-yl) aniline (30C)

3-bromo-5-chloro-4-(cyclopent-1-en-1-yl)aniline

Compound 30B (1g, 3.01mmol), cyclopenten-1-ylboronic acid (438mg, 3.91mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (2454g, 0.30mmol) and cesium carbonate (1.96g, 6.02mmol) were placed in a sealed tube, and 15mL1, 4-dioxane and 4mL of water were added to replace nitrogen protection. The temperature is raised to 80 ℃ for reaction for 8 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate for three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound 30C as brown solid (780 mg, 95% yield)

LCMS m/z＝272.0[M+H] ⁺

The third step: tert-butyl (1R, 5S) -3- (7- (5-amino-3-chloro-2- (cyclopent-1-en-1-yl) phenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (30D)

tert-butyl(1R,5S)-3-(7-(5-amino-3-chloro-2-(cyclopent-1-en-1-yl)phenyl)-8-fluoro-2-(((2R,7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan e-8-carboxylate

Intermediate 9B (185mg, 0.33mmol), compound 30C (60mg, 0.22mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (16mg, 0.02mmol) and cesium carbonate (143mg, 0.44mmol) were placed in a sealed tube and 2mL1, 4-dioxane and 0.5mL of water were added to replace the nitrogen blanket. The temperature is raised to 110 ℃ for reaction for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to give compound 30D as a tan solid (112 mg, 72% yield)

LCMS m/z＝707.3[M+H] ⁺

The fourth step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4- (cyclopent-1-en-1-yl) aniline (Compound 30)

Compound 30D (112mg, 0.16mmol) was dissolved in 2.5mL of dichloromethane, and then 0.5mL of trifluoroacetic acid was added dropwise thereto, followed by reaction at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then dichloromethane was added to dissolve it, 0.5ml of n, n-diisopropylethylamine was added dropwise thereto, and then concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 30 (30 mg, yield 31%) as a white powder.

The HPLC preparation method comprises the following steps:

LCMS m/z＝607.3[M+H] ⁺

Example 31: n- (3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4- (trifluoromethyl) phenyl) acetamide (Compound 31)

N-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-(trifluoromethyl)phenyl)acetamide

The first step is as follows: n- [ 3-bromo-4- (trifluoromethyl) phenyl ] acetamide (31A)

N-[3-bromo-4-(trifluoromethyl)phenyl]acetamide

The starting material, 3-bromo-4-trifluoromethylaniline (1.0 g, 4.2mmol) was dissolved in 5ml of dichloromethane, triethylamine (0.848 g,8.4 mmol) and acetyl chloride (0.494g, 6.3mmol) were added, and stirring was carried out at room temperature for 2 hours, after completion of the reaction, concentration under reduced pressure, and column chromatography gave compound 31A (1.0 g, yield 85.12%).

LCMS m/z＝282.1[M+H] ⁺

The second step is that: tert-butyl (1R, 5S) -3- (7- (5-acetylamino-2- (trifluoromethyl) phenyl ] -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (31B)

tert-butyl(1R,5S)-3-(7-(5-acetamido-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorot etrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbo xylate

(31A) (0.15g, 0.52mmol) was dissolved in a mixed solution of 5mL of 1, 4-dioxane and 1mL of water, and 9B (0.23g, 0.42mmol), cesium carbonate (0.3g, 1.04mmol), pd (dppf) Cl and the like were added ₂ (0.038g, 0.052mmol), reaction at 100 ℃ for 2 hours under nitrogen atmosphere, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, extracting the aqueous phase with ethyl acetate (40 mL. Times.1) once, combining the ethyl acetate layers, washing the ethyl acetate layer with saturated brine (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to silica gel column chromatography to give compound (31B) (0.11 g, yield 36.51%)

LCMS m/z＝717.3[M+H] ⁺

The third step: n- (3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4- (trifluoromethyl) phenyl) acetamide (Compound 31)

Compound (31B) (0.11g, 0.15mmol) was dissolved in 5mL of methylene chloride, and 0.5mL of trifluoroacetic acid was added to the solution to conduct a reaction at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, and then dichloromethane was added to dissolve the reaction solution, 0.5ml of n, n-diisopropylethylamine was added dropwise thereto, followed by concentration under reduced pressure, and the residue was purified by HPLC, and the preparation solution was concentrated and lyophilized to give compound 31 (20 mg, yield 21.64%) as a white powder.

The HPLC preparation method comprises the following steps:

Ms m/z(ESI):617.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ10.39(s,1H),7.85–7.73(m,4H),7.15–7.07(m,1H),5.38 –5.16(m,1H),4.26(d,2H),4.04(dd,2H),3.54–3.40(m,4H),3.16–2.98(m,3H),2.87–2.78(m, 1H),2.57–2.52(m,1H),2.19–2.10(m,1H),2.09(s,3H),2.06–1.97(m,2H),1.90–1.73(m,3H), 1.71–1.58(m,4H).

Example 32: n- (3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4- (trifluoromethyl) phenyl) methanesulfonamide (compound 32)

N-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-(trifluoromethyl)phenyl)methanesulfonamide

The first step is as follows: n- [ 3-bromo-4- (trifluoromethyl) phenyl ] methanesulfonamide (32A)

N-[3-bromo-4-(trifluoromethyl)phenyl]methanesulfonamide

The starting material, 3-bromo-4-trifluoromethylaniline (1.0g, 4.2mmol), was dissolved in 5mL of dichloromethane, and triethylamine (0.848 g,8.4 mmol) and methanesulfonyl chloride (0.718g, 6.3mmol) were added, and the mixture was stirred at room temperature for 2 hours, after completion of the reaction, concentrated under reduced pressure, and subjected to column chromatography to give Compound 32A (1.0 g, 74.87% yield).

LCMS m/z＝318.0[M+H] ⁺

The second step: tert-butyl (1R, 5S) -3- (8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (5- (methylsulfonylamino) -2- (trifluoromethyl) phenyl) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (32B)

tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methox y)-7-(5-(methylsulfonamido)-2-(trifluoromethyl)phenyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octa ne-8-carboxylate

(32A) (0.16g, 0.52mmol) was dissolved in a mixed solution of 5mL of 1, 4-dioxane and 1mL of water, and 9B (0.23g, 0.42mmol), cesium carbonate (0.3g, 1.04mmol), pd (dppf) Cl and water were added ₂ (0.038g, 0.052mmol), reaction at 100 ℃ for 2 hours under nitrogen atmosphere, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, extracting the aqueous phase with ethyl acetate (40 mL. Times.1) once, combining the ethyl acetate layers, washing the ethyl acetate layer with saturated brine (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to silica gel column chromatography to give compound (32B) (0.11 g, yield 34.82%)

LCMS m/z＝753.3[M+H] ⁺

The third step: n- (3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4- (trifluoromethyl) phenyl) methanesulfonamide (compound 32)

Compound (32B) (0.11g, 0.15mmol) was dissolved in 5mL of methylene chloride, and 0.5mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dichloromethane was added to dissolve it, 0.5ml of n, n-diisopropylethylamine was added dropwise thereto, then concentration under reduced pressure was carried out, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 32 (20 mg, yield 20.45%) as a white powder.

The HPLC preparation method comprises the following steps:

1. the instrument comprises the following steps: waters 2767 preparation of the liquid phase; a chromatographic column: sunFire @ Prep C18 (19mm. 250mm).

Ms m/z(ESI):653.2[M+H] ⁺

Example 33:7- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -1-isopropyl-1H-indazol-5-amine (Compound 33)

7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-isopropyl-1H-indazol-5-amine

The first step is as follows: 7-bromo-1-isopropyl-5-nitroindazole (33A)

7-bromo-1-isopropyl-5-nitro-indazole

The starting material 7-bromo-5-nitro-1H-indazole (2.0g, 8.3mmol) was dissolved in 20mL of tetrahydrofuran, and 1, 8-diazabicyclo [5.4.0] undec-7-ene (2.52g, 16.6 mmol) and 2-iodopropane (1.7g, 10mmol) were added thereto, and the mixture was stirred at 60 ℃ for 2 hours, after completion of the reaction, concentrated under reduced pressure, and column chromatography was performed to obtain compound 33A (0.9 g, yield 38.10%).

LCMS m/z＝284.1[M+H] ⁺

The second step: 7-bromo-1-isopropyl-indazol-5-amine (33B)

7-bromo-1-isopropyl-indazol-5-amine

After 33A (0.90g, 3.17mmol) was dissolved in 9mL of ethanol and 3mL of water, reduced iron powder (0.90g, 16.0 mmol) and ammonium chloride (1.74g, 31.7 mmol) were added, the mixture was stirred at 80 ℃ for 2 hours, and after completion of the reaction, concentration was performed under reduced pressure, and column chromatography was performed to obtain compound 33B (0.56 g, yield 69.82%).

LCMS m/z＝254.1[M+H] ⁺

The third step: tert-butyl (1R, 5S) -3- (7- (5-amino-1-isopropyl-1H-indazol-7-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (33C)

tert-butyl(1R,5S)-3-(7-(5-amino-1-isopropyl-1H-indazol-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotet rahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy late

(33B) (0.13g, 0.52mmol) was dissolved in a mixed solution of 5mL of 1, 4-dioxane and 1mL of water, and 9B (0.23g, 0.42mmol), cesium carbonate (0.3g, 1.04mmol), pd (dppf) Cl ₂ (0.038g, 0.052mmol), reacting at 100 ℃ for 2h under nitrogen, cooling to room temperature, adding ethyl acetate 40mL and25mL of water, extraction of the aqueous phase with ethyl acetate (40 mL. Times.1) once, combination of ethyl acetate layers, washing of the ethyl acetate layer with saturated brine (40 mL. Times.1), drying over anhydrous sodium sulfate, concentration under reduced pressure, and chromatography of the residue on a silica gel column to give compound (33C) (0.11 g, yield 38.06%)

LCMS m/z＝689.4[M+H] ⁺

The fourth step: 7- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -1-isopropyl-1H-indazol-5-amine (Compound 33)

Compound (33C) (0.11g, 0.11mmol) was dissolved in 5mL of methylene chloride, and 0.5mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, dropwise added to 0.5ml of n, n-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 33 (20 mg, yield 21.25%) as a white powder.

The HPLC preparation method comprises the following steps:

Ms m/z(ESI):589.3[M+H] ⁺

Example 34:7- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -1-ethyl-1H-indazol-5-amine (Compound 34)

7-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-ethyl-1H-indazol-5-amine

The first step is as follows: 7-bromo-1-ethyl-5-nitroindazole (34A)

7-bromo-1-ethyl-5-nitro-indazole

The starting material 7-bromo-5-nitro-1H-indazole (2.0g, 8.3mmol) was dissolved in 20mL of tetrahydrofuran, 1, 8-diazabicyclo [5.4.0] undec-7-ene (2.52g, 16.6 mmol), iodoethane (1.56g, 10mmol) were added, the mixture was stirred at 60 ℃ for 2 hours, and after completion of the reaction, concentration was performed under reduced pressure, and column chromatography was performed to obtain compound 34A (0.9 g, yield 40.30%).

LCMS m/z＝270.1[M+H] ⁺

The second step is that: 7-bromo-1-ethylindazole-5-amine (34B)

7-bromo-1-ethyl-indazol-5-amine

After 34A (0.90g, 3.34mmol) was dissolved in 9mL of ethanol and 3mL of water, reduced iron powder (0.90g, 16.0 mmol) and ammonium chloride (1.74g, 31.7 mmol) were added, the mixture was stirred at 80 ℃ for 2 hours, and after completion of the reaction, concentration was performed under reduced pressure, and column chromatography was performed to obtain compound 34B (0.56 g, 69.86% yield).

LCMS m/z＝240.1[M+H] ⁺

The third step: tert-butyl (1R, 5S) -3- (7- (5-amino-1-ethyl-1H-indazol-7-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (34C)

tert-butyl(1R,5S)-3-(7-(5-amino-1-ethyl-1H-indazol-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(34B) (0.12g, 0.52mmol) was dissolved in a mixed solution of 5mL of 1, 4-dioxane and 1mL of water, and 9B (0.23g, 0.42mmol), cesium carbonate (0.3g, 1.04mmol), pd (dppf) Cl and the like were added ₂ (0.038g, 0.052mmol), reaction at 100 ℃ for 2 hours under nitrogen atmosphere, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, extracting the aqueous phase with ethyl acetate (40 mL. Times.1) once, combining the ethyl acetate layers, washing the ethyl acetate layer with saturated brine (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to silica gel column chromatography to give compound (34C) (0.11 g, yield 38.85%)

LCMS m/z＝675.3[M+H] ⁺

The fourth step: 7- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -1-ethyl-1H-indazol-5-amine (Compound 34)

Compound (34C) (0.11g, 0.16mmol) was dissolved in 5mL of dichloromethane, and 0.5mL of trifluoroacetic acid was added thereto, followed by reaction at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, 0.5ml of n, n-diisopropylethylamine was added dropwise thereto, then concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 34 (20 mg, yield 21.77%) as a white powder.

The HPLC preparation method comprises the following steps:

Ms m/z(ESI):575.3[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ7.88–7.81(m,2H),7.26(dd,1H),6.87(d,1H),6.70(d, 1H),5.38–5.18(m,1H),4.95(s,2H),4.36–4.22(m,2H),4.16–3.97(m,2H),3.91–3.70(m,2H), 3.57–3.41(m,4H),3.19–2.96(m,4H),2.88–2.77(m,1H),2.21–1.97(m,3H),1.89–1.72(m, 3H),1.72–1.59(m,4H),0.91(t,3H).

Example 35:5- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2, 4-bis (trifluoromethyl) aniline (Compound 35)

5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro lizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2,4-bis(trifluoromethyl)aniline

The first step is as follows: (5-bromo-2-iodo-4- (trifluoromethyl) phenyl) carbamic acid tert-butyl ester (35A)

tert-butyl(5-bromo-2-iodo-4-(trifluoromethyl)phenyl)carbamate

Compound 25B (1g, 2.73mmol) was dissolved in 12mL of tetrahydrofuran, and bis-trimethylsilylaminolithium (6.0 mL, 1M) was added under ice-cooling, and the reaction was stirred for 0.5 hour, and di-tert-butyl dicarbonate (656 mg, 3.00mmol) was added and the reaction was continued for 3 hours. Saturated ammonium chloride solution was then added and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound (35A) as a white solid (572 mg, 45% yield)

LCMS m/z＝463.9[M-H] ^-

The second step: 5-bromo-2, 4-bis (trifluoromethyl) aniline (35B)

5-bromo-2,4-bis(trifluoromethyl)aniline

Compound 35A (0.572g, 1.22mmol), methyl fluorosulfonyl difluoroacetate (1.65g, 8.59mmol) was dissolved in N, N-dimethylformamide, and then cuprous iodide (465mg, 2.44mmol) and N, N-diisopropylethylamine (1.11g, 8.59 mmol) were added, and the mixture was placed in a sealed tube and purged with nitrogen. The temperature is increased to 75 ℃ for reaction for 24 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate for three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to give compound 35B as brown solid (132 mg, 35% yield)

LCMS m/z＝306.0[M-H] ^-

The third step: tert-butyl (1R, 5S) -3- (7- (5-amino-2, 4-bis (trifluoromethyl) phenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (35C)

tert-butyl

(1R,5S)-3-(7-(5-amino-2,4-bis(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H -pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Intermediate 9B (159mg, 0.29mmol), compound 35B (60mg, 0.19mmol), bis triphenylphosphine palladium dichloride (14mg, 0.02mmol), and potassium fluoride (41mg, 0.71mmol) were placed in a sealed tube and 2mL1, 4-dioxane and 0.5mL water were added, replacing with nitrogen. The temperature is raised to 100 ℃ for reaction for 18 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to give compound 35C as a brown solid (70 mg, 50% yield)

LCMS m/z＝743.3[M+H] ⁺

The fourth step: 5- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -2, 4-bis (trifluoromethyl) aniline (Compound 35)

Compound 35C (70mg, 0.094mmol) was dissolved in 2.5mL of methylene chloride, and then 0.5mL of trifluoroacetic acid was added dropwise thereto, followed by reaction at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, dropwise added to 0.5mL of N, N-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC preparation, and the preparation was concentrated and lyophilized to give compound 30 (26 mg, yield 43%) as a white powder.

The HPLC preparation method comprises the following steps:

LCMS m/z＝643.2[M+H] ⁺

¹ H NMR(400MHz,CD3OD)δ7.77(d,1H),7.73(s,1H),7.12(dd,1H),6.80(s,1H),5.38–5.22 (m,1H),4.55–4.40(m,2H),4.24(dd,2H),3.65–3.52(m,4H),3.27–3.11(m,3H),3.05–2.96 (m,1H),2.40–2.07(m,4H),2.04–1.94(m,2H),1.92–1.78(m,5H).

Example 36:3- (4- (1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) quinazolin-7-yl) -5-fluoro-4- (trifluoromethyl) aniline (Compound 36)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-fluoro-4-(trifluoromethyl)aniline

The first step is as follows: (3-bromo-5-fluoro-4-iodophenyl) carbamic acid tert-butyl ester (36B)

tert-butyl(3-bromo-5-fluoro-4-iodophenyl)carbamate

At N ₂ Under the protection of (1), firstly dissolving the compound 36A (5.0 g, 15.83mmol) and di-tert-butyl dicarbonate (4.15g, 19.0 mmol) in 20mL of THF, then slowly dropwise adding LiHMDS (6.55 mL) under the condition of ice bath, after the dropwise adding is finished, moving the reaction solution to the normal temperature condition for reaction for 8H, and after the reaction is finished completely, EA/H ₂ O (150 mL/100 mL) was extracted and washed, and the organic layer was concentrated and purified by a column chromatography to give compound 36B (4.50 g, yield: 68.33%).

Ms m/z(ESI):413.9[M-H] ⁺

The second step: (3-bromo-5-fluoro-4- (trifluoromethyl) phenyl) carbamic acid tert-butyl ester (36C)

tert-butyl(3-bromo-5-fluoro-4-(trifluoromethyl)phenyl)carbamate

In N ₂ Under protection of (2.0g, 4.81mmol) of compound 36B, MFSDA (6.47g, 33.67mmol) and CuI (1.37g, 7.21mmol) were sequentially added to a reaction tube, and then DIPEA (4.35g, 33.67mmol) was dissolved in 20mL of DMF and slowly added dropwise to the reaction tube. Continuously reacting for 16H in a 75 ℃ oil bath pan, and after the reaction is finished, EA/H ₂ O (200 mL/150ml × 2) was subjected to extraction washing. The organic layer was finally concentrated and purified by a chromatography column (PE: EA =10: 1) to obtain compound 36C (1.20 g, yield: 69.66% yield.

Ms m/z(ESI):356.0[M-H] ⁺

The third step: tert-butyl (1R, 5S) -3- (7- (5- ((tert-butoxycarbonyl) amino) -3-fluoro-2- (trifluoromethyl) phenyl) -8-fluoro-2- ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -methoxy) quinazolin-4-yl) -3, 8-diazacyclo [3.2.1] octane-8-carboxylate (36D).

tert-butyl(1R,5S)-3-(7-(5-((tert-butoxycarbonyl)amino)-3-fluoro-2-(trifluoromethyl)phenyl)-8-fluoro -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicycl o[3.2.1]octane-8-carboxylate

Intermediate 9B (200mg, 0.36mmol) and compound 36C (160.0mg, 0.43mmol) were placed in a sealed tube, and 2mL of a 1, 4-dioxane solution was added thereto to dissolve, followed by addition of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (26.0 mg,0.036 mmol) and cesium carbonate (230.0mg, 0.72mmol) in this order. Under nitrogen protection, the mixture was raised to 110 ℃ for 5h, the solvent was removed under reduced pressure, 50mL of water and 100mL of ethyl acetate were added to dissolve, the aqueous phase was washed with 50mL of × 2 ethyl acetate, the organic phases were combined, the organic phase was washed once with 40mL of saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, spin-dried, and column chromatography (DCM: meOH = 15) gave compound 36D (200.0 mg, yield: 70.07%).

Ms m/z(ESI):793.3[M+H] ⁺

The fourth step: 3- (4- (1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) quinazolin-7-yl) -5-fluoro-4- (trifluoromethyl) aniline (Compound 36)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro lizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-fluoro-4-(trifluoromethyl)aniline

Compound 36D (200mg, 0.25mmol) was dissolved in 10mL of DCM, then 1mL of trifluoroacetic acid was added dropwise at room temperature, the system was reacted for an additional 3h, the reaction was concentrated under reduced pressure, the residue was purified by preparative HPLC, the preparation was concentrated and lyophilized to give the objective compound 36 (100 mg, yield: 67.5% yield).

The HPLC preparation method comprises the following steps:

3. Mobile phase A: acetonitrile; b: purified water (containing 1% NH4HCO3); gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

Ms m/z(ESI):593.2[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.86(d,1H),7.30(dd,1H),6.54(d,1H),6.33(s,1H),5.67– 5.47(m,1H),4.76–4.59(m,4H),4.24(s,2H),4.09–3.78(m,5H),3.55–3.44(m,1H),2.82– 2.52(m,3H),2.48–2.30(m,3H),2.23–2.10(m,4H).

Example 37:2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4-amino-6-chlorobenzonitrile (Compound 37)

The first step is as follows: 4-amino-2-bromo-5-chlorobenzonitrile (37A)

4-amino-2-bromo-6-chlorobenzonitrile

Intermediate 30B (500mg, 1.50mmol) was dissolved in 4mL of N, N-dimethylformamide, nitrogen was blown for three minutes, and cuprous cyanide (130mg, 1.50mmol) was added, followed by reaction at microwave 100 ℃ for 1 hour. Diluting with water, and extracting with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound (37A) as a pale yellow solid (259 mg, 75% yield)

LCMS m/z＝230.9[M+H] ⁺

The second step: tert-butyl (1R, 5S) -3- (7- (5-amino-3-chloro-2-cyanophenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (37B)

tert-butyl(1R,5S)-3-(7-(5-amino-3-chloro-2-cyanophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Intermediate 9B (150mg, 0.27mmol), compound 37A (62mg, 0.27mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (22mg, 0.03mmol) and cesium carbonate (180mg, 0.54mmol) were placed in a sealed tube, 2.5mL1, 4-dioxane and 0.5mL of water were added, and nitrogen was replaced. The temperature is raised to 110 ℃ for reaction for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound 37B as brown solid (83 mg, 46% yield)

LCMS m/z＝666.3[M+H] ⁺

The third step: 2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4-amino-6-chlorobenzonitrile (Compound 37)

2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-amino-6-chlorobenzonitrile

Compound 37B (80mg, 0.12mmol) was dissolved in 3mL of methylene chloride, and then 0.5mL of trifluoroacetic acid was added dropwise thereto, followed by reaction at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, dropwise added to 0.5ml of n, n-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 37 (34 mg, yield 50%) as a white powder.

The HPLC preparation method comprises the following steps:

LCMS m/z＝566.2[M+H] ⁺

Example 38:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4-cyclopropylphenol (Compound 38)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro lizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-cyclopropylphenol

The first step is as follows: tert-butyl (1R, 5S) -3- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -8-fluoro-2- ((((2R, 7 aS) -2-fluorotetrahydro-1H) -pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (38B)

tert-butyl(1R,5S)-3-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2 -fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate

Intermediate 9B (200mg, 0.36mmol), compound 38A (100mg, 0.34mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (28mg, 0.03mmol) and cesium carbonate (220mg, 0.68mmol) were placed in a sealed tube, and 3mL1, 4-dioxane and 0.8mL of water were added to replace nitrogen gas for protection. The temperature is raised to 110 ℃ for reaction for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound 38B as brown solid (112 mg, 45% yield)

LCMS m/z＝726.3[M+H] ⁺

The second step is that: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4-cyclopropylphenol (Compound 38)

After compound 38B (112mg, 0.15mmol) was dissolved in 2mL of methylene chloride, 2.65mL4N hydrochloric acid-dioxane solution was added dropwise thereto, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, then dissolved by adding dichloromethane, and after dropping 0.8mL of N, N-diisopropylethylamine, concentrated under reduced pressure, the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 38 (57 mg, yield 65%) as a white powder.

The HPLC preparation method comprises the following steps:

3. Mobile phase A: acetonitrile; b: purified water (containing 1%NH4HCO3); gradient elution, wherein the content of the mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

LCMS m/z＝582.2[M+H] ⁺

Example 39:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-amino-2-cyclopropylbenzonitrile (Compound 39)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro lizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-amino-2-cyclopropylbenzonitrile

The first step is as follows: 5-amino-3 bromo-2 iodobenzonitrile (39B)

5-amino-3-bromo-2-iodobenzonitrile

2-amino-5-bromoxynil 39A (2.50g, 12.69mmol) was added, dissolved in methyl tert-butyl ether, followed by the addition of elemental iodine (6.44g, 25.38mmol), dimethyl sulfoxide (3.15mL, 44.41mmol) N ₂ Protecting, stirring and reacting for 3 hours at room temperature, adding water for dilution, extracting for three times by ethyl acetate, combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain a compound 39B which is a yellow solid (1.276 g, 31% of yield)

The second step: 5-amino-3-bromo-2-cyclopropylbenzonitrile (Compound 39C)

5-amino-3-bromo-2-cyclopropylbenzonitrile

Compound 38B (580mg, 1.80mmol), cyclopropylboronic acid (200mg, 2.34mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (150mg, 0.23mmol) and cesium carbonate (750mg, 5.4 mmol) were placed in a sealed tube, and 9L1, 4-dioxane and 3mL of water were added to replace nitrogen protection. The temperature is increased to 80 ℃ for reaction for 8 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to give compound 39C as a yellow solid (163 mg, 38% yield)

LCMS m/z＝237.1[M+H] ⁺

The third step: tert-butyl (1R, 5S) -3- (7- (5-amino-3-cyano-2-cyclopropylphenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (39D)

tert-butyl(1R,5S)-3-(7-(5-amino-3-cyano-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorot etrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbo xylate

Intermediate 9B (170mg, 0.30mmol), compound 39C (71mg, 0.30mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (25mg, 0.03mmol) and cesium carbonate (200mg, 0.60mmol) were placed in a sealed tube, and 4mL of 1, 4-dioxane and 1mL of water were added to replace nitrogen for protection. The temperature is raised to 110 ℃ for reaction for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound 39D as a brownish black solid (123 mg, 61% yield)

LCMS m/z＝672.3[M+H] ⁺

The fourth step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-amino-2-cyclopropylbenzonitrile (Compound 39)

After dissolving compound 39D (120mg, 0.18mmol) in 3mL of dichloromethane, 0.5mL of trifluoroacetic acid was added dropwise thereto, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then dichloromethane was added to dissolve it, 0.5ml of n, n-diisopropylethylamine was added dropwise thereto, followed by concentration under reduced pressure, and the residue was purified by HPLC, and the preparation was concentrated and lyophilized to give compound 39 (58 mg, yield 56%) as a white powder.

The HPLC preparation method comprises the following steps:

LCMS m/z＝572.3[M+H] ⁺

Example 40:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-amino-2- (trifluoromethyl) benzonitrile (Compound 40)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro lizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-amino-2-(trifluoromethyl)benzonitrile

The first step is as follows: (3-bromo-5-cyano-4-iodophenyl) carbamic acid tert-butyl ester (40A)

tert-butyl(3-bromo-5-cyano-4-iodophenyl)carbamate

In N ₂ Under the protection of (1.0 g, 3) of compound 39B10 mmol) and di-tert-butyl dicarbonate (740mg, 3.41mmol) are dissolved in 20mL of THF, 1N LiHMDS (6.79 mL) is slowly dripped in the ice bath, after the dripping is finished, the reaction solution is moved to the normal temperature condition for reaction for 2 hours, saturated ammonium chloride solution is added for dilution, ethyl acetate is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried and filtered, the filtrate is concentrated under reduced pressure and purified by column chromatography, and the compound 40A is obtained and is yellow oil (1.01 g, the yield is 77%)

LCMS m/z＝422.9[M+H] ⁺

The second step is that: (3-bromo-5-cyano-4- (trifluoromethyl) phenyl) carbamic acid tert-butyl ester (40B)

tert-butyl(3-bromo-5-cyano-4-(trifluoromethyl)phenyl)carbamate

In N ₂ Under protection of (2.3224), compound 40A (980mg, 2.32mmol), methyl fluorosulfonyl difluoroacetate (3.12 g, 16.24 mmol) and cuprous iodide (660mg, 3.48mmol) were sequentially added to a reaction tube, and then N, N-diisopropylethylamine (2.69mL, 16.24mmol) was dissolved in 10mL of DMF and slowly added dropwise to the reaction tube. Reacting in 75 deg.C oil bath for 24 hr, cooling to room temperature, diluting with water, extracting with ethyl acetate for three times, mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound 40B as yellow solid (754 mg, 89% yield)

LCMS m/z＝363.0[M-H] ^-

The third step: tert-butyl (1R, 5S) -3- (7- (5- ((tert-butoxycarbonyl) amino) -3-cyano-2- (trifluoromethyl) phenyl) -8-fluoro-2- (((2R, 7aS)) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (40C)

tert-butyl(1R,5S)-3-(7-(5-((tert-butoxycarbonyl)amino)-3-cyano-2-(trifluoromethyl)phenyl)-8-fluoro -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicycl o[3.2.1]octane-8-carboxylate

Intermediate 9B (180mg, 0.32mmol), compound 40B (120mg, 0.32mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (26mg, 0.03mmol) and cesium carbonate (210mg, 0.64mmol) were placed in a sealed tube, and 4mL of 1, 4-dioxane and 1mL of water were added to replace the nitrogen blanket. The temperature is raised to 110 ℃ for reaction for 3 hours. Cooling the reaction to room temperature, diluting with water, extracting with ethyl acetate for three times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound 40C as a reddish brown solid (66 mg, 26% yield)

LCMS m/z＝800.3[M+H] ⁺

The fourth step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] -octan-3-yl) -8-fluoro-2- (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-amino-2- (trifluoromethyl) benzonitrile (Compound 40)

Compound 40C (66mg, 0.08mmol) was dissolved in 3mL of dichloromethane, and then 0.5mL of trifluoroacetic acid was added dropwise thereto, followed by reaction at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, then dichloromethane was added to dissolve it, 0.5ml of n, n-diisopropylethylamine was added dropwise thereto, concentration under reduced pressure was carried out, the residue was purified by HPLC, and the preparation solution was concentrated and lyophilized to obtain compound 40 (30 mg, yield 60%) as a white powder.

The HPLC preparation method comprises the following steps:

3. A mobile phase A: acetonitrile; b: purified water (containing 1% NH4HCO3); gradient elution, wherein the content of a mobile phase A is eluted from 5 to 50 percent; flow rate: 12mL/min; elution time: and (4) 18min.

LCMS m/z＝600.2[M+H] ⁺

Example 41: (2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4-aminophenyl) dimethylphosphine oxide (Compound 41)

(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-aminophenyl)dimethylphosphine oxide.

The first step is as follows: (4-amino-2-bromophenyl) dimethylphosphine oxide (41 c)

(4-amino-2-bromophenyl)dimethylphosphine oxide.

(41 a) (2.86g, 9.6mmol) was placed in a sealed tube, 50mL1, 4-dioxane was added and dissolved, and then (41 b) (500mg, 6.4 mmol), tetrakistriphenylphosphine palladium (1.1g, 0.96mmol), potassium carbonate (1.77g, 12.8mmol) and 5mL of water were sequentially added. After the reaction was completed, the reaction was cooled to room temperature, 40mL of ethyl acetate and 25mL of water were added, followed by stirring and liquid separation, the aqueous phase was extracted once with ethyl acetate (40 mL × 1), the ethyl acetate layers were combined, the ethyl acetate layer was washed once with saturated brine (40 mL × 1), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was subjected to column chromatography on a silica gel column (PE: EA =5

LCMS m/z＝248.0[M+H]+

The second step is that: tert-butyl (1R, 5S) -3- (7- (5-amino-2- (dimethylphosphoryl) phenyl) -8-fluoro-2- ((((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a) (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (41 d)

tert-butyl

(1R,5S)-3-(7-(5-amino-2-(dimethylphosphoryl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H -pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

(41 c) (0.16g, 0.646mmol) was dissolved in a mixed solution of acetonitrile 15mL and water 1.5mL, 9B (180 mg, 0.323 mmol), potassium fluoride (0.070g, 1.21mmol), bis-triphenylphosphine palladium dichloride (0.023g, 0.032mmol) were added and reacted at 100 ℃ for 12 hours under nitrogen protection, the reaction was cooled to room temperature, 40mL of ethyl acetate and 25mL of water were added and stirred, followed by liquid separation, the aqueous phase was extracted once with ethyl acetate (40 mL. Times.1), the ethyl acetate layers were combined, washed once with saturated brine (40 mL. Times.1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (DCM: meOH =96 4) to obtain compound (41 d) (0.15 g, yield: 68%

LCMS m/z＝683.3[M+H] ⁺

The third step: (2- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -4-aminophenyl) dimethylphosphine oxide (Compound 41)

Compound (41 d) (0.15g, 0.22mmol) was dissolved in 5mL of methylene chloride, and 0.5mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then dichloromethane was added to dissolve it, 0.5mL of N, N-diisopropylethylamine was added dropwise thereto, then concentration under reduced pressure was carried out, the residue was purified by HPLC, and the preparation solution was concentrated and lyophilized to give compound 41 (50 mg, yield: 39%) as a white powder.

The HPLC preparation method comprises the following steps:

Ms m/z(ESI):583.2[M+H] ⁺

Example 42:3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4- (prop-1-en-2-yl) aniline (Compound 42)

3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-(prop-1-en-2-yl)aniline.

The first step is as follows: 3-bromo-5-chloro-4- (prop-1-en-2-yl) aniline (42 b)

3-bromo-5-chloro-4-(prop-1-en-2-yl)aniline.

(14 b) (0.628g, 1.89mmol) was dissolved in a mixed solution of acetonitrile 30mL and water 3mL, 42a (265 mg, 1.58 mmol), potassium fluoride (0.343g, 5.9mmol), bis-triphenylphosphine palladium dichloride (0.11g, 0.158mmol) were added, the reaction was reacted at 100 ℃ for 12 hours under nitrogen protection, the reaction was cooled to room temperature, ethyl acetate 40mL and water 25mL were added, liquid separation was performed after stirring, the aqueous phase was extracted once with ethyl acetate (40 mL. Times.1), the ethyl acetate layers were combined, the ethyl acetate layer was washed once with saturated brine (40 mL. Times.1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel chromatography (PE: EA = 5) to obtain compound (42 b) (0.29 g, yield: 75%

LCMS m/z＝246.0[M+H] ⁺

The second step is that: tert-butyl (1R, 5S) -3- (7- (5-amino-3-chloro-2- (prop-1-en-2-yl) phenyl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (42 c)

tert-butyl(1R,5S)-3-(7-(5-amino-3-chloro-2-(prop-1-en-2-yl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fl uorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-c arboxylate.

(42B) (0.09g, 0.365mmol) was dissolved in a mixed solution of acetonitrile 15mL and water 1.5mL, 9B (170 mg, 0.304 mmol), potassium fluoride (0.066 g, 1.137mmol), bis-triphenylphosphine palladium dichloride (0.021g, 0.03mmol) were added and reacted at 100 ℃ for 12 hours under nitrogen protection, the reaction was cooled to room temperature, 40mL of ethyl acetate and 25mL of water were added and liquid was separated with stirring, the aqueous phase was extracted once with ethyl acetate (40 mL. Times.1), the ethyl acetate layers were combined, the ethyl acetate layer was washed once with a saturated saline (40 mL. Times.1), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (DCM: meOH = 96) to obtain compound (42 c) (0.11 g, yield: 53%

LCMS m/z＝681.3[M+H] ⁺

The third step: 3- (4- ((1R, 5S) -3,8-diazabicyclo [3.2.1] octyl-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4- (prop-1-en-2-yl) aniline (Compound 42)

Compound (42 c) (0.11g, 0.26mmol) was dissolved in 5mL of methylene chloride, and 0.5mL of trifluoroacetic acid was added to react at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, then methylene chloride was added to dissolve it, 0.5mL of N, N-diisopropylethylamine was added dropwise thereto, then, concentration under reduced pressure was carried out, the residue was purified by HPLC preparation, and the preparation was concentrated and lyophilized to give compound 42 (51 mg, yield: 54%) as a white powder.

The HPLC preparation method comprises the following steps:

Ms m/z(ESI):581.3[M+H] ⁺

Example 43:4- (4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5,6,7, 8-tetrahydroquinazolin-7-yl) naphthalen-2-ol (Compound 43)

4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-7-yl)naphthalen-2-ol.

The first step is as follows: 3- (3- (methoxymethoxy) naphthalen-1-yl) cyclohex-1-one (43 b)

3-(3-(methoxymethoxy)naphthalen-1-yl)cyclohexan-1-one.

(43 a) (2.0 g, 6.37mmol) was placed in a sealed tube, 40mL1, 4-dioxane was added to dissolve, and cyclohexenone (0.92mL, 9.56mmol), (1, 5-cyclooctadiene) ruthenium (I) chloride dimer (314mg, 0.637mmol), potassium phosphate (4.0 g, 19.11mmol), and 8mL of water were sequentially added. Replacing gas with nitrogen three times, heating to 50 ℃ for reaction for 12h, cooling the reaction to room temperature, adding 40mL of ethyl acetate and 25mL of water, stirring, separating liquid, extracting the aqueous phase once with ethyl acetate (40 mL × 2), combining ethyl acetate layers, washing the ethyl acetate layer once with saturated saline (40 mL × 1), drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the residue with silica gel column chromatography to obtain compound (43 b) (1.7 g, yield: 94%)

LCMS m/z＝285.1[M+H] ⁺

The second step: 4- (3- (methoxymethyloxy) naphthalen-1-yl) -2-oxocyclohexane-1-carboxylic acid ethyl ester (43 c)

ethyl 4-(3-(methoxymethoxy)naphthalen-1-yl)-2-oxocyclohexane-1-carboxylate.

Compound 43b (1.2 g, 4.22mmol) was suspended in 30mL of dry tetrahydrofuran, cooled to-78 ℃ under nitrogen, liHMDS solution in tetrahydrofuran (6.33mL, 1mol/L,6.33 mmol) was slowly added dropwise, and the system was stirred at-78 ℃ for 30min. Ethyl cyanoformate (627mg, 6.33mmol) was added dropwise and the system allowed to warm to room temperature automatically for 2h. The reaction was quenched by the addition of 50mL ice water at 0 ℃. Then extracted three times with ethyl acetate 50mL, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 43c (1.6 g crude) which was used in the next reaction without purification.

LCMS m/z＝357.2[M+H] ⁺

The third step: 7- (3- (methoxymethyloxy) naphthalen-1-yl) -2- (methylthio) -5,6,7, 8-tetrahydroquinazolin-4-ol (43 d)

7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-ol.

Compound 43c (1.6 g crude) was dissolved in a mixed solution of 100mL ethanol and 20mL water, and S-methylisothiourea sulfate (11.75g, 42.2 mmol) and sodium hydrogencarbonate (15.95g, 189.9 mmol) were added. Heating to 50 ℃ under the protection of nitrogen and reacting for 12h. After removing the solvent by concentration under reduced pressure, 50mL of water was added for dilution, the aqueous phase was extracted three times with 50mL of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography separation and purification gave the desired product 43d (950 mg, two-step yield: 59%).

LCMS m/z＝383.1[M+H] ⁺

The fourth step: 7- (3- (methoxymethyloxy) naphthalen-1-yl) -2- (methylthio) -5,6,7, 8-tetrahydroquinazolin-4-yl trifluoromethanesulfonate (43 e)

7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-yl trifluoromethanesulfonate.

Compound 43d (950mg, 2.49mmol) was dissolved in 30mL of dichloromethane, N-diisopropylethylamine (1.65 mL, 9.96mmol) was added, trifluoromethanesulfonic anhydride (0.84mL, 4.98mmol) was added under ice-bath, and the mixture was stirred for 1h under ice-bath. After dilution with 20mL of dichloromethane, the reaction was washed with 20mL of water, the organic phase was washed with 20mL of saturated aqueous sodium bicarbonate solution, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired crude product 43e (940 mg of crude product).

LCMS m/z＝515.1[M+H] ⁺

The fifth step: 3- (7- (3- (methoxymethyloxy) naphthalen-1-yl) -2- (methylthio) -5,6,7, 8-tetrahydroquinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (43 f)

tert-butyl 3-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-yl)-3,8-di azabicyclo[3.2.1]octane-8-carboxylate.

Compound 43e (940 mg of crude product) was dissolved in 20mL of N, N-dimethylacetamide, and N, N-diisopropylethylamine (1.65mL, 9.96mmol) and tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (793mg, 3.74mmol) were added in this order, followed by stirring at room temperature for 3 hours. The mixture was diluted with 100mL of ethyl acetate, the organic phase was washed three times with 20mL of water, once with 20mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography gave the desired crude product 43f (920 mg crude).

LCMS m/z＝577.2[M+H] ⁺

And a sixth step: tert-butyl 3- (7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (methylsulfonyl) -5,6,7, 8-tetrahydroquinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (43 g)

tert-butyl 3-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8-carboxylate.

Compound 43f (920 mg of crude) was dissolved in 20mL of tetrahydrofuran, and m-chloroperoxybenzoic acid (1.72 g, 9.96mmol) was added at room temperature and stirred at room temperature for 2h. 20mL of a saturated aqueous solution of sodium thiosulfate was added, the mixture was stirred for 20min, 50mL of ethyl acetate was added for extraction, and the organic layer was washed with 20mL of a saturated aqueous solution of sodium hydrogencarbonate, concentrated under reduced pressure, and subjected to column chromatography to give 43g of the objective compound (459 mg, three-step yield: 30%).

LCMS m/z＝609.2[M+H] ⁺

The seventh step: 4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ((((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) -5,6,7, 8-tetrahydroquinazoline (43H)

4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydroquinazoline.

43g (459mg, 0.755mmol) of the compound and intermediate 1c-1 (240mg, 1.51mmol) were dissolved in 20mL of toluene, and sodium t-butoxide (109mg, 1.13mmol) was added under ice-cooling, followed by stirring for 1 hour under ice-cooling. The reaction was quenched with 20mL of water, extracted three times with 50mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography separation and purification yielded the objective product 43h (520 mg, yield: 95%).

LCMS m/z＝588.3[M+H] ⁺

Eighth step: 4- (4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5,6,7, 8-tetrahydroquinazolin-7-yl) naphthalen-2-ol (Compound 43)

4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-7-yl)naphthalen-2-ol

Compound (43 h) (0.52g, 0.88mmol) was dissolved in 5mL of dichloromethane, 0.5mL of trifluoroacetic acid was added, the reaction was carried out at room temperature for 10 minutes, and N, N-diisopropylethylamine was immediately added to adjust the pH to alkalinity. Concentrated under reduced pressure, and the residue was purified by preparative HPLC, and the resulting solution was concentrated and lyophilized to give Compound 43 (23 mg, yield: 4.8%).

The HPLC preparation method comprises the following steps:

1. the instrument comprises the following steps: waters 2767 preparation of the liquid phase; a chromatographic column: sunFire @ Prep C ₁₈ (19mm*250mm).

Ms m/z(ESI):544.2[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ8.04(d,1H),7.66(d,1H),7.41–7.27(m,2H),7.03–6.96(m, 2H),5.38–5.18(m,1H),4.23–4.40(m,3H),3.95–3.85(m,1H),3.76–3.66(m,1H),3.58–3.51 (m,2H),3.39–3.33(m,1H),3.26–3.11(m,4H),3.08–2.74(m,4H),2.67–2.57(m,1H),2.33– 2.12(m,3H),2.11–1.74(m,9H).

Biological test example

Biological test 1: in vitro KRAS G12D binding detection assay

The method comprises the following steps:

the human recombinant protein Tag1-RAF1 and Tag2-KRAS-G12D are prepared into 2.5 times of protein solution. mu.L of the compounds at different concentrations and 4. Mu.L of 2.5 Xtag 1-RAF1 and 4. Mu.L of 2.5 Xtag 2-KRAS-G12D were added to the 384-well plate and incubated at room temperature for 60 minutes. After the incubation, 10. Mu.L of the pre-mixed antibody Tag1-Eu and antibody Tag2-XL665 was added to the microplate, and after incubation for 2 hours at normal temperature, excitation light was set at 320nM and emission light was set at 615nM and 665nM using a multifunction microplate reader, and fluorescence signals at 615nM (Eu) and 665nM (d 2) were read. Calculating the signal Ratio according to the formula (1), and calculating the IC by using Prism GraphPad 7.0 software ₅₀ The value is obtained.

Ratio＝[Signal 665]/[Signal 615]*10 ⁴ (formula 1)

The second method comprises the following steps:

compounds of different concentrations diluted in 2 μ L dilution buffer were added to 384-well plates. After 250XTag2-KRAS-G12D protein and 10mM GTP were diluted 50-fold and 200-fold with a dilution buffer, respectively, 4. Mu.L of the mixture was added to the test plate. Diluting 500X Tag1-RAF 100 fold with dilution buffer and adding 4. Mu.L to test plate; the test plate was incubated at 25 ℃ for 15 minutes. After the incubation is finished, the anti-Tag1-Eu and the anti-Tag2-XL665 are diluted by 100 times and 50 times respectively by using detection buffer solution, 10 mu L of mixed solution is added into the test plate, and the incubation is carried out for 2 hours at 4 ℃. After the reaction, a multi-label analyzer is adopted to read signal values, wherein the excitation is 320nm, the emission is 615nm, and 665nm.

The formula Ratio = [ Signal 665 ] is adopted]/[Signal 615]×10 ⁴ Calculating the signal ratio and calculating the inhibition ratio using equation 2, wherein R _sample As ratio of compound pore signals, R _min Signal ratio of control well without KRAS G12D protein, R _max To contain 1% of DMSO solvent control well signal ratio, curve fitting was performed by four parameters using GraphPad Prism software and IC was calculated ₅₀ The value is obtained. The test results are shown in Table 1.

Inhibition％＝(1-(R _sample -R _min )/(R _max -R _min ) 100% (formula 2)

TABLE 1 IC of the Compounds of the invention ₅₀ Value of

Test method	Compound number	IC ₅₀ (nM)
			Method two	Trifluoroacetic acid salt of Compound 2	A
Method two	Compound 3	B
			Method two	Compound 4	A
Method two	Compound 8	A
			Method two	Compound 12	A
Method two	Compound 14	A
			Method two	Compound 15	A
Method two	Compound 19	A
			Method two	Compound 36	A
Method two	Compound 37	A
			Method two	Compound 38	A
Method two	Compound 43	A

A≤100nM；100nM＜B≤1000nM

And (4) conclusion: the compound of the invention has good inhibitory activity on the protein interaction of KRAS G12D and RAF 1.

Biological test 2: cell proliferation inhibition assay

ASPC-1 cell culture conditions: RPMI-1640+10% of the double antibody FBS +1%, cultured at 37 ℃,5% of CO ₂ An incubator. ASPC-1 cells in exponential growth phase plated 96-well culture plates 80. Mu.L per well at a plating density of 1000/well were harvested on day one, at 37 ℃ 5% ₂ Culturing in incubator overnight, and plating while spreading T ₀ And (4) a hole. The following day 20. Mu.L of different concentrations of compounds were added to each well, resulting in a final DMSO concentration of 0.5% per well, at 37 ℃,5% CO ₂ Culturing in incubator for 6 days. The following day dosing was performed while using CellTiter-Glo kit to detect T ₀ Plate, note RLU ₀ . After incubation, 25. Mu.L of assay solution (Cell 4 visual assay, promega) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence readings detected using a Nivo multi-label analyzer (Perkinelmer). Results were processed according to the formula (3), and proliferation inhibition ratios at respective concentrations of the compound were calculated, and the concentration GI of the compound at which the proliferation inhibition ratio was 50% was calculated by curve fitting using GraphPad Prism software using four parameters ₅₀ The value is obtained. RLU _compound For the drug treatment group readings, RLU _control Mean values for the solvent control group. The test results are shown in Table 2.

Inhibition％＝(1-(RLU _compound -RLU ₀ )/(RLU _control -RLU ₀ ) 100% of formula (3)

TABLE 2 proliferation inhibitory Activity of the Compounds of the present invention GI ₅₀ Value of

Compound numbering	GI ₅₀ (nM)
		Trifluoroacetic acid salt of Compound 2	A
Compound 4	A
		Compound 5	B
Compound 6	B
		Compound 8	B
Compound 11	B
		Compound 12	B
Compound 13	B
		Compound 14	B
Compound 15	B
		Compound 16	B
Compound 22	B
		Compound 24	B
Compound 30	B
		Compound 36	B
Compound 38	A
		Compound 43	B

A≤100nM；100nM＜B≤1000nM.

And (4) conclusion: the compound of the present invention has excellent proliferation inhibiting activity on ASPC-1 cell.

Claims

1. A compound of formula (I-a) or a stereoisomer, deuteride, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

X ₁ Or X ₂ Each independently selected from N or CR ^b ；

Ring A is selected from 3-to 12-membered carbocyclyl or 4-to 12-membered heterocyclyl, said carbocyclyl or heterocyclyl optionally further substituted with 0 to 6R ^a Substituted, said heterocyclic radicalContaining 1 to 4 heteroatoms selected from O, S, N;

R ^b each independently selected from H, oxo, halogen, cyano, OH, NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkylthio radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, 3-to 8-membered cycloalkyl, 4-to 8-membered heterocyclyl, -O-3-to 8-membered cycloalkyl, -O-4-to 8-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl or heterocycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl radical, C _1-4 Alkoxy, 4-7 membered heterocyclyl or C _3-6 Cycloalkyl, said heterocyclyl or heterocycloalkyl containing from 1 to 4 heteroatoms selected from O, S, N;

or two R ^a Or two R ^b Taken together with the atoms to which they are attached form a 3-to 12-membered carbocyclyl or a 4-to 12-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, wherein the heterocyclic group contains 1 to 4 hetero atoms selected from O, S and N;

R ^x Selected from H, C _1-6 Alkyl or C _3-6 Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Substituted by a substituent of alkoxy;

R ¹ selected from halogen, OH, cyano, COOH, NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, NH ₂ 、-(CH ₂ ) _q -C(＝O)C _1-6 Alkyl, - (CH) ₂ ) _q -C (= O) -3-to 12-membered heterocycle, - (CH) ₂ ) _q -C(＝O)-C _3-10 Carbocyclic ring, - (CH) ₂ ) _q -3 to 12 membered heterocycle or- (CH) ₂ ) _q -C _3-10 Carbocyclic ring of said CH ₂ Alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4R ^1a (ii) substituted, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

R ^1a each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, -C _1-6 alkylene-OH, - (CH) ₂ ) _q -C _3-10 Carbocyclic ring, - (CH) ₂ ) _q -3 to 12 membered heterocycle, -O-C _3-10 Carbocyclic ring, -O-3 to 12 membered heterocyclic ring, C _1-6 Alkoxy, -N (C) _1-6 Alkyl) C (= O) -3-to 12-membered heterocycle, said alkyl, CH ₂ Alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycleThe ring is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycle or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

R ^2a each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-6 Alkyl), -N (C) _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylthio radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, -O-C _3-6 Cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycloalkyl, heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N; or

R ^2a Each independently selected from-NHC (O) C _1-6 Alkyl, -NHS (O) ₂ C _1-6 Alkyl, -P (O) (C) _1-6 Alkyl radical) ₂ Said alkyl group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 4 substituents selected from O, and,Heteroatoms of S and N;

or two R ^2a Together with the atoms to which they are directly attached form a 3-to 12-membered carbocyclic or 4-to 12-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 Alkoxy, wherein the heterocyclic group contains 1 to 4 hetero atoms selected from O, S and N;

q is each independently selected from 0, 1,2,3 or 4.

2. The compound of claim 1, or a stereoisomer, deutero-compound, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, selected from the group consisting of formula (I-aa),

selected from 4-to 12-membered nitrogen-containing heterocycles selected from one of the following saturated or partially saturated groups: monocyclic, fused, bridged or spirocyclic ring, said nitrogen-containing heterocycle, monocyclic, fused, bridged or spirocyclic ring being optionally further substituted with 0 to 4R ^a Substituted, ring A ₁ Wherein N-H is unsubstituted;

n is selected from 0, 1,2,3 or 4;

provided that

Is not that

m1 is selected from 0, 1 or 2;

with the proviso that the compound is not

3. The compound of claim 2, or a stereoisomer, deuteride, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,

selected from one of the following unsubstituted or substituted groups:

is selected from

To the left of itEdge and L ₂ Is connected, above and to ring A ₁ Connecting;

each m is independently selected from 0, 1,2 or 3.

4. The compound of claim 3, or a stereoisomer, deutero-compound, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,

is selected from

Is selected from

Left side and L of it ₂ Connecting, above and ring A ₁ Connecting;

each m is independently selected from 0, 1,2 or 3.

5. The compound of claim 4, or a stereoisomer, deuteride, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,

L ₂ selected from a bond, O or-C (= O) -;

R ² is selected from C _3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroarylOptionally further substituted by 0 to 5R ^2a (iii) substituted, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

R ^2a Each independently selected from-NHC (O) C _1-4 Alkyl, -NHS (O) ₂ C _1-4 Alkyl, -P (O) (C) _1-4 Alkyl radical) ₂ Said alkyl group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

or two R ^2a Taken together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 4-to 6-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-4 Alkyl or C _1-4 The substituent of the alkoxy is substituted, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N.

6. The compound of claim 5, or a stereoisomer, deutero-compound, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,

R ^1a each independently selected from H, halogen, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ 、-NH(C _1-4 Alkyl), -N (C) _1-4 Alkyl radical) ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, -C _1-4 alkylene-OH, - (CH) ₂ ) _q -C _3-8 Carbocyclic ring, - (CH) ₂ ) _q -3 to 8 membered heterocycle, -O-C _3-8 Carbocyclic ring, -O-3 to 8 membered heterocyclic ring, C _1-4 Alkoxy, -N (C) _1-4 Alkyl) C (= O) -3-to 8-membered heterocyclic substituent, said alkyl, CH ₂ Alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ 、C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 A cycloalkyl group, a,3 to 6 membered heterocycloalkyl, said heterocycle or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

each q is independently selected from 0, 1,2,3 or 4.

7. The compound of claim 6, or a stereoisomer, deutero-compound, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,

R ^2a each independently selected from H, F, cl, br, I, oxo, OH, NH ₂ Cyano, CF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, cyano, oxo, CF, OH ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy; or

R ^2a Each independently selected from-NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, said-CH ₃ Cyclopentenyl, phenyl, pyrazolyl optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, cyano, oxo、CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

or two R ^2a Taken together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 4-to 6-membered heterocyclic group, said carbocyclic or heterocyclic group being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R ^1a each independently selected from H, F, cl, br, I, oxo, OH, cyano, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, said methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy being optionally further substituted by 0 to 4 substituents selected from H, F, cl, br, I, OH, cyano, oxo, CF ₃ 、COOH、NH ₂ Methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy.

8. The compound of claim 7, or a stereoisomer, deutero-compound, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, selected from the group consisting of formula (I-aaa),

L ₂ is selected from a bond or-C (= O) -;

9. The compound of claim 8, or a stereoisomer, deutero-compound, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, selected from the group consisting of formula (I-aaaa),

R ^2a Each independently selected from propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, said-CH ₃ Propenyl, cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropylAnd (4) generation.

10. The compound of claim 8, or a stereoisomer, deutero-isomer, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, selected from the group consisting of formula (I-b)

R ² Selected from the group consisting of phenyl, benzopyrazolyl, benzofuranyl, pyridyl, said phenyl group is substituted with 1 to 4R ^2a Substituted by 0 to 4R ^2a Substitution;

R ^2a each independently selected from F, cl, OH, cyano, NH ₂ 、CF ₃ 、OCF ₃ 、-SCH ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, propenyl, -NHC (O) CH ₃ 、-NHS(O) ₂ CH ₃ 、-P(O)(CH ₃ ) ₂ Cyclopentenyl, phenyl, pyrazolyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, OH, methyl, ethyl or cyclopropyl.

11. The compound of formula (I) according to claim 1, or a stereoisomer, deutero-compound, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:

12. a pharmaceutical composition comprising a compound of any one of claims 1-11, or a stereoisomer, deutero-compound, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, and a pharmaceutically acceptable carrier.

13. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, a deuteride, an N-oxide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with KRAS activity or expression.

14. Use of a compound according to any one of claims 1-11, or a stereoisomer, a deuterode, an N-oxide, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with KRAS G12D activity or expression.

15. The use according to claim 14, wherein the disease is selected from the group consisting of tumors.