A CLASS OF FUSED RING COMPOUNDS, AND PREPARATION AND USE THEREOF

Abstract

The present invention belongs to the technical field of medicines, and relates to a class of fused ring compound, and the preparation and use thereof. Test results show that the compounds can significantly inhibit the ATM kinase activity, have a good selectivity for the ATM target, and have the pharmaceutical use of treating cancer.

##STR00001##

Claims

1. A compound as represented by formula (I) or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, having the following structure: ##STR00314## wherein Y is ##STR00315## X.sub.1 is selected from the group consisting of a bond, hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, O, S, C(O), C(O)O, OC(O), N(R).sub.1xC(O), C(O)N(R.sub.1x), and N(R.sub.1x); R.sub.1x is selected from the group consisting of hydrogen and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of a group to be substituted is independently substituted by a substituent selected from the group consisting of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; when X.sub.1 is hydrogen, deuterium, halogen, hydroxyl, amino, nitro, or cyano, R.sub.1, X.sub.2, R.sub.2, and R.sub.3 are absent; R.sub.1 is absent or selected from the group consisting of a bond, hydrogen, deuterium, and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, 4- to 12-membered bridged ring group, 4- to 12-membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, condensed ring group, and heterocondensed ring group; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of a group to be substituted is independently substituted by R.sub.1a; R.sub.1a is, for each presence, independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, R.sub.1b, OR.sub.1b, SR.sub.1b, S(O)R.sub.1b, SO.sub.2(R.sub.1b), C(O)R.sub.1b, C(O)OR.sub.1b, OC(O)R.sub.1b, NH(R.sub.1b), N(R.sub.1b)(R.sub.1c), C(O)NH(R.sub.1b), C(O)N(R.sub.1b)(R.sub.1c), NHC(O)(R.sub.1b), N(R.sub.1b)C(O)(R.sub.1c), S(O)NH(R.sub.1b), S(O)N(R.sub.1b)(R.sub.1c), SO.sub.2NH(R.sub.1b), SO.sub.2N(R.sub.1b)(R.sub.1c), NHS(O)(R.sub.1b), N(R.sub.1b)S(O)(R.sub.1c), NHSO.sub.2(R.sub.1b), and N(R.sub.1b)SO.sub.2(R.sub.1c); R.sub.1b and R.sub.1c are, for each presence, independently selected from the group consisting of hydrogen, deuterium, and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.1b and R.sub.1c are linked to the same nitrogen atom, R.sub.1b and R.sub.1c, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl which is optionally substituted by one or more of deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; when R.sub.1 is hydrogen or deuterium, X.sub.2, R.sub.2, and R.sub.3 are absent; X.sub.2 is absent or selected from the group consisting of a bond, hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, O, S, P, C(O), C(S), C(?NR.sub.2x), CH?N, C(O)O, C(O)C(O), OC(O), OC(S), OSO.sub.2, OP(O), N?CH, C(O)N(R.sub.2x), N(R.sub.2x)C(O), N(R.sub.2x), S(O), SO.sub.2, S(O)N(R.sub.2x), SO.sub.2N(R.sub.2x), and P(O); R.sub.2x is selected from the group consisting of hydrogen, deuterium, and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of a group to be substituted is independently substituted by a substituent selected from the group consisting of deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; when X.sub.2 is hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, or cyano, R.sub.2 and R.sub.3 are absent; R.sub.2 is absent or selected from the group consisting of a bond, hydrogen, deuterium, and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, 3- to 10-membered heterocycloalkyl, 5- to 12-membered heteroaryl, 4- to 12-membered bridged ring group, 4- to 12-membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, condensed ring group, and heterocondensed ring group; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of a group to be substituted is independently substituted by R.sub.2a; R.sub.2a is, for each presence, independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, R.sub.2b, OR.sub.2b, SR.sub.2b, S(O)(R.sub.2b), SO.sub.2(R.sub.2b), C(O)R.sub.2b, C(O)OR.sub.2b, OC(O)R.sub.2b, NH(R.sub.2b), N(R.sub.2b)(R.sub.2c), C(O)NH(R.sub.2b), C(O)N(R.sub.2b)(R.sub.2c), NHC(O)(R.sub.2b), N(R.sub.2b)C(O)(R.sub.2c), S(O)NH(R.sub.2b), S(O)N(R.sub.2b)(R.sub.2c), SO.sub.2NH(R.sub.2b), SO.sub.2N(R.sub.2b)(R.sub.2c), NHS(O)(R.sub.2b), N(R.sub.2b)S(O)(R.sub.2c), NHSO.sub.2(R.sub.2b), and N(R.sub.2b)SO.sub.2(R.sub.2c); R.sub.2b and R.sub.2c are, for each presence, independently selected from the group consisting of hydrogen, any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.2b and R.sub.2e are linked to the same nitrogen atom, R.sub.2b and R.sub.2c, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl which is optionally substituted by one or more of deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; when R.sub.2 is hydrogen or deuterium, R.sub.3 is absent; R.sub.3 is absent or selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, R.sub.3b, OR.sub.3b, SR.sub.3b, S(O)(R.sub.3b), SO.sub.2(R.sub.3b), C(O)R.sub.3b, C(O)OR.sub.3b, OC(O)R.sub.3b, NH(R.sub.3b), N(R.sub.3b)(R.sub.3c), C(O)NH(R.sub.3b), C(O)N(R.sub.3b)(R.sub.3c), NHC(O)(R.sub.3b), N(R.sub.3b)C(O)(R.sub.3c), S(O)NH(R.sub.3b), S(O)N(R.sub.3b)(R.sub.3c), SO.sub.2NH(R.sub.3b), SO.sub.2N(R.sub.3b)(R.sub.3c), NHS(O)(R.sub.3b), N(R.sub.3b)S(O)(R.sub.3c), NHSO.sub.2(R.sub.3b), and N(R.sub.3b)SO.sub.2(R.sub.3c); R.sub.3b and R.sub.3, are, for each presence, independently selected from the group consisting of hydrogen, deuterium, and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.3b and R.sub.3c are linked to the same nitrogen atom, R.sub.3b and R.sub.3c, together with the nitrogen atom linked thereto, form an optionally substituted group selected from 3- to 20-membered heterocyclyl and 5- to 12-membered heteroaryl; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of a group to be substituted is independently substituted by R.sub.3d; R.sub.3d is, for each presence, independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, R.sub.3e, OR.sub.3e, SR.sub.3e, S(O)(R.sub.3e), SO.sub.2(R.sub.3e), C(O)R.sub.3e, C(O)OR.sub.3e, OC(O)R.sub.3e, NH(R.sub.3e), N(R.sub.3e)(R.sub.3H), C(O)NH(R.sub.3e), C(O)N(R.sub.3e)(R.sub.3f), NHC(O)(R.sub.3e), N(R.sub.3e)C(O)(R.sub.3f), S(O)NH(R.sub.3e), S(O)N(R.sub.3e)(R.sub.3f), SO.sub.2NH(R.sub.3e), SO.sub.2N(R.sub.3e)(R.sub.3f), NHS(O)(R.sub.3e), N(R.sub.3e)S(O)(R.sub.3f), NHSO.sub.2(R.sub.3e), and N(R.sub.3e)SO.sub.2(R.sub.3H); R.sub.3e and R.sub.3f are, for each presence, independently selected from the group consisting of hydrogen, deuterium, and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.3e and R.sub.3f are linked to the same nitrogen atom, R.sub.3e and R.sub.3f, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl which is optionally substituted by one or more of deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; R.sub.4 is, for each presence, independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, amino, cyano, hydroxyl, carboxyl, mercapto, and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 alkthio which is optionally substituted by one or more of deuterium, halogen, hydroxyl, and amino; h is equal to 1 or 2; R.sub.5 is, for each presence, independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkthio, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, 3- to 10-membered heterocycloalkyl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of deuterium, halogen, hydroxyl, amino, and cyano; L is C(R.sub.L) or N; R.sub.L is, for each presence, independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, amino, cyano, hydroxyl, carboxyl, mercapto, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 alkthio; A is ##STR00316## wherein represents a single bond or a double bond; Q.sub.1 is linked to W; t.sub.1, t.sub.2, t.sub.3, t.sub.4, t.sub.5, and t.sub.6 are independently equal to 0 or 1; n.sub.1 and n.sub.2 are independently equal to 0, 1, or 2, and n.sub.1 and n.sub.2 are not simultaneously equal to 0, wherein n.sub.1 represents sequentially linked chain of Q.sub.1 with n.sub.1 repeat units, and n.sub.2 represents sequentially linked chain of Q.sub.2 with n.sub.2 repeat units; two adjacent Q.sub.1 are linked by a single bond or a double bond; two adjacent Q.sub.2 are linked by a single bond or a double bond; W, Q.sub.1, and Q.sub.2 are independently selected from the group consisting of C, O, N, and S; Q.sub.3 is C; when one of the bonds linked to Q.sub.3 is a double bond, R.sub.10 or R.sub.11 is absent; R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, R.sub.6a, OR.sub.6a, SR.sub.6a, S(O)(R.sub.6a), SO.sub.2(R.sub.6a), C(O)R.sub.6a, C(O)OR.sub.6a, OC(O)R.sub.6a, NH(R.sub.6a), N(R.sub.6a)(R.sub.6b), C(O)NH(R.sub.6a), C(O)N(R.sub.6a)(R.sub.6b), NHC(O)(R.sub.6a), N(R.sub.6a)C(O)(R.sub.6b), S(O)NH(R.sub.6a), S(O)N(R.sub.6a)(R.sub.6b), SO.sub.2NH(R.sub.6a), SO.sub.2N(R.sub.6a)(R.sub.6b), NHS(O)(R.sub.6a), N(R.sub.6a)S(O)(R.sub.6b), NHSO.sub.2(R.sub.6a), and N(R.sub.6a)SO.sub.2(R.sub.6b); or any two substituents linked to the same atom among R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 form ?O, ?NR.sub.6a, or ?CHR.sub.6a; or any two adjacent atoms among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, form C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, 4- to 12-membered bridged ring group, 4- to 12-membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, condensed ring group, or heterocondensed ring group which is optionally substituted by R.sub.6e; or any one atom among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, forms C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, monospiro ring group, or heteromonospiro ring group which is optionally substituted by R.sub.6c; R.sub.6a and R.sub.6b are, for each presence, independently selected from the group consisting of hydrogen, deuterium, and any one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, 4- to 12-membered bridged ring group, 4- to 12-membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, condensed ring group, and heterocondensed ring group which is optionally substituted by R.sub.6c; or when R.sub.6a and R.sub.6b are linked to the same nitrogen atom, R.sub.6a and R.sub.6b, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocyclyl or 5- to 12-membered heteroaryl which is optionally substituted by R.sub.6c; R.sub.6e is, for each presence, independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, azido, oxo, R.sub.6d, OR.sub.6d, N(R.sub.6d)R.sub.6e, C(O)R.sub.6d, C(O)N(R.sub.6d)R.sub.6e, N(R.sub.6d)C(O)R.sub.6e, C(O)OR.sub.6d, OC(O)R.sub.6d, S(O)N(R.sub.6d)(R.sub.6e), SO.sub.2N(R.sub.6d)(R.sub.6e), N(R.sub.6d)S(O)(R.sub.6e), N(R.sub.6d)SO.sub.2(R.sub.6e), ?NR.sub.6d, and ?CHR.sub.6d; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; said ?NR.sub.6d means that two hydrogens on the same substitution site are replaced by the same nitrogen to form a double bond, and said nitrogen is substituted by R.sub.6d; said ?CHR.sub.6d means that two hydrogens on the same substitution site are replaced by the same carbon to form a double bond, and said carbon is substituted by R.sub.6d; R.sub.6d and R.sub.6e are, for each presence, independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10 carbocyclyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, monospiro ring group, heteromonospiro ring group, condensed ring group, and heterocondensed ring group; or when R.sub.6d and R.sub.6e are linked to the same nitrogen atom, R.sub.6d and R.sub.6e, together with the nitrogen atom linked thereto, form an optionally substituted group selected from 3- to 10-membered heterocyclyl and 5- to 12-membered heteroaryl; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of a group to be substituted is independently substituted by R.sub.6f; R.sub.6f is, for each presence, independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C(O)C.sub.1-6 alkyl, C(O)OC.sub.1-6 alkyl, OC(O)C.sub.1-6 alkyl, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), C(O)NHC.sub.1-6 alkyl, NHC(O)C.sub.1-6 alkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; when the heterocycloalkyl, heteroaryl, heterocyclyl, heteromonospiro ring group, heterocondensed ring group, and/or heterobridged ring group is present, the heteroatom thereof is independently selected from the group consisting of O, N, and S, and the number of the heteroatom is 1, 2, 3, or 4; or, a compound as represented by formula (I) or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, having the following structure: ##STR00317## wherein Y is ##STR00318## X.sub.1 is selected from the group consisting of a bond, hydrogen, halogen, hydroxyl, amino, nitro, cyano, O, S, C(O), C(O)O, OC(O), N(R.sub.1x)C(O), C(O)N(R.sub.1x), and N(R.sub.1x); R.sub.1x is selected from the group consisting of hydrogen and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of the group to be substituted is independently substituted by a substituent selected from the group consisting of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; when X.sub.1 is hydrogen, halogen, hydroxyl, amino, nitro, or cyano, R.sub.1, X.sub.2, R.sub.2, and R.sub.3 are absent; R.sub.1 is absent or selected from the group consisting of a bond, hydrogen, and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, 4- to 12-membered bridged ring group, 4- to 12-membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, condensed ring group, and heterocondensed ring group; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of the group to be substituted is independently substituted by R.sub.1a; R.sub.1a is, for each presence, independently selected from the group consisting of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, R.sub.1b, OR.sub.1b, SR.sub.1b, S(O)R.sub.1b, SO.sub.2(R.sub.1b), C(O)R.sub.1b, C(O)OR.sub.1b, OC(O)R.sub.1b, NH(R.sub.1b), N(R.sub.1b)(R.sub.1c), C(O)NH(R.sub.1b), C(O)N(R.sub.1b)(R.sub.1c), NHC(O)(R.sub.1b), N(R.sub.1b)C(O)(R.sub.1c), S(O)NH(R.sub.1b), S(O)N(R.sub.1b)(R.sub.1c), SO.sub.2NH(R.sub.1b), SO.sub.2N(R.sub.1b)(R.sub.1c), NHS(O)(R.sub.1b), N(R.sub.1b)S(O)(R.sub.1c), NHSO.sub.2(R.sub.1b), and N(R.sub.1b)SO.sub.2(R.sub.1c); R.sub.1b and R.sub.1c are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.1b and R.sub.1c are linked to the same nitrogen atom, R.sub.1b and R.sub.1c, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; when R.sub.1 is hydrogen, X.sub.2, R.sub.2, and R.sub.3 are absent: X.sub.2 is absent or selected from the group consisting of a bond, hydrogen, halogen, hydroxyl, amino, nitro, mercapto, cyano, O, S, P, C(O), C(S), C(?NR.sub.2x), CH?N, C(O)O, C(O)C(O), OC(O), OC(S), OSO.sub.2, OP(O), N?CH, C(O)N(R.sub.2x), N(R.sub.2x)C(O), N(R.sub.2x), S(O), SO.sub.2, S(O)N(R.sub.2x), SO.sub.2N(R.sub.2x), and P(O); R.sub.2x is selected from the group consisting of hydrogen and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of a group to be substituted is independently substituted by a substituent selected from the group consisting of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond: when X.sub.2 is hydrogen, halogen, hydroxyl, amino, nitro, mercapto, or cyano, R.sub.2 and R.sub.3 are absent: R.sub.2 is absent or selected from the group consisting of a bond, hydrogen and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, 3- to 10-membered heterocycloalkyl, 5- to 12-membered heteroaryl, 4- to 12-membered bridged ring group, 4- to 12-membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, condensed ring group, and heterocondensed ring group; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of a group to be substituted is independently substituted by R.sub.2a; R.sub.2a is, for each presence, independently selected from the group consisting of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, R.sub.2b, OR.sub.2b, SR.sub.2b, S(O)(R.sub.2b), SO.sub.2(R.sub.2b), C(O)R.sub.2b, C(O)OR.sub.2b, OC(O)R.sub.2b, NH(R.sub.2b), N(R.sub.2b)(R.sub.2c), C(O)NH(R.sub.2b), C(O)N(R.sub.2b)(R.sub.2c), NHC(O)(R.sub.2b), N(R.sub.2b)C(O)(R.sub.2c), S(O)NH(R.sub.2b), S(O)N(R.sub.2b)(R.sub.2c), SO.sub.2NH(R.sub.2b), SO.sub.2N(R.sub.2b)(R.sub.2c), NHS(O)(R.sub.2b), N(R.sub.2b)S(O)(R.sub.2c), NHSO.sub.2(R.sub.2b), and N(R.sub.2b)SO.sub.2(R.sub.2c); R.sub.2b and R.sub.2, are, for each presence, independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.2b and R.sub.2, are linked to the same nitrogen atom, R.sub.2b and R.sub.2c, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; when R.sub.2 is hydrogen, R.sub.3 is absent; R.sub.3 is absent or selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, R.sub.3b, OR.sub.3b, SR.sub.3b, S(O)(R.sub.3b), SO.sub.2(R.sub.3b), C(O)R.sub.3b, C(O)OR.sub.3b, OC(O)R.sub.3b, NH(R.sub.3b), N(R.sub.3b)(R.sub.3c), C(O)NH(R.sub.3b), C(O)N(R.sub.3b)(R.sub.3c), NHC(O)(R.sub.3b), N(R.sub.3b)C(O)(R.sub.3c), S(O)NH(R.sub.3b), S(O)N(R.sub.3b)(R.sub.3c), SO.sub.2NH(R.sub.3b), SO.sub.2N(R.sub.3b)(R.sub.3c), NHS(O)(R.sub.3b), N(R.sub.3b)S(O)(R.sub.3c), NHSO.sub.2(R.sub.3b), and N(R.sub.3b)SO.sub.2(R.sub.3c); R.sub.3b and R.sub.3c are, for each presence, independently selected from the group consisting of hydrogen and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.3b and R.sub.3, are linked to the same nitrogen atom, R.sub.3b and R.sub.3c, together with the nitrogen atom linked thereto, form an optionally substituted group selected from 3- to 10-membered heterocycloalkyl and 5- to 12-membered heteroaryl; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of a group to be substituted is independently substituted by R.sub.3d; R.sub.3d is, for each presence, independently selected from the group consisting of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, R.sub.3e, OR.sub.3e, SR.sub.3e, S(O)(R.sub.3e), SO.sub.2(R.sub.3e), C(O)R.sub.3e, C(O)OR.sub.3e, OC(O)R.sub.3e, NH(R.sub.3e), N(R.sub.3e)(R.sub.3f), C(O)NH(R.sub.3e), C(O)N(R.sub.3e)(R.sub.3f), NHC(O)(R.sub.3e), N(R.sub.3e)C(O)(R.sub.3f), S(O)NH(R.sub.3e), S(O)N(R.sub.3e)(R.sub.3f), SO.sub.2NH(R.sub.3e), SO.sub.2N(R.sub.3e)(R.sub.3f), NHS(O)(R.sub.3e), N(R.sub.3e)S(O)(R.sub.3f), NHSO.sub.2(R.sub.3e), and N(R.sub.3e)SO.sub.2(R.sub.3f); R.sub.3e and R.sub.3f are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.3e and R.sub.3f are linked to the same nitrogen atom, R.sub.3e and R.sub.3f, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond: R.sub.4 is selected from the group consisting of hydrogen, halogen, nitro, amino, cyano, hydroxyl, carboxyl, mercapto, and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 alkthio which is optionally substituted by halogen, hydroxyl, or amino; R.sub.5 is selected from the group consisting of hydrogen, halogen, hydroxyl, and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkthio, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, 3- to 10-membered heterocycloalkyl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, and cyano; L is C(R.sub.L) or N; R.sub.L is selected from the group consisting of hydrogen, halogen, nitro, amino, cyano, hydroxyl, carboxyl, mercapto, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and C.sub.1-6 alkthio; A is ##STR00319## wherein represents a single bond or a double bond; Q.sub.1 is linked to W; t.sub.1, t.sub.2, t.sub.3, t.sub.4, t.sub.5, and t.sub.6 are independently equal to 0 or 1: n.sub.1 and n.sub.2 are independently equal to 0, 1, or 2, and n.sub.1 and n.sub.2 are not simultaneously equal to 0, wherein n.sub.1 represents sequentially linked chain of Q.sub.1 with n.sub.1 repeat units, and n.sub.2 represents sequentially linked chain of Q.sub.2 with n.sub.2 repeat units; two adjacent Q.sub.1 are linked by a single bond or a double bond: two adjacent O.sub.2 are linked by a single bond or a double bond: W, Q.sub.1, and 02 are independently selected from the group consisting of C, O, N, and S: Q.sub.3 is C; when one of the bonds linked to O.sub.3 is a double bond, R.sub.10 or Ru is absent: R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, nitro, R.sub.6a, OR.sub.6a, SR.sub.6a, S(O)(R.sub.6a), SO.sub.2(R.sub.6a), C(O)R.sub.6a, C(O)OR.sub.6a, OC(O)R.sub.6a, NH(R.sub.6a), N(R.sub.6a)(R.sub.6b), C(O)NH(R.sub.6a), C(O)N(R.sub.6a)(R.sub.6b), NHC(O)(R.sub.6a), N(R.sub.6a)C(O)(R.sub.6b), S(O)NH(R.sub.6a), S(O)N(R.sub.6a)(R.sub.6b), SO.sub.2NH(R.sub.6a), SO.sub.2N(R.sub.6a)(R.sub.6b), NHS(O)(R.sub.6a), N(R.sub.6a)S(O)(R.sub.6b), NHSO.sub.2(R.sub.6a), and N(R.sub.6a)SO.sub.2(R.sub.6b); or any two substituents linked to the same atom among R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 form ?O, ?NR.sub.6a, or ?CHR.sub.6a; or any two adjacent atoms among W, each present Q.sub.1, each present 02, and 03, together with the substituents linked thereto, form C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, 4- to 12-membered bridged ring group, 4- to 12-membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, condensed ring group, or heterocondensed ring group which is optionally substituted by R.sub.6c; or any one atom among W, each present Q.sub.1, each present 02, and Q.sub.3, together with the substituents linked thereto, forms C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, monospiro ring group, or heteromonospiro ring group which is optionally substituted by R.sub.6c; R.sub.6a and R.sub.6b are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, 4- to 12-membered bridged ring group, 4- to 12-membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, condensed ring group, and heterocondensed ring group which is optionally substituted by R.sub.6e; or when R.sub.6a and R.sub.6b are linked to the same nitrogen atom, R.sub.6a and R.sub.6b, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocyclyl or 5- to 12-membered heteroaryl which is optionally substituted by R.sub.6e; R.sub.6e is, for each presence, independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, nitro, azido, oxo, R.sub.6d, OR.sub.6d, N(R.sub.6d)R.sub.6e, C(O)R.sub.6d, C(O)N(R.sub.6d)R.sub.6e, N(R.sub.6d)C(O)R.sub.6e, C(O)OR.sub.6d, OC(O)R.sub.6d, S(O)N(R.sub.6d)(R.sub.6e), SO.sub.2N(Rd)(R.sub.6e), N(R.sub.6d)S(O)(R.sub.6e), N(R.sub.6d)SO.sub.2(R.sub.6e), ?NR.sub.6d, and ?CHR.sub.6d; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond; said ?NR.sub.6d means that two hydrogens on the same substitution site are replaced by the same nitrogen to form a double bond, and said nitrogen is substituted by R.sub.6d; said ?CHR.sub.6d means that two hydrogens on the same substitution site are replaced by the same carbon to form a double bond, and said carbon is substituted by R.sub.6d; R.sub.6d and R.sub.6e are, for each presence, independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, cyano, and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, monospiro ring group, heteromonospiro ring group, condensed ring group, and heterocondensed ring group; or when R.sub.6d and R.sub.6e are linked to the same nitrogen atom, R.sub.6d and R.sub.6e, together with the nitrogen atom linked thereto, form an optionally substituted group selected from 3- to 10-membered heterocyclyl and 5- to 12-membered heteroaryl; said optionally substituted means that hydrogen on a group to be substituted is not substituted or hydrogen on one or more substitution sites of a group to be substituted is independently substituted by R.sub.6f; R.sub.6f is, for each presence, independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C(O)C.sub.1-6 alkyl, C(O)OC.sub.1-6 alkyl, OC(O)C.sub.1-6 alkyl, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), C(O)NHC.sub.1-6 alkyl, NHC(O)C.sub.1-6 alkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said oxo means that two hydrogens on the same substitution site are replaced by the same oxygen to form a double bond: when the heterocycloalkyl, heteroaryl, heterocyclyl, heteromonospiro ring group, heterocondensed ring group, and/or heterobridged ring group is present, the heteroatom thereof is independently selected from the group consisting of O, N, and S, and the number of the heteroatom is 1, 2, 3, or 4.

2. (canceled)

3. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as represented by formula (I-a): ##STR00320## wherein each substituent is as defined in claim 1; or, the compound has a structure as represented by formula (I-b) or (I-c): ##STR00321## wherein each substituent is as defined in claim 1.

4. (canceled)

5. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein X.sub.1 is selected from the group consisting of a bond, hydrogen, halogen, hydroxyl, amino, nitro, cyano, O, S, C(O), C(O)O, OC(O), N(R.sub.1x)C(O), C(O)N(R.sub.1x), and N(R.sub.1x); R.sub.1x is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or X.sub.1 is selected from the group consisting of a bond, hydrogen, halogen, hydroxyl, amino, nitro, cyano, O, S, C(O), C(O)O, OC(O), N(R.sub.1x)C(O), C(O)N(R.sub.1x), and N(R.sub.1x); R.sub.1x is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; or X.sub.1 is selected from the group consisting of a bond, hydrogen, halogen, hydroxyl, amino, O, S, C(O), C(O)O, OC(O), NHC(O), C(O)NH, NH, and N(CH.sub.3); or, X.sub.1 is selected from the group consisting of a bond, hydrogen, S, NHC(O), and C(O)NH; or, X.sub.1 is a bond.

6-7. (canceled)

8. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.1 is absent or selected from the group consisting of a bond, hydrogen, and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said optionally substituted represents being optionally substituted by R.sub.1a; or R.sub.1 is selected from the group consisting of hydrogen and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said optionally substituted represents being optionally substituted by R.sub.1a; or R.sub.1 is selected from the group consisting of an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; said optionally substituted represents being optionally substituted by R.sub.1a; or R.sub.1 is selected from the group consisting of an optionally substituted group selected from C.sub.2-6 alkynyl and 5- to 12-membered heteroaryl; said optionally substituted represents being optionally substituted by R.sub.1a; or R.sub.1 is an optionally substituted 5- to 12-membered heteroaryl; said optionally substituted represents being optionally substituted by R.sub.1a; or, R.sub.1 is selected from the group consisting of an optionally substituted group selected from C.sub.2-6 alkynyl and 5- to 8-membered heteroaryl, the heteroatom thereof is N, and the number of the heteroatom is 1, 2, or 3; said optionally substituted represents being optionally substituted by R.sub.1a; or R.sub.1 is an optionally substituted 5- to 6-membered heteroaryl, the heteroatom thereof is N, and the number of the heteroatom is 1 or 2; said optionally substituted represents being optionally substituted by R.sub.1a; or R.sub.1 is selected from the group consisting of an optionally substituted group selected from ethynyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, and pyrrolyl; said optionally substituted represents being optionally substituted by R.sub.1a; or R.sub.1 is an optionally substituted pyridinyl; said optionally substituted represents being optionally substituted by R.sub.1a; or, R.sub.1 is an optionally substituted 3- to 10-membered heterocyclyl; said optionally substituted represents being optionally substituted by R.sub.1a; or R.sub.1 is an optionally substituted 5- to 8-membered heterocyclyl, the heteroatom thereof is N, and the number of the heteroatom is 1 or 2; said optionally substituted represents being optionally substituted by R.sub.1a; or R.sub.1 is an optionally substituted dihydropyridinyl; said optionally substituted represents being optionally substituted by R.sub.1a; or, ##STR00322## R.sub.1 is selected from the group consisting of the following optionally substituted groups: wherein the end with an asterisk * is the one linked to X.sub.1, and the other end is the one linked to X.sub.2; said optionally substituted represents being optionally substituted by R.sub.1a; or R.sub.1 is an optionally substituted ##STR00323## wherein the end with an asterisk * is the one linked to X.sub.1, and the other end is the one linked to X.sub.2; said optionally substituted represents being optionally substituted by R.sub.1a; or, R.sub.1 is selected from the group consisting of the following groups: ##STR00324## wherein the end with an asterisk * is the one linked to X.sub.1, and the other end is the one linked to X.sub.2.

9-11. (canceled)

12. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.1a is, for each presence, independently selected from the group consisting of halogen, hydroxyl, amino, oxo, R.sub.1b, OR.sub.1b, SR.sub.1b, S(O)R.sub.1b, SO.sub.2(R.sub.1b), C(O)R.sub.1b, C(O)OR.sub.1b, OC(O)R.sub.1b, NH(R.sub.1b), N(R.sub.1b)(R.sub.1c), C(O)NH(R.sub.1b), C(O)N(R.sub.1b)(R.sub.1c), NHC(O)(R.sub.1b), N(R.sub.1b)C(O)(R.sub.1c), S(O)NH(R.sub.1b), S(O)N(R.sub.1b)(R.sub.1c), SO.sub.2NH(R.sub.1b), SO.sub.2N(R.sub.1b)(R.sub.1c), NHS(O)(R.sub.1b), N(R.sub.1b)S(O)(R.sub.1c), NHSO.sub.2(R.sub.1b), and N(R.sub.1b)SO.sub.2(R.sub.1c); R.sub.1a is, for each presence, independently selected from the group consisting of halogen, hydroxyl, amino, oxo, R.sub.1b, C(O)NH(R.sub.1c), NHC(O)(R.sub.1b), N(R.sub.1b)C(O)(R.sub.1c), S(O)NH(R.sub.1b), SO.sub.2NH(R.sub.1b), NHS(O)(R.sub.1b), NHSO.sub.2(R.sub.1b), and N(R.sub.1b)SO.sub.2(R.sub.1c); or, R.sub.1a is, for each presence, independently selected from the group consisting of halogen, amino, oxo, R.sub.1b, NHC(O)(R.sub.1b), and NHSO.sub.2(R.sub.1b); or, R.sub.1a is, for each presence, independently selected from the group consisting of NHC(O)(R.sub.1b) and NHSO.sub.2(R.sub.1b); or, R.sub.1a is independently selected from the group consisting of H, F, Cl, NH.sub.2, oxo, CH.sub.3, CH.sub.2CH.sub.3, ##STR00325##

13-14. (canceled)

15. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.1b and R.sub.1c are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C.sub.6-g aryl, and 5- to 8-membered heteroaryl; or when R.sub.1b and R.sub.1c are linked to the same nitrogen atom, R.sub.1b and R.sub.1c, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C.sub.6-8 aryl, and 5- to 8-membered heteroaryl; or R.sub.1b and R.sub.1c are, for each presence, independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, and C.sub.6-8 aryl; or R.sub.1b and R.sub.1c are, for each presence, independently selected from the group consisting of C.sub.1-4 alkyl and C.sub.3-4 cycloalkyl; or, R.sub.1b and R.sub.1c are, for each presence, independently selected from the group consisting of methyl, ethyl, cyclopropyl, phenyl, and tetrahydropyranyl; or R.sub.1b and R.sub.1c are, for each presence, independently selected from the group consisting of methyl and cyclopropyl.

16-18. (canceled)

19. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein X.sub.2 is absent or selected from the group consisting of a bond, hydrogen, halogen, hydroxyl, amino, O, S, C(O)O, OC(O), C(O)N(R.sub.2x), N(R.sub.2x)C(O), and N(R.sub.2x); R.sub.2x is selected from the group consisting of hydrogen and C.sub.1-6 alkyl which is optionally substituted by halogen, hydroxyl, or amino; or, X.sub.2 is absent or selected from the group consisting of a bond, hydrogen, halogen, hydroxyl, amino, O, S, C(O)O, OC(O), C(O)NH, NHC(O), NH, N(CH.sub.3), and N(CH.sub.2CH.sub.3); or, X.sub.2 is absent or selected from the group consisting of a bond, O, and N(CH.sub.3).

20-21. (canceled)

22. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.2 is absent or selected from the group consisting of a bond, hydrogen, and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, 3- to 10-membered heterocycloalkyl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C.sub.6-g aryl, and 5- to 8-membered heteroaryl; or R.sub.2 is absent or selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, 3- to 10-membered heterocycloalkyl, and 5- to 12-membered heteroaryl; or, R.sub.2 is absent or selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-4 alkynyl, and 5- to 6-membered heterocycloalkyl, the heteroatom thereof is N or O, and the number of the heteroatom is 1 or 2; or, R.sub.2 is absent or selected from the group consisting of methyl, ethyl, propyl, butyl, ethynyl, piperidinyl, tetrahydropyrrolyl, and tetrahydropyranyl; or R.sub.2 is n-propyl.

23-24. (canceled)

25. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.3 is absent or selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, R.sub.3b, OR.sub.3b, SR.sub.3b, C(O)R.sub.3b, C(O)OR.sub.3b, OC(O)R.sub.3b, N(R.sub.3b)(R.sub.3c), C(O)N(R.sub.3b)(R.sub.3c), C(O)NH(R.sub.3b), NHC(O)(R.sub.3b), N(R.sub.3b)C(O)(R.sub.3c), S(O)N(R.sub.3b)(R.sub.3c), SO.sub.2N(R.sub.3b)(R.sub.3c), N(R.sub.3b)S(O)(R.sub.3c), and N(R.sub.3b)SO.sub.2(R.sub.3c); or R.sub.3 is absent or selected from the group consisting of hydrogen, halogen, hydroxyl, amino, oxo, R.sub.3b, OR.sub.3b, SR.sub.3b, C(O)R.sub.3b, C(O)OR.sub.3b, OC(O)R.sub.3b, N(R.sub.3b)(R.sub.3c), C(O)N(R.sub.3b)(R.sub.3c), C(O)NH(R.sub.3b), and NHC(O)(R.sub.3b); or R.sub.3 is absent or selected from the group consisting of R.sub.3b, OR.sub.3b, and N(R.sub.3b)(R.sub.3c); or R.sub.3 is N(R.sub.3b)(R.sub.3c); or, R.sub.3 is selected from the group consisting of the following optionally substituted groups: ##STR00326## said optionally substituted represents being optionally substituted by R.sub.3d; or R.sub.3 is selected from the group consisting of the following groups: ##STR00327## ##STR00328## or R.sub.3 is selected from the group consisting of the following groups: ##STR00329##

26. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.3b and R.sub.3c are, for each presence, independently selected from the group consisting of hydrogen and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.3b and R.sub.3, are linked to the same nitrogen atom, R.sub.3b and R.sub.3c, together with the nitrogen atom linked thereto, form an optionally substituted group selected from 3- to 10-membered heterocycloalkyl, 4- to 12-membered bicyclic heterocyclyl, and 5- to 12-membered heteroaryl; said optionally substituted represents being optionally substituted by R.sub.3d; or R.sub.3b and R.sub.3c are, for each presence, independently selected from the group consisting of hydrogen and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.3b and R.sub.3c are linked to the same nitrogen atom, R.sub.3b and R.sub.3c, together with the nitrogen atom linked thereto, form an optionally substituted group selected from 3- to 10-membered heterocycloalkyl and 5- to 12-membered heteroaryl; said optionally substituted represents being optionally substituted by R.sub.3d; or R.sub.3b and R.sub.3c are, for each presence, independently selected from the group consisting of hydrogen and an optionally substituted group selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and 3- to 10-membered heterocycloalkyl; said optionally substituted represents being optionally substituted by R.sub.3d; or R.sub.3b and R.sub.3c are, for each presence, independently an optionally substituted C.sub.1-6 alkyl; said optionally substituted represents being optionally substituted by R.sub.3d; or, when R.sub.3b and R.sub.3c are linked to the same nitrogen atom, R.sub.3b and R.sub.3c, together with the nitrogen atom linked thereto, form an optionally substituted 3- to 10-membered heterocycloalkyl; said optionally substituted represents being optionally substituted by R.sub.3d; or when R.sub.3b and R.sub.3c are linked to the same nitrogen atom, R.sub.3b and R.sub.3c, together with the nitrogen atom linked thereto, form an optionally substituted group selected from 5- to 6-membered heterocycloalkyl and 6- to 10-membered bicyclic heterocyclyl, the heteroatom thereof is independently selected from the group consisting of O and N, and the number of the heteroatom is 1, 2, 3, or 4; said optionally substituted represents being optionally substituted by R.sub.3d; or, R.sub.3b and R.sub.3c are, for each presence, independently an optionally substituted C.sub.1-4 alkyl; or when R.sub.3b and R.sub.3c are linked to the same nitrogen atom, R.sub.3b and R.sub.3c, together with the nitrogen atom linked thereto, form an optionally substituted group selected from 5- to 6-membered heterocycloalkyl, 3-/6-membered heteromonospiro ring group, 6-/3-membered heteromonospiro ring group, 4-/6-membered heteromonospiro ring group, 6-/4-membered heteromonospiro ring group, and 4-/4-membered heteromonospiro ring group, the heteroatom thereof is independently selected from the group consisting of O and N, and the number of the heteroatom is 1 or 2; said optionally substituted represents being optionally substituted by R.sub.3d; or, R.sub.3b and R.sub.3c are, for each presence, independently an optionally substituted C.sub.1-6 alkyl; or when R.sub.3b and R.sub.3c are linked to the same nitrogen atom, R.sub.3b and R.sub.3c, together with the nitrogen atom linked thereto, form an optionally substituted 3- to 10-membered heterocycloalkyl; said optionally substituted represents being optionally substituted by R.sub.3d; or R.sub.3b and R.sub.3c are, for each presence, independently an optionally substituted C.sub.1-4 alkyl; or when R.sub.3b and R.sub.3c are linked to the same nitrogen atom, R.sub.3b and R.sub.3c, together with the nitrogen atom linked thereto, form an optionally substituted group selected from 5- to 6-membered heterocycloalkyl and 6- to 10-membered bicyclic heterocyclyl, the heteroatom thereof is independently selected from the group consisting of O and N, and the number of the heteroatom is 1, 2, or 3; said optionally substituted represents being optionally substituted by R.sub.3d; or R.sub.3b and R.sub.3c are, for each presence, independently an optionally substituted C.sub.1-4 alkyl; or when R.sub.3b and R.sub.3c are linked to the same nitrogen atom, R.sub.3b and R.sub.3c, together with the nitrogen atom linked thereto, form an optionally substituted group selected from 5- to 6-membered heterocycloalkyl, 3-/6-membered heteromonospiro ring group, 4-/6-membered heteromonospiro ring group, and 3-/5-membered fused heterocyclyl, the heteroatom thereof is independently selected from the group consisting of O and N, and the number of the heteroatom is 1, 2, or 3; said optionally substituted represents being optionally substituted by R.sub.3d; or, R.sub.3b and R.sub.3c are, for each presence, independently an optionally substituted methyl; or when R.sub.3b and R.sub.3, are linked to the same nitrogen atom, R.sub.3b and R.sub.3c together with the nitrogen atom linked thereto, form an optionally substituted group selected from pyrrolidinyl, piperazinyl, piperidinyl, 2-oxa-7-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, and 6-azaspiro[2.5]octanyl; said optionally substituted represents being optionally substituted by R.sub.3d; or, a group formed by R.sub.3b and R.sub.3c together with the nitrogen atom linked thereto is selected from the group consisting of the following groups: ##STR00330##

27. (canceled)

28. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.3d is, for each presence, independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, R.sub.3e, C(O)R.sub.3e, C(O)OR.sub.3e, N(R.sub.3e)(R.sub.3H), and C(O)NH(R.sub.3e); R.sub.3e and R.sub.3f are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.3e and R.sub.3f are linked to the same nitrogen atom, R.sub.3e and R.sub.3f, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or R.sub.3d is, for each presence, independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, R.sub.3e, C(O)R.sub.3e, C(O)OR.sub.3e, N(R.sub.3e)(R.sub.3H), and C(O)NH(R.sub.3e); R.sub.3e and R.sub.3f are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C.sub.6 aryl, and 5- to 6-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C.sub.6 aryl, and 5- to 6-membered heteroaryl; R.sub.3d is, for each presence, independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), C(O)NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and 3- to 6-membered heterocycloalkyl; or R.sub.3d is, for each presence, independently selected from the group consisting of deuterium, hydroxyl, amino, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), C(O)NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and 5- to 6-membered heterocycloalkyl; R.sub.3d is, for each presence, independently selected from the group consisting of deuterium, fluorine, hydroxyl, amino, cyano, CHO, COCH.sub.3, COOH, COOCH.sub.3, NH(CH.sub.3), N(CH.sub.3)(CH.sub.3), C(O)NH.sub.2, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, piperidinyl, piperazinyl, and tetrahydropyrrolyl; or R.sub.3d is, for each presence, independently selected from the group consisting of deuterium, fluorine, amino, cyano, C(O)NH.sub.2, CH.sub.3, and piperidinyl; or, R.sub.3d is, for each presence, independently selected from the group consisting of halogen, hydroxyl, amino, R.sub.3e, and N(R.sub.3e)(R.sub.3f); R.sub.3e and R.sub.3f are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or when R.sub.3e and R.sub.3f are linked to the same nitrogen atom, R.sub.3e and R.sub.3f, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl which is optionally substituted by one or more of halogen, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C.sub.6-14 aryl, and 5- to 12-membered heteroaryl; or R.sub.3d is, for each presence, independently selected from the group consisting of R.sub.3e and N(R.sub.3e)(R.sub.3f); R.sub.3e and R.sub.3f are, for each presence, independently selected from the group consisting of C.sub.1-6 alkyl and 3- to 8-membered heterocycloalkyl; or when R.sub.3e and R.sub.3f are linked to the same nitrogen atom, R.sub.3e and R.sub.3f, together with the nitrogen atom linked thereto, form 3- to 8-membered heterocycloalkyl; or R.sub.3d is selected from the group consisting of methyl, N(methyl)(methyl), and piperidinyl; or, R.sub.3d is, for each presence, independently selected from the group consisting of deuterium, fluorine, hydroxyl, amino, cyano, NH(CH.sub.3), N(CH.sub.3)(CH.sub.3), C(O)NH.sub.2, CH.sub.3, CH.sub.2CH.sub.3, and CH.sub.2CH.sub.2CH.sub.3; or R.sub.3d is, for each presence, independently selected from the group consisting of deuterium, fluorine, cyano, C(O)NH.sub.2, and CH.sub.3.

29-30. (canceled)

31. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as represented by formula (II-a): ##STR00331## wherein m.sub.1-1 is selected from the group consisting of 0, 1, and 2, R.sub.1a-1 is as defined by R.sub.1a in claim 1, X.sub.2-1 is as defined by X.sub.2 in claim 1, R.sub.2-1 is as defined by R.sub.2 in claim 1, R.sub.3-1 is as defined by R.sub.3 in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-b): ##STR00332## wherein m.sub.1-2 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-2 is as defined by R.sub.1a in claim 1, X.sub.2-2 is as defined by X.sub.2 in claim 1, R.sub.2-2 is as defined by R.sub.2 in claim 1, R.sub.3-2 is as defined by R.sub.3 in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-c): ##STR00333## wherein m.sub.1-4 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-4 is as defined by R.sub.1a in claim 1, X.sub.2-3 is as defined by X.sub.2 in claim 1, R.sub.2-3 is as defined by R.sub.2 in claim 1, R.sub.3-3 is as defined by R.sub.3 in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1: or, the compound has a structure as represented by formula (II-d): ##STR00334## wherein E.sub.1, E.sub.2, E.sub.3, E.sub.4, E.sub.5, and E.sub.6 are independently selected from the group consisting of C and N, m.sub.1-6 is selected from the group consisting of 0, 1, 2, 3, and 4, R.sub.1a-6 is as defined by R.sub.1a in claim 1, X.sub.2-4 is as defined by X.sub.2 in claim 1, R.sub.2-4 is as defined by R.sub.2 in claim 1, R.sub.3-4 is as defined by R.sub.3 in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1: or, the compound has a structure as represented by formula (II-e): ##STR00335## wherein E.sub.7, E.sub.8, E.sub.9, E.sub.10, E.sub.11, and E.sub.12 are independently selected from the group consisting of C and N, m.sub.1-3 is selected from the group consisting of 0, 1, 2, and 3, m.sub.2-1 is selected from the group consisting of 0, 1, 2, 3, and 4, R.sub.1a-13 is as defined by R.sub.1a in claim 1, R.sub.2a-1 is as defined by R.sub.2a in claim 1, R.sub.3-5 is as defined by R.sub.3 in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-f): ##STR00336## wherein m.sub.1-15 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-15 is as defined by R.sub.1a in claim 1, R.sub.3e-2 is as defined by R.sub.3e in claim 1, R.sub.3f-2 is as defined by R.sub.3f in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-g): ##STR00337## wherein R.sub.3b-8 is as defined by R.sub.3b in claim 1, R.sub.3c-8 is as defined by R.sub.3, in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1.

32. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 31, wherein the compound has a structure as represented by formula (II-a.sub.1): ##STR00338## wherein R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-a2): ##STR00339## wherein R.sub.3b-1 is as defined by R.sub.3b in claim 1, R.sub.3-1 is as defined by R.sub.3e in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-b.sub.1): ##STR00340## wherein m.sub.1-3 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-3 is as defined by R.sub.1a in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-ci): ##STR00341## wherein m.sub.1-5 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-5 is as defined by R.sub.1a in claim 1, R.sub.3b-2 is as defined by R.sub.3b in claim 1, R.sub.3c-2 is as defined by R.sub.3c in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-d.sub.1): ##STR00342## wherein m.sub.1-7 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-7 is as defined by R.sub.1a in claim 1, R.sub.3b-3 is as defined by R.sub.3b in claim 1, R.sub.3c-3 is as defined by R.sub.3, in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-d.sub.2): ##STR00343## wherein m.sub.1-8 is selected from the group consisting of 0, 1, and 2, R.sub.1a-6 is as defined by R.sub.1a in claim 1, R.sub.3b-4 is as defined by R.sub.3b in claim 1, R.sub.3c-4 is as defined by R.sub.3, in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-d.sub.3): ##STR00344## wherein m.sub.1-9 is selected from the group consisting of 0, 1, and 2, R.sub.1a-9 is as defined by R.sub.1a in claim 1, R.sub.3b-5 is as defined by R.sub.3b in claim 1, R.sub.3c-5 is as defined by R.sub.3, in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-d.sub.4): ##STR00345## wherein m.sub.1-10 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-10 is as defined by R.sub.1a in claim 1, R.sub.3e0.1 is as defined by R.sub.3e in claim 1, R.sub.3f-1 is as defined by R.sub.3f in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-d.sub.5): ##STR00346## wherein m.sub.1-11 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-11 is as defined by R.sub.1a in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-d.sub.6): ##STR00347## wherein m.sub.1-12 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-12 is as defined by R.sub.1a in claim 1, R.sub.3b-6 is as defined by R.sub.3b in claim 1, R.sub.3c-6 is as defined by R.sub.3c in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (II-e.sub.1): ##STR00348## wherein m.sub.114 is selected from the group consisting of 0, 1, 2, and 3, m.sub.2-2 is selected from the group consisting of 0, 1, 2, 3, and 4, R.sub.1a-14 is as defined by R.sub.1a in claim 1, R.sub.2a-2 is as defined by R.sub.2a in claim 1, R.sub.3b-7 is as defined by R.sub.3b in claim 1, R.sub.3c-7 is as defined by R.sub.3e in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (III-a): ##STR00349## wherein m.sub.1-6 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-16 is as defined by R.sub.1a in claim 1, R.sub.3b-9 is as defined by R.sub.3b in claim 1, R.sub.3c-9 is as defined by R.sub.3, in claim 1, and R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, W, L, t.sub.1, and t.sub.2 are as defined in claim 1; or, the compound has a structure as represented by formula (III-a.sub.1): ##STR00350## wherein m.sub.1-7 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-17 is as defined by R.sub.1a in claim 1, R.sub.3b-10 is as defined by R.sub.3b in claim 1, R.sub.3c-10 is as defined by R.sub.3, in claim 1, and R.sub.4, R.sub.5, R.sub.8, R.sub.9, R.sub.10, R.sub.11, and L are as defined in claim 1; or, the compound has a structure as represented by formula (III-a.sub.2): ##STR00351## wherein m.sub.1-18 is selected from the group consisting of 0, 1, 2, and 3, R.sub.1a-18 is as defined by R.sub.1a in claim 1, R.sub.3b-11 is as defined by R.sub.3b in claim 1, R.sub.3c-11 is as defined by R.sub.3, in claim 1, and R.sub.4, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, and L are as defined in claim 1.

33-49. (canceled)

50. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein Y is selected from the group consisting of the following groups: ##STR00352## ##STR00353## or Y is selected from the group consisting of the following groups: ##STR00354##

51. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.4 is selected from the group consisting of hydrogen, halogen, amino, and C.sub.1-6 alkoxy; or, R.sub.4 is selected from the group consisting of hydrogen, fluorine, and methoxy.

52. (canceled)

53. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.5 is selected from the group consisting of hydrogen, deuterium and C.sub.1-6 alkyl which is optionally substituted by one or more deuteriums; or R.sub.5 is C.sub.1-6 alkyl; or, R.sub.5 is methyl.

54. (canceled)

55. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein L is C(R.sub.L) or N, and R.sub.L is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy; or, L is C(R.sub.L), and R.sub.L is selected from the group consisting of hydrogen, halogen, amino, methyl, and methoxy; or L is CH.

56. (canceled)

57. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein W, Q.sub.1, and Q.sub.2 are independently selected from the group consisting of O, C, S, and N; Q.sub.3 is C; wherein Q.sub.1 is linked to W; or W, Q.sub.1, and Q.sub.2 are independently selected from the group consisting of O, C, and S; Q.sub.3 is C; wherein Q.sub.1 is linked to W; or W is selected from the group consisting of O and N; Q.sub.1 is C; Q.sub.2 is C; Q.sub.3 is C; wherein Q.sub.1 is linked to W.

58. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, R.sub.6a, OR.sub.6a, SO.sub.2(R.sub.6a), C(O)R.sub.6a, C(O)OR.sub.6a, OC(O)R.sub.6a, NH(R.sub.6a), N(R.sub.6a)(R.sub.6b), C(O)NH(R.sub.6a), C(O)N(R.sub.6a)(R.sub.6b), NHC(O)(R.sub.6a), N(R.sub.6a)C(O)(R.sub.6b), SO.sub.2NH(R.sub.6a), SO.sub.2N(R.sub.6a)(R.sub.6b), NHSO.sub.2(R.sub.6a), and N(R.sub.6a)SO.sub.2(R.sub.6b); or any two groups linked to the same atom among R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 form ?O, ?NR.sub.6a, or ?CHR.sub.6a; or any two adjacent atoms among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, form C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, condensed ring group, or heterocondensed ring group which is optionally substituted by R.sub.6c; or any one atom among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, forms C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, monospiro ring group, or heteromonospiro ring group which is optionally substituted by R.sub.6c; or R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, R.sub.6a, OR.sub.6a, SO.sub.2(R.sub.6a), C(O)R.sub.6a, C(O)OR.sub.6a, OC(O)R.sub.6a, NH(R.sub.6a), N(R.sub.6a)(R.sub.6b), C(O)NH(R.sub.6a), C(O)N(R.sub.6a)(R.sub.6b), NHC(O)(R.sub.6a), N(R.sub.6a)C(O)(R.sub.6b), SO.sub.2NH(R.sub.6a), SO.sub.2N(R.sub.6a)(R.sub.6b), NHSO.sub.2(R.sub.6a), and N(R.sub.6a)SO.sub.2(R.sub.6b); or any two groups linked to the same atom among R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 form ?O, ?NR.sub.6a, or ?CHR.sub.6a; or any two adjacent atoms among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, form C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, condensed ring group, or heterocondensed ring group which is optionally substituted by R.sub.6c; or any one atom among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, forms C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, monospiro ring group, or heteromonospiro ring group which is optionally substituted by R.sub.6c; or, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, R.sub.6a, NH(R.sub.6a), and N(R.sub.6a)(R.sub.6b); or any two groups linked to the same atom among R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 form ?O, ?NR.sub.6a, or ?CHR.sub.6a; or any two adjacent atoms among W each present Q.sub.1, each present 02, and Q.sub.3, together with the substituents linked thereto, form C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, condensed ring group, or heterocondensed ring group which is optionally substituted by R.sub.ke; or any one atom among W, each present Q.sub.1, each present 02, and 03, together with the substituents linked thereto, forms C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, or 5- to 12-membered heteroaryl which is optionally substituted by R.sub.6c; or, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, R.sub.6a, NH(R.sub.6a), and N(R.sub.6a)(R.sub.6b) or any two groups linked to the same atom among R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 form ?O, ?NR.sub.6a, or ?CHR.sub.6a; or any two adjacent atoms among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with substituents linked thereto, form C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, condensed ring group, or heterocondensed ring group which is optionally substituted by R.sub.ke; or any one atom among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, forms C.sub.3-10 carbocyclyl or 3- to 10-membered heterocyclyl which is optionally substituted by R.sub.6c; or any one atom among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, forms C.sub.3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl which is optionally substituted by R.sub.6e; or any one atom among W each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, forms C.sub.3-4 cycloalkyl which is optionally substituted by R.sub.6e; or, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of hydrogen, deuterium, and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C.sub.6-8 aryl, 5- to 6-membered heteroaryl, 9- to 10-membered bicyclic heterocyclyl, and 9- to 10-membered bicyclic heteroaryl which is optionally substituted by deuterium, halogen, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C(O)(C.sub.1-6 alkyl), C(O)NH(C.sub.1-6 alkyl), NHC(O)(C.sub.1-6 alkyl), C(O)O(C.sub.1-6 alkyl), C.sub.3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 9- to 10-membered bicyclic heterocyclyl, or 9- to 10-membered bicyclic heteroaryl; or R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C.sub.6-8 aryl, and 5- to 6-membered heteroaryl which is optionally substituted by halogen, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C(O)(C.sub.1-6 alkyl), C(O)NH(C.sub.1-6 alkyl), NHC(O)(C.sub.1-6 alkyl), C(O)O(C.sub.1-6 alkyl), C.sub.3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; or R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl and C.sub.1-6 alkoxy which is optionally substituted by halogen, hydroxyl, amino, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; or R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-3 alkyl and C.sub.1-3 alkoxy which is optionally substituted by halogen, hydroxyl, amino, C.sub.1-3 alkyl, or C.sub.1-3 alkoxy; or R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of the following groups: H, F, Cl, OH, NH.sub.2, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3)CH.sub.3, CH.sub.2CH(CH.sub.3)CH.sub.3, CH.sub.2OH, CH.sub.2CH.sub.2OH, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3)CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3, CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2OCH.sub.3, CH(CH.sub.3)CH.sub.2OCH.sub.3, NHCH.sub.3, N(CH.sub.3)CH.sub.3, CH.sub.2N(CH.sub.3)CH.sub.3, ##STR00355## or R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of the following groups: H, F, Cl, OH, NH.sub.2, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3)CH.sub.3, CH.sub.2CH(CH.sub.3)CH.sub.3, CH.sub.2OH, CH.sub.2CH.sub.2OH, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3)CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3, CH.sub.2CH.sub.2OCH.sub.3, NHCH.sub.3, N(CH.sub.3)CH.sub.3, ##STR00356## CH.sub.2(C.sub.3)H.sub.3, ##STR00357## or R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are, for each presence, independently selected from the group consisting of the following groups: H, F, Cl, OH, NH.sub.2, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3)CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2OCH.sub.3, and CH(CH.sub.3)CH.sub.2OCH.sub.3; or, any two groups linked to the same atom among R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 form ?O or ?CH.sub.2; or, any two adjacent atoms among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, form the following groups: ##STR00358## or, any one atom among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, forms the following groups: ##STR00359## or any one atom among W, each present Q.sub.1, each present Q.sub.2, and Q.sub.3, together with the substituents linked thereto, forms the following groups: ##STR00360##

59-60. (canceled)

61. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.6a and R.sub.6b are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, condensed ring group, and heterocondensed ring group which is optionally substituted by R.sub.6c; or when R.sub.6a and R.sub.6b are linked to the same nitrogen atom, R.sub.6a and R.sub.6b, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocyclyl or 5- to 12-membered heteroaryl which is optionally substituted by R.sub.6c; or, R.sub.6a and R.sub.6b are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-8 aryl, and 5- to 10-membered heteroaryl which is optionally substituted by R.sub.6c; or R.sub.6a and R.sub.6b are, for each presence, independently selected from the group consisting of hydrogen and any one of C.sub.1-3 alkyl and C.sub.1-3 alkoxy which is optionally substituted by R.sub.6a; or R.sub.6a and R.sub.6b are, for each presence, independently selected from the group consisting of hydrogen and any one of methyl and ethyl which is optionally substituted by R.sub.6c.

62. (canceled)

63. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.6e is, for each presence, independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, R.sub.6a, OR.sub.6a, N(R.sub.6a)R.sub.6e, C(O)R.sub.6d, C(O)N(R.sub.6a)R.sub.6e, N(R.sub.6d)C(O)R.sub.6e, and C(O)OR.sub.6d; or R.sub.6e is, for each presence, independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, R.sub.6a, OR.sub.6a, N(R.sub.6a)R.sub.6e, C(O)R.sub.6d, C(O)N(R.sub.6a)R.sub.6e, N(R.sub.6d)C(O)R.sub.6e, and C(O)OR.sub.6d; or, R.sub.6e is, for each presence, independently selected from the group consisting of hydrogen, fluorine, chlorine, hydroxyl, amino, NH(C.sub.1-6 alkyl), N(CH.sub.3)(C.sub.1-6 alkyl), C(O)(C.sub.1-6 alkyl), C(O)NH(C.sub.1-6 alkyl), NHC(O)(C.sub.1-6 alkyl), C(O)O(C.sub.1-6 alkyl), C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-8 aryl, and 5- to 10-membered heteroaryl; or R.sub.6c is, for each presence, independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy; or R.sub.6c is, for each presence, independently selected from the group consisting of hydrogen, fluorine, chlorine, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, and isopropoxy.

64. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.6d and R.sub.6e are, for each presence, independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, cyano, and any one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-14 aryl, 5- to 12-membered heteroaryl, condensed ring group, and heterocondensed ring group which is optionally substituted by halogen, hydroxyl, amino, or C.sub.1-6 alkyl; or when R.sub.6d and R.sub.6e are linked to the same nitrogen atom, R.sub.6d and R.sub.6e, together with the nitrogen atom linked thereto, form 3- to 10-membered heterocyclyl or 5- to 12-membered heteroaryl which is optionally substituted by halogen, hydroxyl, amino, or C.sub.1-6 alkyl; or, R.sub.6d and R.sub.6e are, for each presence, independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C.sub.6-8 aryl, and 5- to 10-membered heteroaryl.

65-77. (canceled)

78. The compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt according to claim 1, wherein the compound is selected from the group consisting of: ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396##

79. A pharmaceutical composition, comprising the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1.

80-81. (canceled)

82. A pharmaceutical composition, comprising the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, as well as at least one additional anti-tumor agent; or, a pharmaceutical composition, comprising the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1, as well as at least one additional anti-tumor agent, said anti-tumor agent being selected from the group consisting of adriamycin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin, epirubicin, olaparib, MEDI4736, AZD1775, and AZD6738.

83. An intermediate for preparing the compound according to claim 1, having a structure as represented by formula (M-1), formula (M-2), or formula (M-3): ##STR00397## wherein R.sub.x1 is selected from the group consisting of halogen and hydrogen, and R.sub.4, R.sub.6, R.sub.7, A, W, L, t.sub.1, t.sub.2, and h are as defined in claim 1; or, having a structure as represented by formula (M-4): ##STR00398## wherein R.sub.x2 is selected from the group consisting of halogen and hydrogen; and R.sub.4, R.sub.6, R.sub.7, A, W, L, t.sub.1, t.sub.2, and h are as defined in claim 1: or, having a structure as represented by formula (M-5): ##STR00399## wherein R.sub.x3 is selected from the group consisting of halogen and hydrogen; and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, t.sub.2, and h are as defined in claim 1: or, having a structure as represented by formula (M-6): ##STR00400## wherein R.sub.x4 is selected from the group consisting of halogen and hydrogen; and R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, t.sub.2, and h are as defined in claim 1.

84. An intermediate as follows for preparing the compound according to claim 1: ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407## ##STR00408## ##STR00409## ##STR00410## ##STR00411## ##STR00412## ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426##

85. A method for preparing the compound according to claim 1, being selected from any one of the following synthetic schemes: synthetic scheme 1: ##STR00427## i) compound I-a1 is converted to compound I-a2 via chemical conversion; ii) compound I-a2 is converted to compound I-a4 via chemical conversion; iii) compound I-a4 is converted to compound I-a5 via chemical conversion; iv) compound I-a5 is converted to compound I-a6 via chemical conversion; v) compound I-a6 is converted to compound I-a7 via chemical conversion; vi) compound I-a7 is converted to compound I-a8 via chemical conversion; vii) compound I-a8 is converted to compound of formula I via chemical conversion; synthetic scheme 2: ##STR00428## wherein i) compound I-b1 is used as a basic starting material to obtain compound I-b2; ii) compound I-b2 and compound I-b3 are used basic starting materials to obtain compound I-b4; iii) compound I-b4 is used as a basic starting material to obtain compound I-b5; iv) compound I-b5 is used as a basic starting material to obtain compound I-b6; v) compound I-b6 is used as a basic starting material to obtain compound I-b7; vi) compound I-b7 is used as a basic starting material to obtain compound I-b8; vii) compound I-b8 is used as a basic starting material to obtain compound I-b9; viii) compound I-b9 is used as a basic starting material to obtain the compound of formula I; synthetic scheme 3: ##STR00429## wherein i) compound I-b1 is used as a basic starting material to obtain compound I-b2; ii) compound I-b2 and compound I-b3 are used basic starting materials to obtain compound I-b5; iii) compound I-b5 is used as a basic starting material to obtain compound I-b6; iv) compound I-b6 is used as a basic starting material to obtain compound I-b7; v) compound I-b7 is used as a basic starting material to obtain compound I-b8; vi) compound I-b8 is used as a basic starting material to obtain compound I-b9; vii) compound I-b9 is used as a basic starting material to obtain the compound of formula I; wherein R.sub.x1 is selected from the group consisting of halogen and hydrogen, and X.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.7, A, W, L, t.sub.1, and t.sub.2 are as defined in claim 1.

86. A method for preventing and/or treating a disease and/or disorder which is at least partially mediated by ATM kinase, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof; or, a method for preventing and/or treating a disease and/or disorder which is at least partially mediated by ATM kinase, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof, wherein said disease and/or disorder which is at least partially mediated by ATM kinase is a cancer; or, a method for preventing and/or treating a disease and/or disorder which is at least partially mediated by ATM kinase, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof, wherein said disease and/or disorder which is at least partially mediated by ATM kinase is a cancer; wherein said cancer includes a solid tumor and a hematological tumor or wherein said cancer includes breast cancer, non-small cell lung cancer, brain glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, and glioblastoma.

87. The method according to claim 86, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1 with at least one additional anti-tumor agent or therapeutic treatment to a subject in need thereof; or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1 with at least one additional anti-tumor agent or therapeutic treatment to a subject in need thereof, wherein said disease and/or disorder which is at least partially mediated by ATM kinase is a cancer; or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1 with at least one additional anti-tumor agent or therapeutic treatment to a subject in need thereof, wherein said cancer includes a solid tumor and a hematological tumor or wherein said cancer includes breast cancer, non-small cell lung cancer, brain glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, and glioblastoma; or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1 with at least one additional anti-tumor agent in need thereof, wherein said anti-tumor agent is selected from the group consisting of adriamycin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin, epirubicin, olaparib, or, a method for preventing and/or treating a disease and/or disorder which is at least partially mediated by ATM kinase, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 1 with at least one additional therapeutic treatment to a subject in need thereof, wherein the therapeutic treatment is radiation therapy.

88. A pharmaceutical composition, comprising the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78.

89. A pharmaceutical composition, comprising the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78, as well as at least one additional anti-tumor agent; or, a pharmaceutical composition, comprising the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78, as well as at least one additional anti-tumor agent, said anti-tumor agent being selected from the group consisting of adriamycin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin, epirubicin, olaparib, MEDI4736, AZD1775, and AZD6738.

90. A pharmaceutical composition, comprising the pharmaceutical composition according to claim 88, as well as at least one additional anti-tumor agent; or, a pharmaceutical composition, comprising the pharmaceutical composition according to claim 88, as well as at least one additional anti-tumor agent, said anti-tumor agent being selected from the group consisting of adriamycin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin, epirubicin, olaparib, MEDI4736, AZD1775, and AZD6738.

91. A method for preventing and/or treating a disease and/or disorder which is at least partially mediated by ATM kinase, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78 to a subject in need thereof; or, a method for preventing and/or treating a disease and/or disorder which is at least partially mediated by ATM kinase, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78 to a subject in need thereof, wherein said disease and/or disorder which is at least partially mediated by ATM kinase is a cancer; or, a method for preventing and/or treating a cancer, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78 to a subject in need thereof, wherein said cancer includes a solid tumor and a hematological tumor or wherein said cancer includes breast cancer, non-small cell lung cancer, brain glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, and glioblastoma.

92. The method according to claim 91, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78 with at least one additional anti-tumor agent or therapeutic treatment to a subject in need thereof, or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78 with at least one additional anti-tumor agent or therapeutic treatment to a subject in need thereof, wherein said disease and/or disorder which is at least partially mediated by ATM kinase is a cancer; or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78 with at least one additional anti-tumor agent or therapeutic treatment to a subject in need thereof, wherein said cancer includes a solid tumor and a hematological tumor or wherein said cancer includes breast cancer, non-small cell lung cancer, brain glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, and glioblastoma; or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78 with at least one additional anti-tumor agent in need thereof, wherein said anti-tumor agent is selected from the group consisting of adriamycin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin, epirubicin, olaparib, MEDI4736, AZD1775, and AZD6738; or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 78 with at least one additional therapeutic treatment to a subject in need thereof, wherein the therapeutic treatment is radiation therapy.

93. A method for preventing and/or treating a disease and/or disorder which is at least partially mediated by ATM kinase, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 88 to a subject in need thereof, or, a method for preventing and/or treating a disease and/or disorder which is at least partially mediated by ATM kinase, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 88 to a subject in need thereof, wherein said disease and/or disorder which is at least partially mediated by ATM kinase is a cancer; or, a method for preventing and/or treating a cancer, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 88 to a subject in need thereof, wherein said cancer includes a solid tumor and a hematological tumor or wherein said cancer includes breast cancer, non-small cell lung cancer, brain glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, and glioblastoma.

94. The method according to claim 93, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 88 with at least one additional anti-tumor agent or therapeutic treatment to a subject in need thereof, or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 88 with at least one additional anti-tumor agent or therapeutic treatment to a subject in need thereof, wherein said disease and/or disorder which is at least partially mediated by ATM kinase is a cancer; or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 88 with at least one additional anti-tumor agent or therapeutic treatment to a subject in need thereof, wherein said cancer includes a solid tumor and a hematological tumor or wherein said cancer includes breast cancer, non-small cell lung cancer, brain glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, and glioblastoma; or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 88 with at least one additional anti-tumor agent in need thereof, wherein said anti-tumor agent is selected from the group consisting of adriamycin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin, epirubicin, olaparib, MEDI4736, AZD1775, and AZD6738; or, wherein the method comprises administering a prophylactically and/or therapeutically effective amount of the compound or the prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof according to claim 88 with at least one additional therapeutic treatment to a subject in need thereof, wherein the therapeutic treatment is radiation therapy.

Description

DETAILED DESCRIPTION

[0389] The present disclosure will be further described in connection with the specific examples below. It should be understood that these embodiments are merely intended to illustrate the present disclosure and not to limit the scope of the present disclosure.

[0390] The experimental methods without specific conditions in the following examples usually follow the conventional conditions or the conditions suggested by the manufacturers. In addition, any method and material similar to or equal to the content as described herein can be applied to the method of the present disclosure.

[0391] Unless otherwise specified, scientific and technical terms used in the following examples have meanings familiar to those skilled in the art. Abbreviations used in the preparation examples, examples, and elsewhere in the context have the meanings as follows. [0392] DCM dichloromethane [0393] TEA triethylamine [0394] DIEA/N,N-diisopropylethylamine [0395] DIPEA [0396] DMF N,N-dimethylformamide [0397] EtOAc ethyl acetate [0398] h hour [0399] mL milliliter [0400] HATU 2-(7-azobenzotriazol-1-yl)-N,N,N,N-tetramethyluronium [0401] hexafluorophosphate [0402] MeOH methanol [0403] TFA trifluoroacetic acid [0404] DMSO-d.sub.6 dimethyl sulfoxide-d.sub.6

[0405] INTERMEDIATE PREPARATION EXAMPLE

[0406] Intermediate preparation example 1: Preparation of (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-1)

##STR00138##

[0407] Step 1: Synthesis of diethyl 2-(((4-bromo-3,5-difluorophenyl)amino)methylene)malonate

[0408] 4-bromo-3,5-difluoroaniline (5.00 g, 24 mmol), diethyl 2-(ethoxymethylene)malonate (7.80 g, 36 mmol), and anhydrous ethanol (50 mL) were added to a 250 mL reaction bottle. The reaction solution was heated to reflux for 8 h. When the reaction was completed as detected by thin-layer chromatography (TLC), the reaction solution was cooled down to 10? C. to precipitate a white solid, and then the solid was collected by suction filtration, rinsed with n-hexane, and dried to afford diethyl 2-(((4-bromo-3,5-difluorophenyl)amino)methylene)malonate (7.3 g, 80.3% yield). ESI-MS (m/z): 378.01/380.01 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.236-1.269 (m, 6H), 4.137 (q, 2H), 4.216 (q, 2H), 7.483-7.506 (t, 2H), 8.308 (d, 1H), 10.613 (d, 1H).

[0409] Step 2: Synthesis of ethyl 6-bromo-5,7-difluoro-4-hydroxyquinoline-3-carboxylate

[0410] Diphenyl ether (80 mL) was added to a 250 mL reaction bottle and heated up to 240? C., followed by adding diethyl 2-(((4-bromo-3,5-difluorophenyl)amino)methylene)malonate (7.30 g, 19.3 mmol) in batches. The reaction solution was reacted for 1 h at 240? C. When the reaction was completed as detected by TLC, the reaction solution was cooled down to 25? C. to precipitate a crystalline solid, the mixture was diluted with ether (80 mL), and the solid was collected by suction filtration, rinsed with n-hexane, and dried to afford ethyl 6-bromo-5,7-difluoro-4-hydroxyquinoline-3-carboxylate (5.50 g, 85.8% yield). ESI-MS (m/z): 331.97/333.96 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.271 (t, 3H), 4.208 (q, 2H), 7.402 (d, 1H), 8.528 (s, 1H), 12.404 (s, 1H).

[0411] Step 3: Synthesis of ethyl 6-bromo-4-chloro-5,7-difluoroquinoline-3-carboxylate

[0412] Thionyl chloride (20 mL) and ethyl 6-bromo-5,7-difluoro-4-hydroxyquinoline-3-carboxylate (1.40 g, 4.2 mmol) were added to a 100 mL reaction bottle. The reaction solution was reacted for 3 h at 80? C. When the reaction was completed as detected by TLC, the reaction solution was cooled down and concentrated to dryness to afford a crude product of ethyl 6-bromo-4-chloro-5,7-difluoroquinoline-3-carboxylate (1.48 g, 100% yield). ESI-MS (m/z): 351.93 [M+H].sup.+.

[0413] Step 4: Synthesis of ethyl (S)-6-bromo-5,7-difluoro-4-((1-hydroxypropan-2-yl)amino)quinoline-3-carboxylate

[0414] DMF (20 mL), ethyl 6-bromo-4-chloro-5,7-difluoroquinoline-3-carboxylate (1.48 g, 4.2 mmol), L-aminopropanol (0.47 g, 6.3 mmol), and DIEA (1.09 g, 8.4 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature followed by adding water to precipitate a solid, and then the solid was collected by suction filtration, rinsed with water, and dried to afford ethyl (S)-6-bromo-5,7-difluoro-4-((1-hydroxypropan-2-yl)amino)quinoline-3-carboxylate (1.2 g, 73.4% yield). ESI-MS (m/z): 389.02/391.02 [M+H].sup.+; .sup.1H NMR (600 MHz, CDCl.sub.3) ?: 1.429 (t, 3H), 1.555 (d, 3H), 4.292-4.356 (m, 2H), 4.420 (q, 2H), 4.638 (d, 1H), 8.010 (s, 1H), 9.048 (s, 1H), 11.557 (s, 1H).

[0415] Step 5: Synthesis of (S)-10-bromo-9-fluoro-3-methyl-3,4-dihydro-2H-[1,4]oxazepino[5,6,7-de]quinoline-5-carboxylic acid

[0416] Tetreahydrofuran (THF) (10 mL), ethyl (S)-6-bromo-5,7-difluoro-4-((1-hydroxypropan-2-yl)amino)quinoline-3-carboxylate (1.20 g, 3.08 mmol), water (5 mL) and sodium hydroxide (0.37 g, 9.24 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 60? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature followed by adjusting pH to 5 with 1N hydrochloric acid to precipitate a solid, and then the solid was collected by suction filtration, rinsed with water and dried to afford (S)-10-bromo-9-difluoro-3-methyl-3,4-dihydro-2H-[1,4]oxazepino[5,6,7-de]quinoline-5-carboxylic acid (0.8 g, 76.1% yield). ESI-MS (m/z): 340.99/342.98 [M+H].sup.+.

[0417] Step 6: Synthesis of (S)-7-bromo-6-fluoro-10-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0418] DMF (15 mL), (S)-10-bromo-9-fluoro-3-methyl-3,4-dihydro-2H-[1,4]oxazepino[5,6,7-de]quinoline-5-carboxylic acid (0.8 g, 2.35 mmol), DIEA (0.46 g, 3.53 mmol), and diphenyl azidophosphate (0.78 g, 2.82 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 60? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature followed by adding water to precipitate a solid, and then the solid was collected by suction filtration, rinsed with water, and dried to afford (S)-7-bromo-6-fluoro-10-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.7 g, 88.1% yield). ESI-MS (m/z): 337.99/339.98 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.443 (d, 3H), 4.593-4.616 (m, 2H), 4.803-4.829 (m, 1H), 7.594 (d, 1H), 8.678 (s, 1H), 11.681 (s, 1H).

[0419] Step 7: Synthesis of (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-1)

[0420] DMF (15 mL) and (S)-7-bromo-6-fluoro-10-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.7 g, 2.07 mmol) were successively added to a 100 mL reaction bottle and cooled down to 0? C. followed by adding NaH (0.124 g, 3.11 mmol), the reaction was conducted at this temperature for 0.5 h, then iodomethane (0.441 g, 3.11 mmol) was added and the reaction was continued overnight at room temperature. When the reaction was completed as detected by TLC, the reaction solution was added with water to precipitate a solid, and then the solid was collected by suction filtration, rinsed with water, and dried to afford (S)-7-bromo-6-fluoro-2,10-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.62 g, 85.1% yield). ESI-MS (m/z): 352.00/354.00 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.451 (d, 3H), 3.536 (s, 3H), 4.590-4.612 (m, 1H), 4.651-4.665 (m, 1H), 4.814-4.841 (m, 1H), 7.635 (d, 1H), 8.925 (s, 1H).

[0421] Intermediate preparation example 2: Preparation of (R)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-2)

##STR00139##

[0422] The synthesis method was the same as that of intermediate preparation example 1, except that D-aminopropanol was used instead of L-aminopropanol to afford (R)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 75.4%. ESI-MS (m/z): 352.20/354.19 [M+H].sup.+.

[0423] Intermediate preparation example 3: Preparation of 7-bromo-6-fluoro-9-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

##STR00140##

[0424] The synthesis method was the same as that of intermediate preparation example 1, except that 2-amino-1-(4-fluorophenyl)ethanol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-9-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 82.4%. ESI-MS (m/z): 432.01/434.01 [M+H].sup.+.

[0425] Intermediate preparation example 4: Preparation of 7-bromo-6-fluoro-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-4)

##STR00141##

[0426] The synthesis method was the same as that of intermediate preparation example 1, except that 2-amino-2-methylpropanol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 82.4%. ESI-MS (m/z): 366.01/368.01 [M+H].sup.+.

[0427] Intermediate preparation example 5: Preparation of 7-bromo-6-fluoro-2-methyl-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-5)

##STR00142##

[0428] The synthesis method was the same as that of intermediate preparation example 1, except that 2-amino-1-(pyridin-2-yl)ethanol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-2-methyl-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one. ESI-MS (m/z): 415.01/417.01 [M+H].sup.+.

[0429] Intermediate preparation example 6: Preparation of (R)-7-bromo-6-fluoro-10-isobutyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-6)

##STR00143##

[0430] The synthesis method was the same as that of intermediate preparation example 1, except that D-leucinol was used instead of L-aminopropanol to afford (R)-7-bromo-6-fluoro-10-isobutyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 30.9%. ESI-MS (m/z): 394.05/396.05 [M+H].sup.+.

[0431] Intermediate preparation example 7: Preparation of (S)-7-bromo-6-fluoro-10-isobutyl-2-methyl-9,10-dihydro-8-oxo-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-7)

##STR00144##

[0432] The synthesis method was the same as that of intermediate preparation example 1, except that L-leucinol was used instead of L-aminopropanol to afford (S)-7-bromo-6-fluoro-10-isobutyl-2-methyl-9,10-dihydro-8-oxo-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 51.0%. ESI-MS (m/z): 393.92/395.87 [M+H].sup.+.

[0433] Intermediate preparation example 8: Preparation of 7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-8)

##STR00145##

[0434] The synthesis method was the same as that of preparation example 1, except that mercaptoethylamine was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 82.1%. ESI-MS (m/z): 353.96/355.97 [M+H].sup.+.

[0435] Intermediate preparation example 9: Preparation of 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (M-9)

##STR00146##

[0436] The synthesis method was the same as that of intermediate preparation example 1, except that (1-aminocyclopropyl)methanol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one with a yield of 43.7%. ESI-MS (m/z): 364.01/366.01 [M+H].sup.+.

[0437] Intermediate preparation example 10: Preparation of 7-bromo-9-(ethoxymethyl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-10)

##STR00147##

[0438] The synthesis method was the same as that of preparation example 1, except that 1-amino-3-ethoxypropan-2-ol was used instead of L-aminopropanol to afford 7-bromo-9-(ethoxymethyl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 49.3%. ESI-MS (m/z): 396.03/398.03 [M+H].sup.+.

[0439] Intermediate preparation example 11: Preparation of (S)-10-benzyl-7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-11)

##STR00148##

[0440] The synthesis method was the same as that of preparation example 1, except that (S)-2-amino-3-phenylpropan-1-ol was used instead of L-aminopropanol to afford (S)-10-benzyl-7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 53.2%. ESI-MS (m/z): 428.03/430.03 [M+H].sup.+.

[0441] Intermediate preparation example 12: Preparation of (R)-10-benzyl-7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-12)

##STR00149##

[0442] The synthesis method was the same as that of preparation example 1, except that (R)-2-amino-3-phenylpropan-1-ol was used instead of L-aminopropanol to afford (R)-10-benzyl-7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 32.6%. ESI-MS (m/z): 428.03/430.03 [M+H].sup.+.

[0443] Intermediate preparation example 13: Preparation of 7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-13)

##STR00150##

[0444] The synthesis method was the same as that of intermediate preparation example 1, except that 2-aminoethanol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 40.7%. ESI-MS (m/z): 337.99/339.99 [M+H].sup.+.

[0445] Intermediate preparation example 14: Preparation of (S)-7-bromo-6-fluoro-10-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-14)

##STR00151##

[0446] The synthesis method was the same as that of intermediate preparation example 1, except that L-valinol was used instead of L-aminopropanol to afford (S)-7-bromo-6-fluoro-10-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 52.3%. ESI-MS (m/z): 380.03/382.03 [M+H].sup.+.

[0447] Intermediate preparation example 15: Preparation of (R)-7-bromo-6-fluoro-10-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-15)

##STR00152##

[0448] The synthesis method was the same as that of intermediate preparation example 1, except that D-valinol was used instead of L-aminopropanol to afford (R)-7-bromo-6-fluoro-10-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 59.3%. ESI-MS (m/z): 380.03/382.03 [M+H].sup.+.

[0449] Intermediate preparation example 16: Preparation of 7-bromo-6-fluoro-9-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-16)

##STR00153##

[0450] The synthesis method was the same as that of intermediate preparation example 1, except that 1-amino-3-methylbutan-2-ol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-9-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 30.6%. ESI-MS (m/z): 380.03/382.03 [M+H].sup.+.

[0451] Intermediate preparation example 17: Preparation of (S)-7-bromo-9-((dimethylamino)methyl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-17)

##STR00154##

[0452] The synthesis method was the same as that of preparation example 1, except that (R)-1-amino-3-(dimethylamino)propan-2-ol was used instead of L-aminopropanol to afford (S)-7-bromo-9-((dimethylamino)methyl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 75.5%. ESI-MS (m/z): 395.04/397.04 [M+H].sup.+.

[0453] Intermediate preparation example 18: Preparation of (S)-7-bromo-6-fluoro-2-methyl-9-(piperidin-1-ylmethyl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-18)

##STR00155##

[0454] The synthesis method was the same as that of intermediate preparation example 1, except that (R)-1-amino-3-(piperidin-1-yl)propan-2-ol was used instead of L-aminopropanol to afford (S)-7-bromo-6-fluoro-2-methyl-9-(piperidin-1-ylmethyl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 72.1%. ESI-MS (m/z): 435.08/437.08 [M+H].sup.+.

[0455] Intermediate preparation example 19: Preparation of 5-bromo-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (M-19)

##STR00156##

[0456] The synthesis method was the same as that of preparation example 1, except that 2-aminocyclohexanol was used instead of L-aminopropanol to afford 5-bromo-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one with a yield of 68.5%. ESI-MS (m/z): 392.03/394.03 [M+H].sup.+.

[0457] Intermediate preparation example 20: Preparation of (R)-7-bromo-10-ethyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-20)

##STR00157##

[0458] The synthesis method was the same as that of intermediate preparation example 1, except that (R)-2-aminobutan-1-ol was used instead of L-aminopropanol to afford (R)-7-bromo-10-ethyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 71.5%. ESI-MS (m/z): 366.02/368.02 [M+H].sup.+.

[0459] Intermediate preparation example 21: Preparation of (S)-7-bromo-10-ethyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-21)

##STR00158##

[0460] The synthesis method was the same as that of intermediate preparation example 1, except that (S)-2-aminobutan-1-ol was used instead of L-aminopropanol to afford (S)-7-bromo-10-ethyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 68.5%. ESI-MS (m/z): 366.02/368.02 [M+H].sup.+.

[0461] Intermediate preparation example 22: Preparation of 7-bromo-6-fluoro-2,9-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-22)

##STR00159##

[0462] The synthesis method was the same as that of intermediate preparation example 1, except that 1-aminopropan-2-ol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-2,9-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 82.4%. ESI-MS (m/z): 352.00/354.00 [M+H].sup.+.

[0463] Intermediate preparation example 23: Preparation of 7-bromo-6-fluoro-9-(2-fluoropyridin-4-yl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-23)

##STR00160##

[0464] The synthesis method was the same as that of intermediate preparation example 1, except that 2-amino-1-(2-fluoropyridin-4-yl)ethanol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-9-(2-fluoropyridin-4-yl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 32.5%. ESI-MS (m/z): 433.00/435.00 [M+H].sup.+.

[0465] Intermediate preparation example 24: Preparation of 7-bromo-10-cyclopropyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-24)

##STR00161##

[0466] The synthesis method was the same as that of intermediate preparation example 1, except that 2-amino-2-cyclopropylethanol was used instead of L-aminopropanol to afford 7-bromo-10-cyclopropyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 28.4%. ESI-MS (m/z): 378.02/380.02 [M+H].sup.+.

[0467] Intermediate preparation example 25: Preparation of 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (M-25)

##STR00162##

[0468] The synthesis method was the same as that of intermediate preparation example 1, except that (1-aminocyclobutyl)methanol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one with a yield of 37.5%. ESI-MS (m/z): 377.93/379.95 [M+H].sup.+.

[0469] Intermediate preparation example 26: Preparation of ethyl (6aR,10aS)-5-bromo-4-fluoro-12-methyl-11-oxo-6a,7,10,10a,11,12-hexahydro-6-oxa-2,8,10b,12-tetraazacyclopentadiene-8(9H)-carboxylate (M-26)

##STR00163##

[0470] The synthesis method was the same as that of intermediate preparation example 1, except that ethyl (3S,4R)-4-amino-3-hydroxypiperidin-1-carboxylate was used instead of L-aminopropanol to afford ethyl (6aR,10aS)-5-bromo-4-fluoro-12-methyl-11-oxo-6a,7,10,10a,11,12-hexahydro-6-oxa-2,8,10b,12-tetraazacyclopentadiene-8(9H)-carboxylate with a yield of 37.5%. ESI-MS (m/z): 464.93/466.95 [M+H].sup.+.

[0471] Intermediate preparation example 27: Preparation of 7-bromo-6-fluoro-10-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-27)

##STR00164##

[0472] The synthesis method was the same as that of intermediate preparation example 1, except that 2-amino-2-(4-fluorophenyl)ethanol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-10-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (100 mg, 32% yield). ESI-MS (m/z): 432.21/434.25 [M+H].sup.+.

[0473] Intermediate preparation example 28: Preparation of 7-bromo-6-methoxy-2-methyl-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-28)

##STR00165## ##STR00166##

[0474] Step 1: Synthesis of 4-bromo-3-fluoro-5-methoxyaniline

[0475] 3-fluoro-5-methoxyaniline (4.1 g, 29.1 mmol) and DMF (50 mL) were successively added to a 250 mL reaction bottle, followed by adding N-bromosuccinimide (NBS) (5.2 g, 29.1 mmol) in batches at room temperature, and the reaction solution was reacted at room temperature for 1 h. After the reaction solution was cooled down, 100 mL of water and 100 mL of ethyl acetate were added into the reaction solution, the target product was extracted into the organic phase, and the organic phase was separated and concentrated to dryness, and then the residue was purified by column chromatography (PE:EA=10:1-2:1) to afford 4-bromo-3-fluoro-5-methoxyaniline (4.90 g). ESI-MS (m/z): 219.98/222.01 [M+H].sup.+.

[0476] Step 2: Synthesis of diethyl 2-(((4-bromo-3-fluoro-5-methoxyphenyl)amino)methylene)malonate

[0477] 4-bromo-3-fluoro-5-methoxyaniline (4.8 g, 21.8 mmol), diethyl 2-(ethoxymethylene)malonate (7.0 g, 32.4 mmol), and 50 mL of anhydrous ethanol were successively added to a 250 mL reaction bottle. The reaction solution was heated to reflux and reacted for 6 h, then cooled down to room temperature and added with 100 mL of n-hexane at room temperature, and then the reaction mixture was filtrated to afford diethyl 2-(((4-bromo-3-fluoro-5-methoxyphenyl)amino)methylene)malonate (5.9 g). ESI-MS (m/z): 390.20/392.18 [M+H].sup.+.

[0478] Step 3: Synthesis of ethyl 6-bromo-5-fluoro-4-hydroxy-7-methoxyquinoline-3-carboxylate

[0479] 40 mL of diphenyl ether was added to a 250 mL reaction bottle and heated up to 240? C., followed by adding diethyl 2-(((4-bromo-3-fluoro-5-methoxyphenyl)amino)methylene)malonate (5.9 g, 15.1 mmol) in batches. The reaction solution was reacted at this temperature for 1 h, then cooled down to room temperature and added with 100 mL of n-hexane at room temperature, and then the reaction mixture was filtrated to afford ethyl 6-bromo-5-fluoro-4-hydroxy-7-methoxyquinoline-3-carboxylate (4.6 g). ESI-MS (m/z): 344.14/346.18 [M+H].sup.+.

[0480] Step 4: Synthesis of ethyl 6-bromo-4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate

[0481] Ethyl 6-bromo-5-fluoro-4-hydroxy-7-methoxyquinolin-3-carboxylate (800 mg, 2.32 mmol) and thionyl chloride (10 mL) were added to a 100 mL reaction bottle, and added dropwise with DMF (two drops). After refluxing for 4 h, the reaction was completed, and the concentration under reduced pressure was carried out to dryness to afford ethyl 6-bromo-4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate (840 mg). ESI-MS (m/z): 361.91/363.99 [M+H].sup.+.

[0482] Step 5: Synthesis of ethyl 6-bromo-5-fluoro-4-((2-hydroxy-1-(pyridin-2-yl)ethyl)amino)-7-methoxyquinoline-3-carboxylate

[0483] Ethyl 6-bromo-4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate (840 mg, 2.32 mmol), DMF (10 mL), DIPEA (1500 mg, 11.6 mmol), and 2-amino-2-(pyridin-2-yl)ethanol (600 mg, 2.84 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. to react for 2 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature, added with water, and then filtrated, and the filter cake was dried to afford ethyl 6-bromo-5-fluoro-4-((2-hydroxy-1-(pyridin-2-yl)ethyl)amino)-7-methoxyquinoline-3-carboxylate (1.1 g). ESI-MS (m/z): 464.29/466.30 [M+H].sup.+.

[0484] Step 6: Synthesis of 10-bromo-9-methoxy-3-(pyridin-2-yl)-3,4-dihydro-2H-[1,4]oxazepino[5,6,7-de]quinoline-5-carboxylic acid

[0485] Ethyl 6-bromo-5-fluoro-4-((2-hydroxy-1-(pyridin-2-yl)ethyl)amino)-7-methoxyquinoline-3-carboxylate (1100 mg, 2.37 mmol), THF (10 mL), water (5 mL), and sodium hydroxide (520 mg, 13.0 mmol) were added to a 100 mL reaction bottle. The reaction solution was heated up to 60? C. to react for 8 h. When the reaction was completed, THF was removed under reduced pressure, the pH value was adjusted to 3 with 6N hydrochloric acid, and filtration was carried out to afford 10-bromo-9-methoxy-3-(pyridin-2-yl)-3,4-dihydro-2H-[1,4]oxazepino[5,6,7-de]quinoline-5-carboxylic acid (0.3 g). ESI-MS (m/z): 416.19/418.20 [M+H].sup.+.

[0486] Step 7: Synthesis of 7-bromo-6-methoxy-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0487] 10-bromo-9-methoxy-3-(pyridin-2-yl)-3,4-dihydro-2H-[1,4]oxazepino[5,6,7-de]quinoline-5-carboxylic acid (300 mg, 0.72 mmol), DMF (10 mL), triethylamine (150 mg, 1.48 mmol), and DPPA (300 mg, 1.09 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. to react for 2 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature followed by adding water to precipitate a solid, and then the solid was filtrated to afford 7-bromo-6-methoxy-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.3 g). ESI-MS (m/z): 412.19/414.23 [M+H].sup.+.

[0488] Step 8: Synthesis of 7-bromo-6-methoxy-2-methyl-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0489] 7-bromo-6-methoxy-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (300 mg, 0.72 mmol), cesium carbonate (474 mg, 1.45 mmol), and DMF (10 mL) were successively added to a reaction bottle, followed by adding iodomethane (155 mg, 1.10 mmol) at room temperature, and the reaction solution was reacted for 1.5 h at room temperature. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature followed by adding water to precipitate a solid, and the solid was filtrated to afford 7-bromo-6-methoxy-2-methyl-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.2 g) with a yield of 64.5%. ESI-MS (m/z): 427.03/429.03 [M+H].sup.+.

[0490] Intermediate preparation example 29: Preparation of (S)-7-bromo-6-methoxy-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-29)

##STR00167##

[0491] The synthesis method was the same as that of intermediate preparation example 1, except that 4-bromo-3-fluoro-5-methoxyaniline was used instead of 4-bromo-3,5-difluoroaniline to afford (S)-7-bromo-6-methoxy-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 82.4%. ESI-MS (m/z): 364.02/366.02 [M+H].sup.+.

[0492] Intermediate preparation example 30: Preparation of (R)-7-bromo-6-methoxy-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-30)

##STR00168##

[0493] The synthesis method was the same as that of intermediate preparation example 1, except that 4-bromo-3-fluoro-5-methoxyaniline was used instead of 4-bromo-3,5-difluoroaniline, and (R)-2-aminopropan-1-ol was used instead of (S)-2-aminopropan-1-ol, to afford (R)-7-bromo-6-methoxy-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 82.4%. ESI-MS (m/z): 364.02/366.02 [M+H].sup.+.

[0494] Intermediate preparation example 31: Preparation of 5-bromo-4-methoxy-12-methyl-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (M-31)

##STR00169##

[0495] Step 1: Synthesis of ethyl 6-bromo-5-fluoro-4-((2-hydroxyphenyl)amino)-7-methoxyquinoline-3-carboxylate

[0496] Ethyl 6-bromo-4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate (840 mg, 2.32 mmol), 2-aminophenol (280 mg, 2.57 mmol), and glacial acetic acid (10 mL) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 60? C. to react for 1 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature and added with water and ethyl acetate. Then the organic phase was separated, washed twice with saturated sodium bicarbonate, and concentrated to dryness under reduced pressure to afford ethyl 6-bromo-5-fluoro-4-((2-hydroxyphenyl)amino)-7-methoxyquinoline-3-carboxylate (1.0 g).

[0497] Step 2: Synthesis of 6-bromo-5-methoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylic acid

[0498] Ethyl 6-bromo-5-fluoro-4-((2-hydroxyphenyl)amino)-7-methoxyquinoline-3-carboxylate (1000 mg, 2.30 mmol), THF (10 mL), water (5 mL), and sodium hydroxide (460 mg, 11.5 mmol) were added to a 100 mL reaction bottle. The reaction solution was heated up to 60? C. to react for 8 h. After the reaction was completed, THF was removed under reduced pressure, the pH value was adjusted to 3 with 6N hydrochloric acid, and filtration was carried out to afford 6-bromo-5-methoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylic acid (0.86 g).

[0499] Step 3: Synthesis of 5-bromo-4-methoxy-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one

[0500] 6-bromo-5-methoxy-12H-benzo[2,3][1,4]oxazepino [5,6,7-de]quinoline-1-carboxylic acid (860 mg, 2.22 mmol), DMF (10 ml), triethylamine (450 mg, 4.45 mmol), and DPPA (917 mg, 3.33 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. to react for 2 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature followed by adding water to precipitate a solid, and then the solid was filtrated to afford 5-bromo-4-methoxy-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (0.84 g).

[0501] Step 4: Synthesis of 5-bromo-4-methoxy-12-methyl-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one

[0502] 5-bromo-4-methoxy-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (840 mg, 2.19 mmol), cesium carbonate (1420 mg, 4.36 mmol), and DMF (10 ml) were successively added to a reaction bottle, followed by adding iodomethane (466 mg, 3.28 mmol) dropwise at room temperature, then the reaction solution was reacted for 1.5 h at room temperature. When the reaction was completed as detected by TLC, the reaction solution was added with water to precipitate a solid, and then the solid was filtrated to afford 5-bromo-4-methoxy-12-methyl-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (0.76 g, 87.3% yield). ESI-MS (m/z): 398.01/400.01 [M+H].sup.+.

[0503] Intermediate preparation example 32: Preparation of 5-bromo-4-methoxy-12-methyl-6-oxa-2,9,10b,12-tetraazacyclopenta[gh]pleiaden-11(12H)-one (M-32)

##STR00170##

[0504] The synthesis method was the same as that of intermediate preparation example 31, except that 3-amino-4-hydroxypyridine was used instead of 2-aminophenol to afford 5-bromo-4-methoxy-12-methyl-6-oxa-2,9,10b,12-tetraazacyclopenta[gh]pleiaden-11(12H)-one with a yield of 27.3%. ESI-MS (m/z): 398.99/400.96 [M+H].sup.+.

[0505] Intermediate preparation example 33: Preparation of (6aS,9aR)-5-(6-bromopyridin-3-yl)-4-fluoro-11-methyl-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulen-10(11H)-one (M-33)

##STR00171##

[0506] The synthesis method was the same as that of intermediate preparation example 1, except that (3 S,4R)-4-aminotetrahydrofuran-3-ol was used instead of L-aminopropanol to afford (6aS,9aR)-5-(6-bromopyridin-3-yl)-4-fluoro-11-methyl-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulen-10(11H)-one with a yield of 60.3%. ESI-MS (m/z): 379.94/381.95 [M+H].sup.+.

[0507] Intermediate preparation example 34: Preparation of (6aR,9aS)-5-bromo-4-fluoro-11-methyl-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulen-10(11H)-one (M-34)

##STR00172##

[0508] The synthesis method was the same as that of intermediate preparation example 1, except that (3R,4S)-4-aminotetrahydrofuran-3-ol was used instead of L-aminopropanol to afford (6aR,9aS)-5-bromo-4-fluoro-11-methyl-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulen-10(11H)-one with a yield of 82.4%. ESI-MS (m/z): 380.00/382.00 [M+H].sup.+.

[0509] Intermediate preparation example 35: Preparation of 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,3-oxetan]-1-one (M-35)

##STR00173##

[0510] The synthesis method was the same as that of intermediate preparation example 1, except that 3-amino-3-(hydroxymethyl)oxetane was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,3-oxetan]-1-one with a yield of 32.1%. ESI-MS (m/z): 380.00/381.99 [M+H].sup.+.

[0511] Intermediate preparation example 36: Preparation of 7-bromo-6-methoxy-10-(hydroxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-36)

##STR00174##

[0512] The synthesis method was the same as that of intermediate preparation example 31, except that 2-aminopropane-1,3-diol was used instead of 2-aminophenol to afford 7-bromo-6-methoxy-10-(hydroxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 28.0%. ESI-MS (m/z): 380.02/382.02 [M+H].sup.+.

[0513] Intermediate preparation example 37: Preparation of 7-bromo-6-fluoro-10-(hydroxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-37)

##STR00175##

[0514] The synthesis method was the same as that of intermediate preparation example 1, except that 2-aminopropane-1,3-diol was used instead of L-aminopropanol to afford 7-bromo-6-fluoro-10-(hydroxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 74.2%. ESI-MS (m/z): 367.96/370.02 [M+H].sup.+.

[0515] Intermediate preparation example 38: Preparation of 5-bromo-8-fluoro-4-methoxy-12-methyl-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (M-38)

##STR00176##

[0516] The synthesis method was the same as that of intermediate preparation example 31, except that 2-amino-5-fluorophenol was used instead of 2-aminophenol to afford 5-bromo-8-fluoro-4-methoxy-12-methyl-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one with a yield of 74.5%. ESI-MS (m/z): 416.20/418.20 [M+H].sup.+.

[0517] Intermediate preparation example 39: Preparation of 7-bromo-6-methoxy-2-methyl-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-39)

##STR00177##

[0518] The synthesis method was the same as that of intermediate preparation example 28, except that 2-amino-1-(pyridin-2-yl)ethanol was used instead of 2-amino-2-(pyridin-2-yl)ethanol to afford 7-bromo-6-methoxy-2-methyl-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 63.8%. ESI-MS (m/z): 427.03/429.03 [M+H].sup.+.

[0519] Intermediate preparation example 40: Preparation of (R)-7-bromo-6-methoxy-2-methyl-10-phenyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-40)

##STR00178##

[0520] The synthesis method was the same as that of intermediate preparation example 28, except that (R)-2-amino-2-phenylethanol was used instead of 2-amino-2-(pyridin-2-yl)ethanol to afford (R)-7-bromo-6-methoxy-2-methyl-10-phenyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one with a yield of 67.2%. ESI-MS (m/z): 426.04/428.04 [M+H].sup.+.

[0521] Intermediate preparation example 41: Preparation of ethyl 5-fluoro-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate (M-41)

##STR00179##

[0522] Ethyl 4-chloro-5,7-difluoroquinoline-3-carboxylate (0.20 mmol), o-aminophenol (0.24 mmol), DIPEA (0.4 mmol), and DMF (20 mL) were successively added to a 100 mL round-bottomed flask, and the reaction mixture was stirred at 90? C. for 2 h. When no starting material was found as detected by TLC, the reaction solution was no longer heated, but cooled down to room temperature, then added with water and ethyl acetate. The target product was extracted into the organic phase, and the organic phase was separated and concentrated under reduced pressure, the resultant crude product was purified by column chromatography to afford ethyl 5-fluoro-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 83.7%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 11.590 (s, 1H), 9.130 (s, 1H), 7.388 (d, J=10.2 Hz, 1H), 7.238-7.250 (m, 1H), 7.105-7.126 (m, 2H), 7.025-7.061 (m, 2H), 4.470 (q, J=6.6 Hz, 2H), 1.470 (t, J=6.6 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 168.78, 165.44, 163.76, 156.80 (d, J=13.5 Hz), 153.05 (d, J=13.5 Hz), 152.54, 151.39, 148.82, 133.76, 125.85, 125.54, 121.70, 110.35 (d, J=19.5 Hz), 107.28 (d, J=27 Hz), 102.71, 61.51, 14.39; HR-MS (ESI): calculated for C.sub.18H.sub.14FN.sub.2O.sub.3 [M+H].sup.+: 325.1734, found: 325.1732.

[0523] Intermediate preparation example 42: Preparation of ethyl 5-fluoro-12H-benzo[2,3][1,4]thiazepino[5,6,7-de]quinoline-1-carboxylate (M-42)

##STR00180##

[0524] The synthesis method was the same as that of intermediate preparation example 41 to afford ethyl 5-fluoro-12H-benzo[2,3][1,4]thiazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 81.6%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 11.885 (s, 1H), 9.181 (s, 1H), 7.549 (d, J=7.2 Hz, 1H), 7.500 (d, J=7.8 Hz, 1H), 7.429-7.442 (m, 1H), 7.295-7.320 (m, 1H), 7.134-7.167 (m, 2H), 4.495 (q, J=7.2 Hz, 2H), 1.484 (t, J=6.6 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 168.99, 164.33, 162.63, 154.39, 154.00 (d, J=13.5 Hz), 152.55, 144.81, 135.75 (d, J=9.0 Hz), 131.88, 129.85, 128.59, 126.04, 123.62, 119.35 (d, J=24 Hz), 113.95 (d, J=21 Hz), 104.93, 61.71, 14.41; HR-MS (ESI) calculated for C.sub.18H.sub.14FN.sub.2O.sub.2S [M+H].sup.+: 341.0957, found: 341.0959.

[0525] Intermediate preparation example 43: Preparation of ethyl 5-fluoro-7,12-dihydrobenzo[2,3][1,4]diazepino[5,6,7-de]quinoline-1-carboxylate (M-43)

##STR00181##

[0526] The synthesis method was the same as that of intermediate preparation example 41 to afford ethyl 5-fluoro-7,12-dihydrobenzo[2,3][1,4]diazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 86.4%. .sup.1H NMR (600 MHz, CD.sub.3OD+CF.sub.3COOH) ? 9.040 (s, 1H), 7.021-7.035 (m, 1H), 6.958-6.976 (m, 1H), 6.875-6.900 (m, 1H), 6.793-6.806 (m, 2H), 6.757-6.778 (m, 1H), 4.496 (q, J=7.2 Hz, 2H), 1.474 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, CD.sub.3OD+CF.sub.3COOH) ? 168.10, 156.01, 145.60, 135.97, 124.63, 123.84, 120.84, 118.89, 117.00, 115.12, 113.23, 106.01 (d, J=25.5 Hz), 104.73, 102.73, 99.08 (d, J=25.5 Hz), 64.20, 55.61, 14.30; HR-MS (ESI) calculated for C.sub.18H.sub.15FN.sub.3O.sub.2 [M+H].sup.+: 324.1171, found: 324.1173.

[0527] Intermediate preparation example 44: Preparation of ethyl 5,9-difluoro-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate (M-44)

##STR00182##

[0528] The synthesis method was the same as that of intermediate preparation example 41 to afford ethyl 5,9-difluoro-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 80.3%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 11.585 (s, 1H), 9.161 (s, 1H), 7.439 (d, J=8.4 Hz, 1H), 7.022-7.060 (m, 3H), 6.888-6.899 (m, 1H), 4.476 (q, J=7.2 Hz, 2H), 1.475 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 168.84, 165.48, 163.67, 160.62, 158.98, 156.30 (d, J=15 Hz), 156.05, 152.63, 151.25, 130.27, 122.36 (d, J=9 Hz), 112.90 (d, J=25.5 Hz), 110.76 (d, J=19.5 Hz), 109.35 (d, J=24 Hz), 107.48 (d, J=25.5 Hz), 102.77, 61.65, 14.43; HR-MS (ESI) calculated for C.sub.18H.sub.13F.sub.2N.sub.2O.sub.3 [M+H].sup.+: 343.2013, found: 343.2011.

[0529] Intermediate preparation example 45: Preparation of ethyl 5-fluoro-10-methoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate (M-45)

##STR00183##

[0530] The synthesis method was the same as that of intermediate preparation example 41 to afford ethyl 5-fluoro-10-methoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 85.6%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 11.542 (s, 1H), 9.124 (s, 1H), 7.370-7.390 (m, 1H), 7.136 (d, J=9.0 Hz, 1H), 6.987-7.006 (m, 1H), 6.215-6.634 (m, 1H), 6.536 (m, 1H), 4.462 (q, J=7.2 Hz, 2H), 3.768 (s, 3H), 1.467 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 168.82, 165.52, 163.84, 157.39, 157.20 (d, J=13.5 Hz), 152.50 (d, J=13.5 Hz), 152.42, 151.62, 142.84, 134.35, 122.24, 111.14, 110.51 (d, J=3 Hz), 110.14 (d, J=21 Hz), 107.10 (d, J=25.5 Hz), 106.39, 102.70, 61.56, 55.93, 14.40; HR-MS (ESI) calculated for C.sub.19H.sub.16FN.sub.2O.sub.4 [M+H].sup.+: 355.0978, found: 355.0980.

[0531] Intermediate preparation example 46: Preparation of ethyl 5-fluoro-12H-pyrido[3,4:2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate (M-46)

##STR00184##

[0532] The synthesis method was the same as that of intermediate preparation example 41 to afford ethyl 5-fluoro-12H-pyrido[3,4:2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 95.8%. .sup.1H NMR (600 MHz, CD.sub.3OD) ? 9.425 (s, 1H), 8.932 (s, 1H), 8.585 (d, J=4.8 Hz, 1H), 7.636-7.736 (m, 3H), 4.619 (q, J=6.6 Hz, 2H), 1.528 (t, J=6.6 Hz, 3H); .sup.13C NMR (150 MHz, CD.sub.3OD+CF.sub.3COOH) ? 168.23, 166.68, 156.40 (d, J=15 Hz), 152.15, 150.11, 145.83 (d, J=18 Hz), 142.15, 139.35, 119.32, 117.80, 116.99, 115.89, 111.65 (d, J=28.5 Hz), 110.61, 106.95, 64.53, 14.31; HR-MS (ESI) calculated for C.sub.17H.sub.13FN.sub.3O.sub.3 [M+H].sup.+: 326.0832, found: 326.0830.

[0533] Intermediate preparation example 47: Preparation of ethyl 5-fluoro-12H-pyrido[4,3:2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate (M-47)

##STR00185##

[0534] The synthesis method was the same as that of intermediate preparation example 41 to afford ethyl 5-fluoro-12H-pyrido[4,3:2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 94.5%. .sup.1H NMR (600 MHz, CF.sub.3COOH+CDCl.sub.3) ? 13.144 (s, 1H), 9.406 (s, 1H), 8.799 (s, 1H), 8.588 (d, J=4.2 Hz, 1H), 7.927 (d, J=7.8 Hz, 1H), 7.584 (d, J=5.4 Hz, 1H), 7.422 (d, J=7.8 Hz, 1H), 4.571 (q, J=7.2 Hz, 2H), 1.485 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, CF.sub.3COOH+CDCl.sub.3) ? 167.84, 166.63, 166.09, 156.08, 154.78 (d, J=13.5 Hz), 153.43, 146.80, 144.71, 140.78, 129.00, 118.64, 116.56, 117.69 (d, J=27 Hz), 107.99, 106.15 (d, J=24 Hz), 104.00, 64.24, 13.93; HR-MS (ESI) calculated for C.sub.17H.sub.13FN.sub.3O.sub.3 [M+H].sup.+: 326.1438, found: 326.1440.

[0535] Intermediate preparation example 48: Preparation of ethyl 5-methoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate (M-48)

##STR00186##

[0536] Step 1: Synthesis of diethyl 2-(((3-fluoro-5-methoxyphenyl)amino)methylene)malonate

[0537] 3-fluoro-5-methoxyaniline (1.41 g, 0.01 mol), diethyl 2-(ethoxymethylene)malonate (2.16 g, 0.01 mol), and 25 mL of anhydrous ethanol were successively added to a 100 mL reaction bottle, and the reaction solution was heated to reflux and reacted for 6 h and then cooled down to room temperature, the solvent was removed by rotary evaporation to afford diethyl 2-(((3-fluoro-5-methoxyphenyl)amino)methylene)malonate as a colorless and transparent liquid (2.76 g, 88.7% yield). HR-MS (ESI) calculated for C.sub.15H.sub.19FNO.sub.5 [M+H].sup.+: 312.0755, found: 312.0756; .sup.1H NMR (600 MHz, CDCl.sub.3) ?: 10.841-10.862 (m, 1H), 8.322-8.344 (m, 1H), 6.304-6.395 (m, 3H), 4.165-4.239 (m, 4H), 3.716-3.726 (m, 3H), 1.243-1.316 (m, 6H).

[0538] Step 2: Synthesis of ethyl 5-fluoro-7-methoxy-4-oxo-1,4-difluoroquinoline-3-carboxylate

[0539] 40 mL of diphenyl ether was added to a 100 mL reaction bottle and heated up to 240? C., followed by adding diethyl 2-(((3-fluoro-5-methoxyphenyl)amino)methylene)malonate (3.11 g, 0.01 mol), the reaction solution was maintained at the temperature to react for 1 h and then cooled down to room temperature, followed by adding 100 mL of n-hexane at room temperature, and then filtrated to afford ethyl 5-fluoro-7-methoxy-4-oxo-1,4-difluoroquinoline-3-carboxylate (2.24 g, 84.4% yield) as a white solid, HR-MS (ESI) calculated for C.sub.13H.sub.12FNO.sub.4 [M+H].sup.+: 266.1326, found: 266.1328; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 12.071 (s, 1H), 8.396 (s, 1H), 6.833-6.844 (m, 1H), 6.758-6.780 (m, 1H), 4.155-4.201 (m, 2H), 3.853 (s, 3H), 1.244-1.286 (m, 3H).

[0540] Step 3: Synthesis of ethyl 4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate

[0541] Ethyl 5-fluoro-7-methoxy-4-oxo-1,4-difluoroquinoline-3-carboxylate (1.30 g, 4.90 mmol) and thionyl chloride (10 mL) were added to a 50 mL reaction bottle, and added dropwise with DMF (two drops), after refluxing for 4 h, the reaction was completed. The reaction mixture was concentrated to dryness under reduced pressure to afford ethyl 4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate (1.21 g, 87.1% yield) as a yellow solid. HR-MS (ESI) calculated for C.sub.13H.sub.12ClFNO.sub.3 [M+H].sup.+: 283.1184, found: 283.1186; .sup.1H NMR (600 MHz, CDCl.sub.3) ?: 9.152 (s, 1H), 7.785 (m, 1H), 6.955-6.976 (m, 1H), 4.522 (q, J=7.2 Hz, 2H), 4.025 (s, 3H), 1.444 (t, J=7.2 Hz, 3H).

[0542] Step 4: Synthesis of ethyl of 5-methoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate

[0543] Ethyl 4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate (0.20 mmol), o-aminophenol (0.24 mmol), DIPEA (0.4 mmol), and DMF (20 mL) were successively added to a 100 mL round-bottomed flask, and the reaction mixture was stirred at 90? C. for 2 h. When no starting material was found as detected by TLC, the reaction solution was no longer heated, but cooled down to room temperature and then added with water and ethyl acetate. The target product was extracted into the organic phase, and the organic phase was separated and concentrated under reduced pressure, and the resultant crude product was purified by column chromatography to afford ethyl 5-methoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 75.0%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 11.535 (s, 1H), 9.122 (s, 1H), 7.276-7.290 (m, 1H), 7.081-7.169 (m, 4H), 6.937-6.941 (m, 1H), 4.483 (q, J=7.2 Hz, 2H), 3.959 (s, 3H), 1.494 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 168.99, 163.05, 156.11, 153.64, 152.18, 151.32, 149.00, 134.20, 125.58, 125.24, 121.79, 121.61, 108.68, 107.97, 105.52, 101.94, 61.27, 55.91, 14.46; HR-MS (ESI) calculated for C.sub.19H.sub.14N.sub.2O.sub.4 [M+H].sup.+: 337.1074, found: 337.1076.

[0544] Intermediate preparation example 49: Preparation of ethyl 5-methoxy-12H-benzo[2,3][1,4]thiazepino[5,6,7-de]quinoline-1-carboxylate (M-49)

##STR00187##

[0545] The synthesis method was the same as that of intermediate preparation example 48 to afford ethyl 5-methoxy-12H-benzo[2,3][1,4]thiazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 64.0%. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ? 11.565 (s, 1H), 9.051 (s, 1H), 7.611 (d, J=7.2 Hz, 1H), 7.399-7.422 (m, 1H), 7.338 (d, J=3.0 Hz, 2H), 7.279 (d, J=3.0 Hz, 1H), 7.197-7.242 (m, 2H), 4.454 (q, J=7.2 Hz, 2H), 3.909 (s, 3H), 1.417 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 169.10, 161.96, 154.33, 154.13, 151.90, 145.07, 134.17, 131.88, 129.59, 128.77, 125.74, 123.49, 121.56, 116.46, 108.45, 104.12, 61.50, 55.87, 14.45; HR-MS (ESI) calculated for C.sub.19H.sub.17N.sub.2O.sub.3S [M+H].sup.+: 353.1283, found: 353.1284.

[0546] Intermediate preparation example 50: Preparation of ethyl 5-methoxy-7,12-dihydrobenzo[2,3][1,4]diazepino[5,6,7-de]quinoline-1-carboxylate (M-50)

##STR00188##

[0547] The synthesis method was the same as that of intermediate preparation example 48 to afford ethyl 5-methoxy-7,12-dihydrobenzo[2,3][1,4]diazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 79.0%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 11.641 (s, 1H), 9.109 (s, 1H), 6.899-6.963 (m, 4H), 6.772-6.785 (m, 1H), 6.406-6.409 (m, 1H), 6.085 (s, 1H), 4.431 (q, J=7.2 Hz, 2H), 3.878 (s, 3H), 1.452 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 169.20, 162.68, 153.63, 152.28, 151.58, 144.79, 135.46, 131.39, 124.64, 122.84, 121.62, 119.15, 105.33, 104.62, 102.77, 101.68, 61.20, 55.61, 14.41; HR-MS (ESI) calculated for C.sub.19H.sub.18N.sub.3O.sub.3 [M+H].sup.+: 336.0512, found: 336.0513.

[0548] Intermediate preparation example 51: Preparation of ethyl 9-fluoro-5-methoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate (M-51)

##STR00189##

[0549] The synthesis method was the same as that of intermediate preparation example 48 to afford ethyl 9-fluoro-5-methoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 56.3%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 11.481 (s, 1H), 9.102 (s, 1H), 7.169-7.173 (m, 1H), 7.002-7.035 (m, 2H), 6.902-6.906 (m, 1H), 6.839-6.871 (m, 1H), 4.458 (q, J=6.6 Hz, 2H), 3.942 (s, 3H), 1.468 (t, J=6.6 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 168.99, 163.07, 160.43, 158.80, 155.60, 152.13, 151.12, 149.48 (d, J=10.5 Hz), 130.61, 122.18 (d, J=10.5 Hz), 112.53 (d, J=22.5 Hz), 109.34 (d, J=24 Hz), 108.85, 107.73, 105.75, 101.97, 61.38, 56.00, 14.43; HR-MS (ESI) calculated for C.sub.19H.sub.16FN.sub.2O.sub.4 [M+H].sup.+: 355.1337, found: 355.1338.

[0550] Intermediate preparation example 52: Preparation of ethyl 5,10-dimethoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate (M-52)

##STR00190##

[0551] The synthesis method was the same as that of intermediate preparation example 48 to afford ethyl 5,10-dimethoxy-12H-benzo[2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 59.4%. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ? 10.955 (s, 1H), 9.766 (s, 1H), 8.894 (s, 1H), 8.582 (s, 1H), 8.321 (s, 1H), 7.165 (m, 1H), 6.194-6.199 (m, 1H), 4.435 (q, J=7.2 Hz, 2H), 3.939 (s, 3H), 3.737 (s, 3H), 1.408 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 168.98, 163.32, 157.24, 156.53, 153.29, 151.88, 151.63, 143.03, 134.70, 122.35, 111.01, 108.57, 108.09, 106.30, 105.11, 101.93, 61.38, 55.96, 14.46; HR-MS (ESI) calculated for C.sub.20H.sub.18N.sub.2O.sub.5 [M+H].sup.+: 367.1534, found: 367.1535.

[0552] Intermediate preparation example 53: Preparation of ethyl 5-methoxy-12H-pyrido[4,3:2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate (M-53)

##STR00191##

[0553] The synthesis method was the same as that of intermediate preparation example 48 to afford ethyl 5-methoxy-12H-pyrido[4,3:2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 81.2%. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ? 11.456 (s, 1H), 9.058 (s, 1H), 8.493 (s, 1H), 8.350 (d, J=5.4 Hz, 1H), 7.442 (d, J=5.4 Hz, 1H), 7.265 (d, J=2.4 Hz, 1H), 7.161 (d, J=2.4 Hz, 1H), 4.464 (q, J=7.2 Hz, 2H), 3.962 (s, 3H), 1.427 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 175.53, 158.63, 163.25, 153.84, 152.10, 151.08, 150.34, 145.88, 142.68, 130.14, 116.44, 109.87, 106.14, 105.17, 102.37, 61.81, 56.12, 14.34; HR-MS (ESI) calculated for C.sub.18H.sub.16N.sub.3O.sub.4 [M+H].sup.+: 338.1382, found: 338.1382.

[0554] Intermediate preparation example 54: Preparation of ethyl 5-methoxy-12H-pyrido[3,4:2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate (M-54)

##STR00192##

[0555] The synthesis method was the same as that of preparation example 48 to afford ethyl 5-methoxy-12H-pyrido[3,4:2,3][1,4]oxazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 89.4%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 11.831 (s, 1H), 9.145 (s, 1H), 8.508 (s, 1H), 8.273 (s, 1H), 7.182 (m, 1H), 6.948-6.988 (m, 2H), 4.471 (q, J=7.2 Hz, 2H), 3.946 (s, 3H), 1.473 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 168.99, 163.10, 154.94, 153.65, 151.98, 149.68, 146.62, 144.38, 143.81, 140.10, 115.09, 109.56, 107.02, 106.06, 102.75, 61.74, 56.02, 14.40; HR-MS (ESI) calculated for C.sub.18H.sub.16N.sub.3O.sub.4 [M+H].sup.+: 338.1438, found: 338.1440.

[0556] Intermediate preparation example 55: Preparation of ethyl 5-fluoro-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diazepino[5,6,7-de]quinoline-1-carboxylate (M-55)

##STR00193##

[0557] The synthesis method was the same as that of intermediate preparation example 41 to afford ethyl 5-fluoro-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 95.7%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 10.086 (s, 1H), 8.911 (s, 1H), 6.860-6.880 (m, 1H), 6.215-6.236 (m, 1H), 4.485 (s, 1H), 4.422 (q, J=7.2 Hz, 2H), 3.228-3.267 (m, 1H), 3.099-3.139 (m, 1H), 2.189-2.212 (m, 1H), 2.036-2.057 (m, 1H), 1.807-1.814 (m, 2H), 1.296-1.528 (m, 7H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 169.38, 165.53, 163.38, 156.22, 154.47 (d, J=15 Hz), 152.68, 149.54 (d, J=13.5 Hz), 105.52, 103.58 (d, J=21 Hz), 99.35, 99.20, 99.03, 60.50 (d, J=15 Hz), 59.35, 32.89, 32.39, 23.79 (d, J=6 Hz), 14.47; HR-MS (ESI) calculated for C.sub.18H.sub.20FN.sub.3O.sub.2 [M+H].sup.+: 330.1237, found: 330.1238.

[0558] Intermediate preparation example 56: Preparation of ethyl 5-fluoro-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diazepino[5,6,7-de]quinoline-1-carboxylate (M-56)

##STR00194##

[0559] The synthesis method was the same as that of intermediate preparation example 41 to afford ethyl 5-fluoro-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 96.4%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 10.637 (s, 1H), 8.923 (s, 1H), 6.909-6.928 (m, 1H), 6.300-6.321 (m, 1H), 5.383 (s, 1H), 4.349 (q, J=6.6 Hz, 2H), 3.708-3.722 (m, 2H), 3.584-3.596 (m, 2H), 1.401 (t, J=6.6 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 169.81, 169.25, 165.82, 164.05, 157.74, 151.56, 104.78, 102.76, 99.41 (d, J=21 Hz), 99.17, 60.95, 47.47, 46.83, 14.47; HR-MS (ESI) calculated for C.sub.14H.sub.15FN.sub.3O.sub.2 [M+H].sup.+: 276.0974, found: 276.0973.

[0560] Intermediate preparation example 57: Preparation of ethyl 5-methoxy-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diazepino[5,6,7-de]quinoline-1-carboxylate (M-57)

##STR00195##

[0561] The synthesis method was the same as that of intermediate preparation example 48 to afford ethyl 5-methoxy-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diazepino[5,6,7-de]quinoline-1-carboxylate with a yield of 95.4%. .sup.1H NMR (600 MHz, CDCl.sub.3) ? 10.333 (s, 1H), 8.825 (s, 1H), 6.827-6.830 (m, 1H), 6.209-6.212 (m, 1H), 4.782 (s, 1H), 4.321 (q, J=7.2 Hz, 2H), 3.816 (s, 3H), 3.294-3.335 (m, 1H), 3.287-3.127 (m, 1H), 2.211-2.234 (m, 1H), 2.139-2.160 (m, 1H), 1.821-1.836 (m, 2H), 1.315-1.528 (m, 7H); .sup.13C NMR (150 MHz, CDCl.sub.3) ? 168.69, 163.32, 156.43, 149.30, 149.02, 102.72, 100.86, 98.63, 97.86, 61.10, 61.05, 58.72, 55.68, 32.70, 32.40, 29.83, 23.82, 23.73, 14.46; HR-MS (ESI) calculated for C.sub.19H.sub.24N.sub.3O.sub.3 [M+H].sup.+: 342.2013, found: 342.2011.

[0562] Intermediate preparation example 58: Preparation of ethyl 9-methoxy-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinoline-3-carboxylate (M-58)

##STR00196##

[0563] The synthesis method was the same as that of preparation example 48 to afford ethyl 9-methoxy-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinoline-3-carboxylate with a yield of 97.1%. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ? 10.219 (s, 1H), 8.664 (s, 1H), 7.182 (s, 1H), 6.487-6.492 (m, 1H), 6.261-6.265 (m, 1H), 4.461 (q, J=7.2 Hz, 2H), 3.771 (s, 3H), 3.610-3.627 (m, 2H), 3.374-3.390 (m, 2H), 1.314 (t, J=7.2 Hz, 3H); .sup.13C NMR (150 MHz, DMSO-d.sub.6) ? 168.38, 161.84, 156.80, 154.00, 151.06, 150.82, 101.75, 99.14, 98.06, 97.11, 59.93, 54.97, 47.07, 45.79, 14.31; HR-MS (ESI) calculated for C.sub.15H.sub.18N.sub.3O.sub.3 [M+H].sup.+: 288.0876, found: 276.0878.

[0564] Examples

[0565] Example 1: (S)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-1)

##STR00197##

[0566] Step 1: Synthesis of (S)-6-fluoro-7-(6-fluoropyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0567] 1,4-dioxane (15 mL), (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.62 g, 1.76 mmol), (6-fluoropyridine-3-yl)boronic acid (0.315 g, 2.11 mmol), potassium carbonate (0.607 g, 4.4 mmol), water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0.203 g, 0.18 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection and reacted for 2.5 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=60:1) to afford (S)-6-fluoro-7-(6-fluoropyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.43 g, 66.3% yield). ESI-MS (m/z): 369.11 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.541 (d, 3H), 3.632 (s, 3H), 4.525-4.660 (m, 2H), 4.707-4.739 (m, 1H), 7.213-7.231 (m, 1H), 7.565 (d, 1H), 8.105 (t, 1H), 8.343 (s, 1H), 8.837 (s, 1H).

[0568] Step 2: Preparation of (S)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0569] THF (4 mL) and 3-(piperidin-1-yl)propan-1-ol (115 mg, 0.8 mmol) were added to a 100 mL reaction bottle and cooled down to 0? C., followed by adding NaH (56 mg, 1.4 mmol) and the reaction was conducted at this temperature for 0.5 h, then (S)-6-fluoro-7-(6-fluoropyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (147 mg, 0.4 mmol) was added, and the reaction was continued at room temperature overnight. When the reaction was completed as detected by TLC, the reaction solution was quenched with water and concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-15:1) to afford (S)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (63 mg, 32% yield). ESI-MS (m/z): 492.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.495-1.533 (m, 5H), 1.620-1.657 (m, 4H), 2.027-2.053 (m, 2H), 2.507-2.577 (m, 6H), 3.610 (s, 3H), 4.373 (t, J=6.0 Hz, 2H), 4.467-4.612 (m, 2H), 4.630-4.701 (m, 1H), 6.899 (d, J=8.4 Hz, 1H), 7.480 (d, J=10.8 Hz, 1H), 7.794 (d, J=8.4 Hz, 1H), 8.209 (s, 1H), 8.767 (s, 1H).

[0570] Example 2: (S)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-2)

##STR00198##

[0571] The synthesis method was the same as that of example 1, except that 3-(dimethylamino)propan-1-ol was used instead of 3-(piperidin-1-yl)propan-1-ol to afford (S)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (30 mg, 32.0% yield). ESI-MS (m/z): 452.20 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.526 (d, J=7.2 Hz, 3H), 2.040-2.066 (m, 2H), 2.390 (s, 6H), 2.662 (t, J=7.8 Hz, 2H), 3.610 (s, 3H), 4.398 (t, J=6.0 Hz, 2H), 4.467-4.632 (m, 2H), 4.689-4.702 (m, 1H), 6.912 (d, J=8.4 Hz, 1H), 7.476 (d, J=11.4 Hz, 1H), 7.800 (d, J=9.0 Hz, 1H), 8.215 (s, 1H), 8.765 (s, 1H).

[0572] Example 3: (R)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-3)

##STR00199##

[0573] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (R)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, 27.1% yield). ESI-MS (m/z): 452.20 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.536 (d, J=7.2 Hz, 3H), 2.001-2.048 (m, 2H), 2.310 (s, 6H), 2.565 (t, J=7.8 Hz, 2H), 3.620 (s, 3H), 4.388 (t, J=6.0 Hz, 2H), 4.484-4.641 (m, 2H), 4.698-4.712 (m, 1H), 6.915 (d, J=9.0 Hz, 1H), 7.509 (d, J=11.4 Hz, 1H), 7.803-7.818 (m, 1H), 8.226 (s, 1H), 8.792 (s, 1H).

[0574] Example 4: (R)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-4)

##STR00200##

[0575] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (R)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (63 mg, 32% yield). ESI-MS (m/z): 492.20 [M+H].sup.+; .sup.1H NMR (600 MHz, CDCl.sub.3) ?: 1.577-1.588 (m, 4H), 1.590-2.100 (m, 6H), 2.211-3.199 (m, 7H), 3.629 (s, 3H), 4.366-4.388 (m, 1H), 4.465 (t, J=6.0 Hz, 2H), 4.582-4.608 (m, 1H), 4.735-4.749 (m, 1H), 6.848 (d, J=8.4 Hz, 1H), 7.607 (d, J=10.8 Hz, 1H), 7.732-7.746 (m, 1H), 8.291 (s, 1H), 8.691 (s, 1H).

[0576] Example 5: 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-9-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-5)

##STR00201##

[0577] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-9-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (15 mg, 13.0% yield). ESI-MS (m/z): 532.21 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.230-1.236 (m, 2H), 1.937 (t, J=6.6 Hz, 2H), 2.349 (s, 6H), 2.610-2.618 (m, 2H), 3.533 (s, 3H), 4.220-4.242 (m, 1H), 4.315 (t, J=6.0 Hz, 2H), 6.864 (d, J=8.4 Hz, 1H), 6.871-7.180 (m, 3H), 7.501-7.522 (m, 2H), 7.800-7.814 (m, 1H), 8.234 (s, 1H), 8.788 (s, 1H).

[0578] Example 6: 6-fluoro-2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-6)

##STR00202##

[0579] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (70 mg, 33.2% yield). ESI-MS (m/z): 506.25 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.383 (s, 2H), 1.482-1.518 (m, 4H), 1.639 (s, 6H), 1.883-1.928 (m, 2H), 2.348-2.405 (m, 4H), 2.498-2.510 (m, 2H), 3.503 (s, 3H), 4.335 (t, J=6.6 Hz, 2H), 4.441 (s, 2H), 6.937-6.952 (m, 1H), 7.560 (d, J=10.8 Hz, 1H), 7.824-7.844 (m, 1H), 8.276 (s, 1H), 8.899 (s, 1H).

[0580] Example 7: 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-7)

##STR00203##

[0581] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (63 mg, 32.0% yield). ESI-MS (m/z): 555.2 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO) ?: 1.439 (brs, 2H), 1.382-1.579 (m, 4H), 1.970-1.997 (m, 2H), 2.487-2.500 (m, 2H), 2.520-2.750 (m, 4H), 3.581 (s, 3H), 4.228-4.239 (m, 1H), 4.332 (d, J=6.6 Hz, 2H), 4.887 (d, J=13.8 Hz, 1H), 5.858 (d, J=9.6 Hz, 1H), 6.855 (d, J=9.0 Hz, 1H), 7.177 (d, J=8.4 Hz, 1H), 7.370-7.391 (m, 1H), 7.663 (d, J=10.8 Hz, 1H), 7.733 (d, J=7.2 Hz, 1H), 7.711-7.752 (m, 1H), 7.818 (d, J=8.4 Hz, 1H), 8.242 (s, 1H), 8.600 (d, J=4.2 Hz, 1H), 8.963 (s, 1H).

[0582] Example 8: (R)-6-fluoro-10-isobutyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-8)

##STR00204##

[0583] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (R)-6-fluoro-10-isobutyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (53 mg, 45.3% yield). ESI-MS (m/z): 534.28 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 0.980 (s, 3H), 1.239 (s, 3H), 1.395 (s, 2H), 1.515 (s, 4H), 1.567-1.616 (m, 1H), 1.695-1.762 (m, 2H), 1.921 (s, 2H), 2.287-2.492 (m, 6H), 3.550 (s, 3H), 4.344 (t, J=6.6 Hz, 2H), 4.516 (d, J=13.2 Hz, 1H), 4.595-4.701 (m, 1H), 4.722 (d, J=3.0 Hz, 1H), 6.948 (d, J=8.4 Hz, 1H), 7.594 (d, J=10.8 Hz, 1H), 7.837 (d, J=8.4 Hz, 1H), 8.278 (s, 1H), 8.913 (s, 1H).

[0584] Example 9: (S)-6-fluoro-10-isobutyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-9)

##STR00205##

[0585] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (S)-6-fluoro-10-isobutyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (60 mg, 46.0% yield). ESI-MS (m/z): 534.28 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 0.920-0.930 (d, J=6.0 Hz, 3H), 0.970-0.980 (d, J=6.0 Hz, 3H), 1.400-1.402 (m, 2H), 1.518-1.600 (m, 6H), 1.706-1.741 (m, 1H), 1.918-1.924 (m, 2H), 2.345-2.392 (m, 6H), 3.550 (s, 3H), 4.334-4.356 (t, J=6.6 Hz, J=6.6 Hz, 2H), 4.505-4.527 (d, J=13.2 Hz, 1H), 4.606-4.615 (d, J=5.4 Hz, 1H), 4.697-4.724 (m, 1H), 6.941-6.956 (d, J=9.0 Hz, 1H), 7.586-7.604 (d, J=10.8 Hz, 1H), 7.830-7.845 (d, J=9.0 Hz, 1H), 8.279 (s, 1H), 8.914 (s, 1H).

[0586] Example 10: 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-10)

##STR00206##

[0587] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (90 mg, 45.2% yield). ESI-MS (m/z): 494.12 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.424-1.425 (m, 3H), 1.560-1.562 (m, 5H), 1.910-1.980 (m, 2H), 2.420-2.421 (m, 2H), 2.631-2.632 (m, 2H), 3.350-3.353 (m, 2H), 3.565 (s, 3H), 4.297-4.366 (m, 4H), 6.952-6.966 (d, J=8.4 Hz, 1H), 7.719-7.774 (m, 2H), 8.126-8.130 (d, J=8.4 Hz, 1H), 8.996 (s, 1H).

[0588] Example 11: 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (A-11)

##STR00207##

[0589] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (50 mg, 21.2% yield). ESI-MS (m/z): 504.23 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.062-1.064 (m, 2H), 1.425-1.557 (m, 2H), 1.557-1.574 (m, 4H), 1.915-2.207 (m, 4H), 2.508-2.587 (m, 5H), 3.90-3.475 (m, 4H), 4.33-4.354 (t, J=6.6 Hz, 2H), 4.464 (s, 2H), 6.939 (d, J=8.4 Hz, 1H), 7.594 (d, J=10.8 Hz, 1H), 7.812 (m 1H), 8.254 (s, 1H), 8.896 (s, 1H).

[0590] Example 12: 9-(ethoxymethyl)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-12)

##STR00208##

[0591] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 9-(ethoxymethyl)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (86 mg, 51.0% yield). ESI-MS (m/z): 536.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.110-1.134 (m, 3H), 1.594 (s, 2H), 1.744-1.762 (m, 4H), 2.145-1.172 (m, 2H), 2.870-2.918 (m, 6H), 3.423-3.489 (m, 2H), 3.612-3.720 (m, 5H), 3.987-4.026 (m, 1H), 4.419-4.439 (m, 2H), 4.545 (d, J=13.8 Hz, 1H), 4.657 (d, J=9.6 Hz, 1H), 6.921 (d, J=8.4 Hz, 1H), 7.513 (d, J=10.8 Hz, 1H), 7.884 (dd, J.sub.1=1.2 Hz, J.sub.2=8.4 Hz, 1H), 8.285 (s, 1H), 8.788 (s, 1H).

[0592] Example 13: (S)-10-benzyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-13)

##STR00209##

[0593] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (S)-10-benzyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (30 mg, 20.2% yield). ESI-MS (m/z): 568.26 [M+H].sup.+; .sup.1HNMR (600 MHz, DMSO-d.sub.6) ?: 1.463-1.624 (m, 6H), 2.055-2.103 (m, 2H), 2.695-2.713 (m, 4H), 3.104-3.190 (m, 4H), 3.569 (s, 3H), 4.297-4.440 (m, 4H), 4.692-4.714 (m, 1H), 6.985 (d, J=8.4 Hz, 1H), 7.246-7.349 (m, 5H), 7.626 (d, J=11.4 Hz, 1H), 7.928 (d, J=8.4 Hz, 1H), 8.343 (s, 1H), 8.952 (s, 1H).

[0594] Example 14: (R)-10-benzyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-14)

##STR00210##

[0595] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (R)-10-benzyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (53 mg, 41.5% yield). ESI-MS (m/z): 568.26 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.463-1.624 (m, 6H), 2.055-2.103 (m, 2H), 2.695-2.713 (m, 4H), 3.104-3.190 (m, 4H), 3.569 (s, 3H), 4.297-4.440 (m, 4H), 4.692-4.714 (m, 1H), 6.976-6.990 (d, J=8.4 Hz, 1H), 7.246-7.349 (m, 5H), 7.616-7.635 (d, J=11.4 Hz, 1H), 7.921-7.935 (d, J=8.4 Hz, 1H), 8.343 (s, 1H), 8.952 (s, 1H).

[0596] Example 15: 7-(6-(3-dimethylamino-propoxy)-pyridin-3-yl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-15)

##STR00211##

[0597] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 7-(6-(3-dimethylamino-propoxy)-pyridin-3-yl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (15 mg, 48.2% yield). ESI-MS (m/z): 438.42 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 2.076-2.102 (m, 2H), 2.467 (s, 6H), 2.747-2.773 (m, 2H), 3.624 (s, 3H), 4.325-4.330 (m, 2H), 4.407-4.427 (m, 2H), 4.608-4.620 (m, 2H), 6.939 (d, J=8.4 Hz, 1H), 7.534 (d, J=16.8 Hz, 1H), 7.832 (d, J=14.4 Hz, 1H), 8.236 (s, 1H), 8.807 (s, 1H).

[0598] Example 16: (S)-6-fluoro-10-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-16)

##STR00212##

[0599] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (S)-6-fluoro-10-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (50 mg, 24% yield). ESI-MS (m/z): 520.26 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 0.933 (d, J=7.2 Hz, 3H), 1.013 (d, J=6.6 Hz, 3H), 1.400-1.537 (m, 6H), 1.922-1.954 (m, 2H), 2.221-2.258 (m, 1H), 2.433-2.514 (m, 6H), 3.558 (s, 3H), 4.282-4.351 (m, 3H), 4.445-4.468 (m, 1H), 4.828-4.856 (m, 1H), 6.935 (d, J=8.4 Hz, 1H), 7.566 (d, J=10.8 Hz, 1H), 7.828-7.813 (m, 1H), 8.260 (s, 1H), 8.909 (s, 1H).

[0600] Example 17: (R)-6-fluoro-10-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-17)

##STR00213##

[0601] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (R)-6-fluoro-10-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (45 mg, 24% yield). ESI-MS (m/z): 520.26 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 0.947 (d, J=6.6 Hz, 3H), 1.022 (d, J=6.6 Hz, 3H), 1.415-1.544 (m, 6H), 1.933-1.963 (m, 2H), 2.240-2.261 (m, 1H), 2.449-2.529 (m, 6H), 3.560 (s, 3H), 4.296-4.365 (m, 3H), 4.459-4.482 (m, 1H), 4.839-4.867 (m, 1H), 6.949 (d, J=8.4 Hz, 1H), 7.579 (d, J=10.8 Hz, 1H), 7.840-7.825 (m, 1H), 8.271 (s, 1H), 8.920 (s, 1H).

[0602] Example 18: 6-fluoro-9-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-18)

##STR00214##

[0603] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-9-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (58 mg, 44.3% yield). ESI-MS (m/z): 519.26 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO) S: 0.635 (d, J=7.2 Hz, 3H), 0.798 (d, J=6.6 Hz, 3H), 1.305-1.892 (m, 6H), 1.909-1.962 (m, 1H), 2.012-2.198 (m, 2H), 2.753-2.965 (m, 2H), 3.137-3.326 (m, 4H), 3.547 (s, 3H), 3.994-4.032 (m, 1H), 4.290-4.378 (m, 4H), 6.961 (d, J=8.4 Hz, 1H), 7.590 (d, J=10.8 Hz, 1H), 7.852-7.840 (m, 1H), 8.267 (s, 1H), 8.921 (s, 1H).

[0604] Example 19: (S)-9-((dimethylamino)methyl)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-19)

##STR00215##

[0605] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (S)-9-((dimethylamino)methyl)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (100 mg, 55.0% yield). ESI-MS (m/z): 535.28 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.600 (s, 2H), 1.746-1.763 (m, 4H), 2.149-2.193 (m, 8H), 2.650-2.671 (m, 2H), 2.813-2.864 (m, 6H), 3.648 (s, 3H), 4.016-4.055 (q, 1H), 4.448 (t, J=6.0 Hz, 2H), 4.660 (d, J=13.2 Hz, 2H), 6.960 (d, J=9.0 Hz, 1H), 7.550 (d, J=10.8 Hz, 1H), 7.797 (d, J=8.4 Hz, 1H), 8.290 (s, 1H), 8.833 (s, 1H).

[0606] Example 20: (S)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9-(piperidin-1-ylmethyl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-20)

##STR00216##

[0607] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (S)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9-(piperidin-1-ylmethyl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (150 mg, 29.6% yield). ESI-MS (m/z): 575.31 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.396 (s, 2H), 1.478-1.515 (m, 4H), 1.550 (s, 2H), 1.678-1.716 (m, 4H), 2.092-2.119 (m, 2H), 2.329 (s, 4H), 2.607-2.700 (m, 8H), 3.627 (s, 3H), 3.973-4.013 (m, 1H), 4.415-4.587 (m, 2H), 4.611-4.915 (m, 2H), 6.942 (d, J=9.0 Hz, 1H), 7.521 (d, J=10.8 Hz, 1H), 7.902-7.921 (m, 1H), 8.318 (s, 1H), 8.785 (s, 1H).

[0608] Example 21: 4-fluoro-12-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (A-21)

##STR00217##

[0609] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 4-fluoro-12-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (200 mg, 38.5% yield). ESI-MS (m/z): 532.26 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.635-1.693 (m, 4H), 1.788-1.830 (m, 7H), 2.120 (d, J=12.0 Hz, 1H), 2.179-2.225 (m, 2H), 2.954-2.999 (m, 7H), 3.593 (s, 3H), 3.691 (d, J=13.2 Hz, 1H), 4.305-4.339 (m, 2H), 4.456-4.476 (m, 2H), 6.961 (d, J=8.4 Hz, 1H), 7.517 (d, J=10.8 Hz, 1H), 7.852-7.869 (m, 1H), 8.271 (s, 1H), 8.794 (s, 1H).

[0610] Example 22: (R)-10-ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-22)

##STR00218##

[0611] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (R)-10-ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (150 mg, 14.3% yield). ESI-MS (m/z): 506.25 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.099-1.111 (m, 3H), 1.560 (s, 2H), 1.693-1.730 (m, 4H), 1.942-1.979 (m, 2H), 2.091-2.138 (m, 2H), 2.682-2.749 (m, 6H), 3.640 (s, 3H), 4.410-4.460 (m, 3H), 4.510-4.525 (m, 1H), 4.815-4.842 (m, 1H), 6.938 (d, J=8.4 Hz, 1H), 7.505 (d, J=10.8 Hz, 1H), 7.825 (d, J=8.4 Hz, 1H), 8.238 (s, 1H), 8.802 (s, 1H).

[0612] Example 23: (S)-10-ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-23)

##STR00219##

[0613] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (S)-10-ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (180 mg, 42.6% yield). ESI-MS (m/z): 506.25 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.099-1.111 (m, 3H), 1.533 (s, 2H), 1.663-1.701 (m, 4H), 1.932-1.969 (m, 2H), 2.065-2.112 (m, 2H), 2.643-2.712 (m, 6H), 3.625 (s, 3H), 4.390-4.441 (m, 2H), 4.442 (d, J=13.2 Hz, 1H), 4.484-4.512 (m, 1H), 4.798-4.825 (m, 1H), 6.922 (d, J=8.4 Hz, 1H), 7.512 (d, J=10.8 Hz, 1H), 7.807-7.824 (m, 1H), 8.229 (s, 1H), 8.802 (s, 1H).

[0614] Example 24: 6-fluoro-2,9-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-24)

##STR00220##

[0615] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-2,9-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (68 mg, 33.2% yield). ESI-MS (m/z): 491.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.448 (d, J=5.4 Hz, 3H), 1.537 (m, 2H), 1.663-1.701 (m, 4H), 2.067-2.114 (m, 2H), 2.579-2.654 (m, 6H), 3.620 (s, 3H), 3.932-3.971 (m, 1H), 4.405-4.432 (m, 3H), 4.677-4.702 (m, 1H), 6.942 (d, J=8.4 Hz, 1H), 7.504 (d, J=10.8 Hz, 1H), 7.831-7.849 (m, 1H), 8.245 (s, 1H), 8.777 (s, 1H), 1.448 (d, 3H), 1.537 (m, 2H), 1.663-1.701 (m, 4H), 2.067-2.114 (m, 2H), 2.579-2.654 (m, 6H), 3.620 (s, 3H), 3.932-3.971 (m, 1H), 4.405-4.432 (m, 3H), 4.677-4.702 (m, 1H), 6.942 (d, 1H), 7.504 (d, 1H), 7.831-7.849 (m, 1H), 8.245 (s, 1H), 8.777 (s, 1H).

[0616] Example 25: 6-fluoro-9-(2-fluoropyridin-4-yl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-25)

##STR00221##

[0617] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-9-(2-fluoropyridin-4-yl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (85 mg, 26.8% yield). ESI-MS (m/z): 573.23 [M+H].sup.+; .sup.1H NMR (600 MHz, MeOD) ? 1.530-1.687 (m, 6H), 2.025-2.089 (m, 2H), 2.649-2.675 (m, 6H), 3.645 (s, 3H), 4.187-4.227 (m, 1H), 4.365 (t, J=6.6 Hz, 2H), 4.646-4.669 (m, 1H), 5.808-5.824 (m, 1H), 6.781 (d, J=7.8 Hz, 1H), 6.974 (s, 1H), 7.305 (d, J=4.8 Hz, 1H), 7.597 (d, J=10.8 Hz, 1H), 7.751 (d, J=8.4 Hz, 1H), 8.161-8.199 (m, 2H), 8.860 (s, 1H).

[0618] Example 26: 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-26)

##STR00222##

[0619] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, 1900 yield). ESI-MS (m/z): 478.22 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.356-1.450 (m, 2H), 1.514-1.532 (m, 4H), 1.916-1.939 (m, 2H), 2.406-2.461 (m, 6H), 3.540 (s, 3H), 4.204-4.212 (m, 2H), 4.331-4.353 (t, J=6.6 Hz, 2H), 4.607-4.619 (t, J=3.6 Hz, 2H), 6.943 (d, J=8.4 Hz, 1H), 7.585 (d, J=10.8 Hz, 1H), 7.821 (d, J=8.4 Hz, 1H), 8.257 (s, 1H), 8.903 (s, 1H).

[0620] Example 27: 10-cyclopropyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-27)

##STR00223##

[0621] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 10-cyclopropyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (40 mg, 39.0% yield). ESI-MS (m/z): 518.25 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ? 0.495-0.535 (m, 3H), 0.863-0.901 (m, 1H), 1.281-1.358 (m, 1H), 1.388-1.490 (m, 2H), 1.501-1.592 (m, 4H), 1.901-1.992 (m, 2H), 2.385-2.502 (m, 6H), 3.550 (s, 3H), 3.924-3.943 (m, 1H), 4.336-4.358 (t, J=6.6 Hz, 2H), 4.535-4.557 (d, J=13.2 Hz, 1H), 4.698-4.725 (m, 1H), 6.945-6.960 (m, 1H), 7.586-7.605 (d, J=11.4 Hz, 1H), 7.838-7.854 (m, 1H), 8.285 (s, 1H), 8.913 (s, 1H).

[0622] Example 28: 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (A-28)

##STR00224##

[0623] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (70 mg, 44.2% yield). ESI-MS (m/z): 518.25 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.410-1.541 (m, 8H), 1.910-1.964 (m, 6H), 2.466-2.508 (m, 6H), 3.524 (s, 3H), 4.344-4.365 (t, J=6.6 Hz, 2H), 4.647 (m, 2H), 6.953-6.967 (d, J=8.4 Hz, 1H), 7.577-7.595 (d, J=10.8 Hz, 1H), 7.839-7.853 (d, J=8.4 Hz, 1H), 8.286 (s, 1H), 8.900 (s, 1H).

[0624] Example 29: 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (A-29)

##STR00225##

[0625] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (47 mg, 39.1% yield). ESI-MS (m/z): 464.20 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.058-1.061 (m, 2H), 1.962-2.194 (m, 4H), 2.383 (s, 6H), 2.660-2.663 (m, 2H), 3.478 (s, 3H), 4.338-4.359 (t, J=6.6 Hz, 2H), 4.468 (m, 2H), 6.927-6.941 (d, J=8.4 Hz, 1H), 7.599-7.618 (d, J=11.4 Hz, 1H), 7.817-7.832 (d, J=9.0 Hz, 1H), 8.256 (s, 1H), 8.916 (s, 1H).

[0626] Example 30: 6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-30)

##STR00226##

[0627] 7-bromo-6-methoxy-2-methyl-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-trazanaphtho[2,1,8-cde]azulen-1(2H)-one (200 mg, 0.47 mmol), cesium carbonate (382 mg, 1.17 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (90 mg, 0.71 mmol), tetrakis(triphenylphosphine)palladium (55 mg, 0.05 mmol), and 1,4-dioxane (20 mL) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 120? C. under N.sub.2 protection to react for 4 h. The reaction solution was cooled down to room temperature, concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=40:1-30:1) to afford 6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (80 mg, 40.1% yield). ESI-MS (m/z): 429.16 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.525 (s, 3H), 3.943-3.967 (m, 6H), 4.867-4.916 (m, 2H), 5.206 (m, 1H), 7.039 (s, 1H), 7.233-7.255 (m, 1H), 7.533 (d, J=8.4 Hz, 1H), 7.755-7.783 (m, 1H), 8.234 (s, 1H), 8.274 (d, J=3.6 Hz, 1H), 8.372 (s, 1H), 8.669 (s, 1H).

[0628] Example 31: (S)-6-methoxy-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-31)

##STR00227##

[0629] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (S)-6-methoxy-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (68 mg, 33.2% yield). ESI-MS (m/z): 504.25 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.543 (d, J=6.6 Hz, 3H), 1.573-1.626 (m, 2H), 1.781 (m, 4H), 2.170-2.196 (m, 2H), 2.945 (brs, 6H), 3.637 (s, 3H), 3.925 (s, 3H), 4.436 (t, J=6.0 Hz, 2H), 4.465-4.571 (m, 2H), 4.685-4.699 (m, 1H), 6.916 (d, J=9.0 Hz, 1H), 7.308 (s, 1H), 7.749-7.767 (m, 1H), 8.152-8.156 (m, 1H), 8.743 (s, 1H).

[0630] Example 32: (R)-6-methoxy-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-32)

##STR00228##

[0631] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (R)-6-methoxy-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (68 mg, 33.2% yield). ESI-MS (m/z): 504.25 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.509 (d, J=6.6 Hz, 3H), 1.597 (brs, 2H), 1.739-1.776 (m, 4H), 2.134-2.181 (m, 2H), 2.881-2.938 (m, 6H), 3.604 (s, 3H), 3.893 (s, 3H), 4.407 (t, J=6.0 Hz, 2H), 4.426-4.538 (m, 2H), 4.651-4.665 (m, 1H), 6.878-6.893 (m, 1H), 7.268 (s, 1H), 7.717-7.735 (m, 1H), 8.119-8.123 (m, 1H), 8.703 (s, 1H).

[0632] Example 33: 4-methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (A-33)

##STR00229##

[0633] Except starting materials were changed, the synthesis method was the same as that of example 30 to afford 4-methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (120 mg, 31.5% yield). ESI-MS (m/z): 400.41 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.585 (s, 3H), 3.970-3.998 (m, 6H), 7.192-7.208 (m, 1H), 7.271-7.299 (m, 1H), 7.316-7.344 (m, 2H), 8.005 (s, 1H), 8.251 (s, 1H), 8.414-8.431 (m, 1H), 8.866 (s, 1H).

[0634] Example 34: (S)-9-(dimethylamino)methyl)-6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-34)

##STR00230##

[0635] Except starting materials were changed, the synthesis method was the same as that of example 30 to afford (S)-9-(dimethylamino)methyl)-6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (60 mg, 50% yield). ESI-MS (m/z): 397.17 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 2.235 (s, 6H), 2.729-2.801 (m, 2H), 3.533 (s, 3H), 3.935 (s, 4H), 4.523-4.546 (m, 1H), 4.779-4.787 (m, 1H), 7.555 (d, J=13.2 Hz, 1H), 7.996 (d, J=2.4 Hz, 1H), 8.488 (s, 1H), 8.851 (s, 1H).

[0636] Example 35: 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-35)

##STR00231##

[0637] Except starting materials were changed, the synthesis method was the same as that of example 30 to afford 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.15 g, 50% yield). ESI-MS (m/z): 356.23 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.362 (t, J=4.8 Hz, 2H), 3.561 (s, 3H), 3.954 (s, 3H), 4.347 (t, J=4.8 Hz, 2H), 7.589 (s, 1H), 7.708 (d, J=10.2 Hz, 1H), 7.948 (s, 1H), 8.952 (s, 1H).

[0638] Example 36: 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one 8-oxide (A-36)

##STR00232##

[0639] 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazinaphthalo[2,1,8-cde]azulen-1(2H)-one (0.05 g, 0.14 mmol) was dissolved in dichloromethane (20 mL), and followed by adding m-chloroperoxybenzoic acid (0.03 g, 0.17 mmol) into the vessel of reaction mixture in an ice bath, and the system was stirred for 1 h in the ice bath. A small amount of starting material was found as detected by TLC. The reaction solution was washed with a saturated aqueous solution of sodium thiosulfate (10 mL?2) and a saturated aqueous solution of sodium chloride (10 mL?2), then dried with anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (DCM:MeOH=50:1-25:1) to afford final product 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one 8-oxide (0.04 g, 77% yield). ESI-MS (m/z): 372.23 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.651 (m, 3H), 3.842-3.793 (m, 1H), 3.994 (s, 3H), 4.053-4.022 (m, 1H), 4.541-4.530 (m, 1H), 4.567-4.552 (m, 1H), 7.751 (s, 1H), 8.104 (d, J=10.8 Hz, 1H), 8.153 (s, 1H), 9.048 (s, 1H).

[0640] Example 37: 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one 8,8-dioxide (A-37)

##STR00233##

[0641] 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazinaphthalo [2,1,8-cde]azulen-1(2H)-one (0.05 g, 0.14 mmol) was dissolved in dichloromethane (20 mL), and followed by adding m-chloroperoxybenzoic acid (0.05 g, 0.28 mmol) into the vessel of reaction mixture in an ice bath, and the system was stirred for 24 h at room temperature. No starting material was found as detected by TLC. The reaction solution was washed with a saturated aqueous solution of sodium thiosulfate (10 mL?2) and a saturated aqueous solution of sodium chloride (10 mL?2), then dried with anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (DCM:MeOH=50:1-30:1) to afford 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one 8,8-dioxide (0.015 g, 27.3% yield). ESI-MS (m/z): 388.34 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.590 (s, 3H), 3.941 (s, 3H), 4.202 (t, J=4.8 Hz, 2H), 4.423 (t, J=4.8 Hz, 2H), 7.634 (s, 1H), 7.974 (s, 1H), 8.193 (d, J=10.2 Hz, 1H), 9.112 (s, 1H).

[0642] Example 38: Ethyl (6aR,10aS)-4-fluoro-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-11-oxo-6a,7,10,10a,11,12-hexahydro-6-oxa-2,8,10b,12-tetraazacyclopentadiene-8(9H)-carboxylate (A-38)

##STR00234##

[0643] Except starting materials were changed, the synthesis method was the same as that of example 30 to afford ethyl (6aR,10aS)-4-fluoro-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-11-oxo-6a,7,10,10a,11,12-hexahydro-6-oxa-2,8,10b,12-tetraazacyclopentadiene-8(9H)-carboxylate (0.10 g, 59% yield). ESI-MS (m/z): 467.2 [M+H].sup.+.

[0644] Example 39: 6-fluoro-10-(4-fluorophenyl)-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-39)

##STR00235##

[0645] Except starting materials were changed, the synthesis method was the same as that of example 30 to afford 6-fluoro-10-(4-fluorophenyl)-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.05 g, 50% yield). ESI-MS (m/z): 434.2 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.561 (s, 3H), 3.882 (s, 3H), 4.833 (d, J=13.2 Hz, 1H), 5.134 (d, J=13.2 Hz, 1H), 5.820 (s, 1H), 7.171-7.141 (m, 2H), 7.282-7.262 (m, 2H), 7.603 (d, J=12.6 Hz, 1H), 7.774 (s, 1H), 8.070 (s, 1H), 8.941 (s, 1H).

[0646] Example 40: 4-methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,9,10b,12-tetraazacyclopenta[gh]pleiaden-11(12H)-one (A-40)

##STR00236##

[0647] Except starting materials were changed, the synthesis method was the same as that of example 30 to afford 4-methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,9,10b,12-tetraazacyclopenta[gh]pleiaden-11(12H)-one (12 mg, 30% yield). ESI-MS (m/z): 401.11 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 3.597 (s, 3H), 3.973 (s, 3H), 4.001 (s, 3H), 7.261 (d, J=5.4 Hz, 1H), 7.399 (s, 1H), 7.953 (s, 1H), 8.230 (s, 1H), 8.455 (d, J=5.4 Hz, 1H), 8.923 (s, 1H), 9.714 (s, 1H).

[0648] Example 41: (6aS,9aR)-4-fluoro-11-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulen-10(11H)-one (A-41)

##STR00237##

[0649] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (6aS,9aR)-4-fluoro-11-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulen-10(11H)-one (40 mg, 33.6% yield). ESI-MS (m/z): 520.19 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.590 (s, 2H), 1.749 (t, J=10.8 Hz, 4H), 2.136-2.172 (m, 2H), 2.855-2.913 (m, 6H), 3.563 (s, 3H), 3.791 (t, J=16.8 Hz, 1H), 4.144 (t, J=19.8 Hz, 1H), 4.209 (t, J=16.8 Hz, 1H), 4.420 (t, J=12.0 Hz, 2H), 4.628-4.671 (m, 1H), 4.879 (s, 1H), 5.194 (dd, J=1=8.4 Hz, J.sub.2=16.2 Hz, 1H), 6.915 (d, J=8.4 Hz, 1H), 7.545 (d, J=10.8 Hz, 1H), 7.804 (d, J=7.8 Hz, 1H), 8.210 (s, 1H), 8.791 (s, 1H).

[0650] Example 42: (6aR,9aS)-4-fluoro-11-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulen-10(11H)-one (A-42)

##STR00238##

[0651] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford (6aR,9aS)-4-fluoro-11-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulen-10(11H)-one. ESI-MS (m/z): 520.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.550 (brs, 2H), 1.674-1.711 (m, 4H), 2.071-2.118 (m, 2H), 2.679-2.743 (m, 6H), 3.581 (s, 3H), 3.807 (t, J=8.4 Hz, 1H), 4.148-4.180 (m, 1H), 4.218 (t, J=8.4 Hz, 1H), 4.397 (t, J=6.0 Hz, 2H), 4.678-4.722 (m, 1H), 4.910-4.937 (m, 1H), 5.230 (q, J=8.4 Hz, 1H), 6.908 (d, J=8.4 Hz, 1H), 7.572 (d, J=13.2 Hz, 1H), 7.801 (d, J=8.4 Hz, 1H), 8.206 (s, 1H), 8.824 (s, 1H).

[0652] Example 43: 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,3-oxetan]-1-one (A-43)

##STR00239##

[0653] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,3-oxetan]-1-one (74 mg, 40.4% yield). ESI-MS (m/z): 520.23 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.380-1.405 (m, 2H), 1.500-1.589 (m, 4H), 1.947-1.956 (m, 2H), 2.465-2.737 (m, 6H), 3.557 (s, 3H), 4.348-4.370 (t, J=6.6 Hz, 2H), 4.348-4.500 (m, 2H), 4.875-4.960 (m, 2H), 5.424-5.592 (m, 2H), 6.958-6.972 (d, J=8.4 Hz, 1H), 7.621-7.639 (d, J=10.8 Hz, 1H), 7.860-7.874 (d, J=8.4 Hz, 1H), 8.298 (s, 1H), 8.952 (s, 1H).

[0654] Example 44: 6-methoxy-10-(hydroxymethyl)-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-44)

##STR00240##

[0655] Except starting materials were changed, the synthesis method was the same as that of example 30 to afford 6-methoxy-10-hydroxymethyl-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (180 mg, 90.2% yield). ESI-MS (m/z): 370.1 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO) ?: 3.332 (s, 3H), 3.718-3.740 (m, 2H), 3.916 (s, 3H), 3.945 (s, 3H), 4.373-4.415 (m, 1H), 4.993-5.019 (m, 1H), 5.326-5.345 (m, 1H), 7.229 (s, 1H), 7.924 (s, 1H), 8.125 (s, 1H), 8.729 (s, 1H).

[0656] Example 45: 6-methoxy-2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-45)

##STR00241##

[0657] DMF (10 mL) and methanol (8 mg, 0.24 mmol) were added to a 100 mL reaction bottle and cooled down to 0? C., followed by adding NaH (60%, 15 mg, 0.36 mmol), and the reaction was conducted at this temperature for 0.5 h. Then 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (60 mg, 0.12 mmol) was added, and the reaction was conducted at 65? C. for 24 h. When the reaction was completed as detected by TLC, water was added into the reaction solution to quench the reaction, and then the reaction mixture was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH=20:1-15:1) to afford 6-methoxy-2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (36 mg, 58.2% yield). ESI-MS (m/z): 518.27 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.370-1.405 (m, 2H), 1.490-1.520 (m, 4H), 1.609 (s, 6H), 1.862-1.910 (m, 2H), 2.356-2.410 (m, 6H), 3.474 (s, 3H), 3.383 (s, 3H), 4.300-4.339 (m, 4H), 6.871 (d, J=8.4 Hz, 1H), 7.269 (s, 1H), 7.688-7.706 (m, 1H), 8.138 (d, J=1.8 Hz, 1H), 8.784 (s, 1H).

[0658] Example 46: 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-46)

##STR00242##

[0659] The synthesis method was the same as that of example 1, except that 3-(dimethylamino)propan-1-ol was used instead of 3-(piperidin-1-yl)propan-1-ol to afford 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (40 mg, 41.5% yield). ESI-MS (m/z): 466.22 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.639 (s, 6H), 1.874-1.898 (m, 2H), 2.156 (s, 6H), 2.366 (t, J=7.2 Hz, 2H), 3.504 (s, 3H), 4.340 (t, J=6.6 Hz, 2H), 4.443 (s, 2H), 6.948 (d, J=8.4 Hz, 1H), 7.598 (d, J=11.4 Hz, 1H), 7.827-7.843 (m, 1H), 8.276 (s, 1H), 8.901 (s, 1H).

[0660] Example 47: 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (A-47)

##STR00243##

[0661] Except starting materials were changed, the synthesis method was the same as that of example 45 to afford 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (25 mg, 49.2% yield). ESI-MS (m/z): 504.22 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 0.999-1.050 (m, 2H), 1.130-1.283 (m, 2H), 1.400-1.596 (m, 2H), 1.604-1.710 (m, 4H), 2.067-2.174 (m, 4H), 2.508-2.873 (m, 4H), 3.451 (s, 3H), 3.836 (s, 3H), 4.327-4.348 (m, 4H), 6.860 (d, J=8.4 Hz, 1H), 7.294 (s, 1H), 7.680-7.697 (m, 1H), 8.115 (d, J=1.8 Hz, 1H), 8.803 (s, 1H).

[0662] Example 48: 6-fluoro-10-(hydroxymethyl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-48)

##STR00244##

[0663] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 6-fluoro-10-(hydroxymethyl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.10 g, 48.3% yield). ESI-MS (m/z): 508.21 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.427-1.568 (m, 6H), 1.984-1.985 (m, 2H), 2.500-2.506 (m, 6H), 3.547 (s, 3H), 3.630-3.721 (m, 2H), 4.350-4.371 (t, J=6.6 Hz, 2H), 4.438-4.444 (m, 1H), 4.505-4.527 (m, 1H), 4.820-4.846 (m, 1H), 5.268-5.287 (t, J=11.4 Hz, 1H), 6.947-6.962 (d, J=9.0 Hz, 1H), 7.590-7.609 (d, J=11.4 Hz, 1H), 7.844-7.858 (d, J=8.4 Hz, 1H), 8.288 (s, 1H), 8.918 (s, 1H).

[0664] Example 49: 6-fluoro-10-(methoxymethyl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-49)

##STR00245##

[0665] Step 1: Synthesis of 7-bromo-6-fluoro-10-(methoxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0666] THF (10 mL) and 7-bromo-6-fluoro-10-(hydroxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.10 g, 0.27 mmol) were successively added to a 100 mL reaction bottle, cooled down to 0? C. followed by adding NaH (0.03 g, 0.82 mmol), and the reaction was conducted at this temperature for 0.5 h. Then iodomethane (0.08 g, 0.54 mmol) was added, and the reaction was rewarmed to room temperature and reacted for 5 h. When the reaction was completed as detected by TLC, water was added into the reaction solution to quench the reaction, and then the reaction mixture was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH=50:1-25:1) to afford 7-bromo-6-fluoro-10-(methoxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (30 mg, 29.4% yield). ESI-M (m/z): 381.95 [M+H].sup.+.

[0667] Step 2: Synthesis of 6-fluoro-10-(methoxymethyl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0668] 1,4-dioxane (15 mL), 7-bromo-6-fluoro-10-(methoxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.03 g, 0.08 mmol), (6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)boronic acid (0.03 g, 0.12 mmol), cesium carbonate (0.05 g, 0.16 mmol), water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated to 90? C. under nitrogen protection to react for 2.5 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=50:1-10:1) to afford 6-fluoro-10-(methoxymethyl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.16 g, 39.2% yield). ESI-MS (m/z): 522.15 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.400-1.528 (m, 6H), 1.926-1.947 (m, 2H), 2.434-2.497 (m, 6H), 3.307 (s, 3H), 3.570 (s, 3H), 3.578-3.713 (m, 2H), 4.330-4.351 (t, J=6.6 Hz, 2H), 4.526-4.548 (m, 1H), 4.647-4.734 (m, 1H), 4.752-4.757 (m, 1H), 6.939-6.953 (d, J=8.4 Hz, 1H), 7.593-7.612 (d, J=11.4 Hz, 1H), 7.826-7.840 (d, J=8.4 Hz, 1H), 8.272 (s, 1H), 8.920 (s, 1H).

[0669] Example 50: 6-methoxy-10-(methoxymethyl)-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-50)

##STR00246##

[0670] Anhydrous tetrahydrofuran (10 mL) and 10-(hydroxymethyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrrole-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (50 mg, 0.13 mmol) were added to a 50 mL reaction bottle, then sodium hydride (25 mg, 0.65 mmol) was added into the vessel of the reaction mixture in an ice bath, and then the reaction mixture was stirred in an ice bath for 30 min followed by adding iodomethane (22 mg, 0.15 mmol). The reaction was conducted under nitrogen protection at room temperature for 2 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=30:1) to afford 6-methoxy-10-(methoxymethyl)-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (20 mg, 40.4% yield). ESI-MS (m/z): 396.16 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.336 (s, 3H), 3.501 (s, 3H), 3.608-3.633 (m, 1H), 3.733-3.764 (m, 1H), 3.915 (s, 3H), 3.941 (s, 3H), 4.409-4.431 (m, 1H), 4.614-4.636 (m, 1H), 4.904-4.926 (m, 1H), 7.233 (s, 1H), 7.780 (s, 1H), 8.089 (s, 1H), 8.734 (s, 1H).

[0671] Example 51: 6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-10-methylene-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-51)

##STR00247##

[0672] Anhydrous tetrahydrofuran (2 mL) and 10-(hydroxymethyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrrole-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (20 mg, 0.05 mmol) were added to a 50 mL reaction bottle, followed by DMF (1 mL), then sodium hydride (25 mg, 0.65 mmol) was added into the reaction bottle in an ice bath, and then the reaction solution was stirred in an ice bath for 30 min followed by adding p-toluenesulfonyl chloride (15 mg, 0.08 mmol). The reaction was conducted under nitrogen protection at room temperature for 2 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=30:1) to afford 6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-10-methylene-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (10 mg, 48.2% yield). ESI-MS (m/z): 364.13 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.352 (s, 3H), 3.915 (s, 3H), 3.962 (s, 3H), 4.954 (s, 2H), 5.396 (s, 1H), 6.182 (s, 1H), 7.283 (s, 1H), 7.925 (s, 1H), 8.157 (s, 1H), 8.835 (s, 1H).

[0673] Example 52: 10-((dimethylamino)methyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-52)

##STR00248##

[0674] Step 1: Synthesis of 10-(aminomethyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0675] Anhydrous N,N-dimethyl formamide (2 mL), 6-methoxy-10-(hydroxymethyl)-2-methyl-7-(1-methyl-1H-pyrrole-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (50 mg, 0.13 mmol), triphenylphosphine (138 mg, 0.524 mmol), and phthaldiamide (29 mg, 0.19 mmol) were successively added to a 50 mL reaction bottle, diisopropyl azodicarboxylate (106 mg, 0.524 mmol) was added under nitrogen protection, and then the reaction was conducted under nitrogen protection at room temperature for 2 h. When the reaction was completed as detected by TLC, the reaction solution was added with 50 mL of water and extracted with 30 mL of dichloromethane for 4 times, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to dryness for instant use in the next step. To the residue, methanol (15 mL) and hydrazine hydrate (2 mL) were added, and the reaction was conducted under nitrogen protection at room temperature for 2 h, and completed as detected by TLC. The reaction solution was concentrated under reduced pressure to remove methanol, and then extracted with 30 mL of dichloromethane for 4 times, the organic phases were combined, dried with anhydrous sodium sulfate, and then purified by column chromatography (DCM:MeOH=20:1) to afford 10-(aminomethyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (29 mg, 58.1% yield). ESI-MS (m/z): 381.16 [M+H].sup.+.

[0676] Step 2: Synthesis of 10-((dimethylamino)methyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0677] Anhydrous methanol (6 mL) and 10-(aminomethyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (29 mg, 0.08 mmol) were added to a 50 mL reaction bottle, followed by adding an aqueous solution of formaldehyde (2 mL) and acetic acid (10 ?L), and then the reaction solution was stirred at room temperature for 30 min, followed by adding sodium triacetoxyborohydride (49 mg, 0.23 mmol). The reaction was rewarmed to room temperature and reacted for 12 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=15:1) to afford 10-((dimethylamino)methyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (7 mg, 27.3% yield). ESI-MS (m/z): 409.19 [M+H].sup.+; .sup.1H NMR (600 MHz, CDCl.sub.3) ?: 2.503 (s, 6H), 2.694-2.712 (d, J=10.8 Hz, 1H), 3.121 (s, 1H), 3.594 (s, 3H), 4.007 (s, 3H), 4.019 (s, 3H), 4.269-4.290 (d, J=12.6 Hz, 1H), 4.646-4.659 (d, J=7.8 Hz, 1H), 5.166-5.187 (d, J=12.6 Hz, 1H), 7.265 (s, 1H), 7.310 (s, 1H), 8.102 (s, 1H), 8.555 (s, 1H).

[0678] Example 53: 8-fluoro-4-methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,10b,12-triazanaphtho[gh]pleiaden-11(12H)-one (A-53)

##STR00249##

[0679] Except starting materials were changed, the synthesis method was the same as that of example 30 to afford 8-fluoro-4-methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,10b,12-triazanaphtho[gh]pleiaden-11(12H)-one (200 mg, 66.6% yield). ESI-MS (m/z): 418.12 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.577 (s, 3H), 3.967-3.998 (m, 6H), 6.934-6.943 (m, 1H), 7.253 (s, 1H), 7.349 (s, 1H), 7.972 (s, 1H), 8.235 (s, 1H), 8.475 (s, 1H), 8.872 (s, 1H).

[0680] Example 54: 6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-54)

##STR00250##

[0681] Except starting materials were changed, the synthesis method was the same as that of example 30 to afford 6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (230 mg, 63.9% yield). ESI-MS (m/z); 429.16 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.523 (s, 3H), 3.773 (s, 3H), 3.937 (s, 3H), 4.369-4.406 (m, 1H), 4.674-4.698 (m, 1H), 5.734 (d, J=9.0 Hz, 1H), 7.259 (s, 1H), 7.435-7.446 (m, 2H), 7.662 (s, 1H), 7.849-7.906 (m, 2H), 8.653 (s, 1H), 8.763 (s, 1H).

[0682] Example 55: (R)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-10-phenyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-55)

##STR00251##

[0683] Except starting materials were changed, the synthesis method was the same as that of example 30 to afford (R)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-10-phenyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (130 mg, 43.3% yield). ESI-MS (m/z); 428.16 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 3.522 (s, 3H), 3.830 (s, 3H), 3.939 (s, 3H), 4.747-4.769 (m, 1H), 5.008-5.034 (m, 1H), 5.746 (s, 1H), 7.174-7.187 (m, 2H), 7.261-7.275 (m, 2H), 7.296-7.321 (m, 2H), 7.689 (s, 1H), 7.945 (s, 1H), 8.821 (s, 1H).

[0684] Example 56: (S)-6-fluoro-2,10-dimethyl-7-(6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-56)

##STR00252##

[0685] Step 1: Synthesis of (6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)boronic acid

[0686] Acetonitrile (20 mL), 1-(but-3-yn-1-yl)piperidine (1.37 g, 10.0 mmol), (2-bromopyridine-5-yl)boronic acid (2.01 g, 10.0 mmol), tetrakis(triphenylphosphine)palladium (0.40 g, 0.35 mmol), cuprous iodide (0.07 g, 0.35 mmol), and triethylamine (2 mL) were successively added to a 50 mL reaction bottle. The reaction was conducted under nitrogen protection at room temperature for 6 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was subject to column chromatography (DCM:MeOH=30:1) to afford (6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)boronic acid (1.26 g, 61.1% yield). ESI-MS (m/z): 259.15 [M+H].sup.+.

[0687] Step 2: Synthesis of (S)-6-fluoro-2,10-dimethyl-7-(6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0688] 1,4-dioxane (10 mL), (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (170 mg, 0.48 mmol), (6-(4-(piperidin-1-yl) but-1-yn-1-yl)pyridin-3-yl)boronic acid, potassium carbonate (132 mg, 0.96 mmol), water (1 mL), and tetrakis(triphenylphosphine)palladium (55 mg, 0.048 mmol) were successively added to a 50 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-10:1) to afford (S)-6-fluoro-2,10-dimethyl-7-(6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (35 mg, 15% yield). ESI-MS (m/z): 486.22 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.532-1.543 (m, 6H), 1.722 (s, 4H), 2.775 (s, 2H), 2.812-2.836 (m, 2H), 2.931 (s, 2H), 3.632 (s, 4H), 4.531-4.553 (m, 1H), 4.639-4.661 (m, 1H), 4.722-4.731 (m, 1H), 7.569 (d, J=11.4 Hz, 1H), 7.630 (d, J=8.4 Hz, 1H), 7.981 (d, J=7.8 Hz, 1H), 8.622 (s, 1H), 8.842 (s, 1H).

[0689] Example 57: 5-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (A-57)

##STR00253##

[0690] Step 1: Synthesis of 4-fluoro-5-(6-fluoropyridin-3-yl)-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]azulen-11(12H)-one

[0691] 1,4-dioxane (15 mL), 5-bromo-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (0.69 g, 1.76 mmol), (6-fluoropyridine-3-yl)boronic acid (0.315 g, 2.23 mmol), potassium carbonate (0.607 g, 4.4 mmol), water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0.203 g, 0.18 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection to react for 2.5 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=60:1) to afford 4-fluoro-5-(6-fluoropyridin-3-yl)-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]azulene-11(12H)-one (0.35 g, 48.7% yield). ESI-MS (m/z): 409.31 [M+H].sup.+.

[0692] Step 2: Synthesis of 5-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (A-57)

[0693] DMSO (10 mL), DIPEA (3 mL), 4-fluoro-5-(6-fluoropyridin-3-yl)-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]azulen-11(12H)-one (170 mg, 0.417 mmol) and N,N-dimethylpiperidin-4-amine hydrochloride (167 mg, 0.834 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 150? C. to react for 12 h, then cooled down to room temperature and washed with ethyl acetate and a saturated saline solution for 2 to 3 times, and then the organic phase was dried and concentrated to afford a crude product. The crude product was purified by column chromatography (DCM:MeOH=30:1-6:1) to afford 5-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopenta[gh]pleiaden-11(12H)-one (30 mg, 13.9% yield). ESI-MS (m/z): 517.24 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 1.280-1.353 (m, 2H), 1.412-1.466 (m, 2H), 1.533-1.641 (m, 1H), 1.656-1.667 (m, 1H), 1.713-1.728 (m, 1H), 1.915 (d, 2H), 2.098 (d, 1H), 2.357 (s, 6H), 2.615-2.636 (m, 1H), 2.860 (t, J=12.6 Hz, 2H), 3.491 (s, 3H), 3.554-3.576 (m, 2H), 4.218-4.259 (m, 1H), 4.373-4.391 (m, 3H), 6.973 (d, J=9.0 Hz, 1H), 7.543 (d, J=10.8 Hz, 1H), 7.647 (d, J=8.4 Hz, 1H), 8.197 (s, 1H), 8.856 (s, 1H).

[0694] Example 58: (S)-6-fluoro-2,10-dimethyl-7-(2-oxo-1-(3-(piperidin-1-yl)propyl)-1,2-dihydropyridin-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-146)

##STR00254##

[0695] Step 1: Synthesis of 4-bromo-1-(3-(piperidin-1-yl)propyl)pyridin-2(1H)-one

[0696] Acetonitrile (30 mL), 1-(3-bromopropyl)piperidine hydrobromide (1.81 g, 6.32 mmol), 4-bromo-2-hydroxypyridine (1.0 g, 5.75 mmol), and potassium carbonate (1.98 g, 14.37 mmol) were successively added to a 100 mL reaction bottle and heated to reflux for 5 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-15:1) to afford 4-bromo-1-(3-(piperidin-1-yl)propyl)pyridin-2(1H)-one (1.24 g, 72.0% yield). ESI-M (m/z): 299.07/301.07 [M+H].sup.+.

[0697] Step 2: Synthesis of 1-(3-(piperidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

[0698] 1,4-dioxane (25 mL), 4-bromo-1-(3-(piperidin-1-yl)propyl)pyridin-2(1H)-one (1.24 g, 4.14 mmol), bis(pinacolato)diboron (2.10 g, 8.28 mmol), potassium acetate (1.22 g, 12.42 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (0.30 g, 0.41 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-15:1) to afford 1-(3-(piperidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1.13 g, 79% yield).

[0699] Step 3: Synthesis of (S)-6-fluoro-2,10-dimethyl-7-(2-oxo-1-(3-piperidin-1-yl)propyl)-1,2-dihydropyridin-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0700] 1,4-dioxane (5 mL), 1-(3-(piperidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (156 mg, 0.45 mmol), (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (106 mg, 0.3 mmol), potassium carbonate (83 mg, 0.6 mmol), water (0.5 mL), and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) were successively added to a 50 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-10:1) to afford (S)-6-fluoro-2,10-dimethyl-7-(2-oxo-1-(3-piperidin-1-yl)propyl)-1,2-dihydropyridin-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, 17% yield). ESI-M (m/z): 492.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.561-1.572 (m, 5H), 1.707-1.726 (m, 4H), 2.100-2.148 (m, 2H), 2.665 (brs, 6H), 3.657 (s, 3H), 4.146 (t, J=7.2 Hz, 2H), 4.559-4.580 (m, 1H), 4.689-4.715 (m, 1H), 4.745-4.779 (m, 1H), 6.582 (d, J=6.6 Hz, 1H), 6.727 (s, 1H), 7.560 (d, J=11.4 Hz, 1H), 7.795 (d, J=6.6 Hz, 1H), 8.868 (s, 1H).

[0701] Example 59: (S)-6-fluoro-2,10-dimethyl-7-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-148)

##STR00255##

[0702] Step 1: Synthesis of 5-bromo-2-((2-(piperidin-1-yl)ethoxy)methyl)pyridine

[0703] THF (30 mL) and N-hydroxyethylpiperidine (1.0 g, 7.74 mmol) were successively added to a 100 mL reaction bottle, and cooled down to 0? C., followed by adding NaH (0.62 g, 15.48 mmol), the reaction was conducted at this temperature for 0.5 h, then 5-bromo-2-(bromomethyl)pyridine (1.94 g, 7.74 mmol) was added, and the reaction was rewarmed to room temperature and reacted for 5 h. When the reaction was completed as detected by TLC, water was added into the reaction solution to quench the reaction, and concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-15:1) to afford 5-bromo-2-((2-(piperidin-1-yl)ethoxy)methyl)pyridine (1.97 g, 85.0% yield). ESI-MS (m/z): 299.07/301.07 [M+H].sup.+.

[0704] Step 2: Synthesis of 2-((2-(piperidin-1-yl)ethoxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0705] 1,4-dioxane (25 mL), 5-bromo-2-((2-(piperidin-1-yl)ethoxy)methyl)pyridine (1.97 g, 6.58 mmol), bis(pinacolato)diboron (3.34 g, 13.16 mmol), potassium acetate (1.61 g, 16.45 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (0.48 g, 0.66 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness to afford a crude product of 2-((2-(piperidin-1-yl)ethoxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for instant use in the next step.

[0706] Step 3: Synthesis of (S)-6-fluoro-2,10-dimethyl-7-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0707] 1,4-dioxane (5 mL), 2-((2-(piperidin-1-yl)ethoxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (156 mg, 0.45 mmol), (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (106 mg, 0.3 mmol), potassium carbonate (83 mg, 0.6 mmol), water (0.5 mL), and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) were successively added to a 50 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection and reacted for 3 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-10:1) to afford (S)-6-fluoro-2,10-dimethyl-7-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, 17% yield). ESI-MS (m/z): 492.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.463-1.624 (m, 5H), 1.693-1.711 (m, 4H), 2.748 (brs, 4H), 2.881 (brs, 2H), 3.622 (s, 3H), 3.835 (t, J=5.4 Hz, 2H), 4.520-4.542 (m, 1H), 4.613-4.634 (m, 1H), 4.711-4.726 (m, 3H), 7.533 (d, J=11.4 Hz, 1H), 7.676 (d, J=8.4 Hz, 1H), 8.004 (d, J=8.4 Hz, 1H), 8.630 (s, 1H), 8.811 (s, 1H).

[0708] Example 60: N-(2-(3-(dimethylamino)propoxy)-5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,4a1(7a),6-pentanen-7-yl)pyridin-3-yl)cyclopropanecarboxamide (A-155)

##STR00256##

[0709] Step 1: Synthesis of 3-((5-bromo-3-nitropyridin-2-yl)oxy)-N,N-dimethylpropane-1-amine

[0710] Anhydrous THF (4 mL) and 3-(dimethylamino)propan-1-ol (1.7 g, 16.4 mmol) were successively added to a 250 mL reaction bottle, and cooled down to 0? C., followed by adding NaH (0.66 g, 16.4 mmol), and the reaction solution was rewarmed to room temperature with stirring for 0.5 h. The reaction solution was cooled down under N.sub.2 protection, and a solution of 5-bromo-2-chloro-3-nitropyridine (3 g, 12.6 mmol) in THF (30 mL) was added dropwise at ?5? C., and then the reaction solution was rewarmed to room temperature to react for 3 h. When the reaction was completed as shown by LC-MS, a saturated ammonium chloride solution was added to quench the reaction, then water was added to dilute the reaction solution, followed by adding ethyl acetate, stirring, and separating the phases, and the organic phase was concentrated to dryness under reduced pressure, and then the residue was purified by column chromatography (DCM:MeOH=40:1-10:1) to afford 3-((5-bromo-3-nitropyridin-2-yl)oxy)-N,N-dimethylpropane-1-amine (2.1 g, 54.5% yield). ESI-MS (m/z): 304.02/306.02 [M+H].sup.+.

[0711] Step 2: Synthesis of 5-bromo-2-(3-(dimethylamino)propoxy)pyridine-3-amine

[0712] AcOH (50 mL), 3-((5-bromo-3-nitropyridin-2-yl)oxy)-N,N-dimethylpropane-1-amine (2.1 g, 6.9 mmol), and iron powder (2.0 g, 35.7 mmol) were added to a 250 mL reaction bottle and reacted at room temperature for 2 h. When the reaction was completed as detected by LC-MS, THF (50 mL) and DCM (100 mL) were added, then the reaction solution was filtered, the filter cake was washed with DCM, the filtrate was concentrated to dryness under reduced pressure, and then the residue was purified by column chromatography (DCM:MeOH=80:1-5:1) to afford 5-bromo-2-(3-(dimethylamino)propoxy)pyridine-3-amine (1.4 g, 73.7% yield). ESI-MS (m/z): 274.05/276.02 [M+H].sup.+.

[0713] Step 3: Synthesis of N-(5-bromo-2-(3-(dimethylamino)propoxy)pyridin-3-yl)cyclopropanecarboxamide

[0714] DCM (20 mL), 5-bromo-2-(3-(dimethylamino)propoxy)pyridin-3-amine (0.50 g, 1.8 mmol), and TEA (0.46 g, 4.5 mmol) were successively added to a 100 mL reaction bottle, and cooled down to 0? C., followed by adding cyclopropanecarbonyl chloride (0.25 g, 2.4 mol) dropwise at this temperature. After addition, the reaction was rewarmed to room temperature and reacted for 2 h. When the reaction was completed as shown by LC-MS, water was added to quench the reaction, the reaction solution was subjected to phase separation, then the organic phase was concentrated to dryness under reduced pressure, and then the residue was purified by column chromatography (DCM:MeOH=30:1-10:1) to afford N-(5-bromo-2-(3-(dimethylamino)propoxy)pyridin-3-yl)cyclopropanecarboxamide (0.5 g, 80.6% yield). ESI-MS (m/z): 342.07/344.07 [M+H].sup.+.

[0715] Step 4: Synthesis of N-(2-(3-(dimethylamino)propoxy)-5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,4a1(7a),6-pentanen-7-yl)pyridin-3-yl)cyclopropanecarboxamide

[0716] DMF (20 mL), N-(5-bromo-2-(3-(dimethylamino)propoxy)pyridin-3-yl)cyclopropanecarboxamide (0.5 g, 1.5 mmol), bis(pinacolato)diboron (0.76 g, 3.0 mmol), PdCl.sub.2(dppf) (0.11 g, 0.15 mmol), and potassium acetate (0.37 g, 3.8 mmol) were successively added to a 100 mL reaction bottle and reacted for 4 h under nitrogen protection at 90? C. Then the reaction solution was cooled down, and 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (0.57 g, 1.5 mmol), potassium carbonate (0.62 g, 4.5 mmol), water (1 mL), and tetra (triphenylphosphine)palladium (0.17 g, 0.15 mmol) were added. The reaction solution was heated up to 90? C. under nitrogen protection to react for 4 h. The reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-5:1) to afford N-(2-(3-(dimethylamino)propoxy)-5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,4a1(7a),6-pentanen-7-yl)pyridin-3-yl)cyclopropanecarboxamide (35 mg, 4.3% yield). ESI-MS (m/z): 561.25 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.907-0.987 (m, 6H), 1.318-1.329 (m, 5H), 1.942-1.957 (m, 1H), 1.995-2.009 (m, 1H), 2.102-2.137 (m, 3H), 2.367 (s, 6H), 2.626-2.651 (m, 2H), 3.589 (s, 3H), 4.540-4.561 (m, 2H), 7.491 (d, J=10.8 Hz, 1H), 7.973 (s, 1H), 8.484 (s, 1H), 8.769 (s, 1H).

[0717] Example 61: N-(5-(6-fluoro-2-methyl-1-oxo-1, 2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,4a1(7a),6-pentanen-7-yl)-2-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)cyclopropanecarboxamide (A-156)

##STR00257##

[0718] Except starting materials were changed, the synthesis method was the same as that of example 60 to afford N-(5-(6-fluoro-2-methyl-1-oxo-1, 2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,4a1(7a),6-pentanen-7-yl)-2-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)cyclopropanecarboxamide (40 mg, 35.5% yield). ESI-MS (m/z): 601.29 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.897-0.985 (m, 6H), 1.273-1.295 (m, 5H), 1.629-1.639 (m, 2H), 1.648-1.666 (m, 1H), 1.891-1.995 (m, 1H), 2.000-2.007 (m, 1H), 2.014-2.139 (m, 4H), 2.533-2.579 (m, 4H), 2.592-2.604 (m, 2H), 3.582 (s, 3H), 4.518-4.528 (m, 2H), 4.539-4.604 (m, 2H), 7.468 (d, J=10.8 Hz, 1H), 7.958 (s, 1H), 8.487 (s, 1H), 8.749 (s, 1H).

[0719] Example 62: N-(2-(3-(dimethylamino)propoxy)-5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,4a1(7a),6-pentanen-7-yl)pyridin-3-yl)methanesulfonamide (A-157)

##STR00258##

[0720] Except starting materials were changed, the synthesis method was the same as that of example 60 to afford N-(2-(3-(dimethylamino)propoxy)-5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,4a1(7a),6-pentanen-7-yl)pyridin-3-yl)methanesulfonamide (28 mg, 25.2% yield). ESI-MS (m/z): 571.21 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.885-0.908 (m, 2H), 1.284 (s, 3H), 1.912-1.930 (m, 1H), 2.069-2.087 (m, 1H), 2.132-2.154 (m, 2H), 2.542 (s, 6H), 2.831-2.854 (m, 2H), 3.020 (s, 3H), 3.585 (s, 3H), 4.502-4.522 (m, 2H), 4.462 (s, 2H), 7.496 (d, J=10.8 Hz, 1H), 7.870 (s, 1H), 7.946 (s, 1H), 8.764 (s, 1H).

[0721] Example 63: (S)-7-(6-((3-(dimethylamino)propyl)amino)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-158)

##STR00259##

[0722] The synthesis method was the same as that of example 57 except that the starting material in step 1 was changed to (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one, and N,N-dimethyl-1,3-diaminopropane was used instead of N,N-dimethylpiperidin-4-amine hydrochloride in step 2, to afford (S)-7-(6-((3-(dimethylamino)propyl)amino)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (88 mg, 47.5% yield). ESI-MS (m/z): 451.22 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.549 (d, J=6.6 Hz, 3H), 2.004 (m, 2H), 2.777 (s, 6H), 3.028 (t, J=6.6 Hz, 2H), 3.488 (t, J=6.0 Hz, 2H), 3.627 (s, 3H), 4.501 (d, J=13.2 Hz, 1H), 4.641 (m, 1H), 4.717 (m, 2H), 6.700 (d, J=8.4 Hz, 1H), 7.515 (d, J=11.4 Hz, 1H), 7.617 (d, J=9.0 Hz, 1H), 8.143 (s, 1H), 8.802 (s, 1H).

[0723] Example 64: (S)-7-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-159)

##STR00260##

[0724] The synthesis method was the same as that of example 57 except that the starting material in step 1 was changed to (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one, to afford (S)-7-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (31 mg, 16.7% yield). ESI-MS (m/z): 477.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.538 (d, J=6.6 Hz, 3H), 1.619-1.666 (m, 2H), 2.091 (d, J=12.6H, 2H), 2.609 (s, 6H), 2.966 (m, 3H), 3.616 (s, 3H), 4.465-4.532 (m, 3H), 4.611-4.637 (m, 1H), 4.699 (d, J=5.4 Hz, 1H), 6.977 (d, J=9.0 Hz, 1H), 7.484 (d, J=11.4 Hz, 1H), 7.697 (d, J=9.0 Hz, 1H), 8.216 (s, 1H), 8.771 (s, 1H).

[0725] Example 65: (S)-1-(3-((5-(6-fluoro-2-methyl-1-oxo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-7-yl)pyridin-2-yl)oxy)propyl)pyrrolidine-3-carbonitrile (A-160)

##STR00261##

[0726] Step 1: Synthesis of (S)-1-(3-hydroxypropyl)pyrrolidine-3-carbonitrile

[0727] (S)-3-cyanopyrrolidine hydrochloride (0.95 g, 7.13 mmol), acetonitrile (20 mL), potassium carbonate (3.94 g, 28.54 mmol), and 3-bromopropan-1-ol (1.19 g, 8.56 mmol) were added to a 100 mL reaction bottle. The reaction solution was heated up to 80? C. to react for 5 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature and subjected to suction filtration, the filtrate was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=50:1-20:1) to afford (S)-1-(3-hydroxypropyl)pyrrolidine-3-carbonitrile (0.62 g, 56.4% yield). ESI-MS (m/z): 155.11 [M+H].sup.+.

[0728] Step 2: Synthesis of (S)-1-(3-((5-(6-fluoro-2-methyl-1-oxo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-7-yl)pyridin-2-yl)oxy)propyl)pyrrolidine-3-carbonitrile

[0729] Anhydrous THF (4 mL) and (S)-1-(3-hydroxypropyl)pyrrolidine-3-carbonitrile (78 mg, 0.51 mmol) were added to a 50 mL reaction bottle and cooled down to 0? C., followed by adding NaH (35 mg, 0.89 mmol) in batches. After 0.5 h of reaction at room temperature, 6-fluoro-7-(6-fluoropyridin-3-yl)-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (100 mg, 0.25 mmol) was added, and the reaction was continued at room temperature overnight. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness and the residue was purified by column chromatography (DCM:MeOH=20:1-10:1) to afford a crude product. The crude product was further purified by preparative thin-layer chromatography to afford (S)-1-(3-((5-(6-fluoro-2-methyl-1-oxo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-7-yl)pyridin-2-yl)oxy)propyl)pyrrolidine-3-carbonitrile (23 mg, 17.4%). ESI-MS (m/z): 529.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.886-0.909 (m, 2H), 1.288-1.320 (m, 2H), 1.929-1.948 (m, 1H), 2.031-2.099 (m, 4H), 2.295-2.311 (m, 1H), 2.655-2.950 (m, 6H), 3.195-3.306 (m, 1H), 3.599 (s, 3H), 4.426 (t, J=6.0 Hz, 2H), 4.840 (brs, 2H), 6.938 (d, J=8.4 Hz, 1H), 7.515 (d, J=10.8 Hz, 1H), 7.833 (d, J=8.4 Hz, 1H), 8.252 (s, 1H), 8.787 (s, 1H).

[0730] Example 66: (S)-6-fluoro-7-(6-(3-(3-fluoropyrrolidin-1-yl)propoxy)pyridin-3-yl)-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (A-161)

##STR00262##

[0731] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford (S)-6-fluoro-7-(6-(3-(3-fluoropyrrolidin-1-yl)propoxy)pyridin-3-yl)-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (30 mg, 29.2% yield). ESI-MS (m/z): 522.22 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.693 (m, 1H), 1.444-1.457 (m, 1H), 1.703-1.727 (m, 1H), 1.923-1.955 (m, 2H), 2.010-2.078 (m, 4H), 2.198-2.255 (m, 1H), 2.482-2.495 (m, 1H), 2.704-2.755 (m, 3H), 2.955-3.306 (m, 2H), 3.588 (s, 3H), 4.271-4.293 (m, 1H), 4.402-4.423 (m, 2H), 4.892 (s, 2H), 6.929 (d, J=8.4 Hz, 1H), 7.481 (d, J=10.8 Hz, 1H), 7.823 (d, J=8.4 Hz, 1H), 8.240 (s, 1H), 8.760 (s, 1H).

[0732] Example 67: 6-fluoro-2-methyl-7-(6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (A-162)

##STR00263##

[0733] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford 6-fluoro-2-methyl-7-(6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (28 mg, 27.9% yield). ESI-MS (m/z): 504.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.885-0.905 (m, 2H), 1.285 (s, 2H), 1.834-1.854 (m, 4H), 1.913-1.948 (m, 1H), 2.049-2.096 (m, 3H), 2.638 (s, 4H), 2.710-2.736 (m, 2H), 3.575 (s, 3H), 4.396-4.417 (m, 2H), 4.571 (s, 2H), 6.918 (d, J=8.4 Hz, 1H), 7.455 (d, J=10.8 Hz, 1H), 7.807 (d, J=8.4 Hz, 1H), 8.227 (s, 1H), 8.728 (s, 1H).

[0734] Example 68: 7-(6-(3-(4,4-difluoropiperidin-1-yl)propoxy)pyridin-3-yl)-6-fluoro-2-methyl-9-H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (A-163)

##STR00264##

[0735] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford 7-(6-(3-(4,4-difluoropiperidin-1-yl)propoxy)pyridin-3-yl)-6-fluoro-2-methyl-9-H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (48 mg, 20.1% yield). ESI-MS (m/z): 554.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.897 (t, J=7.2 Hz, 2H), 1.288 (m, 2H), 1.925-1.988 (m, 2H), 1.998-2.091 (m, 6H), 2.649 (t, J=7.2 Hz, 6H), 3.596 (s, 3H), 4.419 (t, J=6.6 Hz, 2H), 4.605 (brs, 2H), 6.932 (d, J=8.4 Hz, 1H), 7.505 (d, J=11.4 Hz, 1H), 7.822-7.837 (m, 1H), 8.247 (s, 1H), 8.778 (s, 1H).

[0736] Example 69: 6-fluoro-2-methyl-7-(6-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-3-yl)-9-H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (A-164)

##STR00265##

[0737] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford 6-fluoro-2-methyl-7-(6-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-3-yl)-9-H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (38 mg, 19.7% yield). ESI-MS (m/z): 533.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.897 (t, J=6.6H, 2H), 1.288 (m, 2H), 1.907-1.957 (m, 2H), 2.023-2.090 (m, 3H), 2.336 (s, 3H), 2.564-2.632 (m, 9H), 3.591 (s, 3H), 4.410 (t, J=6.0 Hz, 2H), 4.595 (brs, 2H), 6.925 (d, J=8.4 Hz, 1H), 7.490 (d, J=10.8 Hz, 1H), 7.822 (d, J=8.4 Hz, 1H), 8.240 (s, 1H), 8.763 (s, 1H).

[0738] Example 70: 6-fluoro-7-(6-(3-(4-fluoropiperidin-1-yl)propoxy)pyridin-3-yl)-2-methyl-9-H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (A-165)

##STR00266##

[0739] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford 6-fluoro-7-(6-(3-(4-fluoropiperidin-1-yl)propoxy)pyridin-3-yl)-2-methyl-9-H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (23 mg, 16.3% yield). ESI-MS (m/z): 536.24 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.850-1.855 (m, 4H), 1.908-1.942 (m, 4H), 2.032-2.068 (m, 5H), 2.501 (s, 2H), 2.591-2.671 (m, 4H), 3.569 (s, 3H), 4.396 (t, J=6.0 Hz, 2H), 4.562 (brs, 1H), 4.633 (s, 1H), 6.907 (d, J=8.4 Hz, 1H), 7.430 (d, J=10.8 Hz, 1H), 7.796 (d, J=8.4 Hz, 1H), 8.216 (s, 1H), 8.705 (s, 1H).

[0740] Example 71: 1-(3-((5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9-H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentanen-7-yl)pyridin-2-yl)oxy)propyl)piperidin-4-carbonitrile (A-166)

##STR00267##

[0741] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford 1-(3-((5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9-H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentanen-7-yl)pyridin-2-yl)oxy)propyl)piperidin-4-carbonitrile (41 mg, 22.6% yield). ESI-MS (m/z): 543.24 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.886-2.056 (m, 12H), 2.446 (d, J=14.4 Hz, 2H), 2.599 (s, 2H), 2.618 (d, J=7.2 Hz, 2H), 2.832 (s, 1H), 3.599 (s, 3H), 4.407 (t, J=6.6 Hz, 2H), 4.609 (brs, 2H), 6.933 (d, J=8.4 Hz, 1H), 7.513 (d, J=10.8 Hz, 1H), 7.833 (d, J=8.4 Hz, 1H), 8.251 (s, 1H), 8.787 (s, 1H).

[0742] Example 72: 7-(6-(3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propoxy)pyridin-3-yl)-6-fluoro-2-methyl-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (A-167)

##STR00268##

[0743] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford 7-(6-(3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propoxy)pyridin-3-yl)-6-fluoro-2-methyl-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (64 mg, 32.5% yield). ESI-MS (m/z): 560.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.851-2.068 (m, 12H), 2.471 (s, 3H), 2.572 (t, J=7.8 Hz, 3H), 3.554 (s, 3H), 4.379 (t, J=6.6 Hz, 2H), 4.424 (s, 4H), 4.532 (s, 2H), 6.891 (d, J=8.4 Hz, 1H), 7.394 (d, J=10.8 Hz, 1H), 7.782 (d, J=8.4 Hz, 1H), 8.200 (s, 1H), 8.671 (s, 1H).

[0744] Example 73: (S)-1-(3-((5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentanen-7-yl)pyridin-2-yl)oxy)propyl)pyrrolidine-2-carboxamide (A-168)

##STR00269##

[0745] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford (S)-1-(3-((5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentanen-7-yl)pyridin-2-yl)oxy)propyl)pyrrolidine-2-carboxamide (22 mg, 22.1% yield). ESI-MS (m/z): 547.24 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.897-0.909 (m, 2H), 1.287 (s, 3H), 1.843 (s, 3H), 1.895-1.975 (m, 1H), 2.024-2.107 (m, 3H), 2.209 (s, 1H), 2.381 (s, 1H), 2.626 (s, 1H), 2.908-3.007 (m, 2H), 3.596 (s, 3H), 4.420-4.499 (m, 2H), 4.597 (s, 2H), 6.934 (d, J=8.4 Hz, 1H), 7.504 (d, J=10.8 Hz, 1H), 7.833 (d, J=8.4 Hz, 1H), 8.250 (s, 1H), 8.780 (s, 1H).

[0746] Example 74: (S)-1-(3-((5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentanen-7-yl)pyridin-2-yl)oxy)propyl)pyrrolidine-2-carbonitrile (A-169)

##STR00270##

[0747] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford (S)-1-(3-((5-(6-fluoro-2-methyl-1-oxo-1,2-dihydro-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentanen-7-yl)pyridin-2-yl)oxy)propyl)pyrrolidine-2-carboxamide (15 mg, 18.6% yield). ESI-MS (m/z): 529.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.885-0.908 (m, 2H), 1.926-1.953 (m, 4H), 2.055-2.088 (m, 4H), 2.219-2.245 (m, 1H), 2.622-2.649 (m, 1H), 2.773-2.793 (m, 1H), 2.805-2.937 (m, 2H), 3.595 (s, 5H), 3.935-3.953 (m, 2H), 4.424-4.499 (m, 2H), 6.941 (d, J=8.4 Hz, 1H), 7.501 (d, J=10.8 Hz, 1H), 7.830 (d, J=8.4 Hz, 1H), 8.247 (s, 1H), 8.777 (s, 1H).

[0748] Example 75: 7-(6-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)pyridin-3-yl)-6-fluoro-2-methyl-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (A-170)

##STR00271##

[0749] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford 7-(6-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)pyridin-3-yl)-6-fluoro-2-methyl-9H-8-oxa-2,4,10a-triazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (75 mg, 38.8% yield). ESI-MS (m/z): 516.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.451-0.485 (m, 1H), 0.665-0.686 (m, 1H), 0.896 (t, J=6.6 Hz, 1H), 1.276 (s, 1H), 1.486 (t, J=3.6 Hz, 2H), 1.900-2.100 (m, 4H), 2.555 (d, J=9.0 Hz, 2H), 2.734 (t, J=7.8 Hz, 2H), 3.134 (d, J=9.0 Hz, 2H), 3.581 (s, 3H), 4.367-4.580 (m, 2H), 4.866 (s, 2H), 6.911 (d, J=9.0 Hz, 1H), 7.460 (d, J=11.4 Hz, 1H), 7.802-7.818 (m, 1H), 8.226 (s, 1H), 8.737 (s, 1H).

[0750] Example 76: (S)-7-(6-(3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-171)

##STR00272##

[0751] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford (S)-7-(6-(3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (79 mg, 37.8% yield). ESI-MS (m/z): 534.24 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.540 (d, J=6.6 Hz, 3H), 1.919 (s, 4H), 2.035 (t, J=7.8 Hz, 2H), 2.453 (s, 3H), 2.557 (t, J=7.8 Hz, 3H), 3,624 (s, 3H), 4.383 (t, J=6.6 Hz, 2H), 4.430 (s, 4H), 4.501 (d, J=13.2 Hz, 1H), 4.617 (d, J=2.4 Hz, 1H), 4.637-4.714 (m, 1H), 6.908 (d, J=8.4 Hz, 1H), 7.522 (d, J=10.8 Hz, 1H), 7.812 (d, J=8.4 Hz, 1H), 8.227 (s, 1H), 8.802 (s, 1H).

[0752] Example 77: 1-(3-((5-(6-fluoro-2-methyl-1-oxo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-7-yl)pyridin-2-yl)oxy)propyl)piperidine-2-carboxamide (A-172)

##STR00273##

[0753] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford 1-(3-((5-(6-fluoro-2-methyl-1-oxo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-7-yl)pyridin-2-yl)oxy)propyl)piperidine-2-carboxamide (20 mg, 26.5% yield). ESI-MS (m/z): 561.25 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 0.848-0.871 (m, 2H), 1.223-1.274 (m, 3H), 1.445-1.494 (m, 2H), 1.515-1.576 (m, 1H), 1.644-1.677 (m, 2H), 1.917-1.969 (m, 5H), 2.226-2.247 (m, 1H), 2.499-2.505 (m, 1H), 2.578-2.600 (m, 1H), 3.071-3.090 (m, 1H), 3.525 (s, 3H), 4.039-4.327 (m, 1H), 4.382-4.399 (m, 1H), 4.651 (s, 2H), 6.946 (d, J=8.4 Hz, 1H), 6.979 (s, 1H), 7.075 (s, 1H), 7.590 (d, J=10.8 Hz, 1H), 7.838 (d, J=8.4 Hz, 1H), 8.284 (s, 1H), 8.906 (s, 1H).

[0754] Example 78: 1-(3-((5-(6-fluoro-2-methyl-1-oxo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-7-yl)pyridin-2-yl)oxy)propyl)piperidine-2-carbonitrile (A-173)

##STR00274##

[0755] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford 1-(3-((5-(6-fluoro-2-methyl-1-oxo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-7-yl)pyridin-2-yl)oxy)propyl)piperidine-2-carbonitrile (25 mg, 27.1% yield). ESI-MS (m/z): 543.24 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 0.848-0.860 (m, 1H), 1.244-1.261 (m, 2H), 1.351-1.461 (m, 2H), 1.604-1.732 (m, 3H), 1.815-1.837 (m, 1H), 1.917-1.962 (m, 4H), 2.142-2.185 (m, 1H), 2.499-2.563 (m, 2H), 2.808-2.828 (m, 1H), 3.526 (s, 3H), 4.203 (s, 1H), 4.346-4.367 (m, 2H), 4.650 (s, 2H), 6.963 (d, J=8.4 Hz, 1H), 7.591 (d, J=10.8 Hz, 1H), 7.848 (d, J=8.4 Hz, 1H), 8.287 (s, 1H), 8.907 (s, 1H).

[0756] Example 79: (S)-7-(6-(3-(6-azaspiro[2.5]octan-6-yl)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-174)

##STR00275##

[0757] Except starting materials were changed, the synthesis method was the same as that of example 65 to afford (S)-7-(6-(3-(6-azaspiro[2.5]octan-6-yl)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (45 mg, 30.6% yield). ESI-MS (m/z): 518.25 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.357 (s, 4H), 1.535-1.561 (m, 7H), 2.095-2.142 (m, 2H), 2.740-2.773 (m, 6H), 3.627 (s, 3H), 4.410-4.430 (m, 2H), 4.496-4.518 (m, 1H), 4.616-4.642 (m, 1H), 4.705-4.717 (m, 1H), 6.929 (d, J=8.4 Hz, 1H), 7.528 (d, J=10.8 Hz, 1H), 7.826 (d, J=8.4 Hz, 1H), 8.242 (s, 1H), 8.809 (s, 1H).

[0758] Example 80: (S)-6-fluoro-2,10-dimethyl-7-(6-(3-(4-methylpiperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-175)

##STR00276##

[0759] Except starting materials were changed, the synthesis method was the same as that of example 65 except that 3-(4-methylpiperidin-1-yl)propan-1-ol was used instead of 3-(piperidin-1-yl)propan-1-ol, to afford (S)-6-fluoro-2,10-dimethyl-7-(6-(3-(4-methylpiperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (50 mg, 29.8% yield). ESI-MS (m/z): 506.25 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.885-0.908 (m, 3H), 1.350-1.394 (m, 2H), 1.531-1.565 (m, 4H), 1.792-1.815 (m, 2H), 2.138-2.164 (m, 2H), 2.458-2.496 (m, 2H), 2.904-2.916 (m, 2H), 3.242-3.309 (m, 2H), 3.625 (s, 3H), 4.402-4.440 (m, 2H), 4.494-4.516 (m, 1H), 4.609-4.635 (m, 1H), 4.704-4.717 (m, 1H), 6.931 (d, J=8.4 Hz, 1H), 7.522 (d, J=10.8 Hz, 1H), 7.830 (d, J=8.4 Hz, 1H), 8.243 (s, 1H), 8.807 (s, 1H).

[0760] Example 81: 2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (A-176)

##STR00277##

[0761] Step 1: Synthesis of 3-bromo-2-fluoro-6-((2-nitrovinyl)amino)benzoic acid

[0762] Sodium hydroxide (6.4 g, 160 mmol) and water (30 mL) were added to a 100 mL reaction bottle. Nitromethane (3.66 g, 60 mmol) was added dropwise to the reaction bottle at 25? C. to 30? C., after addition, the reaction solution was heated up to 45? C. to react for 5 min, and then cooled down to room temperature, and poured into a mixture of ice (14.5 g) and concentrated hydrochloric acid (14.5 mL) to afford a solution of nitroacetaldoxime. To a 500 mL reaction bottle, 6-amino-3-bromo-2-fluorobenzoic acid (4.68 g, 20 mmol), concentrated hydrochloric acid (23 mL), and water (132 mL) were successively added as a reaction solution, and the resultant nitroacetaldoxime solution as mentioned above was added dropwise to the reaction solution at room temperature, after addition, the reaction was continued at room temperature overnight. When the reaction was completed, the reaction solution was subjected to suction filtration. The filter cake was rinsed with water and dried to afford 3-bromo-2-fluoro-6-((2-nitrovinyl)amino)benzoic acid (5.08 g, 83.1% yield). ESI-MS (m/z): 304.95/306.95 [M+H].sup.+.

[0763] Step 2: Synthesis of 6-bromo-5-fluoro-3-nitroquinoline-4-ol

[0764] Acetic anhydride (100 mL) and 3-bromo-2-fluoro-6-((2-nitrovinyl)amino)benzoic acid (4.88 g, 16 mmol) were added to a 250 mL reaction bottle, and the reaction solution was heated up to 70? C. until the starting materials were completely dissoluted, and then cooled down to 40? C., followed by adding potassium acetate (1.88 g, 19.2 mmol). The reaction solution was reacted for 1.5 h at 90? C. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature, added with water (18 mL), stirred for 2 h, and then filtrated, the filter cake was rinsed with acetic acid and n-hexane respectively, and dried to afford 6-bromo-5-fluoro-3-nitroquinoline-4-ol (2.4 g, 51.0% yield). ESI-MS (m/z): 286.94/288.94 [M+H].sup.+.

[0765] Step 3: Synthesis of 6-bromo-4-chloro-5-fluoro-3-nitroquinoline

[0766] Thionyl chloride (6 mL) and 6-bromo-5-fluoro-3-nitroquinoline-4-ol (430 mg, 1.5 mmol) were added to a 50 mL reaction bottle. The reaction solution was reacted for 3 h at 80? C. When the reaction was completed as detected by TLC, the reaction solution was cooled down and concentrated to dryness to afford a crude product of 6-bromo-4-chloro-5-fluoro-3-nitroquinoline (457 mg, 100% yield). ESI-MS (m/z): 306.90 [M+H].sup.+.

[0767] Step 4: Synthesis of 10-bromo-5-nitro-2,4-dihydrospiro[[1,4]oxazepino[5,6,7-de]quinoline-3,1-cyclobutane]

[0768] DMF (5 mL), 6-bromo-4-chloro-5-fluoro-3-nitroquinoline (457 mg, 1.5 mmol), (1-aminocyclobutyl)methanol (228 mg, 2.25 mmol), and DIEA (580 mg, 45 mmol) were successively added to a 50 mL reaction bottle. The reaction solution was heated up to 90? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature, followed by adding water to precipitate a solid, and then the solid was collected by suction filtration, rinsed with water and dried to afford 10-bromo-5-nitro-2,4-dihydrospiro[[1,4]oxazepino[5,6,7-de]quinoline-3,1-cyclobutane] (420 mg, 80.0% yield). ESI-MS (m/z): 350.01/352.0 [M+H].sup.+.

[0769] Step 5: Synthesis of 10-bromo-2,4-dihydrospiro[[1,4]oxazepino[5,6,7-de]quinoline-3,1-cyclobutane]-5-amine

[0770] Ethanol (10 mL), 10-bromo-5-nitro-2,4-dihydrospiro[[1,4]oxazepino[5,6,7-de]quinoline-3,1-cyclobutane] (420 mg, 1.2 mmol), water (3 mL), iron powder (257 mg, 4.8 mmol), and ammonium chloride (268 mg, 4.8 mmol) were successively added to a 50 mL reaction bottle. The reaction solution was heated up to 80? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature and concentrated to dryness, and then purified by column chromatography (DCM:MeOH=15:1-10:1) to afford 10-bromo-2,4-dihydrospiro[[1,4]oxazepino[5,6,7-de]quinoline-3,1-cyclobutane]-5-amine (382 mg, 100% yield). ESI-MS (m/z): 320.03/322.03 [M+H].sup.+.

[0771] Step 6: Synthesis of 7-bromo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one

[0772] DMF (8 mL), 10-bromo-2,4-dihydrospiro[[1,4]oxazepino[5,6,7-de]quinoline-3,1-cyclobutane]-5-amine (382 mg, 1.2 mmol), DIEA (310 mg, 2.4 mmol), and carbonyl diimidazole (CDI) (292 mg, 1.8 mmol) were successively added to a 50 mL reaction bottle. The reaction solution was heated up to 80? C. to react for 8 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature, followed by adding water to precipitate a solid, and then the solid was collected by suction filtration, rinsed with water and dried to afford 7-bromo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (345 mg, 83.3% yield). ESI-MS (m/z): 346.01/348.01 [M+H].sup.+.

[0773] Step 7: Synthesis of 7-bromo-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one

[0774] DMF (5 mL), 7-bromo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropane]-1-one (345 mg, 1.0 mmol), cesium carbonate (652 mg, 2.0 mmol), and iodomethane (213 mg, 1.5 mmol) were successively added to a 50 mL reaction bottle, and then reacted at room temperature for 1 h. When the reaction was completed as detected by TLC, the reaction solution was added with water and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to dryness, and then purified by column chromatography (DCM:MeOH=70:1-60:1) to afford 7-bromo-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (90 mg, 25.0% yield). ESI-MS (m/z): 360.03/362.02 [M+H].sup.+.

[0775] Step 8: Synthesis of 2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one

[0776] 1,4-dioxane (4 mL), 7-bromo-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (90 mg, 0.25 mmol), (6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)boronic acid (132 mg, 0.50 mmol), potassium carbonate (104 mg, 0.75 mmol), water (1 mL), and tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol) were successively added to a 50 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection to react for 4 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness and the residue was purified by column chromatography (DCM:MeOH=20:1-10:1) to afford a crude product, and then the crude product was further purified by high-pressure preparative liquid chromatography to afford 2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (42 mg, 33.6% yield). ESI-MS (m/z): 500.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.513 (brs, 2H), 1.640-1.678 (m, 4H), 1.931-1.990 (m, 1H), 2.054-2.080 (m, 3H), 2.559-2.632 (m, 6H), 3.615 (s, 3H), 4.393 (t, J=6.0 Hz, 2H), 4.625 (brs, 2H), 6.923 (d, J=8.4 Hz, 1H), 7.652 (d, J=9.0 Hz, 1H), 7.819 (d, J=9.0 Hz, 1H), 7.972-7.990 (m, 1H), 8.387 (d, J=2.4 Hz, 1H), 8.784 (s, 1H).

[0777] Example 82: (S)-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-177)

##STR00278##

[0778] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford (S)-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, 27.1% yield). ESI-MS (m/z): 474.43 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.561 (brs, 2H), 1.615 (d, J=6.6 Hz, 3H), 1.692-1.720 (m, 4H), 2.101-2.127 (m, 2H), 2.670-2.722 (m, 6H), 3.672 (s, 3H), 4.424 (t, J=6.0 Hz, 2H), 4.516-4.699 (m, 2H), 4.747-4.758 (m, 1H), 6.940 (d, J=8.4 Hz, 1H), 7.700 (d, J=9.0 Hz, 1H), 7.867 (d, J=8.4 Hz, 1H), 7.988-8.006 (m, 1H), 8.402 (d, J=1.8 Hz, 1H), 8.838 (s, 1H).

[0779] Example 83: (S)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-178)

##STR00279##

[0780] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford (S)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, 27.1% yield). ESI-MS (m/z): 434.21 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.587 (d, J=7.2 Hz, 3H), 2.048-2.074 (m, 2H), 2.408 (s, 6H), 2.675-2.688 (m, 2H), 3.644 (s, 3H), 4.401 (t, J=6.0 Hz, 2H), 4.487-4.675 (m, 2H), 4.718-4.732 (m, 1H), 6.916 (d, J=9.0 Hz, 1H), 7.672 (d, J=9.0 Hz, 1H), 7.869 (d, J=9.0 Hz, 1H), 7.961-7.979 (m, 1H), 8.375 (d, J=2.4 Hz, 1H), 8.809 (s, 1H).

[0781] Example 84: 2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (A-68)

##STR00280##

[0782] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford 2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (25 mg, 27.1% yield). ESI-MS (m/z): 486.47 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.126 (brs, 2H), 1.524 (brs, 2H), 1.662-1.681 (m, 4H), 2.056-2.083 (m, 2H), 2.347 (brs, 2H), 2.614-2.663 (m, 6H), 3.564 (s, 3H), 4.378 (t, J=6.0 Hz, 2H), 4.414 (brs, 2H), 6.886 (d, J=8.4 Hz, 1H), 7.754 (d, J=8.4 Hz, 1H), 7.837 (d, J=8.4 Hz, 1H), 7.937-7.955 (m, 1H), 8.345 (d, J=1.8 Hz, 1H), 8.784 (s, 1H).

[0783] Example 85: 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (A-179)

##STR00281##

[0784] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropan]-1-one (25 mg, 27.1% yield). ESI-MS (m/z): 456.44 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.124 (brs, 2H), 2.045-2.071 (m, 2H), 2.342 (brs, 2H), 2.419 (s, 6H), 2.698 (t, J=7.2 Hz, 2H), 3.563 (s, 3H), 4.379-4.412 (m, 4H), 6.893 (d, J=8.4 Hz, 1H), 7.652 (d, J=9.0 Hz, 1H), 7.834 (d, J=9.0 Hz, 1H), 7.940-7.958 (m, 1H), 8.348 (d, J=2.4 Hz, 1H), 8.781 (s, 1H).

[0785] Example 86: 2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-67)

##STR00282##

[0786] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford 2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (90 mg, 38.3% yield). ESI-MS (m/z): 488.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.591 (s, 2H), 1.750 (s, 10H), 2.136-2.162 (m, 2H), 2.859-2.916 (m, 6H), 3.581 (s, 3H), 4.374-4.423 (m, 4H), 6.903 (d, J=9.0 Hz, 1H), 7.615 (d, J=8.4 Hz, 1H), 7.796 (d, J=9.0 Hz, 1H), 7.938-7.956 (m, 1H), 8.354 (s, 1H), 8.754 (s, 1H).

[0787] Example 87: 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-180)

##STR00283##

[0788] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (72 mg, 36.7% yield). ESI-MS (m/z): 448.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.758 (s, 6H), 2.048-2.095 (m, 2H), 2.443 (s, 6H), 2.728 (t, J=7.8 Hz, 2H), 3.586 (s, 3H), 4.387-4.411 (m, 4H), 6.908 (d, J=8.4 Hz, 1H), 7.635 (d, J=9.0 Hz, 1H), 7.812 (d, J=8.4 Hz, 1H), 7.946-7.964 (m, 1H), 8.363 (d, J=2.4 Hz, 1H), 8.766 (s, 1H).

[0789] Example 88: (R)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-181)

##STR00284##

[0790] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford (R)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (158 mg, 42.5% yield). ESI-MS (m/z): 434.21 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.567-1.578 (m, 3H), 2.178-2.224 (m, 2H), 2.760 (s, 6H), 3.122 (t, J=7.8 Hz, 2H), 3.634 (s, 3H), 4.444-4.489 (m, 3H), 4.632-4.658 (m, 1H), 4.706-4.717 (m, 1H), 6.935 (d, J=9.0 Hz, 1H), 7.647 (d, J=8.4 Hz, 1H), 7.816 (d, J=9.0 Hz, 1H), 7.962-7.980 (m, 1H), 8.375 (d, J=2.4 Hz, 1H), 8.790 (s, 1H).

[0791] Example 89: (R)-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-182)

##STR00285##

[0792] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford (R)-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (78 mg, 29.1% yield). ESI-MS (m/z): 474.24 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.574-1.585 (m, 5H), 1.707-1.724 (m, 4H), 2.103-2.127 (m, 2H), 2.746-2.801 (m, 6H), 3.637 (s, 3H), 4.405 (t, J=6.0 Hz, 2H), 4.473-4.495 (m, 1H), 4.643-4.665 (m, 1H), 4.712-4.723 (m, 1H), 6.909 (d, J=8.4 Hz, 1H), 7.656 (d, J=8.4 Hz, 1H), 7.824 (d, J=8.4 Hz, 1H), 7.952-7.970 (m, 1H), 8.368 (s, 1H), 8.796 (s, 1H).

[0793] Example 90: (S)-7-(6-(3-(6-azaspiro[2.5]octan-6-yl)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-183)

##STR00286##

[0794] Except starting materials were changed, the synthesis method the same as that of example 81 to afford (S)-7-(6-(3-(6-azaspiro[2.5]octan-6-yl)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (45 mg, 30.6% yield). ESI-MS (m/z): 500.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.402 (s, 4H), 1.579-1.590 (m, 7H), 2.155-2.179 (m, 2H), 2.921 (s, 6H), 3.643 (s, 3H), 4.423-4.443 (m, 2H), 4.486-4.507 (m, 1H), 4.647-4.669 (m, 1H), 4.718-4.729 (m, 1H), 6.918 (d, J=8.4 Hz, 1H), 7.667 (d, J=8.4 Hz, 1H), 7.836 (d, J=8.4 Hz, 1H), 7.966-7.984 (m, 1H), 8.382 (s, 1H), 8.808 (s, 1H).

[0795] Example 91: (S)-7-(6-(3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-184)

##STR00287##

[0796] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford (S)-7-(6-(3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (48 mg, 30.8% yield). ESI-MS (m/z): 516.25 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.581-1.592 (m, 3H), 1.960 (s, 4H), 2.060-2.084 (m, 2H), 2.593-2.676 (m, 6H), 3.644 (s, 3H), 4.383-4.509 (m, 7H), 4.646-4.851 (m, 2H), 6.905 (d, J=8.4 Hz, 1H), 7.668 (d, J=8.4 Hz, 1H), 7.838 (d, J=8.4 Hz, 1H), 7.957-7.975 (m, 1H), 8.368-8.371 (m, 1H), 8.810 (s, 1H).

[0797] Example 92: 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (A-185)

##STR00288##

[0798] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1-one (75.8% yield). ESI-MS (m/z): 460.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.311 (brs, 1H), 1.962-2.141 (m, 5H), 2.423 (s, 6H), 2.698 (t, J=7.8 Hz, 2H), 3.638 (s, 3H), 4.433 (t, J=6.6 Hz, 2H), 4.638 (brs, 2H), 6.954 (d, J=8.4 Hz, 1H), 7.670 (d, J=9.0 Hz, 1H), 7.837 (d, J=9.0 Hz, 1H), 7.997-8.016 (m, 1H), 8.413 (d, J=2.4 Hz, 1H), 8.800 (s, 1H).

[0799] Example 93: (S)-10-ethyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-186)

##STR00289##

[0800] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford (S)-10-ethyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (65.6% yield). ESI-MS (m/z): 488.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.122 (t, J=7.2 Hz, 3H), 1.535 (brs, 2H), 1.666-1.703 (m, 4H), 1.994-2.030 (m, 2H), 2064-2.101 (m, 2H), 2.648-2.705 (m, 6H), 3.643 (s, 3H), 4.396 (t, J=6.0 Hz, 2H), 4.420-4.443 (m, 1H), 4.499-4.513 (m, 1H), 4.836-4.853 (m, 1H), 6.905-6.920 (m, 1H), 7.662 (d, J=9.0 Hz, 1H), 7.828 (d, J=9.0 Hz, 1H), 7.950-7.969 (m, 1H), 8.370 (d, J=1.8 Hz, 1H), 8.805 (s, 1H).

[0801] Example 94: (R)-10-ethyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-187)

##STR00290##

[0802] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford (R)-10-ethyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (85 mg, 35.5% yield). ESI-MS (m/z): 488.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.117-1.129 (m, 3H), 1.551 (s, 2H), 1.685-1.723 (m, 4H), 1.985-2.019 (m, 2H), 2.102-2.118 (m, 2H), 2.711-2.777 (m, 6H), 3.638 (s, 3H), 4.389-4.429 (m, 3H), 4.485-4.515 (m, 1H), 4.828-4.833 (m, 1H), 6.909 (d, J=8.4 Hz, 1H), 7.649 (d, J=8.4 Hz, 1H), 7.815 (d, J=8.4 Hz, 1H), 7.943-7.961 (m, 1H), 8.362-8.366 (m, 1H), 8.793 (s, 1H).

[0803] Example 95: (R)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-10-ethyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-188)

##STR00291##

[0804] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford (R)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-10-ethyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (67 mg, 33.2% yield). ESI-MS (m/z): 448.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.104-1.129 (m, 3H), 1.984-2.067 (m, 4H), 2.397 (s, 6H), 2.660-2.685 (m, 2H), 3.636 (s, 3H), 4.384-4.426 (m, 3H), 4.488-4.512 (m, 1H), 4.829-4.833 (m, 1H), 6.909 (d, J=8.4 Hz, 1H), 7.648 (d, J=8.4 Hz, 1H), 7.812 (d, J=8.4 Hz, 1H), 7.939-7.957 (m, 1H), 8.359-8.363 (m, 1H), 8.789 (s, 1H).

[0805] Example 96: (S)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-10-ethyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-189)

##STR00292##

[0806] Except starting materials were changed, the synthesis method was the same as that of example 81 to afford (S)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-10-ethyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (58.7% yield). ESI-MS (m/z): 448.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.124 (t, J=7.2 Hz, 3H), 1.979-2.009 (m, 2H), 2.071-2.118 (m, 2H), 2.476 (s, 6H), 2.761 (t, J=7.2 Hz, 2H), 3.642 (s, 3H), 4.383-4.426 (m, 3H), 4.495 (t, J=6.6 Hz, 1H), 4.483-4.856 (m, 1H), 6.917 (d, J=8.4 Hz, 1H), 7.633 (d, J=8.4 Hz, 1H), 7.796 (d, J=8.4 Hz, 1H), 7.935-7.953 (m, 1H), 8.358 (d, J=1.8 Hz, 1H), 8.770 (s, 1H).

[0807] Example 97: 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-190)

##STR00293##

[0808] Step 1: Synthesis of ethyl 6-bromo-4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5,7-difluoroquinoline-3-carboxylate

[0809] DMF (20 mL), ethyl 6-bromo-4-chloro-5,7-difluoroquinoline-3-carboxylate (1.48 g, 4.2 mmol), N-Boc-ethane-1,2-diamine (0.94 g, 6.3 mmol), and DIEA (1.09 g, 8.4 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature, followed by adding water to precipitate a solid, and then the solid was collected by suction filtration, rinsed with water and dried to afford ethyl 6-bromo-4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5,7-difluoroquinoline-3-carboxylate (2.0 g, 100% yield). ESI-MS (m/z): 474.08/476.08 [M+H].sup.+.

[0810] Step 2: Synthesis of 6-bromo-4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5,7-difluoroquinoline-3-carboxylic acid

[0811] THF (10 mL), ethyl 6-bromo-4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5,7-difluoroquinoline-3-carboxylate (2.00 g, 4.2 mmol), water (5 mL), and sodium hydroxide (0.84 g, 21.0 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 60? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature, followed by adjusting the pH value to 5 with 1N hydrochloric acid to precipitate a solid, and then the solid was collected by suction filtration, rinsed with water and dried to afford 6-bromo-4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5,7-difluoroquinoline-3-carboxylic acid (1.5 g, 79.8% yield). ESI-MS (m/z): 446.04/448.04 [M+H].sup.+.

[0812] Step 3: Synthesis of tert-butyl (2-(8-bromo-7,9-difluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate

[0813] DMF (15 mL), 6-bromo-4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5,7-difluoroquinoline-3-carboxylic acid (1.5 g, 3.36 mmol), DIEA (0.87 g, 6.73 mmol), and diphenyl azidophosphate (1.40 g, 5.04 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 60? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature, followed by adding water to precipitate a solid, and then the solid was collected by suction filtration, rinsed with water and dried to afford tert-butyl (2-(8-bromo-7,9-difluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate (1.2 g, 80.5% yield). ESI-MS (m/z): 443.05/445.05 [M+H].sup.+.

[0814] Step 4: Synthesis of tert-butyl (2-(8-bromo-7,9-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate

[0815] Anhydrous THF (15 mL), tert-butyl (2-(8-bromo-7,9-difluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate (1.2 g, 2.70 mmol), and cesium carbonate (0.164 g, 4.11 mmol) were successively added to a 100 mL reaction bottle, then iodomethane (0.58 g, 4.11 mmol) was added at room temperature, and the reaction was continued at room temperature for 2 h. When the reaction was completed as detected by TLC, the reaction solution was added with water to precipitate a solid, and then the solid was collected by suction filtration, rinsed with water and dried to afford tert-butyl (2-(8-bromo-7,9-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate (0.90 g, 72.6% yield). ESI-MS (m/z): 457.06/459.06 [M+H].sup.+.

[0816] Step 5: Synthesis of tert-butyl (2-(7,9-difluoro-8-(6-fluoropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate

[0817] 1,4-dioxane (15 mL), tert-butyl (2-(8-bromo-7,9-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate (0.80 g, 1.76 mmol), (6-fluoropyridine-3-yl)boronic acid (0.315 g, 2.11 mmol), potassium carbonate (0.607 g, 4.4 mmol), water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0.203 g, 0.18 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection to react for 2.5 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=60:1) to afford tert-butyl (2-(7,9-difluoro-8-(6-fluoropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate (0.63 g, 76.0% yield). ESI-MS (m/z): 474.17 [M+H].sup.+.

[0818] Step 6: Synthesis of tert-butyl 6-fluoro-2-methyl-1-oxo-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulene-8(2H)-carboxylate

[0819] THF (4 mL) and 3-(piperidin-1-yl)propan-1-ol (115 mg, 0.8 mmol) were added to a 100 mL reaction bottle and cooled down to 0? C., followed by adding NaH (56 mg, 1.4 mmol) and the reaction was conducted at this temperature for 0.5 h, then tert-butyl (2-(7,9-difluoro-8-(6-fluoropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate (190 mg, 0.4 mmol) was added, and the reaction was continued at room temperature overnight. When the reaction was completed as detected by TLC, water was added into the reaction solution to quench the reaction. The reaction mixture was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-15:1) to afford tert-butyl 6-fluoro-2-methyl-1-oxo-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulene-8(2H)-carboxylate (100 mg, 43.3% yield). ESI-MS (m/z): 577.29 [M+H].sup.+.

[0820] Step 7: Synthesis of 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-155)

[0821] DCM (20 mL) and tert-butyl 6-fluoro-2-methyl-1-oxo-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulene-8(2H)-carboxylate (100 mg, 0.17 mmol) were successively added to a 100 mL reaction bottle, followed by the addition of trifluoroacetic acid (4 mL) at room temperature, and the reaction was continued at room temperature for 2 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-5:1) to afford 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (40 mg, 48.2% yield). ESI-MS (m/z): 477.23 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.570 (s, 2H), 1.715-1.734 (m, 4H), 2.116-2.142 (m, 2H), 2.775-2.882 (m, 6H), 3.593 (s, 6H), 4.086 (s, 2H), 4.425 (s, 2H), 6.980 (d, J=8.4 Hz, 1H), 7.512 (d, J=9.6 Hz, 1H), 7.693-7.711 (m, 1H), 8.126-8.129 (m, 1H), 8.689 (s, 1H).

[0822] Example 98: (S)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-191)

##STR00294##

[0823] Except starting materials were changed, the synthesis method was the same as that of example 97 to afford (S)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, 26.8% yield). ESI-MS (m/z): 491.25 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.395-1.408 (m, 3H), 1.510 (s, 2H), 1.639-1.676 (m, 4H), 2.043-2.090 (m, 2H) 2.556-2.632 (m, 6H), 3.461-3.485 (m, 1H), 3.604 (s, 3H), 3.646-3.690 (m, 1H), 4.391-4.412 (m, 2H), 4.601-4.616 (m, 1H), 5.768 (s, 1H), 6.977 (d, J=8.4 Hz, 1H), 7.157 (d, J=10.8 Hz, 1H), 7.696-7.714 (m, 1H), 8.131-8.135 (m, 1H), 8.696 (s, 1H).

[0824] Example 99: 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-8,9-dihydrospiro[2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1(2H)-one (A-192)

##STR00295##

[0825] Except starting materials were changed, the synthesis method was the same as that of example 97 to afford 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-8,9-dihydrospiro[2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1(2H)-one (25 mg, 26.8% yield). ESI-MS (m/z): 517.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.535 (brs, 2H), 1.672-1.709 (m, 5H), 0.798-1.817 (m, 1H), 2.008-2.115 (m, 3H), 2.350 (brs, 1H), 2.662-2.721 (m, 7H), 3.549 (s, 3H), 3.720-4.150 (m, 2H), 4.300 (t, J=6.0 Hz, 1H), 4.406 (t, J=6.0 Hz, 2H), 6.972 (d, J=8.4 Hz, 1H), 7.126 (d, J=10.2 Hz, 1H), 7.661-7.703 (m, 1H), 8.086-8.124 (m, 1H), 8.628 (s, 1H).

[0826] Example 100: 6-fluoro-2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-193)

##STR00296##

[0827] Except starting materials were changed, the synthesis method was the same as that of example 97 to afford 6-fluoro-2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (75 mg, 35.5% yield). ESI-MS (m/z): 505.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.500 (s, 2H), 1.642-1.676 (m, 10H), 2.008-2.073 (m, 2H), 2.511-2.582 (m, 6H), 3.304-3.309 (m, 2H), 3.546 (s, 3H), 4.392-4.402 (m, 2H), 6.967 (d, J=8.4 Hz, 1H), 7.165 (d, J=10.8 Hz, 1H), 7.688-7.705 (m, 1H), 8.124 (s, 1H), 8.673 (s, 1H).

[0828] Example 101: (R)-10-ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-194)

##STR00297##

[0829] Except starting materials were changed, the synthesis method was the same as that of example 97 to afford (R)-10-ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (45 mg, 19.7% yield). ESI-MS (m/z): 505.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.993-1.018 (m, 3H), 1.529 (s, 2H), 1.658 (s, 4H), 1.667-1.878 (m, 2H), 2.061-2.108 (m, 2H), 2.622-2.674 (m, 6H), 3.369-3.394 (m, 1H), 3.603 (s, 3H), 3.836-3.867 (m, 1H), 4.291-4.419 (m, 3H), 6.978 (d, J=8.4 Hz, 1H), 7.136 (d, J=10.8 Hz, 1H), 7.687-7.704 (m, 1H), 8.127 (s, 1H), 8,686 (s, 1H).

[0830] Example 102: (R)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-195)

##STR00298##

[0831] Except starting materials were changed, the synthesis method was the same as that of example 97 to afford (R)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (70 mg, 34.5% yield). ESI-MS (m/z): 491.25 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.407-1.418 (m, 3H), 1.501 (s, 2H), 1.625-1.662 (m, 4H), 2.026-2.073 (m, 2H), 2.541-2.584 (m, 6H), 3.448-3.473 (m, 1H), 3.598 (s, 3H), 3.648-3.686 (m, 1H), 4.381-4.402 (m, 2H), 4.592-4.607 (m, 1H), 6.970 (d, J=8.4 Hz, 1H), 7.145 (d, J=9.6 Hz, 1H), 7.688-7.706 (m, 1H), 8.125-8.128 (m, 1H), 8.683 (s, 1H).

[0832] Example 103: (S)-10-ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-196)

##STR00299##

[0833] Except starting materials were changed, the synthesis method was the same as that of example 97 to afford (S)-10-ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (41.4% yield). ESI-MS (m/z): 505.60 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.033 (t, J=7.2 Hz, 3H), 1.567 (brs, 2H), 1.716-1.734 (m, 4H), 1.819-1.917 (m, 2H), 2.101-2.148 (m, 2H), 2.684-2.738 (m, 6H), 3.399-3.423 (m, 1H), 3.632 (s, 3H), 3.864-3.895 (m, 1H), 4.393-4.452 (m, 3H), 7.008 (d, J=8.4 Hz, 1H), 7.765 (d, J=10.8 Hz, 1H), 7.718-7.735 (m, 1H), 8.155 (d, J=1.8 Hz, 1H), 8.717 (s, 1H).

[0834] Example 104: 2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-197)

##STR00300##

[0835] Step 1: tert-butyl (2-((6-bromo-5-fluoro-3-nitroquinolin-4-yl)amino)-2-methylpropyl)carbamate

[0836] DMF (10 mL), 6-bromo-4-chloro-5-fluoro-3-nitroquinoline (0.58 g, 1.91 mmol), 2-methyl-2-amino-N-tert-butoxycarbonylpropan-1-amine (0.47 g, 2.50 mmol), and TEA (0.97 g, 9.58 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature, added with water without precipitation, and extracted with ethyl acetate for three times, the combined organic phase was washed with water once, concentrated to dryness, and the residue was purified by column chromatography (n-hexane:ethyl acetate=4:1-2:1) to afford tert-butyl (2-((6-bromo-5-fluoro-3-nitroquinolin-4-yl)amino)-2-methylpropyl)carbamate (0.61 g, 70.1% yield). ESI-MS (m/z): 457.06/459.02 [M+H].sup.+.

[0837] Step 2: N.sup.2-(6-bromo-5-fluoro-3-nitroquinolin-4-yl)-2-methylpropane-1,2-diamine

[0838] DCM (10 mL) and tert-butyl (2-((6-bromo-5-fluoro-3-nitroquinolin-4-yl)amino)-2-methylpropyl)carbamate (0.61 g, 1.34 mmol) were successively added to a 100 mL reaction bottle, then trifluoroacetic acid (5 mL) was added at room temperature, and the reaction was continued at room temperature for 2 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness to afford N.sup.2-(6-bromo-5-fluoro-3-nitroquinolin-4-yl)-2-methylpropane-1,2-diamine. ESI-MS (m/z): 357.08/359.08 [M+H].sup.+. The intermediate was ready for instant use in the next step without treatment.

[0839] Step 3: 8-bromo-5,5-dimethyl-3-nitro-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinoline

[0840] DMF (10 mL), N.sup.2-(6-bromo-5-fluoro-3-nitroquinolin-4-yl)-2-methylpropane-1,2-diamine (crude) and TEA (8 mL) were successively added to a 100 mL reaction bottle, the pH value of reaction solution was detected as 12, and then the reaction solution was heated up to 90? C. to react for 2 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature, added with 50 mL of water, and subjected to suction filtration. The solid was collected, rinsed with water, and dried to afford 8-bromo-5,5-dimethyl-3-nitro-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinoline (0.36 g, 80% yield). ESI-MS (m/z): 336.88/338.88 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.470 (s, 6H), 3.524 (s, 2H), 7.115 (d, J=9.0 Hz, 1H), 7.866 (d, J=8.4 Hz, 1H), 9.104 (s, 1H).

[0841] Step 4: 8-bromo-5,5-dimethyl-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinolin-3-amine

[0842] Ethanol (10 mL), water (5 mL), 8-bromo-5,5-dimethyl-3-nitro-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinoline (0.36 g, 1.07 mmol), iron powder (0.36 g, 6.43 mmol), and NH.sub.4Cl (0.34 g, 6.35 mmol) were successively added to a 100 mL reaction bottle and heated up to 80? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was subjected to hot filtration, the solid was rinsed with ethanol, and the filtrate was concentrated to dryness and then the residue was purified by column chromatography (DCM:MeOH=30:1-10:1) to afford 8-bromo-5,5-dimethyl-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinolin-3-amine (0.33 g, 100% yield). ESI-MS (m/z): 306.92/308.88 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.446 (s, 6H), 3.580 (s, 2H), 6.891 (d, J=9.0 Hz, 1H), 7.759 (d, J=9.0 Hz, 1H), 7.896 (s, 1H).

[0843] Step 5: 7-bromo-10,10-dimethyl-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0844] DMF (10 mL), 8-bromo-5,5-dimethyl-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinolin-3-amine (0.33 g, 1.07 mmol), CDI (0.43 g, 2.65 mmol), and TEA (0.32 g, 3.16 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 80? C. to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was cooled down to temperature, added with water and ethyl acetate for phase separation, and the organic phase was concentrated to dryness and then the residue was purified by column chromatography (DCM:MeOH=50:1-20:1) to afford 7-bromo-10,10-dimethyl-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.31 g, 87.3% yield). ESI-MS (m/z): 332.94/334.92 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.415 (s, 6H), 4.048 (s, 2H), 5.319 (s, 1H), 7.353 (d, J=9.0 Hz, 1H), 7.681-7.704 (m, 1H), 8.609 (s, 1H).

[0845] Step 6: 7-bromo-2,10,10-trimethyl-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0846] Anhydrous DMF (15 mL), 7-bromo-10,10-dimethyl-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.31 g, 0.93 mmol), and cesium carbonate (0.58 g, 1.78 mmol) were successively added to a 100 mL reaction bottle, then iodomethane (0.19 g, 1.34 mmol) was added at room temperature, and the reaction was rewarmed to room temperature for 1 h. When the reaction was completed as detected by TLC, the reaction solution was added with water (50 mL) to precipitate a solid, and then the solid was subjected to suction filtration, collected, rinsed with water, and dried to afford 7-bromo-2,10,10-trimethyl-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.20 g, 62.5% yield). ESI-MS (m/z): 346.95/348.96 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.418 (s, 6H), 3.640 (s, 3H), 4.068 (s, 2H), 5.319 (s, 1H), 7.376 (d, J=9.0 Hz, 1H), 7.713 (d, J=9.0 Hz, 1H), 8.757 (s, 1H).

[0847] Step 7: 2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-197)

[0848] 1,4-dioxane (15 mL), 7-bromo-2,10,10-trimethyl-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.20 g, 0.58 mmol), (6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)boronic acid (0.23 g, 0.87 mmol), potassium carbonate (0.16 g, 1.16 mmol), water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0.07 g, 0.06 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection to react for 2.5 h. When the reaction was completed as detected by TLC, the reaction solution was added with water and ethyl acetate for phase separation, the organic phase was concentrated to dryness and then purified by column chromatography (DCM:MeOH=30:1-10:1) to afford a crude product (120 mg), and then the crude product was purified by pre-HPLC to afford 2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (100 mg, 35.6% yield). ESI-MS (m/z): 487.27 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.284-1.305 (m, 6H), 1.519 (s, 2H), 1.655-1.674 (m, 4H), 2.049-2.096 (m, 2H), 2.577-2.636 (m, 6H), 3.632 (s, 3H), 4.008 (s, 2H), 4.404 (t, J=6.0 Hz, 2H), 4,732 (s, 1H), 6.974 (d, J=9.0 Hz, 1H), 7.384 (d, J=8.4 Hz, 1H), 7.551 (d, J=8.4 Hz, 1H), 7.763-7.781 (m, 1H), 8.184 (d, J=2.4 Hz, 1H), 8.752 (s, 1H).

[0849] Example 105: (S)-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-198)

##STR00301##

[0850] Except starting materials were changed, the synthesis method was the same as that of example 104 to afford (S)-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (55 mg, 32.5% yield). ESI-MS (m/z): 473.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.451-1.461 (m, 3H), 1.516 (s, 2H), 1.643-1.681 (m, 4H), 2.039-2.086 (m, 2H), 2.573-2.639 (m, 6H), 3.455-3.480 (m, 1H), 3.615 (s, 3H), 3.640-3.684 (m, 1H), 4.375-4.396 (m, 2H), 4.589 (s, 1H), 5.618-5.631 (m, 1H), 6.943 (d, J=8.4 Hz, 1H), 7.339 (d, J=8.4 Hz, 1H), 7.493 (d, J=8.4 Hz, 1H), 7.769-7.787 (m, 1H), 8.200-8.203 (m, 1H), 8.701 (s, 1H).

[0851] Example 106: (R)-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-199)

##STR00302##

[0852] Except starting materials were changed, the synthesis method was the same as that of example 104 to afford (R)-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (50 mg, 30.5% yield). ESI-MS (m/z): 473.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.444-1.455 (m, 3H), 1.525 (s, 2H), 1.655-1.692 (m, 4H), 2.046-2.093 (m, 2H), 2.614-2.675 (m, 6H), 3.439-3.463 (m, 1H), 3.609 (s, 3H), 3.634-3.677 (m, 1H), 4.373-4.394 (m, 2H), 4.586 (s, 1H), 5.617-5.629 (m, 1H), 6.938 (d, J=8.4 Hz, 1H), 7.328 (d, J=8.4 Hz, 1H), 7.485 (d, J=8.4 Hz, 1H), 7.763-7.781 (m, 1H), 8.195-8.198 (m, 1H), 8.688 (s, 1H).

[0853] Example 107: 2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-8,9-dihydro-2,4,8,10a-tetraazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (A-200)

##STR00303##

[0854] Except starting materials were changed, the synthesis method was the same as that of example 104 to afford 2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-8,9-dihydro-2,4,8,10a-tetraazaspiro[cyclobutane-1,10-naphtho[2,1,8-cde]azulen]-2a,3,4a,5,7-pentaen-1(2H)-one (81 mg, 35.4% yield). ESI-MS (m/z): 485.26 [M+H]; .sup.1HNMR (600 MHz, CD.sub.3OD) ?: 0.896-0.936 (m, 4H), 1.528 (s, 2H), 1.652-1.690 (m, 4H), 2.043-2.080 (m, 2H), 2.538-2.606 (m, 6H), 3.640 (s, 3H), 4.057 (brs, 2H), 4.396 (t, J=6.0 Hz, 2H), 6.941 (d, J=8.4 Hz, 1H), 7.532 (d, J=8.4 Hz, 1H), 7.573 (d, J=9.0 Hz, 1H), 7.651-7.669 (m, 1H), 8.090 (d, J=2.4 Hz, 1H), 8.758 (s, 1H).

[0855] Example 108: (R)-10-ethyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-201)

##STR00304##

[0856] Except starting materials were changed, the synthesis method was the same as that of example 104 to afford (R)-10-ethyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (128 mg, 42.1% yield). ESI-MS (m/z): 487.27 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.017-1.042 (m, 3H), 1.512 (s, 2H), 1.634-1.672 (m, 4H), 1.826-1.860 (m, 1H), 1.933-1.948 (m, 1H), 2.034-2.081 (m, 2H), 2.543-2.611 (m, 6H), 3.299-3.395 (m, 1H), 3.620 (s, 3H), 3.841-3.872 (m, 1H), 4.362-4.392 (m, 3H), 5.694-5.706 (m, 1H), 6.948 (d, J=8.4 Hz, 1H), 7.333 (d, J=9.0 Hz, 1H), 7.478 (d, J=8.4 Hz, 1H), 7.766-7.785 (m, 1H), 8.196 (s, 1H), 8,707 (s, 1H).

[0857] Example 109: 2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-8,9-dihydrospiro[2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1(2H)-one (A-202)

##STR00305##

[0858] Except starting materials were changed, the synthesis method was the same as that of example 104 to afford 2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-8,9-dihydrospiro[2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulene-10,1-cyclobutan]-1(2H)-one (54.2% yield). ESI-MS (m/z): 499.27 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.509 (brs, 1H), 1.647-1.664 (m, 4H), 1.918-2.064 (m, 8H), 2.547-2.621 (m, 6H), 3.608 (s, 3H), 4.160 (s, 2H), 4.406 (t, J=6.0 Hz, 2H), 6.987 (d, J=8.4 Hz, 1H), 7.375 (d, J=8.4 Hz, 1H), 7.525 (d, J=8.4 Hz, 1H), 7.817 (d, J=6.6 Hz, 1H), 8.237 (s, 1H), 8.686 (s, 1H).

[0859] Example 110: (S)-10-ethyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-203)

##STR00306##

[0860] Except starting materials were changed, the synthesis method was the same as that of example 104 to afford (S)-10-ethyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (37.6% yield). ESI-MS (m/z): 487.27 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.024 (t, J=7.2 Hz, 3H), 1.528 (brs, 2H), 1.666-1.693 (m, 4H), 1.814-1.934 (m, 2H), 2.050-2.097 (m, 2H), 2.624-2.683 (m, 6H), 3.350-3.374 (m, 1H), 3.612 (s, 3H), 3.832-3.863 (m, 1H), 4.340-4.392 (m, 3H), 6.943 (d, J=8.4 Hz, 1H), 7.319 (d, J=8.4 Hz, 1H), 7.467 (d, J=8.4 Hz, 1H), 7.760-7.778 (m, 1H), 8.194 (d, J=2.4 Hz, 1H), 8.692 (s, 1H).

[0861] Example 111: 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,3,5,6-tetrahydro-9H-8-oxa-2,4,10a-triazaspiro[naphtho[2,1,8-cde]azulene-10,4-pyran]-2a,3,4a,5,7-pentaen-1(2H)-one (A-204)

##STR00307##

[0862] The synthesis method is the same as that of example 1 except that the starting material in step 1 was changed to 7-bromo-6-fluoro-2-methyl-2,3,5,6-tetrahydro-9H-8-oxa-2,4,10a-triazaspiro[naphtho[2,1,8-cde]azulene-10,4-pyran]-2a,3,4a,5,7-pentaen-1(2H)-one (the starting material was synthesized in the same way as that in intermediate preparation example 1, i.e., (4-aminotetrahydro-2H-pyran-4-yl)methanol was used instead of L-aminopropanol) to afford 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,3,5,6-tetrahydro-9H-8-oxa-2,4,10a-triazaspiro[naphtho[2,1,8-cde]azulene-10,4-pyran]-2a,3,4a,5,7-pentaen-1(2H)-one (46 mg, 33.5% yield). ESI-MS (m/z): 548.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.897 (t, J=6.6 Hz, 2H), 1.285 (m, 2H), 1.595 (m, 2H), 1.753 (t, J=5.4 Hz, 4H), 2.136-2.182 (m, 2H), 2.876-2.911 (m, 6H), 3.580 (s, 3H), 3.673-3.711 (m, 2H), 3.952-3.980 (m, 4H), 4.439 (t, J=6.6 Hz, 2H), 6.943 (d, J=8.4 Hz, 1H), 7.539 (d, J=10.8 Hz, 1H), 7.845 (d, J=8.4 Hz, 1H), 8.261 (s, 1H), 8.811 (s, 1H).

[0863] Example 112: (S)-6-fluoro-2,10-dimethyl-7-(6-((3-(piperidin-1-yl)propoxy)methyl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-205)

##STR00308##

[0864] Step 1: Synthesis of 5-bromo-2-((3-(piperidin-1-yl)propoxy)methyl)pyridine

[0865] THF (30 mL) and N-hydroxypropylpiperidine (1.11 g, 7.74 mmol) were successively added to a 100 mL reaction bottle and cooled down to 0? C., followed by adding NaH (0.62 g, 15.48 mmol), and the reaction was conducted at this temperature for 0.5 h, then 5-bromo-2-(bromomethyl)pyridine (1.94 g, 7.74 mmol) was added and the reaction was rewarmed to room temperature and reacted for 5 h. When the reaction was completed as detected by TLC, water was added into the reaction solution to quench the reaction, and the reaction mixture was concentrated to dryness, and then the residue was purified by column chromatography (DCM:MeOH=20:1-15:1) to afford 5-bromo-2-((3-(piperidin-1-yl)propoxy)methyl)pyridine (2.06 g, 85.0% yield). ESI-MS (m/z): 313.08/315.08 [M+H].sup.+.

[0866] Step 2: Synthesis of 2-((3-(piperidin-1-yl)propoxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0867] 1,4-dioxane (25 mL), 5-bromo-2-((2-(piperidin-1-yl)propoxy)methyl)pyridine (2.06 g, 6.58 mmol), bis(pinacolato)diboron (3.34 g, 13.16 mmol), potassium acetate (1.61 g, 16.45 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (0.48 g, 0.66 mmol) were successively added to a 100 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness to afford a crude product 2-((3-(piperidin-1-yl)propoxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for instant use in the next step. ESI-MS (m/z): 361.26 [M+H].sup.+.

[0868] Step 3: Synthesis of (S)-6-fluoro-2,10-dimethyl-7-(6-((3-(piperidin-1-yl)propoxy)methyl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0869] 1,4-dioxane (5 mL), 2-((3-(piperidin-1-yl)propoxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (162 mg, 0.45 mmol), (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (106 mg, 0.3 mmol), potassium carbonate (83 mg, 0.6 mmol), water (0.5 mL), and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) were successively added to a 50 mL reaction bottle. The reaction solution was heated up to 90? C. under nitrogen protection to react for 3 h. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness, and the residue was purified by column chromatography (DCM:MeOH=20:1-10:1) to afford (S)-6-fluoro-2,10-dimethyl-7-(6-((3-(piperidin-1-yl)propoxy)methyl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (26 mg, 17% yield). ESI-MS (m/z): 506.25 [M+H].sup.+.

[0870] Example 113: 7-(6-(3-(bis(methyl-d.sub.3)amino)propoxy)pyridin-3-yl)-6-fluoro-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-206)

##STR00309##

[0871] Except starting materials were changed, the synthesis method was the same as that of example 1 to afford 7-(6-(3-(bis(methyl-d.sub.3)amino)propoxy)pyridin-3-yl)-6-fluoro-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (70 mg, 34.2% yield). ESI-MS (m/z): 472.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.735 (s, 6H), 2.116-2.162 (m, 2H), 2.919-2.945 (m, 2H), 3.575 (s, 3H), 4.393 (s, 2H), 4.426-4.446 (m, 2H), 6.943 (d, J=8.4 Hz, 1H), 7.512 (d, J=10.8 Hz, 1H), 7.837 (d, J=8.4 Hz, 1H), 8.249 (s, 1H), 8.787 (s, 1H).

[0872] Example 114: (S)-7-(6-(3-(4,4-dimethylpiperidin-1-yl)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-207)

##STR00310##

[0873] Step 1: Synthesis of 3-(4,4-dimethylpiperidin-1-yl)propanol

[0874] 4,4-dimethylpiperidine (0.81 g, 7.13 mmol), acetonitrile (20 mL), potassium carbonate (3.94 g, 28.54 mmol), and 3-bromopropan-1-ol (1.19 g, 8.56 mmol) were added to a 100 mL reaction bottle. The reaction solution was heated up to 80? C. to react for 5 h, when the reaction was completed as detected by TLC, the reaction solution was cooled down to room temperature and subjected to suction filtration, and the filtrate was concentrated to dryness and the residue was purified by column chromatography (DCM:MeOH=50:1-20:1) to afford 3-(4,4-dimethylpiperidin-1-yl)propanol (0.56 g, 46.0% yield). ESI-MS (m/z): 172.10 [M+H].sup.+.

[0875] Step 2: Synthesis of (S)-7-(6-(3-(4,4-dimethylpiperidin-1-yl)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0876] Anhydrous THF (4 mL) and 3-(4,4-dimethylpiperidin-1-yl)propanol (87 mg, 0.51 mmol) were added to a 50 mL reaction bottle and cooled down to 0? C., followed by adding NaH (35 mg, 0.89 mmol) in batches. After 0.5 h of reaction at room temperature, (S)-7-(6-fluoropyridin-3-yl)-2,10-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (87 mg, 0.25 mmol) was added, and the reaction was continued at room temperature overnight. When the reaction was completed as detected by TLC, the reaction solution was concentrated to dryness and the residue was purified by column chromatography (DCM:MeOH=20:1-10:1) to afford a crude product, and the crude product was further purified by preparative thin-layer liquid chromatography to afford (S)-7-(6-(3-(4,4-dimethylpiperidin-1-yl)propoxy)pyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (33 mg, 26.3% yield). ESI-MS (m/z): 502.27 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 1.061 (s, 6H), 1.583 (d, J=7.2 Hz, 3H), 1.630-1.649 (m, 4H), 2.207-2.253 (m, 2H), 3.128-3.178 (m, 6H), 3.644 (s, 3H), 4.451-4.512 (m, 3H), 4.637-4.663 (m, 1H), 4.720-4.731 (m, 1H), 6.933 (d, J=9.0 Hz, 1H), 7.665 (d, J=9.0 Hz, 1H), 7.839 (d, J=8.4 Hz, 1H), 7.977-7.995 (m, 1H), 8.389 (d, J=2.4 Hz, 1H), 8.814 (s, 1H).

[0877] Example 115: (S)-2,10-dimethyl-7-(6-(3-(4-methylpiperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-208)

##STR00311##

[0878] Except starting materials were changed, the synthesis method was the same as that of example 114 to afford (S)-2,10-dimethyl-7-(6-(3-(4-methylpiperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (55 mg, 37.7% yield). ESI-MS (m/z): 488.26 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.862-0.908 (m, 2H), 0.997-1.008 (m, 3H), 1.348-1.417 (m, 2H), 1.578-1.606 (m, 3H), 1.829-1.851 (m, 2H), 2.163-2.189 (m, 2H), 2.598 (brs, 2H), 2.994 (brs, 2H), 3.303-3.308 (m, 1H), 3.643 (s, 3H), 4.425-4.445 (m, 2H), 4.487-4.509 (m, 1H), 4.640-4.666 (m, 1H), 4.720-4.731 (m, 1H), 6.923 (d, J=8.4 Hz, 1H), 7.665 (d, J=9.0 Hz, 1H), 7.838 (d, J=9.0 Hz, 1H), 7.969-7.987 (m, 1H), 8.382 (d, J=2.4 Hz, 1H), 8.811 (s, 1H).

[0879] Example 116: (S)-2,10-dimethyl-7-(6-(3-(4-methylpiperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-211)

##STR00312##

[0880] Except starting materials were changed, the synthesis method was the same as that of example 104 to afford (S)-2,10-dimethyl-7-(6-(3-(4-methylpiperidin-1-yl)propoxy)pyridin-3-yl)-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (26 mg, 38.3% yield). ESI-MS (m/z): 486.27 [M+H].sup.+; .sup.1H NMR (600 MHz, CD.sub.3OD) ?: 0.911-0.922 (m, 2H), 0.984-0.994 (s, 3H), 1.475-1.485 (m, 4H), 1.733-1.755 (m, 2H), 2.083-2.108 (m, 2H), 2.186-2.224 (m, 2H), 2.681-2.706 (m, 2H), 3.082-3.100 (m, 2H), 3.466-3.490 (m, 1H), 3.639-3.692 (m, 4H), 4.402-4.617 (m, 2H), 4.887 (s, 1H), 6.967 (d, J=8.4 Hz, 1H), 7.359 (d, J=8.4 Hz, 1H), 7.516 (d, J=9.6 Hz, 1H), 7.803 (d, J=8.4 Hz, 1H), 8.227 (s, 1H), 8.720 (s, 1H).

[0881] Example 117: (S)-7-(6-(3-(4,4-dimethylpiperidin-1-yl)propoxy)pyridin-3-yl)-2,10-dimethyl-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-212)

##STR00313##

[0882] Except starting materials were changed, the synthesis method was the same as that of example 104 to afford (S)-7-(6-(3-(4,4-dimethylpiperidin-1-yl)propoxy)pyridin-3-yl)-2,10-dimethyl-2,8,9,10-tetrahydro-1H-2,4,8,10a-tetraazanaphtho[2,1,8-cde]azulen-1(2H)-one (38 mg, 35.4% yield). ESI-MS (m/z): 500.29 [M+H].sup.+; .sup.1H NMR (600 MHz, DMSO-d.sub.6) ?: 0.904 (s, 6H), 1.337-1.346 (m, 8H), 1.909-1.931 (m, 2H), 2.369-2.515 (m, 6H), 3.534 (s, 3H), 3.636-3.667 (m, 1H), 4.331-4.351 (m, 2H), 4.503 (s, 1H), 5.846 (d, J=7.2 Hz, 1H), 6.943 (d, J=8.4 Hz, 1H), 7.262 (d, J=8.4 Hz, 1H), 7.420 (d, J=8.4 Hz, 1H), 7.780 (d, J=7.2 Hz, 1H), 8.230 (s, 1H), 8.785 (s, 1H).

[0883] Experimental Example

[0884] The activity tests and data of the compounds of the present disclosure are as follows.

1 Test on ATM Inhibitory Activity and Enzymatic Selectivity of the Compounds of the Present Disclosure

1.1 Experimental Materials

[0885]

TABLE-US-00001 Reagent Supplier Article Number PI3K? (p110?/p85?) Invitrogen PV4788 PI3K? (p110?) Eurofins 14-603M PI3K? (p110?/p85?) Invitrogen PV6542 PI3K? (pp110gamma) Invitrogen PR8641C mTOR Millipore 14-770 DNA-PK Promege V4106 ATR Eurofins 14-953 ATM Millipore 14-933 Wortmannin Selleckchem S2758 ATP Sigma A7699-1G PI103 TOCRIS 2930 AZ20 MCE HY-15557 Staurosporine Selleckchem S1421 5-FAM-AK-17 GL 524315 Ulight-4E-BP1 (Thr37/46) Peptide .sup.1 PE TRF0128-M Eu-anti-P-4E-BP1 (Thr37/46) .sup.2 PE TRF0216-M ADP-Glo Kinase Assay Promege V9102 DMSO Sigma D2650 EDTA Sigma E5134 EGTA Sigma E3889-25G 96-well plate Corning 3365 384-well plate Corning 3573 384-well plate Corning 4512 Note: .sup.1 Ulight-4E-BP1 (Thr37/46) Peptide: Ulight-labeled peptide chain of eukaryotic translation initiation factor 4E-binding protein 1 (Thr37/46). .sup.2 EU-anti-P-4E-BP1 (Thr37/46): EU-labeled anti-phosphorylation 4E-BP1 (Thr37/46) antibody.

1.2 Determination of the Inhibitory Activities of Compounds on ATM: Caliper Mobility Shift Assay for ATM

Experimental Procedures

[0886] (1) Preparation of 1? kinase basal buffer and reaction termination solution [0887] 1) 1? kinase basal buffer [0888] 50 mM HEPES, pH 7.5 [0889] 0.0015% Brij-35 (polyoxyethylene lauryl ether) [0890] 100 mM Na.sub.3VO.sub.4 [0891] 5 M NaCl [0892] 1 M MgCl.sub.2 [0893] 1 M MnCl.sub.2 [0894] 2) Reaction termination solution [0895] 100 mM HEPES, pH 7.5 [0896] 0.015% Brij-35 [0897] 0.2% Coating Reagent #3 [0898] 50 mM EDTA [0899] (2) Preparation of test compound [0900] 1) Dissolution and dilution of compound: a compound was dissolved into DMSO to yield a 10 mM or 5 mM stock solution. To a 96-well plate, 98 ?L of DMSO and 2 ?L of the 10 mM stock solution were added and mixed evenly so that the concentration of the solution was 200 ?M. To another 96-well plate, 45 ?L of DMSO and 5 ?L of the 200 ?M solution were added to yield a 20 ?M working solution. [0901] 2) The working solution of the compound was sequentially diluted in the 96-well plate by the way of taking 10 ?L of a solution at a higher concentration to 30 ?L of DMSO to yield a mixed solution at a lower concentration and transferring the mixed solution to the next well, and so on, in order to set up 10 concentration gradients. [0902] 3) 100 ?L of DMSO was added to the blank well and served as a blank control without compound or enzyme. [0903] 4) Preparation of intermediate sample plate: 40 ?L of each of the solutions with gradient concentrations prepared in the 96-well plate was taken and transferred to a new 384-well plate as an intermediate sample plate. [0904] (3) Preparation of test plate [0905] 100 nL of the compound solution was taken from each well of the intermediate sample plate to a 384-well plate as a test plate. [0906] (4) Kinase reaction [0907] 1) The kinase was dissolved in the 1? kinase basal buffer to yield a 2? enzyme solution. [0908] 2) 10 ?L of the 2? enzyme solution was taken to the 384-well test plate. [0909] 3) The 384-well test plate was incubated at room temperature for 10 min. [0910] 4) FAM-labeled polypeptide substrate and ATP were dissolved in the 1? kinase basal buffer to yield a 2? substrate peptide solution. [0911] 5) 10 ?L of the 2? substrate peptide solution was taken to each well of the 384-well test plate, respectively. [0912] 6) Progress and termination of enzymatic reaction: the test plate, to which the enzyme solution and the substrate peptide solution were added, was incubated at 37? C. for a while, and then 35 ?L of the reaction termination solution was added to terminate the reaction. [0913] (5) Reading of the reaction wells [0914] (6) Calculation of inhibitory rates by means of curve fitting to the read values [0915] % inhibitory rate=(max?conversion)/(max?min)*100; wherein max represents the read value of the total reaction well with DMSO but no compound; min represents the read value of the blank control well; conversion represents the read value of the test well.

[0916] Based on the inhibitory rates of the compound at different concentrations, IC.sub.50 was calculated according to the formula: Y=Bottom+(Top?Bottom)/(1+(IC.sub.50/X){circumflex over ()}HillSlope).

1.3 Determination of the Inhibitory Activities of Compounds on PI3K?, PI3K?, PI3K?, and PI3K? Kinase: ADP-Glo Kinase Assay

Experimental procedures [0917] (1) Preparation of 1? kinase buffer [0918] 50 mM HEPES, pH 7.5 [0919] 3 mM MgCl.sub.2 [0920] 1 mM EGTA [0921] 100 mM NaCl [0922] 0.03% CHAPS [0923] 2 mM DTT [0924] (2) Preparation of test compound [0925] 1) Dissolution and dilution of compound: [0926] The compound was dissolved in DMSO to yield a stock solution. Before the assay, the stock solution of the compound was diluted with DMSO in a 384-well plate to yield a 100? solution at a concentration that is 100 times a target concentration for assay. [0927] 50 ?L of DMSO was added, respectively, into two blank wells in the same 384 well plate, corresponding to the total reaction control without compound and the blank control without enzyme. [0928] 2) Preparation of test plate: 50 nL of the compound solution in each of the above wells was taken to a test plate. [0929] (3) Kinase reaction [0930] 1) PI3K?, PI3K?, PI3K?, and PI3K? kinases were dissolved, respectively, in 1? kinase buffer to yield a 2? enzyme solution at a concentration that is twice the final concentration. 2.5 L of the 2? enzyme solution was taken to each well of the test plate. The blank control without enzyme was added with 2.5 ?L of the 1? kinase buffer instead of the enzyme solution. The test plate was shaken for mixing evenly. [0931] 2) PIP2 substrate and ATP were dissolved in the 1? kinase buffer to yield a 2? substrate solution that is twice the final concentration. 2.5 ?L of the 2? substrate solution was taken to each well of the test plate. The test plate was shaken for mixing evenly. [0932] 3) Kinase reaction [0933] Each well of the test plate was covered and incubated at room temperature for 1 h. [0934] (4) Kinase detection [0935] 1) The ADP-Glo reagent was equilibrated at room temperature. [0936] 2) 5 ?L of ADP-Glo reagent was added to each well of the test plate to terminate the reaction. [0937] 3) The plate was centrifuged for a short time to mix evenly, shaken gently, and equilibrated for 120 min. [0938] 4) 10 ?L of kinase detection reagent was added to each well, with shaking for 1 min, after equilibrating for 30 min, fluorescence detection was performed. [0939] (5) Reading of the reaction wells [0940] (6) Calculation of inhibitory rates by means of curve fitting to the read values [0941] % inhibitory rate=(max?sample RLU)/(max?min)*100; wherein max represents the RLU of the total reaction well with DMSO but no compound; min represents the RLU of the blank control well without enzyme and compound. [0942] Based on the inhibitory rates of the compound at different concentrations, IC.sub.50 was calculated according to the formula: Y=Bottom+(Top?Bottom)/(1+(IC.sub.50/X){circumflex over ()}HillSlope).

1.4 Determination of the Inhibitory Activities of Compounds on DNA-PK Kinase: ADP-Glo Kinase Assay

Experimental Procedures

[0943] (1) Preparation of 1? kinase buffer [0944] 40 mM Tris, pH 7.5 [0945] 0.0055% Brij-35 [0946] 20 mM MgCl.sub.2 [0947] 0.05 mM DTT [0948] (2) Preparation of test compound [0949] 1) The compound was dissolved in DMSO to yield a stock solution. Before the assay, the stock solution of the compound was diluted with DMSO to yield a 100? solution at a concentration that is 100 times a target concentration for assay. If the target concentration was M, the stock solution should be diluted to yield a 1 mM solution at this step. [0950] 2) 100 ?L of DMSO was added, respectively, into two blank wells in the same 96 well plate, corresponding to the total reaction control without compound and the blank control without enzyme. [0951] 3) Preparation of test plate: 50 nL of the compound solution in each of the above wells was taken to a 384-well plate as a test plate. [0952] (3) Kinase reaction [0953] 1) DNA-PK kinase was dissolved in 1? kinase buffer to yield a 2? enzyme solution that is twice the final concentration. 2.5 ?L of the 2? enzyme solution was taken to each well of the test plate. The blank control without enzyme was added with 2.5 ?L of the 1? kinase buffer instead of the enzyme solution. The test plate was shaken for mixing evenly. [0954] 2) The substrate and ATP were dissolved in the 1? kinase buffer to yield a 2? substrate solution that is twice the final concentration. 2.5 ?L of the 2? substrate solution was taken to each well of the test plate. The test plate was shaken for mixing evenly. [0955] 3) Kinase reaction [0956] Each well of the test plate was covered and incubated at room temperature for 3 h. [0957] (4) Kinase detection [0958] 1) The ADP-Glo reagent was equilibrated at room temperature. [0959] 2) 5 ?L of ADP-Glo reagent was added to each well of the test plate to terminate the reaction. [0960] 3) The plate was centrifuged for a short time to mix evenly, shaken gently, and equilibrated for 120 min. [0961] 4) 10 ?L of kinase detection reagent was added to each well, with shaking for 1 min, after equilibrating for 30 min, fluorescence detection was performed. [0962] (5) Reading of the reaction wells [0963] (6) Calculation of inhibitory rates by means of curve fitting to the read values. [0964] % inhibitory rate=(max?sample RLU)/(max?min)*100; wherein max represents the RLU of the total reaction well with DMSO but no compound; min represents the RLU of the blank control well without enzyme and compound. [0965] Based on the inhibitory rates of the compound at different concentrations, IC.sub.50 was calculated according to the formula: Y=Bottom+(Top?Bottom)/(1+(IC.sub.50/X){circumflex over ()}HillSlope).
1.5 the Inhibitory Activities of Compounds on mTOR Kinase: LanceUltra Kinase Assay

Experimental Procedures

[0966] (1) Preparation of 1? kinase buffer [0967] 50 mM HEPES, pH 7.5 [0968] 1 mM EGTA [0969] 0.01% Tween-20 [0970] (2) Preparation of test compound [0971] 1) The compound was dissolved in DMSO to yield a stock solution. Before the assay, the stock solution of the compound was diluted with DMSO to yield a 100? solution at a concentration that is 100 times a target concentration for assay. If the target concentration was M, the stock solution should be diluted to yield a 1 mM solution at this step. [0972] 2) 100 ?L of DMSO was added, respectively, into two blank wells in the same 96 well plate, corresponding to the total reaction control without compound and the blank control without enzyme. [0973] 3) Preparation of intermediate sample plate: 4 ?L of the 100? solution was added into a new 96-well plate, then 96 ?L of the 1? kinase buffer was added, and the plate was shaken for 10 min for mixing evenly to serve as an intermediate sample plate. [0974] 4) Preparation of test plate: 2.5 nL of the compound solution was taken from each well of the intermediate sample plate to a 384-well plate. [0975] (3) Kinase reaction [0976] 1) The mTOR kinase was dissolved in the 1? kinase buffer to yield a 4? enzyme solution at a concentration that is 4 times the final concentration. 2.5 ?L of the 2? enzyme solution was taken to each well of the test plate. The blank control without enzyme was added with 2.5 ?L of the 1? kinase buffer instead of the enzyme solution. The test plate was shaken for mixing evenly. [0977] 2) ULight-4E-BP1 polypeptide substrate and ATP were dissolved in the 1? kinase buffer to yield a 2? substrate solution at a concentration that is twice the final concentration. 5 L of the 2? substrate solution was taken to each well of the test plate. The test plate was shaken for mixing evenly. [0978] 3) Kinase reaction: [0979] Each well of the test plate was covered and incubated at room temperature for 30 min. [0980] (4) Kinase detection [0981] 1) The kinase quench buffer (EDTA) and Eu-anti-phospho-4E-BP1 antibody were formulated into a detection buffer at a concentration that is twice the final concentration. 10 ?L of the detection buffer was added to each well of the test plate. [0982] 2) The plate was centrifuged for a short time to mix evenly, shaken gently, and equilibrated at room temperature for 60 min. [0983] (5) Reading of the reaction wells [0984] (6) Calculation of inhibitory rates by means of curve fitting to the read values. [0985] % inhibitory rate=(max?sample fluorescence value)/(max?min)*100; wherein max represents the fluorescence value of the total reaction well with DMSO but no compound; min represents the fluorescence value of the blank control well without enzyme and compound. [0986] Based on the inhibitory rates of the compound at different concentrations, IC.sub.50 was calculated according to the formula: Y=Bottom+(Top?Bottom)/(1+(IC.sub.50/X){circumflex over ()}HillSlope).

1.6 Determination of the Inhibitory Activity of Compounds on ATR: Caliper Mobility Shift Assay for ATR

Experimental Procedures

[0987] (1) Preparation of 1? kinase buffer and reaction termination solution [0988] 1) 1? kinase buffer [0989] 50 mM HEPES, pH 7.5 [0990] 0.0015% Brij-35 [0991] 1 M MnCl.sub.2 [0992] 2) Reaction termination solution [0993] 100 mM HEPES, pH 7.5 [0994] 0.015% Brij-35 [0995] 0.2% Coating Reagent #3 [0996] 50 mM EDTA [0997] (2) Preparation of test compound [0998] 1) The compound was dissolved in DMSO to yield a stock solution. Before the assay, to a 96-well plate, 30 ?L of a 10 mM stock solution was taken and added with 60 ?L of DMSO. The solution was sequentially diluted by the way of taking 30 ?L of a solution at a higher concentration to 60 ?L of DMSO to yield a mixed solution at a lower concentration and transferring the mixed solution to the next well, and so on, and 10 concentration gradients were set up. [0999] 2) 100 ?L of DMSO was added, respectively, into two blank wells in the same 96 well plate, corresponding to the total reaction control without compound and the blank control without enzyme. [1000] 3) Preparation of intermediate sample plate: 40 ?L of the solution in each well of the above 96-well plate was taken and transferred to a new 384-well plate as an intermediate sample plate. [1001] (3) Preparation of test plate [1002] 60 nL of the solution in each well of the intermediate sample plate was taken to a test plate. [1003] (4) Kinase reaction [1004] 1) ATR kinase was dissolved in the 1? kinase buffer to yield a 2? enzyme solution at a concentration that is twice the final concentration. 10 ?L of the 2? enzyme solution was taken to each well of the test plate and incubated at room temperature for 10 min. [1005] 2) FAM-labeled polypeptide substrate and ATP were dissolved in the 1? kinase buffer to yield a 2? substrate solution at a concentration that is twice the final concentration. 10 L of the 2? substrate solution was taken to each well of the test plate. [1006] 3) Kinase reaction: [1007] After incubation at 28? C. for a certain time, 30 ?L of the reaction termination solution was added to terminate the enzymatic reaction. [1008] (5) Reading of the reaction wells [1009] (6) Calculation of inhibitory rates by means of curve fitting to the read values. [1010] % inhibitory rate=(max?sample value)/(max?min)*100; wherein max represents the value of the total reaction well with DMSO but no compound; min represents the value of the blank control well without enzyme and compound. [1011] Based on the inhibitory rates of the compound at different concentrations, IC.sub.50 was calculated according to the formula: Y=Bottom+(Top?Bottom)/(1+(IC.sub.50/X){circumflex over ()}HillSlope).

2 Results of the Test on ATM Inhibitory Activity of the Compounds of the Present Disclosure

[1012]

TABLE-US-00002 Compound IC.sub.50 Compound IC.sub.50 Compound IC.sub.50 No. (nM) No. (nM) No. (nM) A-1 0.79 A-159 0.92 A-186 0.38 A-4 0.90 A-160 0.43 A-187 0.22 A-6 0.37 A-161 0.32 A-188 0.40 A-9 0.20 A-162 0.36 A-189 0.38 A-11 0.54 A-164 0.59 A-191 0.69 A-13 0.40 A-165 0.37 A-192 0.53 A-14 0.42 A-166 0.21 A-193 0.65 A-21 0.45 A-167 0.33 A-194 0.45 A-22 0.52 A-170 0.70 A-195 0.41 A-23 0.42 A-171 0.42 A-196 0.51 A-27 0.28 A-176 0.17 A-197 0.59 A-28 0.28 A-177 0.25 A-198 0.44 A-30 0.27 A-178 0.25 A-199 0.92 A-32 0.94 A-179 0.37 A-201 0.61 A-33 0.08 A-180 0.26 A-202 0.23 A-46 0.52 A-181 0.72 A-203 0.54 A-49 0.86 A-182 0.46 A-204 0.78 A-67 0.26 A-183 0.23 A-207 0.44 A-68 0.37 A-184 0.25 A-208 0.29 A-154 0.71 A-185 0.25 AZD1390 0.20 A-211 0.33 A-212 0.37 Note: as positive control drug, AZD1390 is the compound in Example 2 of patent applicaiton CN 201680052951.0.

[1013] The in vitro enzymatic assay results show that the compound of the present disclosure is a strong inhibitor of ATM kinase. The IC.sub.50 of the inhibitory activity of each compound of the present disclosure on ATM kinase was less than 1 nM; the IC.sub.50 of some of compounds such as A-33 is 0.08 nM, and the inhibitory effect thereof on ATM kinase is higher than that of AZD1390.

3 Results of the Test on Enzymatic Selectivity of the Compounds of the Present Disclosure

[1014]

TABLE-US-00003 Compound IC.sub.50 of kinase inhibitory activity (nM) No. ATR mTOR DNA-PK PI3K ? PI3K ? PI3K ? PI3K ? ATM A-21 >10000 >10000 2226.0 >10000 >10000 >10000 >10000 0.45 A-22 >10000 1275 852.2 6279.2 >10000 >10000 >10000 0.52

[1015] At the level of in vitro enzymatic assay, the kinase inhibitory activities of the compounds of the present disclosure on an ATM-related family were determined. The results show that, as compared to the IC.sub.50 of the inhibitory activity on ATM kinase, the IC.sub.50S of the inhibitory activities of the compound of the present disclosure on ATR, mTOR, DNA-PK, PI3K??, PI3K?, PI3K?, and PI3K? kinases range from several hundred nM to more than 10000 nM, which shows extremely weak or no inhibitory activity, indicating that the compound of the present disclosure is a selective inhibitor of ATM kinase.

4 Inhibition on Intracellular ATM-Phosphorylated KAP1 Level by the Compounds of the Present Disclosure: ICW Assay

4.1 Experimental Materials and Instruments

[1016] Cell: Human breast cancer cell line MCF7 [1017] Materials and reagents:

TABLE-US-00004 Reagent Supplier Article Number DMEM Gibco 10569-010 FBS Gibco 10099-141 Penicillin-Streptomycin Gibco 15140-122 Odyssey Blocking Buffer LI-COR 927-70001 anti-phospho-KAP1(S824) Bethyl A300-767A Laboratories DRAQ5 CST 4048L IRDye 800CW Goat anti- LI-COR 926-32211 Rabbit IgG (H + L) DMSO Solarbio D8371-50

TABLE-US-00005 Article Number Consumable and Instrument Supplier or Model Number 384-Well Polypropylene microplate, Labcyte PP-0200 Clear, Flat Bottom Poly-D-Lysine Black/Clear Microtest Corning 356663 (TM) Tissue-Culture Treated Polystyrene, 384-well plate Plate shaker Thermo 4625-1 CECN/THZ Q Centrifuge Eppendorf 5810R I-DOT One Dispendix 0027 Odyssey Li-COR CLX Vortex IKA MS3 digital

4.2 Experimental Procedures

[1018] (1) Cell inoculation [1019] MCF7 cells were inoculated on a 384-well plate, 10000 cells/well (25 ?L/well), and cultured overnight at 37? C. with 5% CO.sub.2. [1020] (2) Activity detection [1021] 1) The compound was formulated into a 100 mM solution with DMSO and then sequentially diluted with a gradient of 1:3 to yield a total of 10 concentration gradients, wherein the maximum concentration was 100 ?M. [1022] 2) 25 nL of each of the compound solutions with gradient concentrations prepared in step 1) was added to each well of the cell plate (Corning #356663) by using I-DOT One, resulting in a final concentration of 100 nM (maximum dose). [1023] 3) The cell plate containing compound was incubated at 37? C. with 5% CO.sub.2 for 2 h. After 2 h, the cell plate was irradiated with a dose of 10 Gy, and then further incubated for 1 h. [1024] 4) 25 ?L of 8% paraformaldehyde was added to each well, followed by incubating at room temperature for 20 min. [1025] 5) The 8% paraformaldehyde was discarded, followed by adding 0.1% TrintonX-100 and incubating at room temperature for 30 min. [1026] 6) Odessey blocking buffer was added at 50 ?L/well, followed by incubating at room temperature for 1.5 h. [1027] 7) The Odessey blocking buffer was discarded, and then a primary antibody (Phospho-KAP1, 1:2000 dilution) was added, followed by incubating overnight at 4? C. [1028] 8) The primary antibody was removed, followed by washing with PBS+0.1% Tween 20 for 5 times. [1029] 9) DNA dye DRAQ5 coated with a second antibody (IRDye 800CW Goat anti-Rabbit, 1:4000 dilution) was added, followed by incubating at room temperature for 1 h. [1030] 10) The second antibody was removed, followed by washing with PBS+0.1% Tween 20 for 5 times. [1031] 11) PBS+0.1% Tween 20 was sucked off with Odyssey. [1032] (3) Data analysis [1033] 1) the relative ratio of Channel 800/Channel 700 for each well was detected. [1034] 2) % of KAP1 phosphorylation was calculated according to the following formula:

% of KAP1 phosphorylation=[(Ratiocmpd?(Ratio)Positive)/((Ratio)Vehicle?(Ratio)Positive]*100 [1035] (Ratio)Positive: the mean value of the test values of each positive control well in the test cell plate; [1036] (Ratio)Vehicle: the mean value of the test values of each negative control well in the test cell plate. [1037] 3) the IC.sub.50 of each compound was calculated and the dose-effect curve was plotted: % of KAP1 phosphorylation and log of compound's concentration were fit by using Graphpad 8.0 so as to calculate the IC.sub.50.

[00001]$Y=\mathrm{Bottom}+\left(\mathrm{Top}-\mathrm{Bottom}\right)/\left(1+10^\left(\left(\mathrm{Log}{\mathrm{IC}}_{50}-X\right)*\mathrm{HillSlope}\right)\right)$ [1038] X: log of compound's concentration [1039] Y: % of KAP1 phosphorylation

4.3 the Inhibitory Activities of Compounds on Intracellular ATM-Phosphorylated KAP1 Level

[1040]

TABLE-US-00006 Compound No. pKAP1 IC.sub.50 (nM) Compound No. pKAP1 IC.sub.50 (nM) AZD1390 0.45 A-203 0.83 A-198 0.64 A-183 0.22 A-193 1.75 A-184 0.33 A-68 0.90 A-199 0.78 A-177 0.61 A-192 1.44 A-211 0.33 A-212 0.37

[1041] At the cellular level, the compounds have inhibitory effects on ATM KAP phosphorylation. Among those, the inhibitory effects of A-183, A-184, A-211, and A-212 are higher than that of AZD1390 as positive control.

5 Test of the Inhibitory Activities of the Compounds of the Present Disclosure Combined with Radiotherapy on LN18 Cell Proliferation

5.1 Experimental Materials and Instruments

[1042] Cell: Human glioblastoma cell line LN-18

Experimental Materials and Reagents:

[1043]

TABLE-US-00007 Article Reagent Supplier Number Dulbecco's Modified Eagle Medium (D-MEM) invitrogen 11965-092 Fetal Bovine Serum Gibco 10099141 Cell titre glo Promega G7573 DMSO Sigma D8418

Consumables and Instruments:

[1044]

TABLE-US-00008 Article Number Consumable and Instrument Supplier or Model Number V96 MicroWell Plates Nunc 249944 CulturPlate-96 (White) PerkinElmer 6005680 Deep Well Plates Axygen P-DW-11-C-S 50 mL Centrifuge Tube BD-Falcon 352098 15 mL Centrifuge Tube BD-Falcon 352097 5 mL Serological pipet BD-Falcon 357543 10 mL Serological pipet BD-Falcon 357551 25 mL Serological pipet BD-Falcon 357525 Sample grooves Corning 4870 25 cm2 Flask Corning 430639 75 cm2 Flask Corning 430641 225 cm2 Flask Corning 431082 Plate shaker QILINBEIER QB-9002 Centrifuge Eppendorf 5810R X-Ray PRECISION X-RAD 225 Multiplate reader PerkinElmer EnVision 2105

5.2 Experimental Procedures

[1045] (1) Cell inoculation [1046] 1) The cell culture fluid was preheated at 37? C. [1047] 2) A complete culture medium of LN18 cells was prepared, at a ratio of DMEM medium:FBS=95:5 (V/V). [1048] 3) Cells were digested with trypsin, collected to serve as a cell suspension, and counted, the cell suspension was then added into a 96-well plate at 1500 cells/well and 100 ?L of cell fluid/well, and three parallel wells were set. [1049] 4) After inoculated in the plate, the cells were cultured overnight under the condition of 37? C. and 5% CO.sub.2. [1050] (2) Compound addition and incubation [1051] 1) AZD1390 and tested compounds, respectively, were sequentially diluted 5 times with DMSO, starting from the concentration of 10 mM and yielding the concentrations of 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0.000128, and 0.0000256 mM in turn. The compound solutions at the above concentrations were diluted 5000 times with the complete culture medium. The final 2? concentrations were in order 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, and 0.00512 nM. The vehicle control was 0.02% DMSO culture fluid. [1052] 2) A complete culture medium containing 100 ?L of the compound solution was added to each well, and the final concentrations of the compounds in the wells were in order 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0.0128, and 0.00256 nM. The 0.01% DMSO culture fluid was contained in the vehicle control well. After incubated with compound for 1 h, the cells were irradiated at a dose of 1 Gy. [1053] 3) After irradiation, the plate was put into an incubator and incubated under the condition of 37? C. and 5% CO.sub.2 for 6 days. Then detection was performed by adopting CTG assay (100 ?L of liquid from each well was sucked out and discarded, and 50 ?L of CTG reagent was added to each well, and incubated at room temperature for 30 min, and the luminescence intensity was detected). [1054] (3) Data analysis [1055] 1) The Luminescence signal (RLU) of each well was detected. [1056] 2) Proliferation inhibitory activity was calculated according to the formula: % inhibitory activity=RLUtreatment/RLUAvg(Vehicle)*100.
5.3 the Inhibitory Activities of Compounds of the Present Disclosure Combined with Radiotherapy on LN18 Cell Proliferation

TABLE-US-00009 Compound No. IC.sub.50 (nM) Compound No. IC.sub.50 (nM) AZD1390 2.79 A-203 5.66 A-198 5.93 A-183 1.39 A-193 10.08 A-184 3.84 A-68 6.83 A-211 2.71 A-177 5.22 A-212 1.48

[1057] At the cellular level, the compounds have inhibitory effects on LN18 cell proliferation. Among those, the inhibitory effects of A-183, A-211, and A-212 were higher than that of AZD1390 as positive control.

6 Efficacy Test of the Compounds of the Present Disclosure Combined with Irinotecan Liposome Injection on Inhibiting the Growth of Subcutaneous Xenograft Tumor of Human Non-Small Cell Lung Cancer Cell Line NCI-H441

6.1 Experimental Animals: NU/NU Mice, SPF, Female, 20 to 30 g.

6.2 Experimental Materials

[1058] Irinotecan liposome injection (HE072), 43 mg:10 mL, milky white liquid, batch No. B37191202, provided by Preparation Research Institute 2 from CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., diluted to an appropriate concentration with 5% glucose injection while testing.

[1059] NCI-H441 cells, provided by Nanjing Kebai Biotechnology Co., Ltd.; 1640 culture medium (gibco Company):fetal bovine serum (Lanzhou Bailing)=90%:10%, 37? C., 5% CO.sub.2.

6.3 Experimental Process

[1060] NU/NU nude mice were subcutaneously inoculated with NCI-H441 human non-small cell lung cancer cells. When the mean tumor volume reached 170 to 172 mm.sup.3 (15 days after inoculation), the animals were evenly divided into groups according to the tumor volume (d0), with 6 mice in each group. 2.5 mg/kg of HE072 was administered intraperitoneally once a week for 2 times. Vehicle control, 25 mg/kg of A-193, 25 mg/kg of A-182, and 25 mg/kg of AZD1390 were administered intragastrically once a day, from Monday to Thursday every week except Friday to Sunday, for 2 weeks (8 times). The tumor volume was measured twice a week, the body weight of mouse was weighed every day, and the data were recorded. The tumor volume (TV) was calculated according to the formula: TV=??a?b2, wherein a and b represent the long and short diameters of tumor, respectively. Tumor growth inhibitory rate TGI (%)=[1?(Ti?T0)/(Vi?V0)]?100, wherein Ti represents the mean tumor volume of a given treatment group on a certain day; TO represents the mean tumor volume of this treatment group at the beginning of administration; Vi represents the mean tumor volume of the vehicle control group on a certain day (the same day as that in Ti); V0 represents the mean tumor volume of the vehicle control group at the beginning of administration. At the end of the test (d17), the animals were sacrificed, the tumors were stripped and weighed, and the tumor weight inhibitory rates were calculated.

[00002]$\mathrm{Tumor}\mathrm{weight}\mathrm{inhibitory}\mathrm{rate}\left(\%\right)=\left(1-\mathrm{tumor}\mathrm{weight}\mathrm{of}\mathrm{treatment}\mathrm{group}/\mathrm{tumor}\mathrm{weight}\mathrm{of}\mathrm{vehicle}\mathrm{control}\mathrm{group}\right)?100.$

6.4 the Efficacy Test Results of the Compounds of the Present Disclosure Combined with Irinotecan Liposome Injection on Inhibiting the Growth of Subcutaneous Xenograft Tumor of Human Non-Small Cell Lung Cancer Cell Line NCI-H441

TABLE-US-00010 Tumor Compound D0 TV D17 TV D17 Tumor weight dose (MEAN ? (MEAN ? SD, TGI weight inhibitory Group (mg/kg) SD, mm.sup.3) mm.sup.3) % (g) rate % Vehicle control 0 172.9 ? 30.0 605.7 ? 169.6 0.59 ? 0.13 Vehicle 0/2.5 170.9 ? 449.9 ? 80.5** 35.5 0.46 ? 0.11* 21.7 control/Irinotecan 24.8 A-193/Irinotecan 25/2.5 171.6 ? 225.9 ? 69.4***.sup.### 87.5 0.24 ? 0.06***.sup.### 60.2 30.9 A-182/Irinotecan 25/2.5 170.7 ? 278.5 ? 94.1***.sup.## 75.1 0.26 ? 0.07***.sup.### 56.1 31.5 AZD1390/ 25/2.5 171.1 ? 342.8 ? 110.6*** 60.3 0.32 ? 0.09***.sup.## 45.3 Irinotecan 28.5 Compared with the vehicle control, **P < 0.01, ***P < 0.001; compared with irinotecan at a dose of 2.5 mpk, .sup.##P < 0.01, .sup.###P < 0.001.

[1061] The efficacy test results of growth inhibition of NCI-H441 subcutaneous xenograft tumor show that the compounds of the present disclosure significantly inhibit the tumor growth, and the inhibitory effects of A-193 and A-182 on both tumor volume and tumor weight are higher than those of AZD1390.

7 Efficacy Test of the Compounds of the Present Disclosure Combined with Irinotecan Liposome Injection on Inhibiting the Growth of Subcutaneous Xenograft Tumor of Human Colon Cancer Cell Line HT-29

7.1 Experimental Animals: NU/NU Mice, SPF, Female, 20 to 30 g.

7.2 Experimental Materials

[1062] Irinotecan liposome injection (HE072), 43 mg: 10 mL, milky white liquid, batch No. B37191202, provided by Preparation Research Institute 2 from CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., diluted to an appropriate concentration with 5% glucose injection while testing.

[1063] HT-29 cell, provided by Nanjing Kebai Biotechnology Co., Ltd.; 5A culture medium:fetal bovine serum=90%:10%, 37? C., 5% CO.sub.2.

7.3 Experimental Process

[1064] NU/NU nude mice were subcutaneously inoculated with HT-29 human colon cancer cells. When the mean tumor volume reached about 170 mm.sup.3 (9 days after inoculation), the animals were evenly divided into groups according to the tumor volume (d0), with 6 mice in each group. 10 mg/kg of HE072 was administered intraperitoneally once a week for 1 time. Vehicle control, 25 mg/kg of A-6, 25 mg/kg of A-46, and 25 mg/kg of AZD1390 were administered intragastrically once a day, from Monday to Thursday every week except Friday to Sunday, for 1 week (4 times). The tumor volume was measured twice a week, the body weight of mouse was weighed every day, and the data were recorded. The tumor volume (TV) was calculated according to the formula: TV=??a?b2, wherein a and b represent the long and short diameters of tumor, respectively. Tumor growth inhibitory rate TGI (%)=[1?(Ti?T0)/(Vi?V0)]?100, wherein Ti represents the mean tumor volume of a given treatment group on a certain day; TO represents the mean tumor volume of this treatment group at the beginning of administration; Vi represents the mean tumor volume of the vehicle control group on a certain day (the same day as that in Ti); V0 represents the mean tumor volume of the vehicle control group at the beginning of administration. At the end of the test (d17), the animals were sacrificed, the tumors were stripped and weighed, and the tumor weight inhibitory rates were calculated.

[00003]$\mathrm{Tumor}\mathrm{weight}\mathrm{inhibitory}\mathrm{rate}\left(\%\right)=\left(1-\mathrm{tumor}\mathrm{weight}\mathrm{in}\mathrm{treatment}\mathrm{group}/\mathrm{tumor}\mathrm{weight}\mathrm{in}\mathrm{vehicle}\mathrm{control}\mathrm{group}\right)?100.$

7.4 the Efficacy Test Results of the Compounds of the Present Disclosure Combined with Irinotecan Liposome Injection on Inhibiting the Growth of Subcutaneous Xenograft Tumor of Human Colon Cancer Cell Line HT-29

TABLE-US-00011 Tumor Compound D 0 TV D 16 TV D 16 Tumor weight dose (MEAN ? SD, (MEAN ? SD, TGI weight inhibitory Group (mg/kg) mm.sup.3) mm.sup.3) % (g) rate % Vehicle control 0 166.4 ? 59.3 916.5 ? 412.3.sup. 0.69 ? 0.29.sup. Vehicle 0/10 166.6 ? 51.3 577.4 ? 225.3**.sup. 45.2 0.45 ? 0.16**.sup. 34.5 control/Irinotecan A-6/Irinotecan 25/10 166.9 ? 56.6 163.8 ? 62.8***.sup.### 100.4 0.12 ? 0.03***.sup.### 82.4 A-46/Irinotecan 25/10 166.2 ? 51.6 149.5 ? 67.4***.sup.### 102.2 0.12 ? 0.06***.sup.### 82.0 AZD1390/Irinotecan 25/10 166.0 ? 54.9 244.2 ? 192.8***.sup.### 89.6 0.18 ? 0.18***.sup.### 74.7 Compared with the vehicle control, **P < 0.01, ***P < 0.001; compared with irinotecan at a dose of 10 mpk, .sup.###P < 0.001.

[1065] The efficacy test results of growth inhibition of HT-29 subcutaneous xenograft tumor show that the compounds of the present disclosure significantly inhibit the tumor growth, and the inhibitory effects of A-6 and A-46 on both tumor volume and tumor weight are higher than those of AZD1390.

8 Efficacy Test of the Compounds of the Present Disclosure Combined with Radiotherapy in the Intracranial Murine Glioma GL-261-Luc Model

8.1 Experimental Animals: C57BL/6 Mice, SPF, Female, 19 to 22 g.

8.2 Experimental Materials and Instruments

[1066] GL-261-Luc tumor cells, DMEM medium:fetal bovine serum=90%:10%, accompanied by adding 4 ?M L-Glu, 37? C., 5% CO.sub.2.

[1067] X-ray irradiator, model: RS2000 X-Ray, supplier: RadSource

8.3 Experimental Process

(1) Construction of In-Situ Tumor Model

[1068] Female C57BL/6 mice were anesthetized with Shutai 50 (60 mg/mL) and thiazine (1.5 mg/mL). Buprenorphine (0.1 mg/kg) was injected subcutaneously 30 min before operation and 6 h after operation to relieve pain. The operation area was disinfected with 70% ethanol solution. A sagittal incision was made on the parietal-occipital bone of anesthetized mice with a sterile scalpel, after cleaning the exposed skull surface with 3% hydrogen peroxide solution, tumor cells were injected. After injection, the skull was cleaned with 3% hydrogen peroxide solution, dried with a sterile dry cotton swab, and the incision was sutured. The state of mice was examined continuously to ensure that mice fully recovered from anesthesia.

(2) Bioluminescence Detection

[1069] The inoculated mice were weighed and intraperitoneally injected with fluorescein (150 mg/kg). After 10 min injection, the animals were anesthetized with a mixture of oxygen and isoflurane. When the animal was completely anesthetized, it was moved into the imaging room for bioluminescence detection. The bioluminescence signal of the whole animal was measured and recorded for the image.

(3) Grouping

[1070] Bioluminescence detection was performed on the second day after operation, and the tumor-bearing mice were randomly divided into groups according to the intensity of bioluminescence. The specific groups were as follows. The administration route was intragastric administration and then JR 1 h after administration.

TABLE-US-00012 Irradiation Compound Total dose dose Period and No. number Group (Gy) (mg/kg) Dosing route frequency 1 7 Vehicle 0 0 Intragastric qd ? 5 control administration 2 7 Vehicle 2 0 Intragastric qd ? 5 control/IR administration 3 7 A-193/IR 2 10 Intragastric qd ? 5 administration 4 7 A-182/IR 2 10 Intragastric qd ? 5 administration 5 7 AZD1390/IR 2 10 Intragastric qd ? 5 administration

(4) Evaluation Index

[1071] After grouping, bioluminescence detection was performed 1 to 2 times a week, according to the bioluminescence data, tumor growth inhibitory rate was calculated as follows: TGI (%)=[1?(Ti?T0)/(Vi?V0)]?100, wherein Ti represents the mean bioluminescence data of a given treatment group on a certain day; T0 represents the mean bioluminescence data of this treatment group at the beginning of administration; Vi represents the mean bioluminescence data of the vehicle control group on a certain day (the same day as that in Ti); V0 represents the mean bioluminescence data of the vehicle control group at the beginning of administration.

8.4 the Efficacy Test Results of the Compounds of the Present Disclosure Combined with Radiotherapy in the Intracranial Murine Glioma GL-261-Luc Mode

TABLE-US-00013 Irra- diation Compound dose dose D 0 BLI D17 BLI D 17 Group (Gy) (mg/kg) (LOG10) (LOG10) TGI % Vehicle 0 0 5.49 7.93 control Vehicle 2 0 5.50 6.49*** 59.18 control/IR A-193/IR 2 10 5.49 4.94*** 122.49 A-182/IR 2 10 5.49 5.24*** 110.08 AZD1390/IR 2 10 5.49 4.90*** 124.08 Note: Compared with vehicle control, ***P < 0.001.

[1072] The efficacy test results in the intracranial GL-261-Luc tumor model show that the compounds of the present disclosure significantly inhibit the tumor growth, and the anti-tumor activities of A-193 and A-182 are equivalent to that of AZD1390.

9 Efficacy Test of the Compounds of the Present Disclosure Combined with Radiotherapy on Inhibiting the Growth of Subcutaneous Xenograft Tumor of Human Glioblastoma LN-18

9.1 Experimental Animals: NOG Mice, SPF, Female, 18 to 22 g.

9.2 Experimental Materials and Instruments

[1073] LN-18 tumor cells, DMEM medium:fetal bovine serum=95%:5%, accompanied by adding 100 U/mL penicillin and 100 ?g/mL streptomycin, 37? C., 5% CO.sub.2.

[1074] X-ray irradiator, model: X-RAD 225, supplier: PRECISION.

9.3 Experimental Process

(1) Inoculation of Tumor Cells and Grouping

[1075] LN18 tumor cells resuspended in serum-free DMEM medium were inoculated subcutaneously in the right costal region of experimental animals at 1.5*10.sup.7/0.15 mL, and the animals were grouped when the tumor grew to 100 to 150 mm.sup.3. The specific administration regimen is shown in table below. Radiotherapy was performed 1 h after administration of compounds.

TABLE-US-00014 Irradiation Compound Total dose dose Period and No. number Group (Gy) (mg/kg) Dosing route frequency 1 6 Vehicle 0 0 Intragastric qd ? 5 control administration 2 6 Vehicle 1 0 Intragastric qd ? 5 control/IR administration 3 6 A-177/IR 1 5 Intragastric qd ? 5 administration 4 6 A-198/IR 1 5 Intragastric qd ? 5 administration 5 6 A-193/IR 1 10 Intragastric qd ? 5 administration 6 6 A-68/IR 1 5 Intragastric qd ? 5 administration 7 6 A-182/IR 1 20 Intragastric qd ? 5 administration 8 6 A-203/IR 1 5 Intragastric qd ? 5 administration 9 6 A-183/IR 1 5 Intragastric qd ? 5 administration 10 6 A-191/IR 1 10 Intragastric qd ? 5 administration 11 6 A-192/IR 1 20 Intragastric qd ? 5 administration 12 6 AZD1390/IR 1 10 Intragastric qd ? 5 administration

(2) Detection Index

[1076] Tumor volume: The tumor volume was measured twice a week with a vernier caliper, and the long diameter and short diameter of tumor were measured. The tumor volume was calculated as follows: tumor volume (TV)=0.5?long diameter?short diameter.sup.2. Tumor growth inhibitory rate (TGI %) was calculated according to the tumor volume. TV.sub.Xn represents the mean tumor volume on day n of the treatment group, TV.sub.X0 represents the mean tumor volume on day 0 of the treatment group, TV.sub.Mn represents the mean tumor volume on day n of the control group, and TV.sub.M0 represents the mean tumor volume on day 0 of the control group.

[00004]$\mathrm{TGI}=\left[1-\frac{\left({\mathrm{TV}}_{\mathrm{Xn}}-{\mathrm{TV}}_{X0}\right)\text{?}}{\left({\mathrm{TV}}_{\mathrm{Mn}}-{\mathrm{TV}}_{M0}\right)\text{?}}\right]?100\%\text{?}$$\text{?}\text{indicates text missing or illegible when filed}$

[1077] Response of animals after administration: the mice were weighed while the tumor volume was measured. The relationship between body weight change of a mouse and administration time was recorded. At the same time, the survival and health status of mice were observed, such as animal activities, feeding and other general states during the administration.

9.4 the Efficacy Test Results of the Compounds of the Present Disclosure Combined with Radiotherapy on Inhibiting the Growth of Subcutaneous Xenograft Tumor of Human Glioblastoma LN-18

TABLE-US-00015 Irradiation Compound D 0 TV D 17 TV D 17 Group dose (Gy) dose (mg/kg) (MEAN ? SD, mm.sup.3) (MEAN ? SD, mm.sup.3) TGI (%) Vehicle control 0 0 141 ? 11 1029 ? 83.sup. Vehicle control/IR 1 0 142 ? 7 .sup.574 ? 110*** 51.4 A-177/IR 1 5 142 ? 8 338 ? 67***.sup. 77.9 A-198/IR 1 5 142 ? 11 326 ? 77***.sup.# 79.3 A-193/IR 1 10 142 ? 6 310 ? 61***.sup.# 81.1 A-68/IR 1 5 142 ? 7 285 ? 61***.sup.# 83.9 A-182/IR 1 20 142 ? 7 271 ? 107***.sup.# 85.5 A-203/IR 1 5 142 ? 10 .sup.396 ? 121*** 71.4 A-183/IR 1 5 142 ? 7 269 ? 89***.sup.# 85.7 A-191/IR 1 10 142 ? 8 347 ? 64***.sup. 76.9 A-192/IR 1 20 142 ? 6 323 ? 114***.sup.# 79.6 AZD1390/IR 1 10 141 ? 10 294 ? 52***.sup.# 82.8 Compared with vehicle control, ***P < 0.001; compared with vehicle control/IR, .sup.#P < 0.05.

[1078] The results of efficacy test of growth inhibition of LN-18 subcutaneous xenograft tumor show that the compounds of the present disclosure significantly inhibit the growth in tumor volume, compared with the vehicle control group.