The present application claims the priorities of Chinese patent application CN202010208625.2 filed on Mar. 23, 2020 and Chinese patent application CN202010984379.X filed on Sep. 18, 2020. The contents of the above Chinese patent applications are incorporated herein by reference in its entireties.

TECHNICAL FIELD

The present disclosure belongs to the field of pharmaceutical chemistry, and particularly relates to a novel aminopyrimidine compound as a selective EGFR inhibitor, a pharmaceutical composition comprising the compound, an intermediate useful for preparing the compound, and a method for treating a cell proliferative disease, such as a cancer, by using the compound of the present disclosure.

BACKGROUND

Lung Cancer is the cancer with the highest incidence and mortality, which seriously threatens human health and life. Lung cancer is mainly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), of which about 80% are NSCLC.

Epidermal growth factor receptor (EGFR) is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells and other cells. The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, which can account for 40% to 50%. Therefore, EGFR has always been one of the most popular targets in pharmaceutical industry research.

At present, there are first-, second- and third-generation EGFR inhibitors on the market. The first generation is reversible targeted drugs, such as gefitinib, erlotinib, and icotinib. The second-generation is irreversible targeted drugs, such as afatinib and dacomitinib. Although the first- and second-generation targeted drugs are effective, most patients will develop drug resistance after using drugs for 1-2 years. Among patients with EGFR inhibitor resistance, 50% of the drug resistance is related to the T790M mutation. The third-generation EGFR-targeted drug osimertinib can bind to the T790M mutation site of EGFR-sensitive mutation and inhibit the drug resistance of tumor caused by T790M mutation. Its advent has brought good survival benefits to more lung cancer patients. However, the third-generation targeted drugs also inevitably develop drug resistance, and the main reason for the drug resistance is C797S mutation. The C797S mutation is reflected in the mutation of the cysteine residue into serine. This mutation destroys the binding of the EGFR protein to the third-generation targeted drugs, thereby failing to prevent the unilateral phosphorylation of EGFR and the activation of downstream signaling pathways. At present, there is no mature treatment method for the two main cis-triple mutations after osimertinib drug resistance: de119/T790M/C797S and L858R/T790M/C797S, and the clinical demands are imminent. The present disclosure is based on solving this problem.

CONTENT OF THE PRESENT INVENTION

The present disclosure provides a compound represented by formula (I′), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof or an isotope-labeled derivative thereof,

[Image Omitted]

wherein,

R₁is selected from H, halogen, —CN, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-6cycloalkyl, 3-6-membered heterocycloalkyl, C_3-6cycloalkyloxy, 3-6-membered heterocycloalkyloxy, and C_2-6alkenyloxy;

M is selected from N or CR₁₀;

R₁₀and R₁may form a 5-8-membered heterocycloalkyl or a 5-7-membered heteroaryl; the 5-8-membered heterocycloalkyl and the 5-7-membered heteroaryl are optionally substituted by one or more R₁₁groups;

Y is selected from N and CR₂;

R₂is selected from H, halogen, —CN, —OH, —NH₂, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, carbonylamino, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl , C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, C_3-6heterocycloalkenyl, phenyl and

[Image Omitted]

wherein, the —OH, —NH₂, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, carbonylamino, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl , C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, C_3-6heterocycloalkenyl, phenyl and

[Image Omitted]

are optionally substituted by one or more R₁₂groups;

R₃is selected from —CN, sulfoximino, -L₁-C_6-10aryl, -L₁-5-12-membered heteroaryl, -L₁-C_3-6cycloalkenyl and

[Image Omitted]

wherein, the —CN, sulfoximino, -L₁-C_6-10aryl, -L₁-5-12-membered heteroaryl, -L₁-C_3-6cycloalkenyl and

[Image Omitted]

are optionally substituted by one or more R₁₃groups;

L₁is independently selected from a linking bond, C_1-4alkyl and C_1-4heteroalkyl, wherein the C_1-4alkyl and C_1-4heteroalkyl are optionally substituted by one or more groups selected from —OH, —NH₂and halogen;

R₄and R₅are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl;

or, R₄and R₅are cyclized to 4-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 4-6-membered aryl or 4-6-membered heteroaryl;

R₆is selected from amino, amido, aminocarbonyl, sulfonyl, thiophosphonyl, phosphonyl, phosphonoamino, sulfonylamino, aminosulfonyl and sulfoximino, wherein the amino, amido, aminocarbonyl, sulfonyl, thiophosphonyl, phosphonyl, phosphonoamino, sulfonylamino, aminosulfonyl and sulfoximino are optionally substituted by one or more R₁₄groups;

Z₃is selected from N or CR₇;

Z₄is selected from N or CR₉;

R₇, R₈and R₉are each independently selected from H, halogen, —CN, —OH, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3-6-membered heterocycloalkyl and 5-7-membered heteroaryl;

or, R₇and R₈are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl or 5-7-membered heteroaryl;

or, R₈and R₉are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl or 5-7-membered heteroaryl;

R₁₀is selected from H, halogen, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl and C_1-6haloalkoxy;

R₁₁is selected from H, halogen, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, —C_0-4alkyl-NR_aR_b, alkyl-O—C_1-4alkyl, —C_1-4alkyl—OH, —O—C_1-4alkyl, —C_0-4alkyl-C_3-6cycloalkyl and —C_0-4alkyl-3-6-member heterocycloalkyl;

R₁₂is selected from H, halogen, —CN, —OH, —NH₂, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, 3-14-membered heterocycloalkyl, hydroxy-C_1-6alkyl-, C_3-8cycloalkylalkyl-, C_3-8cycloalkyloxy-, C_3-8heterocycloalkylalkyl-, C_3-8heterocycloalkyloxy-, C_3-8cycloalkyl-C_1-6alkoxy-, C_3-8heterocycloalkyl-C_1-6alkoxy-, C_1-6alkylsulfonyl, C_3-6cycloalkylsulfonyl, NR_aR_bCO—, C_1-6alkylcarbonyl, C_3-8cycloalkylcarbonyl, C_1-6alkoxy-C_1-6alkyl- , C_3-6cycloalkenyl, 5-12-membered heteroaryl, C_6-10aryl, NR_aR_bS(O)₂—, —(CH₂)_mNR_aR_b, —(CH₂)_mO(CH₂)_nCH₃and —O(CH₂)_mNR_aR_b; wherein the R_aand R_bare independently H, C_1-6alkyl or C_1-6alkoxy, or R_aand R_btogether form a C_3-8cycloalkyl or 3-8-membered heterocycloalkyl; wherein the m and n are independently optionally 0, 1, 2 or 3, the C_3-8cycloalkyl and 3-8-membered heterocycloalkyl are optionally substituted by a group selected from halogen, —OH, —NH₂, —CN, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl and —C_0-4alkyl-O—C_1-4alkyl;

R₁₃is selected from H, halogen, —CN, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-8cycloalkyl, 3-8-membered heterocycloalkyl, C_3-6cycloalkylsulfonyl, 5-6-membered heteroaryl and phenyl;

R₁₄is selected from H, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl.

In some embodiments of the present disclosure, in the compound represented by formula (I′), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof,

R₁is selected from H, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl and C_1-4haloalkoxy;

M is selected from N or CR₁₀;

R₁₀and R₁may form a 5-8-membered heterocycloalkyl and a 5-7-membered heteroaryl; the 5-8-membered heterocycloalkyl and the 5-7-membered heteroaryl are optionally substituted by one or more R₁₁groups;

Y is selected from N and CR₂;

R₂is selected from H, halogen, —NH₂, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, C_3-6heterocycloalkenyl and

[Image Omitted]

wherein, the —NH₂, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, C_3-6heterocycloalkenyl and

[Image Omitted]

are optionally substituted by one or more R₁₂groups;

R₃is selected from —CN, 5-12-membered heteroaryl and

[Image Omitted]

wherein, the —CN, 5-12-membered heteroaryl and

[Image Omitted]

are optionally substituted by one or more R₁₃groups;

R₄and R₅are each independently selected from H, halogen, —CN, C_1-4alkyl, C_1-4haloalkyl, and C_3-6cycloalkyl;

or, R₄and R₅are cyclized to 4-6-membered aryl or 4-6-membered heteroaryl;

R₆is selected from amido, sulfonyl, thiophosphonyl, phosphonyl, sulfonylamino and aminosulfonyl, wherein the amido, sulfonyl, thiophosphonyl, phosphonyl, sulfonylamino and aminosulfonyl are optionally substituted by one or more R₁₄groups;

Z₃is selected from CR₇;

Z₄is selected from CR₉;

R₇, R₈and R₉are each independently selected from H and C_1-4alkyl;

or, R₇and R₈are cyclized to C_4-6cycloalkyl or 5-7-membered heteroaryl;

or, R₈and R₉are cyclized to C_4-6cycloalkyl or 5-7-membered heteroaryl;

R₁₀is selected from H, halogen and C_1-4alkyl;

R₁₁is selected from H, C_1-4alkyl, —C_1-4alkyl-NR_aR_band 3-6-membered heterocycloalkyl;

R₁₂is selected from H, halogen, —OH, —NH₂, C_1-6alkyl, C_1-6haloalkyl, C_3-8cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C_1-6alkyl, 6-14-membered spiro heterocyclyl, —C_1-4alkyl-O—C_1-4alkyl, —O—C_1-4alkyl, —C_1-4alkyl-C_3-6cycloalkyl, —O—C_0-4alkyl-C_3-6cycloalkyl, —C_1-4alkyl-3-6-membered heterocycloalkyl, —O—C_0-4alkyl-3-6-membered heterocycloalkyl, —(CH₂)_mNR_aR_b, —O(CH₂)_mNR_aR_b, C_1-6alkylsulfonyl, C_3-6cycloalkylsulfonyl, NR_aR_bCO—, C_1-6alkylcarbonyl and C_3-6cycloalkylcarbonyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by R_ab, and the R_abis selected from H, halogen, —OH, —NH₂, —CN, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl and —C_0-4alkyl-O—C_1-4alkyl;

R_aand R_bare independently H or C_1-4alkyl;

m is optionally 0, 1, 2 or 3;

R₁₃is selected from H, halogen, C_1-4alkyl, C_1-4haloalkyl, hydroxy-C_1-6alkyl and C_3-6cycloalkylsulfonyl;

R₁₄is selected from H, C_1-4alkyl, C_1-4alkoxy and C_3-8cycloalkyl.

In some embodiments of the present disclosure, in the compound represented by formula (I′), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof, the compound represented by formula (I′), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof may be a compound represented by formula (I), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof or an isotope-labeled derivative thereof,

[Image Omitted]

wherein, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉and M are defined as above.

In some embodiments of the present disclosure, in the compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof,

R₁is selected from H, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl and C_1-4haloalkoxy;

M is selected from N or CR₁₀;

R₁₀and R₁may form a 5-8-membered heterocycloalkyl, and the 5-8-membered heterocycloalkyl is optionally substituted by one or more R₁₁groups;

R₂is selected from H, halogen, —NH₂, phosphonyl, sulfonyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl and C_3-6heterocycloalkenyl; wherein, the —NH₂, phosphonyl, sulfonyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl and C_3-6heterocycloalkenyl are optionally substituted by one or more R₁₂groups;

R₃is selected from 5-12-membered heteroaryl optionally substituted by one or more R₁₃groups;

R₄and R₅are each independently selected from H, halogen, —CN, C_1-4alkyl, C_1-4haloalkyl, and C_3-6cycloalkyl;

or, R₄and R₅are cyclized to aryl or 4-6-membered heteroaryl;

R₆is selected from amido, sulfonyl, thiophosphonyl, phosphonyl, sulfonylamino and aminosulfonyl, wherein the amino, amido, sulfonyl, thiophosphonyl, phosphonyl, sulfonylamino and aminosulfonyl are optionally substituted by one or more R₁₄groups;

R₇, R₈and R₉are each independently selected from H and C_1-4alkyl;

or, R₇and R₈are cyclized to C_4-6cycloalkyl or 5-7-membered heteroaryl;

or, R₈and R₉are cyclized to C_4-6cycloalkyl or 5-7-membered heteroaryl;

R₁₀is optionally selected from H, halogen and C_1-4alkyl;

R₁₁is optionally selected from H, C_1-4alkyl, —C_1-4alkyl-NR_aR_band 3-6-membered heterocycloalkyl;

R₁₂is selected from H, halogen, —OH, —NH₂, C_1-6alkyl, C_1-6haloalkyl, C_3-8cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C_1-6alkyl, 6-14-membered spiro heterocyclyl, —C_1-4alkyl-O—C₁₄alkyl, —O—C_1-4alkyl, —C_1-4alkyl-C_3-6cycloalkyl, —O—C_0-4alkyl-C3,6 cycloalkyl, —C_1-4alkyl-3-6-membered heterocycloalkyl, —O—C_0-4alkyl-3-6-membered heterocycloalkyl, —(CH₂)_mNR_aR_b, —O(CH₂)_mNR_aR_b, C_1-6alkylsulfonyl, C_3-6cycloalkylsulfonyl, NR_aR_bCO—, C_1-6alkylcarbonyl and C_3-6cycloalkylcarbonyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by R_ab, and the R_abis selected from H, halogen, —OH, —NH₂, —CN, C_1-4alkyl, C_1-4alkoxy, C_1-4haloalkyl and —C_0-4alkyl-O—C_1-4alkyl; R_aand R_bare H or C_1-4alkyl; m is optionally 0, 1, 2 or 3;

R₁₃is selected from H, halogen, C_1-4alkyl, C_1-4haloalkyl and C_3-6cycloalkylsulfonyl;

R₁₄is selected from H, C_1-4alkyl, C_1-4alkoxy and C_3-8cycloalkyl.

In some embodiments of the present disclosure, the Z₃is selected from CR₇, and R₇is defined as above.

In some embodiments of the present disclosure, the Z₄is selected from CR₉, and R₉is defined as above.

In some embodiments of the present disclosure, the M is selected from CR₁₀, and R₁₀is defined as above.

In some embodiments of the present disclosure, the R₁₀is selected from H, fluorine and methyl.

In some embodiments of the present disclosure, the R₁₀is selected from H.

In some embodiments of the present disclosure, the R₁₁is independently selected from H, methyl, —CH₂CH₂N(CH₃)₂and

[Image Omitted]

In some embodiments of the present disclosure, the R₁₂is selected from H, F, —OH, —NH₂, C_1-4alkyl, C_1-4fluoroalkyl, C_1-4alkoxy, —O—C_1-4alkyl-C_3-6cycloalkyl, —O—C_1-4alkyl-NR_aR_b, —C_1-4alkyl-O—C_0-4alkyl,

[Image Omitted]

and R_a, R_b, R_aband n are defined as above.

In some embodiments of the present disclosure, the R₁₂is selected from H, F, —OH, —NH₂, methyl, ethyl, isopropyl, —CH₂F, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CHF₂, —CH₂CH₂CF₃, —CH(CH₃)CF₃, —CH(CH₃)CH₂F, —C(CH₃)₂CH₂F,

[Image Omitted]

—OCH₃, —OCH(CH₃)CH₃,

[Image Omitted]

In some embodiments of the present disclosure, the R₁₂is selected from H, methyl, —CH₂CH₂F, —CH₂CH₂OCH₃, —CH₂CHF₂, —CH₂CF₃,

[Image Omitted]

—CH(CH₃)CH₂F, —CH₂CH₂F and

[Image Omitted]

In some embodiments of the present disclosure, the R₁₃is selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, trichloromethyl, cyclopropyl and

[Image Omitted]

In some embodiments of the present disclosure, the R₁₃is selected from H, fluorine, methyl, ethyl, difluoromethyl and

[Image Omitted]

In some embodiments of the present disclosure, the R₁₃is selected from H, fluorine, methyl, ethyl and difluoromethyl.

In some embodiments of the present disclosure, the R₁₃is selected from methyl.

In some embodiments of the present disclosure, the R₁₄is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy and cyclopropyl.

In some embodiments of the present disclosure, the R₁₄is selected from methyl, isopropyl, cyclopropyl and ethoxy.

In some embodiments of the present disclosure, the R₁₄is selected from methyl.

In some embodiments of the present disclosure, the R₁is selected from H, halogen, —CN, C_1-3alkyl, C_1-3alkoxy, C_1-3haloalkyl and C_1-3haloalkoxy.

In some embodiments of the present disclosure, the R₁is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy and 2,2,2-trifluoroethoxy.

In some embodiments of the present disclosure, the R₁is selected from H, methyl, methoxy, ethoxy and 2,2,2-trifluoroethoxy.

In some embodiments of the present disclosure, the R₁is selected from methoxy.

In some embodiments of the present disclosure, the R₂is selected from H, halogen, —CN, —OH, —NH₂, phosphonyl, sulfonyl, C_3-7cycloalkyl, 3-7-membered heterocycloalkyl, C_6-14spiro cyclyl, C_6-14fused cyclyl, C_6-14bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl, 6-14-membered fused heterocyclyl and

[Image Omitted]

wherein, the —NH₂, phosphonyl, sulfonyl, C_3-7cycloalkyl, 3-7-membered heterocycloalkyl, C_6-14spiro cyclyl, C_6-14fused ring, C_6-14bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl, 6-14-membered fused heterocyclyl and

[Image Omitted]

are optionally substituted by one or more R₁₂groups, and the R₁₂group is defined as above.

In some embodiments of the present disclosure, the R₂is selected from H, halogen, —CN, —OH, —NH₂, —NHR₁₂, —NR₁₂R₁₂,

[Image Omitted]

wherein the R₁₂, m and n are defined as above.

In some embodiments of the present disclosure, the R₂is selected from H, fluorine, chlorine, bromine, iodine, —NH₂,

[Image Omitted]

In some embodiments of the present disclosure, the R₂is selected from

[Image Omitted]

wherein the R₁₂and n are defined as above.

In some embodiments of the present disclosure, the R₂is selected from

[Image Omitted]

In some embodiments of the present disclosure, the R₂is selected from

[Image Omitted]

In some embodiments of the present disclosure, the R₃is selected from —CN, phenyl, 5-6-membered heteroaryl and

[Image Omitted]

and the phenyl, 5-6-membered heteroaryl and

[Image Omitted]

are optionally substituted by one or more R₁₃groups.

In some embodiments of the present disclosure, the R₃is selected from —CN, phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl and

[Image Omitted]

and the phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl and

[Image Omitted]

are optionally substituted by one or more R₁₃groups, wherein the R₁₃group is defined as above.

In some embodiments of the present disclosure, the R₃is selected from —CN,

[Image Omitted]

wherein the R₁₃is defined as above.

In some embodiments of the present disclosure, the R₃is selected from 5-6-membered heteroaryl optionally substituted by one or more R₁₃groups.

In some embodiments of the present disclosure, the R₃is selected from —CN,

[Image Omitted]

In some embodiments of the present disclosure, the R₃is selected from

[Image Omitted]

wherein the R₁₃is defined as above.

In some embodiments of the present disclosure, the R₃is selected from

[Image Omitted]

In some embodiments of the present disclosure, the R₄and R₅are each independently selected from H, F, Cl, Br, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl.

In some embodiments of the present disclosure, the R₄and R₅are each independently selected from H, F, Cl, Br, CN, methyl, ethyl, trifluoromethyl and cyclopropyl.

In some embodiments of the present disclosure, the R₄is selected from H, and R₅is selected from H, F, Cl, Br, CN, methyl, ethyl, trifluoromethyl and cyclopropyl.

In some embodiments of the present disclosure, the R₄is selected from H, and R₅is selected from Br.

In some embodiments of the present disclosure, the R₄and R₅form C_5-6alkyl or 5-6-membered heteroaryl.

In some embodiments of the present disclosure, the R₆is selected from

[Image Omitted]

In some embodiments of the present disclosure, the R₆is selected from

[Image Omitted]

In some embodiments of the present disclosure, the R₆is selected from

[Image Omitted]

In some embodiments of the present disclosure, R₇and R₈are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl or 5-7-membered heteroaryl, or R₈and R₉are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl or 5-7-membered heteroaryl.

In some embodiments of the present disclosure, R₇and R₈or R₈and R₉are independently cyclized to cyclobutane, cyclopentane, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydropyran ring, thiophene ring, imidazole ring, pyrazole ring, pyrrole ring, oxazole ring, thiazole ring, isoxazole ring, piperazine ring, isothiazole ring, benzene ring, pyridine ring, piperidine ring, pyrimidine ring, pyridazine ring or pyrazine ring.

In some embodiments of the present disclosure, R₇and R₈or R₈and R₉are independently cyclized to cyclobutane, pyridine ring or pyrazine ring.

In some embodiments of the present disclosure, R₇and R₈are independently cyclized to cyclobutane, pyridine ring or pyrazine ring.

In some embodiments of the present disclosure, R₇and R₈are independently cyclized to pyrazine ring.

In some embodiments of the present disclosure, R₉and R₈are independently cyclized to cyclobutane.

In some embodiments of the present disclosure, R₇, R₈and R₉are all H.

In some embodiments of the present disclosure, the compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein, X₁is independently selected from CR_cand N;

X₂is independently selected from —CR_cR_d—, —NR_c— and —O—;

Z₁and Z₂are each independently selected from —(CR_eR_f)_m(CR_eR_f)_n—;

the R_c, R_d, R_e, and R_fare each independently selected from H, halogen, —CN, —OH, —NR_aR_b, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, phenyl, —(CH₂)_mNR_aR_b, hydroxy-C_1-6alkyl-, —O(CH₂)_mNR_aR_b, C_3-8cycloalkylalkyl-, C_3-8heterocycloalkylalkyl-, C_3-8cycloalkyl-C_1-6alkoxy-, C_3-8heterocycloalkyl-C_1-6alkoxy-, C_1-6alkylcarbonyl-, C_3-8cycloalkylcarbonyl-, NR_aR_bCO—, C_1-6alkylcarbonylsulfonyl-, C_3-8cycloalkylsulfonyl-, C_1-6alkyl-O—C_1-6alkyl- and 6-14-membered spiro heterocyclyl, wherein the R_a, R_b, m and n are defined as above;

or, R_cand R_dtogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl;

or, R_eand R_ftogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl;

or, R_cand R_e, or R_cand R_f, or R_dand R_e, or R_dand R_ftogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl;

wherein, a ring formed by X₁, X₂, Z₁and Z₂and a ring further formed by substituent groups R_c, R_d, R_eand R_fthereof are optionally substituted by one or more R₁₂groups;

R₁, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₂and M are defined as above.

In some embodiments of the present disclosure, the compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein, the ring formed by X₁, X₂, Z₁and Z₂and the ring further formed by substituent groups thereof are optionally substituted by one or more R₁₂groups;

X₁, X₂, Z₁, Z₂, R₁, R₄, R₅, R₆, R₇, R₉, R₁₂, R₁₃and M are defined as above.

In some embodiments of the present disclosure, the compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein, ring A is selected from C_5-7cycloalkyl and 5-7-membered heterocycloalkyl;

a monocyclic ring, a bicyclic ring, a spiro ring, a fused ring formed by X₁and X₂and ring A are optionally substituted by one or more R₁₂groups;

X₁, X₂, R₁, R₅, R₆, m, n, M, R₁₂and R₁₃are defined as above.

In some embodiments of the present disclosure, the compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

X₁, X₂, R₁, R₅, R₆, m, n, M, R₁₂and R₁₃are defined as above.

In some embodiments of the present disclosure, the compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein X₁, X₂, R₁₂, m and n are defined as above.

In some embodiments of the present disclosure, the compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

In some embodiments of the present disclosure, the compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein R₁₂is defined as above.

The present disclosure further provides a compound represented by the following formula, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof or a isotope-labeled derivative thereof, which is selected from,

[Image Omitted]

[Image Omitted]

The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent and excipient. The pharmaceutical composition may be formulated for specific routes of administration, such as oral administration, parenteral administration, rectal administration, and the like. Oral administration, for example, a tablet, a capsule (including a sustained release or timed release prescription), a pill, a powder, a granule, an elixir, a tincture, a suspension (including a nano-suspension, a micro-suspension, a spray-dried dispersant), a syrup and an emulsion; sublingual administration; buccal administration; parenteral administration, for example, by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (for example, as a sterile injectable aqueous solution or non-aqueous solution or a mixed suspension); nasal administration, including administration to the nasal mucosa, for example, by inhalation spray; topical administration, for example, in the form of a cream or an ointment; or rectal administration, for example, in the form of a suppository. They can be administered alone, but they are usually administered together with a pharmaceutical carrier selected according to the selected route of administration and standard pharmaceutical practice.

“Pharmaceutically acceptable carrier” refers to a medium generally acceptable in the art for delivering a biologically active agent to animals, particularly mammals, including, for example, an adjuvant, an excipient or a vehicle, such as a diluent, a preservative, a filler, a flow regulator, a disintegrant, a wetting agent, an emulsifier, a suspending agent, a sweetener, a flavor, a fragrance, an antibacterial agent, an antifungal agent, a lubricants agent and a dispersant, according to the mode of administration and the nature of dosage forms. The pharmaceutically acceptable carrier is formulated according to a large number of factors within the purview of those of ordinary skill in the art, including, but not limited to, the type and nature of the active agent formulated, the subjects to which the composition containing the agent is to be administered, the expected route of administration of the composition, and the target therapeutic indication. The pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. In addition to the active agent, such carriers include many different ingredients and additives, and such additional ingredients included in prescriptions for a variety of reasons (e.g., stabilizing the active agent and an adhesive, etc.) are well known to those of ordinary skill in the art.

As a general guideline, when used for the indicated effects, the daily oral dosage of various active ingredients is in the range of about 0.001- about 5000 mg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredients per day; the most preferred dose intravenously during a constant rate infusion is in the range of about 0.01 to about 10 mg/kg/min. The compounds of the present disclosure may be administered in a single daily dose, or the total daily dose may be administered in divided doses of 2, 3 or 4 times per day.

It is certain that administration regimens for the compounds of the present disclosure may vary depending on known factors, such as the pharmacodynamic characteristics of a specific drug and its mode and route of administration, the species, age, sex, health, medical condition and weight of the recipient, nature and extent of symptoms, types of coexisting treatments, frequency of treatments, routes of administration, renal and hepatic function of the patient, and desired effects. A therapeutically effective dose of the compound, a pharmaceutical composition or a combination thereof depends on the species, weight, age and individual condition of the subject, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill may readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.

The present disclosure also provides use of the above compound or the pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the manufacture of a medicament for the treatment of cancer.

Epidermal growth factor receptor (EGFR) is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells and other cells. The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, which can account for 40% to 50%. Therefore, the compounds of the present disclosure can be used to treat cancers caused by high expression of EGFR. The above cancers comprise lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, mesothelioma, multiple myeloma and melanoma.

In some embodiments of the present disclosure, the above cancer is lung cancer.

The present disclosure also provides a method for treating cancer, comprising administering a therapeutically effective amount of the above compound or the pharmaceutically acceptable salt thereof or the above pharmaceutical composition to a patient. The above cancers comprise lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, mesothelioma, multiple myeloma and melanoma.

In some embodiments of the present disclosure, the above cancer is lung cancer.

The present disclosure also provides an intermediate compound represented by formula (V), and the intermediate compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is used in the manufacture of the above compound,

[Image Omitted]

wherein R₁, R₂, R₃and M are defined as above in formula (I).

In some embodiments of the present disclosure, the compound represented by formula (V) is selected from,

[Image Omitted]

wherein, X₁, X₂, R₁, R₁₃, M, ring A, m and n are defined in the above formulas (IIIa)-(IIIe).

In some embodiments of the present disclosure, the compound represented by formula (V) is selected from,

[Image Omitted]

wherein X₁, X₂, R₁₂and n are defined in formula (II).

In some embodiments of the present disclosure, the compound represented by formula (V) is selected from,

[Image Omitted]

The present disclosure provides a compound represented by formula (I-A), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof or an isotope-labeled derivative thereof,

[Image Omitted]

wherein,

R₁is selected from H, halogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-6cycloalkyl, 3-6-membered heterocycloalkyl, C_3-6cycloalkyloxy, 3-6-membered heterocycloalkyloxy and C_2-6alkenyloxy;

M is selected from N or CR₁₀;

R₁₀and R₁may form a 5-8-membered heterocycloalkyl, and the 5-8-membered heterocycloalkyl is optionally substituted by one or more R₁₁groups;

R₂is selected from H, halogen, —CN, —OH, —NH₂, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, C_3-6heterocycloalkenyl and phenyl; wherein, the —NH₂, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, C_3-6heterocycloalkenyl and phenyl are optionally substituted by one or more R₁₂groups;

R₃is selected from C_6-10aryl, 5-12-membered heteroaryl, 3-8-membered heterocycloalkyl, C_3-8cycloalkyl and C_3-6cycloalkenyl, wherein the C_6-10aryl, 5-12-membered heteroaryl, 3-8-membered heterocycloalkyl, C_3-8cycloalkyl and C_3-6cycloalkenyl are optionally substituted by one or more R₁₃groups;

R₄and R₅are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl;

R₆is selected from amino, amido, sulfonyl, phosphonyl, sulfonylamino and aminosulfonyl, wherein the amino, amido, sulfonyl, phosphonyl, sulfonylamino and aminosulfonyl are optionally substituted by one or more R₁₄groups;

R₇, R₈and R₉are each independently selected from H, halogen, —CN, —OH, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3-6-membered heterocycloalkyl and 5-7-membered heteroaryl;

or, R₇and R₈are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl, or 5-7-membered heteroaryl;

or, R₈and R₉are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl, or 5-7-membered heteroaryl;

R₁₀, R₁₁, R₁₂, R₁₃and R₁₄are each independently selected from H, halogen, —CN, —OH, —NH₂, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C_1-6alkyl, C_3-8cycloalkylalkyl, C_3-8cycloalkyl-C_1-6alkoxy, C_1-6alkylsulfonyl, C_3-6cycloalkylsulfonyl, aminocarbonyl, C_3-8cycloalkylcarbonyl, C_1-6alkoxy-C_1-6alkyl, C_3-6cycloalkenyl, phenyl, —(CH₂)_mNR_aR_band —(CH₂)_mO(CH₂)_nCH₃; wherein R_aand R_bare H, C_1-6alkyl or C_1-6alkoxy, or R_aand R_btogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl; wherein m and n are independently optionally 0, 1, 2 or 3, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl are optionally substituted by halogen, —OH, —NH₂, C_1-6alkyl, C_1-6alkoxy and C_1-6haloalkyl.

In some embodiments of the present disclosure, the R₃is selected from C_6-10aryl, 5-12-membered heteroaryl and C_3-6cycloalkenyl.

In some embodiments of the present disclosure, the R₁is selected from H, halogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-6cycloalkyl, 3-6-membered heterocycloalkyl, C_3-6cycloalkyloxy, 3-6-membered heterocycloalkyloxy and C_2-6alkenyloxy;

M is selected from N or CR₁₀;

R₁₀and R₁may form a 5-8-membered heterocycloalkyl, and the 5-8-membered heterocycloalkyl is optionally substituted by one or more R₁₁groups;

R₂is selected from H, halogen, —CN, —OH, —NH₂, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, C_3-6heterocycloalkenyl and phenyl; wherein, the —NH₂, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, C_3-6heterocycloalkenyl and phenyl are optionally substituted by one or more R₁₂groups;

R₃is selected from C_6-10aryl, 5-12-membered heteroaryl and C_3-6cycloalkenyl; wherein the C_6-10aryl, 5-12-membered heteroaryl and C_3-6cycloalkenyl are optionally substituted by one or more R₁₃groups;

R₄and R₅are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl;

R₆is selected from amino, amido, sulfonyl, phosphonyl, sulfonylamino and aminosulfonyl, wherein the amino, amido, sulfonyl, phosphonyl, sulfonylamino and aminosulfonyl are optionally substituted by one or more R₁₄groups;

R₇, R₈and R₉are each independently selected from H, halogen, —CN, —OH, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3-6-membered heterocycloalkyl and 5-7-membered heteroaryl;

or, R₇and R₈are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl, or 5-7-membered heteroaryl;

or, R₈and R₉are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl, or 5-7-membered heteroaryl;

R₁₀and R₁₁are each independently selected from H, halogen, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl and C_1-6haloalkoxy;

R₁₂is selected from H, halogen, —CN, —OH, —NH₂, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C_1-6alkyl, C_3-8cycloalkylalkyl, C_3-8cycloalkyl-C_1-6alkoxy, C_1-6alkylsulfonyl, C_3-6cycloalkylsulfonyl, aminocarbonyl, C_3-8cycloalkylcarbonyl, C_1-6alkoxy-C_1-6alkyl, C_3-6cycloalkenyl, phenyl, —(CH₂)_mNR_aR_band —(CH₂)_mO(CH₂)_nCH₃; wherein R_aand R_bare H, C_1-6alkyl or C_1-6alkoxy, or R_aand R_btogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl; wherein m and n are independently optionally 0, 1, 2 or 3, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl are optionally substituted by halogen, —OH, —NH₂, C_1-6alkyl, C_1-6alkoxy and C_1-6haloalkyl;

R₁₃is selected from H, halogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, hydroxy-C_1-6alkyl, C_1-6haloalkoxy, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl;

R₁₄is selected from H, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl.

In some embodiments of the present disclosure, the R₁is selected from H, halogen, —CN, C_1-3alkyl, C_1-3alkoxy, C_1-3haloalkyl and C_1-3haloalkoxy.

In some embodiments of the present disclosure, the R₁is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy and 2,2,2-trifluoroethoxy.

In some embodiments of the present disclosure, the R₂is selected from H, halogen, —NH₂, C_3-7cycloalkyl, 3-7-membered heterocycloalkyl, C_6-14spiro cyclyl, C_6-14fused cyclyl, C_6-14bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl and 6-14-membered fused heterocyclyl; wherein, the —NH₂, C_3-7cycloalkyl, 3-7-membered heterocycloalkyl, C_6-14Spiro cyclyl, C_6-14fused cyclyl, C_6-14bridged cyclyl, 6-14-membered Spiro heterocyclyl, 6-14-membered bridged heterocyclyl and 6-14-membered fused heterocyclyl are optionally substituted by one or more R₁₂groups, and the R₁₂group is defined as above.

In some embodiments of the present disclosure, the R₂is selected from H, halogen, —CN, —OH, —NH₂, —NHR₁₂, —NR₁₂R₁₂,

[Image Omitted]

wherein the R₁₂, m and n are defined as above.

In some embodiments of the present disclosure, the R₂is selected from H, fluorine, chlorine, bromine, iodine, —NH₂,

[Image Omitted]

In some embodiments of the present disclosure, the R₂is selected from

[Image Omitted]

In some embodiments of the present disclosure, the R₃is selected from phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl and cyclohexyl, and the phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally substituted by one or more R₁₃groups, wherein the R₁₃group is defined as above.

In some embodiments of the present disclosure, the R₃is selected from

[Image Omitted]

wherein the R₁₃is defined as above.

In some embodiments of the present disclosure, the R₃is selected from

[Image Omitted]

wherein the R₁₃is defined as above.

In some embodiments of the present disclosure, the R₄and R₅are each independently selected from H, F, Cl, Br, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl.

In some embodiments of the present disclosure, the R₆is selected from

[Image Omitted]

In some embodiments of the present disclosure, the R₆is selected from

[Image Omitted]

In some embodiments of the present disclosure, R₇and R₈are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl or 5-7-membered heteroaryl, or R₈and R₉are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl or 5-7-membered heteroaryl.

In some embodiments of the present disclosure, R₇and R₈or R₈and R₉are independently cyclized to cyclobutane, cyclopentane, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydropyran ring, thiophene ring, imidazole ring, pyrazole ring, pyrrole ring, oxazole ring, thiazole ring, isoxazole ring, piperazine ring, isothiazole ring, benzene ring, pyridine ring, piperidine ring, pyrimidine ring, pyridazine ring or pyrazine ring.

In some embodiments of the present disclosure, R₇and R₈or R₈and R₉are independently cyclized to cyclobutane, pyridine ring or pyrazine ring.

In some embodiments of the present disclosure, the above compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein, X₁is independently selected from CR_cand N;

X₂is independently selected from —CR_cR_d—, —NR_c— and —O—;

Z₁and Z₂are each independently selected from —(CR_eR_f)_m(CR_eR_f)_n—;

the R_c, R_d, R_e, and R_fare each independently selected from H, halogen, —CN, —OH, —NH₂, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, phenyl, —(CH₂)_mNR_aR_band —(CH₂)_mO(CH₂)_nCH₃; wherein the R_a, R_b, m and n are defined as above;

or, R_cand R_dtogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl;

or, R_eand R_ftogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl;

or, R_cand R_e, or R_cand R_f, or R_dand R_e, or R_dand R_ftogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl;

wherein, a ring formed by X₁, X₂, Z₁and Z₂and a ring further formed by substituent groups R_c, R_d, R_eand R_fthereof are optionally substituted by one or more R₁₂groups;

R₁, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₂and M are defined as above.

In some embodiments of the present disclosure, the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein, the ring formed by X₁, X₂, Z₁and Z₂and the ring further formed by substituent groups thereof are optionally substituted by one or more R₁₂groups;

X₁, X₂, Z₁, Z₂, R₁, R₄, R₅, R₆, R₇, R₉, R₁₂, R₁₃and M are defined as above.

In some embodiments of the present disclosure, the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein, ring A is selected from C_5-7cycloalkyl and 5-7-membered heterocycloalkyl;

a monocyclic ring, a bicyclic ring, a spiro ring, a fused ring formed by X₁and X₂and ring A are optionally substituted by one or more R₁₂groups;

X₁, X₂, R₁, R₅, R₆, m, n, M, R₁₂and R₁₃are defined as above.

In some embodiments of the present disclosure, the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein X₁, X₂, R₁₂and n are defined as above.

The present disclosure further provides a compound represented by the following formula, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof or an isotope-labeled derivative thereof, which is selected from,

Compound
Structural formula

68

[Image Omitted]

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

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106

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The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent and excipient. The pharmaceutical composition may be formulated for specific routes of administration, such as oral administration, parenteral administration, rectal administration, and the like. Oral administration, for example, a tablet, a capsule (including a sustained release or timed release prescription), a pill, a powder, a granule, an elixir, a tincture, a suspension (including a nano-suspension, a micro-suspension, a spray-dried dispersant), a syrup and an emulsion; sublingual administration; buccal administration; parenteral administration, for example, by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (for example, as a sterile injectable aqueous solution or non-aqueous solution or a mixed suspension); nasal administration, including administration to the nasal mucosa, for example, by inhalation spray; topical administration, for example, in the form of a cream or an ointment; or rectal administration, for example, in the form of a suppository. They can be administered alone, but they are usually administered together with a pharmaceutical carrier selected according to the selected route of administration and standard pharmaceutical practice.

“Pharmaceutically acceptable carrier” refers to a medium generally acceptable in the art for delivering a biologically active agent to animals, particularly mammals, including, for example, an adjuvant, an excipient or a vehicle, such as a diluent, a preservative, a filler, a flow regulator, a disintegrant, a wetting agent, an emulsifier, a suspending agent, a sweetener, a flavor, a fragrance, an antibacterial agent, an antifungal agent, a lubricants agent and a dispersant, according to the mode of administration and the nature of dosage forms. The pharmaceutically acceptable carrier is formulated according to a large number of factors within the purview of those of ordinary skill in the art, including, but not limited to, the type and nature of the active agent formulated, the subjects to which the composition containing the agent is to be administered, the expected route of administration of the composition, and the target therapeutic indication. The pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. In addition to the active agent, such carriers include many different ingredients and additives, and such additional ingredients included in prescriptions for a variety of reasons (e.g., stabilizing the active agent and an adhesive, etc.) are well known to those of ordinary skill in the art.

As a general guideline, when used for the indicated effects, the daily oral dose of various active ingredients is in the range of about 0.001- about 5000 mg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredients per day; the most preferred dose intravenously during a constant rate infusion is in the range of about 0.01 to about 10 mg/kg/min. The compounds of the present disclosure may be administered in a single daily dose, or the total daily dose may be administered in divided doses of 2, 3 or 4 times per day.

It is certain that administration regimens for the compounds of the present disclosure may vary depending on known factors, such as the pharmacodynamic characteristics of a specific drug and its mode and route of administration, the species, age, sex, health, medical condition and weight of the recipient, nature and extent of symptoms, types of coexisting treatments, frequency of treatments, routes of administration, renal and hepatic function of the patient, and desired effects. A therapeutically effective dose of the compound, a pharmaceutical composition or a combination thereof depends on the species, weight, age and individual condition of the subject, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill may readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.

The present disclosure also provides use of the above compound or the pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the manufacture of a medicament for the treatment of cancer.

Epidermal growth factor receptor (EGFR) is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells and other cells. The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, which can account for 40% to 50%. Therefore, the compounds of the present disclosure can be used to treat cancers caused by high expression of EGFR. The above cancers comprise lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, mesothelioma, multiple myeloma and melanoma.

In some embodiments of the present disclosure, the above cancer is lung cancer.

The present disclosure also provides an intermediate compound represented by formula (V), and the intermediate compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is used in the manufacture of the above compound.

[Image Omitted]

wherein, R₁, R₂, R₃and M are defined in formula (I).

In some embodiments of the present disclosure, the compound represented by formula (V) is selected from,

[Image Omitted]

wherein, X₁, X₂, R₁, R₁₃, M, ring A, m and n are defined in the above formulas (IIIa)-(IIIe).

In some embodiments of the present disclosure, the compound represented by formula (V) is selected from,

[Image Omitted]

wherein X₁, X₂, R₁₂and n are defined in formula (II).

The present disclosure provides a compound represented by formula (I), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof or an isotope-labeled derivative thereof,

[Image Omitted]

wherein,

R₁is selected from H, halogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-6cycloalkyl, 3-6-membered heterocycloalkyl, C_3-6cycloalkyloxy, 3-6-membered heterocycloalkyloxy and C_2-6alkenyloxy;

M is selected from N or CR₁₀;

R₁₀and R₁may form a 5-8-membered heterocycloalkyl, and the 5-8-membered heterocycloalkyl is optionally substituted by one or more R₁₁groups;

R₂is selected from H, halogen, —CN, —OH, —NH₂, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, C_3-6heterocycloalkenyl and phenyl; wherein, the —OH, —NH₂, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, C_3-6heterocycloalkenyl and phenyl are optionally substituted by one or more R₁₂groups;

R₃is selected from C_6-10aryl, 5-12-membered heteroaryl, 3-8-membered heterocycloalkyl, C_4-8cycloalkyl and C_3-6cycloalkenyl, wherein the C_6-10aryl, 5-12-membered heteroaryl, 3-8-membered heterocycloalkyl, C_3-8cycloalkyl and C_3-6cycloalkenyl are optionally substituted by one or more R₁₃groups;

R₄and R₅are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl;

or, R₄and R₅are cyclized to 4-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 4-6-membered aryl or 4-6-membered heteroaryl;

R₆is selected from amino, amido, sulfonyl, thiophosphonyl, phosphonyl, sulfonylamino and aminosulfonyl, wherein the amino, amido, sulfonyl, phosphonyl, sulfonylamino and aminosulfonyl are optionally substituted by one or more R₁₄groups;

R₇, R₈and R₉are each independently selected from H, halogen, —CN, —OH, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3-6-membered heterocycloalkyl and 5-7-membered heteroaryl;

or, R₇and R₈are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl, or 5-7-membered heteroaryl;

or, R₈and R₉are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl, or 5-7-membered heteroaryl;

R₁₀and R₁₁are each independently selected from H, halogen, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl and C_1-6haloalkoxy;

R₁₂is selected from H, halogen, —CN, —OH, —NH₂, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C_1-6alkyl, C_3-8cycloalkylalkyl-, C_3-8heterocycloalkylalkyl-, C_3-8cycloalkyl-C_1-6alkoxy-, C_1-6alkylsulfonyl, C_3-6cycloalkylsulfonyl, NR_aR_bCO—, C_1-6alkylcarbonyl, C_3-8cycloalkylcarbonyl, C_1-6alkoxy-C_1-6alkyl-, C_3-6cycloalkenyl, phenyl, NR_aR_bS(O)₂—, —(CH₂)_mNR_aR_b, —(CH₂)_mO(CH₂)_nCH₃and —O(CH₂)_mNR_aR_b; wherein the R_aand R_bare H, C_1-6alkyl or C_1-6alkoxy, or R_aand R_btogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl; wherein m and n are independently optionally 0, 1, 2 or 3, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl are optionally substituted by halogen, —OH, —NH₂, —CN, C_1-6alkyl, C_1-6alkoxy and C_1-6haloalkyl;

R₁₃is selected from H, halogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl;

R₁₄is selected from H, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-8cycloalkyl and 3-8-membered heterocycloalkyl.

In some embodiments of the present disclosure, the R₃is selected from C_6-10aryl, 5-12-membered heteroaryl and C_3-6cycloalkenyl.

In some embodiments of the present disclosure, the R₁₀and R₁₁are each independently selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy and 2,2,2-trifluoroethoxy.

In some embodiments of the present disclosure, the R₁₃is selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, trichloromethyl and cyclopropyl.

In some embodiments of the present disclosure, the R₁₃is selected from H, fluorine, methyl, ethyl and difluoromethyl.

In some embodiments of the present disclosure, the R₁₄is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy and cyclopropyl.

In some embodiments of the present disclosure, the R₁is selected from H, halogen, —CN, C_1-3alkyl, C_1-3alkoxy, C_1-3haloalkyl and C_1-3haloalkoxy.

In some embodiments of the present disclosure, the R₁is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy and 2,2,2-trifluoroethoxy.

In some embodiments of the present disclosure, the R₂is selected from H, halogen, —CN, —OH, —NH₂, C_3-7cycloalkyl, 3-7-membered heterocycloalkyl, C_6-14spiro cyclyl, C_6-14fused cyclyl, C_6-14bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl and 6-14-membered fused heterocyclyl; wherein, the —NH₂, C_3-7cycloalkyl, 3-7-membered heterocycloalkyl, C_6-14spiro cyclyl, C_6-14fused cyclyl, C_6-14bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl and 6-14-membered fused heterocyclyl are optionally substituted by one or more R₁₂groups, and the R₁₂group is defined as above.

In some embodiments of the present disclosure, the R₂is selected from H, halogen, —CN, —OH, —NH₂, —NHR₁₂, —NR₁₂R₁₂,

[Image Omitted]

wherein the R₁₂, m and n are defined as above.

In some embodiments of the present disclosure, the R₂is selected from H, fluorine, chlorine, bromine, iodine, —NH₂,

[Image Omitted]

In some embodiments of the present disclosure, the R₂is selected from

[Image Omitted]

In some embodiments of the present disclosure, the R₃is selected from phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl and cyclohexyl, and the phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally substituted by one or more R₁₃groups, wherein the R₁₃group is defined as above.

In some embodiments of the present disclosure, the R₃is selected from

[Image Omitted]

wherein the R₁₃is defined as above.

In some embodiments of the present disclosure, the R₃is selected from

[Image Omitted]

wherein the R₁₃is defined as above.

In some embodiments of the present disclosure, the R₄and R₅are each independently selected from H, F, Cl, Br, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl.

In some embodiments of the present disclosure, the R₆is selected from

[Image Omitted]

In some embodiments of the present disclosure, the R₆is selected from

[Image Omitted]

In some embodiments of the present disclosure, R₇and R₈are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl or 5-7-membered heteroaryl, or R₈and R₉are cyclized to C_4-6cycloalkyl, 4-6-membered heterocycloalkyl, C_5-6aryl or 5-7-membered heteroaryl.

In some embodiments of the present disclosure, R₇and R₈or R₈and R₉are independently cyclized to cyclobutane, cyclopentane, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydropyran ring, thiophene ring, imidazole ring, pyrazole ring, pyrrole ring, oxazole ring, thiazole ring, isoxazole ring, piperazine ring, isothiazole ring, benzene ring, pyridine ring, piperidine ring, pyrimidine ring, pyridazine ring or pyrazine ring.

In some embodiments of the present disclosure, R₇and R₈or R₈and R₉are independently cyclized to cyclobutane, pyridine ring or pyrazine ring.

In some embodiments of the present disclosure, the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein, X₁is independently selected from CR_cand N;

X₂is independently selected from —CR_cR_d—, —NR_c— and —O—;

Z₁and Z₂are each independently selected from —(CR_eR_f)_m(CR_eR_f)_n—;

the R_c, R_d, R_e, and R_fare each independently selected from H, halogen, —CN, —OH, —NR_aR_b, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, 3-14-membered heterocycloalkyl, C_3-6cycloalkenyl, phenyl, —(CH₂)_mNR_aR_b, hydroxy-C_1-6alkyl-O(CH₂)_mNR_aR_b, C_3-8cycloalkylalkyl-, C_3-8heterocycloalkylalkyl-, C_3-8cycloalkyl-C_1-6alkoxy-, C_3-8heterocycloalkyl-C_1-6alkoxy-, C_1-6alkylcarbonyl-, C_3-8cycloalkylcarbonyl-, NR_aR_bCO—, C_1-6alkylcarbonylsulfonyl- and C_3-8cycloalkylsulfonyl-, wherein the R_a, R_b, m and n are defined as above;

or, R_cand R_dtogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl;

or, R_eand R_ftogether form C_3-8cycloalkyl or 3-8-membered heterocycloalkyl;

or, R_cand R_e, or R_cand R_f, or R_dand R_e, or R_dand R_ftogether form C_3-8-membered cycloalkyl or 3-8-membered heterocycloalkyl;

wherein, a ring formed by X₁, X₂, Z₁and Z₂and a ring further formed by substituent groups R_c, R_d, R_eand R_fthereof are optionally substituted by one or more R₁₂groups;

R₁, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₂and M are defined as above.

In some embodiments of the present disclosure, the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein, the ring formed by X₁, X₂, Z₁and Z₂and the ring further formed by substituent groups thereof are optionally substituted by one or more R₁₂groups;

X₁, X₂, Z₁, Z₂, R₁, R₄, R₅, R₆, R₇, R₉, R₁₂, R₁₃and M are defined as above.

In some embodiments of the present disclosure, the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein, ring A is selected from C_5-7cycloalkyl and 5-7-membered heterocycloalkyl;

a monocyclic ring, a bicyclic ring, a spiro ring, a fused ring formed by X₁and X₂and ring A are optionally substituted by one or more R₁₂groups;

X₁, X₂, R₁, R₅, R₆, m, n, M, R₁₂and R₁₃are defined as above.

In some embodiments of the present disclosure, the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein X₁, X₂, R₁₂, m and n are defined as above.

In some embodiments of the present disclosure, the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof is selected from,

[Image Omitted]

wherein R₁₂is defined as above.

The present disclosure further provides a compound represented by the following formula, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof or an isotope-labeled derivative thereof, which is selected from,

Com-

pound
Structural formula

1

[Image Omitted]

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