CN112110918B - Spiro substituted pyrimido cyclic compounds, process for their preparation and their use in medicine - Google Patents

Abstract

The invention discloses a spirocyclic substituted pyrimidocyclic compound and its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, which have a selective inhibitory effect on KRAS gene mutation, as represented by formula (I) For the definition of each group or symbol in the formula, please refer to the specification. In addition, the invention also discloses a pharmaceutical composition containing the compound and its application in preparing cancer medicine.

Description

Spirocyclic substituted pyrimidocyclic compounds, their preparation methods and medical uses

Technical Field

The present invention relates to the field of medical technology, and in particular to a spiro-substituted pyrimidocyclic compound, and its application as a selective inhibitor of KRAS gene mutation, and a pharmaceutical composition prepared therefrom.

Background Art

Lung cancer is the cancer with the highest incidence rate in the world. In China, the incidence rate of lung cancer ranks first among all cancers. It is also the cancer with the highest incidence and mortality rate in China. According to data released by the American Cancer Society in 2016, about 1.8 million people in the world are diagnosed with lung cancer each year, of which nearly 80% are non-small cell lung cancer (NSCLC).

RAS is a group of closely related monomeric globular proteins (21kDa molecular weight) with 188-189 amino acids and bound to guanosine diphosphate GDP or guanosine triphosphate GTP. RAS subfamily members include HRAS, KRAS and NRAS. RAS acts as a molecular switch. When RAS contains bound GDP, it is in a dormant or closed position and "inactive". When cells are exposed to certain growth-promoting stimuli, RAS is induced to convert its bound GDP into GTP. When bound to GTP, RAS is "switched on" and is able to interact with other downstream target proteins and activate these proteins. The inherent ability of RAS protein to hydrolyze GTP and restore it to GDP (thereby converting itself to the closed state) is extremely low. Exogenous protein GTPase activating protein (GAP) is required to restore it to the closed state. The interaction of GAP with RAS greatly accelerates the conversion of GTP to GDP.

Any mutation in RAS will affect the interaction of RAS with GAP and the ability to convert GTP to GDP, which will lead to a prolonged activation of the protein, thus prolonging cell signaling, which in turn leads to continued cell growth and division. Because this signaling causes cell growth and division, overactive RAS signaling can ultimately lead to cancer.

In lung cancer, mutations in the RAS gene have been confirmed in about 32% of lung cancers, and mutations in any of the three major subtypes of the RAS gene (HRAS, NRAS or KRAS) can lead to the occurrence of human tumors. It has been reported that the KRAS gene has the highest mutation frequency among RAS genes, and KRAS mutations have been detected in 25-30% of tumors. In comparison, the rate of oncogenic mutations in NRAS and HRAS family members is much lower (8% and 3%, respectively). The most common KRAS mutations are found on residues G12 and G13 in the P loop and on residue Q61. The G12C mutation is a frequent mutation of the KRAS gene (glycine-12 mutates to cysteine). This mutation has been found in about 13% of cancers, about 43% of lung cancers, and almost 100% of MYH-related polyposis (familial colon cancer syndrome).

Therefore, developing inhibitors that selectively inhibit KRAS mutations is a better direction. In order to improve the inhibitory activity against KRAS mutations while reducing the inhibitory activity against wild-type KRAS, it is of great significance to develop new RAS mutant selective inhibitors with higher activity, better selectivity and lower toxicity.

Summary of the invention

The present invention provides a spiro-substituted pyrimidocyclic compound, which serves as a selective inhibitor of KRAS mutation and has the advantages of high activity, good selectivity, low toxicity and side effects.

In one aspect, the present invention provides a spiro-substituted pyrimidocyclic compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the structure of the compound is shown in formula (I):

In the formula,

X is NC(O)-CR _X3 =CR _X1 R _X2 or NC(O)-CCR _X4 ;

wherein R _X1 and R _X2 are each independently hydrogen, halogen, cyano, NR ^a R ^b , C _1-3 alkyl, halogenated C _1-3 alkyl, -C _1-3 alkyl-hydroxy, -C _1-3 alkyl-cyano, -C _1-3 alkyl-C _1-3 alkoxy, -C _1-3 alkyl-NR ^a R ^b , -C _1-3 alkyl-3 to 6-membered heterocycloalkyl, -C _1-3 alkyl-5 or 6-membered monocyclic heteroaryl;

_RX3 is hydrogen, halogen, _-OC1-3alkyl , -O-halogenated _C1-3alkyl , _{-OC3-6cycloalkyl} or -O-halogenated _{C3-6cycloalkyl} ;

_RX4 is hydrogen, halogenated _C1-3 alkyl, _-C1-3 alkyl-hydroxy, _-C1-3 alkyl-cyano, _-C1-3 alkyl- _C1-3 alkoxy;

wherein ^Ra and ^Rb are each independently hydrogen or _C1-3 alkyl;

m and n are each independently 1, 2 or 3; and m and n are not 1 at the same time;

R ₁ is halogen, -OR ₁₁ , -NH-R ₁₁ or -N(R ₁₁ )R ₁₂ ; wherein R ₁₁ and R ₁₂ are each independently substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted 3 to 6-membered heterocycloalkyl, substituted or unsubstituted C _6-10 aryl, substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl or substituted or unsubstituted 8 to 10-membered bicyclic heteroaryl; or R ₁₁ , R ₁₂ and the nitrogen atom to which they are connected together form a substituted or unsubstituted 3 to 6-membered heterocycloalkyl; and when m=n=2, R ₁ is not halogen; wherein the 3 to 6-membered heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl, 8 to 10-membered bicyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

L is a bond, -CR _L1 R _L2 -, -O-(CR _L1 R _L2 ) _t1 - or -NH-(CR _L3 R _L4 ) _t2 -; wherein R _L1 , R _L2 , R _L3 , and R _L4 are the same or different and are each independently hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, C _1-3 alkyl or oxo; t1 and t2 are each independently 0, 1, 2, 3 or 4;

R ₂ is halogen, hydroxy, -SO ₂ C _1-6 alkyl, substituted or unsubstituted 3 to 20-membered heterocycloalkyl, substituted or unsubstituted C _3-20 cycloalkyl, substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl, or NR ₂₁ R ₂₂ ; wherein R ₂₁ and R ₂₂ are each independently hydrogen, substituted or unsubstituted C _1-6 alkyl, -SO ₂ C _1-6 alkyl, -SO ₂ C _3-6 cycloalkyl, -C(O)C _1-6 alkyl, or -C(O)halogenated C _1-6 alkyl; or R ₂₁ and R ₂₂ together with the nitrogen atom to which they are connected form a substituted or unsubstituted 3 to 20-membered heterocycloalkyl; wherein the 3 to 20-membered heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

Z is N or CR ₃ ; wherein R ₃ is hydrogen, halogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 alkoxy, substituted or unsubstituted C _2-8 alkenyl, substituted or unsubstituted C _2-8 alkynyl or substituted or unsubstituted C _3-20 cycloalkyl;

E is CR ₄ or N; wherein R ₄ is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 alkoxy, substituted or unsubstituted C _3-20 cycloalkyl, substituted or unsubstituted C _3-20 cycloalkoxy, -NH-(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ ;

The term "substituted" refers to 1, 2, 3 or 4 hydrogen atoms in the group being replaced by substituents independently selected from Group S;

The substituents in group S are selected from the group consisting of hydroxyl, halogen, nitro, oxo, C _{1-6 alkyl, C 1-6 alkyl} substituted with hydroxyl, benzyl, -(CH ₂ ) _u -cyano, -(CH ₂ ) _u -C _1-6 alkoxy, -(CH ₂ ) _u -halogenated C _1-6 alkoxy, -(CH ₂ ) _u -halogenated C _1-6 alkyl, -(CH ₂ ) _u -3 to 6 membered heterocycloalkyl, -(CH ₂ ) _u -5 or 6 membered monocyclic heteroaryl, -(CH ₂ ) _u -C _3-8 cycloalkyl, -(CH ₂ ) _u -O-(CH ₂ ) _v -C _3-8 cycloalkyl, -(CH ₂ ) _u -O-(CH ₂ ) _v -C _1-6 alkoxy, -(CH ₂ ) _u -O-(CH ₂ ) _v OH, -(CH ₂ ) _u -SO ₂ C _wherein the 3- _{to 6} - _{membered heterocycloalkyl} group _and the 5- _{or 6} - _membered monocyclic _heteroaryl group each _{independently} have 1, ₂ or 3 heteroatoms _{selected from N , O} and S as _ring atoms; the _3- to 6-membered heterocycloalkyl group and the _5- or ₆ -membered monocyclic heteroaryl group are optionally substituted by 1, 2 or 3 heteroatoms selected from halogen, cyano, C _1-3 alkyl, _{C 1-3} alkoxy and C _1-6 alkyl. substituted by a substituent of a _3-6 cycloalkyl group; u and v are each independently 0, 1, 2, 3 or 4; R _a0 and R _b0 are each independently hydrogen or C _1-3 alkyl;

B is C _6-10 aryl, 5- or 6-membered monocyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl; wherein the 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C _6-10 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R _s1 ; or

B is a structure shown in formula (B):

wherein the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring; the B2 ring is a 5- or 6-membered heterocycloalkyl ring fused to the B1 ring or a 5- or 6-membered cycloalkyl ring fused to the B1 ring; wherein the 5- or 6-membered monocyclic heteroaryl ring and the 5- or 6-membered heterocycloalkyl ring each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

(R _s1 ) _p means that the hydrogen atoms on the B1 ring are replaced by p R _s1s , where p is 0, 1, 2 or 3, and each R _s1 is the same or different;

(R _s2 ) _q means that the hydrogen atoms on the B2 ring are replaced by q R _s2 , q is 0, 1, 2 or 3, and each R _s2 is the same or different;

_Rs1 and _Rs2 are each independently hydroxy, halogen, nitro, oxo, C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, benzyl, -(CH ₂ ) _u1 -cyano, -(CH ₂ ) _u1 -C _1-6 alkoxy, -(CH ₂ ) _u1 -halogenated C _1-6 alkoxy, -(CH ₂ ) _u1 -halogenated C _1-6 alkyl, -(CH ₂ ) _u1 -3 to 6-membered heterocycloalkyl, -(CH ₂ ) _u1 -5 or 6-membered monocyclic heteroaryl, -(CH ₂ ) _u1 -C _3-8 cycloalkyl, -(CH ₂ ) _u1 -O-(CH ₂ ) _v1 -C _3-8 cycloalkyl, -(CH ₂ ) _u1 -O-(CH ₂ ) _v1 -C _1-6 alkoxy, -(CH ₂ ) _u1 -O-(CH ₂ ) _v1 OH, -(CH ₂ ) _u1 -SO ₂ C _1-6 alkyl, -(CH ₂ ) _u1 -NR _a0 R _b0 , -(CH ₂ ) _u1 -C(O)NR _a0 R _b0 , -(CH ₂ ) _u1 -C(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, NR _a0 C(O)-(CH ₂ ) _u1 -NR _a0 R _b0 , NR _a0 C(O)-(CH ₂ ) _u1 OH, NR _a0 C(O)-halogenated C _1-6 alkyl; wherein the 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl groups each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl groups are optionally replaced by 1, 2 or 3 heteroatoms selected from halogen, cyano, C _1-3 alkyl, C _u1 and v1 are each independently 0, 1, 2, ₃ or 4; R _a0 and R _b0 are each independently hydrogen or C _1-3 alkyl.

In one embodiment of the present invention, X is NC(O) _-CRX3 = _CRX1RX2 ; wherein _RX1 and _RX2 are each independently hydrogen, halogen, cyano, amino, _NHCH3 , N( _CH3 ) ₂ , methyl, ethyl, n _- propyl, isopropyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, _-CH2 -hydroxy, _-CH2 -cyano, _-CH2 -methoxy, _-CH2 -ethoxy, _-CH2 -propoxy, _-CH2 -isopropoxy, -CH2 _- NH2, _-CH2 -NHCH3, _-CH2 -N( _CH3 ) ₂ , _-CH2-3 to ₆ -membered _{heterocycloalkyl} , _-CH2 -5 or 6-membered monocyclic heteroaryl; the 3 to 6-membered heterocycloalkyl is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran; the 5 or 6-membered monocyclic heteroaryl is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine; the 3 to 6-membered heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl is optionally substituted with 1 or 2 halogens or C _1-3 alkyl; _RX3 is hydrogen, halogen, methoxy, ethoxy, propoxy or isopropoxy.

In one embodiment of the present invention, X is NC(O)-CCR _X4 ; wherein _RX4 is hydrogen, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH2-hydroxy, _-CH2 -cyano, _-CH2 -methoxy, _-CH2 -ethoxy, _{-CH2 -} propoxy, _-CH2 -isopropoxy.

In one embodiment of the present invention, R ₁ is halogen, -OR ₁₁ , -NH-R ₁₁ , or -N(R ₁₁ )R ₁₂ ; wherein R ₁₁ and R ₁₂ are each independently substituted or unsubstituted C _1-3 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5 or 6 membered monocyclic heteroaryl, or substituted or unsubstituted 8 to 10 membered bicyclic heteroaryl; or R ₁₁ , R ₁₂ and the nitrogen atom to which they are connected together form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; and when m=n=2, R ₁ is not halogen; wherein the 3- to 6-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from Group S.

In one embodiment of the present invention, R ₁ is halogen, -OR ₁₁ , -NH-R ₁₁ , or -N(R ₁₁ )R ₁₂ ; wherein R ₁₁ and R ₁₂ are each independently substituted or unsubstituted C _1-3 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 or 6 membered monocyclic heteroaryl; or R ₁₁ , R ₁₂ and the connected nitrogen atom together form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; and when m=n=2, R ₁ is not halogen; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S; the C The _3-6 membered cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the 3 to 6 membered heterocycloalkyl group is selected from the group consisting of aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran; the 5 or 6 membered monocyclic heteroaryl group is selected from the group consisting of thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine and pyrazine.

In one embodiment of the present invention, R ₂ is halogen, hydroxyl, -SO ₂ C _1-3 alkyl, substituted or unsubstituted 3 to 6-membered heterocycloalkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl, or NR ₂₁ R ₂₂ ; wherein R ₂₁ and R ₂₂ are each independently hydrogen, substituted or unsubstituted C 1-3 alkyl, -SO ₂ C 1-3 alkyl, -SO 2 C 3-6 cycloalkyl, -C(O)C 1-3 alkyl or -C(O)halogenated C 1-3 alkyl; or R ₂₁ and R 22 are each independently hydrogen, substituted or unsubstituted C _1-3 alkyl, -SO 2 C _1-3 alkyl, -SO ₂ C _3-6 cycloalkyl, -C(O)C _1-3 alkyl or -C(O)halogenated C _1-3 alkyl. ₂₂ together with the connected nitrogen atom forms a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group; wherein the 3- to 6-membered heterocycloalkyl group and the 5- or 6-membered monocyclic heteroaryl group each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from Group S.

In one embodiment of the present invention, R ₂ is halogen, hydroxyl, -SO ₂ C _1-3 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted 5 or 6 membered monocyclic heteroaryl, or NR ₂₁ R ₂₂ ; wherein R ₂₁ and R ₂₂ are each independently hydrogen, substituted or unsubstituted C _1-3 alkyl, -SO ₂ C _1-3 alkyl, -SO ₂ C _3-6 cycloalkyl, -C(O)C _1-3 alkyl or -C(O)halogenated C _1-3 alkyl; or R ₂₁ and R ₂₂ together with the connected nitrogen atom form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S; the C The _3-6 membered cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the 3 to 6 membered heterocycloalkyl group is selected from the group consisting of aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran; the 5 or 6 membered monocyclic heteroaryl group is selected from the group consisting of thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine and pyrazine.

In one embodiment of the present invention, Z is N or CR ₃ ; wherein R ₃ is hydrogen, halogen, substituted or unsubstituted C _1-3 alkyl, substituted or unsubstituted C _1-3 alkoxy, substituted or unsubstituted C _2-4 alkenyl, substituted or unsubstituted C _2-4 alkynyl or substituted or unsubstituted C _3-6 cycloalkyl; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S.

In one embodiment of the present invention, Z is N or CR ₃ ; wherein R ₃ is hydrogen, halogen, substituted or unsubstituted C _1-3 alkyl, substituted or unsubstituted C _1-3 alkoxy, substituted or unsubstituted C _2-4 alkenyl, substituted or unsubstituted C _2-4 alkynyl or substituted or unsubstituted C _3-6 cycloalkyl; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S; the C _3-6 cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

In one embodiment of the present invention, E is CR ₄ or N; wherein R ₄ is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C _1-3 alkyl, substituted or unsubstituted C _1-3 alkoxy, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted C _3-6 cycloalkoxy, -NH-(C _1-3 alkyl) or -N(C _1-3 alkyl) ₂ ; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S.

In one embodiment of the present invention, E is _CR4 or N; wherein _R4 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted _C1-3 alkyl, substituted or unsubstituted _C1-3 alkoxy, substituted or unsubstituted _C3-6 cycloalkyl, substituted or unsubstituted _C3-6 cycloalkyloxy, -NH-( _C1-3 alkyl) or -N( _C1-3 alkyl) ₂ ; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S; the _C3-6 cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the _C3-6 cycloalkoxy is selected from: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

In one embodiment of the present invention, the substituents in group S are selected from: hydroxyl, halogen, nitro, oxo, C _1-3 alkyl, C _1-3 alkyl substituted with hydroxyl, benzyl, -(CH ₂ ) _u -cyano, -(CH ₂ ) _u -C _1-3 alkoxy, -(CH ₂ ) _u -halogenated C _1-3 alkoxy, -(CH ₂ ) _u -halogenated C _1-3 alkyl, -(CH ₂ ) _u -3 to 6 membered heterocycloalkyl, -(CH ₂ ) _u -5 or 6 membered monocyclic heteroaryl, -(CH ₂ ) _u -C _3-6 cycloalkyl, -(CH ₂ ) _u -O-(CH ₂ ) _v -C _3-6 cycloalkyl, -(CH ₂ ) _u -O-(CH ₂ ) _v -C _1-3 alkoxy, -(CH ₂ ) _u -O-(CH ₂ ) _v OH, -(CH ₂ ) _{u -SO2C1-3alkyl} , -( _CH2 ) _{u- NRa0Rb0} , -( _CH2 ) _{u - C} (O) _NRa0Rb0 , - ₍ CH2) _u -C(O) _C1-3alkyl , -C(O ₎ OC1-3alkyl, NRa0C( _O )-( _CH2 ) _{u - NRa0Rb0} , _NRa0C (O)-( _CH2 ) _uOH , _NRa0C (O) _{-halogenatedC1-3alkyl} ; wherein _the 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl are optionally replaced by 1, 2 or 3 heteroatoms selected from halogen, cyano, _C1-3alkyl , _C1-3alkoxy and C1-3alkyl. u and v are each independently 0, 1, 2, 3 or 4; R _a0 and R _b0 are each independently hydrogen or C _{1-3 alkyl} .

In one embodiment of the present invention, the substituent group S is halogen.

In one embodiment of the present invention, the S group substituents are selected from: C _1-3 alkyl, -(CH ₂ ) _u -3 to 6 membered heterocycloalkyl, -(CH ₂ ) _u -SO ₂ C _1-3 alkyl, -(CH ₂ ) _u -NR _a0 R _b0 ; wherein the 3 to 6 membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3 to 6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 substituents selected from halogen, cyano, C _1-3 alkyl, C _1-3 alkoxy and C _3-6 cycloalkyl; u is 0, 1, 2, 3 or 4; R _a0 and R _b0 are each independently hydrogen or C _1-3 alkyl.

In one embodiment of the present invention, in the substituent group S, the 3- to 6-membered heterocycloalkyl group is selected from: aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran.

In one embodiment of the present invention, in the substituent group S, the C _3-6 cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In one embodiment of the present invention, in the substituent group S, the 5- or 6-membered monocyclic heteroaryl group is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, and pyrazine.

In one embodiment of the present invention, _Rs1 and _Rs2 are each independently selected from the group consisting of hydroxy, halogen, nitro, oxo, _C1-3 alkyl, hydroxy-substituted _C1-3 alkyl, benzyl, -( _CH2 ) _u1 -cyano, -( _CH2 )u1- _C1-3 alkoxy, -(CH2) _u1 -halogenated _C1-3 alkoxy, -( _CH2 ) _u1 -halogenated _C1-3 alkyl, -( _CH2 ) _u1-3 to 6-membered heterocycloalkyl, -( _CH2 ) _u1-5 or 6-membered monocyclic heteroaryl, -( _CH2 )u1- _C3-6 cycloalkyl, -( _CH2 ) _u1 -O-( _CH2 )v1-C3-6 cycloalkyl, -( _CH2 ) _u1 -O-(CH2) _v1 - _C1-3 alkoxy, -(CH2) _u1-3 to 6-membered heterocycloalkyl, -( _CH2 ) _{u1-5 or 6 -} membered monocyclic heteroaryl, -( _CH2 ) _u1 - _C3-6 cycloalkyl, -O-(CH ₂ ) _v1 OH, -(CH ₂ ) _u1 -SO ₂ C _1-3 alkyl, -(CH ₂ ) _u1 -NR _a0 R _b0 , -(CH ₂ ) _u1 -C(O)NR _a0 R _b0 , -(CH ₂ ) _u1 -C(O)C _1-3 alkyl, -C(O)OC _1-3 alkyl, NR _a0 C(O)-(CH ₂ ) _u1 -NR _a0 R _b0 , NR _a0 C(O)-(CH ₂ ) _u1 OH, NR _a0 C(O)-halogenated C _1-3 alkyl; wherein the 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl are optionally replaced by 1, 2 or 3 heteroatoms selected from halogen, cyano, C The present invention is substituted by a substituent selected from the group consisting of _{C 1-3} alkyl, C _1-3 alkoxy and C _3-6 cycloalkyl; u1 and v1 are each independently 0, 1, 2, 3 or 4; _Ra0 and _Rb0 are each independently hydrogen or C _1-3 alkyl.

In one embodiment of the present invention, R _s1 and R _s2 are each independently halogen.

In one embodiment of the present invention, R _s1 and R _s2 are each independently selected from: C _1-3 alkyl, -(CH ₂ ) _u1 -3 to 6 membered heterocycloalkyl, -(CH ₂ ) _u1 -SO ₂ C _1-3 alkyl, -(CH ₂ ) _u1 -NR _a0 R _b0 ; wherein the 3 to 6 membered heterocycloalkyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3 to 6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 substituents selected from halogen, cyano, C _1-3 alkyl, C _1-3 alkoxy and C _3-6 cycloalkyl; u1 is 0, 1, 2, 3 or 4; R _a0 and R _b0 are each independently hydrogen or C _1-3 alkyl.

In one embodiment of the present invention, in R _s1 and R _s2 , the 3- to 6-membered heterocycloalkyl is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran.

In one embodiment of the present invention, in R _s1 and R _s2 , the C _3-6 cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In one embodiment of the present invention, in R _s1 and R _s2 , the 5- or 6-membered monocyclic heteroaryl group is selected from the group consisting of thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine and pyrazine.

In one embodiment of the present invention, m is 2 and n is 1.

In one embodiment of the present invention, m is 1 and n is 2.

In one embodiment of the present invention, m is 2; n is 2.

In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (II) or a compound represented by formula (III):

In each formula, R ₁ , R ₂ , X, B, E, Z and L have the same meanings as above.

In one embodiment of the present invention, R ₁ is halogen or -OR ₁₁ .

In one embodiment of the present invention, in formula (III), R ₁ is -OR ₁₁ .

In one embodiment of the present invention, in formula (II), R ₁ is halogen.

In one embodiment of the present invention, R ₁ is chloro or fluoro.

In one embodiment of the present invention, R ₁₁ is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C _6-10 aryl, substituted or unsubstituted 5 or 6 membered monocyclic heteroaryl or substituted or unsubstituted 8 to 10 membered bicyclic heteroaryl; wherein the 3 to 6 membered heterocycloalkyl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from Group S.

In one embodiment of the present invention, R ₁₁ is substituted or unsubstituted C _1-3 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5 or 6 membered monocyclic heteroaryl; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S; the C The _3-6 membered cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the 3 to 6 membered heterocycloalkyl group is selected from the group consisting of aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran; the 5 or 6 membered monocyclic heteroaryl group is selected from the group consisting of thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine and pyrazine.

In one embodiment of the present invention, E is CR ₄ .

In one embodiment of the present invention, _R4 is hydrogen.

In one embodiment of the present invention, E is N.

In one embodiment of the present invention, Z is CR ₃ .

In one embodiment of the present invention, R ₃ is hydrogen or halogen.

In one embodiment of the present invention, R ₃ is hydrogen or fluorine.

In one embodiment of the present invention, Z is N.

In one embodiment of the present invention, L is a bond; R ₂ is NR ₂₁ R ₂₂ ; wherein R ₂₁ and R ₂₂ together with the connected nitrogen atom form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl, a substituted or unsubstituted 6 to 10 membered fused heterocycloalkyl, or a substituted or unsubstituted 7 to 11 membered spiroheterocycloalkyl; wherein the 3 to 6 membered heterocycloalkyl, 6 to 10 membered fused heterocycloalkyl, 7 to 11 membered spiroheterocycloalkyl each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from Group S.

In one embodiment of the present invention, L is -CR _L1 R _L2 -, -O-(CR _L1 R _L2 ) _t1 -, or -NH-(CR _L3 R _L4 ) _t2 -; R ₂ is halogen, hydroxy, -SO ₂ C _1-6 alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted 6- to 10-membered fused heterocycloalkyl, substituted or unsubstituted 7- to 11-membered spiroheterocycloalkyl, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, or NR ₂₁ R ₂₂ ;

wherein R _L1 , R _L2 , R _L3 , and R _L4 are the same or different, and are each independently hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, C _1-3 alkyl, or oxo; t1 and t2 are each independently 0, 1, 2, 3, or 4;

R ₂₁ and R ₂₂ are each independently hydrogen, substituted or unsubstituted C _1-6 alkyl, -SO ₂ C _1-6 alkyl, -SO ₂ C _3-6 cycloalkyl, -C(O)C _1-6 alkyl, -C(O)halogenated C _1-6 alkyl; or R ₂₁ and R ₂₂ together with the nitrogen atom to which they are connected form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted 6- to 10-membered fused heterocycloalkyl, or a substituted or unsubstituted 7- to 11-membered spiroheterocycloalkyl;

Wherein, the 3- to 6-membered heterocycloalkyl, 6- to 10-membered fused heterocycloalkyl, and 7- to 11-membered spiroheterocycloalkyl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the "substitution" refers to that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents each independently selected from Group S.

In one embodiment of the present invention, in R ₁ and B, the C _6-10 aryl group is independently phenyl or naphthyl.

In one embodiment of the present invention, when the C _6-10 aryl group is a phenyl group, B is selected from the following structures:

Wherein, R _s1 and R _s2 are defined as above.

In one embodiment of the present invention, in R ₁ , R ₂ , and B, the 5- or 6-membered monocyclic heteroaryl group is independently selected from the group consisting of thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, and pyrazine.

In one embodiment of the present invention, in R ₁ and B, the 8- to 10-membered bicyclic heteroaryl is each independently a 9- to 10-membered bicyclic heteroaryl formed by condensing a benzene ring with a 5- or 6-membered monocyclic heteroaryl ring, or an 8- to 10-membered bicyclic heteroaryl formed by condensing a 5- or 6-membered monocyclic heteroaryl ring with a 5- or 6-membered monocyclic heteroaryl ring; wherein the 9- to 10-membered bicyclic heteroaryl formed by condensing a benzene ring with a 5- or 6-membered monocyclic heteroaryl ring, and the 8- to 10-membered bicyclic heteroaryl formed by condensing a 5- or 6-membered monocyclic heteroaryl ring with a 5- or 6-membered monocyclic heteroaryl ring, each independently has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms.

In one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl ring forming the bicyclic heteroaryl is selected from the group consisting of a thiophene ring, a furan ring, a thiazole ring, an isothiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, a 1,3,4-oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring or a pyrazine ring.

In one embodiment of the present invention, the 5- or 6-membered monocyclic heteroaryl ring forming the bicyclic heteroaryl is selected from the following structures: in The two ring atoms represented as being connected are adjacent pairs of atoms that are shared when fused to other rings.

In one embodiment of the present invention, in R ₁ and B, the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the group consisting of benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine and naphthyridine.

In one embodiment of the present invention, in the B1 ring, the 5- or 6-membered monocyclic heteroaryl ring is selected from: a thiophene ring, a furan ring, a thiazole ring, an isothiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, a 1,3,4-oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring or a pyrazine ring.

In one embodiment of the present invention, in the B1 ring, the 5- or 6-membered monocyclic heteroaryl ring is selected from the following structures: in The two ring atoms represented as being connected are adjacent pairs of atoms that are shared when fused to other rings.

In one embodiment of the present invention, in the B2 ring, the 5- or 6-membered cycloalkyl ring fused to the B1 ring is selected from: a cyclopentyl ring, a cyclopentenyl ring, a cyclohexyl ring, a cyclohexenyl ring, a cyclohexadienyl ring, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, and cyclohexane-1,3-dione.

In one embodiment of the present invention, in the B2 ring, the 5- or 6-membered heterocycloalkyl ring fused to the B1 ring is selected from the group consisting of oxazolidine, pyrrolidine-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidine-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholine-3-one, morpholine-2-one, thiomorpholine-3-one 1,1-dioxide , thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4-dioxane-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin- 4(3H)-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydropyridin-2(1H)-one, 5,6-dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-dihydro-1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxole, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,3-dihydro-2H-pyrrole-2-one, 1, 5-dihydro-2H-pyrrol-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxol-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazole-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine.

In one embodiment of the present invention, B is selected from the following structures:

wherein Z _1e is NR _1e , O or S; Z _1f is N or CR _1f ; Z _1g is N or CR _1g ; Z _1h is N or CR _1h ; Z _1i is N or CR _1i ;

Z _2e is N or CR _2e ; Z _2f is N or CR _2f ; Z _2h is N or CR _2h ; Z _2i is N or CR _2i ;

R _1e , R _1f , R _1g , R _1h , R _1i , R _1j , R _2e , R _2f , R _2g , R _2h , R _2i , and R _2j are each independently hydrogen, halogen, C _1-3 alkyl, -CONH ₂ , -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , cyano, nitro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, acetyl, hydroxymethyl, hydroxyethyl, carboxyl, NH ₂ , NHC _1-3 alkyl, N(C _1-3 alkyl) ₂ , halogenated C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyloxy, C _2-4 alkenyl, C _2-4 alkynyl, -C(O)OC _1-3 alkyl, -CHO, -OC(O)C _1-3 alkyl, -SO ₂ C _1-3 alkyl, -SO ₂ -phenyl or -CO-phenyl.

In one embodiment of the present invention, in R ₁ and B, the 8- to 10-membered bicyclic heteroaryl group is selected from the following structures:

In one embodiment of the present invention, in R ₁ and B, the 8- to 10-membered bicyclic heteroaryl group is selected from the following structures:

In one embodiment of the present invention, in R ₁ and B, the 8- to 10-membered bicyclic heteroaryl group is selected from the following structures:

In one embodiment of the present invention, B is a structure represented by formula (B), wherein: Selected from the following structures:

In one embodiment of the present invention, B is a structure represented by formula (B), and formula (B) is selected from the following structures:

In one embodiment of the present invention, B is selected from the following structures:

In one embodiment of the present invention, -LR ₂ in formula (I) is selected from the following structures:

In one embodiment of the present invention, in R ₂ , the 5- or 6-membered monocyclic heteroaryl group is selected from:

In one embodiment of the present invention, in R ₂ , the 3 to 20-membered heterocycloalkyl is a 3 to 6-membered heterocycloalkyl, a 6 to 10-membered fused heterocycloalkyl, a 7 to 11-membered spiroheterocycloalkyl, or a 7 to 10-membered bridged heterocycloalkyl.

In one embodiment of the present invention, in _R2 , the _C3-20 cycloalkyl group is a _C3-8 cycloalkyl group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, and cyclohexane-1,3-dione; the above _C3-8 cycloalkyl group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from Group S.

In one embodiment of the present invention, the 3- to 20-membered heterocycloalkyl group formed by R ₂₁ and R ₂₂ together with the nitrogen atom to which they are attached is a 3- to 6-membered nitrogen-containing heterocycloalkyl group, a 6- to 10-membered nitrogen-containing fused heterocycloalkyl group, or a 7- to 11-membered nitrogen-containing spiroheterocycloalkyl group.

In one embodiment of the present invention, the 3- to 6-membered nitrogen-containing heterocycloalkyl group formed by R ₂₁ and R ₂₂ together with the connected nitrogen atom is selected from the following structures: The above 3- to 6-membered nitrogen-containing heterocycloalkyl group is unsubstituted or substituted by 1, 2, 3 or 4 substituents each independently selected from Group S.

In one embodiment of the present invention, X, n, m, R ₁ , B, E, Z, L, and R ₂ are each independently a corresponding group in each specific compound in the examples.

In one embodiment of the present invention, the compound of formula (I) is selected from the specific compounds noted in the Examples.

In one embodiment of the present invention, the compound of formula (II) or (III) is selected from the compounds prepared in the examples of the present application.

In one embodiment of the present invention, the compound of formula (I) is selected from the group consisting of:

In another aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.

As used herein, the term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium that can deliver an effective amount of active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or the subject, and is a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary preparation or any type of auxiliary material. Representative carriers include water, oil, vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, transdermal enhancers, etc. Their preparations are well known to those skilled in the field of cosmetics or topical medicines.

In an embodiment of the present invention, the pharmaceutical composition can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an explanted reservoir. When administered orally, the compound of the present invention can be prepared into any oral acceptable formulation form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions. The carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate may also be added. The diluents used in capsule preparations generally include lactose and dry corn starch. Aqueous suspension preparations are usually mixed with active ingredients and suitable emulsifiers and suspending agents. If necessary, some sweeteners, aromatics or coloring agents may also be added to the above oral preparation forms. When used topically, especially for treating affected areas or organs that are easily accessible by topical application, such as eyes, skin or lower intestinal neurological diseases, the compounds of the present invention can be prepared into different topical preparations according to different affected areas or organs. When applied topically to the eye, the compounds of the present invention can be formulated into a preparation form of a micronized suspension or solution, and the carrier used is isotonic sterile saline of a certain pH, to which a preservative such as benzyl chloride alkoxide may or may not be added. For ophthalmic use, the compounds can also be prepared into an ointment form such as vaseline. When applied topically to the skin, the compounds of the present invention can be prepared into a suitable ointment, lotion or cream preparation form, in which the active ingredient is suspended or dissolved in one or more carriers. The carriers that can be used for ointment preparations include, but are not limited to, mineral oil, liquid vaseline, white vaseline, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; the carriers that can be used for lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water. The compounds of the present invention can also be used in the form of sterile injection preparations, including sterile injection water or oil suspension or sterile injection solution. The carriers and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterilized non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.

In another aspect, the present invention provides use of the aforementioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating cancer.

In one embodiment of the present invention, the cancer is pancreatic ductal carcinoma, colorectal cancer, multiple myeloma, lung cancer, skin melanoma, endometrioid carcinoma, uterine carcinosarcoma, thyroid cancer, acute myeloid leukemia, bladder urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung cancer, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver cancer, breast invasive carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenal cortical carcinoma, prostate cancer, neuroblastoma, brain low-grade glioma, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdoid tumor, sarcoma, small intestinal neuroendocrine tumor, T-cell prolymphocytic leukemia.

In one embodiment of the present invention, the cancer is lung cancer, preferably non-small cell lung cancer.

In another aspect, the present invention provides use of the aforementioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the aforementioned pharmaceutical composition in the preparation of a KRAS mutation inhibitor (preferably, the KRAS mutation is a KRAS G12C mutation).

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and can retain the biological effectiveness of the free base without other side effects. Such salts include: acid addition salts formed with inorganic acids or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, trifluoroacetic acid, formic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or salts formed when the acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions, such as sodium salts, potassium salts, calcium salts and magnesium salts, etc. Or a coordination compound formed with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in the form of free acid or base are prepared by reacting with a stoichiometric amount of an appropriate base or acid. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. In addition to the form of salts, the compounds provided by the present invention also exist in the form of prodrugs. The prodrugs of the compounds described herein are easily chemically changed under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

As used herein, the terms "solvate" and "solvate" refer to a substance formed by the combination of a compound of the present invention and a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, ethanol, acetic acid, and the like. Solvates include stoichiometric solvents and non-stoichiometric solvents, preferably hydrates. Certain compounds of the present invention may exist in non-solvated or solvated forms, including hydrate forms. Generally speaking, solvated forms are comparable to non-solvated forms and are included within the scope of the present invention.

As used herein, "stereoisomers" include conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers, etc. The compounds of the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesomorphs, racemates, equal mixtures of atropisomers, etc. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes cis-isomers and trans-isomers, and any combination thereof.

As used herein, the term "heteroatom" is selected from nitrogen, oxygen or sulfur, wherein the nitrogen may be optionally substituted; the sulfur may also be optionally substituted, such as oxo, i.e. forming S(O) _t3 (wherein t3 is an integer from 0 to 2).

As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms. The term "C _1-10 alkyl" refers to a straight or branched chain alkyl having 1 to 10 carbon atoms, more preferably a straight or branched chain alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, i.e., a C _1-6 alkyl, more preferably a C _1-4 alkyl, and most preferably a C _1-3 alkyl. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof.

As used herein, the term "alkoxy" refers to a group having an -O-alkyl structure, wherein the alkyl group is defined as above. The term "C _1-10 alkoxy" refers to an alkoxy group having 1 to 10 carbon atoms, preferably a C _1-6 alkoxy group, more preferably a C _1-4 alkoxy group, and more preferably a C _1-3 alkoxy group. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, and the like.

As used herein, the term "alkenyl" refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position of the chain, and the term " _C2-8 alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds, i.e., _C2-6 alkenyl. More preferably, an alkenyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds, i.e., _C2-4 alkenyl. Specific examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like.

As used herein, the term "alkynyl" refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any position of the chain, and the term " _C2-8alkynyl " refers to an alkynyl group having 2 to 8 carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds, i.e., _C2-6alkynyl . More preferably, an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds, i.e., _C2-4alkynyl . Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1, 2, ₃ , 4 or 5) halogens, wherein the definition of alkyl is as described above. The term "halogenated C _1-10 alkyl" refers to a haloalkyl group having 1 to 10 carbon atoms. Preferably, it is a haloalkyl group, more preferably a _haloalkyl group, more preferably a haloalkyl group. Specific examples include, but are not limited to, _{monochloromethyl} , dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.

As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more (such as 1, 2, 3, 4 or 5) halogens, wherein the definition of alkoxy is as described above. The term "halogenated C _1-10 alkoxy" refers to a halogenated alkoxy group having 1 to 10 carbon atoms. Preferably, it is a halogenated C _1-6 alkoxy group, more preferably a halogenated C _1-4 alkoxy group, and more preferably a halogenated C _1-3 alkoxy group. Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, etc.

As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups. The term "cycloalkyl" may be a cycloalkyl group containing 3 to 20 carbon atoms ( _C3-20 cycloalkyl), preferably a cycloalkyl group containing 3 to 12 carbon atoms ( _C3-12 cycloalkyl), more preferably a cycloalkyl group containing 3 to 10 carbon atoms ( _C3-10 cycloalkyl), and more preferably a cycloalkyl group containing 3 to 6 carbon atoms ( _C3-6 cycloalkyl). The ring carbon atoms of the cycloalkyl group may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure. When it is a monocyclic cycloalkyl, it is preferably a monocyclic cycloalkyl containing 3 to 8 ring carbon atoms (i.e., 3 to 8 members or C _3-8 ), and "C _3-8 monocyclic cycloalkyl" and "C _3-8 cycloalkyl" can be used interchangeably herein, and more preferably a monocyclic cycloalkyl containing 3 to 6 ring carbon atoms (i.e., 3 to 6 members or C _3-6 ), and non-limiting examples of monocyclic cycloalkyl (or C _3-6 monocyclic cycloalkyl) include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione, etc. Generally, the cycloalkyl containing 3 to 6 carbon atoms (C _3-6 cycloalkyl) is a monocyclic cycloalkyl (C _3-6 monocyclic cycloalkyl). As used herein, "3- to 6-membered monocyclic ring", "3- to 6-membered monocyclic cycloalkyl", "C _3-6 monocyclic cycloalkyl" and "C _3-6 cycloalkyl" are used interchangeably and refer to a saturated or partially unsaturated all-carbon monocyclic ring containing 3 to 6 ring atoms. The ring carbon atoms of the monocyclic ring may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure. Examples of 3- to 6-membered monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione, etc.

When it is a polycyclic cycloalkyl, the polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl ring, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups described in the present application.

As used herein, the terms "heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, and one or more (preferably 1 to 4 or 1 to 3 or 1 to 2) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _t3 (wherein t3 is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The term "heterocycloalkyl" may be a heterocycloalkyl containing 3 to 20 ring atoms (i.e., 3 to 20 members); preferably a 3 to 12-membered heterocycloalkyl; more preferably a 3 to 10-membered heterocycloalkyl, more preferably a 3 to 6-membered heterocycloalkyl; wherein one or more (preferably 1 to 4) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _t3 (wherein t3 is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or any substituent defined herein). The ring carbon atoms of the heterocycloalkyl may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.

In some embodiments of the present invention, "heterocycloalkyl" refers to a monocyclic heterocycloalkyl, which is saturated or partially unsaturated, preferably containing 3 to 8 ring atoms (i.e., 3 to 8 members), of which 1, 2 or 3 are heteroatoms. Monocyclic heterocycloalkyls more preferably contain 3 to 6 ring atoms (i.e., 3 to 6 members), of which 1, 2 or 3 are heteroatoms. Monocyclic heterocycloalkyls most preferably contain 5 or 6 ring atoms (i.e., 5 or 6 members), of which 1, 2 or 3 are heteroatoms. As used herein, the term "3 to 6 member heterocycloalkyl" is used interchangeably with "3 to 6 member monocyclic heterocycloalkyl", and the term "5 or 6 member heterocycloalkyl" is used interchangeably with "5 or 6 member monocyclic heterocycloalkyl". When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or other substituents defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be optionally oxidized (ie, S(O) _t3 , t3 is an integer from 0 to 2). The ring carbon atoms of the monocyclic heterocycloalkyl may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Non-limiting examples of monocyclic heterocycloalkyls include: aziridine, oxirane, azetidine, azetidine-2-one, oxetane, oxetane-2-one, oxazolidine, pyrrolidine-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidine-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholine-3-one, morpholine-2-one, thiophene, Morpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4-dioxane-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin-4(3H)-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydropyridin-2(1H)-one, 5,6-dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-dihydro-1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxole, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,3-dihydro-2H-pyrrole-2- ketone, 1,5-dihydro-2H-pyrrol-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxol-2-one, oxazole-2(3H)-one, 1,3-dihydro-2H-imidazole-2-one, furan-2,5-dione, 3,6-dihydropyridine-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, etc.

Typically, 3 to 6 membered heterocycloalkyl is a 3 to 6 membered monocyclic heterocycloalkyl. As used herein, "3 to 6 membered monocyclic heterocyclic ring" or "3 to 6 membered monocyclic heterocycloalkyl" are used interchangeably and refer to 1, 2 or 3 carbon atoms in a 3 to 6 membered saturated or partially unsaturated monocyclic ring substituted by a heteroatom selected from nitrogen, oxygen or S(O) _t5 (wherein t5 is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members. The ring carbon atoms of the monocyclic heterocyclic ring may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Examples of 3- to 6-membered monocyclic heterocycles include, but are not limited to, aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, and the like.

The two ring atoms connected to the above-mentioned monocyclic heterocycloalkyl, including C-C and N-C, can be optionally fused with a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group such as a monocyclic cycloalkyl ring, a monocyclic heterocycloalkyl ring, a monoaryl ring, a 5- or 6-membered monocyclic heteroaryl ring as defined in the present invention to form a fused polycyclic ring, and the two ring atoms connected to the monocyclic heterocycloalkyl that forms a fused ring with other rings are preferably C-C.

In some embodiments of the present invention, "heterocycloalkyl" refers to polycyclic heterocycloalkyl groups, including spiro heterocycloalkyl groups, fused heterocycloalkyl groups, and bridged heterocycloalkyl groups.

As used herein, the term "spiroheterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl group, in which the monocyclic rings in the system share one atom (called a spiro atom), wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _t4 (wherein t4 is an integer from 0 to 2), and the remaining ring atoms are carbon. The term "saturated spiroheterocycloalkyl" refers to a spiroheterocycloalkyl system without any unsaturated bonds. The term "partially unsaturated spiroheterocycloalkyl" refers to a spiroheterocycloalkyl system in which one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. The term "spiroheterocycloalkyl" may be a spiroheterocycloalkyl containing 5 to 20 ring atoms (i.e., 5 to 20 members), wherein the 3 to 8 members (i.e., containing 3 to 8 ring atoms) of the monocyclic rings share one atom (called a spiro atom), preferably a 6 to 14 membered spiroheterocycloalkyl, more preferably a 7 to 11 membered spiroheterocycloalkyl; wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _t4 (wherein t4 is an integer from 0 to 2), and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or other substituents defined herein). Each monocyclic ring may contain one or more double bonds, but no ring has a completely conjugated π electron system. According to the number of spiro atoms shared between rings, the spiroheterocycloalkyl is divided into a monospiroheterocycloalkyl, a bispiroheterocycloalkyl or a polyspiroheterocycloalkyl, preferably a monospiroheterocycloalkyl and a bispiroheterocycloalkyl. More preferably, it is a 7-membered (4-membered monocycle/4-membered monocycle), 8-membered (4-membered monocycle/5-membered monocycle), 9-membered (4-membered monocycle/6-membered monocycle, 5-membered monocycle/5-membered monocycle), 10-membered (5-membered monocycle/6-membered monocycle) or 11-membered (6-membered monocycle/6-membered monocycle) monospiro heterocycloalkyl. Non-limiting examples of spiro heterocycloalkyl include:

As used herein, the term "fused heterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl, each ring in the system shares a pair of adjacent atoms with other rings in the system, and one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms in the system are heteroatoms selected from nitrogen, oxygen or S(O) _t4 (wherein t4 is an integer from 0 to 2), and the remaining ring atoms are carbon. The term "saturated fused heterocycloalkyl" refers to the absence of any unsaturated bonds in the fused heterocycloalkyl system. The term "partially unsaturated fused heterocycloalkyl" refers to one or more rings in the fused heterocycloalkyl system that may contain one or more double bonds, but no ring has a completely conjugated π electron system. The term "fused heterocycloalkyl" may be a fused heterocycloalkyl containing 5 to 20 ring atoms (i.e., 5 to 20 members), preferably a 6 to 14 member fused heterocycloalkyl, more preferably a 6 to 10 member fused heterocycloalkyl, more preferably an 8 to 10 member fused heterocycloalkyl; one or more ring atoms in the system are heteroatoms selected from nitrogen, oxygen or S(O) _t4 (wherein t4 is an integer from 0 to 2), and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or other substituents defined herein). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl, preferably a bicyclic or tricyclic, more preferably an 8-member (5-membered monocyclic fused with a 5-membered monocyclic fused), 9-membered (5-membered monocyclic fused with a 6-membered monocyclic fused) or 10-membered (6-membered monocyclic fused with a 6-membered monocyclic fused) bicyclic fused heterocycloalkyl. Non-limiting examples of fused heterocycloalkyl include:

As used herein, the term "bridged heterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl group, in which any two rings in the system share two atoms that are not directly connected, wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _t3 (wherein t3 is an integer from 0 to 2), and the remaining ring atoms are carbon. The term "saturated bridged heterocycloalkyl" refers to the absence of any unsaturated bonds in the bridged heterocycloalkyl system. The term "partially unsaturated bridged heterocycloalkyl" refers to one or more rings in the bridged heterocycloalkyl system that may contain one or more double bonds, but no ring has a completely conjugated π electron system. The term "bridged heterocycloalkyl" may be a bridged heterocycloalkyl containing 5 to 20 ring atoms (i.e., 5 to 20 members), preferably a 6 to 14-membered bridged heterocycloalkyl, and more preferably a 7 to 10-membered bridged heterocycloalkyl; wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _(t3 where t3 is an integer from 0 to 2), and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocycloalkyl include:

In the present invention, the above-mentioned various types of heterocycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups described in the present application.

As used herein, the terms "aryl", "aryl ring" and "aromatic ring" are used interchangeably and refer to fully unsaturated aliphatic hydrocarbon groups. They can be all-carbon monocyclic, all-carbon polycyclic (rings are connected by covalent bonds and are not fused) or all-carbon fused polycyclic (that is, rings that share adjacent carbon atom pairs) groups containing 6 to 14 ring atoms (i.e., 6 to 14 members or C _6-14 ), and at least one ring in the ring system is aromatic, i.e., has a conjugated π electron system. Preferably, it is an aryl group containing 6 to 10 ring atoms (i.e., 6 to 10 members or C _6-10 ). Each ring in the ring system contains 5 or 6 ring atoms.

In some embodiments of the present invention, "aryl" refers to a monoaryl or polyaryl ring, non-limiting examples of which include: phenyl, biphenyl, and the like.

In some embodiments of the present invention, "aryl" refers to an aromatic fused polycyclic ring, which is a polycyclic group in which a single aromatic ring is fused to one or more single aromatic rings, and non-limiting examples thereof include naphthyl, anthracenyl, and the like.

In some embodiments of the present invention, the aryl ring described herein (e.g., a monocyclic aromatic ring, preferably a phenyl group) may be fused with one or more non-aromatic rings to form a polycyclic group, wherein the ring connected to the parent structure is an aromatic ring or a non-aromatic ring, and the non-aromatic ring includes, but is not limited to: a 3- to 6-membered monocyclic heterocycloalkyl ring, preferably a 5- or 6-membered monocyclic heterocycloalkyl ring (the ring carbon atoms of the monocyclic heterocycloalkyl ring may be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring, preferably a 5- or 6-membered monocyclic cycloalkyl ring (the ring carbon atoms of the monocyclic cycloalkyl ring may be substituted by 1 or 2 oxo groups to form a cyclic ketone structure), etc. The above-mentioned polycyclic group in which the monocyclic aromatic ring is fused with one or more non-aromatic rings may be connected to other groups or the parent structure through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a monocyclic aromatic ring or a non-aromatic ring. Non-limiting examples thereof include:

In the present invention, the above-mentioned various types of aryl groups may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups described in the present application.

As used herein, the terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" are used interchangeably and refer to a fully unsaturated aliphatic hydrocarbon group containing heteroatoms. It can be a monocyclic or fused polycyclic (i.e., a ring that shares adjacent carbon atoms or heteroatoms) group having 5 to 14 ring atoms (i.e., 5 to 14 members), preferably 5 to 10 ring atoms (i.e., 5 to 10 members), more preferably 5, 6, 8, 9 or 10 ring atoms, wherein 1 to 4 heteroatoms are included as ring atoms, and the heteroatoms are selected from oxygen, sulfur and nitrogen. Wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heteroaryl group preferably has 6, 10 or 14 shared π electrons in the ring system. At least one ring in the ring system is aromatic.

In some embodiments of the present invention, "heteroaryl" refers to a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring). Non-limiting examples of monocyclic heteroaryl groups include: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

In some embodiments of the present invention, "heteroaryl" refers to a fused polyheteroaryl ring (preferably an 8- to 10-membered bicyclic heteroaryl ring). The fused polyheteroaryl ring includes a polycyclic group (preferably a 9- or 10-membered bicyclic heteroaryl ring) fused with a monocyclic aryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring), and also includes a polycyclic group (preferably an 8- to 10-membered bicyclic heteroaryl ring) fused with a monocyclic heteroaryl (preferably a 5- or 6-membered monocyclic heteroaryl) and a monocyclic heteroaryl (preferably a 5- or 6-membered monocyclic heteroaryl).

Any two ring atoms connected on the above monocyclic heteroaryl ring, including CC, NC, NN, can be fused with a monocyclic cycloalkyl ring, a monocyclic heterocycloalkyl ring, a monoaryl ring, a 5- or 6-membered monocyclic heteroaryl ring, or other cycloalkyl, heterocycloalkyl, aryl or heteroaryl group defined in the present invention to form a fused polycyclic ring. The two ring atoms connected on the monocyclic heteroaryl ring that forms a fused ring with other rings are preferably CC, including but not limited to the following forms:

Non-limiting examples of fused polyheteroaryl rings include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, and the like.

The above-mentioned monocyclic heteroaryl, or a polycyclic group in which a monocyclic aryl ring is fused to a monocyclic heteroaryl ring, or a polycyclic group in which a monocyclic heteroaryl is fused to a monocyclic heteroaryl, can be connected to other groups or a parent structure through a nitrogen atom or a carbon atom. When it is a polycyclic group, the ring connected to the parent structure is a heteroaryl ring, an aryl ring, a monocyclic cycloalkyl ring, or a monocyclic heterocycloalkyl ring, and its non-limiting examples include:

In some embodiments of the present invention, the heteroaryl ring described in the present invention (e.g., a monocyclic heteroaryl ring, preferably a 5- or 6-membered monocyclic heteroaryl ring) can be fused with one or more non-aromatic rings to form a polycyclic group, wherein the ring connected to the parent structure is a heteroaryl ring or a non-aromatic ring, and the non-aromatic ring includes but is not limited to: a 3- to 6-membered (preferably 5- or 6-membered) monocyclic heterocycloalkyl ring (the ring carbon atoms of the monocyclic heterocycloalkyl ring can be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered (preferably 5- or 6-membered) monocyclic cycloalkyl ring (the ring carbon atoms of the monocyclic cycloalkyl ring can be substituted by 1 or 2 oxo groups to form a cyclic ketone structure), and the like.

The above-mentioned polycyclic group in which the monocyclic heteroaryl ring is fused with one or more non-aromatic rings can be connected to other groups or parent structures through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a heteroaryl ring or a non-aromatic ring. Non-limiting examples thereof include:

In the present invention, the above-mentioned various heteroaryl groups may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups described in the present application.

As used herein, the term "hydroxy" refers to an -OH group.

As used herein, the term "hydroxymethyl" refers to _-CH2OH , and " _hydroxyethyl " refers to _-CH2CH2OH or _-CHOHCH3 .

As used herein, the term "cyanomethyl" refers to _-CH2CN and " _cyanoethyl " refers to _-CH2CH2CN or _-CHCNCH3 .

As used herein, the term "amino" refers to _-NH2 .

As used herein, the term "cyano" refers to -CN.

As used herein, the term "nitro" refers to _-NO2 .

As used herein, the term "benzyl" refers to _-CH2 -benzene.

As used herein, the term "oxo" refers to =0.

As used herein, the term "carboxy" refers to -C(O)OH.

As used herein, the term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl).

As used herein, the term "acetyl" refers to _-COCH3 .

As used herein, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include variants of deuterium and hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. Oxo substitution does not occur on aromatic groups. The term "optionally substituted" or "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent may be arbitrary on a chemically achievable basis.

When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

Herein, C _1-10 may be preferably C _1-6 ; more preferably C _1-4 ; more preferably C _1-3 . For example, C _1-10 alkyl may be preferably C _1-6 alkyl; more preferably C _{1-4 alkyl; more preferably C 1-3 alkyl. For example, C 1-10 alkoxy may be preferably C 1-6 alkoxy; more preferably C 1-4 alkoxy ; more preferably} C _1-3 alkoxy.

Herein, C _3-20 may be preferably C _3-10 , more preferably C _3-8 , more preferably C _3-6 , more preferably C _3-5 . For example, C _3-20 cycloalkyl may be preferably C _3-8 cycloalkyl, more preferably C _3-6 cycloalkyl, more preferably C _3-6 cycloalkyl.

In one embodiment of the present invention, in any group, the 3-20 membered heterocycloalkyl is a 3-6 membered heterocycloalkyl, a 6-10 membered fused heterocycloalkyl, a 7-11 membered spiroheterocycloalkyl or a 7-10 membered bridged heterocycloalkyl; wherein the 3-6 membered heterocycloalkyl, the 6-10 membered fused heterocycloalkyl, the 7-11 membered spiroheterocycloalkyl and the 7-10 membered bridged heterocycloalkyl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms.

In one embodiment of the present invention, in any group, the C _3-6 cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

In one embodiment of the present invention, in any group, the 3- to 6-membered heterocycloalkyl group is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, and tetrahydropyran.

In one embodiment of the present invention, in any group, the 5- or 6-membered monocyclic heteroaryl is selected from the group consisting of thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, and pyrazine.

In one embodiment of the present invention, in any group, the 8- to 10-membered bicyclic heteroaryl is selected from the group consisting of benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, and naphthyridine.

DETAILED DESCRIPTION

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

The present invention is described in detail below by way of examples, but it is not intended to limit the present invention in any adverse way. The present invention has been described in detail herein, and its specific embodiments are also disclosed. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. If specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

As used herein, room temperature refers to about 20-25°C.

Example 1: Preparation of Z1

Step 1: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (298 mg, 0.9 mmol) was dissolved in dichloromethane/acetonitrile (3 mL/3 mL) and cooled to 0°C. Triethylamine (136 mg, 1.35 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (200 mg, 0.94 mmol) were added and stirred at room temperature for 3 hours. Dichloromethane (30 x 2 mL) was extracted, the organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and desolventized by rotary evaporation to obtain tert-butyl 6-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (yellow solid, 620 mg, Y: crude). ES-API: [M+H]+＝506.

Step 2: tert-Butyl 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (620 mg, 1.2 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (1.17 g, 3.6 mmol), triethylenediamine (20 mg, 0.18 mmol) and 1-methylpiperidin-4-ol (423 mg, 3.6 mmol) were added thereto. The reaction solution was reacted at 80°C for 16 hours. The mixture was extracted with ethyl acetate (50 mL x 2), the organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and evaporated through a column (dichloromethane/methanol=20/1-10/1) to give tert-butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (yellow solid, 360 mg, Y: 50%). ES-API: [M+H]+=584.9.

Step 3: tert-Butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (360 mg, 0.62 mmol) was dissolved in 1,4-dioxane/water (8 mL/2 mL), and (5-methyl-1H-indazol-4-yl)boric acid (217 mg, 1.23 mmol), tris(dibenzylacetone)dipalladium (55 mg, 0.06 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (50 mg, 0.12 mmol), potassium phosphate (261 mg, 1.23 mmol) were added. The reaction solution was stirred at 100°C under nitrogen protection for 16 hours. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous magnesium sulfate, and passed through a column (dichloromethane/methanol = 10/1-5/1) to obtain 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (yellow solid, 278 mg, yield: 71%). ES-API: [M+H]+ = 636.

Step 4: tert-Butyl 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (278 mg, 0.437 mmol) was dissolved in dichloromethane (6 mL), triethylamine (2 mL) was added, the reaction solution was stirred at room temperature for 1 hour, and 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)-4-(2,6-diazaspiro[3.4]octane-6-yl)quinazoline (brown solid, 234 mg, Y: crude product) was directly used in the next step without purification. ES-API: [M+H]+＝536.

Step 5: 6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazoline (234 mg, 0.437 mmol) was dissolved in dichloromethane (6 mL), the reaction solution was cooled to 0°C, triethylamine (133 mg, 1.3 mmol) and acrylic anhydride (49. 6mg, 0.39mmol), the reaction solution was reacted at 0℃ for 1 hour, desolventized, and preparative liquid phase separation was performed to obtain 1-(6-chloro-8-fluoro-7-(5-methyl-1H-indolazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one (Z1, white solid, 35mg, Y: 19%). ES-API: [M+H]+＝590. ¹ H NMR (400MHz, CDCl ₃ ) δ 12.95 (s, 1H), 8.06 (s, 1H), 7.59-7.50 (m, 2H), 7.39 (d, J=8.6Hz, 1H), 6.40 (d, J=17.0Hz, 1H), 6.22 (dd, J=16.9, 10.3Hz, 1H), 5.74 (d, J=10.3Hz, 1H), 5.52 (s, 1H), 4.33-4.10 (m, 10H), 3.43-3.25 (m, 4H), 2.80 (d, J=3.9Hz, 4H), 2.48-2.31 (m, 4H), 2.27 (s, 3H).

Example 2: Preparation of Z2

Step 1: tert-Butyl 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (200 mg, 0.395 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (140 mg, 1.185 mmol), cesium carbonate (687 mg, 0.185 mmol) and 1,4-diazabicyclo[2.2.2]octane (10 mg, 0.079 mmol) were added to anhydrous tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL), and argon was replaced three to five times. After stirring the reaction solution at 60°C for 16 hours, it was cooled to room temperature and poured into ice water. It was extracted three times with ethyl acetate (10 mL x 3), and the organic phases were combined. The organic phase was washed with water and saturated brine in turn, and then dried over anhydrous sodium sulfate. The reaction mixture was concentrated in vacuo to give a yellow solid crude product (S)-tert-butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (231 mg, yield: 100%). ES-API: [M+H] ⁺ =586.3.

Step 2: (S)-tert-butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (231 mg, 0.396 mmol, crude), (5-methyl-1H-indazol-4-yl)boronic acid (105 mg, 0.594 mmol), sodium carbonate (84 mg, 0.792 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.0198 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (17 mg, 0.0396 mmol) were added to dioxane (2.0 mL) and water (2.0 mL), and the argon atmosphere was replaced three to five times. The reaction solution was heated at 100°C in a microwave and stirred for 90 minutes. The reaction solution was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate three times (10 mL x 3), and the organic phases were combined. The organic phase was washed with water and saturated brine in turn, and then dried over anhydrous sodium sulfate. The crude product was purified to give a white solid 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (75 mg, Y: 30%). ES-API: [M+H] ⁺ = 636.3.

Step 3: 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (75 mg, 0.11 mmol) and dioxane hydrochloride (5.0 mL) were added to methanol (5 mL), and the reaction solution was reacted at 25° C. for 2 hours; the reaction solution was concentrated to obtain a white solid, which was 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,6-diazaspiro[3.4]octane-6-yl)quinazoline hydrochloride (59 mg, yield: 90%). ES-API: [M+H] ⁺ = 536.5.

Step 4: 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazoline (59 mg, 0.109 mmol) was added to dichloromethane (5.0 mL), and then N,N-diisopropylethylamine was added until the reaction solution was weakly alkaline (pH = 6-7), and then a dichloromethane solution of acryloyl chloride (10.0 mg, 0.109 mmol) was slowly added at -70°C. The reaction solution was stirred at -70°C for 30 minutes, and methanol was added to quench the reaction. The reaction solution was then heated to 25°C and concentrated. The obtained product was prepared by reverse phase to obtain a white solid, 1-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one (Z2, 30 mg, yield: 40%). ES-API: [M+H] ⁺ = 590.6. ¹ HNMR (400 MHz, DMSO-d ₆ )δ9.88(br,1H),δ8.28(s,1H),δ7.60(d,J＝8.0Hz,1H),δ7.57(s,1H),δ7.40(d,J＝8.0Hz,1H),δ6.36(m,2H),δ6.15(m,2H),δ5.71(m,1H),δ4.73(m,1H), δ4.61(d,J＝8.0Hz,1H), δ4.35 (m,1H),δ4.23(d,J＝8.0Hz,3H),δ4.06(d,J＝8.0Hz,3H),δ3.94(d,J＝8.0Hz,2H),δ3.83(m,1H),δ3.60(m,1H),δ3.14(m,1H),δ2.96(m,2H),δ2.26(m,3H ), δ2.07(m,1H), δ1.95(m,3H).

Example 3: Preparation of Z3

Step 1: tert-Butyl 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (200 mg, 0.395 mmol), methylpiperazine (119 mg, 1.185 mmol), cesium carbonate (687 mg, 0.185 mmol) and 1,4-diazabicyclo[2.2.2]octane (10 mg, 0.079 mmol) were added to anhydrous tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL), and argon was replaced three to five times. After stirring the reaction solution at 60°C for 16 hours, it was cooled to room temperature and poured into ice water, and extracted with ethyl acetate three times (10.0 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, and then dried over anhydrous sodium sulfate. The mixture was then concentrated in vacuo to give a yellow solid crude product, tert-butyl 6-(7-bromo-6-chloro-8-fluoro-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (225 mg, yield: 100%). ES-API: [M+H]+=586.3.

Step 2: tert-Butyl 6-(7-bromo-6-chloro-8-fluoro-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (225 mg, 0.396 mmol, crude), (5-methyl-1H-indazol-4-yl)boric acid (105 mg, 0.594 mmol), sodium carbonate (84 mg, 0.792 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.0198 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (17 mg, 0.0396 mmol) were added to dioxane (2.0 mL) and water (2.0 mL), and the atmosphere was replaced with argon three to five times. The reaction solution was then heated to 100°C in a microwave, stirred for 90 minutes, cooled to room temperature, filtered, and the filtrate was extracted three times with ethyl acetate (10.0 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, and then dried over anhydrous sodium sulfate. The crude product was purified to give a white solid 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazine-1-yl)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (70 mg, Y: 28%). ES-API: [M+H] ⁺ = 621.2.

Step 3: 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazine-1-yl)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (70 mg, 0.11 mmol) and dioxane hydrochloride (5.0 mL) were added to methanol (5 mL), and the reaction solution was reacted at 25° C. for 2 hours. The reaction solution was concentrated to obtain a yellow solid of 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazine-1-yl)-4-(2,6-diazaspiro[3.4]octane-6-yl)quinazoline (60 mg, yield: 90%). ES-API: [M+H] ⁺ = 521.3.

Step 4: 6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazine-1-yl)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazoline (60 mg, 0.115 mmol) was added to dichloromethane (5.0 mL), and then N,N-diisopropylethylamine was added until the reaction solution was weakly alkaline (pH = 6-7). Then, a dichloromethane solution of acryloyl chloride (11.0 mg, 0.115 mmol) was slowly added at -70°C. After the reaction solution was stirred at -70°C for 30 minutes, methanol was added to quench the reaction. Then the reaction solution was heated to 25°C and concentrated. The obtained product was prepared by reverse phase to give white solid 1-(6-chloro-8-fluoro-7-(5-methyl-1H-indolazol-4-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one (Z3, 10 mg, yield: 14%). ES-API: [M+H] ⁺ =575.6. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.65(br,1H), δ8.12(s,1H), δ7.58(d,J＝8.0Hz,1H), δ7.49(s,1H), δ7.39(d,J＝8.0Hz,1H), δ6.36(m,1H), δ6.14(m,1H), δ4.83(m ,2H),δ4.33(d,J＝8.0Hz,1H),δ4.31(m,3H),δ4.04(d,J＝8.0Hz,2H),δ3.95(m,3H),δ3.24(m,3H),δ3.05(s,3H),δ2.84(s,3H),δ2.25(m,2H),δ2.15(s,3 H).

Example 4: Preparation of Z4

Step 1: tert-Butyl 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (200 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide/tetrahydrofuran (4/0.4 mL), (S)-(1-methylpyrrolidin-2-yl)methanol (140 mg, 0.2 mmol), triethylenediamine (10 mg, 0.08 mmol) and cesium carbonate (400 mg, 1.2 mmol) were added to the reaction solution, and the reaction solution was reacted at 25°C for 16 hours; then, the reaction solution was poured into water (20 mL) and extracted with a mixture of dichloromethane and methanol (20/1) (20 mL x 3). The organic phases were combined, washed with water (20 mL x 3), dried and concentrated, and passed through a silica gel column (dichloromethane/methanol = 30/1 to 20/1, 0.3% aqueous ammonia) to give a yellow solid of 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]]octane-2-carboxylic acid methyl ester (120 mg, Y: 50%). ES-API: [M+H] ⁺ = 584.1.

Step 2: 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]]octane-2-carboxylic acid methyl ester (120 mg, 0.2 mmol), 2-fluoro-6-hydroxyphenylboronic acid (310 mg, 2 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), sodium carbonate (400 mg, 3 mmol) and dioxane/water (4/1, 2.5 mL) were added to a 5 ml microwave reaction tube, purged with argon for 1 minute and then sealed, microwaved at 110 ° C for 3 hours, cooled and added with water (10 mL), extracted with a mixture of dichloromethane and methanol (20/1) (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3), dried and concentrated, and purified using a preparative plate (200 x 200 mL) to give a yellow solid of 6-(6-chloro-2-(cyclopentylmethoxy)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-tert-butyl carboxylate (100 mg, yield: 79%). ES-API: [M+H] ⁺ = 616.2.

Step 3: 6-(6-chloro-2-(cyclopentylmethoxy)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-tert-butyl carboxylate (100 mg, 0.16 mmol) was added to a mixture of hydrochloric acid/dioxane (4M, 2 mL) and methanol (2 mL), stirred at room temperature for 1 hour, and then concentrated in vacuo to obtain a yellow solid of 2-(6-chloro-2-(cyclopentylmethoxy)-8-fluoro-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-7-yl)-3-fluorophenol hydrochloride crude product (100 mg, Y: 100%), which was directly used in the next step. ES-API: [M+H] ⁺ = 516.2.

Step 4: The crude hydrochloride of 2-(6-chloro-2-(cyclopentylmethoxy)-8-fluoro-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-7-yl)-3-fluorophenol (100 mg, 0.16 mmol) was dissolved in anhydrous dichloromethane solution (5 mL) of triethylamine (500 mg, 5 mmol). After stirring for half an hour under argon protection, the mixture was cooled to about -70°C in a dry ice-ethanol bath, and acryloyl chloride (50 mg, 0.5 mmol) was added dropwise. After stirring for 20 minutes, methanol (1 mL) was added dropwise, the mixture was returned to room temperature, and vacuum concentrated to obtain a yellow solid, which was crude 2-(4-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-3-fluorophenyl acrylate (100 mg, Y: 100%), which was directly used in the next step. ES-API: [M+H] ⁺ = 624.6.

Step 5: The crude product of 2-(4-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-3-fluorophenyl acrylate (100 mg, 0.16 mmol) was dissolved in a mixture of saturated aqueous LiOH solution (3 mL) and methanol (6 mL). After stirring at room temperature for 20 minutes, saturated aqueous ammonium chloride solution (20 mL) was added. Extracted with dichloromethane/methanol (20/1) (20 mL x 3), the organic phases were combined and washed with water (20 mL x 1), concentrated, and purified by pre-HPLC (0.1% TFA) to obtain a preparative solution. Most of the acetonitrile was removed by vortexing and then freeze-dried to obtain 1-(6-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one (Z4, 5.1 mg, yield: 5%). ES-API: [M+H] ⁺ = 569.2. ¹ H NMR (400MHz, DMSO-d ₆ ): δ10.30 (s, 1H), 9.82-9.80 (b, 1H), 8.18 (s, 1H), 7.35 (q, J = 8, 1H), 6.86-6.80 (m, 2H), 6.35-6.28 (m, 1H), 6.12 (dd, J ₁ = 2, J ₂ ＝16.8,1H),5.69(dd,J ₁ ＝1.6,J ₂ ＝10,1H),4.75-4.72(m,1H),4.60-4.54(m,1H),4.32(d,J＝9.6),4.03-3.78(m,1H),4.32(d,J＝9.6),4.20(d,J＝8.4,3H),4.03-3.78(m,4H),3.53- 3.47(m,4H),2.95(s,3H),2.09-2.01(m,1H),1.95-1.90(m,2H).

Example 5: Preparation of Z5

Step 1: 4-bromo-5-fluoro-2-nitrobenzoic acid (6.0 g, 22.7 mmol) was dissolved in methanol (80 mL), and sodium methoxide (3.7 g, 68.2 mmol) was added at room temperature. Heat to 60 ° C for 18 hours. Cool to room temperature and add 3M HCl until pH = 2. Extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with brine (50 mL), and dry over anhydrous sodium sulfate. Filter and spin dry the filtrate to obtain a light yellow solid 4-bromo-5-methoxy-2-nitrobenzoic acid (6.0 g, yield: 50%). ES-API: [MH] ^- = 276.1

Step 2: 4-Bromo-5-methoxy-2-nitrobenzoic acid (5.0 g, 18.1 mmol) was dissolved in ethanol (200 mL) and glacial acetic acid (10.9 g, 181 mmol) and iron powder (5.1 g, 90.5 mmol) were added at room temperature. Heat to 70°C and react for 18 hours. Filter and spin-dry the filtrate to obtain a red solid 2-amino-4-bromo-5-methoxybenzoic acid (3.0 g. Yield: 68%). ES-API: [MH] ^- = 244.1.

Step 3: A mixture of 2-amino-4-bromo-5-methoxybenzoic acid (2.9 g, 11.8 mmol) and urea (60.0 g, 1000 mmol) was heated to 200°C and stirred for 3 hours. After cooling to room temperature, water (500 mL) was added and extracted with ethyl acetate (200 mL/min). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 7-bromo-6-methoxyquin-2,4(1H,3H)-dione (3.0 g, yield: 90%) ES-API: [M+H] ⁺ = 273.0.

Step 4: 7-bromo-6-methoxyquin-2,4(1H,3H)-dione (1.9 g, 7.0 mmol) was dissolved in phosphorus oxychloride (20 mL). Heat to 80 °C for 3 hours. Cool to room temperature, pour the reaction solution into cold water, and extract with ethyl acetate (50 mL x 2). The extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid 7-bromo-2,4-dichloro-6-methoxyquin (2.0 g, yield: 60%).

Step 5: 7-bromo-2,4-dichloro-6-methoxyquinoline (1.9 g, 6.2 mmol) was dissolved in dioxane (30 mL), and triethylamine (3.1 g, 31.0 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (2.1 g, 9.3 mmol) were added in sequence at room temperature. The mixture was heated to 50°C and reacted for 3 hours. The mixture was directly purified by column using dichloromethane as eluent to obtain yellow solid 7-(7-bromo-2-chloro-6-methoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (500 mg, yield: 16%). ES-API: [M+H] ⁺ = 497.1.

Step 6: tert-Butyl 7-(7-bromo-2-chloro-6-methoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (450 mg, 0.9 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1-methylpiperidin-4-ol (125 mg, 1.1 mmol), 1,4-diazabicyclo[2.2.2]octane (202 mg, 1.8 mmol), and cesium carbonate (586 mg, 1.8 mmol) were added to the reaction solution at room temperature. Heat to 60 ° C for 3 hours and cool to room temperature. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL x 3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. Purification by column with dichloromethane:methanol=100/1 to 20/1 as eluent gave a pale yellow solid as tert-butyl 7-(7-bromo-6-methoxy-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (80 mg, yield: 15%). ES-API: [M+H] ⁺ =578.2.

Step 7: tert-butyl 7-(7-bromo-6-methoxy-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (70 mg, 0.12 mmol) was dissolved in dioxane/water = 10/1 (2 mL), and (5-methyl-1H-indazol-4-yl)boric acid (26 mg, 0.15 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (20 mg, 0.048 mmol), potassium phosphate (76 mg, 0.36 mmol), tris(dibenzylidene-BASE acetone)dipalladium (22 mg, 0.024 mmol) were added in sequence at room temperature. The argon gas was replaced three times, and the reaction was carried out at 100°C in a microwave for 1.5 hours, and then cooled to room temperature. Water (50 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL x 3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried to give a crude product. Column purification was performed using dichloromethane:methanol = 100/1 to 20/1 as eluent to give a pale yellow solid of tert-butyl 7-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (40 mg, yield: 55%). ES-API: [M+H] ⁺ = 628.3.

Step 8: tert-Butyl 7-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (40 mg, 0.06 mmol) was dissolved in methanol (1 mL), and hydrochloric acid/dioxane (1 mL, 4 M) was slowly added dropwise to the reaction solution at room temperature, and stirred at room temperature for 1 hour. Concentrate and spin dry to obtain a light yellow solid 6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline (40 mg, Y: 99%). ES-API: [M+H] ⁺ = 528.3.

Step 9: 6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]non-7-yl)quinazoline (40 mg, 0.06 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (30 mg, 0.3 mmol) and acryloyl chloride (8 mg, 0.09 mmol) were added to the reaction solution at -70°C. The reaction was continued at -70°C for 0.5 hours. Methanol (1 mL) was added dropwise to quench the reaction, and the reaction solution was spin-dried and purified by HPLC to obtain a yellow solid 1-(7-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Z5, 3.7 mg, Y: 10%). ES-API: [M+H] ⁺ = 582.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.2 (s, 1H), 9.48 (s, 1H), 7.52-7.30 (m, 5H), 6.39-5.36 (m, 4H), 4.10-3.94 (m, 12H), 3.22-1.98 (m, 17H).

Example 6: Preparation of Z6

Step 1: 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (300 mg, 0.59 mmol), 1-(methylsulfonyl)piperidin-4-ol (159 mg, 0.89 mmol), cesium carbonate (481 mg, 1.475 mmol) and 1,4-diazabicyclo[2.2.2]octane (13 mg, 0.12 mmol) were added to anhydrous tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL), and argon was replaced three to five times. After the reaction solution was stirred at room temperature for 24 hours, it was cooled to room temperature and poured into ice water, and extracted with ethyl acetate three times (50 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, and then dried over anhydrous sodium sulfate. The mixture was then concentrated under vacuum to give a crude yellow oily product, tert-butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (400 mg, yield: 100%). ES-API: [M+H]+=647.9.

Step 2: tert-Butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (400 mg, 0.59 mmol, crude), (5-methyl-1H-indazol-4-yl)boric acid (156 mg, 0.885 mmol), sodium carbonate (125 mg, 1.18 mmol), tris(dibenzylideneacetone)dipalladium (26 mg, 0.028 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (24 mg, 0.059 mmol) were added to dioxane (5 mL) and water (0.5 mL), and the atmosphere was replaced with argon three to five times. The reaction solution was then heated to 100°C in a microwave, stirred for 60 minutes, cooled to room temperature, filtered, water (30 mL) was added to the filtrate, and extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The crude product was purified by silica gel column (petroleum ether: acetone equal to 3 to 2) to obtain a yellow oil, 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (280 mg, yield 68%). ES-API: [M+H] ⁺ = 700.2.

Step 3: 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (280 mg, 0.40 mmol) and dioxane hydrochloride (4 mol/L, 2 mL) were added to methanol (2 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a yellow solid as 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)oxy)-4-(2,6-diazaspiro[3.4]octane-6-yl)quinazoline hydrochloride (254 mg, yield 100%). ES-API: [M+H] ⁺ = 600.1.

Step 4: 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)oxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazoline hydrochloride (254 mg, 0.40 mmol) was added to dichloromethane (5 mL), and then N,N-diisopropylethylamine (413 mg, 3.2 mmol) was added. Then, a dichloromethane solution (1 mL) of acryloyl chloride (36 mg, 0.40 mmol) was slowly added at -70°C. After the reaction solution was stirred at -70°C for 30 minutes, methanol was added to quench the reaction. The reaction solution was then heated to 25°C and concentrated under reduced pressure. The yellow oil was purified by reverse phase liquid chromatography to give a white solid, 1-(6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one (Z6, 37 mg, yield 14%). ES-API: [M+H] ⁺ = 654.1. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.25(s,1H),7.59(d,J＝8.8Hz,1H),7.52(s,1H),7.39(d,J＝8.8Hz,1H),6.29-6.36(m,1H),6.12(dd,J＝17.2,2.4Hz,1H),5.69(dd,J＝10.4,2.0Hz,1H),5 .24-5.26(m,2H), 4.33-4.35(m,2H),4.20-4.22(m,2H),3.99-4.07(m,4H),3.92-3.94(m,2H),3.35-3.40(m,2H),3.12-3.18(m,2H),2.25-2.28(m,2H),2.09-2.16 (m,5H),1.84-1.87(m,2H).

Example 7: Preparation of Z7

Step 1: tert-Butyl 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (300 mg, 0.592 mmol), 1-methylpyrrolidin-3-ol (90 mg, 0.889 mmol), cesium carbonate (580 mg, 1.779 mmol) and 1,4-diazabicyclo[2.2.2]octane (15 mg, 0.118 mmol) were added to anhydrous tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL), and argon was replaced three to five times. After stirring the reaction solution at 60°C for 2 hours, it was cooled to room temperature and poured into ice water, and extracted with ethyl acetate three times (10.0 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, and then dried over anhydrous sodium sulfate. The mixture was then concentrated under vacuum to give a yellow solid crude product, tert-butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-3-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (339 mg, yield: 100%). ES-API: [M+H]+=572.3.

Step 2: tert-Butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-3-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (339 mg, 0.594 mmol, crude), (5-methyl-1H-indazol-4-yl)boric acid (160 mg, 0.891 mmol), sodium carbonate (130 mg, 1.188 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.0297 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (25 mg, 0.0594 mmol) were added to dioxane (5.0 mL) and water (2.0 mL), and the atmosphere was replaced with argon three to five times. The reaction solution was then heated to 100°C in a microwave, stirred for 90 minutes, cooled to room temperature, filtered, and the filtrate was extracted three times with ethyl acetate (10.0 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, and then dried over anhydrous sodium sulfate. The crude product was purified to give white solid tert-butyl 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-3-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (80 mg, Y: 20%). ES-API: [M+H] ⁺ = 622.6.

Step 3: 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-3-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (60 mg, 0.096 mmol) and dioxane hydrochloride (5.0 mL) were added to methanol (5 mL), and the reaction solution was reacted at 25° C. for 2 hours. The reaction solution was concentrated to obtain a yellow solid of 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-3-yl)oxy)-4-(2,6-diazaspiro[3.4]octane-6-yl)quinazoline (49 mg, yield: 90%). ES-API: [M+H] ⁺ = 522.4.

Step 4: 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-3-yl)oxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazoline (49 mg, 0.094 mmol) was added to dichloromethane (5.0 mL), and then N,N-diisopropylethylamine was added until the reaction solution was weakly alkaline (pH = 6-7). Then, a dichloromethane solution of acryloyl chloride (10.0 mg, 0.094 mmol) was slowly added at -70°C. After the reaction solution was stirred at -70°C for 30 minutes, methanol was added to quench the reaction. Then the reaction solution was heated to 25°C and concentrated. The obtained product was prepared by reverse phase to obtain a white solid, 1-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-3-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one (Z7, 30 mg, yield: 50%). ES-API: [M+H] ⁺ = 576.2. ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.28(br,1H),δ8.26(s,1H),δ7.60(d,J＝8.0Hz,1H),δ7.49(s,1H),δ7.40(d,J＝8.0Hz,1H),δ6.35(m,1H),δ6.14(m,1H),δ5.70(m,2H),δ4.34(m,1H ), δ4.22(d,J＝8.0Hz,2H), δ4.06(m,2H), δ3.98(m,2H), δ3.94(d,J＝8.0Hz,2H), δ3.84(m,2H), δ2.92(s,1H), δ2.86(m,2H), δ2.32(s,1H), δ2.26(s,3H) ), δ2.15(s,4H).

Example 8: Preparation of Z8

Step 1: tert-Butyl 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (200 mg, 0.395 mmol), N,N-dimethylazacyclo-3-amine (80 mg, 0.800 mmol), cesium carbonate (391 mg, 1.2 mmol) and 1,4-diazabicyclo[2.2.2]octane (10 mg, 0.079 mmol) were added to anhydrous tetrahydrofuran (1.0 mL) and N,N-dimethylformamide (5.0 mL), and argon was replaced three to five times. After the reaction solution was stirred at room temperature for 16 hours, it was diluted with water (30 mL) and extracted with ethyl acetate three times (10.0 mL x 3). The organic phases were combined, washed with water (10 mL x 3), and dried over anhydrous sodium sulfate. Then, the mixture was concentrated in vacuo, mixed with silica gel, and passed through a silica gel column (DCM/MeOH=30/1) to obtain a yellow solid product 6-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-tert-butyl ester carboxylic acid (100 mg, yield: 45%). ES-API: [M+H]+=569.1.

Step 2: 6-(7-Bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-tert-butyl ester carboxylic acid (100 mg, 0.175 mmol), (5-methyl-1H-indazol-4-yl)boric acid (105 mg, 0.594 mmol), sodium carbonate (84 mg, 0.792 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.0198 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (17 mg, 0.0396 mmol) were added to dioxane (4.0 mL) and water (1.0 mL), and the atmosphere was replaced with argon three to five times. The reaction solution was then heated to 100 ° C in a microwave, stirred for 90 minutes, cooled to room temperature, filtered, and the filtrate was extracted three times with ethyl acetate (10.0 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, and then dried over anhydrous sodium sulfate. The crude product was purified by preparative plate (DCM/MeOH=13/1) to give a white solid 6-(6-chloro-2-(3-(dimethylamino)azetidine-1-yl)-8-fluoro-7-(5-methyl-1H-indazole-4-yl)quinazolin-4-yl)tert-butyl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid methyl ester (80 mg, yield: 80%). ES-API: [M+H] ⁺ = 621.3.

Step 3: 6-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)tert-butyl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid methyl ester (80 mg, 0.129 mmol) and dioxane hydrochloride (5.0 mL) were added to methanol (5 mL), stirred at room temperature for 1 hour and concentrated to give a yellow solid of 1-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-2-yl)-N,N-dimethylazacyclo-3-amine (100 mg crude product, yield: 100%). ES-API: [M+H] ⁺ = 521.2.

Step 4: 1-(6-chloro-8-fluoro-7-(5-methyl-1H-indazole-4-yl)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-2-yl)-N,N-dimethylazacyclo-3-amine (100 mg crude product, 0.129 mmol) was added to dichloromethane (5.0 mL), and triethylamine (1 mL) was added and stirred at room temperature for 1 hour. Then acryloyl chloride (33.0 mg, 0.36 mmol) was slowly added at -70°C. After the reaction solution was stirred at -70°C for 30 minutes, methanol (1 mL) was added to quench, the temperature was raised to room temperature, and concentrated. The crude product was prepared by reverse phase to give a white solid, 1-(6-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one (Z8, 15.5 mg, yield: 21%). ES-API: [M+H] ⁺ =575.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.25(br,1H),10.49(br,1H),8.14(s,1H),7.58(d,J＝8.4Hz,1H),7.49(s,1H),7.38(d,J＝8.4Hz,1H),6.36-6.32(m,1H),6.15- 6.10(m,1H),5.71-5.68(m,1H),4.36-4.18(m,13H),4.10-3.92(m,6H),2.25(t,J＝6.4,2H),2.15(s,3H).

Example 8-1: Preparation of Z8-1 and Z8-2

Compound Z8 (500 mg) obtained in Example 8 was chirally resolved (Co-Solvent: 30% EtOH 1% MA; column: OJ 250 mm*4.6 mm 5 um); flow rate: 1.0 ml/min; column temperature: 40.3°C) to obtain: Compound Z8-1 (retention time: 1.014 min), the arbitrary structure of which was designated as (S)-1-(6-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one (270 mg, P: 100%, ee value: 100%). ES-API: [M+H] ⁺ = 575.1. Compound Z8-2 (retention time: 1.707 min), the arbitrary structure of which was designated as (R)-1-(6-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one (200 mg, P: 100%, ee value: 100%). ES-API: [M+H] ⁺ = 575.1.

Example 9: Preparation of Z9

Step 1: 4-Bromo-5-fluoro-2-nitrobenzoic acid (5.0 g, 18.9 mmol) was dissolved in tetrahydrofuran (50 mL), and Raney nickel (1.0 g, 17.0 mmol) was added at room temperature. The mixture was reacted at room temperature for 18 hours under the protection of a hydrogen balloon. The mixture was filtered and the filtrate was dried to obtain a yellow solid 2-amino-4-bromo-5-fluorobenzoic acid (2.8 g, yield: 64%). ES-API: [M+H] ^+- = 236.1.

Step 2: A mixture of 2-amino-4-bromo-5-fluorobenzoic acid (2.3 g, 9.8 mmol) and urea (50.0 g, 84.9 mmol) was heated to 200°C and stirred for 3 hours. After cooling to room temperature, water (500 mL) was added and extracted with ethyl acetate (200 mL/min). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 7-bromo-6-fluoroquinoline-2,4(1H,3H)-dione (2.5 g, yield: 90%). ES-API: [MH] ^- = 259.0.

Step 3: 7-bromo-6-fluoroquine-2,4(1H,3H)-dione (2.5 g, 9.7 mmol) was dissolved in phosphorus oxychloride (30 mL). Heat to 80 °C for 3 hours. Cool to room temperature, pour the reaction solution into cold water, and extract with ethyl acetate (50 mL x 2). The extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid 7-bromo-2,4-dichloro-6-fluoroquine (1.3 g, yield: 50%).

Step 4: 7-bromo-2,4-dichloro-6-fluoroquine (1.4 g, 4.7 mmol) was dissolved in dioxane (20 mL), and triethylamine (1.4 g, 14.1 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (1.0 g, 4.7 mmol) were added at room temperature. Heat to 50 ° C for 1 hour. Add water (50 mL) to quench the reaction. Extract with ethyl acetate (50 mL x 3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. Purification by column with dichloromethane:methanol=100/1 to 20/1 as eluent gave a pale yellow solid of tert-butyl 6-(7-bromo-2-chloro-6-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (600 mg, yield: 27%). ES-API: [M+H] ⁺ =471.1.

Step 5: 6-(7-bromo-2-chloro-6-fluoroquinazoline-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (500 mg, 1.1 mmol) was dissolved in N,N-dimethylformamide (10 mL), and (S)-(1-methylpyrrolidin-2-yl)methanol (150 mg, 1.3 mmol), 1,4-diazabicyclo[2.2.2]octane (246 mg, 2.2 mmol), and cesium carbonate (717 mg, 2.2 mmol) were added to the reaction solution at room temperature. Heat to 60 ° C for 3 hours and cool to room temperature. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL x 3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. Purification by column with dichloromethane:methanol=100/1 to 20/1 as eluent gave a pale yellow solid as (S)-tert-butyl 6-(7-bromo-6-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (450 mg, yield: 75%). ES-API: [M+H] ⁺ =550.2.

Step 6: (S)-6-(7-bromo-6-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (350 mg, 0.64 mmol) was dissolved in dioxane/water = 10/1 (5 mL), and (5-methyl-1H-indazol-4-yl)boric acid (120 mg, 0.76 mmol), potassium phosphate (410 mg, 1.92 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (95 mg, 0.13 mmol) were added in sequence at room temperature. The argon gas was replaced three times, and the reaction was carried out at 100°C in a microwave for 1.5 hours, and then cooled to room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried to give a crude product. Column purification was performed using dichloromethane:methanol = 100/1 to 20/1 as eluent to give a light yellow solid of 6-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (150 mg, yield: 40%). ES-API: [M+H] ⁺ = 582.3.

Step 7: 6-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (150 mg, 0.26 mmol) was dissolved in methanol (1 mL), and hydrochloric acid/dioxane (1 mL, 4 M) was slowly added dropwise to the reaction solution at room temperature, and stirred at room temperature for 1 hour. Concentrate and spin dry to obtain a light yellow solid 3-fluoro-2-(6-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-7-yl)phenol (150 mg, yield: 99%). ES-API: [M+H] ⁺ = 482.2.

Step 8: 3-Fluoro-2-(6-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-7-yl)phenol (150 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (130 mg, 1.3 mmol) and acryloyl chloride (46 mg, 0.39 mmol) were added to the reaction solution at -70°C. The reaction was carried out at -70°C for 0.5 hours. Methanol (1 mL) was added dropwise to quench the reaction, and the reaction solution was spin-dried to obtain a yellow solid crude product, 2-(4-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-3-fluorophenyl acrylate (300 mg, yield: 99%). ES-API: [M+H] ⁺ = 590.3.

Step 9: 2-(4-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-3-fluorophenyl acrylate (300 mg, 0.26 mmol) was dissolved in tetrahydrofuran/water = 4/1 (10 mL), and lithium hydroxide (25 mg, 1.04 mmol) was added at room temperature. Heat to 50°C and react for 3 hours. The reaction solution was spin-dried and purified by HPLC to obtain a yellow solid 1-(6-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)prop-2-en-1-one (Z9, 10.5 mg, yield: 7%). ES-API: [M+H] ⁺ =536.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.32(s,1H),9.93(s,1H),8.13-5.67(m,8H),4.77-3.61(m,12H),3.17-2.82(m,4H),3.30-1.84(m,8H).

Example 10: Preparation of Z10

Step 1: tert-Butyl 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (300 mg, 0.59 mmol), (1-methylpiperidin-4-yl)methanol (115 mg, 0.89 mmol), cesium carbonate (481 mg, 1.475 mmol) and 1,4-diazabicyclo[2.2.2]octane (13 mg, 0.12 mmol) were added to anhydrous tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL), and argon was replaced three to five times. After stirring the reaction solution at room temperature for 24 hours, it was cooled to room temperature and poured into ice water, and extracted with ethyl acetate three times (50 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, and then dried over anhydrous sodium sulfate. The mixture was then concentrated in vacuo to give a yellow oily crude product, tert-butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (350 mg, yield 99%). ES-API: [M+H]+=598.0.

Step 2: tert-Butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (350 mg, 0.59 mmol, crude), (5-methyl-1H-indazol-4-yl)boric acid (156 mg, 0.885 mmol), sodium carbonate (125 mg, 1.18 mmol), tris(dibenzylideneacetone)dipalladium (26 mg, 0.028 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (24 mg, 0.059 mmol) were added to dioxane (5 mL) and water (0.5 mL), and the atmosphere was replaced with argon three to five times. The reaction solution was then heated to 100°C in a microwave, stirred for 60 minutes, cooled to room temperature, filtered, water (30 mL) was added to the filtrate, and extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The crude product was purified by silica gel column (dichloromethane: methanol 10 to 1) to obtain a yellow oil, 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (140 mg, yield 36%). ES-API: [M+H] ⁺ = 650.2.

Step 3: 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (140 mg, 0.22 mmol) and dioxane hydrochloride (4 mol/L, 1 mL) were added to methanol (1 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a yellow solid of 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)methoxy)-4-(2,6-diazaspiro[3.4]octane-6-yl)quinazoline hydrochloride (129 mg, yield 100%). ES-API: [M+H] ⁺ = 550.1.

Step 4: 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)methoxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazoline hydrochloride (129 mg, 0.22 mmol) was added to dichloromethane (3 mL), and then N,N-diisopropylethylamine (284 mg, 2.2 mmol) was added. Then, a dichloromethane solution (1 mL) of acryloyl chloride (20 mg, 0.22 mmol) was slowly added at -70°C. After the reaction solution was stirred at -70°C for 30 minutes, methanol was added to quench the reaction. The reaction solution was then heated to 25°C and concentrated under reduced pressure. The yellow oil was purified by reverse phase liquid chromatography to give a white solid, which was 1-(6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one trifluoroacetate (Z10, 14 mg, yield 9%). ES-API: [M+H] ⁺ = 604.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.24 (s, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.50 (s, 1H), 7.39 (d, J = 8.4Hz, 1H), 6.29-6.36 (m, 1H), 6.12 (dd, J = 17.2, 2.4Hz, 1H), 5.69 (m, 1H),3.40-4.30(m,10H),2.92-3.01(m,2H),2.76(m,3H),2.53-2.57(m,3H),2.25(m,2H),2.16(s,3H),1.95-1.99(m,3H),1.49-1.53(m,2H).

Example 11: Preparation of Z11

Step 1: 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (800 mg, 1.58 mmol), N-methylpiperidin-4-amine (360 mg, 3.16 mmol), cesium carbonate (1.54 g, 4.74 mmol) and 1,4-diazabicyclo[2.2.2]octane (40 mg, 0.32 mmol) were added to anhydrous tetrahydrofuran (4.0 mL) and N,N-dimethylformamide (20.0 mL), and argon was replaced three to five times. After the reaction solution was stirred at room temperature for 16 hours, it was diluted with water (50 mL) and extracted with ethyl acetate three times (20.0 mL x 3). The organic phases were combined, washed with water (50 mL x 2), and dried over anhydrous sodium sulfate. Then, the product was concentrated in vacuo, mixed with silica gel, and passed through a silica gel column (DCM/MeOH=30/1) to obtain a yellow solid product, 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (500 mg, yield: 53.9%). ES-API: [M+H]+=583.1.

Step 2: 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (400 mg, 0.69 mmol), 5-methyl-1H-indazole-4-boronic acid (182 mg, 1.04 mmol), sodium carbonate (146 mg, 1.38 mmol), tris(dibenzylideneacetone)dipalladium (31 mg, 0.035 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (28 mg, 0.069 mmol) were added to dioxane (10.0 mL) and water (1.0 mL), and argon was replaced three to five times. Then the reaction solution was heated to 100°C in a microwave, stirred for 90 minutes, cooled to room temperature, filtered, and the filtrate was extracted three times with ethyl acetate (10.0 mL x 3). The organic phases were combined, washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The crude product was purified by preparative plate (DCM/MeOH=10/1) to give a white solid 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (120 mg, yield: 27.6%). ES-API: [M+H] ⁺ = 635.2.

Step 3: 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (120 mg, 0.189 mmol) and dioxane hydrochloride (10 mL) were added to methanol (5 mL), stirred at room temperature for 1 hour and concentrated to give a yellow solid of 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-N-(1-methylpiperidin-4-yl)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-2-amine hydrochloride (100 mg crude product, yield: 92.6%). ES-API: [M+H] ⁺ = 535.1.

Step 4: 6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-N-(1-methylpiperidin-4-yl)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazoline-2-amine hydrochloride (100 mg crude product, 0.175 mmol) was added to dichloromethane (10 mL), and triethylamine (1 mL) was added and stirred at room temperature for 1 hour. Then acryloyl chloride (19 mg, 0.21 mmol) was slowly added at -70°C. After the reaction solution was stirred at -70°C for 30 minutes, methanol (5 mL) was added to quench, warmed to room temperature, and concentrated. The crude product was prepared by reverse phase to give a white solid, 1-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one (Z11, 8.5 mg, yield: 8.3%). ES-API: [M+H] ⁺ =589.5. ¹ H NMR (400MHz, CDCl ₃ ) δ10.79 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.49-7.47 (d, J = 8.8Hz, 1H), 7.36-7.34 (d, J = 8.4Hz, 1H), 6.41-6.37 (m, 1H), 6.25-6.18 ( m,1H),5.74-5.71(m,1H),4.30-3.95(m,10H),2.78(m,2H),2.33-2.30(m,5H),2.24-2.20(m,5H),2.10-2.01(m,2H),1.62-1.54(m,2H).

Example 12: Preparation of Z13

Step 1: A mixture of tert-butyl 7-(7-bromo-2-chloro-6-methoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (10 g, 20.1 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (34.7 g, 301 mmol) and cesium carbonate (19.6 g, 60.3 mmol) was stirred at 120°C for 1 hour. After the reaction was completed, the reaction solution was poured into 500 mL of ethyl acetate and washed three times with 200 mL of water. The obtained organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by column chromatography (DCM:MeOH (1% Et ₃ N), 0-5%) to give (R)-7-(7-bromo-6-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (9.5 g) as a pale yellow solid. ES-API: [M+H] ⁺ =576.1.

Step 2: (R)-7-(7-bromo-6-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (4.5 g, 7.81 mmol), (5-methyl-1H-indazol-4-yl)boric acid (2.06 g, 11.71 mmol), tris(dibenzylideneacetone)dipalladium (714 mg, 0.78 mmol), SPhos (320 mg, 0.78 mmol) and potassium phosphate (4.97 g, 23.43 mmol) were dissolved in 80 mL of 1,4-dioxane and 20 mL of water, and the mixture was replaced with nitrogen three times. Under nitrogen protection, the reaction was carried out at 120°C for 1 hour. The reaction solution was dissolved in 300 mL of ethyl acetate and washed three times with 100 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by flash silica gel column (methanol/dichloromethane, 0-10%) to obtain yellow solid tert-butyl 7-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl])-2,7-diazaspiro[3.5]nonane-2-carboxylate (4.5 g). ES-API: [M+H] ⁺ = 628.2.

Step 3: A solution of tert-butyl 7-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl])-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.2 g, 1.91 mmol) in dichloromethane (12 mL) was cooled to 0°C and trifluoroacetic acid (3 mL) was slowly added. After the addition, the mixture was returned to room temperature and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a yellow viscous substance 6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]]nonyl-7-yl)quinazoline (1.01 g). ES-API: [M+H] ⁺ =508.2.

Step 4: In an ice bath, triethylamine (1 mL) and acrylic anhydride (229 mg, 1.82 mmol) were slowly added to a mixture of 6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]]nonyl-7-yl)quinazoline (1.01 g, 1.91 mmol) in dichloromethane (20 mL) and the mixture was reacted for 5 minutes. The reaction mixture was washed with water (10 mL). The reaction mixture was quenched, extracted with dichloromethane (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC to give a white solid 1-(7-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl])-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en- ¹ -one (Z13, 580 mg, P: 99.37%, yield: 45%). NMR (500MHz, DMSO) δ13.04(s,1H),7.51-7.46(m,2H),7.42(s,1H),7.33-7.29(m,2H),6.36(dd,J＝17.0,10.3Hz,1H),6.13(dd,J＝17.0,2.2Hz,1H),5.69(dd,J ＝10.3,2.2Hz,1H),4.42-4.35(m,1H) ,4.19(s,1H),4.05(s,2H),3.79(s,3H),3.77(s,2H),3.69(s,4H),3.03(s,1H),2.67(d,J＝25.9Hz,1H),2.43(s,3H),2.29(s,1H),2.17(s,3H),2. 02-1.89(m,5H),1.79-1.61(m,3H).ES-API:[M+H] ⁺ =582.2.

Example 13 Preparation of Z14

Step 1: (S)-7-bromo-6-methoxy-2-(((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (3.8 g, 6.59 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (2.04 g, 13.18 mmol), SPhos Pd G2 (356 mg, 0.494 mmol), Sphos (203 mg, 0.494 mmol) and K ₃ PO ₄ (4.2 g, 19.77 mmol) was added to a mixture of 1,4-dioxane (120 mL) and water (12 mL), replaced with nitrogen three times, heated to 120°C, stirred for 1.5 hours, and the reaction was completed. The mixture was cooled to room temperature, filtered, concentrated, and 100 ml of ethyl acetate was added. The mixture was washed with water (3x50 ml) and saturated brine in turn, dried over anhydrous sodium sulfate, concentrated, and column chromatography (methanol/dichloromethane: 0-10%) was performed to obtain (S)-7-(2-fluoro-6-hydroxyphenyl)-6-methoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (3.08 g, Y77%). ES-API: [M+H] ⁺ = 608.2.

Step 2: Dissolve (S)-7-(2-fluoro-6-hydroxyphenyl)-6-methoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (3.08 g, 5.07 mmol) in 20 ml of dichloromethane. Slowly add 7 ml of trifluoroacetic acid dropwise at room temperature. After reacting for 2 hours, add 10 ml of dichloromethane and concentrate under reduced pressure to obtain 3-fluoro-2-(6-methoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-7-yl)phenol (2.57 g, crude product), which is directly used in the next step. ES-API: [M+H] ⁺ = 508.1

Step 3: Dissolve 3-fluoro-2-(6-methoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-7-yl)phenol (2.57 g, 5.07 mmol) in dichloromethane, add triethylamine (1.53 g, 15.21 mmol) and acrylic anhydride (511 mg, 4.06 mmol) dropwise under ice-water bath, and stir for 10 minutes under ice-water bath. After the reaction, add 100 ml DCM, washed with water (50 ml) and saturated brine in sequence, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give (1-(7-(7-(2-fluoro-6-hydroxyphenyl)-6-methoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propen-2-one (Z14, 950 mg, yield: 35%), ES-API: [M+H] ⁺ =562.1. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.85(s,1H),7.38(s,1H),7.30-7.16(m,2H),6.86-6.64(m,2H),6.34(dd,J＝17.0,10.3Hz,1H),6.12(dd,J＝17.0,2.3Hz,1H),5.68(dd,J＝10.3,2.3Hz, 1H),4.34(m,1H),4.12(m,1H),4.02(s,2H),3.80(s,3H),3.74(s,2H),3.65(m,4H),2.96(m,1H),2.58(s,1H),2.37(s,3H),2.18(m,1H),1.95(m, 5H),1.74-1.56(m,3H).

Example 14 Preparation of Z15

Step 1: Add methyl 2-amino-4-bromo-5-methoxybenzoate (50.0 g, 192.2 mmol) and urea (200 g, 3300.3 mmol) to a 1 L reaction bottle. Stir the reaction at 200 ° C for 1 hour. The reaction system was cooled to room temperature, and 1 L of water was added and refluxed at 100 ° C for 1 hour, filtered, and the filter cake was dried under vacuum to obtain the target product 7-bromo-6-methoxyquinazoline-2,4 (1H, 3H) -dione (51 g, yield: 82.3%), an off-white solid. ES-API: [M + H] ⁺ = 270.09

Step 2: Dissolve 7-bromo-6-methoxyquinazoline-2,4(1H,3H)-dione (1.0g, 3.68mmol) in toluene (5mL), add phosphorus oxychloride (5.66g, 36.91mmol), and slowly drop N,N-diisopropylethylamine (1.41g, 10.91mmol). Stir the reaction at 105°C for 0.5 hours. The reaction solution was concentrated and evaporated to dryness under reduced pressure, quenched by adding 50ml of ice water, extracted with ethyl acetate three times (15ml*3), and dried under vacuum to obtain the target product 7-bromo-2,4-dichloro-6-methoxyquinazoline (1.0g, yield: 88%), a yellow solid. ES-API: [M+H] ⁺ = 306, 308

Step 3: Dissolve 7-bromo-2,4-dichloro-6-methoxyquinazoline (340 mg, 1.1 mmol) in 5 ml 1,4-dioxane solution, and add 2,6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (200 mg, 0.94 mmol) and N,N-diisopropylethylamine (340 mg, 2.634 mmol) in sequence. Stir the reaction at 50 ° C for 1 hour. Add 30 ml of ammonium chloride solution to the reaction solution, extract twice with 50 ml of ethyl acetate, dry and concentrate, and purify the crude product with a rapid silica gel column (ethyl acetate/petroleum ether: 0-20%) to obtain the target product 6- (7-bromo-2-chloro-6-methoxyquinazoline-4-yl) -2,6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (250 mg, yield: 46.8%), off-white solid. ES-API: [M+H] ⁺ = 482, 484

Step 4: Dissolve tert-butyl 6-(7-bromo-2-chloro-6-methoxyquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (200 mg, 0.413 mmol) in 1-methylpiperidin-4-ol (3 g, 26.04 mmol), add cesium carbonate (400 mg, 1.22 mmol), heat to 120°C and stir to react for 3-4 hours. 30 ml of ammonium chloride solution was added to the reaction solution, and the mixture was extracted twice with 50 ml of ethyl acetate. The mixture was dried and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-30%) to obtain the target product 6-(7-bromo-6-methoxy-2-(((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (180 mg, yield: 77.4%) as an off-white solid. ES-API: [M+H] ⁺ = 562

Step 5: Dissolve tert-butyl 6-(7-bromo-6-methoxy-2-(((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (180 mg, 0.32 mmol) in 5 ml 1,4-dioxane and 1 ml of water were added with (5-methyl-1H-indazol-4-yl)boric acid (57.58 mg, 0.384 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (20 mg, 0.048 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.024 mmol), and potassium phosphate (203.52 mg, 0.96 mmol). The system was replaced with nitrogen three times. Then, the mixture was protected with a nitrogen balloon. The reaction mixture was stirred at 120°C for 1 hour. 150 mL of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 100 mL of saturated brine, dried and concentrated, and the crude product was purified by a rapid silica gel column (ethyl acetate/petroleum ether: 0-20%) to obtain the target product, tert-butyl 6-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (80 mg, yield: 50%), as an off-white solid. ES-API: [M+H] ⁺ = 614.

Step 6: Tert-butyl 6-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octan-2-carboxylate (80 mg, 0.130 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. Stirring was carried out at room temperature for 2 hours, and the reaction solution was concentrated to obtain the target product 6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazoline (90 mg, crude product), which was directly used in the next step. ES-API: [M+H] ⁺ =514.

Step 7: 6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazoline (66 mg, 0.130 mmol) was dissolved in dichloromethane (5 mL) and N,N-diisopropylethylamine (20.16 mg, 0.156 mmol) was added. The reaction was cooled to 0°C and acrylic anhydride (19.67 mg, 0.156 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 100 mL of saturated NaHCO3 aqueous solution and 80 mL of saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-60%) to obtain the target product 1-(6-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]-2-acryloyl-1-one (15 mg, yield: 20%), off-white solid. ES-API: [M+H] ⁺ = 569.2. ¹ H NMR (500 MHz, CDCl ₃ )δ7.62(d,J＝1.1Hz,1H),7.59(s,1H),7.52(s,1H),7.45(d,J＝8.5Hz,1H),7.34(d,J＝8.6Hz,1H),6.39(dd,J＝17.0,1.8Hz,1H),6.22(dd,J＝16.9,10.3Hz,1 H),5.74(dd,J＝10.4,1.7 Hz,1H),5.41(s,1H),4.31(d,J＝6.4Hz,1H),4.24(d,J＝8.5Hz,1H),4.15(d,J＝14.9Hz,6H),3.79(s,3H),3.26(s,3H),2.74(s,3H),2.43(s,2H),2.35( t,J＝6.4Hz,2H),2.24(s,6H).

The following compounds were prepared according to the similar methods as above (except that different starting materials were replaced) or according to conventional synthetic methods.

Example 15 Preparation of Z30

Step 1: Compound (R)-7-(7-bromo-6-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (570 mg, 0.99 mmol), 2-fluoro-5-hydroxyphenylboronic acid (230 mg, 1.48 mmol), SPhos Pd G2 (143 mg, 0.20 mmol), SPhos (81 mg, 0.20 mmol) and potassium phosphate (630 mg, 2.97 mmol) were dissolved in 8 mL of 1,4-dioxane and 1.6 mL of water, and microwaved at 120 ° C for 1 hour under nitrogen protection. The reaction solution was dissolved in 30 mL of ethyl acetate and washed three times with 10 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by flash silica gel column (methanol/dichloromethane, 0-10%) to give yellow solid tert-butyl (S)-7-(7-(2-fluoro-5-hydroxyphenyl)-6-methoxy-2-(((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (600 mg). ES-API: [M+H] ⁺ ＝608.2.

Step 2: A solution of the compound tert-butyl (S)-7-(7-(2-fluoro-5-hydroxyphenyl)-6-methoxy-2-(((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (600 mg, 0.98 mmol) in dichloromethane (5 mL) was cooled to 0°C and trifluoroacetic acid (2.5 mL) was slowly added. After the addition, the mixture was returned to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a yellow viscous substance (S)-4-fluoro-3-(6-methoxy-2-(((1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-7-yl)phenol trifluoroacetate (580 mg). ES-API: [M+H] ⁺ = 508.2.

Step 4: In an ice bath, triethylamine (500 mg, 4.95 mmol) and acrylic anhydride (100 mg, 0.79 mmol) were slowly added to a mixture of (S)-4-fluoro-3-(6-methoxy-2-(((1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-7-yl)phenol trifluoroacetate (580 mg, 0.96 mmol) in dichloromethane (10 mL) and reacted for 30 min. The reaction solution was quenched with water (10 mL), extracted with dichloromethane (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC to give a white solid (S)-1-(7-(7-(2-fluoro-5-hydroxyphenyl)-6-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one (260 mg). ES-API: [M+H] ⁺ =562.2.

Example 16 Preparation of Z31

Step 1: Add 4-bromo-3,5-dimethoxybenzoic acid (30 g, 115.4 mmol), acetic anhydride (31.8 g, 311.5 mmol), and concentrated sulfuric acid (565 mg, 5.77 mmol) to dichloromethane (300 mL), cool the reaction solution to 0 degrees, then slowly add 70% concentrated nitric acid (10.9 g, 121.2 mmol), keep the reaction at 15 degrees for 4 hours, pour the reaction solution into ice water to quench, extract with ethyl acetate, dry the organic phase, and concentrate under reduced pressure to obtain crude 4-bromo-3,5-dimethoxy-2-nitrobenzoic acid (36 g, yield 100%). ES-API: [M-1] ^- = 304.0

Step 2: 4-bromo-3,5-dimethoxy-2-nitrobenzoic acid (36 g, 118 mmol) was dissolved in methanol (400 mL) and stannous chloride (213 g, 944 mmol), and the mixture was reacted at 60°C for 16 hours. The reaction solution was concentrated under reduced pressure to dry the solvent to obtain crude 2-amino-4-bromo-3,5-dimethoxybenzoic acid (200 g, yield 100%). ES-API: [M-1] ^- = 274.0

Step 3: 2-amino-4-bromo-3,5-dimethoxybenzoic acid (30.0 g, 0.11 mmol) was dissolved in water (450 mL), acetic acid (9.9 g, 0.165 mmol) was added, and then potassium cyanate was dissolved in water and slowly added dropwise, heated to 40 degrees for 1 hour, the reaction solution was cooled, solid sodium hydroxide (88 g, 2.2 mmol) was added, heated to 90 degrees for 1 hour, the reaction solution was cooled with ice water, solid was precipitated, filtered, and dried to obtain 7-bromo-6,8-dimethoxyquinazoline-2,4-diol (3.1 g, yield: 9.5%). ES-API: [M+1] ⁺ = 301.1.

Step 4: 7-bromo-6,8-dimethoxyquinazoline-2,4-diol (3.7 g, 12.3 mmol) was dissolved in phosphorus oxychloride (30 mL), heated to 115 degrees for 16 hours, cooled, and most of the solvent was concentrated under reduced pressure, dissolved in dichloromethane, slowly poured into ice water to quench, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain 7-bromo-2,4-dichloro-6,8-dimethoxyquinazoline (3.2 g, yield 77.5%). ES-API: [M+1] ⁺ = 337.1.

Step 5: 7-bromo-2,4-dichloro-6,8-dimethoxyquinazoline (2 g, 5.95 mmol), 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.35 g, 5.95 mmol) were dissolved in dichloromethane (20 mL), triethylamine (1.2 g, 11.9 mmol) was added under ice-water cooling, and the reaction was carried out at room temperature for 1 hour. The reaction solution was quenched with water, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain crude 7-(7-bromo-2-chloro-6,8-dimethoxyquinazoline-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (3.2 g, yield 100%). ES-API: [M+1] ⁺ = 527.1.

Step 6: tert-Butyl 7-(7-bromo-2-chloro-6,8-dimethoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (3.2 g, 5.95 mmol) was added to (S)-(1-methylpyrrolidin-2-yl)methanol (20 mL), followed by potassium fluoride (3.45 g, 59.5 mmol), and the mixture was heated to 100°C for 16 hours. LCMS detection showed that the reaction was complete. The reaction solution was cooled to room temperature. Warm, add 200 mL of water, extract with ethyl acetate (100 mL*3), dry the organic phase, spin dry to obtain a crude product, and purify the crude product by column (petroleum ether/ethyl acetate=30-100%) to obtain (S)-tert-butyl 7-(7-bromo-6,8-dimethoxy-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (2.0 g, yield: 55.6%). ES-API: [M+1] ⁺ =606.2.

Step 7: (S)-tert-Butyl 7-(7-bromo-6,8-dimethoxy-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (2 g, 3.31 mmol), (5-methyl-1H-indazol-4-yl)boric acid (1.164 g, 6.62 mmol), potassium carbonate (1.4 g, 6.62 mmol), 2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl (271 mg, 0.662 mmol), tris(dibenzylideneacetone)dipalladium (303 mg, 0.331 mmol) were added sequentially to dioxane (20 mL) and water (4 mL). The atmosphere was replaced with nitrogen three times and then the temperature was raised to 100 degrees for reaction for 16 hours. After cooling to room temperature, ethyl acetate (30 mL) was added, the mixture was washed once with brine, dried over anhydrous sodium sulfate, and dried under reduced pressure. The mixture was purified by column chromatography (dichloromethane/methanol = 0-10%) to give tert-butyl 7-(6,8-dimethoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.6 g, yield 73.7%). ES-API: [M+1] ⁺ = 658.4.

Step 8: Tert-butyl 7-(6,8-dimethoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.6 g, 2.44 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (8 mL) was added and reacted at room temperature for 0.5 hour, and the mixture was spin-dried to obtain crude 6,8-dimethoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazoline (2 g, yield 100%). ES-API: [M+1] ⁺ =558.4.

Step 9: 6,8-dimethoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazoline (2 g, crude product, 2.44 mmol) was dissolved in dichloromethane (20 mL), cooled with ice water, triethylamine (5 mL) was added, and then acrylic anhydride (246 mg, 1.95 mmol) was added dropwise, and the reaction was kept at 0 degrees for 0.5 hours. 20 mL of water and DCM (20 mL*3) were added to the reaction solution for extraction, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and dried under reduced pressure. Purification was performed by chromatography (chromatographic column information: Ultimate XB-C18, 50*250mm, 10um, mobile phase system: A: purified water B: pure acetonitrile, flow rate: 80ml/min, gradient: within 40 minutes, B% = 20%-100%, wavelength: 214nm, column temperature: room temperature) to obtain the product 1-(7-(6,8-dimethoxy-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazoline (160mg, yield 10.7%). ES-API: [M+1] ⁺ = 612.3. ¹ H NMR (400MHz, CDCl ₃ )δ7.57(s,1H),7.44(d,J＝8.4Hz,1H),7.35(d,J＝8.6Hz,1H),6.99(s,1H),6.38(d,J＝17.1Hz,1H),6.23(dd,J＝17.0,10.2Hz,1H),5.70(d,J＝10.2Hz,1H), 4.60(s,1H),4.36 (d,J＝9.1Hz,1H),4.01(s,2H),3.91(s,2H),3.80-3.58(m,10H),3.16(s,1H),2.83(s,1H),2.54(s,3H),2.38-2.31(m,1H),2.20(s,3H),2.05(t,J＝ 5.2Hz,6H),1.86(s,2H).

Example 16-1: Preparation of Z31-1 and Z31-2

The compound Z31 prepared in Example 16 was chirally resolved (Co-Solvent::ACN-IPA-DEA=90-10-0.2; column: IC 250mm*4.6mm 5um); flow rate: 1.0ml/min; column temperature: 30.0°C) to obtain: Compound Z31-1 (retention time: 14.696min): The structure of the compound was arbitrarily designated as 1-(7-((R)-6,8-dimethoxy-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (40mg, P: 99.1%, ee value: 99.5%). ES-API: [M+H] ⁺ = 612.3. Compound Z31-2 (retention time: 21.400 min): The structure of the compound was arbitrarily designated as 1-(7-((S)-6,8-dimethoxy-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (40 mg, P: 98.5%, ee value: 98.9%). ES-API: [M+H] ⁺ = 612.3.

Example 17 Preparation of Z32

Step 1: 3-(Trifluoromethoxy)benzoic acid (50g, 0.24mol) was dissolved in concentrated sulfuric acid (500mL), and potassium nitrate (31.9g, 0.32mol) was added in batches under ice bath, and the mixture was reacted at room temperature for one hour. TLC showed that the raw material reacted completely, and the reaction solution was poured into ice water (3L), extracted with ethyl acetate (1.5L x 2), and the organic phases were combined and washed with water (1L x 3), washed with brine (1L), dried over anhydrous sodium sulfate, filtered and dried to obtain a white solid 2-nitro-5-(trifluoromethoxy)benzoic acid (65g, yield 100%).

Step 2: 2-nitro-5-(trifluoromethoxy)benzoic acid (25.1 g, 0.1 mol) was dissolved in concentrated sulfuric acid (100 mL), and N-bromosuccinimide (17.8 g, 0.1 mol) was added at once after the temperature was raised to 80 degrees, and the mixture was kept warm for 2 hours. N-bromosuccinimide (8.9 g, 0.05 mol) was added, and the mixture was kept warm for 2 hours. TLC showed that the raw material reacted by about 60% (two batches were added in parallel), and the reaction solution was cooled and poured into ice water (1 L), extracted with ethyl acetate (1 L x 2), and the organic phases were combined and washed with water (1 L x 2), washed with brine (1 L), dried over anhydrous sodium sulfate, filtered and dried to obtain a brown oily crude product 4-bromo-2-nitro-5-(trifluoromethoxy)benzoic acid (52 g, yield 100%).

Step 3: 4-bromo-2-nitro-5-(trifluoromethoxy)benzoic acid (50g, 0.15mol) was added to isopropanol (300mL) and saturated ammonium chloride solution (200mL), and zinc powder (98.5g, 1.5mol) was added in batches after heating to 50 degrees. After adding, the mixture was kept warm for 1 hour. After cooling, the reaction solution was poured into a mixed solvent of ethyl acetate (1L) and water (1L), filtered, and the aqueous phase was extracted with ethyl acetate (1L x2), the organic phase was combined, washed with water (1L x 2), washed with brine (1L), dried over anhydrous sodium sulfate, filtered and dried to obtain a brown oily crude product of 2-amino-4-bromo-5-(trifluoromethoxy)benzoic acid (45g, yield 100%). ES-API: [M+1] ⁺ = 300.0 302.0.

Step 4: Heat urea (270g, 4.5mol) to 190 degrees to dissolve, then stir and add 2-amino-4-bromo-5-(trifluoromethoxy)benzoic acid (45g, 0.15mol), and keep warm until the reactant solidifies, about 3 hours. Cool to 100 degrees, add water (1L), and keep warm and stir for one hour. The filtered solid crude product is added to ethanol (0.5L) and stirred for one hour. After filtering, the mother liquor is dried by spin drying, and methyl tert-butyl ether (0.2L) is beaten to obtain 7-bromo-6-(trifluoromethoxy)quinazoline-2,4-diol (5.6g, yield 11%). ES-API: [M+1] ⁺ = 325.0 327.0.

Step 5: 7-bromo-6-(trifluoromethoxy)quinazoline-2,4-diol (5.6 g, 0.017 mol) was added to phosphorus oxychloride (60 mL), and the temperature was raised to 100 degrees for 16 hours. After the reaction solution was cooled, it was poured into ice water (200 mL), extracted with ethyl acetate (100 mL x 2), washed with water, washed with brine, dried and spin-dried, and then purified by column chromatography (petroleum ether: ethyl acetate = 0-5:1) to obtain a yellow solid 7-bromo-2,4-dichloro-6-(trifluoromethoxy)quinazoline (1.3 g, yield 21%). ES-API: [M+1] ⁺ = 362.8.

Step 6: 7-bromo-2,4-dichloro-6-(trifluoromethoxy)quinazoline (1.3 g, 3.6 mmol), N,N-diisopropylethylamine (929 mg, 7.2 mmol), dissolved in dichloromethane (20 mL), cooled in an ice bath, added tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (813 mg, 3.6 mmol), and kept warm for one hour. The reaction solution was spin-dried and slurried (methyl tert-butyl ether: petroleum ether = 1:10 20 mL) and filtered to obtain tert-butyl 7-(7-bromo-2-chloro-6-(trifluoromethoxy)quinazoline-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (2.1 g, yield 100%). ES-API: [M+1] ⁺ = 552.8. ¹ H NMR (400MHz CDCl ₃ ) δ8.09(s,1H),7.69(s,1H),3.73(s,8H),1.96(s,4H),1.44(s,9H).

Step 7: (S)-(1-Methylpyrrolidin-2-yl)methanol (1.1 g, 9.24 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0°C, sodium hydroxide (185 mg, 4.62 mmol) was added, and the mixture was stirred for 0.5 hours. 7-(7-bromo-2-chloro-6-(trifluoromethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.7 g, 3.08 mmol) was added to the reaction solution, and the mixture was reacted for 1 hour. The reaction solution was poured into ethyl acetate (100 mL), the organic phase was washed with water (20 mL x 2), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and dried to obtain a yellow oil (S)-7-(7-bromo-2-((1-methylpyrrolidin-2-yl)methoxy)-6-(trifluoromethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonylbutyl ester-2-carboxylic acid (3 g, yield 100%). ES-API: [M+1] ⁺ = 630.1632.1.

Step 8: (S)-7-(7-bromo-2-((1-methylpyrrolidin-2-yl)methoxy)-6-(trifluoromethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonylbutyl ester-2-carboxylic acid (3 g, 4.76 mmol), (5-methyl-1H-indazol-4-yl)boric acid (1.7 g, 9.52 mmol), tripotassium phosphate (2 g, 9.52 mmol), tris(dibenzylidene indeneacetone)dipalladium (300 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (300 mg) were added sequentially to dioxane (60 mL) and water (10 mL), replaced with nitrogen three times, and then heated to 105 degrees for reaction for 2 hours. After cooling to room temperature, ethyl acetate (100 mL) was added, washed once with brine and purified by silica gel column (methanol: dichloromethane = 0-1:10) to obtain yellow foaming solid 7-(7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(trifluoromethoxy)quinazoline-4-tert-butyl ester)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid methyl ester (1.3 g, yield 40%). ES-API: [M+1] ⁺ = 682.1.

Step 9: 7-(7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(trifluoromethoxy)quinazoline-4-tert-butyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid methyl ester (1150 mg, 1.68 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added and reacted at room temperature for 1 hour, and then dried to obtain a crude yellow oil 7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)-6-(trifluoromethoxy)quinazoline (1 g, yield 100%). ES-API: [M+1] ⁺ = 582.1

Step 10: 7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)-6-(trifluoromethoxy)quinazoline (1 g, 1.68 mmol) and triethylamine (521 mg, 5.15 mmol) were dissolved in dichloromethane (10 mL), cooled to 0 degrees, and acrylic anhydride (325 mg, 2.58 mmol) was added, and the reaction was kept at 0 degrees for 1 hour. The reaction solution was dried and then purified by flash column (dichloromethane: methanol: ammonia water = 95:4:1) to obtain the product 1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(trifluoromethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (700 mg, yield 56%). ES-API: [M+1] ⁺ = 318.7 636.3. ¹ H NMR (400 MHz, CDCl ₃ )δ10.72(s,1H),7.79(s,1H),7.70(s,1H),7.62(s,1H),7.48(d,J＝8.5Hz,1H),7.32(d,J＝8.5Hz,1H),6.38(d,J＝16.9Hz,1H),6.23(dd,J＝16.8,10.3Hz, 1H),5.71(d,J＝10.3Hz,1H),4.67(s,1H),4.42(s,1H), 4.02(s,2H),3.92(s,2H),3.74(d,J＝20.7Hz,4H),3.31(s,1H),3.07(dt,J＝29.6,14.8Hz,2H),2.65(s,3H),2.48(s,1H),2.24(s,3H),2.14(s,1H), 2.04(s,4H),1.89(d,J＝19.7Hz,2H),1.33(t,J＝7.2Hz,1H).

Example 17-1 Preparation of Z32-1 and Z32-2

Compound Z32 (41 mg) prepared in Example 17 was chirally resolved (Co-Solvent: Hex: EtOH: AMMN = 40: 60: 0.2; column: IC 250 mm*4.6 mm 5 um); flow rate: 1.0 ml/min; column temperature: 30.0°C) to obtain: Compound Z32-1 (retention time: 9.296 min): The structure of the compound was arbitrarily designated as 1-(7-((R)-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(trifluoromethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (16 mg, P: 94.35%, ee value: 95%). ES-API: [M+H] ⁺ = 636.2. Compound Z32-2 (retention time: 13.960 min): The structure of this compound was arbitrarily designated as 1-(7-((S)-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(trifluoromethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (14 mg, P: 96.52%, ee value: 94%). ES-API: [M+H] ⁺ = 636.2.

Example 18 Preparation of Z33

Step 1: Add 4-bromo-5-fluoro-2-nitrobenzoic acid methyl ester (14 g, 50.4 mmol) and cesium carbonate (29.6 g, 90.72 mmol) to 40 mL of N,N-dimethylformamide, then add cyclopropanol (4.38 g, 75.6 mmol) at room temperature and stir overnight. After TLC detection, the reaction is complete, the reaction solution is poured into a large amount of water, stirred, and filtered to obtain 4-bromo-5-cyclopropyloxy-2-nitrobenzoic acid methyl ester (yellow solid, 18 g, yield: crude product).

Step 2: Add methyl 4-bromo-5-cyclopropyloxy-2-nitrobenzoate (6.0 g, 19.05 mmol) to methanol/water (40 mL/10 mL), then add ammonium chloride (3.56 g, 66.68 mmol) and iron powder (3.7 g, 66.68 mmol) at room temperature, and stir at 80 ° C for 2 hours. Concentrate under reduced pressure, extract with ethyl acetate, and concentrate the organic phase to obtain methyl 2-amino-4-bromo-5-cyclopropyloxybenzoate (yellow solid, 2.2 g, yield: 40%). ES-API: [M+H] ⁺ = 288.0.

Step 3: Dissolve methyl 2-amino-4-bromo-5-cyclopropyloxybenzoate (2.2 g, 7.7 mmol) in 20 mL of methanol and 4 mL of water, add lithium hydroxide (970 mg, 23.1 mmol) at room temperature, and stir at 40°C overnight. Cool to room temperature, remove methanol by rotary evaporation, extract with ethyl acetate and water, adjust the pH of the aqueous phase to 6-7 with 2M dilute hydrochloric acid, and filter to obtain the product 2-amino-4-bromo-5-cyclopropyloxybenzoic acid (yellow solid, 2.2 g, yield: crude product). ES-API: [M+H] ⁺ = 274.0.

Step 4: 2-amino-4-bromo-5-cyclopropyloxybenzoic acid (1.5 g, 5.5 mmol) and urea (6.6 g, 110 mmol) were stirred at 200°C for 2 hours. The reaction was then cooled to 100°C, and 100 mL of water was added and stirred for 20 min. The reaction solution was filtered to obtain 7-bromo-6-cyclopropyloxy)quinazoline-2,4-diol (yellow solid, 1.2 g, yield: 74%). ES-API: [M+H] ⁺ = 297.0.

Step 5: Dissolve 7-bromo-6-cyclopropyloxy)quinazoline-2,4-diol (1.2 g, 4.05 mmol) in phosphorus oxychloride (15 mL), add DIEA (2.6 g, 20.25 mmol) dropwise at room temperature, and stir the reaction at 120 ° C overnight. Cool to room temperature, remove the solvent by vacuum rotary evaporation, dilute with ethyl acetate (50 mL), pour into 50 mL of ice water for separation and extraction. The organic phase is concentrated and dried to obtain 7-bromo-2,4-dichloro-6-cyclopropyloxyquinazoline (yellow solid, 2.0 g, yield: crude product). ES-API: [M+H] ⁺ = 334.9.

Step 6: Add 7-bromo-2,4-dichloro-6-cyclopropyloxyquinazoline (2.0 g, 6.02 mmol) and triethylamine (1.82 g, 18.06 mmol) to DCM (20 mL), and add 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (2.04 g, 9.03 mmol) in an ice-water bath. The reaction was then stirred at room temperature overnight. The reaction solution was then concentrated and purified by a forward silica gel column to obtain 7-(7-bromo-2-chloro-6-(cyclopropyloxy)quinazoline-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (yellow solid, 1.4 g, yield: 83%). ES-API: [M+H] ⁺ = 525.0.

Step 7: (S)-(1-methylpyrrolidin-2-yl)methanol (661.3 mg, 5.75 mmol) and sodium hydride (230 mg, 5.75 mmol) were dissolved in THF (5 mL), and the reaction solution was stirred in an ice-water bath for 30 min, and then 7-(7-bromo-2-chloro-6-(cyclopropyloxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (600 mg, 1.15 mmol) was added to the reaction system and reacted at room temperature for 2 hours. After the reaction was completed, it was quenched with ice water, extracted with ethyl acetate, and the organic phase was separated and concentrated to obtain (S)-7-(7-bromo-6-cyclopropyloxy-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (yellow liquid, 1.4 g, yield: crude product). ES-API: [M+H] ⁺ = 602.3.

Step eight: Dissolve (S)-tert-butyl 7-(7-bromo-6-cyclopropyloxy-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (300 mg, crude), (5-methyl-1H-indazol-4-yl)boronic acid (116.2 mg, 0.66 mmol), potassium phosphate (140 mg, 0.66 mmol), x-phos (40 mg), and Pd ₂ (dba) ₃ (40 mg) in 1,4-dioxane (5 mL) and water (1 mL), and the reaction was stirred at 110° C. for 2 hours and detected by TLC. The reaction solution was extracted with ethyl acetate and water, the organic phase was concentrated and passed through a normal silica gel column to give tert-butyl 7-(6-cyclopropyloxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl])-2,7-diazaspiro[3.5]nonane-2-carboxylate (yellow solid, 170 mg, yield: 80%).

Step 9: Dissolve tert-butyl 7-(6-cyclopropyloxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl])-2,7-diazaspiro[3.5]nonane-2-carboxylate (170 mg, 0.26 mmol) in DCM/TFA (3 mL/1 mL), stir in an ice-water bath for 20 min, and monitor the reaction by TLC spot plate. Then concentrate to give 6-cyclopropyloxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]]nonyl-7-yl)quinazoline (yellow solid, 144 mg, crude product).

Step 10: 6-Cyclopropyloxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]]nonyl-7-yl)quinazoline (144 mg, 0.26 mmol) was dissolved in 3 mL of dichloromethane, and triethylamine (131.3 mg, 1.3 mmol) and acrylic anhydride (90.72 mg, 0.72 mmol) were added under ice-water bath. The reaction was stirred at room temperature for 30 min, and then purified by silica gel column to obtain Z33 (yellow solid, 9.1 mg, yield: 6%). ES-API: [M+H] ⁺ = 608.3. ¹ H NMR (400 MHz, CDCl ₃ )δ7.64(s,1H),7.57(s,1H),7.22(d,J＝8.4Hz,1H),7.31(d,J＝8.8Hz,1H),6.37(d,J＝16.8Hz,1H),6.26-6.23(m,1H),5.71(d,J＝10.4Hz,1H),5.20(s,1 H),4.74(s ,1H),4.41(s,1H),4.03(s,2H),3.92(s,2H),3.80-3.71(m,4H),3.06(s,3H),2.89(m,1H),2.35(s,2H),2.19(s,3H),2.07(s,4H),1.25(s,4H),0 .91-0.66(m,4H).

Example 19 Preparation of Z34

Step 1: Dissolve 5-bromo-6-methoxy-pyridinic acid (2.5 g, 10.7 mmol) in concentrated sulfuric acid (20.8 g, 212 mmol), stir and cool in an ice bath, slowly add 65% nitric acid (5.22 g, 53.8 mmol), after the dropwise addition, heat the resulting reaction mixture to 50 ° C, stir at this temperature overnight (about 22 hours), cool to room temperature and slowly pour it into ice water (200 g), then add 25% ammonia water (32 g, 470 mmol), extract three times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, spin dry to obtain a crude product, pass through a silica gel column, and elute with dichloromethane/methanol (100:1 to 100:15) to obtain the product 5-bromo-6-methoxy-3-nitropyridine acid (light yellow solid, 1.45 g, yield: 49%).

Step 2: Dissolve 5-bromo-6-methoxy-3-nitropyridine acid (1.45 g, 5.2 mmol) in methanol (15 mL), add 5 drops of concentrated sulfuric acid with a disposable plastic dropper under stirring, and stir the resulting reaction solution in an oil bath at 70°C for reflux reaction over the weekend (about 68 hours). Concentrate to dryness under reduced pressure, add sodium bicarbonate solution dropwise, adjust the pH value to 8-9, then extract with ethyl acetate, and concentrate the organic phase to obtain the product 5-bromo-6-methoxy-3-nitropyridine carboxylic acid methyl ester (light yellow solid, 1.45 g, yield: 95%). ES-API: [M+H] ⁺ = 291.0. ¹ H NMR (400 MHz, CDCl ₃ ): δ8.58 (s, 1H), 4.14 (s, 3H), 4.01 (s, 3H).

Step 3: Dissolve 5-bromo-6-methoxy-3-nitropyridine carboxylic acid methyl ester (1.84 g, 6.3 mmol) and dihydrate stannous chloride (3.06 g, 18.9 mmol) in 50 mL of ethanol, add 10 mL of 0.5 N dilute hydrochloric acid, and stir the resulting mixture at 60°C for 3 hours. TLC tracking reaction is complete, cool to room temperature, remove ethanol by rotary evaporation, dissolve the residue in ethyl acetate, add saturated sodium bicarbonate aqueous solution, stir well, filter, separate, and dry the organic phase to obtain a crude product, pass through a silica gel column, and elute with petroleum ether/ethyl acetate (5:1 to 3:15) to obtain the product 5-bromo-6-methoxy-3-aminopicolinic acid methyl ester (light grayish yellow solid, 0.48 g, yield: 29%). ES-API: [M+H] ⁺ = 261.0.

Step 4: 3-amino-5-bromo-6-methoxypicolinic acid methyl ester (1.5 g, 5.5 mmol) was dissolved in methanol (10 mL) and lithium chloride (10 mL, 2 M) and stirred at room temperature for 1 hour. TLC monitored the reaction to be complete. The methanol was evaporated, the residue was acidified with dilute hydrochloric acid, and the product was extracted with ethyl acetate (3 x 50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purification by silica gel column (PE/EA = 3:1) gave 3-amino-5-bromo-6-methoxypicolinic acid (yellow solid 2.1 g, yield: 58.5%). ES-API: [M+H] ⁺ = 248, 250.

Step 5: Dissolve 3-amino-5-bromo-6-methoxypicolinic acid (1.1 g, 4.45 mmol), ammonium chloride (1.19 g, 22.25 mmol) and sodium bicarbonate (1.87 g, 22.25 mmol) in DMF (30 mL), then add HATU (2.54 g, 6.68 mmol) in batches and react at room temperature for 2 hours. The product was extracted with ethyl acetate (3 x 80 mL), the organic phase was washed with saturated brine (3 x 50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purification by silica gel column (PE/EA = 2: 1) gave 3-amino-5-bromo-6-methoxypicolinamide (white solid 2.1 g, yield: 100%). ES-API: [M+H] ⁺ = 247, 249.

Step 6: Dissolve 3-amino-5-bromo-6-methoxypicolinamide (1.1 g, 4.47 mmol) in dioxane (15 mL), add BTC (664 mg, 2.24 mmol, 5 mL of dioxane) dropwise at 0 °C, and react at 110 °C for 0.5 h. Cool to room temperature, evaporate the solvent, and obtain a crude product. Purify by silica gel column (PE/EA=1:1) to obtain 7-bromo-6-methoxypyridine [3,2-d] pyrimidine-2,4-diol (white solid, 1.21 g, yield: 99.5%). ES-API: [M+H] ⁺ = 273, 275.

Step 7: Dissolve 7-bromo-6-methoxypyridinium[3,2-d]pyrimidine-2,4-diol (1.21 g, 4.45 mmol) in trichlorophosphine (10 mL), add DIEA (1 mL) dropwise at 0°C, and react at 120°C for 16 h. Cool to room temperature, evaporate the solvent, and add toluene (10 mL) to obtain the residual liquid, which is then spin-dried. Repeat this operation twice to obtain 7-bromo-2,4-dichloro-6-methoxypyridinium[3,2-d]pyrimidine (black oil 1.51 g, crude product). ES-API: [M+H] ⁺ = 308, 310.

Step 8: Dissolve 7-bromo-2,4-dichloro-6-methoxypyridinium [3,2-d] pyrimidine (1.37 g, 4.45 mmol) in DCM (20 mL) and add DIEA (2.87 g, 22.25 mmol) at 0°C, stir at 0°C for 2 min, and then add tert-butyl 2,7-diazaspiro [3.5] nonane-2-carboxylate (1.51 g, 6.675 mmol) in batches. The reaction was then stirred at room temperature overnight. The product was washed with DCM (3x80 mL), and the organic phase was washed with saturated brine (2x60 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purification by silica gel column (DCM/MeOH=10:1) gave tert-butyl 7-(7-bromo-2-chloro-6-methoxypyrido[3,2-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (yellow solid 1.45 g, yield: 65.3%). ES-API: [M+H] ⁺ =498,500.

Step 9: Dissolve (S)-(1-methylpyrrolidin-2-yl)methanol (1.035 g, 9.0 mmol) in THF (15 mL) at 0°C, add sodium hydride (360 mg, 9.0 mmol) in batches, continue to react at 0°C for 30 min, then add 7-(7-bromo-2-chloro-6-methoxypyridin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (900 mg, 1.8 mmol) in batches, and react the reaction solution at 0°C to room temperature overnight. After the reaction is completed, place at 0°C, dilute with ethyl acetate (60 mL), add ice water, extract the product with ethyl acetate (3x30 mL), wash with saturated brine (2x20 mL), dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. Purification by silica gel column gave (S)-7-(7-bromo-6-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)pyridin[3,2-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (off-white solid 700 mg, yield: 67.45%). ES-API: [M+H] ⁺ =577,579.

Step 10: Dissolve (S)-7-(7-bromo-6-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)pyridin[3,2-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (300 mg, 0.52 mmol), potassium phosphate (331 mg, 1.56 mmol), (5-methyl-1H-indazol-3-yl)boric acid (110 mg, 0.624 mmol), Xan-phos (25 mg, 0.052), Pd ₂ (dba) ₃ (48 mg, 0.052 mmol) in 1,4-dioxane (5 mL) and water (1 mL), stir at 110° C. for 2 hours, and detect by TLC. The product was extracted with ethyl acetate (3x30 mL), washed with saturated brine (2x20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purification by silica gel column gave tert-butyl 7-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridin[3,2-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (yellow solid, 360 mg, yield: 100%). ES-API: [M+H] ⁺ =629,631.

Step 11: Dissolve tert-butyl 7-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridin[3,2-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (330 mg, 0.525 mmol). Dissolve in DCM (3.0 mL), add TFA (1 mL) at 0°C. React at room temperature for 1 hour. The reaction solution was concentrated to obtain 6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)pyridin[3,2-d]pyrimidine (brown solid 300 mg, crude product). ES-API: [M+H] ⁺ =529,3631.

Step 12: 6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)pyridin[3,2-d]pyrimidine (300 mg, 0.568 mmol) was dissolved in DCM (6 mL), and triethylamine (172 mg, 1.707 mmol) was added at 0°C. After stirring for 2 min, acrylic anhydride (71.6 mg, 0.568 mmol, 1.0 mL DCM) was added dropwise. After the addition was completed, the reaction was maintained at 0°C for 1 h. Saturated sodium bicarbonate (10 mL) was added to the reaction solution, and the product was extracted with DCM (3 x 30 mL), and then washed with saturated sodium bicarbonate (2 x 20 mL) and saturated brine (2 x 20 mL), and the solvent was concentrated to obtain a crude product. The product was purified by silica gel column (DCM/MeOH=10:1) and TLC (DCM/MeOH=20:1) to give 1-(7-(6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridin[3,2-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (white solid, 50.8 mg, yield: 16.3%). ES-API: [M+H] ⁺ =583. ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.77-1.92(m,8H),2.16(s,3H),2.76-2.88(m,4H),3.4-3.5(m,2H),3.73-4.01(m,9H),4.32-4.57(m,6H),5.66(d,J＝10.3Hz, 1H),6.10(d,J＝16.9Hz,1H),6.32(dd,J＝16.9,10.4Hz,1H),7.29(d,J＝8.5Hz,1H),7.49-7.56(m,2H),7.76(s,1H),13.14(s,1H).

Example 20 Preparation of Z35

Step 1: tert-Butyl 7-(7-bromo-2-chloro-6-methoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (3 g, 6.05 mmol) was dissolved in DCM (30 mL), the reaction solution was cooled to 0 degrees, and then boron tribromide (7.56 g, 30.25 mmol) was slowly added, stirred for 1 hour, and LCMS detection showed that the reaction was complete. The reaction was quenched with water + tetrahydrofuran, and the reaction solution was directly used for the next step. ES-API: [M+1] ⁺ = 383.0.

Step 2: The pH of the reaction solution in the previous step was adjusted to 8-9 with sodium carbonate, di-tert-butyl dicarbonate (1.32 g, 6.05 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, the organic phase was washed with brine, dried with sodium sulfate, and spin-dried to obtain the crude product 7-(7-bromo-2-chloro-6-hydroxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (4.0 g, yield 100%). ES-API: [M+1] ⁺ = 583.0.

Step 3: tert-Butyl 7-(7-bromo-2-chloro-6-hydroxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (4.0 g, 6.05 mmol), sodium difluorochloroformate (2.31 g, 15.13 mmol), cesium carbonate (3.94 g, 12.1 mmol), dissolved in N,N-diformamide/water (49/7 mL), stirred at room temperature for 15 minutes, then heated to 100 degrees for 2 hours, the reaction solution cooled to room temperature, 30 mL of water was added, extracted with ethyl acetate, the organic phase was dried, spin-dried, and purified by column (ethyl acetate/petroleum ether/=0-30%) to obtain tert-butyl 7-(7-bromo-2-chloro-6-(difluoromethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.4 g, yield: 43.5%). ES-API: [M+1] ⁺ = 533.1.

Step 4: tert-Butyl 7-(7-bromo-2-chloro-6-(difluoromethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.4 g, 2.63 mmol) was added to (S)-(1-methylpyrrolidin-2-yl)methanol (15 mL), and then KF (458 mg, 7.89 mmol) was added, and the mixture was heated to 100 degrees for two hours. LCMS detection showed that the reaction was complete. After the reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and spin-dried to give a crude product (S)-tert-butyl 7-(7-bromo-6-(difluoromethoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.8 g, yield: 100%). ES-API: [M+1] ⁺ = 612.2

Step 5: (S)-tert-butyl 7-(7-bromo-6-(difluoromethoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.7 g, 2.78 mmol), (5-methyl-1H-indazol-4-yl)boric acid (980 mg, 5.56 mmol), potassium phosphate (1.18 mg, 5.56 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (260 mg, 0.556 mmol), tris(dibenzylideneacetone)dipalladium (255 mg, 0.278 mmol) were added to dioxane (30 mL) and water (5 mL) in sequence. The mixture was replaced with nitrogen three times and then heated to 100 degrees for reaction for 16 hours. After cooling to room temperature, the mixture was poured into ethyl acetate and water, washed once with brine, dried over anhydrous sodium sulfate, and dried under reduced pressure. The mixture was purified by column chromatography (ethyl acetate/petroleum ether/=30-100%) to give tert-butyl 7-(6-(difluoromethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.1 g, yield 59.8%). ES-API: [M+1] ⁺ =664.3.

Step 6: Tert-butyl 7-(6-(difluoromethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.1 g, 1.66 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added and reacted at room temperature for 0.5 hour, and then dried to give crude 6-(difluoromethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazoline (1.2 g, yield 100%). ES-API: [M+1] ⁺ =564.3.

Step 7: 6-(Difluoromethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazoline (1.2 g, 1.66 mmol) and triethylamine (3 mL) were dissolved in dichloromethane (10 mL), cooled to 0 degrees and then added with acrylic anhydride (167 mg, 1.33 mmol), and kept at 0 degrees for 0.5 hours. The reaction solution was extracted with 20 mL of water and dichloromethane (20 mL), the organic phase was washed with brine, dried over anhydrous sodium sulfate, and dried under reduced pressure for preparation and purification (chromatographic column information: Ultimate XB-C18, 50*250mm, 10um, mobile phase system: A: purified water; B: pure acetonitrile, flow rate: 80ml/min, gradient: within 40 minutes, B% = 20%-100%, wavelength: 214nm, column temperature: room temperature) to obtain the product 1-(7-(6-(difluoromethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazoline (212mg, yield 20.7%). ES-API: [M+1] ⁺ = 618.3. ¹ HNMR (400MHz, CDCl ₃ )δ7.73(s,1H),7.69(s,1H),7.64(s,1H),7.47(d,J＝8.6Hz,1H),7.32(s,1H),6.41-6.33(m,1H),6.23(dd,J＝17.0,10.3Hz,1H),6.15(s,1H),5.71(d, J＝10.4Hz,1H),4.55(dt,J＝8.8,4.3Hz,1H),4.37 -4.26(m,1H),4.02(s,2H),3.91(s,2H),3.73(q,J＝14.7,13.5Hz,4H),3.13(d,J＝8.7Hz,1H),2.78(s,1H),2.52(s,3H),2.32(q,J＝9.6,8.8Hz,1H),2. 25(s,3H),2.11-1.99(m,6H),1.91-1.80(m,3H).

Example 21 Preparation of Z36

Step 1: tert-Butyl 7-(7-bromo-8-fluoro-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (350 mg, 0.51 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium ethoxide (7 mg, 1.02 mmol) was added. After the addition, the temperature was raised to 65 degrees and the reaction was allowed to proceed for 48 hours. After the reaction solution was cooled to room temperature, it was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 4 ). 2), column chromatography (dichloromethane: methanol = 10: 1) gave tert-butyl 7-(7-bromo-6-iodo-8-ethoxy-2-(((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.3 g, yield 58%). ES-API: [M-55] ⁺ = 660.1 662.1.

Step 2: tert-Butyl 7-(7-bromo-6-iodo-8-ethoxy-2-(((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (280 mg, 0.39 mmol), cyclopropylboronic acid (37 mg, 0.43 mmol), sodium carbonate (83 mg, 0.78 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (30 mg) were added to dioxane (3 mL) and water (0 .5mL) in a mixed solvent and reacted at 90 degrees for 1 hour. After the reaction solution was cooled, it was poured into ethyl acetate for extraction (50mL), washed with brine, dried and spin-dried, and then purified by column chromatography (methanol: dichloromethane = 0-1:10) to obtain a yellow oily substance 7-(7-bromo-6-cyclopropyl-8-ethoxy-2-(((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (130 mg, yield 54%). ES-API: [M-55] ⁺ = 574.2 576.2

Step 3: tert-Butyl 7-(7-bromo-6-cyclopropyl-8-ethoxy-2-(((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (50 mg, 0.079 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (19 mg, 0.12 mmol), tripotassium phosphate (50 mg, 0.24 mmol), Sphos-Pd-G2 (5 mg), S-Phos (10 mg) were added to dioxane (0.5 mL) water ( 0.1mL), replaced with nitrogen three times and then microwaved at 120 degrees for 0.5 hours. After cooling to room temperature, pour into ethyl acetate (20mL), wash once with brine and purify on a preparative plate (methanol: dichloromethane = 0-1:10) to obtain a yellow foaming solid 7-(6-cyclopropyl-8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (15mg, yield 28%). ES-API: [M-55] ⁺ = 606.3

Step 4: tert-Butyl 7-(6-cyclopropyl-8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (15 mg, 0.023 mmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added and reacted at room temperature for 1 hour, and the mixture was spin-dried to obtain a crude yellow oily product 2-(6-cyclopropyl-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-7-yl)-3-fluorophenol (13 mg, yield 100%), which was directly used in the next step.

Step 5: 2-(6-cyclopropyl-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-7-yl)-3-fluorophenol (13 mg, 0.023 mmol) and triethylamine (7 mg, 0.069 mmol) were dissolved in dichloromethane (0.5 mL), cooled to 0 degrees, and acrylic anhydride (3 mg, 0.025 mmol) was added, and the reaction was kept at 0 degrees for 1 hour. The reaction solution was dried and purified (chromatographic column information: Ultimate XB-C18, 50*250mm, 10um, mobile phase system: A: purified water B: pure acetonitrile, flow rate: 80ml/min, gradient: within 50 minutes, B/A=20%-90%, wavelength: 214nm, column temperature: room temperature) to obtain the product 1-(7-(6-cyclopropyl-8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Z36, 1.5mg, yield 9.5%). ES-API: [M/2+1] ⁺ =308.8. ¹ H NMR (400MHz, CDCl ₃ ) δ12.10(s,1H),6.93(s,1H),6.77(s,1H),6.38(d,J＝16.7Hz,1H),6.23(s,1H),5.72(s,1H),5.34(s,2H),3.96(d,J＝39.6Hz,4H) ,3.34(s,3H),3.10(s,8H),2.80(s,3H),2.65(s,1H),2.21(s,2H),2.02(s,6H),1.11(s,3H),0.56(d,J＝45.1Hz,4H).

Example 22 Preparation of Z37

Step 1: Dissolve 7-bromo-2,4,6-tri-8-fluoroquinazoline (1g, 3mmol) in dichloromethane (8mL) and acetonitrile (8mL), stir and cool to 0°C, add triethylamine (0.9g, 9mmol) and a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (0.68g, 3mmol) dissolved in dichloromethane (4mL) dropwise, and react the reaction solution at this temperature for 1 hour. Pour the reaction solution into water, extract with dichloromethane three times (30mL*3), and spin dry the extracted organic phase to obtain the crude product 7-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.5g, yield: 96%), which is used directly in the next step without purification. ES-API: [M+1] ⁺ = 521.0.

Step 2: 1-Methyl-4-piperidinol (180 mg, 1.5 mmol), cesium carbonate (0.96 mg, 3 mmol) and triethylenediamine (20 mg, 0.2 mmol) were dissolved in dry N,N-dimethylformamide (10 mL), and tert-butyl 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (520 mg, 1 mmol) was added. The reaction solution was stirred at room temperature overnight for about 18 hours. The reaction was complete when the liquid chromatography-mass spectrometry test showed that the reaction was complete. 20 50 ml of ethyl acetate and 0.5N dilute hydrochloric acid, stirred for 1 minute, then washed with ethyl acetate (50 mL*2), the organic phase was discarded, the aqueous phase was adjusted to pH 8-9 with a saturated aqueous solution of sodium bicarbonate, then extracted with ethyl acetate (50 mL*3), the organic phase was dried over sodium sulfate, and rotary evaporated to dryness to obtain the product 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (0.55 g, yield: 91%). ES-API: [M+1] ⁺ ＝600.0(M-56+H) ⁺

Step 3: tert-Butyl 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.55 g, 0.91 mmol) was dissolved in dry tetrahydrofuran (10 mL), and solid sodium ethanol (93 mg, 1.37 mmol) was added. The reaction solution was stirred at 65 ° C for 2 hours, the reaction solution was mixed with silica gel powder and dried by rotation, and passed through a fast silica gel column (20 g column, methanol/methanol+dichloromethane=5%~20%) to obtain the product tert-butyl 7-(7-bromo-6-chloro-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (240 mg, yield: 42%). ES-API:[M+1] ⁺ =570.0/626.0.

Step 4: tert-butyl 7-(7-bromo-6-chloro-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (240 mg, 0.38 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (126 mg, 0.76 mmol), tripotassium phosphate (244 mg, 1.15 mmol), chloro(2-dicyclohexylphosphino-2 ',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (60 mg, 0.076 mmol) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (36 mg, 0.076 mmol) were added to the reaction bottle. After nitrogen replacement three times, dioxane (8 mL) and water (2 mL) were added. Under argon protection, the temperature was raised to 100 degrees and the reaction was carried out for 4 hours. After cooling to room temperature, water (50 mL) was added, and then extracted with ethyl acetate (30 mL). The organic phase after extraction was dried and evaporated to dryness to obtain a crude product, which was passed through a silica gel column [10% methanol ethyl acetate solution/(petroleum ether+10% methanol ethyl acetate solution)=20% to 50%] to obtain the product 7-(-6-chloro-8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidinyl-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester as a solid (306 mg, yield 42%). ES-API: [M+1] ⁺ =300.6/600.2/656.2.

Step 5: tert-Butyl 7-(-6-chloro-8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidinyl-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (120 mg, 0.18 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added and reacted at room temperature for 1 hour. LCMS detection showed that the reaction was complete, and rotary evaporation was performed to obtain a yellow viscous oily crude product 2-(6-chloro-8-ethoxy-2-((1-methylpiperidinyl-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)-quinazolin-7-yl)-3-fluorophenol (200 mg, yield 100%). ES-API: [M+1] ⁺ = 278.5/556.1.

Step 6: 2-(6-Chloro-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)-quinazolin-7-yl)-3-fluorophenol (200 mg, 0.18 mmol) and triethylamine (92 mg) were dissolved in dichloromethane (6 mL). After cooling to 0 degrees, a solution of acrylic anhydride diluted in dichloromethane (18 mg, 0.14 mmol) was added dropwise. The mixture was kept at 0 degrees for 20 minutes and the reaction was followed by LC-MS/MS until completion. The reaction solution was added with 30 ml of dichloromethane, then washed with water three times (20 mL*3), the organic phase was dried and evaporated to dryness to obtain 150 mg of crude product, which was passed through a silica gel column (20 g silica gel, methanol/dichloromethane = 1/20 to 3.5/20) to obtain the product 1-(7-(6-chloro-8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)prop-2-enamide (20 mg, yield 18%). ES-API: [M+1] ⁺ = 610.1. ¹ H NMR (400 MHz, CDCl ₃ )δ7.68(s,1H),7.36-7.28(m,1H),6.83(d,J＝32.0Hz,2H),6.37(d,J＝16.8Hz,1H),6.23(s,1H),5.70(d,J＝10.6Hz,1H),5.14(s,1H),4.39(s,1H),4.11 (s,1H),3.95(d,J＝42.7Hz,4H),3.68(s,4H),2.89(s,2H),2.37(s,3H),2.20(s,2H),2.02(s,6H),1.59(s,2H),1.25(s,2H),1.14(s,3H).

Example 24 Preparation of Z39

Step 1: 4-bromo-5-fluoro-2-nitrobenzoic acid (5 g, 19 mmol), dimethylamine hydrochloride (2.43 g, 30 mmol), sodium carbonate (6.36 g, 60 mmol) were added to DMF (80 mL), heated and stirred at 70 degrees with argon sealed for 2 hours, cooled and diluted with water (300 mL), extracted with EA (100 mL x 3), combined organic phases were washed with water (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4-bromo-5-(dimethylamino)-2-nitrobenzoic acid (yellow solid, 5.5 g, yield: 100%). ES-API: [M+H] ⁺ = 289.

Step 2: 4-bromo-5-(dimethylamino)-2-nitrobenzoic acid (19mmol, 5.5g), Raney Ni (catalytic amount, one spoon) and ammonia (3mL) were added to a methanol (60mL) solution, stirred at room temperature overnight under a hydrogen atmosphere (air bag pressure), and filtered through diatomaceous earth. The filtrate was dried to give 2-amino-4-bromo-5-(dimethylamino)benzoic acid (yellow solid, 5g, yield: 99%). ES-API: [M+H] ⁺ = 259.

Step 3: Mix 2-amino-4-bromo-5-(dimethylamino)benzoic acid (5 g, 17.7 mmol) and urea (10.6 g, 177 mmol) and heat to 200 degrees and stir for 3 hours. After cooling, add water and filter. Filter out the solid and dry to obtain 7-bromo-6-(dimethylamino)quinazoline-2,4(1H,3H)-dione (yellow solid, crude product 3.3 g, yield: 60%). ES-API: [M+H] ⁺ = 284,286.

Step 4: 7-Bromo-6-(dimethylamino)quinazoline-2,4(1H,3H)-dione (3.53mmol, 1g), phosphorus oxychloride (36mmol, 5.51g) and DIEA (11mmol, 1.3g) were added to toluene (20mL), heated and stirred at 110 degrees under argon protection overnight, and concentrated after cooling (with argon protection throughout the process, not exposed to air) to obtain 7-bromo-2,4-dichloro-N,N-dimethylquinazoline-6-amine (crude yellow solid 2g, yield: 100%).

Step 5: 7-bromo-2,4-dichloro-N,N-dimethylquinazolin-6-amine (crude product 2g, 3.53mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (0.96g, 4.24mmol) and TEA (1g, 10mmol) were added to anhydrous DMF (15mL) and stirred at room temperature for 2 hours, then EA (50mL) was added to dissolve and washed with water (20mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate and passed through a silica gel column to obtain tert-butyl 7-(7-bromo-2-chloro-6-(dimethylamino)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (yellow solid, 590mg, yield: 33%). ES-API: [M+H] ⁺ = 510.

Step 6: tert-Butyl 7-(7-bromo-2-chloro-6-(dimethylamino)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (300 mg, 0.6 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (210 mg, 1.8 mmol), DABCO (13 mg, 0.12 mmol) and cesium carbonate (600 mg, 1.8 mmol) were added to anhydrous DMF (5 mL) and stirred at 60 degrees under argon protection overnight. After cooling, EA (50 mL) was added and washed with water (20 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-tert-butyl 7-(7-bromo-6-(dimethylamino)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (yellow solid, 400 mg, yield: 94%). ES-API: [M+H] ⁺ =589.

Step 7: (S)-7-(7-bromo-6-(dimethylamino)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (435 mg, 0.74 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (391 mg, 2.22 mmol), Pd ₂ (dba) ₃ (68 mg, 0.074 mmol), Sphos (62 mg, 0.15 mmol) and sodium carbonate (400 mg, 3.8 mmol) were added to dioxane/water (4/1, 5 mL), stirred at 110 degrees in a microwave under argon protection for 6 hours, and purified on a preparative plate after cooling to give tert-butyl 7-(6-(dimethylamino)-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (yellow solid 100 mg, yield: 25%).

Step 8: tert-Butyl 7-(6-(dimethylamino)-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (100 mg, 0.16 mmol) was dissolved in a mixture of dioxane hydrochloride (4M) and methanol (2/2 mL) and stirred at room temperature for 1 hour, then dried by rotation to give N,N-dimethyl-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-6-amine (white hydrochloride solid 110 mg, yield: 100%).

Step 9: N,N-dimethyl-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-6-amine (100 mg, 0.16 mmol) was dissolved in a solution of TEA (160 mg, 1.6 mmol) in DCM (2 mL) and stirred at room temperature for 30 minutes. The mixture was cooled to -70 degrees and acryloyl chloride (28 mg, 0.32 mmol) was added dropwise. l), continued stirring for 30 minutes, then added methanol (2 mL) to return to the temperature, dried by rotation, purified by preparative plate to obtain a white solid, and then purified by pre-HPLC to obtain 1-(7-(6-(dimethylamino)-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Z39, cyan solid 2.8 mg, Y: 4%). ES-API: [M+H] ⁺ = 595. ¹ H NMR (400MHz, DMSO-d ₆ ) δ.13.11(br,1H),9.96(br,1H),7.58-7.32(m,5H),6.39-6.32(m,1H),6.13(d,J＝17.2,1H),5.69(d,J＝11.6,1H),4.79-4.76(m, 1H),4.62-4.58(m,1H),4.07(s,1H),3.90-3.73(m,8H),3.30-3.24(m,1H),2.97(s,3H),2.47(s,6H),2.29-2.22(m,4H),2.05-1.88(m,7H).

Example 25 Preparation of Z40

Step 1: Add 4-bromo-3,5-difluorobenzoic acid (20g, 0.084mol) to concentrated sulfuric acid (100mL), add potassium nitrate (8.5g, 0.084mol), stir evenly and heat to 80 degrees for 3 hours. After cooling, pour the reaction solution into water (500mL), extract with ethyl acetate (300mL x 3), wash with water and brine, dry and spin dry to obtain a yellow solid product 4-bromo-3,5-difluoro-2-nitrobenzoic acid (18g, yield 75%). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.84(d,J＝8.1Hz,1H).

Step 2: Add cyclopropanol (2.68g, 0.046mol) to tetrahydrofuran (400mL), cool to 0 degrees, add sodium hydrogen (5.5g, 0.14mol), stir evenly, add 4-bromo-3,5-difluoro-2-nitrobenzoic acid (13g, 0.046mol), and react at room temperature overnight. Add water (20mL) to quench the reaction solution, spin off most of the tetrahydrofuran, adjust the pH to 4-5 with dilute hydrochloric acid, extract with ethyl acetate (100mL x 3), wash with water and brine, dry and spin dry to obtain a yellow solid product 4-bromo-3-cyclopropyloxy-5-fluoro-2-nitrobenzoic acid (13g, yield 80%). 1H NMR (400MHz, DMSO-d ₆ ) δ7.65 (s, 1H), 4.47-4.38 (m, 1H), 0.69 (d, J = 12.1Hz, 2H), 0.65-0.57 (m, 2H).

Step 3: 4-bromo-3-cyclopropyloxy-5-fluoro-2-nitrobenzoic acid (13 g, 0.04 mol) was dissolved in methanol (80 mL), and a methanol solution of sodium methoxide (16 mL, 5 M) was added, and the mixture was heated to 50 degrees for 2 hours. The reaction solution was quenched with water (10 mL), most of the methanol was removed by vortexing, and the pH was adjusted to 4-5 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL x 3), washed with water and brine, and dried to obtain a yellow solid product, 4-bromo-3-cyclopropyloxy-5-methoxy-2-nitrobenzoic acid (10 g, yield 75%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.34 (s, 1H), 4.40-4.35 (m, 1H), 3.98 (s, 3H), 0.72-0.67 (m, 2H), 0.59 (d, J = 6.8 Hz, 2H).

Step 4: Add 4-bromo-3-cyclopropyloxy-5-methoxy-2-nitrobenzoic acid (9.6 g, 28.91 mmol) to thionyl chloride (100 mL), heat to 80 degrees for 3 hours, and spin-dry the crude product for direct use in the next step.

Step 5: 4-bromo-3-cyclopropyloxy-5-methoxy-2-nitrobenzoyl chloride (10.1 g, 28.91 mmol) was dissolved in ultra-dry tetrahydrofuran (100 mL), and added dropwise to 0-degree ammonia water (100 mL). After addition, the mixture was reacted at room temperature for 3 hours. The mixture was extracted with ethyl acetate (100 mL x 3), washed with water and brine, and dried to obtain the product 4-bromo-3-cyclopropyloxy-5-methoxy-2-nitrobenzamide (9 g, yield 90%). ES-API: [M+H] ⁺ = 334

Step 6: Add 4-bromo-3-cyclopropyloxy-5-methoxy-2-nitrobenzamide (8.9 g, 0.027 mol) to a mixed solvent of acetic acid (140 ml) and water (70 mL), heat to 60 degrees, add iron powder (15.1 g, 0.27 mol) in batches, and keep warm for 2 hours after the addition. After the reaction solution is cooled, add ethyl acetate (500 mL), filter and spin dry to obtain a crude product, slurry (10% ethyl acetate/petroleum ether 50 mL) to obtain a white solid 2-amino-4-bromo-3-cyclopropyloxy-5-methoxybenzamide (4 g, yield 49%). ES-API: [M+H] ⁺ = 302

Step 7: 2-amino-4-bromo-3-cyclopropyloxy-5-methoxybenzamide (4g, 0.013mol) was dissolved in tetrahydrofuran (65ml), cooled to 0 degrees, sodium hydrogen (2.7g, 0.066mol) was added, and carbonyl diimidazole (3.2g, 0.02mol) was slowly added after stirring for 0.5 hours, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was quenched by adding water (5mL) dropwise at 0 degrees, most of the tetrahydrofuran was dried, and the product 7-bromo-8-cyclopropyloxy-6-methoxyquinazoline-2,4-diol (3.5g, yield 82%) was obtained after slurrying (10% ethyl acetate/petroleum ether 50mL). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.42 (s, 1H), 10.58 (s, 1H), 7.25 (s, 1H), 4.40-4.33 (m, 1H), 3.87 (s, 3H), 0.99 (p, J = 5.2Hz, 2H), 0.55-0.46 (m, 2H). ES-API: [M+H ] ⁺ =329

Step 8: 7-bromo-8-cyclopropyloxy-6-methoxyquinazoline-2,4-diol (2g, 6.1mol) was added to phosphorus oxychloride (30ml), heated to 100 degrees, and N,N-diisopropylethylamine was slowly added to the reaction solution until it was dissolved (3ml), heated to 130 degrees for 2 hours, and the reaction solution was cooled and most of the phosphorus oxychloride was removed and poured into water (100ml), washed with water and salt water, dried and then spin-dried to obtain crude 7-bromo-2,4-dichloro-8-cyclopropyloxy-6-methoxyquinazoline (2.2g, yield 95%).

Step 9: Dissolve the compound 7-bromo-2,4-dichloro-8-cyclopropyloxy-6-methoxyquinazoline (2g, 5.49mol) in tetrahydrofuran (50ml), add (S) tert-butyl 3-methylpiperazine-1-carboxylate (1.2g, 6.04mol) and triethylamine (1.7g, 16.48mol). Heat to 60 degrees for 5 hours, add ethyl acetate (100ml) after the reaction solution is cooled, wash with water, ammonium chloride solution, and brine, dry and spin-dry, and then purify by column (petroleum ether: ethyl acetate = 3:1) to obtain a yellow foamy solid (S) tert-butyl 4-(7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazoline-4-yl)-3-methylpiperazine-1-carboxylate (3g, yield 100%). ES-API: [M+H] ⁺ = 529.

Step 10: (S)-(1-methylpyrrolidin-2-yl)methanol (20 mL) was cooled to 0°C and sodium hydrogen hydride (318 mg, 7.96 mmol) was added. Then, (S)-4-(7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.4 g, 2.65 mmol) was added. After stirring evenly, the mixture was heated to 110°C for 1 hour. After cooling, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), and purified by column chromatography (methanol: dichloromethane = 0-1:10) to obtain a yellow foamy solid (S)-tert-butyl 4-(7-bromo-8-cyclopropyloxy-6-methoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylic acid* (1 g, yield 58%). ES-API: [1/2M+H] ⁺ = 303.6.

Step 11: (S)-tert-butyl 4-(7-bromo-8-cyclopropyloxy-6-methoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylic acid (1 g, 1.65 mmol), (5-methyl-1H-indazol-4-yl)boric acid (435 mg, 2.47 mmol), tripotassium phosphate (1.05 g, 4.95 mmol), tris(dibenzylidene indeneacetone)dipalladium (100 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (200 mg) were added to dioxane in sequence. (10mL) water (2mL), nitrogen replaced three times, then heated to 110 degrees for 16 hours. After cooling to room temperature, pour into ethyl acetate (50mL), wash once with brine and purify with silica gel column (methanol: dichloromethane = 0-1:10) to obtain yellow foaming solid (3S) tert-butyl 4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl))methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (550mg, yield 50%). ES-API: [1/2M+H] ⁺ = 329.6

Step 12: (3S) tert-butyl 4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl))methoxy)quinazoline-4-yl)-3-methylpiperazine-1-carboxylate (550 mg, 0.84 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added and reacted at room temperature for 1 hour, and the mixture was dried to obtain a yellow oily crude product 8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-4-((S)-2-methylpiperazin-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline (468 mg, yield 100%)

Step 13: 8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-4-((S)-2-methylpiperazin-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline (468 mg, 0.84 mmol) and triethylamine (255 mg, 2.52 mmol) were dissolved in dichloromethane (4 mL), cooled to 0 degrees, and then acrylic anhydride (95 mg, 0.76 mmol) was added. The temperature was kept at 0 degrees for 1 hour. Water (10 mL) and dichloromethane (10 mL x 3) extraction, drying and spin drying to obtain a white solid 1-((3S)-4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl))methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Z40, 60 mg, yield 11%). ES-API: [M+H] ⁺ = 515.3. ¹ H NMR(400MHz,cdcl3)δ10.16(s,1H),7.59(s,1H),7.43(d,J＝8.6Hz,1H),7.33(d,J＝8.6Hz,1H),6.97(s,1H),6.61(dd,J＝30.7,11.0Hz,1H),6.38(d,J＝16.4Hz ,1H),5.77(d,J＝10.9Hz,1H),4.75-4.33(m,5H), 4.11(s,1H),3.70(d,J＝25.7Hz,5H),3.28(d,J＝13.7Hz,1H),3.11(s,1H),2.75(s,1H),2.50(s,3H),2.28(s,1H),2.21(s,3H),2.07(s,1H),1.79(d ,J＝21.6Hz,4H),1.43(d,J＝6.7Hz,3H),0.26-0.10(m,4H).

Example 25-1 Preparation of Z40-1 and Z40-2

Compound Z40 (55 mg) prepared in Example 25 was chirally resolved (Co-Solvent: HEX: ETOH: DEA = 40: 60: 02; column: IG 250 mm * 4.6 mm 5 um); flow rate: 1.0 ml / min; column temperature: 30.0 ° C) to obtain: Compound Z40-1 (retention time: 6.171 min): The structure of the compound was arbitrarily designated as 1-((S)-4-((R)-8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidinone-pyridin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (19 mg, P: 99.5%, ee value: 99.3%). ES-API: [M+H] ⁺ =612.3; Compound Z40-2 (retention time: 7.600 min): The structure of this compound was arbitrarily designated as 1-((S)-4-((S)-8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidinone-pyridin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (23 mg, P: 98%, ee value: 99%). ES-API: [M+H] ⁺ =612.3.

Example 23 Preparation of Z38

Step 1: Dissolve 7-bromo-2,4-dichloro-8-cyclopropyloxy-6-methoxyquinazoline (2.1 g, 5.78 mol) in tetrahydrofuran (50 ml), add piperazine-1-carboxylic acid tert-butyl ester (1.6 g, 8.68 mol) and triethylamine (1.75 g, 17.34 mol). Heat to 60 degrees for 5 hours, add ethyl acetate (100 ml) after the reaction solution is cooled, wash with water, ammonium chloride solution, and brine, dry and spin-dry, and purify by column (petroleum ether: ethyl acetate = 3:1) to obtain yellow foaming solid 4-(7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazoline-4-yl) piperazine-1-carboxylic acid tert-butyl ester (1.1 g, yield 50%). ES-API: [M+H] ⁺ = 513.1.

Step 2: (S)-(1-methylpyrrolidin-2-yl)methanol (15 mL) was cooled to 0°C and sodium hydrogen hydride (390 mg, 9.73 mmol) was added. Then, tert-butyl 4-(7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl)piperazine-1-carboxylate (1 g, 1.95 mmol) was added. After stirring evenly, the mixture was heated to 110°C for 1 hour. After cooling, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), and purified by column chromatography (methanol: dichloromethane = 0-1:10) to give a yellow foamy solid ((S)-4-(7-bromo-8-cyclopropyloxy-6-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (750 mg, yield 68%). ES-API: [M+H] ⁺ = 592.2.

Step 3: ((S)-4-(7-bromo-8-cyclopropyloxy-6-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (750 mg, 1.26 mmol), (5-methyl-1H-indazol-4-yl)boric acid (450 mg, 2.52 mmol), tripotassium phosphate (850 mg, 3.78 mmol), tris(dibenzylidene indeneacetone)dipalladium (100 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (60 mg) were added to dioxygen 4-nitropropane. Hexacyclic (8 mL) water (2 mL), nitrogen replaced three times, then heated to 110 degrees for 16 hours. After cooling to room temperature, pour into ethyl acetate (50 mL), wash once with brine and purify with silica gel column (methanol: dichloromethane = 0-1:10) to obtain yellow foaming solid tert-butyl 4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate crude product (200 mg, yield 30%). ES-API: [M+H] ⁺ = 644.3.

Step 4: tert-Butyl 4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (200 mg, 0.3 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added and reacted at room temperature for 1 hour, and then dried to obtain a crude yellow oil 8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline (169 mg, yield 100%). ES-API: [M+H] ⁺ = 544.3

Step 5: 8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline (169 mg, 0.3 mmol) was dissolved in dichloromethane (4 mL), cooled to 0 degrees, and triethylamine (2 mL) and acrylic anhydride (32 mg, 0.25 mmol) were added. The temperature was kept at 0 degrees for 1 hour. Water (10 mL) was added to the reaction solution, and dichloromethane (10 mL x 3) was used for extraction. After drying, the product was spin-dried and purified by chromatography (chromatographic column: Ultimate XB-C18, 50*250mm, 10um; mobile phase: acetonitrile/water = 10/90-90/10, 40min) to obtain a white solid product 1-(4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (8.5mg, yield 10%). ES-API: [M+H] ⁺ = 598.3. ¹ H NMR (400MHz, CDCl ₃ )δ12.57(s,1H),7.55(s,1H),7.46(d,J＝8.5Hz,1H),7.32(d,J＝8.5Hz,1H),7.01(s,1H),6.63(dd,J＝16.8,10.5Hz,1H),6.37(d,J＝16.7Hz,1H),5.78(d, J＝10.5Hz,1H),5.20(s,1H),4.85 (d,J＝12.4Hz,1H),4.15(d,J＝15.5Hz,2H),3.90(d,J＝29.1Hz,9H),3.74(d,J＝2.6Hz,3H),3.07(s,3H),3.01-2.81(m,2H),2.34(s,2H),2.20(s,3H),2. 09(s,1H),0.15(d,J＝14.5Hz,4H).

Example 26 Preparation of Z41

Step 1: Dissolve the compound 7-bromo-2,4-dichloro-8-cyclopropyloxy-6-methoxyquinazoline (2.1 g, 5.78 mol) in tetrahydrofuran (50 ml), add (S)-2-(piperazine-2-yl)acetonitrile (3.2 g, 16.5 mol) and triethylamine (3.3 g, 33 mol). Heat to 60 degrees for 2 hours, add ethyl acetate (100 ml) after the reaction solution is cooled, wash with water, wash with ammonium chloride solution, wash with brine, dry and spin dry to obtain a yellow solid (S)-2-(4-(7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazoline-4-yl)piperazine-2-yl)acetonitrile (2.7 g, yield 55%). ES-API: [M+1]+＝452.0

Step 2: Compound (S)-2-(4-(7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl)piperazin-2-yl)acetonitrile (3.7 g, 8.2 mol) was dissolved in tetrahydrofuran and water (40/20 ml), and then solid sodium hydroxide (984 mg, 24.6 mmol) and di-tert-butyl dicarbonate (9 g, 41 mmol) were added. The reaction was stirred at room temperature for 16 hours. After monitoring that the reaction was complete, the reaction solution was cooled and ethyl acetate (100 ml) was added. The mixture was washed with water, ammonium chloride solution, and brine. The organic phase was dried and spin-dried and purified by column (petroleum ether/ethyl acetate = 5/1) to obtain a light yellow foamy solid (S)-4-(7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (2.78 g, yield 62%). ES-API: [M+1]+=552.1

Step 3: Dissolve (S)-4-(7-bromo-2-chloro-8-cyclopropyloxy-6-methoxyquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 4.5 mmol) in (S)-(1-methylpyrrolidin-2-yl)methanol (20 mL), then add potassium fluoride (1.3 g, 22.7 mmol), stir evenly, and heat to 110 degrees for 2 hours. After cooling, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), and purified by column chromatography (methanol: dichloromethane = 0-1:10) to obtain yellow foamy solid tert-butyl (S)-4-(7-bromo-8-cyclopropyloxy-6-methoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethylpiperazine-1-carboxylate (2 g, yield 71%). ES-API: [M+1]+ = 631.2

Step 4: tert-Butyl (S)-4-(7-bromo-8-cyclopropyloxy-6-methoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethylpiperazine-1-carboxylate (2 g, 3.17 mmol), (5-methyl-1H-indazol-4-yl)boric acid (1.13 g, 6.35 mmol), tripotassium phosphate (2 g, 9.51 mmol), tris(dibenzylidene indeneacetone)dipalladium (290 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (150 mg) were added to dioxane (16 mL) water (4 mL), replaced with nitrogen three times, and then heated to 110 degrees for 16 hours. After cooling to room temperature, ethyl acetate (100 mL) was added, washed once with brine, and purified by silica gel column (methanol: dichloromethane = 0-1:10) to obtain a yellow foaming solid (2S)-2-(cyanomethyl)-4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-ylpiperazine-1-carboxylic acid tert-butyl ester (910 mg, yield 43%). ES-API: [M+1]+ = 683.2

Step 5: (2S)-2-(cyanomethyl)-4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-ylpiperazine-1-carboxylic acid tert-butyl ester (910 mg, 1.33 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added and reacted at room temperature for 1 hour, and then dried to obtain a crude yellow oil 2-((2S)-4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl))methoxy)quinazolin-4-ylpiperazine-2-ylacetonitrile (770 mg, yield 100%). ES-API: [M+1]+＝583.1

Step 6: 2-((2S)-4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidin-2-yl))methoxy)quinazolin-4-ylpiperazin-2-ylacetonitrile (770 mg, 1.33 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 degrees, and triethylamine (3 mL) and acrylic anhydride (150 mg, 1.2 mmol) were added, and the temperature was kept at 0 degrees for 1 hour. Water (10 mL) and dichloromethane (30 mL x 10 mL) were added to the reaction solution. 3) Extraction, drying and spin drying to obtain a white solid product 2-((2S)-1-acryloyl-4-(8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidinone-2-yl)methoxy)quinazolin-4-ylpiperazin-2-yl)acetonitrile (8.2 mg, yield 10%) ES-API: [M+1]+=636.2. ¹ H NMR (400 MHz, CDCl ₃ )δ7.58(d,J＝3.8Hz,1H),7.44(d,J＝8.5Hz,1H),7.33(d,J＝8.5Hz,1H),7.02(d,J＝17.0Hz,1H),6.63(s,1H),6.42(d,J＝16.6Hz,1H),5.84(d,J＝10.5Hz,1H ),4.69(s,1H),4.45(s,1H),4.31(d,J＝11. 7Hz,3H),3.75(s,3H),3.73(s,1H),3.61(d,J＝12.4Hz,1H),3.32(d,J＝39.7Hz,2H),3.07-2.75(m,3H),2.62(s,3H),2.45(s,1H),2.21(d,J＝3.3Hz,4H ),2.14(s,1H),1.87(s,4H),0.23-0.10(m,4H).

Example 26-1 Preparation of Z41-1 and Z42-2

Compound Z41 (42 mg) prepared in Example 26 was chirally resolved (Co-Solvent::CAN:IPA:DEA=90:10:0.2; column: IC 254 nm @ 4.8 nm); flow rate: 1.0 ml/min; column temperature: 30.0°C) to give: Compound Z41-1 (retention time: 4.966 min): The structure of the compound was arbitrarily designated as 2-((S)-1-acryloyl-4-((R)-8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-ylpiperazin-2-yl)acetonitrile (23 mg, P: 94.58%, ee value: 99.6%). ES-API: [M+H] ⁺ =637.3; Compound Z41-2 (retention time: 6.381 min): The structure of this compound was arbitrarily designated as 2-((S)-1-acryloyl-4-((S)-8-cyclopropyloxy-6-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-((((S-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-ylpiperazin-2-yl)acetonitrile (19 mg, P: 93.55%, ee value: 100%). ES-API: [M+H] ⁺ =637.3.

Test Example 1 Cell Proliferation Inhibition Experiment

NCI-H358 is a human non-small cell lung cancer cell line with Kras G12C mutation, cultured in 10% FBS RPMI-1640 medium; A549 is a human lung adenocarcinoma cell line with Kras G12S mutation, cultured in 10% FBS F-12K medium. Cells in the logarithmic growth phase were collected and counted by trypsin EDTA digestion, and H358 was adjusted to 1.8E4 cells/ml using 2% FBS RPMI-1640 medium, and A549 was adjusted to 8.9E3 cells/ml using 2% FBS F-12K medium; 800 (45 μl) H358 or 400 (45 μl) A549 cells were inoculated in 384-well spheroid plates, respectively, and cultured overnight to establish a 3D cell model. Use DMSO to prepare 1000X compound 3.16-fold gradient concentration stock solution, use 2% FBS medium to dilute 100 times to 10X compound stock solution, and add 5 μl of 10X compound stock solution to each cell culture well on the second day after cell inoculation, with a final concentration of 1X and a DMSO content of 0.1%. Use DMSO as the experimental control (control), and 2% FBS medium as the blank control (blank). After adding the compound and culturing the cells for 5 days, 25 μl of CellTiter-Glo working solution was added to each well, mixed at 400 rpm and incubated for 30 minutes. After standing at room temperature for 30 minutes, 40 μl of the mixed solution was transferred to a white bottom transparent 384-well plate, and the luminescence chemiluminescence value was read to calculate the cell proliferation inhibition rate IR (%) = (RLU control-RLU compound)/(RLU control-RLU blank) × 100%. The Prism 6 four-parameter method was used to fit the compound gradient dilution concentration and the corresponding cell proliferation inhibition rate to calculate the IC ₅₀ value. The results showed that the compounds of the present invention had a high inhibitory activity against Kras G12C mutant NCI-H358 cells, and the IC ₅₀ was lower than 1000 nM; even lower than 500 nM, even lower than 300 nM or lower than 200 nM, and some compounds had an IC ₅₀ lower than 100 nM, or even lower than 50 nM; while the inhibitory activity against A549 cells was lower, and the IC _{The IC 50 of some} compounds exceeds 1000 nM, even exceeds 5000 nM, and some compounds have IC ₅₀ exceeding 10000 nM, even exceeding 15000 nM or 20000 nM. The results of the exemplary compounds are shown in Table 1 below.

Table 1 Inhibitory activity of compounds on H358 and A549 cells

As can be seen from Table 1, the exemplary compounds of the present invention have higher inhibitory activity against NCI-H358 cells with Kras G12C mutation, but lower inhibitory activity against A549 cells, and have obvious selective inhibitory activity.

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (17)

1. A spirocyclic substituted pyrimidocyclic compound or a pharmaceutically acceptable salt thereof, the structure of the compound is as shown in formula (I): In the formula, X is NC (O)-CR _X3 =CR _X1 R _X2 ; Wherein, R _X1 and R _X2 are hydrogen or -C _1-3 alkyl-NR ^a R ^b ; R _X3 is hydrogen or -OC _1-3 alkyl; Wherein, R ^a and R ^b are each independently hydrogen or C _1-3 alkyl; m and n are each independently 1, 2 or 3; and m and n are not 1 at the same time; R ₁ is halogen, -OR ₁₁ , -NH-R ₁₁ or -N(R ₁₁ )R ₁₂ ; wherein, R ₁₁ and R ₁₂ are each independently substituted or unsubstituted C _1-6 alkyl, C _{3- 6} cycloalkyl or 3 to 6 membered heterocycloalkyl or R ₁₁ , R ₁₂ together with the connected nitrogen atom form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; and when m=n=2, R ₁ is not halogen; wherein, the 3 to 6 membered heterocycloalkyl has 1 O heteroatom as a ring atom; L is a bond, -O-(CR _L1 R _L2 ) _t1 or -NH-(CR _L3 R _L4 ) _t2 -; wherein, R _L1 , R _L2 , R _L3 , and R _L4 are the same or different, each independently hydrogen Or C _1-3 alkyl; t1, t2 are each independently 0, 1, 2, 3 or 4; R ₂ is a substituted or unsubstituted 3- to 20-membered heterocycloalkyl group or NR ₂₁ R ₂₂ ; R ₂₁ and R ₂₂ form a substituted or unsubstituted 3- to 20-membered heterocycloalkyl group together with the connected nitrogen atom; wherein, The 3 to 20 membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; Z is CR ₃ ; wherein, R ₃ is hydrogen, halogen or substituted or unsubstituted C _1-6 alkoxy; E is CR ₄ or N; Wherein, R ₄ is hydrogen; The "substitution" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from Group S; The substituent group S is selected from: hydroxyl, halogen, nitro, oxo, C _1-6 alkyl, C _1-6 alkyl substituted by hydroxyl, benzyl, -(CH ₂ ) _u -cyano, -(CH ₂ ) _u -C _1-6 alkoxy, -(CH ₂ ) _u -halogenated C _1-6 alkoxy, -(CH ₂ ) _u -halogenated C _1-6 alkyl, -( CH ₂ ) _u -3 to 6 membered heterocycloalkyl, -(CH ₂ ) _u -5 or 6 membered monocyclic heteroaryl, -(CH ₂ ) _u -C _3-8 cycloalkyl, -(CH ₂ ) _u -O-(CH ₂ ) _v -C _3-8 cycloalkyl, -(CH ₂ ) _u -O-(CH ₂ ) _v -C _1-6 alkoxy, -(CH ₂ ) _u -O -(CH ₂ ) _v OH, -(CH ₂ ) _u -SO ₂ C _1-6 alkyl, -(CH ₂ ) _u -NR _a0 R _b0 , -(CH ₂ ) _u -C(O)NR _a0 R _b0 , -(CH ₂ ) _u -C(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, NR _a0 C(O)-(CH ₂ ) _u -NR _a0 R _b0 , NR _a0 C(O)-(CH ₂ ) _u OH, NR _a0 C(O)-halogenated C _1-6 alkyl; wherein, the 3 to 6-membered heterocycloalkyl, 5 or 6-membered monocyclic hetero The aryl groups each independently have 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3 to 6 membered heterocycloalkyl, 5 or 6 membered monocyclic heteroaryl are optionally 1, 2 or 3 substituents selected from halogen, cyano, C _1-3 alkyl, C _1-3 alkoxy and C _3-6 cycloalkyl; u, v are each independently 0, 1 , 2, 3 or 4; R _a0 , R _b0 are each independently hydrogen or C _1-3 alkyl; B is C _6-10 aryl or 8 to 10 membered bicyclic heteroaryl; wherein, the C _6-10 The aryl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from R _s1 ; the 8 to 10-membered bicyclic heteroaryl is selected from the following structures: ; R _s1 is hydroxyl or halogen; Provided that the compound of formula (I) is not 1-(6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)- 1 methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one, 1-(6-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy )quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one, 1-(6-(6-chloro-8-fluoro -7-(3-Hydroxynaphthalen-1-yl)-2-(((S)-1methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,6-di Azaspiro[3.4]oct-2-yl)prop-2-en-1-one, 1-(6-(6-chloro-2-(3-(dimethylamino)azetidine-1 -yl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl ) prop-2-en-1-one, 1-(6-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-( 2-fluoro-6-hydroxyphenyl)-quinazolin-4-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one, 1-( 6-(6-Chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinazoline-4 base)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one, or 1-(6-(6-chloro-7-(5-methyl-1H -Indazol-4-yl)-2-(((S)-1methylpyrrolidin-2-yl)methoxy)-8-(2,2,2-trifluoroethoxy)quinazoline -5-yl)-2,6-diazaspiro[3.4]oct-2-yl)prop-2-en-1-one. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound shown in formula (I) is a compound shown in formula (II) or a compound shown in formula (III): In each formula, R ₁ , R ₂ , X, B, E, Z, and L are as defined above. 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the C _6-10 aryl group in B is phenyl. 4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein B is selected from the following structures: , wherein R _s1 and R _s2 are each independently hydroxyl or halogen. 5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein B is selected from the following structures: . 6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein B is . 7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ₁ is halogen or -OR ₁₁ . 8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond; R ₂ is NR ₂₁ R ₂₂ ; wherein, R ₂₁ and R ₂₂ are in common with the connected nitrogen atom Form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl, a substituted or unsubstituted 6 to 10 membered condensed heterocycloalkyl, or a substituted or unsubstituted 7 to 11 membered spiroheterocycloalkyl; wherein, the 3 to 6 membered heterocycloalkyl, 6 to 10 membered condensed heterocycloalkyl, 7 to 11 membered spiroheterocycloalkyl each independently have 1, 2 or 3 heteroatoms selected from N, O and S as the ring atom; the "substitution" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from the S group. 9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is -O-(CR _L1 R _L2 ) _t1 - or -NH-(CR _L3 R _L4 ) _t2 -; R ₂ is halogen, hydroxyl, -SO ₂ C _1-6 alkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted 6 to 10 membered condensed heterocycloalkyl, substituted or unsubstituted 7 to 11 membered spiroheterocycloalkyl, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted 5 or 6 membered monocyclic heteroaryl or NR ₂₁ R ₂₂ ; Wherein, R _L1 , R _L2 , R _L3 , and R _L4 are the same or different, each independently hydrogen or C _1-3 alkyl; t1, t2 are each independently 0, 1, 2, 3 or 4; R ₂₁ and R ₂₂ are each independently hydrogen, substituted or unsubstituted C _1-6 alkyl, -SO ₂ C _1-6 alkyl, -SO ₂ C _3-6 cycloalkyl, -C(O)C _1-6 alkyl or -C (O) halogenated C _1-6 alkyl; or R ₂₁ and R ₂₂ together with the connected nitrogen atom form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted Substituted 6- to 10-membered fused heterocycloalkyl or substituted or unsubstituted 7- to 11-membered spiroheterocycloalkyl; Wherein, the 3 to 6 membered heterocycloalkyl, 6 to 10 membered condensed heterocycloalkyl, and 7 to 11 membered spiroheterocycloalkyl each independently have 1, 2 or 3 members selected from N, O and S Heteroatoms are used as ring atoms; the "substitution" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from the S group. 10. A compound represented by the following structure, or a pharmaceutically acceptable salt thereof: . 11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 12. Use of the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a drug for preventing and/or treating cancer. 13. purposes as claimed in claim 12, it is characterized in that, described cancer is pancreatic ductal carcinoma, colorectal cancer, multiple myeloma, lung cancer, skin melanoma, uterine endometrial carcinoma, uterine carcinosarcoma, thyroid cancer, Acute myeloid leukemia, bladder urothelial carcinoma, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, squamous cell carcinoma of the lung, small cell lung cancer, Papillary cell carcinoma of the kidney, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver cancer, invasive carcinoma of the breast, squamous cell carcinoma of the cervix, serous adenocarcinoma of the ovary, adrenocortical carcinoma, prostate cancer, neuroblastoma, low brain Glioma, glioblastoma, medulloblastoma, squamous cell carcinoma of the esophagus, clear cell carcinoma of the kidney, osteosarcoma, small cell carcinoma of the ovary, rhabdoid tumor, sarcoma, neuroendocrine tumor of the small intestine, or T cell neoplasm lymphocytic leukemia. 14. Use according to claim 12, characterized in that the cancer is lung cancer, pancreatic ductal cancer or colorectal cancer. 15. The use according to claim 12, wherein the cancer is non-small cell lung cancer. 16. Use of the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a KRAS mutation inhibitor. 17. The use according to claim 16, wherein the KRAS mutation is a KRAS G12C mutation.