CN115490709A - A KRASG12D inhibitor and its application in medicine - Google Patents

Abstract

A KRASG12D inhibitor and its application in medicine. The present invention relates to a compound described in general formula (I-a) or its stereoisomer, deuterium, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, Its intermediate and preparation method, as well as its application in the preparation of medicines for treating diseases related to KRASG12D activity or expression.

Description

A KRAS G12D inhibitor and its application in medicine

technical field

The present invention relates to a compound described in general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and its intermediate and preparation method , and the application in the preparation of medicines for treating diseases related to KRASG12D activity or expression.

Background technique

RAS protein is expressed by RAS gene (Rat Sarcoma viral oncogene), which is an intracellular guanine nucleotide binding protein and belongs to GTPase (weak hydrolysis activity). RAS proteins exist in two distinct states: an inactive GDP-bound state and an active GTP-bound state. The activated RAS protein conducts signal transduction by interacting with different downstream effectors, and has effects on cell growth, differentiation, cytoskeleton, protein transport and secretion. Activation of RAS signaling is regulated by guanine nucleotide exchange factor (GEF, which causes GDP-GTP exchange) or GTPase activating protein (GAP, which causes the RAS protein to switch from an active to an inactive state), and mutant RAS The protein can cause resistance to GAP and lead to the continuous activation of RAS protein, causing uncontrolled cell growth and eventually developing into cancerous tissue (Molecular Cancer, 2018, 17:33).

RAS gene mutation is a common type of gene mutation in cancer patients (Nat.Rev.Drug Discov.2014, 13, 828-851). To 97.7%, 52.2%, 42.6% and 32.2%. 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 for KRAS gene to be activated is point mutation. 95% of KRAS mutations mainly occur in codons 12 and 13 of exon 2. Common mutations include KRAS G12C mutation (39%), KRAS G12V (18-21%) and KRAS G12D (17-18%) mutations.

KRAS mutant protein inhibitors have received a lot of attention since the discovery of KRAS mutant proteins in cancer and the observation that inhibiting these mutant proteins can inhibit tumor proliferation. KRAS has long been considered a "non-druggable target": RAS has a high affinity (picomolar level) for GTP/GDP, and the entire protein lacks other "ligand binding pockets" (Clin. Cancer Res.2015, 21, 1810–1818).

The KRAS G12D mutation affects about 180,000 patients in Europe and the United States. KRAS G12D was found in 36% of pancreatic cancer patients, 12% of colon cancer patients, 4% of NSCLC adenocarcinoma patients, and 6% of endometrial cancer patients. At present, inhibitors against KRAS G12D mutation are still in the early stage, no compound has entered clinical research, and only a few companies have published related patents in this field. For example, Mirati Therapeutics has applied for a KRAS G12D inhibitor patent (WO2021041671) . Therefore, it is necessary to develop compounds capable of inhibiting KRAS G12D protein for the treatment of related diseases caused by KRASG12D mutations.

Contents of the invention

The object of the present invention is to provide a compound capable of inhibiting KRAS G12D protein or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and its intermediate and preparation method, And the application in preparation of medicines for treating diseases related to KRAS G12D activity or expression.

The present invention provides a compound described in general formula (I-a) or its stereoisomer, deuterated substance, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein

_In some embodiments, X or X are each independently selected from N or CR ^b _;

In some embodiments, X ₁ , X ₂ are selected from N;

In some embodiments, X ₁ , X ₂ are selected from CR ^b ;

In some embodiments, X ₁ is selected from N, and X ₂ is selected from CR ^b ;

In some embodiments, X ₁ is selected from CR ^b and X ₂ is selected from N;

In some embodiments, Ring A is selected from a 3- to 12-membered carbocyclyl or a 4- to 12-membered heterocyclyl, and said carbocyclyl or heterocyclyl is optionally further substituted by 0 to 6 R ^a , said The heterocyclyl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;

In some embodiments, each of L ₁ , L ₂ or L ₃ is independently selected from a bond, O, -CH ₂ -, -OCH ₂ -, -CH ₂ O-, -C(=O)-, S, or NR ^x ;

In some embodiments, R ^{x is} selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) are substituted by substituents selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy;

In some embodiments, _L is selected from a bond;

选自

In some embodiments,

selected from

选自4至12元含氮杂环，所述的含氮杂环选自饱和或部分饱和的如下基团之一：单环、并环、桥环或螺环，所述的含氮杂环、单环、并环、桥环或螺环任选进一步被0至4个(例如0、1、2、3或4个)R^a取代，环A₁中N-H不被取代；In some embodiments,

Selected from 4 to 12 membered nitrogen-containing heterocyclic rings, the nitrogen-containing heterocyclic rings are selected from one of the following saturated or partially saturated groups: monocyclic, parallel rings, bridged rings or spiro rings, and the nitrogen-containing heterocyclic rings , monocyclic ring, parallel ring, bridging ring or spiro ring are optionally further substituted by 0 to 4 (for example 0, 1, 2, 3 or 4) R ^a , and NH in ring _A is not substituted;

选自未被取代的或者取代的如下基团之一：

当被取代时，任选进一步被0至4个(例如0、1、2、 3或4个)R^a取代基所取代，环A₁中N-H不被取代；In some embodiments,

One of the following unsubstituted or substituted groups:

When substituted, it is optionally further substituted by 0 to 4 (eg 0, ₁ , 2, 3 or 4) substituents R, and NH in ring ^A is not substituted;

选自未被取代的或者取代的

当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)R^a取代基所取代，环A₁中N-H 不被取代；In some embodiments,

selected from unsubstituted or substituted

When substituted, it is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R substituents, and NH in ring ^A ₁ is not substituted;

选自

In some embodiments,

selected from

In some embodiments, each R ^a is independently selected from H, oxo, halogen, cyano, OH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, 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 heterocyclic Cycloalkyl, the alkyl, alkoxy, cycloalkyl, and heterocyclic groups are optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) selected from H, halogen, OH, Substituted by cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, the heterocyclic group contains 1 to 4 selected from O, S, N heteroatom;

In some embodiments, each R ^a is independently selected from H, oxo, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, 3 to 6 membered cycloalkyl, 4 to 6 membered hetero Cyclic group, -O-3 to 6-membered cycloalkyl group, -O-4 to 6-membered heterocycloalkyl group, the alkyl group, alkoxy group, cycloalkyl group and heterocyclyl group are optionally further replaced by 0 to 4 substituents (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;

In some embodiments, each R ^a is 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, the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy are optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, propoxy or Substituents of isopropoxy are substituted;

In some embodiments, each R ^a is independently selected from H, oxo, F, Cl, Br, I, cyano, OH, NH ₂ , methyl, ethyl, methoxy, ethoxy, propoxy , isopropoxy, cyclopropyl, -O-cyclopropyl, the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, propoxy, isopropoxy, Cyclopropyl is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , formazan Substituted by radical, ethyl, propyl, methoxy, ethoxy or propoxy;

In some embodiments, each R ^a is independently selected from H;

In some embodiments, two R ^a together form a 3 to 12 membered carbocyclyl or a 4 to 12 membered heterocyclyl, and the carbocyclyl or heterocyclyl is optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-6 alkyl), -N(C _{1- 6} alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 (such as 1, 2, 3 or 4) selected from Heteroatoms of O, S, N;

In some embodiments, two R ^a together form a 3-6 membered carbocyclyl or a 4-6 membered heterocyclyl, and the carbocyclyl or heterocyclyl is optionally further replaced 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, the heterocyclic group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;

In some embodiments, Ring B is selected from ₃ to 8 membered carbocyclyl, 5 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl or phenyl, said carbocyclyl, heterocyclyl, heteroaryl The base or phenyl group is optionally further substituted by 0 to 7 (eg 0, 1, 2, 3, 4, 5, 6, 7) R ^b , and the heterocyclic or heteroaryl group contains 1 to 4 Heteroatoms selected from O, S, N;

选自

In some embodiments,

selected from

其左边与L₂连接，上方与环A₁连接；

Its left side is connected with L ₂ , and its upper part is connected with ring A ₁ ;

选自

其左边与L₂连接，上方与环A₁连接；In some embodiments,

selected from

Its left side is connected with L ₂ , and its upper part is connected with ring A ₁ ;

选自

其左边与L₂连接，上方与环A₁连接；In some embodiments,

selected from

Its left side is connected with L ₂ , and its upper part is connected with ring A ₁ ;

选自

其左边与 L₂连接，上方与环A₁连接；In some embodiments,

selected from

Its left side is connected with L ₂ , and its upper part is connected with ring A ₁ ;

选自

其左边与L₂连接，上方与环 A₁连接；In some embodiments,

selected from

Its left side is connected with L ₂ , and its upper part is connected with ring A ₁ ;

选自

其左边与L₂连接，上方与环 A₁连接；In some embodiments,

selected from

Its left side is connected with L ₂ , and its upper part is connected with ring A ₁ ;

In some embodiments, each R ^b is independently selected from H, oxo, halogen, cyano, OH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 alkylthio, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, 3 to 8 membered cycloalkyl, 4 to 8 membered hetero Cyclic group, -O-3 to 8-membered cycloalkyl group, -O-4 to 8-membered heterocycloalkyl group, said alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, cycloalkyl group, Heterocyclyl or heterocycloalkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , Substituents of C _1-4 alkyl, C _1-4 alkoxy, 4-7 membered heterocyclyl or C _3-6 cycloalkyl, the heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

In some embodiments, two R ^b together form a 3- to 12-membered carbocyclyl or a 4- to 12-membered heterocyclyl, and the carbocyclyl or heterocyclyl is optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-6 alkyl), -N(C _{1- 6} alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 (such as 1, 2, 3 or 4) selected from Heteroatoms of O, S, N;

In some embodiments, each R ^b is independently selected from H, oxo, halogen, cyano, C _1-4 alkyl, C _1-4 alkylthio, C _2-4 alkenyl, 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 heterocyclyl, said The alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl or heterocycloalkyl groups are optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4 ) is substituted by a substituent selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, and the heterocyclic or hetero Cycloalkyl contains 1 to 4 heteroatoms selected from O, S, N;

In some embodiments, two R ^b together form a 3-6 membered carbocyclyl or a 4-6 membered heterocyclyl, and the carbocyclyl or heterocyclyl is optionally further replaced by 0 to 4 one (eg 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 Substituted, the heterocyclic group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;

In some embodiments, each R ^b is independently selected from H, oxo, F, Cl, Br, I, cyano, OH, NH ₂ , methyl, ethyl, propyl, isopropyl, vinyl, propylene radical, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O -Cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, the methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy , propoxy, isopropoxy are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, oxo, CF _3. Substituents of COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

In some embodiments, each R ^b is independently selected from H, oxo, F, Cl, Br, I, cyano, OH, NH ₂ , methyl, ethyl, methoxy, ethoxy, propoxy , isopropoxy, cyclopropyl, -O-cyclopropyl, vinyl, ethynyl, the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, propoxy , isopropoxy, vinyl, ethynyl, cyclopropyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, Cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy or propoxy;

In some embodiments, R ^is selected from H, F, Cl, cyano, OH, _NH2 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, -O-cyclopropyl;

In some embodiments, L ₁ is selected from -O- and -O-CH ₂ -;

In some embodiments, R ¹ is selected from halogen, OH, cyano, COOH, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, 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 carbocycle, -(CH ₂ ) _q -3 to 12 membered heterocycle or -(CH ₂ ) _q -C _3-10 carbocycle, the CH ₂ , alkyl, Alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^1a , said heterocycle containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;

在一些实施方案中，R^1a各自独立地选自H、卤素、oxo、OH、氰基、CF₃、COOH、NH₂、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、C_1-6烷基、 C_2-6烯基、C_2-6炔基、-C_1-6亚烷基-OH、-(CH₂)_q-C_3-10碳环、-(CH₂)_q-3至12元杂环、-O-C_3-10碳环、-O-3至12元杂环、C_1-6烷氧基、-N(C_1-6烷基)C(＝O)-3至12元杂环的取代基所取代，所述的烷基、CH₂、烷氧基、烯基、炔基、亚烷基、碳环或杂环任选进一步被0至4个(例如0、1、 2、3或4个)选自H、卤素、OH、氰基、oxo、CF₃、COOH、NH₂、C_1-6烷基、C_1-6烷氧基、 C_3-6环烷基、3至6元杂环烷基的取代基所取代，所述的杂环或杂环烷基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子；In some embodiments, -L ₁ -R ₁ is selected from

In some embodiments, each R ^1a is independently selected from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 Alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _1-6 alkylene-OH, -(CH ₂ ) _q -C _3-10 carbocycle , -(CH ₂ ) _q -3 to 12-membered heterocycle, -OC _3-10 carbocycle, -O-3 to 12-membered heterocycle, C _1-6 alkoxy, -N(C _1-6 alkyl )C(=O)-substituted by a substituent of a 3- to 12-membered heterocycle, said alkyl, CH ₂ , alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle are optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 Substituents of alkoxy, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, said heterocycle or heterocycloalkyl contain 1 to 4 (for example 1, 2, 3 or 4 a) a heteroatom selected from O, S, N;

In some embodiments, each R ^1a is independently selected from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 Alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -C _1-4 alkylene-OH, -(CH ₂ ) _q -C _3-8 carbocycle , -(CH ₂ ) _q -3 to 8-membered heterocycle, -OC _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 substituents, said alkyl, CH ₂ , alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle are optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 Substituents of alkoxy, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, said heterocycle or heterocycloalkyl contain 1 to 4 (for example 1, 2, 3 or 4 a) a heteroatom selected from O, S, N;

In some embodiments, each R ^1a is independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, - O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, the methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy Base, propoxy, isopropoxy are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, oxo, Substituents of CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

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

In some embodiments, -L ₁ -R ₁ is selected from

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

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

_In some embodiments, L is selected from a bond;

In some embodiments, R is selected from C _1-6 alkyl, C _3-10 carbocyclyl, ³ to 10 membered heterocyclyl, C _6-10 aryl or 5 to 10 membered heteroaryl, said The alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl of is optionally further substituted by 0 to 7 (eg 0, 1, 2, 3, 4, 5, 6 or 7) R ^2a , the The heterocyclic group or heteroaryl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;

^In some embodiments, R is selected from C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the carbocyclyl, heterocyclic The radical, aryl or heteroaryl is optionally further substituted by 0 to 5 (eg 0, 1, 2, 3, 4 or 5) R ^2a , and the heterocyclyl or heteroaryl contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;

^In some embodiments, R is selected from substituted or unsubstituted one of the following groups: phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, iso Oxazolyl, imidazolyl, pyrazolyl, indazole, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuryl, benzopyrimidinyl, benzopyridyl or Pyridyl, when substituted, is optionally substituted by 0 to 5 (eg 0, 1, 2, 3, 4 or 5) R ^2a ;

^In some embodiments, R is selected from one of substituted or unsubstituted phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuryl, benzopyrazolyl, or naphthalene The group, when substituted, is optionally substituted by 0 to 5 (eg 0, 1, 2, 3, 4 or 5) R ^2a ;

^In some embodiments, R is selected from one of the following substituted groups: phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuryl, benzopyrazolyl, or naphthyl, when substituted , substituted by 1 to 5 (eg 1, 2, 3, 4 or 5) R ^2a , each R ^2a 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, the methyl, Ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl or cyclopentyl are optionally further replaced by 0 to 4 selected from H, F, Substituents of Cl, OH, methyl, ethyl or cyclopropyl, provided that at least one R ^2a is selected from cyclopropyl, cyclobutyl or cyclopentyl;

^In some embodiments, R is selected from phenyl, benzopyrazolyl, benzofuryl, pyridyl, said phenyl is substituted by 1 to 4 R ^2a , said benzopyrazolyl, Benzofuryl and pyridyl are substituted by 0 to 4 R ^2a ;

In some embodiments, each R ^2a is independently selected from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 Alkyl) ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, -OC _3-6 cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 aryl or 5 to 10 membered heteroaryl, the alkyl , alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4 ) is selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered hetero Substituents of cycloalkyl, said heterocycloalkyl, heterocyclyl or heteroaryl contain 1 to 4 (for example 1, 2, 3 or 4) heteroatoms selected from O, S, N ;

In some embodiments, each R ^2a is independently selected from -NHC(O)C _1-6 alkyl, -NHS(O) ₂ C _1-6 alkyl, -P(O)(C _1-6 alkyl ) ₂ , the alkyl group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , Substituents of C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, and 3 to 6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1 to 4 ( For example 1, 2, 3 or 4) heteroatoms selected from O, S, N;

In some embodiments, two R ^2a together form a 3- to 12-membered carbocyclyl or a 4- to 12-membered heterocyclyl, which is optionally further replaced by 0 to 4 one (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy Substituents are substituted, and the heterocyclic group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;

In some embodiments, each R ^2a is independently selected from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 Alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _2-4 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, -OC _3-6 cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 aryl or 5 to 10 membered heteroaryl, the alkyl , alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4 ) is selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3 to 6 membered hetero Substituents of cycloalkyl, said heterocycloalkyl, heterocyclyl or heteroaryl contain 1 to 4 (for example 1, 2, 3 or 4) heteroatoms selected from O, S, N ;

In some embodiments, each R ^2a is independently selected from -NHC(O)C _1-4 alkyl, -NHS(O) ₂ C _1-4 alkyl, -P(O)(C _1-4 alkyl ) ₂ , the alkyl group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , Substituents of C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, and 3 to 6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1 to 4 ( For example 1, 2, 3 or 4) heteroatoms selected from O, S, N;

In some embodiments, two R ^2a together form a 3 to 6 membered carbocyclyl or a 4 to 6 membered heterocyclyl, which is optionally further replaced by 0 to 4 one (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy Substituents are substituted, and the heterocyclic group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;

In some embodiments, each R ^2a is independently selected from H, F, Cl, Br, I, oxo, OH, NH ₂ , cyano, CF ₃ , -SCH ₃ , methyl, ethyl, propyl, iso Propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O -cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, the methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, Proynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further replaced by 0 to 4 (for example 0, 1, 2 , 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, Substituents of propoxy or isopropoxy;

In some embodiments, each R ^2a is independently selected from -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , -P(O)(CH ₃ ) ₂ , cyclopentenyl, phenyl, pyridine Azolyl, the -CH ₃ , cyclopentenyl, phenyl, pyrazolyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Substituents of Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

In some embodiments, two R ^2a together form a 3 to 6 membered carbocyclyl or a 4 to 6 membered heterocyclyl, which is optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, Substituted by a substituent of methoxy, ethoxy, propoxy or isopropoxy, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;

In some embodiments, each R ^2a is 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, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, Ethynyl, propynyl, cyclopropyl, cyclobutyl or cyclopentyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, OH, methyl, ethyl or cyclopropyl ;

In some embodiments, each R ^2a is independently selected from propenyl, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , -P(O)(CH ₃ ) ₂ , cyclopentenyl, benzene Base, pyrazolyl, the -CH ₃ , propenyl, cyclopentenyl, phenyl, pyrazolyl are optionally further selected from 0 to 4 selected from H, F, Cl, OH, methyl, ethyl or Cyclopropyl substituents are substituted;

In some embodiments, each R ^2a is 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, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropanyl Cyclobutyl, cyclopentyl, propenyl, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , -P(O)(CH ₃ ) ₂ , cyclopentenyl, phenyl, pyridine Azolyl is optionally further substituted by 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;

不为

m1选自0、1或2；Optionally, the condition is

not for

m1 is selected from 0, 1 or 2;

或

Optionally, with the proviso that the compound is not

or

As the first embodiment of the present invention, the compound represented by the aforementioned general formula (I-a) or its stereoisomer, deuterated substance, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,

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

Ring A is selected from 3 to 12 membered carbocyclic groups or 4 to 12 membered heterocyclic groups, said carbocyclic group or heterocyclic group is optionally further substituted by 0 to 6 R ^a , and said heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;

Ring B is 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 by 0 to 7 R ^b , said heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;

R ^a is each independently selected from H, oxo, halogen, cyano, OH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl , 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 The alkyl, alkoxy, cycloalkyl, and heterocyclic groups are optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C Substituted by _1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;

R ^b are each independently selected from H, oxo, halogen, cyano, OH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl , C _1-6 alkylthio, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, 3 to 8 membered cycloalkyl, 4 to 8 membered heterocyclic group, -O- 3 to 8-membered cycloalkyl, -O-4 to 8-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl or heterocyclic Alkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 4-7 member Substituents of heterocyclyl or C _3-6 cycloalkyl, said heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

Or two R ^a or two R ^b together form a 3 to 12 membered carbocyclic group or a 4 to 12 membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally further replaced by 0 to 4 one selected from H, halogen, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-4 alkyl or Substituted by C _1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;

L ₁ , L ₂ or L ₃ are each independently selected from a bond, O, -CH ₂ -, -OCH ₂ -, -CH ₂ O-, -C(=O)-, S or NR ^x ;

R ^{x is} selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, oxo , CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents;

R ¹ is selected from halogen, OH, cyano, COOH, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, 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 carbocycle, -(CH ₂ ) _q -3 to 12-membered heterocycle or -(CH ₂ ) _q -C _3-10 carbocycle, the CH ₂ , alkyl, alkenyl, alkynyl, Alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 R ^1a , said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

Each R ^1a is independently selected from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _1-6 alkylene-OH, -(CH ₂ ) _q -C _3-10 carbocycle, -(CH ₂ ) _q -3 to 12-membered heterocycle, -OC _3-10 carbocycle, -O-3 to 12-membered heterocycle, C _1-6 alkoxy, -N(C _1-6 alkyl)C(=O) -substituted by a substituent of a 3- to 12-membered heterocycle, said alkyl, CH ₂ , alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle is optionally further selected from 0 to 4 From H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkane The substituent of the group is substituted, and the heterocycle or heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, N;

R is selected from C ^1-6 _alkyl , C _3-10 carbocyclyl, 3-10 membered heterocyclic group, C _6-10 aryl or 5-10 membered heteroaryl, the alkyl, carbocyclic Base, heterocyclyl, aryl or heteroaryl are optionally further substituted by 0 to 7 R ^2a , said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

R ^2a are each independently selected from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycle Alkyl, -OC _3-6 cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 aryl or 5 to 10 membered heteroaryl, said alkyl, alkoxy, alkane Thio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally further selected from 0 to 4 selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, Substituents of NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, said heterocycloalkyl, heterocycle radical or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N; or

R ^2a are each independently selected from -NHC(O)C _1-6 alkyl, -NHS(O) ₂ C _1-6 alkyl, -P(O)(C _1-6 alkyl) ₂ , the Alkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 Cycloalkyl, 3 to 6-membered heterocycloalkyl substituents, the heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N;

Or two R ^2a and the atoms directly connected together form a 3 to 12-membered carbocyclic group or a 4 to 12-membered heterocyclic group, and the described carbocyclic group or heterocyclic group is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from Heteroatoms of O, S, N;

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

As the second embodiment of the present invention, the compound represented by the following general formula (I-aa) or its stereoisomer, deuterium, N-oxide, solvate, prodrug, metabolite, pharmaceutically available Accepted salts or co-crystals,

选自4至12元含氮杂环，所述的含氮杂环选自饱和或部分饱和的如下基团之一：单环、并环、桥环或螺环，所述的含氮杂环、单环、并环、桥环或螺环任选进一步被0 至4个R^a取代，环A₁中N-H不被取代；

Selected from 4 to 12 membered nitrogen-containing heterocyclic rings, the nitrogen-containing heterocyclic rings are selected from one of the following saturated or partially saturated groups: monocyclic, parallel rings, bridged rings or spiro rings, and the nitrogen-containing heterocyclic rings , monocyclic ring, parallel ring, bridging ring or spiro ring are optionally further substituted by 0 to ₄ R, and NH in ring ^A is not substituted;

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

不为

m1选自0、1或2；requirement is

not for

m1 is selected from 0, 1 or 2;

provided that the compound is not

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

As the third embodiment of the present invention, the compound represented by the aforementioned general formula (I-aa) or its stereoisomer, deuterated substance, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,

选自未被取代的或者取代的如下基团之一：

当被取代时，任选进一步被0至4个R^a取代基所取代，环A₁中N-H不被取代；

One of the following unsubstituted or substituted groups:

When substituted, optionally further substituted by 0 to ₄ R substituents, NH in ring ^A is not substituted;

选自

其左边与L₂连接，上方与环A₁连接；

selected from

Its left side is connected with L ₂ , and its upper part is connected with ring A ₁ ;

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 the fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I-aa) or its stereoisomer, deuterated substance, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,

选自

selected from

选自

其左边与L₂连接，上方与环A₁连接；

selected from

Its left side is connected with L ₂ , and its upper part is connected with ring A ₁ ;

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

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

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

L is 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, the carbocyclyl, heterocyclyl, aryl or heterocyclyl The aryl is optionally further substituted by 0 to 5 R ^2a , and the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;

R ^2a are each independently selected from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _2-4 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 6 membered heterocycle Alkyl, -OC _3-6 cycloalkyl, -O-3 to 6 membered heterocycloalkyl, C _6-10 aryl or 5 to 10 membered heteroaryl, said alkyl, alkoxy, alkane Thio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally further selected from 0 to 4 selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, Substituents of NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, the heterocycloalkyl, heterocycle radical or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N; or

R ^2a are each independently selected from -NHC(O)C _1-4 alkyl, -NHS(O) ₂ C _1-4 alkyl, -P(O)(C _1-4 alkyl) ₂ , the Alkyl is optionally further replaced by 0 to 4 members selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 Cycloalkyl, 3 to 6-membered heterocycloalkyl substituents, the heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N;

Or two R ^2a together form a 3 to 6-membered carbocyclyl or a 4 to 6-membered heterocyclic group, and the carbocyclyl or heterocyclic group is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from Heteroatoms of O, S, N;

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

As the sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I-aa) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal ,

R ^b are each independently selected from H, oxo, halogen, cyano, C _1-4 alkyl, C _1-4 alkylthio, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkane Oxygen, 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 are optionally further selected from 0 to 4 selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, Substituents of NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, the heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

Or two R ^b and the atoms to which they are connected jointly form a 3-6 membered carbocyclic group or a 4-6 membered heterocyclic group, and the described carbocyclic group or heterocyclic group is optionally further replaced by 0 to 4 members selected from H, Halogen, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms;

Each R ^1a is independently selected from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -C _1-4 alkylene-OH, -(CH ₂ ) _q -C _3-8 carbocycle, -(CH ₂ ) _q -3 to 8-membered heterocycle, -OC _3-8 carbocycle, -O-3 to 8-membered heterocycle, C _1-4 alkoxy, -N(C _1-4 alkyl)C(=O) -substituted by a substituent of a 3- to 8-membered heterocycle, said alkyl, CH ₂ , alkoxy, alkenyl, alkynyl, alkylene, carbocycle or heterocycle is optionally further selected from 0 to 4 From H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkane The substituent of the group is substituted, and the heterocycle or heterocycloalkyl group contains 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 the first, second, third, fourth or fifth embodiment of the present invention.

As the seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I-aa) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal ,

R is selected from one of substituted or unsubstituted following 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 by 0 to 5 R ^2a ;

R ^2a are each independently selected from H, F, Cl, Br, I, oxo, OH, NH ₂ , cyano, CF ₃ , -SCH ₃ , methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, - O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy Base, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further selected from 0 to 4 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 are each independently selected from -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , -P(O)(CH ₃ ) ₂ , cyclopentenyl, phenyl, pyrazolyl, and the -CH ₃ , cyclopentenyl, phenyl, pyrazolyl are optionally further replaced by 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , Substituents of methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy;

Or two R ^2a together form a 3 to 6-membered carbocyclyl or a 4 to 6-membered heterocyclic group, and the carbocyclyl or heterocyclic group is optionally further replaced by 0 to 4 members selected from H, Substitution by F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy Substituted by a group, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;

R ^b are each independently selected from H, oxo, F, Cl, Br, I, cyano, OH, NH ₂ , methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propane Alkynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, - O-cyclopentyl, -O-cyclohexyl, the methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, iso Propoxy is optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy , ethoxy, propoxy or isopropoxy substituents;

Each R ^1a is independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, the methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, Isopropoxy is optionally further replaced by 0 to 4 members selected from H, F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy Substituents of ethoxy, propoxy or isopropoxy;

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

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

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

R ^b are 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, the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, propoxy, isopropoxy, Vinyl, ethynyl, and cyclopropyl are optionally further replaced by 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, Propyl, methoxy, ethoxy or propoxy;

R ^is selected from one of substituted or unsubstituted phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuryl, benzopyrazolyl or naphthyl, when substituted , optionally substituted by 0 to 5 R ^2a ;

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

R ^2a are each independently selected from propenyl, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , -P(O)(CH ₃ ) ₂ , cyclopentenyl, phenyl, pyrazolyl, The -CH ₃ , propenyl, cyclopentenyl, phenyl, pyrazolyl are optionally further substituted by 0 to 4 substituents selected from H, F, Cl, OH, methyl, ethyl or cyclopropyl replaced by

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

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

R ^b is selected from H, F, Cl, cyano, OH, NH ₂ , methyl, ethyl, methoxy, ethoxy, cyclopropyl, -O-cyclopropyl;

R ^is selected from one of substituted or unsubstituted phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuryl, benzopyrazolyl or naphthyl, when substituted , optionally substituted by 0 to 5 R ^2a ;

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

R ^2a are each independently selected from propenyl, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , -P(O)(CH ₃ ) ₂ , cyclopentenyl, phenyl, pyrazolyl, The -CH ₃ , propenyl, cyclopentenyl, phenyl, pyrazolyl are optionally further replaced by 0 to 4 substituents selected from H, F, Cl, OH, methyl, ethyl or cyclopropyl replaced.

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

R ² is selected from phenyl, benzopyrazolyl, benzofuryl, pyridyl, the phenyl is substituted by 1 to 4 R ^2a , and the benzopyrazolyl, benzofuryl, pyridine The group is substituted by 0 to 4 R ^2a ;

R ^2a are 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 are optionally further 0 to 4 substituents selected from H, F, Cl, OH, methyl, ethyl or cyclopropyl.

As the eleventh embodiment of the present invention, the compound represented by the following general formula (I-aaaa) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,

R ^b is selected from H, F, Cl, cyano, OH, NH ₂ , methyl, ethyl, methoxy, ethoxy, cyclopropyl, -O-cyclopropyl;

R is selected from one of the following substituted groups: phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuryl, benzopyrazolyl or naphthyl, when substituted, by ¹ to 5 R ^2a replaces;

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

with the proviso that at least one ^R2a is selected from cyclopropyl, cyclobutyl or cyclopentyl.

As the twelfth embodiment of the present invention, the compound represented by the following general formula (I-c) or (I-d) or its stereoisomer, deuterium, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,

R ^b is selected from H, F, Cl, cyano, OH, NH ₂ , methyl, ethyl, methoxy, ethoxy, cyclopropyl, -O-cyclopropyl;

R ^is selected from one of substituted or unsubstituted phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuryl, benzopyrazolyl or naphthyl, when substituted , optionally substituted by 0 to 5 R ^2a ;

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

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

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), X ₁ or X ₂ are each independently selected from N or CR ^b .

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), X ₁ , X ₂ are selected from N.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), X ₁ , X ₂ are selected from CR ^b .

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), X ₁ is selected from N, X ₂ is selected from CR ^b .

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), X ₁ is selected from CR ^b , and X ₂ is selected from N.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), ring A is selected from 3 to 12 membered carbocyclic groups or 4 to 12 membered heterocyclic groups, and the carbon The cyclic or heterocyclic group is optionally further substituted by 0 to 6 R ^a , and the heterocyclic group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N .

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), L ₁ , L ₂ or L ₃ are each independently selected from a bond, O, -CH ₂ -, -OCH ₂ -, -CH ₂ O-, -C(=O)-, S or NR ^x .

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), R ^{x is} selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, said Alkyl or cycloalkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _{1 -4} alkyl or C _1-4 alkoxy substituents.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), L ₃ is selected from a bond.

选自

In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from

选自4至12元含氮杂环，所述的含氮杂环选自饱和或部分饱和的如下基团之一：单环、并环、桥环或螺环，所述的含氮杂环、单环、并环、桥环或螺环任选进一步被0至4个(例如0、1、2、3或4个)R^a取代，环A₁中N-H不被取代。In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

Selected from 4 to 12 membered nitrogen-containing heterocyclic rings, the nitrogen-containing heterocyclic rings are selected from one of the following saturated or partially saturated groups: monocyclic, parallel rings, bridged rings or spiro rings, and the nitrogen-containing heterocyclic rings , monocyclic ring, parallel ring, bridging ring or spiro ring are optionally further substituted by 0 to 4 (for example 0, 1, 2, 3 or 4) R ^a , and NH in ring _A is not substituted.

选自未被取代的或者取代的如下基团之一：

当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)R^a取代基所取代，环A₁中N-H不被取代。In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

One of the following unsubstituted or substituted groups:

When substituted, optionally further substituted by 0 to 4 (eg 0, ₁ , 2, 3 or 4) R substituents, NH in ring ^A is unsubstituted.

选自未被取代的或者取代的

当被取代时，任选进一步被0至4个(例如0、1、2、3或4 个)R^a取代基所取代，环A₁中N-H不被取代。In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from unsubstituted or substituted

When substituted, optionally further substituted by 0 to 4 (eg 0, ₁ , 2, 3 or 4) R substituents, NH in ring ^A is unsubstituted.

选自

In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), R ^a each independently selected from H, oxo, halogen, cyano, OH, NH ₂ , -NH( C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 alkoxy, 3 to 8 membered cycloalkyl, 4 to 8 membered heterocyclic group , -O-3 to 8-membered cycloalkyl, -O-4 to 8-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, and heterocyclyl are optionally further replaced by 0 to 4 ( For example, 0, 1, 2, 3 or 4) are substituted by substituents selected from H, halogen, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy , the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), R ^a each independently selected from H, oxo, halogen, cyano, C _1-4 alkyl, 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 alkane radical, alkoxy, cycloalkyl, heterocyclyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, CF ₃ , COOH, Substituted by NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N.

The present invention relates to some embodiments of general formula (Ia), (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, the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, iso Propoxy is optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , formazan Substituents of radical, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), 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, the methyl, ethyl, propyl, methyl Oxygen, ethoxy, propoxy, propoxy, isopropoxy, cyclopropyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) 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 general formula (Ia), (I-aa), (I-aaa), R ^a is each independently selected from H.

The present invention relates to some embodiments of the general formula (Ia), (I-aa), (I-aaa), two R ^a together form a 3 to 12 membered carbocyclyl or a 4 to 12 membered hetero Cyclic group, the carbocyclyl or heterocyclic group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, CF ₃ , COOH, Substituents of NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy, the hetero Cyclic groups contain 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formula (Ia), (I-aa), (I-aaa), two R ^a and the atoms to which they are connected together form a 3 to 6 membered carbocyclyl or a 4 to 6 membered heterocyclyl Cyclic group, the carbocyclyl or heterocyclic group is optionally further replaced by 0 to 4 selected from H, halogen, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _{1- 4} alkoxy substituents, the heterocyclic group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), ring B ₁ is selected from 3 to 8 membered carbocyclyl, 5 to 7 membered heterocyclyl, 5 to 6 Member heteroaryl or phenyl, said carbocyclyl, heterocyclyl, heteroaryl or phenyl is optionally further replaced by 0 to 7 (such as 0, 1, 2, 3, 4, 5, 6, 7 ) R ^b is substituted, and the heterocyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N.

选自

其左边与L₂连接，上方与环A₁连接。In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from

It is connected to L ₂ on the left and ring A ₁ above.

选自

其左边与L₂连接，上方与环A₁连接。In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from

It is connected to L ₂ on the left and ring A ₁ above.

选自

其左边与L₂连接，上方与环A₁连接。In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from

It is connected to L ₂ on the left and ring A ₁ above.

选自

其左边与L₂连接，上方与环A₁连接。In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from

It is connected to L ₂ on the left and ring A ₁ above.

选自

其左边与L₂连接，上方与环A₁连接；In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from

Its left side is connected with L ₂ , and its upper part is connected with ring A ₁ ;

选自

其左边与L₂连接，上方与环A₁连接。In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from

It is connected to L ₂ on the left and ring A ₁ above.

选自

其左边与L₂连接，上方与环A₁连接。In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from

It is connected to L ₂ on the left and ring A ₁ above.

选自

其左边与L₂连接，上方与环A₁连接。本发明涉及通式(I-a)、(I-aa)、(I-aaa)、(I-aaaa)、(I-c)的一些实施方案中，R^b各自独立的选自H、oxo、卤素、氰基、OH、NH₂、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、C_1-6烷基、C_1-6烷硫基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、3至8元环烷基、4至8元杂环基、-O-3至8元环烷基、-O-4至8元杂环烷基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、杂环基或杂环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、卤素、OH、氰基、oxo、CF₃、COOH、NH₂、C_1-4烷基、C_1-4烷氧基、4-7元杂环基或C_3-6环烷基的取代基所取代，所述的杂环基或杂环烷基含有1至4个选自O、S、N的杂原子。In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa),

selected from

It is connected to L ₂ on the left and ring A ₁ above. The present invention relates to some embodiments of the general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ic), R ^b each independently selected from H, oxo, halogen, cyanide radical, OH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 alkylthio, C _2-6 alkene Base, 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 are optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 4-7 membered hetero Substituents of cyclic group or C _3-6 cycloalkyl group, said heterocyclic group or heterocycloalkyl group contain 1 to 4 heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ic), two R ^b together form 3 to 12 A membered carbocyclic group or a 4- to 12-membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy The substituent is substituted, and the heterocyclic group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ic), R ^b each independently selected from H, oxo, halogen, cyanide C _1-4 alkyl, C _1-4 alkylthio, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, 3 to 6 membered cycloalkyl, 4 to 6 Heterocyclyl, -O-3 to 6-membered cycloalkyl, -O-4 to 6-membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkane The group, heterocyclyl or heterocycloalkyl is optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH _2. Substituents of C _1-4 alkyl or C _1-4 alkoxy.

The present invention relates to some embodiments of the general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ic), two R ^b together form 3 to 6 A membered carbocyclyl or a 4 to 6 membered heterocyclic group, said carbocyclyl or heterocyclic group is optionally further selected from 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 (such as 1, 2, 3 or 4) heteroatoms selected from O, S, and N, and the heterocyclic group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ic), R ^b each independently selected from H, oxo, F, Cl , Br, I, cyano, OH, NH ₂ , methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy , isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, the The methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy groups are optionally further replaced by 0 to 4 (for example 0 , 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy, Substituents of ethoxy, propoxy or isopropoxy.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ic), 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, the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, propoxy, isopropoxy, vinyl, ethynyl, cyclopropyl are optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propane Substituted by radical, methoxy, ethoxy or propoxy.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ic), R ^b is selected from H, F, Cl, cyano, OH , NH ₂ , methyl, ethyl, methoxy, ethoxy, cyclopropyl, -O-cyclopropyl.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), L ₁ is selected from -O- and -O-CH ₂ -.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), R ¹ is selected from halogen, OH, cyano, COOH, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, 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 carbocycle, -(CH ₂ ) _q -3 to 12-membered heterocycle or -(CH ₂ ) _q -C _3-10 carbocycle, said CH ₂ , alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle is optionally further replaced by 0 to 4 (for example 0, 1, 2 , 3 or 4) R ^1a is substituted, and the heterocyclic ring contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa), -L ₁ -R ₁ is selected from

The present invention relates to some embodiments of the general formula (Ia), (I-aa), (I-aaa), each R ^1a is independently selected from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH _2. -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _{1- 6} alkylene-OH, -(CH ₂ ) _q -C _3-10 carbocycle, -(CH ₂ ) _q -3 to 12 membered heterocycle, -OC _3-10 carbocycle, -O-3 to 12 membered Heterocyclic, C _1-6 alkoxy, -N(C _1-6 alkyl)C(=O)-3 to 12-membered heterocyclic substituents, the alkyl, CH ₂ , alkoxy Base, alkenyl, alkynyl, alkylene, carbocycle or heterocycle are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo , CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, the hetero A ring or heterocycloalkyl group contains 1 to 4 (eg 1 , 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formula (Ia), (I-aa), (I-aaa), each R ^1a is independently selected from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH _2. -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -C _{1- 4} alkylene-OH, -(CH ₂ ) _q -C _3-8 carbocycle, -(CH ₂ ) _q -3 to 8 membered heterocycle, -OC _3-8 carbocycle, -O-3 to 8 membered Heterocyclic, C _1-4 alkoxy, -N(C _1-4 alkyl)C(=O)-3 to 8-membered heterocyclic substituents, the alkyl, CH ₂ , alkoxy Base, alkenyl, alkynyl, alkylene, carbocycle or heterocycle are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo , CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, the hetero A ring or heterocycloalkyl group contains 1 to 4 (eg 1 , 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (Ia), (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, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, the methyl, ethyl, propyl , vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy are optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4 ) is selected from H, F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, propoxy or iso Propoxy substituents are substituted.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), the present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa) Among them, R ^1a is selected from F.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), the present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa) Among them, -L ₁ -R ₁ is selected from

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), L2 is selected from a bond, O or _-C (=O)-.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), L2 is selected from a bond or _-C (=O)-.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I _- aaa), L2 is selected from a bond.

In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), R ² is selected from C _{1 -6} alkyl, C _3-10 carbocyclyl, 3 to 10 membered heterocyclic group, C _6-10 aryl or 5 to 10 membered heteroaryl, the alkyl, carbocyclyl, heterocyclic group, Aryl or heteroaryl is optionally further substituted by 0 to 4 (for example 0, 1, 2, 3 or 4) R ^2a , and said heterocyclyl or heteroaryl contains 1 to 4 (for example 1, 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (Ib), (Ic), (Id), R ² is selected from C _3-10 carbocyclyl, 3 to 10 membered heterocyclic group, C _6-10 aryl group or 5 to 10 membered heteroaryl group, said carbocyclic group, heterocyclic group, aryl group or heteroaryl group are optionally further replaced by 0 to 7 (for example 0, 1, 2, 3, 4, 5, 6 or 7) R ^2a is substituted, and the heterocyclyl or heteroaryl contains 1 to 4 (such as 1, 2, 3 or 4) selected from O , S, N heteroatoms.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (Ib), (Ic), (Id), R ² is selected from substituted or unsubstituted as follows One of the 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 replaced by 0 to 5 (eg 0 , 1, 2, 3, 4 or 5) R ^2a is substituted.

In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id ⁾ , R is selected from substituted Or unsubstituted one of the following groups: phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuryl, benzopyrazolyl or naphthyl, when substituted, optionally by 0 to 5 (eg 0, 1, 2, 3, 4 or 5) R ^2a substitutions.

In some embodiments of the present invention related to general formula (Ia), (I-aa), (I-aaa), (I ^- aaaa, (Ib), (Ic), (Id), R is selected from phenyl, Benzopyrazolyl, benzofuryl, pyridyl, the phenyl is substituted by 1 to 4 R ^2a , and the benzopyrazolyl, benzofuryl, pyridyl are 0 to 4 R ^2a replaces;

The present invention relates to some embodiments of general ^formula (Ia), (I-aa), (I-aaa), (I-aaaa, (Ib), (Ic), (Id), R is selected from the following substituted One of the groups: phenyl, pyridine, benzothiazolyl, benzothienyl, benzofuryl, benzopyrazolyl or naphthyl, when substituted, is substituted by 1 to 5 R ^2a , R ^2a 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, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclo Propyl, cyclobutyl or cyclopentyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, OH, methyl, ethyl or cyclopropyl, provided that there is at least one ^R selected from cyclopropyl, cyclobutyl or cyclopentyl.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), R ^2a each independently selected from from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, -OC _{3 -6} cycloalkyl, -O-3 to 6-membered heterocycloalkyl, C _6-10 aryl or 5 to 10-membered heteroaryl, the alkyl, alkoxy, alkylthio, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, said A heterocycloalkyl, heterocyclyl or heteroaryl group contains 1 to 4 (eg 1 , 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), R ^2a each independently selected from From -NHC(O)C _1-6 alkyl, -NHS(O) ₂ C _1-6 alkyl, -P(O)(C _1-6 alkyl) ₂ , the alkyl is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkane Oxygen, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl substituents, the heterocycloalkyl contains 1 to 4 (such as 1, 2, 3 or 4) selected from O, S, N heteroatoms.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), R ^2a each independently selected from 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, benzene Base, pyrazolyl, the 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 are optionally further selected from 0 to 4 Substituents of H, F, Cl, OH, methyl, ethyl or cyclopropyl.

The present invention relates to some embodiments of the general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), two R ^2a are directly related to The atoms connected together form 3 to 12 membered carbocyclic groups or 4 to 12 membered heterocyclic groups, and the described carbocyclic group or heterocyclic group is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4 Each) is substituted by a substituent selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, and the heterocyclic group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), R ^2a each independently selected from from H, halogen, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _2-4 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, -OC _{3 -6} cycloalkyl, -O-3 to 6-membered heterocycloalkyl, C _6-10 aryl or 5 to 10-membered heteroaryl, the alkyl, alkoxy, alkylthio, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said A heterocycloalkyl, heterocyclyl or heteroaryl group contains 1 to 4 (eg 1 , 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (Ia) and (I-aa), R ^2a are each independently selected from -NHC(O)C _1-4 alkyl, -NHS(O) ₂ C _1-4 alkane group, -P(O)(C _1-4 alkyl) ₂ , the alkyl group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH , cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the heterocycloalkyl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of the general formulas (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), two R ^2a corresponding to The atoms connected together form a 3-6 membered carbocyclyl or a 4-6 membered heterocyclyl, and said carbocyclyl or heterocyclyl is optionally further replaced by 0 to 4 (for example 0, 1, 2, 3 or 4 Each) is substituted by a substituent selected from H, halogen, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, and the heterocyclic group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), R ^2a each independently selected from From H, F, Cl, Br, I, oxo, OH, NH ₂ , cyano, CF ₃ , -SCH ₃ , methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, the methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, Propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Substituents of Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy replace.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), R ^2a each independently selected from From -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , -P(O)(CH ₃ ) ₂ , cyclopentenyl, phenyl, pyrazolyl, the -CH ₃ , cyclopentyl Alkenyl, phenyl, pyrazolyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, oxo, CF _3. Substituents of COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy.

The present invention relates to some embodiments of the general formulas (Ia), (I-aa), (I-aaa), (Ib), (Ic), (Id), two R ^2a and the atoms to which they are connected together form 3 to 6-membered carbocyclyl or 4 to 6-membered heterocyclyl, and said carbocyclyl or heterocyclyl is optionally further selected from 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, Substitution by F, Cl, Br, I, OH, cyano, oxo, CF ₃ , COOH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, propoxy or isopropoxy base replaced.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), R ^2a each independently selected from From H, F, Cl, OH, cyano, NH ₂ , CF ₃ , OCF ₃ , -SCH ₃ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propane Alkynyl, cyclopropyl, cyclopentyl or cyclohexyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclopentyl The radical or cyclohexyl is 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 general formula (Ia), (I-aa), (I-aaa), (I-aaaa), (Ib), (Ic), (Id), R ^2a each independently selected from From propenyl, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , -P(O)(CH ₃ ) ₂ , cyclopentenyl, phenyl, pyrazolyl, the -CH ₃ , Propyl, cyclopentenyl, phenyl, pyrazolyl are optionally further selected from 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, OH, methyl, ethyl Or substituted by a cyclopropyl substituent.

The present invention relates to some embodiments of general formula (I-a), (I-aa), (I-aaa), q is each independently selected from 0, 1, 2, 3 or 4.

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

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

不为

m1选自0、1或2。The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), with the proviso that

not for

m1 is selected from 0, 1 or 2.

The present invention relates to some embodiments of general formula (Ia), (I-aa), (I-aaa), with the proviso that the compound is not

The present invention relates to a pharmaceutical composition, comprising the compound of the present invention or its stereoisomer, deuterated substance, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, And to be academically acceptable carrier.

The present invention relates to a compound or its stereoisomer, deuterium, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal used in the preparation of therapeutically related KRAS activity or expression level Drug application in related diseases.

The present invention relates to a compound or its stereoisomer, deuterium, N-oxide, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal for use in the preparation of a treatment with KRAS G12D activity or Application in medicine for diseases related to expression level, wherein the diseases are selected from tumors.

Unless stated otherwise, 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, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include ¹² C, ¹³ C and ¹⁴ C, and the isotopes of hydrogen include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes include ¹⁴ N and ¹⁵ N, the isotopes of fluorine include ¹⁷ F and ¹⁹ F, the isotopes of chlorine include ³⁵ Cl and ³⁷ Cl, and the isotopes of bromine include ⁷⁹ Br and ⁸¹ Br.

"Halogen" means F, Cl, Br or I.

"Halogen substituted" refers to F, Cl, Br or I substitution, 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 substituted by a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted" is simply referred to as "halo".

"Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to an alkyl group of 1 to 20 carbon atoms, an alkyl group of 1 to 8 carbon atoms, an alkyl group of 1 to 6 An alkyl group of carbon atoms, an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched chain isomers; Alkyl group appearing in this article, its definition is consistent with this definition. Alkyl groups can be monovalent, divalent, trivalent or tetravalent.

"Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) replace. Non-limiting examples include -X(CH ₂ )vX(CH ₂ )vX(CH ₂ )vH (v is an integer from 1 to 5, each of X is independently selected from a bond or a heteroatom, and the heteroatom includes but is not limited to N , O or S, and at least one X is selected from heteroatoms, and N or S in heteroatoms can be oxidized into various oxidation states). Heteroalkyl groups can be monovalent, divalent, trivalent or tetravalent.

"Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH ₂ ) _v - (v is an integer from 1 to 10), examples of alkylene include but not Limited to methylene, ethylene, propylene and butylene, etc.

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

"Cycloalkyl" means a substituted or unsubstituted saturated or unsaturated non-aromatic carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl , cyclopentenyl, cyclohexenyl, cyclohexyl or cycloheptyl, etc. As used herein, cycloalkyl is as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 atoms selected from N, O or The heteroatoms of S, the selectively substituted N and S in the ring of heterocycloalkyl can be oxidized into various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include ring Oxyethyl, aziridyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent

"Alkenyl" refers to a substituted or unsubstituted straight chain and branched unsaturated hydrocarbon group, which has at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain includes but is not limited to 2 to 10 1, 2 to 6, or 2 to 4 carbon atoms, alkenyl examples 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-1-but Alkenyl, 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-octene base, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-Hexadiene, etc.; alkenyl groups appearing in this text have the same definition as this one. Alkenyl groups can be monovalent, divalent, trivalent or tetravalent.

"Alkynyl" means a substituted or unsubstituted straight and branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain comprising 2 to 10 Carbon atoms, including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain, alkynyl examples include but 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-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 Base, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be a valence, divalent, trivalent or quadrivalent.

"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-hexyloxy, cyclopropyl Oxygen and Cyclobutoxy.

“碳环基”或“碳环”可以是一价、二价、三价或四价。"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered Bicyclic or 10- to 15-membered tricyclic ring system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring is optionally a monocyclic, bridged or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclo Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,

A "carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

“杂环基”或“杂环”可以是一价、二价、三价或四价。"Heterocyclic group" or "heterocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, the aromatic ring or non-aromatic ring can be 3 to 8 membered single ring, 4 to 12 membered A bicyclic ring or a 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, and the ring of the heterocyclyl group is selected from Sexually substituted N and S can be oxidized into various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane , aziridyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyryl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorph Linyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl Base, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl , benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azadi Cyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl alkyl,

A "heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spiro ring" or "spirocyclic group" refers to a polycyclic group that shares one atom (called spiro atom) between substituted or unsubstituted monocyclic rings. The number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any Optional may contain 0 to 5 heteroatoms selected from N, O or S(=O) _n .

“螺环”或“螺环基”可以是一价、二价、三价或四价。

A "spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

“并环”或“并环基”可以是一价、二价、三价或四价。"Acyl ring" or "annyl 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 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 ring system may contain from 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to be selected from N, S(=O) _n or O, n being 0, 1 or 2). The number of ring atoms in the double ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

"Alkyl" or "alkyl" may be monovalent, divalent, trivalent or tetravalent.

立方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, may contain 0 or more double bonds, and any ring in the ring system It may contain 0 to 5 groups selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, wherein 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, adamantane. A "bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

"Carbospiro", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" whose ring system consists only of carbon atoms. The definitions of "carbospirocycle", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing herein are consistent with spirocycle.

"Carbocyclic", "paracyclic carbocyclyl", "paracarbocyclyl" or "carbocyclyl" refers to a "carbocyclyl" whose ring system consists only of carbon atoms. The definition of "carbocyclyl", "paracyclic carbocyclyl", "paracarbocyclyl" or "carbocyclyl" used herein is consistent with that of paracyclyl.

"Carbobridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged cycloyl" refers to a "bridged ring" whose ring system consists only of carbon atoms. The definitions of "carbon bridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged ring" appearing in this article are consistent with those of bridged ring.

"Heterocyclic group", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to the "heterocyclic group" or "heterocyclic group" of a monocyclic ring system, and the heterocyclic group, "monocyclic heterocyclic group" appearing herein group" or "heteromonocyclic group", the definition of which is consistent with that of heterocycle.

"Heterocyclyl", "heterocyclyl", "heterocyclic heterocyclyl" or "heterocyclyl" refers to "heterocycles" that contain heteroatoms. The definition of heterocyclic ring, "heterocyclic group", "heterocyclic heterocyclic group" or "heterocyclic group" used herein is consistent with that of parallel ring.

"Heterospiro", "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" that contains heteroatoms. As used herein, heterospirocycle, "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" have the same definition as spirocycle.

"Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "heterobridged ring group" refers to a "bridged ring" that contains heteroatoms. The definition of heterobridged ring, "heterobridged ring group", "bridged ring heterocyclyl group" or "heterobridged ring group" used herein is consistent with bridged ring.

“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a single ring or a condensed ring, and the number of ring atoms in the aromatic ring includes but is 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, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples include benzene, naphthalene,

"Aryl" or "aromatic ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于杂芳基环上。"Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 selected heteroatoms or groups containing heteroatoms (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 include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples include

Where heteroaryl appears herein, its definition is consistent with this definition. Heteroaryl groups can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the heteroaryl ring.

"5-membered ring and 5-membered heteroaromatic ring" refers to a 5-membered condensed heteroaromatic ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, and non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolopyrrole ring, pyrazolofuran ring, pyrrolothiophene ring, pyrazolothiophene ring.

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

"Substituted" or "substituted" means substituted by 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, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl, 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 -ene -R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR ^b R ^c Such groups, wherein R ^b and R ^c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethane Sulfonyl, as an option, R ^b and R ^c can form a five- or six-membered cycloalkyl or heterocyclic group.

"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 by 0 to X substituents" means substituted by 0, 1, 2, 3...X substituents, X is selected from any integer between 1 and 10. For example, "substituted by 0 to 4 substituents" means substituted by 0, 1, 2, 3 or 4 substituents. For example, "substituted by 0 to 5 substituents" means substituted by 0, 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally further substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H or F base replaced.

X-Y-membered rings (X is selected from integers less than Y and greater than 3, Y is selected from any integer between 4 and 12) include X+1, X+2, X+3, X+4...Y-membered rings. Rings include heterocycles, carbocycles, aryls, aryls, heteroaryls, cycloalkyls, heteromonocycles, heteroheterocycles, heterospirocycles or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to 5-, 6-, 7-, and 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.

"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 occur. For example: "Alkyl optionally substituted by F" means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention maintains the biological effectiveness and characteristics of free acid or free base, and the free acid is mixed with a non-toxic inorganic base or Organic base, the salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.

"Pharmaceutical composition" refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of co-crystals and other chemical components, wherein "other chemical components" refer to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.

"Carrier" refers to a material that does not produce significant irritation to an organism and that 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 the 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 agents and disintegrants.

"Prodrug" refers to a compound of the present invention that can be transformed into a biologically active compound through in vivo metabolism. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups of the compounds of the present invention, which modifications can be removed by routine manipulation or in vivo to obtain the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

"Co-crystal" refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonding or other non-covalent bonds, wherein the pure state of API and CCF are both solid, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal, including both a binary co-crystal formed between two neutral solids and a multi-element 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 domestic animals, preferably humans, horses or dogs.

"Stereoisomer" refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

"Tautomer" refers to a functional group isomer produced by a certain atom in a molecule moving rapidly at two positions, such as keto-enol isomerization and amide-imino alcohol isomerization.

"Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes the circumstances in which the event or circumstance occurs and the circumstances in which it is not what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group, and cases where the heterocyclyl group is not substituted with an alkyl group. Condition.

" _IC50 " is the concentration of drug or inhibitor required to inhibit a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.) by half.

detailed description

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

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD ), internal standard is tetramethylsilane (TMS);

For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

The determination of HPLC uses Agilent 1260DAD high pressure liquid chromatography (Zorbax SB-C18 100×4.6mm, 3.5 μM);

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF ₂₅₄ or Qingdao GF ₂₅₄ silica gel plate, the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm-0.5mm;

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

Boc: tert-butoxycarbonyl;

Ts: p-toluenesulfonyl;

Cbz: benzyloxycarbonyl;

TMS: Trimethylsilyl;

TIPS: Triisopropylsilyl;

Bpin: Nalcohol borate;

MOM: methylene methyl ether;

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

LiHMDS: lithium bistrimethylsilylamide;

EA: ethyl acetate;

MFSDA: methyl fluorosulfonyl difluoroacetate;

DIPEA: N,N-Diisopropylethylamine;

DMF: N,N-dimethylformamide;

PE: petroleum ether;

DCM: dichloromethane;

NIS: N-iodosuccinimide;

Pd(dppf)Cl ₂ : 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride;

NBS: N-bromosuccinimide;

ACN: acetonitrile;

TFA: trifluoroacetic acid;

THF: Tetrahydrofuran.

Example 1: 4-(2-{[((2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy]-4-(3,8-diazabicyclo [3.2.1] Oct-3-yl)pyridyl[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]octan-3-yl) pyrido[2,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.

The first step: tertiary 3-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Butyl ester (1b);

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) was dissolved in 10mL of dichloromethane, under the protection of nitrogen, the system was placed in an ice bath and stirred for 5min, then in Under this condition, N,N-diisopropylethylamine (0.42 mL, 2.558 mmol), 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 1.41 mmol), slowly rise to room temperature for 2h. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (PE:EA=3:1) to obtain the target compound (1b) (520 mg, yield: 99%).

Ms m/z(ESI):410.1[M+H] ⁺

The second step: 3-(7-chloro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin7a(5H)-yl)methoxy)pyridyl[2,3- d] tert-butyl pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1e);

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 (1b) (240mg, 0.585mmol) and compound ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (1c-1) (186mg, 1.17mmol) Dissolve in 10 mL of ultra-dry 1,4-dioxane solution, then add N,N-diisopropylethylamine (0.29 mL, 1.755 mmol) and 4A molecular sieves (300 mg). Under the protection of nitrogen, the temperature was raised to 100°C for 24 h, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (DCM:MeOH=20:1) to obtain the target compound (1e) (210 mg, yield: 67%).

Ms m/z(ESI):533.2[M+H] ⁺

The third step: 3-(7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-( ((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin7a(5H)-yl)methoxy)pyridyl[2,3-d]pyrimidin-4-yl)-3,8- tert-butyl diazabicyclo[3.2.1]octane-8-carboxylate (1f);

tert-butyl 3-(7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethylnyl) 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 (1e) (210 mg, 0.394 mmol) and compound ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1d-1) (404mg, 0.788mmol) was placed in a sealed tube, and 15mL of 1,4-bis The oxane solution was dissolved, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (32mg, 0.04mmol), cesium carbonate (385mg, 1.18mmol) and 1.5mL of water were added successively . Under nitrogen protection, rise to 100°C for 3 hours, remove the solvent under reduced pressure, add 15mL water and 30mL ethyl acetate to dissolve, wash the aqueous phase with 20mL×2 ethyl acetate, combine the organic phases, and wash the organic phase once with 10mL saturated brine , and then the organic phase was dried with anhydrous sodium sulfate, spin-dried, and column chromatography (DCM:MeOH=15:1) gave the target compound (1f) 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]octane-3-yl)-2-(((((2R,7aS)-2-fluorotetrahydro-1H -pyrrolazin-7a(5H)-yl)methoxy)pyrido[2,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl) Naphthalene-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 (1f) (230mg, 0.26mmol) was dissolved in 5mL of acetonitrile, then 2mL of hydrochloric acid 1,4-dioxane solution was added dropwise at room temperature, the system continued to react for 3h, and the excess acid and solvent were removed under reduced pressure to obtain The crude compound (1 g), (240 mg) was directly 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-pyrrolazin-7a-yl]methoxy]-4-(3,8-diazabicyclo [3.2.1] Oct-3-yl)pyridyl[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]octan-3-yl) pyrido[2,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.

Crude compound (1 g) (240 mg) from the previous step was dissolved in 2 mL of N,N-dimethylformamide, then cesium fluoride (200 mg, 1.3 mmol) was added at room temperature. After the addition, continue to react for 12 h under the protection of nitrogen, add 30 mL of ethyl acetate to the system to dilute, then wash the organic phase with 10 mL of saturated sodium bicarbonate, 10 mL×3 water, and 10 mL of saturated saline, and dry the organic phase with anhydrous sodium sulfate , concentrated, and the residue was subjected to silica gel column chromatography (DCM:MeOH=5:1) to obtain the target compound (compound 1) as a yellow solid (30 mg, two-step yield: 20%).

Ms m/z(ESI):583.3[M+H] ⁺

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

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

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

2-amino-4-bromo-3-fluorobenzamide

Dissolve 2-amino-4-bromo-3fluorobenzoic acid (2A) (5g, 21.46mmol) in 60mL of N,N-dimethylformamide, add HATU (12.24g, 32.18mmol), N,N -Diisopropylethylamine (5.53g, 42.92mmol) and ammonium chloride (11.48g, 214.60mmol), and continue the reaction at room temperature for 3h. The reaction solution was slowly poured into 120 mL of ice water and stirred at room temperature for 10 min. 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: 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

Dissolve (2B) (4.9 g, 21.12 mmol) in 100 mL of tetrahydrofuran, add triphosgene (9.4 g, 31.68 mmol), and react at 65° C. for 3 h after the addition. The reaction was cooled to room temperature and concentrated under reduced pressure to obtain compound (2C) (4.7 g, yield 86.23%)

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

Dissolve (2C) (1.5g, 5.81mmol) in 30mL of toluene, add phosphorus oxychloride (4.45g, 29.07mmol), N,N-diisopropylethylamine (2.25g, 17.44mmol), and After completion, react at 110°C for 5h. The reaction was cooled to room temperature and concentrated under reduced pressure to directly obtain compound (2D) as a brown liquid, which was directly used in the next reaction.

the fourth step:

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

tert-butyl

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

Dissolve (2D) in 30 mL of dry dichloromethane, slowly add N,N-diisopropylethylamine (2.25 g, 17.44 mmol), intermediate 1 (1.23 g, 5.81 mmol) under ice-cooling, after the addition is complete Slowly rise to room temperature and react for 2 h. After concentration under reduced pressure, the residue was chromatographed on a silica gel column to obtain compound (2E) (0.71 g, two-step yield 26.00%).

LCMS m/z=471.1[M+H] ⁺

the fifth step:

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

分子筛500mg，氮气保护下室温下反应10min，将化合物2E(0.4g，0.85mmol)溶解于N,N-二甲基甲酰胺2mL中，并将其缓慢加入反应液中，加完后室温反应4h，缓慢加入水40mL，乙酸乙酯(40mL×2)萃取两次，合并乙酸乙酯层，乙酸乙酯层水(40mL×2)洗涤两次，并饱和食盐水洗涤一次(40mL×1)，无水硫酸钠干燥，减压浓缩后，残留物用硅胶色谱柱柱层析得到化合物(2F)(0.36g，产率71.42％)Intermediate 2 (0.4g, 2.51mmol) was dissolved in N,N-dimethylformamide 15mL, cesium carbonate (0.55g, 1.70mmol), triethylenediamine (0.03g, 0.26mmol) were added, and

Molecular sieves 500mg, reaction at room temperature for 10min under nitrogen protection, dissolving compound 2E (0.4g, 0.85mmol) in 2mL of N,N-dimethylformamide, and slowly adding it to the reaction solution, and reacting at room temperature for 4h after the addition , slowly add 40 mL of water, extract twice with ethyl acetate (40 mL×2), combine the ethyl acetate layers, wash the ethyl acetate layer with water (40 mL×2) twice, and wash once with saturated brine (40 mL×1), After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the residue was chromatographed on a silica gel column to obtain compound (2F) (0.36 g, yield 71.42%)

LCMS m/z=594.1[M+H] ⁺

Step six:

3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-(7-fluoro-3-(methoxy Methyl)-8-(2-(tri(propan-2-yl)silyl)ethynyl)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2. 1] tert-butyl octane-8-carboxylate (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

Dissolve (2F) (0.36g, 0.60mmol) in a mixed solution of 1,4-dioxane 15mL and water 3mL, add intermediate 3 (0.62g, 1.20mmol), cesium carbonate (0.39g, 1.20mmol ), Pd(dppf)Cl ₂ dichloromethane complex (0.10g, 0.12mmol), reacted at 100°C for 5h under nitrogen protection, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, and reused the aqueous phase Extract with ethyl acetate (40mL×1) once, combine the ethyl acetate layers, wash the ethyl acetate layer with saturated brine once (40mL×1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, the residue is chromatographed on a silica gel column Column chromatography obtained compound (2G) (0.24g, yield 44.03%)

LCMS m/z=900.1[M+H] ⁺

Step seven:

4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolazin-7a-yl]methoxy}-4-[3,8-diazabicyclo[3.2.1] Octane-3-yl]-8-fluoroquinazolin-7-yl)-6-fluoro-5-(2-(tri(propane-2-yl)silyl)ethynyl)naphthalene-2-alcohol ( 2H)

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

Dissolve compound (2G) (0.15g, 0.16mmol) in 10mL of dichloromethane, add 0.5mL of trifluoroacetic acid, react at room temperature for 3h after addition, and concentrate under reduced pressure to obtain compound (2H) directly for the next reaction .

LCMS m/z=756.1[M+H] ⁺

Step Eight:

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

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

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% TFA); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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-pyrrolazine -7a(5H)-yl)methoxy)furo[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: 3-(4-bromo-7-chlorofuro[2,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-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,N-diisopropylethylamine (2.76g, 21.35mmol) was added, followed by slowly dropwise addition of trichloro Phosphorus (6.55 g, 42.7 mmol). After the dropwise addition, the system was heated to 100° C. for 3 hours under the protection of nitrogen. Cool to room temperature, remove excess phosphorus oxychloride and solvent under reduced pressure, and obtain the crude product as a brown oily liquid. Dissolve the residue in 10 mL of dichloromethane. Under nitrogen protection, place the system in an ice bath and add N successively. N-diisopropylethylamine (2.76g, 21.35mmol), 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.91g, 4.27mmol), added slowly Raised to room temperature for 2h. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (PE:EA=3:1) to obtain the target compound 3b (0.16 g, yield 7.6%)

LCMS m/z=493.0[M+1] ⁺

The second step: 3-(4-bromo-7-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)furan[2,3- f] quinazoline-9-yl)-3,8-diazabicyclo[3.2.1]octane-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

分子筛，氮气保护室温反应6h。反应完全后，加入15mL水，用乙酸乙酯萃取2次，合并有机相，有机相用10mL饱和食盐水洗一次，然后有机相用无水硫酸钠干燥，浓缩，残余物经硅胶柱层析分离纯化得到目标化合物3c(140mg，产率81％)Starting material 3b (140 mg, 0.28 mmol), ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (89 mg, 0.56 mmol), cesium carbonate (270 mg, 0.84 mmol) ), triethylenediamine (6mg, 0.056mmol) was dissolved in 10mL DMF, added

Molecular sieves, under nitrogen protection, reacted at room temperature for 6h. After the reaction is complete, add 15 mL of water, extract twice with ethyl acetate, combine the organic phases, wash the organic phase with 10 mL of saturated brine once, then dry the organic phase with anhydrous sodium sulfate, concentrate, and the residue is separated and purified by silica gel column chromatography Obtain target compound 3c (140mg, yield 81%)

LCMS m/z=616.2[M+1] ⁺

The third step: 3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-7-( (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)furo[2,3-f]quinazolin-9-yl)-3,8 - tert-butyl diazabicyclo[3.2.1]oct-8-carboxylate

3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethylnyl)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 (140 mg, 0.23 mmol) and compound ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxo Boroboran-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (240mg, 0.46mmol) was placed in a sealed tube, 10mL of 1,4-dioxane solution was added to dissolve, and then [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (50 mg, 0.069 mmol), cesium carbonate (220 mg, 0.69 mmol) and 2 mL of water were added. Under the protection of nitrogen, rise to 100°C for 3 hours, cool to room temperature, remove the solvent under reduced pressure, add 15mL water and 30mL ethyl acetate to dissolve, wash the aqueous phase with 20mL×2 ethyl acetate, combine the organic phase, and use 10mL Washed once with saturated brine, then the organic phase was dried over anhydrous sodium sulfate, concentrated, and column chromatography gave 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- Pyrrolazin-7a(5H)-yl)methoxy)furo[2,3-f]quinazolin-4-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl) Naphthalene-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

The raw material 3d (150 mg, 0.16 mmol) was dissolved in 10 mL of acetonitrile, and then 2 mL of hydrochloric acid/1,4-dioxane solution was added dropwise at room temperature. The system continued to react for 1 h, and the excess hydrochloric acid and solvent were removed under reduced pressure to obtain the crude product Compound 3e was directly used in 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-pyrrolazine -7a(5H)-yl)methoxy)furo[2,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-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)-5-ethynyl-6-fluoronaphthalen-2-ol

The raw material 3e (100mg, 0.13mmol) was dissolved in 3mL DMF, cesium fluoride (103mg, 0.65mmol) was added, stirred at room temperature for 16h, and compound 3 (40mg, yield 49.5%) was obtained by separation and purification by reverse phase C18 column chromatography.

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,7aS)-2-fluoro-hexahydro-1H-pyrrolazin-7a-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-diazabicyclo[3.2.1] octan-3-yl]-8-fluoroquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

The first step: (1R,5S)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolazin-7a-yl]methoxy}-7-(8-acetylene Base-7-fluoro-3-(methoxymethyl)naphthalen-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 - tert-butyl carboxylate (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 (0.35 g, 0.39 mmol) was dissolved in 8 mL of N,N-dimethylformamide, cesium fluoride (0.295 mg, 1.95 mmol) was added, and stirred at room temperature for 3 hours. Slowly add 20 mL of water, and extract twice with ethyl acetate (20 mL×2), combine the ethyl acetate layers, wash the ethyl acetate layer twice with water (20 mL×2), once with 20 mL of saturated sodium chloride solution, and finally wash with Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, the residue is separated and purified by silica gel column chromatography to obtain compound 4B (230 mg, yield 79.58%)

Ms m/z(ESI):744.3[M+H] ⁺

The second step: (1R,5S)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolazin-7a-yl]methoxy}-7-(8-ethane Base-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane - tert-butyl 8-carboxylate (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-carboxylate

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

Ms m/z(ESI):748.1[M+H] ⁺

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

Dissolve 4C (0.16 mg, 0.21 mmol) in 8 mL of dichloromethane, add 0.5 mL of trifluoroacetic acid, stir at room temperature for 1 hour, concentrate under reduced pressure to remove residual solvent, and prepare the residue to obtain compound 4 (8 mg, yield 6.2 %)

Preparation:

Instrument: SHIMADZU LC-20AP;

Preparative column: Phenomenex C18;

Mobile phase: A is 10mmol/L NH ₄ HCO ₃ aqueous solution; B is acetonitrile;

Elution method: B gradient elution from 32% to 62% for 12 minutes;

Flow rate: 25mL/min;

Column temperature: room temperature;

Detection wavelength: 220nm;

Ms m/z(ESI):604.1[M+1] ⁺

Example 5: 5-(4-(1R,5S)-3,8-diazoepoxy[3.2.1]-octane-3-yl)-8-fluoro-2-(2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolidone-7a(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: 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 ammonia methanol solution (10mL) were sequentially added to a 120mL pressure vessel, and Stirring was continued for 8 h at 80°C. The reaction was cooled to room temperature. Concentrate under reduced pressure to remove the solvent, then extract with water (30 mL)/dichloromethane (40 mL) and separate the layers, and the organic layer is dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure to obtain the crude product (5B) (1.80 g, 91.04%), which was directly used in the next reaction without further purification.

Ms m/z(ESI):258.1[M+H] ⁺

The second step: 3-fluoro-5-(4,4,5,5-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 nitrogen protection, 5B (1.80g, 6.98mmol), diboronic acid pinacol ester (2.66g, 10.46mmol), Pd(dppf)Cl ₂ (0.51g, 0.70mmol) and KOAc (2.05g, 20.93 mmol) was added to a 50 mL round bottom flask, and then a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL) was added, and the reaction was continuously stirred at 90° C. for 4 h. Cool to room temperature, remove the solvent under reduced pressure, add 30 mL of water, then extract with ethyl acetate (20 mL×3), combine the organic phases, dry with anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography After purification, the target compound 5C (1.50 g, 70.48%) was obtained.

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-pyrrolazin-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

Under nitrogen protection, (5C) (0.5g, 1.64mmol) was dissolved in a mixed solution of 1,4-dioxane (10mL) and water (2mL), and then intermediate 2F (0.65g, 1.09mmol), cesium carbonate (0.71g, 2.19mmol) and Pd(dppf)Cl ₂ (0.12g, 0.11mmol), react at a temperature of 110°C for 5h, cool the reaction to room temperature, add ethyl acetate 40mL and water 25 mL , the aqueous phase was extracted once more with ethyl acetate (40mL×1), the ethyl acetate layers were combined, the ethyl acetate layer was washed once with saturated brine (40mL×1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the residual The compound (5E) (0.61g, 79.27%) was obtained by silica gel column chromatography

Ms m/z(ESI):693.3[M+H] ⁺

The fourth step: 5-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-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

Dissolve compound (5D) (0.60g, 0.87mmol) in 10mL of dichloromethane, add 0.5mL of trifluoroacetic acid, react at room temperature for 3h after the addition, and then directly concentrate the reaction under reduced pressure to remove the solvent, and the residue is reversed phase The target compound 5 (0.4 g, 77.93%) was obtained by separation and purification by column chromatography.

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-pyrrolazin-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: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (6A)

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

Dissolve 7-bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione (2.0g, 6.85mmol) in toluene 30mL, add phosphorus oxychloride (5.25g, 34.24mmol), N,N-diisopropylethylamine (2.65g, 20.54mmol), reacted at 110°C for 5h. The reaction was cooled to room temperature and concentrated under reduced pressure to directly obtain the crude compound (6A) which was directly 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 tert-butyl alkane-8-carboxylate (6B)

tert-butyl

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

Dissolve compound 6A in 30 mL of dry dichloromethane, slowly add N,N-diisopropylethylamine (2.65 g, 20.54 mmol) and intermediate 1 (1.45 g, 6.85 mmol) under ice-cooling, and slowly add Return to room temperature and react for 2h. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography to obtain 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-pyrrolazin-7a-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 nitrogen protection, Intermediate 2 (0.5g, 3.14mmol) was dissolved in N,N-dimethylformamide 15mL, cesium carbonate (0.64g, 1.98mmol), triethylenediamine (0.04g, 0.35mmol) were added ), and 500 mg of molecular sieves were added, and after stirring at room temperature for 10 min, 2 mL of N,N-dimethylformamide of compound 6B (0.5 g, 0.99 mmol) was slowly added to the reaction liquid, and reacted at room temperature for 4 h after the addition. Slowly add 40 mL of water, extract twice with ethyl acetate (40 mL×2), combine the ethyl acetate layers, wash the ethyl acetate layer with water (40 mL×2) twice, and wash once with saturated brine (40 mL×1). Dry over sodium sulfate, concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography to obtain compound (6C) (0.46g, yield 74.19%)

LCMS m/z=628.1[M+H] ⁺

The first step: 3-(4,4,5,5-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 nitrogen protection, 3-bromo-5-(trifluoromethyl)aniline (6D) (2g, 8.33mmol), pinacol diboronate (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 ring, heated to 90°C, and reacted 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 obtain compound (6E) (2 g, yield 84%).

LCMS m/z=288.1[M+H] ⁺

The second step: (1R,5S)-3-(7-(3-amino-5-(trifluoromethyl)phenyl)-6-chloro-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H)-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- tert-butyl carboxylate (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

Under nitrogen protection, the 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, and 4.5mL of 1,4-dioxane and 1mL of water were added. The temperature was raised to 105° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound (6F) (118 mg, yield 69%)

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-pyrrolazin-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

Compound (6F) (118 mg, 0.17 mmol) was dissolved in 2.5 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is purified by preparative HPLC, and the preparation solution is concentrated and freeze-dried to obtain compound 6 ( 55 mg, yield 53%).

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% NH ₄ HCO ₃ ); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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-pyrrolazin-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: (1R,5S)-3-(7-(3-amino-5-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolazin-7a) (5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl Esters (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 nitrogen protection, intermediate 2F (110mg, 0.19mmol), compound 6E (107mg, 0.37mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complexed (16mg, 0.019mmol) and cesium carbonate (124mg, 0.38mmol) were placed in a sealed tube, 3mL of 1,4-dioxane and 0.6mL of water were added, and the temperature was raised to 105°C for 3 hours. The reaction was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound (7A) (115mg, product rate 90%)

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-pyrrolazin-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

Compound 7A (115 mg, 0.17 mmol) was dissolved in 2.5 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 7 ( 45 mg, yield 46%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

LCMS m/z=575.3[M+H] ⁺

Example 8: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3yl)-6-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-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: (1R,5S)-3-(7-(5-amino-2-(trifluoromethyl)phenyl)-6-chloro-8-fluoro-2-(((2R,7aS) -2-Fluorotetrahydro-1H)-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 - tert-butyl carboxylate (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) di Palladium (36mg, 0.039mmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (37mg, 0.08mmol), tetrabutylammonium bromide (13mg, 0.039mmol) and sodium carbonate (83mg, 0.78mmol) were placed in a sealed tube, 4mL 1,4-dioxane and 1mL water were added, and the temperature was raised to 105°C for 3 hours. The reaction was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound (8B) (76 mg, yield rate 27%)

LCMS m/z=709.3[M+H] ⁺

The third step: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3 base)-6-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-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

Compound 8B (76 mg, 0.11 mmol) was dissolved in 2.5 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 8 ( 12 mg, yield 17.9%).

HPLC preparation method:

Instrument: SHIMADZU LC-20AP;

Chromatographic column: Phenomenex C18;

Mobile phase: A is 10mmol NH ₄ HCO ₃ aqueous solution; B is acetonitrile;

Elution method: gradient elution of 30% to 60% A solution of B for 12 minutes;

Flow rate: 25mL/min;

Column temperature: room temperature;

Detection wavelength: 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-pyrrolazin-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: 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

The raw material 3-fluoro-5-bromoaniline (15g, 78.94mmol) was dissolved in 200ml N,N-dimethylformamide, and N-chlorosuccinimide (11g, 82.89mmol ), stirred at room temperature for 16 hours, added water to quench the reaction, added 200ml ethyl acetate to extract once, the organic phase was washed twice with water (150ml×2), washed once with 150ml saturated saline, the organic phase was dried with anhydrous sodium sulfate, and reduced pressure Concentration, the residue was analyzed and purified by column chromatography to obtain compound 9A-1 (5g, yield 28%), compound 9A-2 (8g, 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: (4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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

Dissolve (2F) (1.2g, 2.02mmol) in a mixed solution of 1,4-dioxane 15mL and water 3mL, add biboronic acid pinacol ester (0.62g, 2.42mmol), potassium acetate (0.4g , 4.04mmol), Pd(dppf)Cl ₂ (0.15g, 0.2mmol), reacted at 100°C for 3h under the protection of nitrogen, cooled the reaction to room temperature, filtered it with diatomaceous earth, concentrated the filtrate under reduced pressure, reversed phase column chromatography Obtained compound 9B (1 g, yield 88.5%)

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-pyrrolazin-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

Dissolve (9A-1) (0.11g, 0.49mmol) in a mixed solution of 1,4-dioxane 5mL and water 1mL, add 9B (0.22g, 0.39mmol), cesium carbonate (0.32g, 0.98mmol ), Pd(dppf)Cl ₂ (0.036g, 0.049mmol), reacted at 100°C under nitrogen protection for 2h, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, and then used ethyl acetate (40mL× 1) Extract once, combine the ethyl acetate layers, wash the ethyl acetate layer once with saturated brine (40mL×1), dry over anhydrous sodium sulfate, and concentrate under reduced pressure, the residue is chromatographed on a silica gel column to obtain the compound ( 9C) (0.13g, 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-pyrrolazin-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

Compound (9C) (0.13 g, 0.87 mmol) (0.13 g, 0.87 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve, add dropwise 0.5mL N, N-diisopropylethylamine, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 9 (20 mg, yield 20%), white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% NH ₄ HCO ₃ ); gradient elution, the content of mobile phase A is eluted from 5% to 50%; 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-pyrrolazin-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: 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-carboxylic acid Esters (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

Dissolve (9A-2) (0.11g, 0.49mmol) in a mixed solution of 1,4-dioxane 5mL and water 1mL, add 9B (0.22g, 0.39mmol), cesium carbonate (0.32g, 0.98mmol ), Pd(dppf)Cl ₂ (0.036g, 0.049mmol), react at 100°C for 2h under the protection of nitrogen, cool the reaction to room temperature, add 40mL of ethyl acetate and 25mL of water and stir to separate the liquids, and the aqueous phase is then washed with ethyl acetate Ethyl acetate (40mL×1) was extracted once, the ethyl acetate layers were combined, the ethyl acetate layer was washed once with saturated brine (40mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Compound (10A) (0.13 g, yield 40.25%) was obtained by analysis

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-pyrrolazin-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

Compound (10A) (0.13 g, 0.87 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 10( 20mg, yield 20%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% NH ₄ HCO ₃ ); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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-pyrrolazin-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: 2,3,4-trifluoro-5-iodoaniline (11A)

2,3,4-trifluoro-5-iodoaniline

Dissolve the raw material 2,3,4-trifluoroaniline (1.0g, 6.8mmol) in 5ml of trifluoromethanesulfonic acid, add NIS (2.3g, 10.2mmol), stir at room temperature for 5h, add 30ml of water to dilute, and dilute with 30ml of acetic acid Extracted once with ethyl ester, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography gave compound 11A (1.2 g, yield 64.6%).

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

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

Dissolve raw material 11A (0.3g, 1.1mmol) in 5ml of acetic acid, add NCS (0.16g, 1.21mmol), stir at room temperature for 5h, add 30ml of water to dilute, extract once with 30ml of ethyl acetate, dry over anhydrous sodium sulfate, reduce Concentrate under reduced pressure, and obtain compound 11B (0.16 g, yield 47.3%) by column chromatography.

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-pyrrolazin-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

Dissolve (11B) (0.16g, 0.52mmol) in a mixed solution of 1,4-dioxane 5mL and water 1mL, add 9B (0.23g, 0.42mmol), cesium carbonate (0.3g, 1.04mmol), Pd(dppf)Cl ₂ (0.038g, 0.052mmol), reacted at 100°C under nitrogen protection for 2h, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, and then used ethyl acetate (40mL×1) for the aqueous phase Extract once, combine the ethyl acetate layers, wash the ethyl acetate layer once with saturated brine (40mL×1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is chromatographed on a silica gel column to obtain compound (11C) (0.11g, 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-pyrrolazin-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

Compound (11C) (0.11 g, 0.16 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 11( 20 mg, yield 21%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrroline-7a(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: 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-carboxylic acid Esters (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 (160 mg, 0.27 mmol), 12A (120 mg, 0.41 mmol), Pd(dppf)Cl ₂ ·DCM (22 mg, 0.03 mmol) and cesium carbonate (260 mg, 0.81 mmol) were added to 1,4-dioxo In a mixed solvent of hexacyclic (8mL) and water (2mL). Under a nitrogen blanket, the reaction was stirred at 105°C for 5 hours. After the reaction was cooled to room temperature, the solvent was removed under reduced pressure, 100mL of water was added, and then extracted with ethyl acetate (50mL×3). Chromatographic separation and purification gave 12B (140 mg, yield: 76.85%).

Ms m/z(ESI):675.4[M+H] ⁺

The second step: 3-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((2R, 7aS)- 2-Fluorotetrahydro-1H-pyrroline-7a(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 (140 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL), then 3 mL of TFA was added at room temperature, and the reaction was continued to stir at room temperature for another 1 hour. The excess acid and solvent were removed under reduced pressure, and the target compound 12 (40 mg, yield: 33.15%) was purified by preparative HPLC.

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-pyrroline-7a(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: 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-carboxylic acid Esters (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-carboxylate

Intermediate 2F (150 mg, 0.25 mmol), 13A (110 mg, 0.38 mmol), Pd(dppf)Cl ₂ ·DCM (20 mg, 0.025 mmol) and cesium carbonate (240 mg, 0.75 mmol) were added to 1,4-dioxo Hexacyclic (10mL) and water (2mL) mixed solvent. Under a nitrogen blanket, the reaction was stirred at 105°C for 3 hours. After the reaction was cooled to room temperature, the solvent was removed under reduced pressure, 100mL of water was added, and then extracted with ethyl acetate (50mL×3). Chromatographic separation and purification gave 13B (140 mg, yield: 81.08%).

Ms m/z(ESI):691.3[M+H] ⁺

The second step: 3-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((2R, 7aS)- 2-Fluorotetrahydro-1H-pyrroline-7a(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

13b (140 mg, 0.20 mmol) was dissolved in dichloromethane (8 mL), then 2 mL of TFA was added at room temperature, and the reaction was continued to stir at room temperature for another 1 hour. The excess acid and solvent were removed under reduced pressure, and the target compound 13 (20 mg, yield: 16.93%) was purified by preparative HPLC.

Ms m/z(ESI):591.2[M+H] ⁺

Example 14: 3-(1R,5S)-3,8-diazoepoxy[3.2.1]-octane-3-yl)-5-fluoro-3-(2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolidone-7a(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: 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 successively added into a 50mL round bottom flask, and the stirring was continued at room temperature for 3h. After the reaction is complete, extract with water (30mL)/ethyl acetate (40mL), dry over anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the target compound (14B) (1.30 g, 80.76%).

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

3-bromo-5-chloro-4-cyclopropylaniline

Under nitrogen protection, (14B) (1.30g, 3.91mmol), cyclopropylboronic acid (0.40g, 4.69mmol), Pd(dppf)Cl ₂ (0.28g, 0.39mmol) and Cs ₂ CO ₃ (2.55 g, 7.82mmol) was added to a 50mL round bottom flask, and then a mixed solvent of 1,4-dioxane (15mL) and water (3mL) was added, and the reaction was continued to stir at 110°C for 4h. After the reaction is complete, cool to room temperature, remove the solvent under reduced pressure, add 30 mL of water, then extract with ethyl acetate (20 mL×3), combine the organic phases, dry with anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and Purified by silica gel column chromatography (PE:EA=10:1), the target compound 14C was obtained (0.80 g, 82.96% yield).

The third step: 3-chloro-4-cyclopropyl-5-(4,4,5,5-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 nitrogen protection, (14C) (0.80g, 3.25mmol), diboronic acid pinacol ester (0.99g, 3.89mmol), Pd(dppf)Cl ₂ (0.23g, 0.33mmol) and KOAc (0.96g , 9.74mmol) into a 50mL round bottom flask, and then a mixed solvent of 1,4-dioxane (15mL) and water (3mL), and the reaction was stirred at 90°C for 4h. Cool to room temperature, remove the solvent under reduced pressure, add 30 mL of water, then extract with ethyl acetate (20 mL×3), combine the organic phases, dry with anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography After purification, the target compound (14D) (0.8 g, 83.97%) was obtained.

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-fluorotetra Hydrogen-1H-pyrrolidone-7a(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

Under nitrogen protection, (14D) (0.12g, 0.40mmol) was dissolved in a mixed solution of 1,4-dioxane (5mL) and water (1mL), and then intermediate 2F (0.20g, 0.33mmol), cesium carbonate (0.22g, 0.67mmol) and Pd(dppf)Cl ₂ (0.02g, 0.03mmol), react at a temperature of 110°C for 5h, cool the reaction to room temperature, add ethyl acetate 40mL and water 25 mL , stirred and separated, the aqueous phase was extracted once with ethyl acetate (40mL×1), the ethyl acetate layers were combined, the ethyl acetate layer was washed once with saturated brine (40mL×1), dried over anhydrous sodium sulfate, and reduced After concentrated under reduced pressure, the residue was chromatographed on a silica gel column to obtain compound (14E) (0.20 g, 87.27%)

Ms m/z(ESI):681.3[M+H] ⁺

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

Dissolve compound (14E) (0.20g, 0.29mmol) in 10mL of dichloromethane, add 0.3mL of trifluoroacetic acid, react at room temperature for 3h after the addition, and then directly concentrate the reaction under reduced pressure to remove the solvent, and the residue is reversed phase The target compound 14 (0.18 g, 90.00%) was obtained by separation and purification by column chromatography.

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]-octane-3-yl)-8-fluoro-2-(2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolidone-7a(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: (3-bromo-5-chloro-4-iodophenyl) tert-butyl carbamate (15A)

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

Under the protection of N ₂ , first dissolve compound 14B (0.5g, 1.5mmol), di-tert-butyl dicarbonate (0.36g, 1.65mmol) in 2mL of THF, and then slowly dropwise add LiHMDS (0.55g, 3.30mL), after the dropwise addition, the reaction solution was moved to normal temperature for 3h reaction, after the reaction was completely completed, EA/H ₂ O (150mL/100mL) was extracted and washed, the organic layer was concentrated, and the The compound 15A (0.45 g, yield: 69.37%) was obtained by chromatography column purification.

Ms m/z(ESI):431.9[MH] ⁺

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

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

Under the protection of _N2 , compound 15A (0.1g, 0.23mmol), MFSDA (0.31g, 1.61mmol) and CuI (53.0mg, 0.28mmol) were added to the reaction test tube in turn, and then DIPEA (0.21g, 1.61 mmol) was dissolved in 5 mL of DMF and slowly added dropwise to the reaction tube. The reaction was continued in an oil bath at 75° C. for 16 hours. After the reaction was completed, EA/H ₂ O (200 mL/150 mL*2) was used for extraction and washing. Finally, the organic layer was concentrated and purified by column chromatography (PE:EA=10:1) to obtain compound 15B (80.0 mg, yield: 92.86% yield).

Ms m/z(ESI):373.9[MH] ⁺

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-7a(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-(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 (200 mg, 0.36 mmol) and compound 15B (0.16 mg, 0.43 mmol) were placed in a sealed tube, 5 mL of 1,4-dioxane solution was added to dissolve, and then [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride (26.0 mg, 0.036 mmol), cesium carbonate (230.0 mg, 0.72 mmol). Under the protection of nitrogen, rise to 110 ° C for 5 h, remove the solvent under reduced pressure, add 50 mL of water and 100 mL of ethyl acetate to dissolve, wash the water phase with 50 mL×2 ethyl acetate, combine the organic phase, and wash the organic phase once with 40 mL of saturated saline , and then the organic phase was dried with anhydrous sodium sulfate, spin-dried, and column chromatography (DCM:MeOH=15:1) 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]-octane-3-yl)-8-fluoro-2-(2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolidone-7a(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 (270 mg, 0.33 mmol) was dissolved in 10 mL of DCM, then 1 mL of trifluoroacetic acid was added dropwise at room temperature, the system continued to react for 3 h, the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC, and the preparative solution was concentrated and frozen Drying gave the target compound 15 (150 mg, yield: 74.63%).

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

Ms m/z(ESI):609.2[M+H] ⁺

Example 16: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]-octane-3-yl)-8-fluoro-2-(2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolidone-7a(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: 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 successively added into a 100mL round bottom flask, and the stirring was continued at room temperature for 3h. After the reaction is complete, extract with water (100 mL)/ethyl acetate (150 mL), dry over anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the target 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) (3.0g, 9.50mmol), cyclopropylboronic acid (0.98g, 11.40mmol), Pd(dppf)Cl ₂ (0.70g, 0.95mmol) and Cs ₂ CO ₃ (6.19 g, 19.00mmol) was added to a 100mL round bottom flask, and then a mixed solvent of 1,4-dioxane (15mL) and water (3mL) was added, and the reaction was stirred continuously at 110°C for 4h. After the reaction is complete, cool to room temperature, remove the solvent under reduced pressure, add 100mL of water, and then extract with ethyl acetate (100mL×3), combine the organic phases, dry with anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and Purified by silica gel column chromatography (PE:EA=10:1), the target compound 16C (1.40 g, yield: 64.05%) was obtained.

The third step: 3-fluoro-4-cyclopropyl-5-(4,4,5,5-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 nitrogen protection, (16C) (1.40g, 6.08mmol), diboronic acid pinacol ester (1.85g, 7.30mmol), Pd(dppf)Cl ₂ (0.45g, 0.61mmol) and KOAc (1.79g , 18.24mmol) into a 50mL round bottom flask, and then a mixed solvent of 1,4-dioxane (15mL) and water (3mL), and the reaction was stirred at 90°C for 4h. Cool to room temperature, remove the solvent under reduced pressure, add 30 mL of water, then extract with ethyl acetate (40 mL×3), combine the organic phases, dry with anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography Purified to obtain the target 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-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolidone-7a(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-carboxylate

Under nitrogen protection, (16D) (0.11g, 0.41mmol) was dissolved in a mixed solution of 1,4-dioxane (5mL) and water (1mL), and then intermediate 2F (0.20g, 0.34mmol), cesium carbonate (0.10g, 1.02mmol) and Pd(dppf)Cl ₂ (25.0mg, 0.03mmol), reacted at a temperature of 110°C for 5h, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, Stir and separate the liquids, extract the aqueous phase once more with ethyl acetate (40mL×1), combine the ethyl acetate layers, wash the ethyl acetate layer once with saturated brine (40mL×1), dry over anhydrous sodium sulfate, and reduce pressure After concentration, the residue was chromatographed on a silica gel column to obtain compound 16E) (0.18g, yield: 79.64%)

Ms m/z(ESI):665.3[M+H] ⁺

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

Dissolve compound (14E) (0.18g, 0.27mmol) in 2.0mL of dichloromethane, add 0.2mL of trifluoroacetic acid, react at room temperature for 3h after the addition is complete, then directly concentrate the reaction under reduced pressure to remove the solvent, and the residue is subjected to reaction The target compound 16 (0.10 g, yield: 65.59%) was obtained by separation and purification by column chromatography.

Ms m/z(ESI):565.3[M+H] ⁺

Example 17: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((2R,7aS)- 2-Fluorotetrahydrofuran-1H-pyrrolin-7a(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

Step 1: 6-Amino-4-(4,4,5,5-Tetramethyl-1,3,2-Dioxybenzaldehyde-2-yl)benzofuran-7-carbonitrile 6-amino- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-7-carbonitrile

Under nitrogen protection, (17A) (0.2g, 0.84mmol), diboronic acid pinacol ester (10.26g, 1.01mmol), Pd(dppf)Cl ₂ (0.06g, 0.084mmol) and KOAc (0.16g , 1.68mmol) was added to a 50mL round bottom flask, and then 1,4-dioxane (3mL) solvent was added, and the reaction was continuously stirred at 90°C for 6h. Cool to room temperature, remove the solvent under reduced pressure, add 30 mL of water, then extract with ethyl acetate (300 mL×3), combine the organic phases, dry with anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography After purification, the target compound 17B was obtained (0.2 g, yield: 83.8%).

Ms m/z(ESI):285.1[M+H] ⁺

The second step: tert-butyl (1R, 5S)-3-(7-(6-amino-7-cyanobenzofuran-4-yl)-8-fluoro-2-((2R, 7aS)-2 -Fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid Ester (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 (130.0 mg, 0.22 mmol) and compound 17B (75.0 mg, 0.26 mmol) were placed in a sealed tube, 2 mL of 1,4-dioxane solution was added to dissolve, and then [1,1'-bis (Diphenylphosphino)ferrocene]palladium dichloride (16.0 mg, 0.022 mmol), cesium carbonate (140.0 mg, 0.44 mmol). Under the protection of nitrogen, rise to 110°C to react for 6h, remove the solvent under reduced pressure, add 30mL water and 60mL ethyl acetate to dissolve, wash the aqueous phase with 100mL×2 ethyl acetate, combine the organic phase, and wash the organic phase once with 80mL saturated brine , and then the organic phase was dried with anhydrous sodium sulfate, spin-dried, and column chromatography (DCM:MeOH=15:1) 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]octane-3-yl)-8-fluoro-2-((2R, 7aS)- 2-Fluorotetrahydrofuran-1H-pyrrolin-7a(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

Compound 17C (100mg, 0.15mmol) was dissolved in 1mL DCM, then 0.1mL trifluoroacetic acid was added dropwise at room temperature, the system continued to react for 3h, the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC, the preparative solution was concentrated and lyophilized The target compound 17 (50.0 mg, yield: 58.31%) was obtained.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-7a(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: 2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)aniline (18B)

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

Under nitrogen protection, (18A) (2.28g, 9.35mmol), diboronic acid pinacol ester (3.97g, 15.61mmol), Pd(dppf)Cl ₂ (1.37g, 1.87mmol) and KOAc (1.84g , 18.7mmol) was added to a 100mL round bottom flask, and then 1,4-dioxane (30mL) solvent was added, and the reaction was continuously stirred at 90°C for 6h. Cool to room temperature, remove the solvent under reduced pressure, add 100mL of water, then extract with ethyl acetate (300mL×3), combine the organic phases, dry with anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography After purification, the target compound 18B was obtained (1.4 g, yield: 83.6%).

Ms m/z(ESI):292.1[M+H] ⁺

The second step: tert-butyl (1R, 5S)-3-(7-(2-amino-3,4,5,6-tetrafluorophenyl)-8-fluoro-2-(((2R, 7aS) -2-Fluorotetrahydro-1H-pyrrolizine-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, the intermediate 2F (0.12g, 0.40mmol) was dissolved in a mixed solution of 1,4-dioxane (5mL) and water (1mL), and then 18B (0.20g, 0.33mmol) was added successively ), cesium carbonate (0.22g, 0.67mmol) and Pd(dppf)Cl ₂ (0.02g, 0.03mmol), reacted at a temperature of 110°C for 5h, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, and the aqueous phase Extract once more with ethyl acetate (40mL×1), combine the ethyl acetate layers, wash the ethyl acetate layer once with saturated brine (40mL×1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and wash the residue with silica gel The compound 18C (0.20 g, yield: 86.67%) was obtained by column chromatography.

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-7a(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

Dissolve compound 18C (0.20g, 0.29mmol) in 2.0mL of dichloromethane, add 0.2mL of trifluoroacetic acid, react at room temperature for 3h after the addition, and then directly concentrate the reaction under reduced pressure to remove the solvent, and perform reverse phase column chromatography The target compound 18 (0.1 g, yield: 59.6%) was obtained by separation and purification.

Example 19: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((2R,7aS)- 2-Fluorotetrahydro-1H-pyrroline-7a(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-fluorotetrahydro-1H-pyrro lizin-7a(5H)-yl)methoxy )quinazolin-7-yl)-4-amino-6-fluorobenzonitrile

The first step: 4-bromo-3-chloro-5-fluoroaniline

4-bromo-3-chloro-5-fluoroaniline

19a (1 g, 6.87 mmol) was dissolved in acetic acid (12 mL), then NBS (1.34 g, 7.56 mmol) was added at room temperature, and the reaction was continued to stir at room temperature for another 4 hours. The excess acid was removed under reduced pressure, and the target compound 19b (750 mg, yield: 48.64%) was obtained after 40 g of normal phase column purification (PE:EA=50:1～10:1).

Ms m/z(ESI):224.1[M+H] ⁺

The second step: 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 (5mL), and the reaction was stirred under microwave at 190°C for 1 hour. Add 100mL of water, then extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, spin dry, and the residue is subjected to silica gel column chromatography (PE:EA=50:1～5: 1) Obtain 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-carboxylic acid Ester 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-diazabicyclo[3.2.1]octane-8-carboxylate

Intermediate 9B (150 mg, 0.28 mmol), 19c (72 mg, 0.42 mmol), PdCl2(PPh3)2 (20 mg, 0.028 mmol) and KF (49 mg, 0.84 mmol) were added to a mixture of ACN (8 mL) and water (2 mL) in a mixed solvent. Under nitrogen protection, the reaction was stirred at 100°C for 12 hours in a sealed tube. After the reaction was cooled to room temperature, the solvent was removed under reduced pressure, 100mL of water was added, and then extracted with ethyl acetate (50mL×3). Chromatographic separation and purification gave 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]octane-3-yl)-8-fluoro-2-((2R, 7aS)- 2-Fluorotetrahydro-1H-pyrroline-7a(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-fluorotetrahydro-1H-pyrro lizin-7a(5H)-yl)methoxy )quinazolin-7-yl)-4-amino-6-fluorobenzonitrile

19d (80 mg, 0.12 mmol) was dissolved in dichloromethane (8 mL), then 2 mL of TFA was added at room temperature, and the reaction was continued to stir at room temperature for another 1 hour. The excess acid and solvent were removed under reduced pressure, and the target compound 19 (18 mg, yield: 27.29%) was obtained after purification by preparative HPLC.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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: tert-butyl (1R,5S)-3-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H)-pyrrolazin-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.

Dissolve (20A) (0.132g, 0.672mmol) in a mixed solution of 10mL of acetonitrile and 1mL of water, add 9B (0.188g, 0.336mmol), potassium fluoride (0.073g, 1.257mmol), Pd(PPh) ₂ Cl ₂ (0.023g, 0.034mmol), reacted at 100°C for 12h under nitrogen protection, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water and stirred, then separated the liquid, and extracted the aqueous phase with ethyl acetate (40mL×1) Once, the ethyl acetate layers were combined, and the ethyl acetate layer was washed once with saturated brine (40 mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (DCM:MeOH= 24:1) to obtain compound (20B) (0.15g, yield 66.07%)

LCMS m/z=676.3[M+H] ⁺

The second step: 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolazin-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.

Compound (20B) (0.15 g, 0.22 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 20( 40 mg, yield 31.3%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% NH ₄ HCO ₃ ); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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-pyrrolazin-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: 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 5 mL of concentrated sulfuric acid, and the system was placed in an ice bath for 10 min. Then, a mixed solvent of 5 mL concentrated nitric acid and 15 mL concentrated sulfuric acid was slowly added dropwise. After the dropwise addition, the system automatically rose to room temperature and reacted for 3 hours. After the reaction of the raw materials is complete, pour the system into 100 mL of ice water to quench the reaction, add 100 mL of ethyl acetate and stir, then separate the liquids, extract the water phase with ethyl acetate (40 mL×2) once more, combine the ethyl acetate layers, and The ester layer was washed once with saturated sodium bicarbonate solution (40mL×1) and saturated brine (40mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound (21B ) (5.7g, 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 heated to 85 The degree of reaction is 1h. After the reaction of the raw materials is complete, the system is cooled to room temperature, and the insoluble matter is filtered out with a pad of diatomaceous earth. The filtrate is concentrated under reduced pressure, and then 100 mL of ethyl acetate is added to dissolve it. 1) Washing once, drying over anhydrous sodium sulfate, and concentrating under reduced pressure, the residue was chromatographed on a silica gel column to obtain compound 21C (3.7 g, yield 73.5%).

The third step: tert-butyl (1R,5S)-3-(7-(3-amino-2,4,6-trifluorophenyl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H)-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy Ester (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.

Dissolve (21C) (0.072g, 0.32mmol) in a mixed solution of acetonitrile 10mL and water 1mL, add 9B (0.09g, 0.16mmol), potassium fluoride (0.035g, 0.6mmol), Pd(PPh) ₂ Cl ₂ (0.011g, 0.016mmol), reacted at 100°C for 12h under nitrogen protection, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water and stirred, then separated the liquid, and extracted the aqueous phase with ethyl acetate (40mL×1) Once, the ethyl acetate layers were combined, and the ethyl acetate layer was washed once with saturated brine (40 mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (DCM: MeOH=24 :1) Obtain compound (21D) (0.063g, yield 59%)

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-pyrrolazin-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.

Compound (21D) (0.063 g, 0.095 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 21( 13 mg, yield 24.3%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% NH ₄ HCO ₃ ); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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-pyrrolazin-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: 3-bromo-4-methyl-5-(trifluoromethyl)benzoic acid (22B)

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

Dissolve (22A) (5.0 g, 24.49 mmol) in 50 mL of concentrated sulfuric acid, add N-bromosuccinimide (4.36 g, 24.49 mmol) at room temperature, and react at room temperature for 3 h. After the reaction of the raw materials is complete, pour the system into 100 mL of ice water to quench the reaction, add 100 mL of ethyl acetate and stir, then separate the liquids, extract the water phase with ethyl acetate (40 mL×2), combine the ethyl acetate layers, and The ester layer was washed once with saturated sodium bicarbonate solution (40mL×1) and saturated brine (40mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound (22B ) (7.1g, yield 99%)

LCMS m/z=283.1[M+H] ⁺

The second step: tert-butyl (3-bromo-4-methyl-5-(trifluoromethyl)phenyl)carbamate (22C)

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

Dissolve (22B) (7.1g, 24.49mmol) in toluene (70mL), then add triethylamine (10.5mL, 73.47mmol) and diphenylphosphoryl azide (8.16mL, 36.7mmol), and place the system at room temperature After stirring for 30 minutes, tert-butanol (70 mL) was added, and then under nitrogen protection, the reaction was stirred at 110° C. for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, added water (50 mL), and extracted with ethyl acetate (70 mL×3), combined the organic phases, washed once with saturated brine (40 mL×1), dried over anhydrous sodium sulfate, After concentration under reduced pressure, the residue was chromatographed on a silica gel column to obtain compound (22C) (7.9 g, yield 89%)

LCMS m/z=354.1[M+H] ⁺

The third step: (4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzene base) tert-butyl carbamate (22D)

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

Under nitrogen protection, (3-bromo-4-methyl-5-(trifluoromethyl)phenyl) tert-butyl carbamate (22C) (2g, 5.65mmol), diboronic acid pinacol ester (1.6g , 6.21mmol), potassium acetate (1.1g, 11.3mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (461mg, 0.57mmol) placed in In the sealed tube, 30 mL of 1,4-dioxane was added, the temperature was raised to 90°C, 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 obtain compound (22D) (1.8 g, yield 78%).

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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylate (22E)

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-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 15mL of 1,4-dioxane and 1.5mL of water were added. The temperature was raised to 105° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound (22E) (170 mg, yield 64%)

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-pyrrolazin-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.

Compound (22E) (0.17 g, 0.216 mmol) was dissolved in 10 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 1 mL of N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, prepare and purify the residue by HPLC, and freeze-dry the preparation solution to obtain compound 22 (96 mg , Yield 75.6%), white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrrolazin-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: tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H)-pyrrolizine-7a(5H)-yl)methanol Oxy)-7-(5-methyl-1H-indazol-6-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid Esters (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 nitrogen protection, 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 (175mg, 0.537mmol) were placed in a sealed tube, and 15mL1 , 4-dioxane and 1.5 mL of water. The temperature was raised to 105° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound (23B) (150 mg, yield 90%)

LCMS m/z=646.3[M+H] ⁺

The second step: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-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

Compound (23B) (0.15 g, 0.23 mmol) was dissolved in 10 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 1 mL of N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, prepare and purify the residue by HPLC, and freeze-dry the preparation solution to obtain compound 23 (73 mg , yield 58.2%), white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% CF ₃ COOH); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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-pyrrolazin-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: 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.

Under nitrogen protection, intermediate 14B (500mg, 1.5mmol), (2,4-difluorophenyl)boronic acid 24A (285mg, 1.8mmol), tetrakistriphenylphosphine palladium (173mg, 0.15mmol) and potassium carbonate ( 414.6mg, 3.0mmol) was placed in a sealed tube, and 30mL of 1,4-dioxane and 6mL of water were added. The temperature was raised to 100° C. for 12 hours. The reaction was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound (24B) (507 mg, yield 88%)

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-di Azabicyclo[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]octane-8-carboxylate .

Dissolve (24B) (0.145g, 0.456mmol) in a mixed solution of acetonitrile 10mL and water 1mL, add 9B (0.17 g, 0.304mmol), potassium fluoride (0.066g, 1.14mmol), Pd(PPh)2Cl2( 0.025g, 0.03mmol), reacted at 100°C for 12h under the protection of nitrogen, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, stirred and separated the liquid, and extracted the water phase with ethyl acetate (40mL×1) once more, The ethyl acetate layers were combined, and the ethyl acetate layer was washed once with saturated brine (40 mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain compound (24C) (0.13g, 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-pyrrolazin-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.

Compound (24C) (0.13 g, 0.17 mmol) was dissolved in 10 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 1 mL of N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, prepare and purify the residue by HPLC, and freeze-dry the prepared solution to obtain compound 24 (30 mg , yield 27%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% CF3COOH); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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-pyrrolazin-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: 5-bromo-2-iodo-4-(trifluoromethyl)aniline (25B)

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

Dissolve 3-bromo-4-(trifluoromethyl)aniline (25A) (4g, 16.67mmol) in 25mL of acetic acid, add N-iodosuccinimide (4.12g, 18.33mmol), and stir the reaction at room temperature 3 hours. Then, saturated aqueous sodium bicarbonate solution 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 obtain compound (25B) as a reddish-brown solid (5.77 g, yield 95%)

LCMS m/z=365.9[M+H] ⁺

The second step: 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 20mL of 1,4-dioxane and 5mL of water were added to replace the nitrogen protection. The temperature was raised to 60° C. for 18 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound (25C) as a tan solid (611mg , yield 29%)

LCMS m/z=254.0[M+H] ⁺

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

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

Compound 25C (345mg, 1.36mmol), pinacol diboronate (517mg, 2.03mmol), potassium acetate (400mg, 4.08mmol), [1,1'-bis(diphenylphosphino)ferrocene] di Palladium chloride dichloromethane complex (114 mg, 0.14 mmol) was placed in a sealed tube, 5 mL of 1,4-dioxane was added, nitrogen was replaced, and the temperature was raised to 90 degrees Celsius for 6 hours of reaction. 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 obtain compound (25D) as a brown solid (232 mg, yield 56%).

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-pyrrolazin-7a(5H)-yl)methoxy)-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylate (25E) tert-butyl(1R,5S)-3-(7-(5-amino-4-methyl-2-(trifluoromethyl)phenyl)-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 2F (120mg, 0.20mmol), compound 25D (117mg, 0.39mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (17mg, 0.02mmol) and cesium carbonate (127mg, 0.39mmol) were placed in a sealed tube, and 2mL of 1,4-dioxane and 0.5mL of water were added to replace the nitrogen protection. The temperature was raised to 105° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound (25E) as a tan solid (123mg , yield 90%)

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-pyrrolazin-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

Compound 25E (123 mg, 0.18 mmol) was dissolved in 2.5 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 3 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, and prepare and purify the residue by HPLC. The preparation solution is concentrated and freeze-dried to obtain compound 25( 45 mg, yield 42%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-fluoro Tetrahydro-1H-pyrrolazin-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: 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, replaced with nitrogen, placed in an ice bath, slowly added an aqueous solution (1mL) of sodium nitrite (169mg, 2.44mmol), and then stirred at room temperature for 12 hours . Saturated sodium bicarbonate adjusted the pH to 7, extracted three times with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to obtain compound 26A as a tan solid (292 mg, produced rate 45%)

LCMS m/z=265.0[M+H] ⁺

The second step: tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy Base)-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-carboxylate

Intermediate 9B (190mg, 0.37mmol), compound 26A (95mg, 0.36mmol), tris(dibenzylidene-BASEacetone)dipalladium (37mg, 0.04mmol), 2-(dicyclohexylphosphine)-3,6 -Dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (43mg, 0.08mmol) and sodium carbonate (76mg, 0.72mmol) were placed in a sealed tube, and 2mL1 , 4-dioxane and 0.5mL of water, replace the nitrogen protection. The temperature was raised to 120° C. for 3 hours to react. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 26B as a tan solid (58 mg, produced rate 23%)

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-fluoro Tetrahydro-1H-pyrrolazin-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 (58 mg, 0.083 mmol) was dissolved in 2.5 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 60 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 26( 20 mg, yield 40%).

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% NH4HCO3); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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-pyrrolazin-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: 6-chloro-4-(trifluoromethyl)pyridin-2-amine (27B)

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

Compound 27A (2.5 g, 11.58 mmol) was placed in an autoclave, 70 mL of ammonia water was added, and the temperature was raised to 100° C. for 24 hours. The reaction was cooled to room temperature, diluted with water, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to obtain compound (27A) as a colorless oil (585mg , yield 26%)

LCMS m/z=197.1[M+H] ⁺

The second step: tert-butyl (1R, 5S)-3-(7-(6-amino-4-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-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 (160 mg, 0.29 mmol), compound 27B (69 mg, 0.35 mmol), bistriphenylphosphine palladium dichloride (21 mg, 0.03 mmol), and potassium fluoride (63 mg, 1.08 mmol) were placed in a locked tube In, add 2mL of acetonitrile and 0.5mL of water to replace the nitrogen protection. The temperature was raised to 100° C. for 18 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 27C as a yellow solid (92mg, yield 48%)

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-pyrrolazin-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

Compound 27C (92 mg, 0.136 mmol) was dissolved in 2.5 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 27( 17 mg, yield 22%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrrolazin-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: 4-amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzonitrile (28B)

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

4-amino-2-bromobenzonitrile (28A) (1.65g, 8.33mmol), biboronic acid pinacol ester (3.17g, 12.50mmol), potassium acetate (3.27g, 33.32mmol), [1,1' -Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (680mg, 0.83mmol) was placed in a sealed tube, and 15mL 1,4-dioxane was added to replace the nitrogen protection. To 90 degrees Celsius, 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 obtain compound 28B as a yellow oil (1.6 g, yield 79%).

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)-pyrrolazin-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 (16mg, 0.02mmol) and cesium carbonate (130mg, 0.40mmol) were placed in a sealed tube, and 2.5mL of 1,4-dioxane and 0.5mL of water were added to replace the nitrogen protection. The temperature was raised to 105° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 28C as a brown solid (116 mg, yield 92%)

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-pyrrolazin-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

Compound 28C (116 mg, 0.18 mmol) was dissolved in 2.5 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 28 ( 39 mg, yield 41%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrrolazin-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: 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 15mL of 1,4-dioxane and 4mL of water were added to replace the nitrogen protection. The temperature was raised to 80° C. for 18 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 29A as a yellow solid (181 mg, yield twenty four%)

LCMS m/z=280.0[M+H] ⁺

The second step: tert-butyl (1R, 5S)-3-(7-(5-amino-4-cyclopropyl-2-(trifluoromethyl)phenyl)-8-fluoro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-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 2mL of 1,4-dioxane and 0.5mL of water were added to replace the nitrogen protection. The temperature was raised to 110° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 29B as a tan solid (133 mg, produced rate 83%)

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-pyrrolazin-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

Compound 29B (133 mg, 0.19 mmol) was dissolved in 2.5 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 29( 48 mg, yield 41%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% NH4HCO3); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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-pyrrolazin-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: 3-bromo-5-chloro-4-iodoaniline (30B)

3-bromo-5-chloro-4-iodoaniline

Dissolve 3-bromo-5-chloroaniline (30A) (5g, 24.22mmol) in 25mL of N,N-dimethylformamide, add N-iodosuccinimide (5.99g, 26.64mmol), room temperature The reaction was stirred for 3 hours. Then a saturated sodium thiosulfate solution 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 obtain compound (30B) as a reddish-brown solid (7.49 g, yield 93%)

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]dichloropalladium dichloromethane Compound (245mg, 0.30mmol) and cesium carbonate (1.96g, 6.02mmol) were placed in a sealed tube, and 15mL of 1,4-dioxane and 4mL of water were added to replace the nitrogen protection. The temperature was raised to 80° C. for 8 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 30C as a brown solid (780 mg, yield 95%)

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-pyrrolazin-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 2mL of 1,4-dioxane and 0.5mL of water were added to replace the nitrogen protection. The temperature was raised to 110° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 30D as a tan solid (112 mg, produced rate 72%)

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-pyrrolazin-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

Compound 30D (112 mg, 0.16 mmol) was dissolved in 2.5 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 30( 30 mg, yield 31%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrrolazin-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: N-[3-bromo-4-(trifluoromethyl)phenyl]acetamide (31A)

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

Dissolve the raw material 3-bromo-4-trifluoromethylaniline (1.0g, 4.2mmol) in 5ml of dichloromethane, add triethylamine (0.848g, 8.4mmol) acetyl chloride (0.494g, 6.3mmol), room temperature After stirring for 2 h, after the reaction was completed, it was concentrated 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: tert-butyl (1R,5S)-3-(7-(5-acetylamino-2-(trifluoromethyl)phenyl]-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy Ester (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

Dissolve (31A) (0.15g, 0.52mmol) in a mixed solution of 1,4-dioxane 5mL and water 1mL, add 9B (0.23g, 0.42mmol), cesium carbonate (0.3g, 1.04mmol), Pd(dppf)Cl ₂ (0.038g, 0.052mmol), reacted at 100°C under nitrogen protection for 2h, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, and then used ethyl acetate (40mL×1) for the aqueous phase Extract once, combine the ethyl acetate layers, wash the ethyl acetate layer once with saturated brine (40mL×1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is chromatographed on a silica gel column to obtain compound (31B) (0.11g, 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 )

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

Compound (31B) (0.11 g, 0.15 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, prepare and purify the residue by HPLC, and freeze-dry the prepared solution to obtain compound 31( 20 mg, yield 21.64%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrrolazin-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: N-[3-bromo-4-(trifluoromethyl)phenyl]methanesulfonamide (32A)

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

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

LCMS m/z=318.0[M+H] ⁺

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

Dissolve (32A) (0.16g, 0.52mmol) in a mixed solution of 1,4-dioxane 5mL and water 1mL, add 9B (0.23g, 0.42mmol), cesium carbonate (0.3g, 1.04mmol), Pd(dppf)Cl ₂ (0.038g, 0.052mmol), reacted at 100°C under nitrogen protection for 2h, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, and then used ethyl acetate (40mL×1) for the aqueous phase Extract once, combine the ethyl acetate layers, wash the ethyl acetate layer once with saturated brine (40mL×1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is chromatographed on a silica gel column to obtain compound (32B) (0.11g, 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-pyrrolazin-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

Compound (32B) (0.11 g, 0.15 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 32( 20 mg, yield 20.45%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrrolazin-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: 7-bromo-1-isopropyl-5-nitroindazole (33A)

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

The starting material 7-bromo-5-nitro-1H-indazole (2.0 g, 8.3 mmol) was dissolved in 20 mL of tetrahydrofuran, and 1,8-diazabicyclo[5.4.0]undec-7-ene was added (2.52g, 16.6mmol) and 2-iodopropane (1.7g, 10mmol), heated to 60°C and stirred for 2h, after the reaction was completed, concentrated under reduced pressure, and column chromatography gave compound 33A (0.9g, 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

Dissolve 33A (0.90g, 3.17mmol) in 9mL ethanol and 3mL water, add reduced iron powder (0.90g, 16.0mmol) ammonium chloride (1.74g, 31.7mmol), heat up to 80°C and stir for 2h, after the reaction is complete, Concentration under reduced pressure and column chromatography gave 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-pyrrolazin-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-fluororotet rahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy late

Dissolve (33B) (0.13g, 0.52mmol) in a mixed solution of 1,4-dioxane 5mL and water 1mL, add 9B (0.23g, 0.42mmol), cesium carbonate (0.3g, 1.04mmol), Pd(dppf)Cl ₂ (0.038g, 0.052mmol), reacted at 100°C under nitrogen protection for 2h, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, and then used ethyl acetate (40mL×1) for the aqueous phase Extract once, combine the ethyl acetate layers, wash the ethyl acetate layer once with saturated brine (40mL×1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is chromatographed on a silica gel column to obtain compound (33C) (0.11g, 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-pyrrolazin-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

Compound (33C) (0.11 g, 0.16 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 33( 20 mg, yield 21.25%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrrolazin-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: 7-bromo-1-ethyl-5-nitroindazole (34A)

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

The starting material 7-bromo-5-nitro-1H-indazole (2.0 g, 8.3 mmol) was dissolved in 20 mL of tetrahydrofuran, and 1,8-diazabicyclo[5.4.0]undec-7-ene was added (2.52g, 16.6mmol), ethyl iodide (1.56g, 10mmol), heated to 60°C and stirred for 2h, after the reaction was completed, concentrated under reduced pressure, and column chromatography gave compound 34A (0.9g, yield 40.30%).

LCMS m/z=270.1[M+H] ⁺

The second step: 7-bromo-1-ethylindazol-5-amine (34B)

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

Dissolve 34A (0.90g, 3.34mmol) in 9mL ethanol and 3mL water, add reduced iron powder (0.90g, 16.0mmol) ammonium chloride (1.74g, 31.7mmol), heat up to 80°C and stir for 2h, after the reaction is complete, Concentration under reduced pressure and column chromatography gave compound 34B (0.56 g, yield 69.86%).

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-pyrrolazin-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

Dissolve (34B) (0.12g, 0.52mmol) in a mixed solution of 1,4-dioxane 5mL and water 1mL, add 9B (0.23g, 0.42mmol), cesium carbonate (0.3g, 1.04mmol), Pd(dppf)Cl ₂ (0.038g, 0.052mmol), reacted at 100°C under nitrogen protection for 2h, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, and then used ethyl acetate (40mL×1) for the aqueous phase Extract once, combine the ethyl acetate layers, wash the ethyl acetate layer once with saturated brine (40mL×1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, the residue is chromatographed on a silica gel column to obtain compound (34C) (0.11g, 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-pyrrolazin-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

Compound (34C) (0.11 g, 0.16 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 34( 20 mg, yield 21.77%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrrolazin-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: tert-butyl (5-bromo-2-iodo-4-(trifluoromethyl)phenyl)carbamate (35A)

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

Compound 25B (1g, 2.73mmol) was dissolved in 12mL tetrahydrofuran, under ice-cooling, lithium bistrimethylsilylamide (6.0mL, 1M) was added, the reaction was stirred for 0.5 hours, and di-tert-butyl dicarbonate (656mg, 3.00mmol), continue to react for 3 hours. Then a saturated ammonium chloride solution 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 obtain compound (35A) as a white solid (572mg, yield 45%)

LCMS m/z=463.9[MH] ^-

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), dissolved in N,N-dimethylformamide, then added cuprous iodide (465mg, 2.44mmol ) and N,N-diisopropylethylamine (1.11g, 8.59 mmol), placed in a sealed tube, replaced by nitrogen protection. Raise the temperature to 75°C for 24 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 35B as a brown solid (132 mg, yield 35%)

LCMS m/z=306.0[MH] ^-

The third step: tert-butyl (1R,5S)-3-(7-(5-amino-2,4-bis(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-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 (159 mg, 0.29 mmol), compound 35B (60 mg, 0.19 mmol), bistriphenylphosphine palladium dichloride (14 mg, 0.02 mmol), and potassium fluoride (41 mg, 0.71 mmol) were placed in a locked tube In, add 2mL of 1,4-dioxane and 0.5mL of water to replace the nitrogen protection. The temperature was raised to 100° C. for 18 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 35C as a brown solid (70mg, yield 50%)

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-pyrrolazin-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

Compound 35C (70 mg, 0.094 mmol) was dissolved in 2.5 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 30( 26 mg, yield 43%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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]-octane-3-yl)-8-fluoro-2-(2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolazin-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: (3-bromo-5-fluoro-4-iodophenyl) tert-butyl carbamate (36B)

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

Under the protection of _N2 , compound 36A (5.0g, 15.83mmol), di-tert-butyl dicarbonate (4.15g, 19.0mmol) were first dissolved in 20mL of THF, and then slowly dropwise added LiHMDS (6.55mL), after the dropwise addition, the reaction solution was moved to normal temperature for 8h, after the reaction was complete, EA/H ₂ O (150mL/100mL) was extracted and washed, the organic layer was concentrated, and chromatographed Column purification gave compound 36B (4.50 g, yield: 68.33%).

Ms m/z(ESI):413.9[MH] ⁺

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

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

Under the protection of _N2 , compound 36B (2.0g, 4.81mmol), MFSDA (6.47g, 33.67mmol) and CuI (1.37g, 7.21mmol) were added to the reaction test tube in turn, and then DIPEA (4.35g, 33.67mmol) was dissolved in 20mL of DMF and slowly added dropwise to the reaction test tube. The reaction was continued in an oil bath at 75° C. for 16 hours. After the reaction was completed, EA/H ₂ O (200 mL/150 mL*2) was used for extraction and washing. Finally, the organic layer was concentrated and purified by column chromatography (PE:EA=10:1) to obtain compound 36C (1.20 g, yield: 69.66% yield).

Ms m/z(ESI):356.0[MH] ⁺

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-pyrrolazine-7a(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-diazabicyclo[3.2.1]octane-8-carboxylate

Intermediate 9B (200 mg, 0.36 mmol) and compound 36C (160.0 mg, 0.43 mmol) were placed in a sealed tube, 2 mL of 1,4-dioxane solution was added to dissolve, and then [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride (26.0 mg, 0.036 mmol), cesium carbonate (230.0 mg, 0.72 mmol). Under the protection of nitrogen, rise to 110 ° C for 5 h, remove the solvent under reduced pressure, add 50 mL of water and 100 mL of ethyl acetate to dissolve, wash the water phase with 50 mL×2 ethyl acetate, combine the organic phase, and wash the organic phase once with 40 mL of saturated saline , and then the organic phase was dried with anhydrous sodium sulfate, spin-dried, and column chromatography (DCM:MeOH=15:1) 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]-octane-3-yl)-8-fluoro-2-(2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolazin-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 (200 mg, 0.25 mmol) was dissolved in 10 mL of DCM, then 1 mL of trifluoroacetic acid was added dropwise at room temperature, the system continued to react for 3 h, the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC, and the preparative solution was concentrated and frozen The target compound 36 was obtained by drying (100 mg, yield: 67.5% yield).

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% NH4HCO3); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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]-octane-3-yl)-8-fluoro-2-(2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-amino-6-chlorobenzonitrile (compound 37)

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: 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, blown with nitrogen for three minutes, then added cuprous cyanide (130mg, 1.50mmol), followed by microwave at 100°C , reacted for 1 hour. Dilute with water and extract 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 obtain compound (37A) as a light yellow solid (259 mg, yield 75%)

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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid Esters (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, and 2.5mL of 1,4-dioxane and 0.5mL of water were added to replace the nitrogen protection. The temperature was raised to 110° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 37B as a brown solid (83mg, yield 46%)

LCMS m/z=666.3[M+H] ⁺

The third step: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]-octane-3-yl)-8-fluoro-2-(2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-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 (80 mg, 0.12 mmol) was dissolved in 3 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 37 ( 34 mg, yield 50%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

LCMS m/z=566.2[M+H] ⁺

Example 38: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]-octane-3-yl)-8-fluoro-2-(2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-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: tert-butyl (1R, 5S)-3-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-( (((2R, 7aS)-2-fluorotetrahydro-1H)-pyrrolazin-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(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (28mg, 0.03mmol) and cesium carbonate (220mg, 0.68mmol) were placed in a sealed tube, and 3mL of 1,4-dioxane and 0.8mL of water were added to replace the nitrogen protection. The temperature was raised to 110° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 38B as a brown solid (112 mg, yield 45%)

LCMS m/z=726.3[M+H] ⁺

The second step: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]-octane-3-yl)-8-fluoro-2-(2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-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

Compound 38B (112 mg, 0.15 mmol) was dissolved in 2 mL of dichloromethane, then dropped into 2.65 mL of 4N hydrochloric acid-dioxane solution, and reacted at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.8mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 38 ( 57 mg, yield 65%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

LCMS m/z=582.2[M+H] ⁺

Example 39: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]-octane-3-yl)-8-fluoro-2-(2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-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: 5-amino-3 bromo-2 iodobenzonitrile (39B)

5-amino-3-bromo-2-iodobenzonitrile

Add 2-amino-5-bromoxynil 39A (2.50g, 12.69mmol), dissolve with methyl tert-butyl ether, then add iodine (6.44g, 25.38mmol), dimethyl sulfoxide (3.15mL, 44.41mmol ) under _N2 protection, stirred at room temperature for 3 hours, diluted with water, extracted three times with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to obtain compound 39B as yellow Solid (1.276g, 31% 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(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (150mg , 0.23mmol) and cesium carbonate (750mg, 5.4mmol) were placed in a sealed tube, and 9mL of 1,4-dioxane and 3mL of water were added to replace the nitrogen protection. The temperature was raised to 80° C. for 8 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 39C as a yellow solid (163 mg, yield 38%)

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-7a(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 the nitrogen protection. The temperature was raised to 110° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 39D as a brown-black solid (123 mg, produced rate 61%)

LCMS m/z=672.3[M+H] ⁺

The fourth step: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]-octane-3-yl)-8-fluoro-2-(2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-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

Compound 39D (120 mg, 0.18 mmol) was dissolved in 3 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, prepare and purify the residue by HPLC, and freeze-dry the prepared solution to obtain compound 39( 58 mg, yield 56%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

LCMS m/z=572.3[M+H] ⁺

Example 40: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]-octane-3-yl)-8-fluoro-2-(2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-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)benzonitrole

The first step: (3-bromo-5-cyano-4-iodophenyl) tert-butyl carbamate (40A)

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

Under the protection of N ₂ , first dissolve compound 39B (1.0g, 3.10mmol), di-tert-butyl dicarbonate (740mg, 3.41mmol) in 20mL of THF, and then slowly dropwise add 1N LiHMDS (6.79mL), after the dropwise addition, the reaction solution was moved to normal temperature and reacted for 2 hours, diluted with saturated ammonium chloride solution, extracted three times with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, and Purified by column chromatography after concentration under reduced pressure to obtain compound 40A as a yellow oil (1.01 g, yield 77%)

LCMS m/z=422.9[M+H] ⁺

The second step: tert-butyl (3-bromo-5-cyano-4-(trifluoromethyl)phenyl)carbamate (40B)

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

Under the protection of _N2 , compound 40A (980mg, 2.32mmol), methyl fluorosulfonyl difluoroacetate (3.12g, 16.24mmol) and cuprous iodide (660mg, 3.48mmol) were added to the reaction test tube in sequence, Then N,N-diisopropylethylamine (2.69 mL, 16.24 mmol) was dissolved in 10 mL of DMF and slowly added dropwise into the reaction test tube. Continue the reaction in an oil bath at 75°C for 24 hours, cool the reaction to room temperature, add water to dilute, then extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure and pass through the column layer Purified by analysis to obtain compound 40B as a yellow solid (754 mg, yield 89%)

LCMS m/z=363.0[MH] ^-

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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazepine Heterobicyclo[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-diazabicyclo[3.2.1]octane-8-carboxylate

Intermediate 9B (180mg, 0.32mmol), compound 40B (120mg, 0.32mmol), [1,1'-bis(diphenylphosphine)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 protection. The temperature was raised to 110° C. for 3 hours. The reaction was cooled to room temperature, diluted with water, 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 obtain compound 40C as a reddish-brown solid (66 mg, yield rate 26%)

LCMS m/z=800.3[M+H] ⁺

The fourth step: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]-octane-3-yl)-8-fluoro-2-(2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-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)benzonitrole

Compound 40C (66 mg, 0.08 mmol) was dissolved in 3 mL of dichloromethane, then 0.5 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 40( 30mg, yield 60%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

3. Mobile phase A: acetonitrile; B: purified water (containing 1% NH4HCO3); gradient elution, the content of mobile phase A is eluted from 5% to 50%; flow rate: 12mL/min; elution time: 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-pyrrolazin-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: (4-amino-2-bromophenyl) dimethylphosphine oxide (41c)

(4-amino-2-bromophenyl)dimethylphosphine oxide.

Put (41a) (2.86g, 9.6mmol) in a sealed tube, add 50mL of 1,4-dioxane to dissolve, then add (41b) (500mg, 6.4mmol), tetrakistriphenylphosphine palladium (1.1g , 0.96mmol), potassium carbonate (1.77g, 12.8mmol) and 5mL of water. Replace the gas with nitrogen three times, heat to 80°C and react for 12 hours. After the reaction is completed, cool the reaction to room temperature, add 40 mL of ethyl acetate and 25 mL of water, stir and separate the liquids, and extract the water phase with ethyl acetate (40 mL×1) once more , the ethyl acetate layers were combined, and the ethyl acetate layer was washed once with saturated brine (40mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (PE:EA=5: 1) Obtain compound (41c) (1.07g, yield: 67%)

LCMS m/z=248.0[M+H]+

The second step: tert-butyl (1R, 5S)-3-(7-(5-amino-2-(dimethylphosphoryl) phenyl)-8-fluoro-2-((((2R, 7aS) -2-Fluorotetrahydro-1H-pyrrolazin-7a)(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -Carboxylate (41d)

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.

Dissolve (41c) (0.16g, 0.646mmol) in a mixed solution of 15mL of acetonitrile and 1.5mL of water, add 9B (180mg, 0.323mmol), potassium fluoride (0.070g, 1.21mmol), bistriphenylphosphine di Palladium chloride (0.023g, 0.032mmol), reacted at 100°C for 12h under the protection of nitrogen, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, stirred and separated the liquids, and then used ethyl acetate (40mL×1 ) was extracted once, the ethyl acetate layers were combined, and the ethyl acetate layer was washed once with saturated brine (40mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (DCM: MeOH =96:4) Compound (41d) was obtained (0.15g, 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-pyrrolazin-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.

Compound (41d) (0.15 g, 0.22 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 41( 50 mg, yield: 39%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrrolazin-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: 3-bromo-5-chloro-4-(prop-1-en-2-yl)aniline (42b)

3-bromo-5-chloro-4-(prop-1-en-2-yl)aniline.

Dissolve (14b) (0.628g, 1.89mmol) in a mixed solution of 30mL of acetonitrile and 3mL of water, add 42a (265mg, 1.58mmol), potassium fluoride (0.343g, 5.9mmol), bistriphenylphosphine dichloro Palladium chloride (0.11g, 0.158mmol), reacted at 100°C for 12h under the protection of nitrogen, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, stirred and separated the liquids, and then used ethyl acetate (40mL×1) Extract once, combine the ethyl acetate layers, wash the ethyl acetate layer once with saturated brine (40 mL×1), dry over anhydrous sodium sulfate, and concentrate under reduced pressure, the residue is chromatographed on a silica gel column (PE: EA =5:1) to obtain compound (42b) (0.29g, yield: 75%)

LCMS m/z=246.0[M+H] ⁺

The second step: 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2. 1] Octane-8-carboxylate (42c)

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.

Dissolve (42b) (0.09g, 0.365mmol) in a mixed solution of 15mL of acetonitrile and 1.5mL of water, add 9B (170mg, 0.304mmol), potassium fluoride (0.066g, 1.137mmol), bistriphenylphosphine di Palladium chloride (0.021g, 0.03mmol), reacted at 100°C for 12h under the protection of nitrogen, cooled the reaction to room temperature, added 40mL of ethyl acetate and 25mL of water, stirred and separated the liquids, and then used ethyl acetate (40mL×1 ) was extracted once, the ethyl acetate layers were combined, and the ethyl acetate layer was washed once with saturated brine (40mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (DCM: MeOH =96:4) Compound (42c) was obtained (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-pyrrolazin-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.

Compound (42c) (0.11 g, 0.26 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes. Concentrate the reaction solution under reduced pressure, then add dichloromethane to dissolve it, add 0.5mL N,N-diisopropylethylamine dropwise, concentrate under reduced pressure, the residue is prepared and purified by HPLC, the preparation solution is concentrated and freeze-dried to obtain compound 42( 51 mg, yield: 54%), as a white powder.

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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-pyrrole Oxyzin-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: 3-(3-(methoxymethoxy)naphthalene-1-yl)cyclohexan-1-one (43b)

3-(3-(methoxymethoxy)naphthalen-1-yl)cyclohexan-1-one.

Put (43a) (2.0g, 6.37mmol) in a sealed tube, add 40mL of 1,4-dioxane to dissolve, then add cyclohexenone (0.92mL, 9.56mmol), (1,5-cyclooct Diene) ruthenium(I) chloride dimer (314 mg, 0.637 mmol), potassium phosphate (4.0 g, 19.11 mmol) and 8 mL of water. Replace the gas with nitrogen three times, heat to 50°C for 12 hours, cool the reaction to room temperature, add 40 mL of ethyl acetate and 25 mL of water and stir, then separate the liquids, extract the water phase with ethyl acetate (40 mL×2) once more, and combine the ethyl acetate layer, the ethyl acetate layer was washed once with saturated brine (40mL×1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound (43b) (1.7g, yield Rate: 94%)

LCMS m/z=285.1[M+H] ⁺

The second step: ethyl 4-(3-(methoxymethoxy)naphthalen-1-yl)-2-oxocyclohexane-1-carboxylate (43c)

ethyl 4-(3-(methoxymethoxy)naphthalen-1-yl)-2-oxocyclohexane-1-carboxylate.

Compound 43b (1.2g, 4.22mmol) was suspended in 30mL of dry tetrahydrofuran, cooled to -78°C under nitrogen protection, and a solution of LiHMDS in tetrahydrofuran (6.33mL, 1mol/L, 6.33mmol) was slowly added dropwise, and the system was maintained at -78°C Stir for 30min. Then ethyl cyanoformate (627mg, 6.33mmol) was added dropwise, and after the dropwise addition, the system automatically rose to room temperature and reacted for 2h. After cooling to 0°C, 50 mL of ice water was added dropwise to quench the reaction. Then it was extracted three times with 50 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 43c (1.6 g crude product), which was directly used in the next reaction without purification.

LCMS m/z=357.2[M+H] ⁺

The third step: 7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-alcohol ( 43d)

7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-ol.

Compound 43c (1.6g crude product) was dissolved in a mixed solution of 100mL ethanol and 20mL water, and S-methylisothiourea sulfate (11.75g, 42.2mmol) and sodium bicarbonate (15.95g, 189.9mmol) were added. Under the protection of nitrogen, it was heated to 50° C. for 12 h. Concentrate under reduced pressure to remove the solvent, add 50 mL of water to dilute, extract the aqueous phase with 50 mL of ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Separation and purification by column chromatography gave the target product 43d (950 mg, two-step yield: 59%).

LCMS m/z=383.1[M+H] ⁺

The fourth step: 7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-yltri Flate (43e)

7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-yl trifluoromethanesulfonate.

Compound 43d (950 mg, 2.49 mmol) was dissolved in 30 mL of dichloromethane, N,N-diisopropylethylamine (1.65 mL, 9.96 mmol) was added, trifluoromethanesulfonic anhydride (0.84 mL, 4.98 mmol), stirred in ice bath for 1h. Add 20 mL of dichloromethane to dilute, then wash the reaction with 20 mL of water, then wash the organic phase with 20 mL of saturated aqueous sodium bicarbonate solution, dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the target crude product 43e (940 mg of crude product).

LCMS m/z=515.1[M+H] ⁺

The fifth step: 3-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydroquinazoline-4 -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (43f)

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 crude product) was dissolved in 20 mL N,N-dimethylacetamide, N, N-diisopropylethylamine (1.65 mL, 9.96 mmol) and 3,8-diazabicyclo[ 3.2.1] tert-butyl octane-8-carboxylate (793mg, 3.74mmol), then stirred at room temperature for 3h. Add 100 mL of ethyl acetate for dilution, wash the organic phase three times with 20 mL of water and once with 20 mL of saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The target crude product 43f (920 mg crude) was obtained after column chromatography.

LCMS m/z=577.2[M+H] ⁺

The sixth step: tert-butyl 3-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinone Azolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (43g)

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 crude product) was dissolved in 20 mL of tetrahydrofuran, m-chloroperoxybenzoic acid (1.72 g, 9.96 mmol) was added at room temperature, and stirred at room temperature for 2 h. Add 20mL of saturated aqueous sodium thiosulfate solution, stir for 20min, add 50mL of ethyl acetate for extraction, the organic layer is washed with 20mL of saturated aqueous sodium bicarbonate solution, concentrated under reduced pressure, column chromatography to obtain the target compound 43g (459mg, three-step yield: 30 %).

LCMS m/z=609.2[M+H] ⁺

The seventh step: 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-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.

Compound 43g (459mg, 0.755mmol) and intermediate 1c-1 (240mg, 1.51mmol) were dissolved in 20mL toluene, sodium tert-butoxide (109mg, 1.13mmol) was added under ice-cooling, and stirred for 1h under ice-cooling. Add 20 mL of water to quench the reaction, add 50 mL of ethyl acetate to extract three times, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Separation and purification by column chromatography gave the target product 43h (520 mg, yield: 95%).

LCMS m/z=588.3[M+H] ⁺

The eighth step: 4-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-7-yl)naphthalene-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

Dissolve compound (43h) (0.52g, 0.88mmol) in 5mL of dichloromethane, add 0.5mL of trifluoroacetic acid, react at room temperature for 10 minutes, immediately add N,N-diisopropylethylamine to adjust the pH to alkaline . Concentrate under reduced pressure, and the residue is purified by preparative HPLC. The preparation solution is concentrated and then lyophilized to obtain compound 43 (23 mg, yield: 4.8%).

HPLC preparation method:

1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C ₁₈ (19mm*250mm).

2. Dissolve the sample in DMF and filter it with a 0.45 μM filter head to make a sample solution.

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

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 case

Biological test 1: In vitro KRAS G12D binding assay

method one:

Human recombinant protein Tag1-RAF1 and Tag2-KRAS-G12D were prepared into a 2.5× protein solution. Add 2 μL of different concentrations of compounds to a 384-well plate, add 4 μL of 2.5× Tag1-RAF1 and 4 μL of 2.5× Tag2-KRAS-G12D protein, and incubate at room temperature for 60 minutes. After the incubation, add 10 μL pre-mixed antibody Tag1-Eu and antibody Tag2-XL665 to the microwell plate, incubate at room temperature for 2 hours, use a multi-functional microplate reader to set the excitation light to 320nM, the emission light to 615nM and 665nM, read Fluorescent signals at 615nm (Eu) and 665nm (d2). Calculate the signal ratio Ratio according to formula (1), and use PrismGraphPad 7.0 software to calculate the IC ₅₀ value.

Ratio＝[Signal 665]/[Signal 615]*10 ⁴ (Formula 1)

Method Two:

Add 2 μL of the compound at different concentrations diluted in dilution buffer to the 384-well white plate. 250X Tag2-KRAS-G12D protein and 10mM GTP were diluted 50-fold and 200-fold with dilution buffer, respectively, and 4 μL of the mixture was added to the test plate. 500X Tag1-RAF was diluted 100 times with dilution buffer and 4 μL was added to the test plate; the test plate was incubated at 25°C for 15 minutes. After incubation, anti-Tag1-Eu and anti-Tag2-XL665 were diluted 100-fold and 50-fold with detection buffer, respectively, and 10 μL of the mixture was added to the test plate, and incubated at 4°C for 2 hours. After the reaction, use a multi-label analyzer to read the signal value, excitation: 320nm, emission: 615nm, 665nm.

Use the formula Ratio=[Signal 665]/[Signal 615]×10 ⁴ to calculate the signal ratio, and use the formula 2 to calculate the inhibition rate, where R _sample is the signal ratio of compound wells, R _min is the signal ratio of control wells without KRAS G12D protein, R _max is the signal ratio of the control well containing 1% DMSO solvent, and the GraphPad Prism software is used to perform curve fitting with four parameters and calculate the IC ₅₀ value. The test results are shown in Table 1.

Inhibition%＝(1-(R _sample -R _min )/(R _max -R _min ))×100% (Formula 2)

Table 1 IC ₅₀ values of compounds of the present invention

Test Methods Compound number IC₅₀(nM) Method Two Trifluoroacetate 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

Conclusion: the compound of the present invention has good inhibitory activity on the protein interaction between KRAS G12D and RAF1.

Biological Test 2: Cell Proliferation Inhibition Experiment

ASPC-1 cell culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO ₂ incubator. On the first day, collect ASPC-1 cells in the exponential growth phase and plate them on 96-well culture plates, 80 μL per well, at a plate density of 1000 cells/well, and culture overnight in a 5% CO ₂ incubator at 37°C, and plate T ₀ wells at the same time . On the second day, 20 μL of different concentrations of compounds were added to each well so that the final concentration of DMSO in each well was 0.5%, and cultured at 37° C. in a 5% CO ₂ incubator for 6 days. The next day, add the drug and use the CellTiter-Glo kit to detect the T ₀ plate, which is recorded as RLU ₀ . After the incubation, 25 μL of detection solution (Cell4Viability Assay, Promega) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence reading was detected using a Nivo multilabel analyzer (PerkinElmer). The results were processed according to formula (3), and the growth inhibition rate of each concentration of the compound was calculated, and the GraphPad Prism software was used to carry out curve fitting with four parameters, and the concentration GI ₅₀ value of the compound was calculated when the growth inhibition rate was 50%. RLU _compound is the reading of the drug treatment group, and RLU _control is the mean value of the solvent control group. The test results are shown in Table 2.

Inhibition%＝(1-(RLU _compound -RLU ₀ )/(RLU _control -RLU ₀ ))×100% Formula (3)

Table 2 The growth inhibitory activity GI ₅₀ value of the compound of the present invention

Compound number GI₅₀(nM) Trifluoroacetate 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.

Conclusion: the compound of the present invention has good growth inhibitory activity on ASPC-1 cells.

Claims (15)

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;

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 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;

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 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 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 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:

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

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 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 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 ^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 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 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 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 ^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, 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) -;

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 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.

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

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 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 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.