NOVEL AMINOPYRIMIDINE EGFR INHIBITOR

Abstract

The present invention provides a novel aminopyrimidine compound as a fourth-generation EGFR (T790M/C797S mutation) selective inhibitor, a pharmaceutical composition comprising the compound, an intermediate useful for preparing the compound, and a method for treating a cell proliferative disease, such as a cancer, by using the compound of the present invention.

##STR00001##

Claims

1. A compound represented by formula (I), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof or an isotope-labeled derivative thereof, ##STR01023## wherein, R.sub.1 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, 3-6-membered heterocycloalkyl, C.sub.3-6 cycloalkyloxy, 3-6-membered heterocycloalkyloxy, and C.sub.2-6 alkenyloxy; M is selected from N or CR.sub.10; R.sub.10 and R.sub.1 may form a 5-8-membered heterocycloalkyl or a 5-7-membered heteroaryl; the 5-8-membered heterocycloalkyl and the 5-7-membered heteroaryl are optionally substituted by one or more R.sub.11 groups; R.sub.2 is selected from H, halogen, —CN, —OH, —NH.sub.2, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, carbonylamino, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 heterocycloalkenyl, phenyl and ##STR01024## wherein, the —OH, —NH.sub.2, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, carbonylamino, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 heterocycloalkenyl, phenyl and ##STR01025## are optionally substituted by one or more R.sub.12 groups; R.sub.3 is selected from —CN, sulfoximino, -L.sub.1-C.sub.6-10 aryl, -L.sub.1-5-12-membered heteroaryl, -L.sub.1-C.sub.3-6 cycloalkenyl and ##STR01026## wherein, the —CN, sulfoximino, -L.sub.1-C.sub.6-10 aryl, -L.sub.1-5-12-membered heteroaryl, -L.sub.1-C.sub.3-6 cycloalkenyl and ##STR01027## are optionally substituted by one or more R.sub.13 groups; L.sub.1 is independently selected from a linking bond, C.sub.1-4 alkyl and C.sub.1-4 heteroalkyl, wherein the C.sub.1-4 alkyl and C.sub.1-4 heteroalkyl are optionally substituted by one or more groups selected from —OH, —NH.sub.2 and halogen; R.sub.4 and R.sub.5 are each independently selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl; or, R.sub.4 and R.sub.5 are cyclized to 4-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 4-6-membered aryl or 4-6-membered heteroaryl; R.sub.6 is selected from amino, amido, aminocarbonyl, sulfonyl, thiophosphonyl, phosphonyl, phosphonoamino, sulfonylamino, aminosulfonyl and sulfoximino, wherein the amino, amido, aminocarbonyl, sulfonyl, thiophosphonyl, phosphonyl, phosphonoamino, sulfonylamino, aminosulfonyl and sulfoximino are optionally substituted by one or more R.sub.14 groups; R.sub.7, R.sub.8 and R.sub.9 are each independently selected from H, halogen, —CN, —OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, 3-6-membered heterocycloalkyl and 5-7-membered heteroaryl; or, R.sub.7 and R.sub.8 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl or 5-7-membered heteroaryl; or, R.sub.8 and R.sub.9 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl or 5-7-membered heteroaryl; R.sub.10 is selected from H, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl and C.sub.1-6 haloalkoxy; R.sub.11 is selected from H, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, —C.sub.0-4 alkyl-NR.sub.aR.sub.b, —C.sub.1-4 alkyl-O—C.sub.1-4 alkyl, —C.sub.1-4 alkyl-OH, —O—C.sub.1-4 alkyl, —C.sub.0-4 alkyl-C.sub.3-6 cycloalkyl and —C.sub.0-4 alkyl-3-6-member heterocycloalkyl; R.sub.12 is selected from H, halogen, —CN, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, 3-14-membered heterocycloalkyl, hydroxy-C.sub.1-6 alkyl-, C.sub.3-8 cycloalkylalkyl-, C.sub.3-8 cycloalkyloxy-, C.sub.3-8 heterocycloalkylalkyl-, C.sub.3-8 heterocycloalkyloxy-, C.sub.3-8 cycloalkyl-C.sub.1-6 alkoxy-, C.sub.3-8 heterocycloalkyl-C.sub.1-6 alkoxy-, C.sub.1-6 alkylsulfonyl, C.sub.3-6 cycloalkylsulfonyl, NR.sub.aR.sub.bCO—, C.sub.1-6 alkylcarbonyl, C.sub.3-8 cycloalkylcarbonyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl-, C.sub.3-6 cycloalkenyl, 5-12-membered heteroaryl, C.sub.6-10 aryl, NR.sub.aR.sub.bS(O).sub.2—, —(CH.sub.2).sub.mNR.sub.aR.sub.b, —(CH.sub.2).sub.mO(CH.sub.2).sub.nCH.sub.3 and —O(CH.sub.2).sub.mNR.sub.aR.sub.b; wherein the R.sub.a and R.sub.b are independently H, C.sub.1-6 alkyl or C.sub.1-6 alkoxy, or the R.sub.a and R.sub.b together form a C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; wherein the m and n are independently optionally 0, 1, 2 or 3, and the C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl are optionally substituted by a group selected from halogen, —OH, —NH.sub.2, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl and —CO.sub.0-4 alkyl-O—C.sub.1-4 alkyl; R.sub.13 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl, 3-8-membered heterocycloalkyl, C.sub.3-6 cycloalkylsulfonyl, 5-6-membered heteroaryl and phenyl; R.sub.14 is selected from H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl.

2. The compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 1, wherein, the compound is scheme I or scheme II: scheme I: R.sub.1 is selected from H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl and C.sub.1-4 haloalkoxy; M is selected from N or CR.sub.10; R.sub.10 and R.sub.1 may form a 5-8-membered heterocycloalkyl or a 5-7-membered heteroaryl; the 5-8-membered heterocycloalkyl and the 5-7-membered heteroaryl are optionally substituted by one or more R.sub.11 groups; R.sub.2 is selected from H, halogen, —NH.sub.2, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 heterocycloalkenyl and ##STR01028## wherein, the —NH.sub.2, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 heterocycloalkenyl and ##STR01029## are optionally substituted by one or more R.sub.12 groups; R.sub.3 is selected from —CN, 5-12-membered heteroaryl and ##STR01030## wherein, the —CN, 5-12-membered heteroaryl and ##STR01031## are optionally substituted by one or more R.sub.13 groups; R.sub.4 and R.sub.5 are each independently selected from H, halogen, —CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.3-6 cycloalkyl; or, R.sub.4 and R.sub.5 are cyclized to 4-6-membered aryl or 4-6-membered heteroaryl; R.sub.6 is selected from amino, amido, sulfonyl, thiophosphonyl, phosphonyl, sulfonylamino and aminosulfonyl, wherein the amino, amido, sulfonyl, thiophosphonyl, phosphonyl, sulfonylamino and aminosulfonyl are optionally substituted by one or more R.sub.14 groups; R.sub.7, R.sub.8 and R.sub.9 are each independently selected from H and C.sub.1-4 alkyl; or, R.sub.7 and R.sub.8 are cyclized to C.sub.4-6 cycloalkyl or 5-7-membered heteroaryl; or, R.sub.8 and R.sub.9 are cyclized to C.sub.4-6 cycloalkyl or 5-7-membered heteroaryl; R.sub.10 is selected from H, halogen and C.sub.1-4 alkyl; R.sub.11 is selected from H, C.sub.1-4 alkyl, —C.sub.1-4 alkyl-NR.sub.aR.sub.b and 3-6-membered heterocycloalkyl; R.sub.12 is selected from H, halogen, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C.sub.1-6 alkyl, 6-14-membered spiro heterocyclyl, —C.sub.1-4 alkyl-O—C.sub.1-4 alkyl, —O—C.sub.1-4 alkyl, —C.sub.1-4 alkyl-C.sub.3-6 cycloalkyl, —O—C.sub.0-4 alkyl-C.sub.3-6 cycloalkyl, —C.sub.1-4 alkyl-3-6-membered heterocycloalkyl, —O—C.sub.0-4 alkyl-3-6-membered heterocycloalkyl, —(CH.sub.2).sub.mNR.sub.aR.sub.b, —O(CH.sub.2).sub.mNR.sub.aR.sub.b, C.sub.1-6 alkylsulfonyl, C.sub.3-6 cycloalkylsulfonyl, NR.sub.aR.sub.bCO—, C.sub.1-6 alkylcarbonyl and C.sub.3-6 cycloalkylcarbonyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by R.sub.ab, and the R.sub.ab is selected from H, halogen, —OH, —NH.sub.2, —CN, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl and —C.sub.0-4 alkyl-O—C.sub.1-4 alkyl; R.sub.a and R.sub.b are independently H or C.sub.1-4 alkyl; m is optionally 0, 1, 2 or 3; R.sub.13 is selected from H, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, hydroxy-C.sub.1-6 alkyl and C.sub.3-6 cycloalkylsulfonyl; R.sub.14 is selected from H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy and C.sub.3-8 cycloalkyl; scheme II: R.sub.1 is selected from H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl and C.sub.1-4 haloalkoxy; M is selected from N or CR.sub.10; R.sub.10 and R.sub.1 may form a 5-8-membered heterocycloalkyl, and the 5-8-membered heterocycloalkyl is optionally substituted by one or more R.sub.11 groups; R.sub.2 is selected from H, halogen, —NH.sub.2, phosphonyl, sulfonyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl and C.sub.3-6 heterocycloalkenyl; wherein, the —NH.sub.2, phosphonyl, sulfonyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl and C.sub.3-6 heterocycloalkenyl are optionally substituted by one or more R.sub.12 groups; R.sub.3 is selected from 5-12-membered heteroaryl optionally substituted by one or more R.sub.13 groups; R.sub.4 and R.sub.5 are each independently selected from H, halogen, —CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.3-6 cycloalkyl; or, R.sub.4 and R.sub.5 are cyclized to aryl or 4-6-membered heteroaryl; R.sub.6 is selected from amido, sulfonyl, thiophosphonyl, phosphonyl, sulfonylamino and aminosulfonyl, wherein the amino, amido, sulfonyl, thiophosphonyl, phosphonyl, sulfonylamino and aminosulfonyl are optionally substituted by one or more R.sub.14 groups; R.sub.7, R.sub.8 and R.sub.9 are each independently selected from H and C.sub.1-4 alkyl; or, R.sub.7 and R.sub.8 are cyclized to C.sub.4-6 cycloalkyl or 5-7-membered heteroaryl; or, R.sub.8 and R.sub.9 are cyclized to C.sub.4-6 cycloalkyl or 5-7-membered heteroaryl; R.sub.10 is selected from H, halogen and C.sub.1-4 alkyl; R.sub.11 is selected from H, C.sub.1-4 alkyl, —C.sub.1-4 alkyl-NR.sub.aR.sub.b and 3-6-membered heterocycloalkyl; R.sub.12 is selected from H, halogen, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C.sub.1-6 alkyl, 6-14-membered spino heterocyclyl, —C.sub.1-4 alkyl-O—C.sub.1-4 alkyl, —O—C.sub.1-4 alkyl, —C.sub.1-4 alkyl-C.sub.3-6 cycloalkyl, —O—C.sub.0-4 alkyl-C.sub.3-6 cycloalkyl, —C.sub.1-4 alkyl-3-6-membered heterocycloalkyl, —O—C.sub.0-4 alkyl-3-6-membered heterocycloalkyl, —(CH.sub.2).sub.mNR.sub.aR.sub.b, —O(CH.sub.2).sub.mNR.sub.aR.sub.b, C.sub.1-6 alkylsulfonyl, C.sub.3-6 cycloalkylsulfonyl, NR.sub.aR.sub.bCO—, C.sub.1-6 alkylcarbonyl and C.sub.3-6 cycloalkylcarbonyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by R.sub.ab, and the R.sub.ab is selected from H, halogen, —OH, —NH.sub.2, —CN, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl and —C.sub.0-4 alkyl-O—C.sub.1-4 alkyl; R.sub.a and R.sub.b are H or C.sub.1-4 alkyl; R.sub.a and R.sub.b are H or C.sub.1-4 alkyl; m is optionally 0, 1, 2 or 3; R.sub.13 is selected from H, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl and C.sub.3-6 cycloalkylsulfonyl; R.sub.14 is selected from H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy and C.sub.3-8 cycloalkyl.

3. (canceled)

4. The compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 1, wherein, M is selected from CR.sub.10, and R.sub.10 is defined in claim 1; or, R.sub.10 is optionally and independently selected from H, fluorine, and methyl; or, R.sub.11 is independently selected from H, methyl, —CH.sub.2CH.sub.2N(CH.sub.3).sub.2 and ##STR01032## or, R.sub.12 is selected from H, F, —OH, —NH.sub.2, C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, C.sub.1-4 alkoxy, —O—C.sub.1-4 alkyl-C.sub.3-6 cycloalkyl, —O—C.sub.1-4 alkyl-NR.sub.aR.sub.b, —C.sub.1-4 alkyl-O—C.sub.0-4 alkyl, ##STR01033## or, R.sub.13 is selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, trichloromethyl, cyclopropyl and ##STR01034## or, R.sub.14 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy and cyclopropyl; or, R.sub.1 is selected from H, halogen, —CN, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, C.sub.1-3 haloalkoxy and 5-7-membered heteroaryl; or, R.sub.2 is selected from H, halogen, —CN, —OH, —NH.sub.2, phosphonyl, sulfonyl, C.sub.3-7 cycloalkyl, 3-7-membered heterocycloalkyl, C.sub.6-14 spiro cyclyl, C.sub.6-14 fused cyclyl, C.sub.6-14 bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl, 6-14-membered fused heterocyclyl and ##STR01035## wherein, the —NH.sub.2, phosphonyl, sulfonyl, C.sub.3-7 cycloalkyl, 3-7-membered heterocycloalkyl, C.sub.6-14 spiro cyclyl, C.sub.6-14 fused cyclyl, C.sub.6-14 bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl, 6-14-membered fused heterocyclyl and ##STR01036## are optionally substituted by one or more R.sub.12 groups; or, R.sub.3 is selected from —CN, phenyl, 5-6-membered heteroaryl and ##STR01037## and the phenyl, 5-6-membered heteroaryl and ##STR01038## are optionally substituted by one or more R.sub.13 groups; or, R.sub.4 and R.sub.5 are each independently selected from H, F, Cl, Br, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl, or, R.sub.4 and R.sub.5 form C.sub.5-6 aryl or 5-6-membered heteroaryl; or, R.sub.6 is selected from ##STR01039## or, R.sub.7, R.sub.8 and R.sub.9 are all H, or R.sub.7 and R.sub.8 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl or 5-7-membered heteroaryl, or R.sub.8 and R.sub.9 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl or 5-7-membered heteroaryl.

5-15. (canceled)

16. The compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 1, wherein, which is selected from, ##STR01040## wherein, X.sub.1 is independently selected from CR.sub.c and N; X.sub.2 is independently selected from —CR.sub.cR.sub.d—, —NR.sub.c— and —O—; Z.sub.1 and Z.sub.2 are each independently selected from —(CR.sub.eR.sub.f).sub.m(CR.sub.eR.sub.f).sub.n—; the R.sub.c, R.sub.d, R.sub.e, and R.sub.f are each independently selected from H, halogen, —CN, —OH, —NR.sub.aR.sub.b, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, phenyl, —(CH.sub.2).sub.mNR.sub.aR.sub.b, hydroxy-C.sub.1-6 alkyl-, —O(CH.sub.2).sub.mNR.sub.aR.sub.b, C.sub.3-8 cycloalkylalkyl-, C.sub.3-8 heterocycloalkylalkyl-, C.sub.3-8 cycloalkyl-C.sub.1-6 alkoxy-, C.sub.3-8 heterocycloalkyl-C.sub.1-6 alkoxy-, C.sub.1-6 alkylcarbonyl-, C.sub.3-8 cycloalkylcarbonyl-, NR.sub.aR.sub.bCO—, C.sub.1-6 alkylcarbonylsulfonyl-, C.sub.3-8 cycloalkylsulfonyl-, C.sub.1-6 alkyl-O—C.sub.1-6 alkyl-, 6-14-membered spiro heterocyclyl, wherein the R.sub.a, R.sub.b, m and n are defined in claim 1; or, R.sub.c and R.sub.d together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; or, R.sub.e and R.sub.f together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; or, R.sub.c and R.sub.e, or R.sub.c and R.sub.f, or R.sub.d and R.sub.e, or R.sub.d and R.sub.f together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; wherein, a ring formed by X.sub.1, X.sub.2, Z.sub.1 and Z.sub.2 and a ring further formed by substituent groups R.sub.c, R.sub.d, R.sub.e and R.sub.f thereof are optionally substituted by one or more R.sub.12 groups; R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.12 and M are defined in claim 1.

17. The compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 16, wherein, which is selected from, ##STR01041## wherein, the ring formed by X.sub.1, X.sub.2, Z.sub.1 and Z.sub.2 and the ring further formed by substituent groups thereof are optionally substituted by one or more R.sub.12 groups; X.sub.1, X.sub.2, Z.sub.1, Z.sub.2, R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.9, R.sub.12 and M are defined in claim 16; R.sub.13 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl, 3-8-membered heterocycloalkyl, C.sub.3-6 cycloalkylsulfonyl, 5-6-membered heteroaryl and phenyl; preferably, the compound represented by formula (I) is selected from, ##STR01042## wherein, ring A is selected from C.sub.5-7 cycloalkyl and 5-7-membered heterocycloalkyl; a monocyclic ring, a bicyclic ring, a spiro ring, a fused ring formed by X.sub.1 and X.sub.2 and ring A are optionally substituted by one or more R.sub.12 groups; m and n are independently optionally 0, 1, 2 or 3; more preferably, the compound represented by formula (I) is selected from, ##STR01043## ##STR01044## ##STR01045## further more preferably, the compound represented by formula (I) is selected from, ##STR01046## ##STR01047## ##STR01048## for example, the compound represented by formula (I) is selected from, ##STR01049## for another example, the compound represented by formula (I) is selected from, ##STR01050##

18-22. (canceled)

23. The compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 1, wherein, wherein, R.sub.1 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, 3-6-membered heterocycloalkyl, C.sub.3-6 cycloalkyloxy, 3-6-membered heterocycloalkyloxy and C.sub.2-6 alkenyloxy; M is selected from N or CR.sub.10; R.sub.10 and R.sub.1 may form a 5-8-membered heterocycloalkyl, and the 5-8-membered heterocycloalkyl is optionally substituted by one or more R.sub.11 groups; R.sub.2 is selected from H, halogen, —CN, —OH, —NH.sub.2, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 heterocycloalkenyl and phenyl; wherein, the —OH, —NH.sub.2, phosphonyl, sulfonyl, aminosulfonyl, aminocarbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 heterocycloalkenyl and phenyl are optionally substituted by one or more R.sub.12 groups; R.sub.3 is selected from C.sub.6-10 aryl, 5-12-membered heteroaryl and C.sub.3-6 cycloalkenyl, wherein the C.sub.6-10 aryl, 5-12-membered heteroaryl and C.sub.3-6 cycloalkenyl are optionally substituted by one or more R.sub.13 groups; R.sub.4 and R.sub.5 are each independently selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl; or, R.sub.4 and R.sub.5 are cyclized to 4-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 4-6-membered aryl or 4-6-membered heteroaryl; R.sub.6 is selected from amino, amido, sulfonyl, thiophosphonyl, phosphonyl, sulfonylamino and aminosulfonyl, wherein the amino, amido, sulfonyl, phosphonyl, sulfonylamino and aminosulfonyl are optionally substituted by one or more R.sub.14 groups; R.sub.7, R.sub.8 and R.sub.9 are each independently selected from H, halogen, —CN, —OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, 3-6-membered heterocycloalkyl and 5-7-membered heteroaryl; or, R.sub.7 and R.sub.8 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl, or 5-7-membered heteroaryl; or, R.sub.8 and R.sub.9 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl, or 5-7-membered heteroaryl; R.sub.10 and R.sub.11 are each independently selected from H, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl and C.sub.1-6 haloalkoxy; R.sub.12 is selected from H, halogen, —CN, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C.sub.1-6 alkyl-, C.sub.3-8 cycloalkylalkyl-, C.sub.3-8 heterocycloalkylalkyl-, C.sub.3-8 cycloalkyl-C.sub.1-6 alkoxy-, C.sub.1-6 alkylsulfonyl, C.sub.3-6 cycloalkylsulfonyl, NR.sub.aR.sub.bCO—, C.sub.1-6 alkylcarbonyl, C.sub.3-8 cycloalkylcarbonyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl-, C.sub.3-6 cycloalkenyl, phenyl, NR.sub.aR.sub.bS(O).sub.2, —(CH.sub.2).sub.mNR.sub.aR.sub.b, —(CH.sub.2).sub.mO(CH.sub.2).sub.nCH.sub.3 and —O(CH.sub.2).sub.mNR.sub.aR.sub.b; wherein the R.sub.a and R.sub.b are H, C.sub.1-6 alkyl or C.sub.1-6 alkoxy, or R.sub.a and R.sub.b together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; wherein the m and n are independently optionally 0, 1, 2 or 3, and C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl are optionally substituted by halogen, —OH, —NH.sub.2, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 haloalkyl; R.sub.13 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl; R.sub.14 is selected from H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl.

24. The compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 23, wherein, R.sub.10 and R.sub.11 are each independently selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy and 2,2,2-trifluoroethoxy; or, R.sub.13 is selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, trichloromethyl and cyclopropyl; preferably, R.sub.13 is selected from H, fluorine, methyl, ethyl and difluoromethyl; or, R.sub.14 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy and cyclopropyl; or, R.sub.1 is selected from H, halogen, —CN, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl and C.sub.1-3 haloalkoxy; preferably, R.sub.1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy and 2,2,2-trifluoroethoxy; or, R.sub.2 is selected from H, halogen, —CN, —OH, —NH.sub.2, C.sub.3-7 cycloalkyl, 3-7-membered heterocycloalkyl, C.sub.6-14 Spiro cyclyl, C.sub.6-14 fused cyclyl, C.sub.6-14 bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl and 6-14-membered fused heterocyclyl; wherein, the —NH.sub.2, C.sub.3-7 cycloalkyl, 3-7-membered heterocycloalkyl, C.sub.6-14 spiro cyclyl, C.sub.6-14 fused cyclyl, C.sub.6-14 bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl and 6-14-membered fused heterocyclyl are optionally substituted by one or more R.sub.12 groups, and the R.sub.12 group is defined in claim 23; preferably, R.sub.2 is selected from H, halogen, —CN, —OH, —NH.sub.2, —NHR.sub.12, —NR.sub.12R.sub.12, ##STR01051## ##STR01052## wherein the R.sub.12, m and n are defined in claim 23; more preferably, R.sub.2 is selected from H, fluorine, chlorine, bromine, iodine, —NH.sub.2, ##STR01053## ##STR01054## ##STR01055## ##STR01056## ##STR01057## further more preferably, R.sub.2 is selected from ##STR01058## ##STR01059## ##STR01060## ##STR01061## ##STR01062## ##STR01063## ##STR01064## or, R.sub.3 is selected from phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl and cyclohexyl, and the phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally substituted by one or more R.sub.13 groups; preferably, R.sub.3 is selected from ##STR01065## more preferably, R.sub.3 is selected from ##STR01066## wherein the R.sub.13 is defined in claim 23; or, R.sub.4 and R.sub.5 are each independently selected from H, F, Cl, Br, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl; or, R.sub.6 is selected from ##STR01067## preferably, the R.sub.6 is selected from ##STR01068## or, R.sub.7 and R.sub.8 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl or 5-7-membered heteroaryl, or R.sub.8 and R.sub.9 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl or 5-7-membered heteroaryl; preferably, R.sub.7 and R.sub.8 or R.sub.8 and R.sub.9 are independently cyclized to cyclobutane, cyclopentane, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydropyran ring, thiophene ring, imidazole ring, pyrazole ring, pyrrole ring, oxazole ring, thiazole ring, isoxazole ring, piperazine ring, isothiazole ring, benzene ring, pyridine ring, piperidine ring, pyrimidine ring, pyridazine ring or pyrazine ring; more preferably, R.sub.7 and R.sub.8 or R.sub.8 and R.sub.9 are independently cyclized to cyclobutane, pyridine ring or pyrazine ring.

25-32. (canceled)

33. The compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 23, wherein, which is selected from, ##STR01069## wherein, X.sub.1 is independently selected from CR.sub.c and N; X.sub.2 is independently selected from —CR.sub.cR.sub.d—, —NR.sub.c— and —O—; Z.sub.1 and Z.sub.2 are each independently selected from —(CR.sub.eR.sub.f).sub.m(CR.sub.eR.sub.f).sub.n—; the R.sub.c, R.sub.d, R.sub.e, and R.sub.f are each independently selected from H, halogen, —CN, —OH, —NR.sub.aR.sub.b, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, phenyl, —(CH.sub.2).sub.mNR.sub.aR.sub.b, hydroxy-C.sub.1-6 alkyl-O(CH.sub.2).sub.mNR.sub.aR.sub.b, C.sub.3-8 cycloalkylalkyl-, C.sub.3-8 heterocycloalkylalkyl-, C.sub.3-8 cycloalkyl-C.sub.1-6 alkoxy-, C.sub.3-8 heterocycloalkyl-C.sub.1-6 alkoxy-, C.sub.1-6 alkylcarbonyl-, C.sub.3-8 cycloalkylcarbonyl-, NRaR.sub.bCO—, C.sub.1-6 alkylcarbonylsulfonyl- and C.sub.3-8 cycloalkylsulfonyl-, wherein the R.sub.a, R.sub.b, m and n are defined in claim 23; or, R.sub.c and R.sub.d together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; or, R.sub.e and R.sub.f together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; or, R.sub.c and R.sub.e, or R.sub.c and R.sub.f, or R.sub.d and R.sub.e, or R.sub.d and R.sub.f together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; wherein, a ring formed by X.sub.1, X.sub.2, Z.sub.1 and Z.sub.2 and a ring further formed by substituent groups R.sub.c, R.sub.d, R.sub.e and R.sub.f thereof are optionally substituted by one or more R.sub.12 groups; R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.12 and M are defined in claim 23; preferably, the compound represented by formula (I) is selected from, ##STR01070## wherein, the ring formed by X.sub.1, X.sub.2, Z.sub.1 and Z.sub.2 and the ring further formed by substituent groups thereof are optionally substituted by one or more R.sub.12 groups; R.sub.13 is defined in claim 23; more preferably, the compound represented by formula (I) is selected from, ##STR01071## wherein, ring A is selected from C.sub.5-7 cycloalkyl and 5-7-membered heterocycloalkyl; a monocyclic ring, a bicyclic ring, a spiro ring, a fused ring formed by X.sub.1 and X.sub.2 and ring A are optionally substituted by one or more R.sub.12 groups; m and n are independently optionally 0, 1, 2 or 3; further more preferably, the compound represented by formula (I) is selected from, ##STR01072## for example, the compound represented by formula (I) is selected from, ##STR01073##

34-37. (canceled)

38. A compound represented by formula (I-A), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof or an isotope-labeled derivative thereof, ##STR01074## wherein, R.sub.1 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, 3-6-membered heterocycloalkyl, C.sub.3-6 cycloalkyloxy, 3-6-membered heterocycloalkyloxy and C.sub.2-6 alkenyloxy; M is selected from N or CR.sub.10; R.sub.10 and R.sub.1 may form a 5-8-membered heterocycloalkyl, and the 5-8-membered heterocycloalkyl is optionally substituted by one or more R.sub.11 groups; R.sub.2 is selected from H, halogen, —CN, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 heterocycloalkenyl and phenyl; wherein, the —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 heterocycloalkenyl and phenyl are optionally substituted by one or more R.sub.12 groups; R.sub.3 is selected from C.sub.6-10 aryl, 5-12-membered heteroaryl and C.sub.3-6 cycloalkenyl, wherein the C.sub.6-10 aryl, 5-12-membered heteroaryl and C.sub.3-6 cycloalkenyl are optionally substituted by one or more R.sub.13 groups; R.sub.4 and R.sub.5 are each independently selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl; R.sub.6 is selected from amino, amido, sulfonyl, phosphonyl, sulfonylamino and aminosulfonyl, wherein the amino, amido, sulfonyl, phosphonyl, sulfonylamino and aminosulfonyl are optionally substituted by one or more R.sub.14 groups; R.sub.7, R.sub.8 and R.sub.9 are each independently selected from H, halogen, —CN, —OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, 3-6-membered heterocycloalkyl and 5-7-membered heteroaryl; or, R.sub.7 and R.sub.8 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl, or 5-7-membered heteroaryl; or, R.sub.8 and R.sub.9 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl, or 5-7-membered heteroaryl; R.sub.10, R.sub.11, R.sub.12, R.sub.13 and R.sub.14 are each independently selected from H, halogen, —CN, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C.sub.1-6 alkyl, C.sub.3-8 cycloalkylalkyl, C.sub.3-8 cycloalkyl-C.sub.1-6 alkoxy, C.sub.1-6 alkylsulfonyl, C.sub.3-6 cycloalkylsulfonyl, aminocarbonyl, C.sub.3-8 cycloalkylcarbonyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.3-6 cycloalkenyl, phenyl, —(CH.sub.2).sub.mNR.sub.aR.sub.b and —(CH.sub.2).sub.mO(CH.sub.2).sub.nCH.sub.3; wherein R.sub.a and R.sub.b are H, C.sub.1-6 alkyl or C.sub.1-6 alkoxy, or R.sub.a and R.sub.b together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; wherein m and n are independently optionally 0, 1, 2 or 3, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl are optionally substituted by halogen, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.1-6 haloalkyl.

39. The compound represented by formula (I-A), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 38, wherein, R.sub.1 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-6 cycloalkyl, 3-6-membered heterocycloalkyl, C.sub.3-6 cycloalkoxy, 3-6-membered heterocycloalkyloxy and C.sub.2-6 alkenyloxy; M is selected from N or CR.sub.10; R.sub.10 and R.sub.1 may form a 5-8-membered heterocycloalkyl, and the 5-8-membered heterocycloalkyl is optionally substituted by one or more R.sub.11 groups; R.sub.2 is selected from H, halogen, —CN, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 heterocycloalkenyl and phenyl; wherein, the —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 heterocycloalkenyl and phenyl are optionally substituted by one or more R.sub.12 groups; R.sub.3 is selected from C.sub.6-10 aryl, 5-12-membered heteroaryl and C.sub.3-6 cycloalkenyl, wherein the C.sub.6-10 aryl, 5-12-membered heteroaryl and C.sub.3-6 cycloalkenyl are optionally substituted by one or more R.sub.13 groups; R.sub.4 and R.sub.5 are each independently selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl; R.sub.6 is selected from amino, amido, sulfonyl, phosphonyl, sulfonylamino and aminosulfonyl, wherein the amino, amido, sulfonyl, phosphonyl, sulfonylamino and aminosulfonyl are optionally substituted by one or more R.sub.14 groups; R.sub.7, R.sub.8 and R.sub.9 are each independently selected from H, halogen, —CN, —OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, 3-6-membered heterocycloalkyl and 5-7-membered heteroaryl; or, R.sub.7 and R.sub.8 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl, or 5-7-membered heteroaryl; or, R.sub.8 and R.sub.9 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl, or 5-7-membered heteroaryl; R.sub.10 and R.sub.11 are each independently selected from H, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl and C.sub.1-6 haloalkoxy; R.sub.12 is selected from H, halogen, —CN, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C.sub.1-6 alkyl, C.sub.3-8 cycloalkylalkyl, C.sub.3-8 cycloalkyl-C.sub.1-6 alkoxy, C.sub.1-6 alkylsulfonyl, C.sub.3-6 cycloalkylsulfonyl, aminocarbonyl, C.sub.3-8 cycloalkylcarbonyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.3-6 cycloalkenyl, phenyl, —(CH.sub.2).sub.mNR.sub.aR.sub.b and —(CH.sub.2).sub.mO(CH.sub.2).sub.nCH.sub.3; wherein R.sub.a and R.sub.b are H, C.sub.1-6 alkyl or C.sub.1-6 alkoxy, or R.sub.a and R.sub.b together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; wherein m and n are independently optionally 0, 1, 2 or 3, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl are optionally substituted by halogen, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.1-6 haloalkyl; R.sub.13 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl; R.sub.14 is selected from H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl.

40. The compound represented by formula (I-A), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 38, wherein, R.sub.1 is selected from H, halogen, —CN, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl and C.sub.1-3 haloalkoxy; preferably, R.sub.1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy and 2,2,2-trifluoroethoxy; or, R.sub.2 is selected from H, halogen, —NH.sub.2, C.sub.3-7 cycloalkyl, 3-7-membered heterocycloalkyl, C.sub.6-14 spiro cyclyl, C.sub.6-14 fused cyclyl, C.sub.6-14 bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl and 6-14-membered fused heterocyclyl; wherein, the —NH.sub.2, C.sub.3-7 cycloalkyl, 3-7-membered heterocycloalkyl, C.sub.6-14 spiro cyclyl, C.sub.6-14 fused cyclyl, C.sub.6-14 bridged cyclyl, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl and 6-14-membered fused heterocyclyl are optionally substituted by one or more R.sub.12 groups, and the R.sub.12 group is defined in claim 38; preferably, R.sub.2 is selected from H, halogen, —CN, —OH, —NH.sub.2, —NHR.sub.12, —NR.sub.12R.sub.12, ##STR01075## wherein the R.sub.12, m and n are defined in claim 38; more preferably, R.sub.2 is selected from H, fluorine, chlorine, bromine, iodine, —NH.sub.2, ##STR01076## ##STR01077## ##STR01078## further more preferably, R.sub.2 is selected from ##STR01079## ##STR01080## or, R.sub.3 is selected from phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl and cyclohexyl, and the phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally substituted by one or more R.sub.13 groups; preferably, R.sub.3 is selected from ##STR01081## more preferably, R.sub.3 is selected from ##STR01082## wherein the R.sub.13 is defined in claim 38; or, R.sub.4 and R.sub.5 are each independently selected from H, F, Cl, Br, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl; or, R.sub.6 is selected from ##STR01083## preferably, the R.sub.6 is selected from ##STR01084## or, R.sub.7 and R.sub.8 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl or 5-7-membered heteroaryl, or R.sub.8 and R.sub.9 are cyclized to C.sub.4-6 cycloalkyl, 4-6-membered heterocycloalkyl, C.sub.5-6 aryl or 5-7-membered heteroaryl; preferably, R.sub.7 and R.sub.8 or R.sub.8 and R.sub.9 are independently cyclized to cyclobutane, cyclopentane, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydropyran ring, thiophene ring, imidazole ring, pyrazole ring, pyrrole ring, oxazole ring, thiazole ring, isoxazole ring, piperazine ring, isothiazole ring, benzene ring, pyridine ring, piperidine ring, pyrimidine ring, pyridazine ring or pyrazine ring; more preferably, R.sub.7 and R.sub.8 or R.sub.8 and R.sub.9 are independently cyclized to cyclobutane, pyridine ring or pyrazine ring.

41-45. (canceled)

46. The compound represented by formula (I-A), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 38, wherein, which is selected from, ##STR01085## wherein, X.sub.1 is independently selected from CR.sub.c and N; X.sub.2 is independently selected from —CR.sub.cR.sub.d—, —NR.sub.c— and —O—; Z.sub.1 and Z.sub.2 are each independently selected from —(CR.sub.eR.sub.f).sub.m(CR.sub.eR.sub.f).sub.n—; the R.sub.c, R.sub.d, R.sub.e, and R.sub.f are each independently selected from H, halogen, —CN, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, phenyl, —(CH.sub.2).sub.mNR.sub.aR.sub.b and —(CH.sub.2).sub.mO(CH.sub.2).sub.nCH.sub.3; wherein the R.sub.a, R.sub.b, m and n are defined in claim 38; or, R.sub.c and R.sub.d together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; or, R.sub.e and R.sub.f together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; or, R.sub.c and R.sub.e, or R.sub.c and R.sub.f, or R.sub.d and R.sub.e, or R.sub.d and R.sub.f together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; wherein, a ring formed by X.sub.1, X.sub.2, Z.sub.1 and Z.sub.2 and a ring further formed by substituent groups R.sub.c, R.sub.d, R.sub.e and R.sub.f thereof are optionally substituted by one or more R.sub.12 groups; R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.12 and M are defined in claim 38.

47. The compound represented by formula (I-A), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 46, wherein, which is selected from, ##STR01086## wherein, the ring formed by X.sub.1, X.sub.2, Z.sub.1 and Z.sub.2 and the ring further formed by substituent groups thereof are optionally substituted by one or more R.sub.12 groups; X.sub.1, X.sub.2, Z.sub.1, Z.sub.2, R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.9, R.sub.12 and M are defined in claim 46; R.sub.13 is each independently selected from H, halogen, —CN, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, 3-8-membered heterocycloalkyl, hydroxy-C.sub.1-6 alkyl, C.sub.3-8 cycloalkylalkyl, C.sub.3-8 cycloalkyl-C.sub.1-6 alkoxy, C.sub.1-6 alkylsulfonyl, C.sub.3-6 cycloalkylsulfonyl, aminocarbonyl, C.sub.3-8 cycloalkylcarbonyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.3-6 cycloalkenyl, phenyl, —(CH.sub.2).sub.mNR.sub.aR.sub.b and —(CH.sub.2).sub.mO(CH.sub.2).sub.nCH.sub.3; wherein R.sub.a and R.sub.b are H, C.sub.1-6 alkyl or C.sub.1-6 alkoxy, or R.sub.a and R.sub.b together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; wherein m and n are independently optionally 0, 1, 2 or 3, C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl are optionally substituted by halogen, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.1-6 haloalkyl; preferably, the compound represented by formula (I-A) is selected from, ##STR01087## wherein, ring A is selected from C.sub.5-7 cycloalkyl and 5-7-membered heterocycloalkyl; a monocyclic ring, a bicyclic ring, a spiro ring, a fused ring formed by X.sub.1 and X.sub.2 and ring A are optionally substituted by one or more R.sub.12 groups; m and n are independently optionally 0, 1, 2 or 3; more preferably, the compound represented by formula (I-A) is selected from, ##STR01088## ##STR01089##

48-49. (canceled)

50. A compound, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof or an isotope-labeled derivative thereof, which is selected from, ##STR01090## ##STR01091## ##STR01092## ##STR01093## ##STR01094## ##STR01095## ##STR01096## ##STR01097## ##STR01098## ##STR01099## ##STR01100## ##STR01101## ##STR01102## ##STR01103## ##STR01104## ##STR01105## ##STR01106## ##STR01107## ##STR01108## ##STR01109## ##STR01110## ##STR01111## ##STR01112## ##STR01113## ##STR01114## ##STR01115## ##STR01116## ##STR01117## ##STR01118## ##STR01119## ##STR01120## ##STR01121## ##STR01122## ##STR01123## ##STR01124## ##STR01125## ##STR01126## ##STR01127## ##STR01128## ##STR01129## ##STR01130## ##STR01131## ##STR01132## ##STR01133## ##STR01134## ##STR01135## ##STR01136## ##STR01137## ##STR01138## ##STR01139## ##STR01140## ##STR01141## ##STR01142## ##STR01143## ##STR01144## ##STR01145## ##STR01146## ##STR01147## ##STR01148## ##STR01149## ##STR01150## ##STR01151## ##STR01152## ##STR01153## ##STR01154## ##STR01155## ##STR01156## ##STR01157## ##STR01158##

51. A pharmaceutical composition comprising a therapeutically effective amount of a substance A, and a pharmaceutically acceptable carrier, a diluent and an excipient; the substance A is the compound represented by formula (I) or the pharmaceutically acceptable salt as claimed in claim 1.

52. (canceled)

53. A method for treating cancer, comprising administering to a patient a therapeutically effective amount of a substance A; the substance A is the compound represented by formula (I) or the pharmaceutically acceptable salt as claimed in claim 1; preferably, the cancer comprises lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, acute myeloid leukemia, cholangiocarcinoma, renal carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, mesothelioma, multiple myeloma and melanoma; more preferably, the cancer is lung cancer.

54. A compound represented by formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ##STR01159## wherein, R.sub.1, R.sub.2, R.sub.3 and M are defined in claim 1 preferably, the compound represented by formula (V) is selected from, ##STR01160## R.sub.13 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.3-8 cycloalkyl, 3-8-membered heterocycloalkyl, C.sub.3-6 cycloalkylsulfonyl, 5-6-membered heteroaryl and phenyl; m and n are independently optionally 0, 1, 2 or 3; ring A is selected from C.sub.5-7 cycloalkyl and 5-7-membered heterocycloalkyl; a monocyclic ring, a bicyclic ring, a spiro ring, a fused ring formed by Xi and X2 and ring A are optionally substituted by one or more R.sub.12 groups; X.sub.1 is independently selected from CR.sub.c and N; X.sub.2 is independently selected from —CR.sub.cR.sub.d—, —NR.sub.c— and —O—: R.sub.c and R.sub.d are each independently selected from H, halogen, —CN, —OH, —NR.sub.aR.sub.b, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-14 cycloalkyl, 3-14-membered heterocycloalkyl, C.sub.3-6 cycloalkenyl, phenyl, —(CH.sub.2).sub.mNR.sub.aR.sub.b, hydroxy-C.sub.1-6 alkyl-, —O(CH.sub.2).sub.mNR.sub.aR.sub.b, C.sub.3-8 cycloalkylalkyl-, C.sub.3-8 heterocycloalkylalkyl-, C.sub.3-8 cycloalkyl-C.sub.1-6 alkoxy-, C.sub.3-8 heterocycloalkyl-C.sub.1-6 alkoxy-, C.sub.1-6 alkylcarbonyl-, C.sub.3-8 cycloalkylcarbonyl-, NR.sub.aR.sub.bCO—, C.sub.1-6 alkylcarbonylsulfonyl-, C.sub.3-8 cycloalkylsulfonyl-, C.sub.1-6 alkyl-O—C.sub.1-6 alkyl-, 6-14-membered spiro heterocyclyl, wherein the R.sub.a, R.sub.b, m and n are defined in claim 1; or, R.sub.c and R.sub.d together form C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; R.sub.12 is selected from H, halogen, —CN, —OH, —NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, 3-14-membered heterocycloalkyl, hydroxy-C.sub.1-6 alkyl-, C.sub.3-8 cycloalkylalkyl-, C.sub.3-8 cycloalkyloxy-, C.sub.3-8 heterocycloalkylalkyl-, C.sub.3-8 heterocycloalkyloxy-, C.sub.3-8 cycloalkyl-C.sub.1-6 alkoxy-, C.sub.3-8 heterocycloalkyl-C.sub.1-6 alkoxy-, C.sub.1-6 alkylsulfonyl, C.sub.3-6 cycloalkylsulfonyl, NR.sub.aR.sub.bCO—, C.sub.1-6 alkylcarbonyl, C.sub.3-8 cycloalkylcarbonyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl-, C.sub.3-6 cycloalkenyl, 5-12-membered heteroaryl, C.sub.6-10 aryl, NR.sub.aR.sub.bS(O).sub.2—, —(CH.sub.2).sub.mNR.sub.aR.sub.b, —(CH.sub.2).sub.mO(CH).sub.nCH.sub.3 and —O(CH.sub.2).sub.mNR.sub.aR.sub.b; wherein the R.sub.a and R.sub.b are independently H, C.sub.1-6 alkyl or C.sub.1-6 alkoxy, or the R.sub.a and R.sub.b together form a C.sub.3-8 cycloalkyl or 3-8-membered heterocycloalkyl; wherein the m and n are independently optionally 0, 1, 2 or 3, and the C.sub.3-8 cycloalkyl and 3-8-membered heterocycloalkyl are optionally substituted by a group selected from halogen, —OH, —NH.sub.2, —CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl and —C.sub.0-4 alkyl-O—C.sub.1-4 alkyl; more preferably, the compound represented by formula (V) is selected from, ##STR01161## further more preferably, the compound represented by formula (V) is selected from, ##STR01162##

55-57. (canceled)

58. Use of the compound represented by formula (V) in the manufacture of the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 1; the compound represented by formula (V) is selected form, ##STR01163## wherein, R.sub.1, R.sub.2, R.sub.3 and M are defined in claim 1.

59. The compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 4, wherein, R.sub.12 is selected from H, F, —OH, —NH.sub.2, methyl, ethyl, isopropyl, —CH.sub.2F, —CH.sub.2CH.sub.2F, —CH.sub.2CHF.sub.2, —CH.sub.2CF.sub.3, —CH.sub.2CH.sub.2CHF.sub.2, —CH.sub.2CH.sub.2CF.sub.3, —CH(CH.sub.3)CF.sub.3, —CH(CH.sub.3)CH.sub.2F, —C(CH.sub.3).sub.2CH.sub.2F, ##STR01164## —OCH.sub.3, —OCH(CH.sub.3)CH.sub.3, ##STR01165## ##STR01166## or, R.sub.13 is selected from H, fluorine, methyl, ethyl, difluoromethyl and ##STR01167## or, R.sub.14 is selected from methyl, isopropyl, cyclopropyl and ethoxy; or, R.sub.1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy and 2,2,2-trifluoroethoxy; or, R.sub.2 is selected from H, halogen, —CN, —OH, —NH.sub.2, —NHR.sub.12, —NR.sub.12R.sub.12, ##STR01168## ##STR01169## wherein the R.sub.12, m and n are defined in claim 4; or, R.sub.3 is selected from —CN, phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl and ##STR01170## and the phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl and ##STR01171## are optionally substituted by one or more R.sub.13 groups; or, R.sub.4 is selected from H, and R.sub.5 is selected from H, F, Cl, Br, CN, methyl, ethyl, trifluoromethyl and cyclopropyl; or, R.sub.6 is selected from ##STR01172## or, R.sub.7 and R.sub.8 or R.sub.8 and R.sub.9 are independently cyclized to cyclobutane, cyclopentane, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydropyran ring, thiophene ring, imidazole ring, pyrazole ring, pyrrole ring, oxazole ring, thiazole ring, isoxazole ring, piperazine ring, isothiazole ring, benzene ring, pyridine ring, piperidine ring, pyrimidine ring, pyridazine ring or pyrazine ring.

60. The compound represented by formula (I), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof as claimed in claim 59, wherein, R.sub.12 is selected from H, methyl, —CH.sub.2CH.sub.2F, —CH.sub.2CH.sub.2OCH.sub.3, —CH.sub.2CHF.sub.2, —CH.sub.2CF.sub.3, ##STR01173## —CH(CH.sub.3)CH.sub.2F, —CH.sub.2CH.sub.2F and ##STR01174## or, R.sub.13 is selected from H, fluorine, methyl, ethyl and difluoromethyl; preferably, R.sub.13 is selected from methyl; or, R.sub.14 is selected from methyl; or, R.sub.1 is selected from H, methyl, methoxy, ethoxy and 2,2,2-trifluoroethoxy; preferably, R.sub.1 is selected from methoxy; or, R.sub.2 is selected from H, fluorine, chlorine, bromine, iodine, —NH.sub.2, ##STR01175## ##STR01176## ##STR01177## ##STR01178## ##STR01179## ##STR01180## ##STR01181## or, R.sub.3 is selected from —CN, ##STR01182## preferably, R.sub.3 is selected from —CN, ##STR01183## more preferably, R.sub.3 is selected from ##STR01184## or, R.sub.4 is selected from H, and R.sub.5 is selected from Br; or, R.sub.6 is selected from ##STR01185## or, R.sub.7 and R.sub.8 or R.sub.8 and R.sub.9 are independently cyclized to cyclobutane, pyridine ring or pyrazine ring; preferably, R.sub.7 and R.sub.8 are independently cyclized to pyrazine ring, or R.sub.9 and R.sub.8 are independently cyclized to cyclobutane.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0367] FIG. 1 is a graph of tumor growth curves of each group of animals in an in vivo efficacy research experiment A.

[0368] FIG. 2 is a graph of weight curves of each group of animals in the in vivo efficacy research experiment A.

[0369] FIG. 3 is a graph of tumor growth curves of each group of animals in an in vivo efficacy research experiment B.

[0370] FIG. 4 is a graph of weight curves of each group of animals in the in vivo efficacy research experiment B.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0371] The present disclosure will be specifically described below by way of embodiments, but the scope of the present disclosure is not limited thereto. The present disclosure is described in detail herein, and specific embodiments thereof have also been disclosed. For those skilled in the art, it is obvious that various changes and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0372] The structures of the compounds of the present disclosure were determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shift (δ) was given in units of parts per million (ppm). NMR was determined using a Bruker AVANCE III HD 400 or a Bruker AVANCE III HD 300 NMR instrument with deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated methanol (CD.sub.3OD) and deuterated chloroform (CDCl.sub.3) as solvents and tetramethylsilane (TMS) as an internal standard.

[0373] Liquid chromatography-mass spectrometry LC-MS was determined using a SHIMADZU LCMS-2020 mass spectrometer (an ion source was electrospray ionization). HPLC was determined using SHIMADZU LC-20 AP.sub.XR and SPD-M20A high pressure liquid chromatography.

[0374] Thin layer chromatography silica gel plate used Yantai Xinnuo Chemical GF254 silica gel plate. The specification used for TLC was 0.15 mm-0.20 mm. Column chromatography generally used 200-300 mesh silica gel from Yucheng Chemical as a carrier.

[0375] The optical rotation value was detected using the an AutoPol-III instrument.

[0376] The starting materials in the embodiments of the present disclosure are known and commercially available, or can be synthesized by using or following methods known in the art.

Embodiment 1

[0377] Preparation of (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-dimethylphosphine oxide (compound 1)

[0378] Step 1:

##STR00584##

[0379] Compound 1-1 (59 g, 406.4 mmol) was dissolved in 600 mL of N,N-dimethylformamide, and N-iodosuccinimide (NIS for short, 100.6 g, 447.1 mmol) was added in batches at room temperature. The reaction system was stirred at room temperature for 1 hour. After LCMS monitoring showed that the raw materials disappeared, water (3000 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (1000 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (500 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography to obtain 50 g of compound 1-2.

[0380] MS (ESI) m/z: 272.0 [M+H].sup.+.

[0381] Step 2:

##STR00585##

[0382] Compound 1-2 (40 g, 147.6 mmol) was dissolved in N,N-dimethylformamide (400 mL) at room temperature under nitrogen protection. Then, dimethylphosphine oxide (17.3 g, 221.4 mmol), palladium acetate (3.3 g, 14.7 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.8 g, 22.1 mmol) and N,N-diisopropylethylamine (38.1 g, 295.1 mmol) were sequentially added to the reaction. The reaction solution was heated to 120° C. and continued to stir for 16 hours.

[0383] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethanol (100 mL×3 times); the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 30 g of compound 1-3.

[0384] MS (ESI) m/z: 222.0 [M+H].sup.+.

[0385] Step 3:

##STR00586##

[0386] Compound 1-3 (5 g, 22.6 mmol) was dissolved in N,N-dimethylformamide (100 mL) at room temperature under nitrogen protection. Then, sodium hydride (60%, 1.99 g, 49.8 mmol) was added to the reaction solution in batches at 0° C., and continued to stir at this temperature for 30 minutes; then, compound 1-4 (6.18 g, 27.1 mmol) was added to the above reaction solution at 0° C., and the reaction solution was heated to room temperature and continued to stir for 2 hours.

[0387] After LCMS monitoring showed that the raw material disappeared, a saturated ammonium chloride aqueous solution (600 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (200 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (500 mL×1 time), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography to obtain 3 g of compound 1-5.

[0388] MS (ESI) m/z: 411.9, 413.9 [M+H].sup.+.

[0389] Step 4:

##STR00587##

[0390] Compound 1-6 (5 g, 20.0 mmol) was dissolved in N,N-dimethylformamide (30 mL). The anhydrous potassium carbonate (5.5 g, 40.0 mmol) and morpholine (2.1 g, 24.0 mmol) were then added sequentially. The reaction solution was heated to 60° C. and continued to stir for 16 hours.

[0391] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (600 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (250 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (300 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography to obtain 5.4 g of compound 1-7.

[0392] MS (ESI) m/z: 317.3, 319.2 [M+H].sup.+.

[0393] Step 5:

##STR00588##

[0394] Compound 1-7 (8.5 g, 26.8 mmol) was dissolved in dioxane (88 mL) and water (18 mL) at room temperature under nitrogen protection. Then, 1-methyl-1H-4-pyrazoleboronic acid pinacol ester (7.25 g, 34.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (2.19 g, 2.7 mmol) and sodium carbonate (5.68 g, 53.6 mmol) were added thereto; the reaction solution was heated to 80° C. and continued to stir for 16 hours.

[0395] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and added with water (500 mL) to quench. The mixture was extracted with ethyl acetate (300 mL×3 times); the organic phases were combined, and the organic phases were washed with saturated brine (200 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 8 g of compound 1-8.

[0396] MS (ESI) m/z: 319.1 [M+H].sup.+.

[0397] Step 6:

##STR00589##

[0398] Compound 1-8 (8.5 g, 26.7 mmol) was dissolved in ethanol (80 mL); then, platinum dioxide (0.85 g) was added to the above solution; the reaction system was replaced with hydrogen for 3 times, and then stirred at room temperature for 16 hours.

[0399] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was filtered through diatomite, and the filter cake was washed with ethanol (50 mL×3 times). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 6.5 g of compound 1-9.

[0400] MS (ESI) m/z: 289.1 [M+H].sup.+.

[0401] Step 7:

##STR00590##

[0402] Compound 1-9 (2.0 g, 6.9 mmol) was dissolved in N-methylpyrrolidone (15 mL), and then compound 1-5 (2.86 g, 6.9 mmol) and methanesulfonic acid (2.0 g, 20.8 mmol) were added to the above solution sequentially. The reaction solution was heated to 95° C. and further stirred for 16 hours.

[0403] After LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature and directly purified by reversed-phase C18 column. Purification conditions were as follows: chromatographic column 120 g C18 reversed-phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate of 50 mL/min; gradient: acetonitrile increased from 10% to 80% within 30 minutes; detection wavelength of 254 nm. The product was collected and lyophilized under reduced pressure to obtain 2.5 g of compound 1.

[0404] MS (ESI) m/z: 664.2, 666.2 [M+H].sup.+.

[0405] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.85-8.82 (m, 3H), 8.44 (s, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 7.60-7.54 (m, 2H), 6.85 (s, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.77-3.75 (m, 4H), 2.87-2.85 (m, 4H), 2.04 (s, 3H), 2.00 (s, 3H).

Embodiment 2

Preparation of (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (compound 2)

[0406] Step 1:

##STR00591##

[0407] 5-Bromo-2,4-dichloropyrimidine (2 g, 8.8 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then anhydrous potassium carbonate (3.64 g, 26.3 mmol) and (2-aminophenyl)dimethylphosphine oxide (1.48 g, 8.8 mmol) were added sequentially. The reaction solution was heated to 60° C. and further stirred for 12 hours.

[0408] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (150 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (100 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 2.96 g of compound 2-3.

[0409] MS (ESI) m/z: 360.0, 362.0 [M+H].sup.+.

[0410] Step 2:

##STR00592##

[0411] 1-9 (100 mg, 0.35 mmol) was dissolved in N-methylpyrrolidone (1 mL). Then, 2-3 (125 mg, 0.347 mmol) and methanesulfonic acid (100 mg, 1.04 mmol) were sequentially added to the above solution. The reaction solution was heated to 120° C. and further stirred for 12 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature and directly purified by reversed-phase C18 column. Purification conditions were as follows: chromatographic column 40 g C18 reversed-phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate of 30 mL/min; gradient: acetonitrile increased from 35% to 85% within 25 minutes; detection wavelength of 254 nm. The product was collected and lyophilized under reduced pressure to obtain 28 mg of compound 2.

[0412] MS (ESI) m/z: 612.1,614.1 [M+H].sup.+.

[0413] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.96 (s, 1H), 8.35-8.29 (m, 1H), 8.26 (s, 1H), 8.19-8.18 (m, 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.59 (s, 1H), 7.53-7.47 (m, 1H), 7.01-6.97 (m, 2H), 6.81 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.76-3.73 (m, 4H), 2.86-2.84 (m, 4H), 1.78 (s, 3H), 1.74 (s, 3H).

Embodiment 6

Preparation of (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-methylpiperazin-1-yl))phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 6)

[0414] Step 1:

##STR00593##

[0415] Compound 1-6 (10 g, 40.1 mmol) was dissolved in dioxane (100 mL) and water (20 mL) at room temperature under nitrogen protection. Then, 1-methyl-4-pyrazoleboronic acid pinacol ester (14.4 g, 52.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.3 g, 4.0 mmol) and sodium carbonate (8.5 g, 80.0 mmol) were added thereto. The reaction solution was heated to 80° C. and further stirred for 16 hours.

[0416] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and added with water (100 mL) to quench. The mixture was extracted with ethyl acetate (100 mL×3 times); the organic phases were combined, and the organic phases were washed with saturated brine (80 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=15/1) to obtain 9.8 g of compound 6-1.

[0417] MS (ESI) m/z: 252.1 [M+H].sup.+.

[0418] Step 2:

##STR00594##

[0419] Compound 6-1 (500 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (5 mL). Then, anhydrous potassium carbonate (550 mg, 4.0 mmol) and N-methylpiperazine (239 mg, 2.4 mmol) were sequentially added to the above solution. The reaction solution was heated to 90° C. and further stirred for 16 hours.

[0420] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 309 mg of compound 6-2.

[0421] MS (ESI) m/z: 332.2 [M+H].sup.+.

[0422] Step 3:

##STR00595##

[0423] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 6-2 (309 mg, 0.9 mmol) to obtain 259 mg of compound 6-3.

[0424] MS (ESI) m/z: 302.1 [M+H].sup.+.

[0425] Step 4:

##STR00596##

[0426] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 6-3 (64 mg, 0.2 mmol) and N-(5-bromo-2-chloropyrimidin-4-yl)-5-(dimethylphosphoryl)quinoxalin-6-amine (87 mg, 0.2 mmol) to obtain 22 mg of compound 6.

[0427] MS (ESI) m/z: 676.9, 678.9 [M+H].sup.+.

[0428] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 9.00 (dd, J=9.6, 4.2 Hz, 1H), 8.75 (dd, J=11.4, 2.1 Hz, 2H), 8.32 (s, 1H), 8.24 (s, 1H), 7.77 (s, 1H), 7.71 (d, J=9.6 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 6.74 (s, 1H), 3.94 (s, 3H), 3.72 (s, 3H), 3.21 (s, 4H), 3.08 (s, 4H), 2.72 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H).

Embodiment 7

Preparation of (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-6-morpholinylpyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 7)

[0429] Step 1:

##STR00597##

[0430] 6-Chloro-2-methoxy-3-nitropyridine (10 g, 53.0 mmol) was dissolved in a mixed solvent of acetonitrile/N,N-dimethylformamide (2/1 by volume, 200 mL), and then, morpholine (4.6 g, 53.0 mmol) and triethylamine (5.4 g, 53.0 mmol) were sequentially added to the above reaction. The reaction system was stirred at room temperature for 16 hours.

[0431] After LCMS monitoring showed that the raw materials disappeared, water (500 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (300 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (500 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain 6.5 g of compound 7-2.

[0432] MS (ESI) m/z: 240.0 [M+H].sup.+.

[0433] Step 2:

##STR00598##

[0434] Compound 7-2 (6.5 g, 27.2 mmol) was dissolved in acetonitrile (40 mL). Then, N-bromosuccinimide (7.3 g, 27.2 mmol) was added to the above reaction solution in batches at 0° C. The reaction temperature was raised to room temperature, and the mixture was further stirred for 2 hours. After LCMS monitoring showed that the raw materials disappeared, water (100 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (100 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (80 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain 7 g of compound 7-3.

[0435] MS (ESI) m/z: 317.9, 319.9 [M+H].sup.+.

[0436] Step 3:

##STR00599##

[0437] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 7-3 (2 g, 6.3 mmol) to obtain 1.53 g of compound 7-4.

[0438] MS (ESI) m/z: 320.3 [M+H].sup.+.

[0439] Step 4:

##STR00600##

[0440] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 7-4 (1.53 g, 4.8 mmol) to obtain 0.65 g of compound 7-5.

[0441] MS (ESI) m/z: 290.3 [M+H].sup.+.

[0442] Step 5:

##STR00601##

[0443] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 7-5 (42 mg, 0.1 mmol) to obtain 31 mg of compound 7.

[0444] MS (ESI) m/z: 664.8, 666.8 [M+H].sup.+.

[0445] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 13.06 (s, 1H), 8.86 (dd, J=9.6, 4.2 Hz, 1H), 8.78 (dd, J=14.1, 1.8 Hz, 2H), 8.20 (s, 1H), 8.14 (s, 1H), 7.67 (s, 1H), 7.54 (s, 1H), 4.03 (s, 3H), 3.84 (s, 3H), 3.82 (t, J=4.8 Hz, 4H), 3.18 (t, J=4.8 Hz, 4H), 2.18 (s, 3H), 2.13 (s, 3H).

Embodiment 8

Preparation of (6-((5-bromo-2-((5-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)-2-methoxy-4-morpholinylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 8)

[0446] Step 1:

##STR00602##

[0447] Pyrazole-4-boronic acid pinacol ester 8-1 (50 g, 257.7 mmol) was dissolved in tetrahydrofuran (800 mL) at room temperature under nitrogen protection, and then sodium hydride (60%, 15.5 g, 387.5 mmol) was added to the reaction solution in batches at 0° C., and the mixture was further stirred at this temperature for 30 minutes; then cyclopropanesulfonyl chloride (43.3 g, 308 mmol) was slowly added dropwise to the above reaction solution at 0° C.; and the reaction solution was heated to room temperature and further stirred for 16 hours. After LCMS monitoring showed that the raw materials disappeared, water (7 mL) was added to the reaction solution to quench. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL×3 times). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 50 g of compound 8-2.

[0448] MS (ESI) m/z: 299.1 [M+H].sup.+.

[0449] Step 2:

##STR00603##

[0450] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 8-2 (940 mg, 3.2 mmol) to obtain 819 mg of compound 8-3.

[0451] MS (ESI) m/z: 409.3 [M+H].sup.+.

[0452] Step 3:

##STR00604##

[0453] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 8-3 (820 mg, 2.0 mmol) to obtain 650 mg of compound 8-4.

[0454] MS (ESI) m/z: 379.0 [M+H].sup.+.

[0455] Step 4:

##STR00605##

[0456] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 8-4 (55 mg, 0.1 mmol) to obtain 6 mg of title compound 8.

[0457] MS (ESI) m/z: 753.8, 755.8 [M+H].sup.+.

[0458] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 13.10 (s, 1H), 8.85 (d, J=8.4 Hz, 1H), 8.77 (d, J=5.1 Hz, 2H), 8.20 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.71 (d, J=9.3 Hz, 1H), 6.79 (s, 1H), 3.97 (s, 3H), 3.85 (t, J=9.3 Hz, 4H), 2.95 (t, J=9.3 Hz, 4H), 2.69 (m, 1H), 2.20 (s, 3H), 2.15 (s, 3H), 1.42-1.36 (m, 2H), 1.17-1.07 (m, 2H).

Embodiment 13

Preparation of 4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidine-5-carbonitrile (compound 13)

[0459] ##STR00606##

[0460] Compound 1 (220 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature under nitrogen protection. XPhos Pd G2 (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (28 mg, 0.03 mmol), zinc cyanide (51 mg, 0.4 mmol) and anhydrous potassium phosphate (105 mg, 0.5 mmol) were sequentially added to the above reaction solution, and the reaction system was heated to 160° C. with microwave and stirred for 2 hours.

[0461] After LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature and directly purified by reversed-phase C18 column. Purification conditions were as follows: chromatographic column 40 g C18 reversed-phase column; mobile phase water (containing 0.1% formic acid) and methanol; flow rate of 30 mL/min; gradient: acetonitrile increased from 10% to 50% within 10 minutes; detection wavelength of 254 nm. The product was collected and lyophilized under reduced pressure. 50 mg of compound 13 was obtained.

[0462] MS (ESI) m/z: 611.3 [M+H].sup.+.

[0463] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.21 (s, 1H), 9.37 (s, 1H), 8.85 (d, J=7.2 Hz, 2H), 8.66 (s, 1H), 8.55 (s, 1H), 8.14 (s, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 6.87 (s, 1H), 3.82 (s, 6H), 3.77 (m, 4H), 2.89 (m, 4H), 2.04 (s, 3H), 2.01 (s, 3H).

Embodiment 16

Preparation of (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide formate (compound 16)

[0464] Step 1:

##STR00607##

[0465] Prepared according to the method of step 2 in Embodiment 6, the raw materials were replaced with 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane (1.1 g, 4.8 mmol) to obtain 0.75 g of compound 16-1.

[0466] MS (ESI) m/z: 458.2 [M+H].sup.+.

[0467] Step 2:

##STR00608##

[0468] Compound 16-1 (0.65 g, 1.4 mmol) was dissolved in dichloromethane (20 mL), and then trifluoroacetic acid (7 mL) was added to the above reaction solution. The reaction system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure to obtain a crude product of compound 16-2 (500 mg) for direct use in the next step.

[0469] MS (ESI) m/z: 358.4 [M+H].sup.+.

[0470] Step 3:

##STR00609##

[0471] Compound 16-2 (650 mg, crude product) was dissolved in 1,2-dichloroethane (13 mL). Then, an aqueous formaldehyde solution (129 mg, 4.3 mmol) was added to the above reaction solution and the mixture was further stirred for 30 minutes; then, sodium triacetoxyborohydride (907 mg, 4.3 mmol) was added to the above reaction. The reaction system was further stirred at room temperature for 2 hours.

[0472] After LCMS monitoring showed that the raw materials disappeared, water (50 mL) was added to the reaction solution. The mixture was extracted with chloroform (100 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 520 mg of compound 16-3.

[0473] MS (ESI) m/z: 372.2 [M+H].sup.+.

[0474] Step 4:

##STR00610##

[0475] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 16-3 (500 mg, 1.3 mmol) to obtain 420 mg of compound 16-4.

[0476] MS (ESI) m/z: 342.2 [M+H].sup.+.

[0477] Step 5:

##STR00611##

[0478] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 16-4 (50 mg, 0.1 mmol) to obtain 40 mg of compound 16.

[0479] MS (ESI) m/z: 716.9, 718.9 [M+H].sup.+.

[0480] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.67 (s, 1H), 8.85-8.76 (m, 3H), 8.41 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.78 (s, 1H, 7.59-7.52 (m, 2H), 6.80 (s, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.19 (s, 4H), 2.79-2.72 (m, 4H), 2.38 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H), 1.85-1.82 (m, 4H).

Embodiment 17

Preparation of (6-((5-bromo-2-((5-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-2,3-dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 17)

[0481] Step 1:

##STR00612##

[0482] 2-Bromo-3-fluorophenol (50 g, 261.8 mmol) was dissolved in acetonitrile (500 mL), and then anhydrous potassium carbonate (76 g, 549.8 mmol) and 1,2-dibromoethane (98.4 g, 523.6 mmol) were sequentially added to the reaction solution. The reaction solution was heated to 50° C. and further stirred for 38 hours.

[0483] After TLC monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and filtered, and the filter cake was washed with ethyl acetate (20 mL×3 times). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1) to obtain 35 g of compound 17-2 (colorless transparent liquid, yield of 45%).

[0484] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.27-7.22 (m, 1H), 6.85-6.81 (m, 1H), 6.73-6.70 (m, 1H), 4.38 (t, J=6.4 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H).

[0485] Step 2:

##STR00613##

[0486] Compound 17-2 (35 g, 117 mmol) was dissolved in tetrahydrofuran (175 mL). Then, n-butyllithium (2.5 M, 52 mL, 129 mmol) was slowly added dropwise to the reaction solution at −78° C. under nitrogen atmosphere and the mixture was continued to stir at this temperature for 2 hours. After TLC monitoring showed that the raw materials disappeared, water (90 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (200 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (300 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/methyl tert-butyl ether=13/1) to obtain 11.3 g of compound 17-3.

[0487] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 7.13-7.06 (m, 1H), 6.62-6.55 (m, 2H), 4.64 (t, J=8.7 Hz, 2H), 3.27 (t, J=8.7 Hz, 2H).

[0488] Step 3:

##STR00614##

[0489] Compound 17-3 (11.3 g, 82 mmol) was dissolved in acetonitrile (100 mL). Then, N-bromosuccinimide (16 g, 90 mmol) was added to the reaction solution in batches at 0° C. The reaction solution was heated to room temperature and continued to stir for 2 hours. After TLC monitoring showed that the raw materials disappeared, the reaction solution was directly concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/methyl tert-butyl ether=15/1) to obtain 17 g of compound 17-4.

[0490] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 7.30-7.25 (m, 1H), 6.52 (d, J=8.4 Hz, 1H), 4.64 (t, J=8.7 Hz, 2H), 3.28 (t, J=8.7 Hz, 2H).

[0491] Step 4:

##STR00615##

[0492] Compound 17-4 (17 g, 78 mmol) was dissolved in trifluoroacetic acid (240 mL). Then, sodium nitrite (10.8 g, 157 mmol) was added to the above reaction solution in batches at 0° C. under nitrogen atmosphere. The reaction system was heated to room temperature and continued to stir for 16 hours. After TLC monitoring showed that the raw materials disappeared, the reaction solution was poured into water (1000 mL). The mixture was extracted with ethyl acetate (200 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (200 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=7/1) to obtain 13.8 g of compound 17-5.

[0493] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 8.24-8.22 (m, 1H), 4.97 (t, J=8.7 Hz, 2H), 3.42 (t, J=8.7 Hz, 2H).

[0494] Step 5:

##STR00616##

[0495] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with compound 17-5 (500 mg, 1.9 mmol) to obtain 345 mg of compound 17-6.

[0496] MS (ESI) m/z: 329.2, 331.2 [M+H].sup.+.

[0497] Step 6:

##STR00617##

[0498] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 17-6 (380 mg, 1.2 mmol) to obtain 380 mg of compound 17-7.

[0499] MS (ESI) m/z: 331.4 [M+H].sup.+.

[0500] Step 7:

##STR00618##

[0501] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 17-7 (370 mg, 1.1 mmol) to obtain 220 mg of compound 17-8.

[0502] MS (ESI) m/z: 301.4 [M+H].sup.+.

[0503] Step 8:

##STR00619##

[0504] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 17-8 (44 mg, 0.2 mmol) to obtain 21 mg of compound 17.

[0505] MS (ESI) m/z: 675.9, 677.9 [M+H].sup.+.

[0506] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 12.61 (s, 1H), 9.03-8.98 (m, 1H), 8.77 (s, 1H), 8.73 (s, 1H), 8.30 (s, 1H), 7.97 (s, 1H), 7.69-7.63 (m, 2H), 7.58 (s, 1H), 7.00 (s, 1H), 4.65 (t, J=8.4 Hz, 2H), 3.82 (s, 3H), 3.78-3.75 (m, 4H), 3.48 (t, J=8.4 Hz, 2H), 3.03 (s, 4H), 2.17 (s, 3H), 2.12 (s, 3H).

Embodiment 31

Preparation of (6-((5-ethyl-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 31)

[0507] Step 1:

##STR00620##

[0508] Compound 1 (100 mg, 0.2 mmol) was dissolved in dioxane (2 mL) and water (0.4 mL) at room temperature under nitrogen protection; then, pinacol vinylboronate (30 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (17 mg, 0.02 mmol) and potassium carbonate (42 g, 0.3 mmol) were added thereto; the reaction solution was heated to 90° C. and continued to stir for 16 hours.

[0509] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and added with water (10 mL) to quench. The mixture was extracted with ethyl acetate (10 mL×3 times); the organic phases were combined, and the organic phases were washed with saturated brine (10 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 80 g of compound 31-1.

[0510] MS (ESI) m/z: 612.1 [M+H].sup.+.

[0511] Step 2:

##STR00621##

[0512] Compound 31-1 (80 mg, 0.1 mmol) was dissolved in ethanol (5 mL), and then platinum dioxide (8 mg) was added to the above solution; the reaction system was replaced with hydrogen for 3 times, and then stirred at room temperature for 16 hours.

[0513] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was filtered through diatomite, and the filter cake was washed with ethanol (50 mL×3 times). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by reverse preparation (chromatographic column: Gemini-NX C18 AXAI Packed, 21.2×150 mm, 5 □m; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate of 30 mL/min; gradient: acetonitrile increased from 23% to 29% within 8 minutes; detection wavelength of 254 nm. The product was collected and lyophilized under reduced pressure to obtain 20 mg of compound 31.

[0514] MS (ESI) m/z: 614.3 [M+H].sup.+.

[0515] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 13.06 (s, 1H), 9.05 (s, 1H), 8.89 (dd, J=6.9, 2.1 Hz, 2H), 8.11 (s, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 7.68 (s, 2H), 6.89 (s, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.77 (t, J=4.8 Hz, 4H), 2.89 (t, J=4.8 Hz, 4H), 2.63 (q, J=14.7, 7.5 Hz, 2H), 2.08 (s, 3H), 2.03 (s, 3H), 1.21 (t, J=7.5 Hz, 3H).

Embodiment 33

Preparation of (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)amino)-8-methylquinoxalin-5-yl)dimethylphosphine oxide (compound 33)

[0516] Step 1:

##STR00622##

[0517] 2,4-Dinitroaniline (55 g, 0.3 mol) was dissolved in acetic acid (42 mL) and water (420 mL), and then bromine (72 g, 0.45 mol) was slowly added to the reaction solution at 0° C. The reaction solution was heated to 100° C. and continued to stir for 2 hours.

[0518] After TLC monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and poured into ice water (500 g). The pH of the resulting solution was adjusted to 9, and the precipitated solid was filtered. The filter cake was washed with water (100 mL×3 times) and dried. 65 g of compound 33-2 was obtained.

[0519] .sup.1H NMR: (300 MHz, DMSO-d.sub.6) δ 8.83 (d, J=2.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.14 (s, 2H).

[0520] Step 2:

##STR00623##

[0521] Sodium sulfide nonahydrate (27.5 g, 114.5 mmol) was dissolved in ethanol (120 mL) and water (30 mL). Then, sulphur (3.7 g, 114.7 mmol) was added to the above reaction solution; the resulting reaction solution was heated to 100° C. and continued to stir for 1 hour. The reaction solution was cooled to room temperature and added to ethanol (120 mL) and water (210 mL) containing 2-bromo-4,6-dinitroaniline (30 g, 114.5 mmol) and ammonium chloride (6.1 g, 114.4 mmol). The resulting reaction system was heated to 65° C. and continued to stir for 30 minutes. At 65° C., 2 mol/L sodium hydroxide aqueous solution (135 mL) was slowly added dropwise to the reaction system and continued to stir for 15 minutes.

[0522] The reaction system was cooled to room temperature, poured into a mixed solvent of 2 mol/L hydrochloric acid (135 mL) and ice water (100 g). The resulting solution was extracted with ethyl acetate (1.5 L×2 times); the organic phases were combined, and the organic phases were washed with saturated brine (1.5 L×2 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 22 g of compound 33-3.

[0523] .sup.1H NMR: (300 MHz, DMSO-d.sub.6) δ 7.64 (d, J=2.7 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 6.08 (s, 2H), 5.50 (s, 2H).

[0524] Step 3:

##STR00624##

[0525] Compound 33-3 (20 g, 86.2 mmol) was dissolved in water (800 mL). Then, an aqueous solution of glyoxal (40%, 23.6 mL) was added to the above reaction solution. The resulting reaction system was heated to 100° C. and continued to stir for 4 hours.

[0526] After TLC monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature. The precipitated solid was filtered, and the filter cake was washed with water (100 mL×2 times). The filter cake was dried to obtain 20 g of compound 33-4.

[0527] .sup.1H NMR: (300 MHz, DMSO-d.sub.6) δ 9.28-9.22 (m, 2H), 8.95 (d, J=2.7 Hz, 1H), 8.89 (d, J=2.7 Hz, 1H).

[0528] Step 4:

##STR00625##

[0529] Compound 33-4 (59 g, 232 mmol) was dissolved in ethanol (250 mL). Then, ammonium chloride (50 g, 929 mmol), iron powder (65 g, 1.1 mol) and water (170 mL) were added to the above reaction. The resulting reaction system was heated to 90° C. and continued to stir for 2 hours.

[0530] After the LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (100 mL×2 times) and the filtrate was concentrated under reduced pressure. Water (1 L) was added to the resulting residue, and the mixture was extracted with ethyl acetate (1.5 L×2 times). The organic phases were combined, and the organic phases were washed with saturated brine (1 L×2 times) first, and then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain 20 g of compound 33-5.

[0531] MS (ESI) m/z: 224.2, 226.2 [M+H].sup.+.

[0532] Step 5:

##STR00626##

[0533] Compound 33-5 (11.3 g, 50.4 mmol) was dissolved in N,N-dimethylformamide (110 mL), and then, N-iodosuccinimide (12.5 g, 55.6 mmol) was added to the above reaction solution. The reaction system was continued to stir at room temperature for 1 hour. After LCMS monitoring showed that the raw materials disappeared, water (200 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (200 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain 15 g of compound 33-6.

[0534] MS (ESI) m/z: 350.1, 352.1 [M+H].sup.+.

##STR00627##

[0535] Step 6:

[0536] Compound 33-6 (5 g, 14.3 mmol) was dissolved in N,N-dimethylformamide (30 mL) at room temperature under nitrogen protection. Then, anhydrous potassium phosphate (4.55 g, 21.4 mmol), palladium acetate (321 mg, 1.4 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (827 mg, 1.4 mmol) and dimethylphosphine oxide (1.1 g, 14.2 mmol) were sequentially added to the above reaction solution, and the reaction system was heated to 50° C. and continued to stir for 5 hours. After LCMS monitoring showed that the raw materials disappeared, water (400 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (500 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (500 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 1.1 g of compound 33-7.

[0537] MS (ESI) m/z: 300.2, 302.2 [M+H].sup.+.

[0538] Step 7:

##STR00628##

[0539] Compound 33-7 (500 mg, 1.7 mmol) was dissolved in a mixed solvent of dioxane (2 mL) and water (0.5 mL) at room temperature under nitrogen protection; then, methylboronic acid (150 mg, 2.5 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (122 mg, 0.2 mmol) and potassium phosphate (707 mg, 3.3 mmol) were sequentially added to the above reaction solution. The reaction system was heated to 100° C. and continued to stir for 2 hours.

[0540] After LCMS monitoring showed that the raw materials disappeared, water (10 mL) was added to the reaction solution to quench. The mixture was extracted with dichloromethane (20 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=12/1) to obtain 300 mg of compound 33-8.

[0541] MS (ESI) m/z: 236.0 [M+H].sup.+.

[0542] Step 8:

##STR00629##

[0543] Prepared according to the method of step 3 in Embodiment 1, the raw materials were replaced with compound 33-8 (120 mg, 0.5 mmol) to obtain 70 mg of compound 33-9.

[0544] MS (ESI) m/z: 426.0, 428.0 [M+H].sup.+.

[0545] Step 9:

##STR00630##

[0546] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 33-9 (60 mg, 0.1 mmol) to obtain 10 mg of title compound 33.

[0547] MS (ESI) m/z: 678.0, 680.0 [M+H].sup.+.

[0548] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.53 (s, 1H), 8.84 (d, J=4.5 Hz, 1H), 8.74 (dd, J=6.6, 1.8 Hz, 2H), 8.31 (s, 1H), 8.28 (s, 1H), 7.51 (s, 2H), 7.45 (s, 1H), 6.73 (s, 1H), 3.95 (s, 3H), 3.82 (t, J=4.2 Hz, 4H), 3.55 (s, 3H), 2.91 (t, J=4.2 Hz, 4H), 2.38 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H).

Embodiment 35

Preparation of 4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-N,N-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide (compound 35)

[0549] Step 1:

##STR00631##

[0550] 2-Bromo-4-methoxyaniline (5 g, 24.7 mmol) was dissolved in concentrated sulfuric acid (20 mL) at 0° C. Then, potassium nitrate (2.63 g, 26 mmol) was added to the above reaction solution in batches; the reaction system was continued to stir at 0° C. for 1 hour.

[0551] After TLC monitoring showed that the raw materials disappeared, the reaction solution was poured into ice water (100 g), and the pH was adjusted to 8 with 2 mol/L potassium hydroxide; the precipitated solid was filtered, and the filter cake was washed with water (100 mL×3 times). The filter cake was dried to obtain 5.1 g of compound 35-2.

[0552] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.43 (s, 1H), 7.34 (s, 1H), 5.41 (brs, 2H), 3.82 (s, 3H).

[0553] Step 2:

##STR00632##

[0554] Compound 35-2 (10 g, 40.5 mmol) was dissolved in a mixed solvent of water (40 mL) and concentrated hydrochloric acid (40 mL). Then, sodium nitrite (2.8 g, 40.5 mmol) was added to the above reaction solution at 0° C. The reaction system was continued to stir at 0° C. for 10 minutes. Then, a solution of potassium iodide (20.2 g, 121.4 mmol) in water (60 mL) was slowly added dropwise to the above reaction solution at 0° C. The reaction system was heated to room temperature and continued to stir for 30 minutes.

[0555] After TLC monitoring showed that the raw materials disappeared, the reaction system was extracted with dichloromethane (200 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (200 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4/1) to obtain 9.3 g of compound 35-3.

[0556] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.34 (s, 1H), 7.74 (s, 1H), 3.94 (s, 3H).

[0557] Step 3:

##STR00633##

[0558] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 35-3 (6 g, 16.8 mmol) to obtain 2.8 g of compound 35-4.

[0559] MS (ESI) m/z: 312.0, 314.0 [M+H].sup.+.

[0560] Step 4:

##STR00634##

[0561] Compound 35-4 and benzyl mercaptan (438 mg, 3.5 mmol) were dissolved in dioxane (10 mL) at room temperature under nitrogen protection. Then, tris(dibenzylideneacetone)dipalladium (147 mg, 0.16 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (185 mg, 0.32 mmol) and N,N-diisopropylethylamine (828 mg, 6.4 mmol) were added to the above reaction solution. The reaction system was heated to 80° C. and continued to stir for 16 hours.

[0562] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 1.2 g of compound 35-5.

[0563] MS (ESI) m/z: 356.1 [M+H].sup.+.

[0564] Step 5:

##STR00635##

[0565] Compound 35-5 (1.2 g, 3.6 mmol) was dissolved in acetic acid (12 mL). Then, N-chlorosuccinimide (NCS, 1.35 g, 10.8 mmol) and water (1.2 mL) were sequentially added to the above reaction solution. The reaction system was continued to stir at room temperature for 2 hours.

[0566] After LCMS monitoring showed that the raw materials disappeared, water (20 mL) was added to the reaction solution to quench, and the mixture was extracted with dichloromethane (30 mL×3 times). The organic phases were combined, and the organic phases were washed with saturated brine (30 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 0.6 g of compound 35-6.

[0567] MS (ESI) m/z: 332.0, 334.0 [M+H].sup.+.

[0568] Step 6:

##STR00636##

[0569] Compound 35-6 (600 mg, crude product) was dissolved in dichloromethane (6 mL). Then, dimethylamine (122 mg, 2.7 mmol) was added to the above reaction solution and the mixture was continued to stir for 3 hours at room temperature. After LCMS monitoring showed that the raw materials disappeared, water (10 mL) was added to the reaction solution to quench. The mixture was extracted with dichloromethane (20 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1). 250 mg of compound 35-7 was obtained.

[0570] MS (ESI) m/z: 341.0 [M+H].sup.+.

[0571] Step 7:

##STR00637##

[0572] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 35-7 (100 mg, 0.3 mmol) to obtain 90 mg of compound 35-8.

[0573] MS (ESI) m/z: 311.1 [M+H].sup.+.

[0574] Step 8:

##STR00638##

[0575] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 35-8 (45 mg, 0.2 mmol) to obtain 24 mg of compound 35.

[0576] MS (ESI) m/z: 686.1, 688.1 [M+H].sup.+.

[0577] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.79 (s, 1H), 8.90 (s, 2H), 8.78 (dd, J=9.6, 3.9 Hz, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 8.09 (s, 1H), 7.71 (s, 2H), 7.47 (s, 1H), 7.33 (s, 1H), 3.96 (s, 3H), 3.76 (s, 3H), 2.43 (s, 6H), 2.07 (s, 3H), 2.02 (s, 3H).

Embodiment 41 and Embodiment 42

Preparation of (6-((5-cyclopropyl-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 41)

and (6-((2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 42)

[0578] ##STR00639##

[0579] Step 1: Compound 1 (100 mg, 0.15 mmol) was dissolved in dioxane (3 mL) and water (1 mL) under nitrogen protection. Then, cyclopropylboronic acid (39 mg, 0.49 mmol), potassium carbonate (67 mg, 0.48 mmol) and tetrakis(triphenylphosphine)palladium (17 mg, 0.05 mmol) were sequentially added to the reaction solution. The reaction system was heated to 80° C. and continued to stir for 4 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 40 mg of compound 41 and 45 mg of compound 42.

[0580] Compound 41: MS (ESI) M/Z: 626.3 [M+H].sup.+.

[0581] Compound 41: .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.72 (s, 1H), 9.19 (dd, J=10.5, 3.9 Hz, 1H), 8.84-8.80 (m, 2H), 8.05 (s, 1H), 7.93 (s, 1H), 7.92, (s, 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.56 (d, J=9.6 Hz, 1H), 6.84 (s, 1H), 3.84 (s, 3H), 3.77-3.74 (m, 7H), 2.88-2.84 (m, 4H), 2.06 (s, 3H), 2.01 (s, 3H), 1.82-1.73 (m, 1H), 0.96-0.92 (m, 2H), 0.65-0.60 (m, 2H).

[0582] Compound 42: MS (ESI) M/Z: 586.3 [M+H].sup.+

[0583] Compound 42: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.66 (s, 1H), 9.37 (dd, J=9.6, 4.4 Hz, 1H), 8.69 (dd, J=11.6, 1.6 Hz, 2H), 8.34 (s, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 7.52 (d, J=9.2 Hz, 1H), 7.42 (s, 1H), 6.75 (s, 1H), 6.28 (d, J=5.6 Hz, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.84 (t, J=4.4 Hz, 4H), 2.99-2.92 (t, J=4.4 Hz, 4H), 2.14 (s, 3H), 2.11 (s, 3H).

Embodiment 68

Preparation of (6-((5-bromo-2-((2-methoxy-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 68)

[0584] Step 1:

##STR00640##

[0585] Compound 17-1 (5 g, 26.2 mmol) was dissolved in 35 mL of N,N-dimethylformamide, and anhydrous potassium carbonate (5.5 g, 39.3 mmol) and iodomethane (5.6 g, 39.3 mmol) were sequentially added thereto at 0° C. The reaction system was heated to room temperature and continued to stir for 16 hours. After TLC monitoring showed that the raw materials disappeared, water (100 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 5.1 g of compound 68-1.

[0586] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.44-7.36 (m, 1H), 7.00-6.94 (m, 2H), 3.89 (s, 3H).

[0587] Step 2:

##STR00641##

[0588] Compound 68-1 (4.57 g, 22.3 mmol) was dissolved in ethylene glycol dimethyl ether (80 mL) at room temperature under nitrogen protection. Then, methylboronic acid (4 g, 66.9 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.91 g, 1.1 mmol) and potassium phosphate (14.2 g, 66.9 mmol) were sequentially added to the above reaction solution. The reaction system was heated to 80° C. and continued to stir for 16 hours. After TLC monitoring showed that the raw materials disappeared, water (300 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (100 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/methyl tert-butyl ether=5/1) to obtain 1.5 g of compound 68-2.

[0589] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.23-7.15 (m, 1H), 6.82-6.73 (m, 2H), 3.81 (s, 3H), 2.06-2.05 (m, 3H).

[0590] Step 3:

##STR00642##

[0591] Compound 68-2 (1.4 g, 10 mmol) was dissolved in acetonitrile (12 mL). Then, N-bromosuccinimide (NBS, 2.1 g, 12 mmol) was added to the reaction solution in batches at 0° C. The reaction solution was heated to room temperature and continued to stir for 2 hours. After TLC monitoring showed that the raw materials disappeared, the reaction solution was directly concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/methyl tert-butyl ether=15/1) to obtain 1.8 g of compound 68-3.

[0592] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.50-7.44 (m, 1H), 6.81 (dd, J=9.0, 1.5 Hz, 1H), 3.82 (s, 3H), 2.10 (d, J=2.4 Hz, 3H).

[0593] Step 4:

##STR00643##

[0594] Compound 68-3 (1.67 g, 7.6 mmol) was dissolved in trifluoroacetic acid (24 mL). Then, sodium nitrite (1.1 g, 15.7 mmol) was added to the above reaction solution in batches at 0° C. under nitrogen atmosphere. The reaction system was heated to room temperature and continued to stir for 16 hours. After TLC monitoring showed that the raw materials disappeared, the reaction solution was poured into water (100 mL). The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=7/1) to obtain 1.3 g of compound 68-4.

[0595] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.26 (d, J=7.2 Hz, 1H), 3.86 (s, 3H), 2.27 (d, J=2.4 Hz, 3H).

[0596] Step 5:

##STR00644##

[0597] Compound 68-4 (300 mg, 1.1 mmol) was dissolved in N-methylpyrrolidone (2 mL). Then, morpholine (119 mg, 1.4 mmol) and N,N-diisopropylethylamine (734 mg, 5.7 mmol) were sequentially added to the above reaction solution. The reaction system was heated to 150° C. by microwave and continued to stir for 1 hour. After LCMS monitoring showed that the raw materials disappeared, water (30 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/methyl tert-butyl ether=5/1) to obtain 88 mg of compound 68-5.

[0598] MS (ESI, m/z): 317.0, 319.0 [M+H].sup.+[M+H].sup.+.

[0599] Step 6:

##STR00645##

[0600] Prepared according to the method of step 1 in Embodiment 68, the raw materials were replaced with compound 68-5 (81 mg, 0.3 mmol) to obtain 75 mg of compound 68-6.

[0601] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.05 (s, 1H), 3.80 (s, 3H), 3.74 (t, J=4.6 Hz, 4H), 3.20 (s, 4H), 2.33 (s, 3H).

[0602] Step 7:

##STR00646##

[0603] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 68-6 (74 mg, 0.2 mmol) to obtain 70 mg of compound 68-7.

[0604] MS (ESI) m/z: 333.1 [M+H].sup.+.

[0605] Step 8:

##STR00647##

[0606] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 68-7 (66 mg, 0.2 mmol) to obtain 39 mg of compound 68-8.

[0607] MS (ESI) m/z: 303.2 [M+H].sup.+.

[0608] Step 9:

##STR00648##

[0609] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 68-8 (39 mg, 0.1 mmol) to obtain 34 mg of compound 68.

[0610] MS (ESI) m/z: 678.0, 680.0 [M+H].sup.+[M+H].sup.+.

[0611] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.72 (s, 1H), 8.90-8.78 (m, 3H), 8.51 (s, 1H), 8.32 (s, 1H), 7.75 (s, 1H), 7.55 (d, J=9.6 Hz, 1H), 7.44 (s, 2H), 3.83 (s, 3H), 3.65 (s, 3H), 3.64-3.61 (m, 4H), 2.94-2.78 (m, 4H), 2.32 (s, 3H), 2.03 (d, J=14.4 Hz, 6H).

Embodiment 69

Preparation of (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino))pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 69)

[0612] Step 1:

##STR00649##

[0613] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 35-4 (200 mg, 0.6 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (175 mg, 0.8 mmol) to obtain 150 mg of compound 69-1.

[0614] MS (ESI) m/z: 316.0 [M+H].sup.+.

[0615] Step 2:

##STR00650##

[0616] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 69-1 (60 mg, 0.2 mmol) to obtain 40 mg of compound 69-2.

[0617] MS (ESI) m/z: 288.1 [M+H].sup.+.

[0618] Step 3:

##STR00651##

[0619] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 69-2 (40 mg, 0.1 mmol) to obtain 16 mg of compound 69.

[0620] MS (ESI) m/z: 663.2, 665.2 [M+H].sup.+[M+H].sup.+.

[0621] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.90-8.82 (m, 3H), 8.29 (d, J=1.2 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.51 (s, 1H), 7.22 (s, 1H), 7.00 (s, 1H), 4.06-4.01 (m, 2H), 3.97 (s, 3H), 3.81 (s, 3H), 3.51-3.44 (m, 2H), 3.16-3.10 (m, 1H), 2.18 (s, 3H), 2.13 (s, 3H), 1.97-1.83 (m, 2H), 1.69-1.65 (m, 2H).

Embodiment 70

Preparation of (6-((5-bromo-2-((5-(1-methyl-1H-pyrazol-4-yl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 70)

[0622] Step 1:

##STR00652##

[0623] 70-1 (500 mg, 2.1 mmol) was dissolved in the mixed solvent of acetonitrile/N,N-dimethylformamide (2/1 by volume, 10 mL). Then, N-methylpiperazine (253 mg, 2.5 mmol) and triethylamine (0.27 g, 2.65 mmol) were sequentially added to the above reaction. The reaction system was stirred at room temperature for 16 hours.

[0624] After LCMS monitoring showed that the raw materials disappeared, water (25 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (15 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (25 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain 689 mg of compound 70-2.

[0625] MS (ESI) m/z: 300.9, 302.9 [M+H].sup.+[M+H].sup.+.

[0626] Step 2:

##STR00653##

[0627] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 70-2 (689 mg, 2.3 mmol) to obtain 368 mg of compound 70-3.

[0628] MS (ESI) m/z: 303.1 [M+H].sup.+.

[0629] Step 3:

##STR00654##

[0630] Compound 70-3 (368 mg, 1.2 mmol) was dissolved in ethanol (1.5 mL). Then, ammonium chloride (260 mg, 4.8 mmol), iron powder (337 mg, 6 mmol) and water (0.9 mL) were added to the above reaction. The resulting reaction system was heated to 90° C. and continued to stir for 2 hours.

[0631] After the LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (0.6 mL×2 times) and the filtrate was concentrated under reduced pressure. Water (5 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate (7.5 mL×2 times). The organic phases were combined, and the organic phases were washed with saturated brine (5 mL×2 times) first, and then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain 323 mg of compound 70-4.

[0632] MS (ESI) m/z: 273.2 [M+H].sup.+.

[0633] Step 4:

##STR00655##

[0634] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 70-4 (40 mg, 0.1 mmol) to obtain 26 mg of compound 70.

[0635] MS (ESI) m/z: 648.2, 650.2 [M+H].sup.+.

[0636] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.65 (s, 1H), 8.97-8.92 (m, 1H), 8.77-8.73 (m, 2H), 8.29 (s, 1H), 8.24 (d, J=2.7 Hz, 1H), 7.92-7.91 (m, 1H), 7.84-7.82 (m, 2H), 7.73 (s, 1H), 6.91 (s, 1H), 3.91 (s, 3H), 3.22 (s, 4H), 2.60 (s, 4H), 2.41 (s, 3H), 2.14 (d, J=14.1 Hz, 6H).

Embodiment 79

[0637] Preparation of (4-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)amino)bicyclo[4.2.0]octa-1,3,5-trien-3-yl)dimethylphosphine oxide (compound 79)

[0638] Step 1:

##STR00656##

[0639] Compound 79-1 (5 g, 27.3 mmol) was dissolved in dioxane (60 mL) under nitrogen atmosphere. Then, tert-butyl carbamate (4.8 g, 40.9 mmol), palladium acetate (613 mg, 2.7 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (2.0 g, 4.1 mmol) and cesium carbonate (17.8 g, 54.6 mmol) were added to the reaction solution. The reaction system was heated to 100° C. and continued to stir for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (100 mL) was added to the reaction solution to quench. The mixture was extracted with dichloromethane (250 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (200 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain 5.9 g of compound 79-2.

[0640] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.23-7.19 (m, 1H), 7.03-6.98 (m, 1H), 6.96-6.92 (m, 1H), 3.13-3.09 (m, 4H), 1.51 (s, 9H).

[0641] Step 2:

##STR00657##

[0642] Compound 79-2 (5 g, 22.8 mmol) was dissolved in dichloromethane (20 mL), and then trifluoroacetic acid (7 mL) was added to the above reaction solution. The reaction system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure to obtain 2.4 g of compound 79-3.

[0643] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.86 (d, J=7.6 Hz, 1H), 6.60 (dd, J=7.6, 2.0 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.11-3.08 (m, 4H).

[0644] Step 3:

##STR00658##

[0645] Prepared according to the method of step 1 in Embodiment 1, the raw materials were replaced with compound 79-3 (12 g, 101 mmol) to obtain 2.8 g of compound 79-4 and 0.75 g of compound 85-1.

[0646] Compound 79-4: .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.31 (s, 1H), 6.56 (s, 1H), 3.10-3.02 (m, 4H).

[0647] Compound 85-2: .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.79 (d, J=7.6 Hz, 1H), 6.59-6.55 (m, 1H), 3.95 (br s, 2H), 2.97-2.95 (m, 4H).

[0648] Step 4:

##STR00659##

[0649] Prepared according to the method of step 2 in Embodiment 1, the raw materials were replaced with compound 79-4 (1 g, 4.1 mmol) to obtain 0.77 g of compound 79-5.

[0650] MS (ESI) m/z: 196.2 [M+H].sup.+.

[0651] Step 5:

##STR00660##

[0652] Prepared according to the method of step 3 in Embodiment 1, the raw materials were replaced with compound 79-5 (400 mg, 2.1 mmol) to obtain 220 mg of compound 79-6.

[0653] MS (ESI) m/z: 385.9, 387.9 [M+H].sup.+.

[0654] Step 6:

##STR00661##

[0655] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 79-6 (100 mg, 0.3 mmol) to obtain 53 mg of compound 79.

[0656] MS (ESI) m/z: 638.3, 640.3 [M+H].sup.+.

[0657] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.19 (s, 1H), 8.09 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.77 (d, J=3.2 Hz, 1H), 7.57 (s, 1H), 7.33 (d, J=13.2 Hz, 1H), 6.87 (s, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.85-3.80 (m, 4H), 3.11-3.06 (m, 2H), 2.95-2.87 (m, 6H), 1.89 (d, J=13.2 Hz, 6H).

Embodiment 80

Preparation of N-(2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)amino)phenylmethanesulfonamide (compound 80)

[0658] Step 1:

##STR00662##

[0659] Prepared according to the method of step 3 in Embodiment 1, the raw materials were replaced with compound 80-1 (3.1 g, 22.2 mmol) to obtain 3.2 g of compound 80-2.

[0660] MS (ESI) m/z: 328.8, 330.8 [M+H].sup.+[M+H]+.

[0661] Step 2:

##STR00663##

[0662] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 80-2 (200 mg, 0.6 mmol) to obtain 300 mg of compound 80-3.

[0663] MS (ESI) m/z: 581.2, 583.2 [M+H].sup.+.

[0664] Step 3:

##STR00664##

[0665] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 80-3 (250 mg, 0.43 mmol) to obtain 100 mg of compound 80-4.

[0666] MS (ESI) m/z: 551.2, 553.2 [M+H].sup.+.

[0667] Step 4:

##STR00665##

[0668] Compound 80-4 (40 mg, 0.07 mmol) was dissolved in pyridine (4 mL) at room temperature. Then, methanesulfonyl chloride (42 mg, 0.4 mmol) was added to the above reaction solution. The reaction system was heated to 50° C. and continued to stir for 3 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature and directly purified by a reversed-phase C18 column (purification conditions were as follows: chromatographic column: 40 g C18 reversed-phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 35 mL/min; gradient: acetonitrile increased from 20% to 57% within 25 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure.) to obtain 17 mg of compound 80.

[0669] MS (ESI, m/z): 629.1, 631.1 [M+H].sup.+.

[0670] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 8.46 (s, 1H), 8.18 (s, 1H), 8.16 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.83 (s, 1H), 7.60 (s, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.01-6.97 (m, 1H), 6.79 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.75-3.72 (m, 4H), 2.95 (s, 3H), 2.85-2.83 (m, 4H).

Embodiment 82

Preparation of (6-((5-bromo-2-((6-(1-methyl-1H-pyrazol-4-yl)benzo[d][1,3]dioxol-4-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 82)

[0671] Step 1:

##STR00666##

[0672] Compound 82-1 (750 mg, 3 mmol) was dissolved in N,N-dimethylformamide (10 mL). Then, cesium carbonate (1.5 g, 4.6 mmol) and chlorobromomethane (786 mg, 6.1 mmol) were sequentially added to the above reaction solution. The reaction system was heated to 110° C. and continued to stir for 3 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (100 mL) was added thereto to quench. The mixture was extracted with ethyl acetate (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 750 mg of compound 82-2.

[0673] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.43 (d, J=2.1 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 6.22 (s, 2H), 3.83 (s, 3H).

[0674] Step 2:

##STR00667##

[0675] Compound 82-2 (1.00 g, 3.86 mmol) was dissolved in methanol (10 mL). Then, 2 M potassium hydroxide aqueous solution (3.8 mL, 7.7 mmol) was added to the above reaction solution. The reaction system was continued to stir at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure. Then, water (20 mL) was added thereto and the pH of the mixture was adjusted to 5 with concentrated hydrochloric acid, and a solid was precipitated, filtered and dried to obtain 970 mg of compound 82-3.

[0676] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 13.32 (s, 1H), 7.56-7.23 (m, 2H), 6.19 (s, 2H).

[0677] Step 3:

##STR00668##

[0678] Compound 82-3 (500 mg, 2 mmol) was dissolved in tert-butanol (10 mL) under nitrogen atmosphere. Then, triethylamine (826 mg, 8.2 mmol) and diphenylphosphoryl azide (842 mg, 3.1 mmol) were added to the above reaction solution. The reaction system was stirred at room temperature for 2 hours, then heated to 90° C. and continued to stir for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 100 mg of compound 82-4.

[0679] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.44 (d, J=2.0 Hz, 1H), 6.38 (d, J=2.0 Hz, 1H), 5.94 (s, 2H).

[0680] Step 4:

##STR00669##

[0681] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 82-4 (100 mg, 0.5 mmol) to obtain 60 mg of compound 82-5.

[0682] MS (ESI) m/z: 218.2 [M+H].sup.+.

[0683] Step 5:

##STR00670##

[0684] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 82-5 (60 mg, 0.3 mmol) to obtain 20 mg of compound 82.

[0685] MS (ESI) m/z: 593.1, 595.1 [M+H].sup.+.

[0686] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.76 (s, 1H), 9.19 (s, 1H), 8.97 (dd, J=9.6, 3.9 Hz, 1H), 8.86 (d, J=1.8 Hz, 1H), 8.81 (d, J=1.8 Hz, 1H), 8.32 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.65 (d, J=9.3 Hz, 1H), 7.14 (d, J=1.5 Hz, 1H), 7.08 (d, J=1.5 Hz, 1H), 5.98 (s, 2H), 3.77 (s, 3H), 2.02 (d, J=14.4 Hz, 6H).

Embodiment 88

Preparation of (6-((5-bromo-2-((4-(4-isopropylpiperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 88)

[0687] Step 1:

##STR00671##

[0688] Compound 6-1 (500 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (5 mL). Then, anhydrous potassium carbonate (550 mg, 4.0 mmol) and N-isopropylpiperazine (316 mg, 2.4 mmol) were sequentially added to the above solution. The reaction solution was heated to 90° C. and continued to stir for 16 hours.

[0689] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 439 mg of compound 88-1.

[0690] MS (ESI) m/z: 360.2 [M+H].sup.+.

[0691] Step 2:

##STR00672##

[0692] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 88-1 (260 mg, 0.7 mmol) to obtain 280 mg of compound 88-2.

[0693] MS (ESI) m/z: 330.2 [M+H].sup.+.

[0694] Step 3:

##STR00673##

[0695] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 88-2 (48 mg, crude product) to obtain 20 mg of compound 88.

[0696] MS (ESI) m/z: 705.2, 707.2 [M+H].sup.+.

[0697] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 9.02-8.99 (m, 1H), 8.76 (d, J=2.0 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.75 (s, 1H), 7.69-7.67 (m, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 6.77 (s, 1H), 3.92 (s, 3H), 3.71 (s, 3H), 3.17 (s, 5H), 2.96 (s, 4H), 2.15 (d,J=14.4 Hz, 6H), 1.29 (d, J=6.8 Hz, 6H).

Embodiment 93

Preparation of (6-((5-bromo-2-((3-fluoro-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)aminopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 93)

[0698] Step 1:

##STR00674##

[0699] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with 2,3-difluoro-6-nitroanisole (5 g, 26.4 mmol) and 4-piperidone ethylene acetal (4.5 g, 31.7 mmol) to obtain 6.8 g of compound 93-1.

[0700] MS (ESI) m/z: 313.1 [M+H].sup.+.

[0701] Step 2:

##STR00675##

[0702] Prepared according to the method of step 3 in Embodiment 68, the raw materials were replaced with compound 93-1 (6.7 g, 21.5 mmol) to obtain 4.7 g of compound 93-2.

[0703] MS (ESI) m/z: 391.2, 393.2 [M+H].sup.+.

[0704] Step 3:

##STR00676##

[0705] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 93-2 (4.5 g, 11.4 mmol) to obtain 4.38 g of compound 93-3.

[0706] MS (ESI) m/z: 393.1 [M+H].sup.+.

[0707] Step 4:

##STR00677##

[0708] Compound 93-3 (2.00 g, 5.1 mmol) was dissolved in trifluoroacetic acid (15 mL) and water (3 mL) at room temperature. Then, the reaction system was heated to 60° C. and continued to stir for 1.5 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (80 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (100 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (80 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the resulting residue was purified by a reversed-phase C18 column. The purification methods were as follows: mobile phase: water (containing 0.1% ammonium bicarbonate) and acetonitrile; gradient: acetonitrile increased from 30% to 55% within 25 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to obtain 1.1 g of compound 93-4.

[0709] MS (ESI) m/z: 349.3 [M+H].sup.+.

[0710] Step 5:

##STR00678##

[0711] Compound 93-4 (400 mg, 1.1 mmol) was dissolved in 1,2-dichloroethane (13 mL). Then, N-methylpiperazine (230 mg, 2.3 mmol) was added to the above reaction solution and the mixture was continued to stir for 30 minutes; then, sodium triacetoxyborohydride (907 mg, 4.3 mmol) was added to the above reaction. The reaction system was continued to stir at room temperature for 2 hours.

[0712] After LCMS monitoring showed that the raw materials disappeared, water (50 mL) was added to the reaction solution. The mixture was extracted with chloroform (100 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 403 mg of compound 93-5.

[0713] MS (ESI) m/z: 433.2 [M+H].sup.+.

[0714] Step 6:

##STR00679##

[0715] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 93-5 (220 mg, 0.5 mmol) to obtain 202 mg of compound 93-6.

[0716] MS (ESI) m/z: 403.3 [M+H].sup.+.

[0717] Step 7:

##STR00680##

[0718] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 93-6 (202 mg, 0.5 mmol) to obtain 77 mg of compound 93.

[0719] MS (ESI) m/z: 778.4, 780.4 [M+H].sup.+.

[0720] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.70 (s, 1H), 8.89-8.74 (m, 4H), 8.34 (s, 1H), 7.98 (s, 1H), 7.74 (s, 1H), 7.58 (d,J=9.6 Hz, 1H), 7.49 (d,J=2.1 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.09-2.97 (m, 4H), 2.61-2.53 (m, 4H) 2.37-2.29 (m, 5H), 2.16 (s, 3H), 2.03 (d, J=14.4 Hz, 6H), 1.82-1.78 (m, 2H), 1.60-1.48 (m, 2H).

[0721] .sup.19F NMR (282 MHz, DMSO-d.sub.6) δ −137.78.

Embodiment 100

Preparation of (6-((5-bromo-2-((3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 100)

[0722] Step 1:

##STR00681##

[0723] Prepared according to the method of step 3 in Embodiment 68, the raw materials were replaced with compound 100-1 (10 g, 80 mmol) to obtain 11.4 g of compound 100-2.

[0724] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 7.10 (dd, J=8.4, 8.4 Hz, 1H), 6.41 (dd, J=8.8, 1.2 Hz, 1H), 5.37 (s, 2H), 1.99 (d, J=2.0 Hz, 3H).

[0725] Step 2:

##STR00682##

[0726] Compound 100-2 (8.5 g, 41.7 mmol) was dissolved in trifluoroacetic anhydride (TFAA, 87.5 g, 416 mmol). Then, copper nitrate (23.36 g, 125 mmol) was added to the above reaction solution at 0° C. The reaction system was heated to room temperature and continued to stir for 1 hour. After TLC monitoring showed that the raw materials disappeared, the reaction solution was added dropwise into saturated sodium bicarbonate (500 mL) to quench. The mixture was extracted with ethyl acetate (300 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (200 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 8 g of compound 100-3.

[0727] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.76 (s, 1H), 8.41 (d, J=6.8 Hz, 1H), 2.24 (d, J=2.4 Hz, 3H).

[0728] Step 3:

##STR00683##

[0729] Compound 100-3 (890 mg, 2.6 mmol) was dissolved in 1,4-dioxane (8 mL). Then, a dilute sulfuric acid aqueous solution (2 mol/L, 8 mL) was added to the above reaction solution. The reaction system was heated to 100° C. and continued to stir for 2 hours. After TLC monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and diluted with ethyl acetate (50 mL). The pH of the mixture was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (80 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 600 mg of compound 100-4.

[0730] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ 8.20 (d, J=7.5 Hz, 1H), 7.52 (s, 2H), 2.15 (d, J=2.7 Hz, 3H).

[0731] Step 4:

##STR00684##

[0732] Compound 100-4 (600 mg, 2.4 mmol) was dissolved in concentrated sulfuric acid (6 mL). Then, sodium nitrite (382 mg, 5.5 mmol) was added to the above reaction solution at 0° C. and continued to stir at this temperature for 1 hour. Then, ice water (3 g) and a solution of copper sulfate (500 mg, 3.1 mmol) in ethanol (6 mL) were sequentially added to the reaction solution. The reaction system was heated to 80° C. and continued to stir for 1 hour. After TLC monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (100 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (80 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4/1) to obtain 370 mg of compound 100-5.

[0733] .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 8.33 (m, 1H), 8.11-8.08 (m, 1H), 2.48-2.41 (m, 3H).

[0734] Step 5:

##STR00685##

[0735] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with 100-5 (270 mg, 1.2 mmol) to obtain 130 mg of compound 100-6.

[0736] MS (ESI) m/z: 301.1, 303.0 [M+H].sup.+.

[0737] Step 6:

##STR00686##

[0738] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with 100-6 (160 mg, 0.5 mmol) to obtain 130 mg of compound 100-7.

[0739] MS (ESI) m/z: 303.1 [M+H].sup.+.

[0740] Step 7:

##STR00687##

[0741] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 100-7 (130 mg, 0.4 mmol) to obtain 90 mg of compound 100-8.

[0742] MS (ESI) m/z: 273.1 [M+H].sup.+.

[0743] Step 8:

##STR00688##

[0744] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with 100-8 (60 mg, 0.2 mmol) to obtain 62 mg of compound 100.

[0745] MS (ESI) m/z: 648.2, 650.2 [M+H].sup.+.

[0746] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 12.71 (s, 1H), 9.41 (s, 1H), 9.01-8.85 (m, 3H), 8.36 (s, 1H), 7.84-7.80 (m, 2H), 7.46 (s, 1H), 7.41-7.33 (m, 2H), 3.83 (s, 3H), 3.61-3.59 (m, 4H), 2.97 (s, 2H), 2.71 (s, 2H), 2.25 (s, 3H), 2.05 (d, J=14.4 Hz, 6H).

Embodiment 111

Preparation of (6-((5-bromo-2-((4-(cis-2,6-dimethylmorpholinyl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino))pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 111)

[0747] Step 1:

##STR00689##

[0748] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with cis-2,6-dimethylmorpholine (345 mg, 3 mmol) to obtain 580 mg of compound 111-1.

[0749] MS (ESI) m/z: 345.1, 347.1 [M+H].sup.+.

[0750] Step 2:

##STR00690##

[0751] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 111-1 (530 mg, 1.5 mmol) to obtain 500 mg of compound 111-2.

[0752] MS (ESI) m/z: 347.2 [M+H].sup.+.

[0753] Step 3:

##STR00691##

[0754] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 111-2 (160 mg, 0.5 mmol) to obtain 130 mg of compound 111-3.

[0755] MS (ESI) m/z: 317.2 [M+H].sup.+.

[0756] Step 4:

##STR00692##

[0757] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 111-3 (120 mg, 0.4 mmol) to obtain 98 mg of compound 111.

[0758] MS: (ESI, m/z): 691.8, 693.8 [M+H].sup.+.

[0759] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.60 (s, 1H), 8.99 (dd, J=9.2, 4.0 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 7.74 (s, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 6.71 (s, 1H), 3.74 (s, 3H), 3.85-3.79 (m, 2H), 3.76 (s, 3H), 2.96 (d, J=11.2 Hz, 2H), 2.41 (t, J=10.8 Hz, 2H), 2.15 (d, J=14.4 Hz, 6H), 1.20 (d, J=6.0 Hz, 6H).

Embodiment 121

Preparation of (6-((5-bromo-2-((4-(4-hydroxypiperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino]pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 121)

[0760] Step 1:

##STR00693##

[0761] Prepared according to the method of step 1 in Embodiment 88, the raw materials were replaced with 4-piperidone glycol acetal (0.68 g, 4.7 mmol) to obtain 1 g of compound 121-1.

[0762] MS: (ESI, m/z): 375.1 [M+H].sup.+.

[0763] Step 2:

##STR00694##

[0764] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 121-1 (1 g, 2.7 mmol) to obtain 0.7 g of compound 121-2.

[0765] MS (ESI) m/z: 345.3 [M+H].sup.+.

[0766] Step 3:

##STR00695##

[0767] Compound 121-2 (600 mg, 1.7 mmol) and compound 1-5 (719 mg, 1.7 mmol) were dissolved in 1,4-dioxane (6 mL) at room temperature under nitrogen protection. Then, cesium carbonate (1.1 g, 3.5 mmol) and PEPPSI™-IPr (CAS#: 905459-27-0, 118 mg, 0.2 mmol) were added to the reaction solution. The reaction system was heated to 90° C. and continued to stir for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (20 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 400 mg of compound 121-3.

[0768] MS (ESI) m/z: 720.1, 722.1 [M+H].sup.+.

[0769] Step 4:

##STR00696##

[0770] Prepared according to the method of step 4 in Embodiment 93, the raw materials were replaced with compound 121-3 (0.4 g, 0.6 mmol) to obtain 0.11 g of compound 121-4.

[0771] MS (ESI) m/z: 676.0, 678.0 [M+H].sup.+.

[0772] Step 5:

##STR00697##

[0773] Compound 121-4 (50 mg, 0.07 mmol) was dissolved in methanol (1 mL). Then, sodium borohydride (4 mg, 0.1 mmol) was added to the reaction solution at 0° C. The reaction solution was heated to room temperature and continued to stir for 1 hour. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was subjected to reversed-phase preparation: chromatographic column: 80 g C18 reversed-phase column; mobile phase: water (with 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 50 mL/min; gradient: acetonitrile increased from 10% to 60% within 30 minutes; detection wavelength: 254 nm. 25 mg of compound 121 was obtained.

[0774] MS (ESI) m/z: 678.4, 680.4 [M+H].sup.+.

[0775] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.64 (s, 1H), 9.00 (dd, J=9.6, 3.2 Hz, 1H), 8.74 (dd, J=9.0, 1.8 Hz, 2H), 8.30 (s, 1H), 8.22 (s, 1H), 7.81 (s, 1H), 7.63-7.43 (m, 3H), 6.75 (s, 1H), 3.92-3.80 (m, 7H), 3.16-3.12 (m, 2H), 2.75-2.68 (m, 2H), 2.15 (d, J=14.4 Hz, 6H), 2.02-1.98 (m, 2H), 1.76-1.68 (m, 3H).

Embodiment 133

Preparation of (6-((5-bromo-2-((4-(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 133)

[0776] ##STR00698##

[0777] Prepared according to the method of step 1 in Embodiment 88, the raw materials were replaced with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1.22 g, 4.8 mmol) to obtain 1.6 g of compound 133-1.

[0778] MS (ESI) m/z: 486.2 [M+H].sup.+.

[0779] Step 2:

##STR00699##

[0780] Compound 133-1 (1.6 g, 3.3 mmol) was dissolved in dichloromethane (10 mL); and then at 0° C., 1,4-dioxane solution of hydrogen chloride (4 mol/L, 10 mL) was added to the above reaction solution. The reaction system was heated to room temperature and continued to stir for 1 hour; after LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure to obtain 1.38 g of compound 133-2 hydrochloride.

[0781] MS (ESI) m/z: 386.1 [M+H].sup.+.

[0782] Step 3:

##STR00700##

[0783] Compound 133-2 hydrochloride (200 mg, 0.47 mmol) and 1-bromo-2-fluoroethane (132 mg, 1.04 mmol) were dissolved in acetonitrile (5 mL). Then, anhydrous potassium carbonate (359 mg, 2.6 mmol) was added to the above reaction solution. The reaction system was heated to 80° C. and continued to stir for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=8/1) to obtain 130 mg of compound 133-3.

[0784] MS (ESI) m/z: 432.2 [M+H].sup.+.

[0785] Step 4:

##STR00701##

[0786] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 133-3 (130 mg, 0.3 mmol) to obtain 80 mg of compound 133-4.

[0787] MS (ESI) m/z: 401.5 [M+H].sup.+.

[0788] Step 5

##STR00702##

[0789] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 133-4 (70 mg, 0.17 mmol) to obtain 51 mg of compound 133.

[0790] MS (ESI) m/z: 777.2, 779.2 [M+H].sup.+.

[0791] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ 12.67 (s, 1H), 8.85-8.75 (m, 3H), 8.43 (s, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.54 (s, 2H), 6.89 (s, 1H), 4.64-4.60 (m, 1H), 4.48-4.44 (m, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 2.84-2.80 (m, 4H), 2.73-2.67 (m, 1H), 2.60-2.57 (m, 1H), 2.46 (s, 4H), 2.01 (d, J=14.4 Hz, 6H), 1.56 (s, 8H).

[0792] .sup.19F NMR (377 MHz, DMSO-d.sub.6) δ −216.89.

Embodiment 135

Preparation of (6-((5-bromo-2-((4-(trans-2,6-dimethylmorpholinyl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino))pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 135)

[0793] Step 1:

##STR00703##

[0794] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with trans-2,6-dimethylmorpholine (racemic mixture of 2S,6S configuration and 2R,6R, 553 mg, 4.8 mmol) to obtain 1.02 g of compound 135-1.

[0795] MS (ESI, m/z): 345.0, 347.0 [M+H].sup.+.

[0796] Step 2:

##STR00704##

[0797] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 135-1 (1 g, 2.9 mmol) to obtain 828 mg of compound 135-2.

[0798] MS (ESI, m/z): 347.1 [M+H].sup.+.

[0799] Step 3:

##STR00705##

[0800] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 135-2 (150 mg, 0.43 mmol) to obtain 134 mg of compound 135-3.

[0801] MS (ESI) m/z: 317.1 [M+H].sup.+.

[0802] Step 4:

##STR00706##

[0803] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 135-3 (70 mg, 0.2 mmol) to obtain 80 mg of racemic compound 135.

[0804] MS (ESI) m/z: 692.1, 694.1 [M+H].sup.+.

[0805] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.67 (s, 1H), 8.87-8.80 (m, 2H), 8.76 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.59-7.53 (m, 2H), 6.84 (s, 1H), 4.07-4.02 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.32 (s, 2H), 2.98-2.93 (m, 2H), 2.02 (d, J=14.4 Hz, 6H), 1.18 (d, J=6.3 Hz, 6H).

Embodiment 144

Preparation of (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 144)

[0806] Step 1:

##STR00707##

[0807] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (615 mg, 2.4 mmol) to obtain 900 mg of compound 144-1.

[0808] MS (ESI, m/z): 486.1, 488.1 [M+H].sup.+.

[0809] Step 2:

##STR00708##

[0810] Compound 144-1 (900 mg, 1.85 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was then added to the above reaction solution and the mixture was continued to stir at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in methanol (10 mL). Then, glacial acetic acid (223 mg, 3.71 mmol) and formaldehyde aqueous solution (37%, 2 mL) were added to the above reaction solution and the mixture was continued to stir at room temperature for 30 minutes. Sodium triacetoxyborohydride (787 mg, 3.71 mmol) was added to the above reaction solution in batches, and the mixture was continued to stir at room temperature for 1.5 hours. After LCMS monitoring showed that the raw materials disappeared, saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction solution to quench. The mixture was extracted with dichloromethane (80 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 600 mg of compound 144-2 was obtained.

[0811] MS (ESI) m/z: 400.0, 402.0 [M+H].sup.+.

[0812] Step 3:

##STR00709##

[0813] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 144-2 (420 mg, 1.05 mmol) to obtain 310 mg of compound 144-3.

[0814] MS (ESI, m/z): 402.2 [M+H].sup.+.

[0815] Step 4:

##STR00710##

[0816] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 144-3 (300 mg, 0.75 mmol) to obtain 142 mg of compound 144-4.

[0817] MS (ESI) m/z: 372.2 [M+H].sup.+.

[0818] Step 5:

##STR00711##

[0819] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 144-4 (72 mg, 0.2 mmol) to obtain 70 mg of compound 144.

[0820] MS: (ESI, m/z): 747.2, 749.2 [M+H].sup.+.

[0821] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 9.01 (dd, J=9.6, 4.0 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 7.69 (s, 1H), 7.64-7.60 (m, 2H), 7.35 (s, 1H), 6.77 (s, 1H), 3.93 (s, 3H), 3.88 (s, 2H), 3.77 (s, 3H), 2.97-2.84 (m, 4H), 2.65-2.47 (m, 7H), 2.15 (d, J=14.0 Hz, 8H), 1.74 (s, 2H).

Embodiment 147

Preparation of N-(4-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)amino)bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-N-methylmethanesulfonamide (compound 147)

[0822] Step 1:

##STR00712##

[0823] Prepared according to the method of step 4 in Embodiment 80, the raw materials were replaced with compound 79-4 (1 g, 4.1 mmol) to obtain 1.1 g of compound 147-1.

[0824] MS (ESI) m/z: 321.8 [M−H].sup.+.

[0825] Step 2:

##STR00713##

[0826] Compound 147-1 (1.4 g, 4.3 mmol) and anhydrous potassium carbonate (1.2 g, 8.5 mmol) were dissolved in N,N-dimethylformamide (15 mL). Then, iodomethane (909 mg, 6.4 mmol) was added to the above reaction solution and the mixture was continued to stir for 2 hours at room temperature. After LCMS monitoring showed that the raw materials disappeared, water (100 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (100 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 1.3 g of compound 147-2.

[0827] MS (ESI) m/z: 338.1 [M+H].sup.+.

[0828] Step 3:

##STR00714##

[0829] Prepared according to the method of step 1 in Embodiment 79, the raw materials were replaced with compound 147-2 (1.3 g, 3.7 mmol) to obtain 0.52 g of compound 147-3.

[0830] MS (ESI) m/z: 325.0 [M−H].sup.+.

[0831] Step 4:

##STR00715##

[0832] Prepared according to the method of step 2 in Embodiment 79, the raw materials were replaced with compound 147-3 (520 mg, 1.6 mmol) to obtain 250 mg of compound 147-4.

[0833] MS (ESI) m/z: 227.2 [M−H].sup.+.

[0834] Step 5:

##STR00716##

[0835] 5-Bromo-2,4-dichloropyrimidine (2 g, 8.8 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then anhydrous potassium carbonate (3.64 g, 26.3 mmol) and 147-4 (240 mg, 1.1 mmol) were added sequentially. The reaction solution was heated to 60° C. and continued to stir for 12 hours.

[0836] After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (150 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (100 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 200 mg of compound 147-5.

[0837] MS (ESI) m/z: 416.9, 418.9 [M+H].sup.+.

[0838] Step 6:

##STR00717##

[0839] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 147-5 (100 mg, 0.24 mmol) to obtain 62 mg of compound 147.

[0840] MS (ESI) m/z: 669.2, 671.2 [M+H].sup.+.

[0841] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.12 (s, 1H), 8.04 (s, 1H), 7.76 (s, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.26 (s, 1H), 6.83 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.83-3.79 (m, 4H), 3.29 (s, 3H), 3.06 (s, 3H), 3.03-2.97 (m, 2H), 2.91-2.86 (m, 4H), 2.83-2.68 (m, 2H).

Embodiment 148

Preparation of (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(2-methylmorpholinyl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 148)

[0842] ##STR00718##

[0843] Compound 121-6 (50 mg, 0.07 mmol) was dissolved in dichloromethane. Then, glacial acetic acid (8.8 mg, 0.15 mmol) and 2-methylmorpholine (15 mg, 0.15 mmol) were added to the above reaction solution and the mixture was continued to stir at room temperature for 30 minutes. Sodium triacetoxyborohydride (47 mg, 0.2 mmol) was added to the reaction solution, and the mixture was continued to stir at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by C18 column. Purification conditions were as follows: chromatographic column: 20 g C18 reversed-phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate of 15 mL/min; gradient: acetonitrile increased from 10% to 70% within 30 minutes; detection wavelength of 254 nm. The product was collected and lyophilized under reduced pressure to obtain 23 mg of compound 148 (racemic).

[0844] MS (ESI) m/z: 761.2, 763.2 [M+H].sup.+.

[0845] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.60 (s, 1H), 9.01 (dd, J=9.6, 4.2 Hz, 1H), 8.78-8.64 (m, 2H), 8.31 (s, 1H), 8.24 (s, 1H), 7.76 (s, 1H), 7.61 (d, J=9.6 Hz, 1H), 7.54 (s, 1H), 7.34 (s, 1H), 6.72 (s, 1H), 3.92 (s, 4H), 3.79 (s, 5H), 3.26-3.22 (m, 2H), 2.92-2.86 (m, 2H), 2.65-2.57 (m, 2H), 2.32 (s, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.98 (s, 3H), 1.28 (s, 2H), 1.21 (d, J=6.2 Hz, 3H).

Embodiment 150

Preparation of (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 150)

[0846] Step 1:

##STR00719##

[0847] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with 1-tert-butoxycarbonylpiperazine (4.5 g, 24 mmol) to obtain 8 g of compound 150-1.

[0848] MS (ESI, m/z): 416.0, 418.0 [M+H].sup.+.

[0849] Step 2:

##STR00720##

[0850] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 150-1 (7.9 g, 19 mmol) to obtain 7 g of compound 150-2.

[0851] MS (ESI, m/z): 418.1 [M+H].sup.+.

[0852] Step 3:

##STR00721##

[0853] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 150-2 (5.5 g, 13.2 mmol) to obtain 3.6 g of compound 150-3.

[0854] MS (ESI, m/z): 388.3 [M+H].sup.+.

[0855] Step 4:

##STR00722##

[0856] Compounds 1-5 (3.7 g, 9 mmol) and 150-3 (3.5 g, 9.0 mmol) were dissolved in dioxane (5 mL) under nitrogen atmosphere. Then, dichloro-[1,3-bis(diisopropylphenyl)imidazolylidene]-(3-chloropyridyl)palladium (35 mg, 0.05 mmol) and cesium carbonate (249 mg, 0.8 mmol) were added to the above reaction solution. The reaction system was heated to 95° C. and continued to stir for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 3.2 g of compound 150-4.

[0857] MS (ESI, m/z): 763.3, 765.3 [M+H].sup.+.

[0858] Step 5:

##STR00723##

[0859] Prepared according to the method of step 2 in Embodiment 133, the raw materials were replaced with compound 150-4 (1 g, 1.3 mmol) to obtain 0.9 g of compound 150-5.

[0860] MS (ESI, m/z): 663.3, 665.3 [M+H].sup.+.

[0861] Step 6:

##STR00724##

[0862] Prepared according to the method of step 1 in Embodiment 148, the raw materials were replaced with compound 150-5 (150 mg, 0.23 mmol) and 3-oxetanone (49 mg, 0.68 mmol) to obtain 40 mg of compound 150.

[0863] MS (ESI, m/z): 719.4, 721.4 [M+H].sup.+.

[0864] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 8.98 (dd, J=9.6, 4.4 Hz, 1H), 8.72 (dd, J=13.2, 2.0 Hz, 2H), 8.29 (s, 1H), 8.22 (s, 1H), 7.62 (s, 3H), 7.38 (s, 1H), 6.75 (s, 1H), 4.70 (d, J=6.8 Hz, 4H), 3.90 (s, 3H), 3.72 (s, 3H), 3.63 (s, 1H), 3.01 (s, 4H), 2.49 (s, 4H),2.13 (d, J=14.4 Hz, 6H).

Embodiment 153

Preparation of (6-((5-bromo-2-((4-(3-(fluoromethyl)-4-methylpiperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl))phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 153)

[0865] Step 1:

##STR00725##

[0866] tert-Butyl 2-(hydroxymethyl)piperazine-1-carboxylate (2 g, 9.3 mmol) and triethylamine (2.8 g, 27.8 mmol) were dissolved in dichloromethane (25 mL). Benzyl chloroformate (3.2 g, 18.5 mmol) was added to the above reaction solution at 0° C. The reaction system was heated to room temperature and continued to stir for 3 hours. After TLC monitoring showed that the raw materials disappeared, ice water (25 g) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 3 g of compound 153-2.

[0867] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.43-7.27 (m, 5H), 5.09 (s, 2H), 4.83 (s, 1H), 4.13-3.66 (m, 4H), 3.41 (dd, J=16.2, 9.6 Hz, 1H), 3.30 (s, 1H), 2.92 (d, J=10.8 Hz, 3H), 1.40 (s, 9H).

[0868] Step 2:

##STR00726##

[0869] Prepared according to the method of step 2 in Embodiment 144, the raw materials were replaced with compound 153-2 (3 g, 8.6 mmol) to obtain 1.3 g of compound 153-3.

[0870] MS (ESI, m/z): 265.2 [M+H].sup.+.

[0871] Step 3:

##STR00727##

[0872] Compound 153-3 (1.3 g, 4.9 mmol) was dissolved in dichloromethane (20 mL). Then, diethylamino sulfur trifluoride (4.76 g, 29.5 mmol) was added dropwise to the above reaction solution under nitrogen atmosphere at −60° C., and the mixture was continued to stir at this temperature for 30 minutes. The reaction system was heated to room temperature and continued to stir for 16 hours. After LCMS monitoring showed that the raw materials disappeared, sodium hydroxide aqueous solution (1 mol/L, 30 mL) was slowly added dropwise to the reaction solution at 0° C. to quench. The mixture was extracted with dichloromethane (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 0.78 g of compound 153-4.

[0873] MS (ESI, m/z): 267.2 [M+H].sup.+.

[0874] Step 4:

##STR00728##

[0875] Compound 153-4 (780 mg, 2.9 mmol) was dissolved in ethanol (10 mL). Then, wet palladium on carbon (10%, 250 mg) was added to the above solution; the reaction system was replaced with hydrogen for 3 times, and then stirred at room temperature for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was filtered through diatomite, and the filter cake was washed with ethanol (50 mL×3 times). The filtrate was concentrated under reduced pressure to obtain 250 mg of compound 153-5.

[0876] MS (ESI) m/z: 133.3 [M+H].sup.+.

[0877] Step 5:

##STR00729##

[0878] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with compound 153-5 (250 mg, 1.9 mmol) to obtain 400 mg of compound 153-6.

[0879] MS (ESI, m/z): 362.0, 364.0 [M+H].sup.+.

[0880] Step 6:

##STR00730##

[0881] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 153-6 (309 mg, 0.9 mmol) to obtain 220 mg of compound 153-7.

[0882] MS (ESI, m/z): 364.1 [M+H].sup.+.

[0883] Step 7:

##STR00731##

[0884] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 153-7 (120 mg, 0.3 mmol) to obtain 100 mg of compound 153-8.

[0885] MS (ESI, m/z): 334.3 [M+H].sup.+.

[0886] Step 8:

##STR00732##

[0887] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 153-8 (70 mg, 0.2 mmol) to obtain 30 mg of compound 153.

[0888] MS (ESI, m/z): 709.3, 711.3 [M+H].sup.+.

[0889] .sup.1H NMR (300 MHz,CDCl.sub.3) δ 12.56 (s, 1H), 8.97 (dd, J=9.6, 4.2 Hz, 1H), 8.77-8.66 (m, 2H), 8.29 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.66-7.58 (m, 3H), 7.41 (s, 1H), 6.72 (s, 1H), 4.82-4.33 (m, 2H), 3.91 (s, 3H), 3.73 (s, 3H), 3.13-3.01 (m, 4H), 2.83 (s, 1H), 2.54 (s, 5H), 2.16 (s, 3H), 2.11 (s, 3H).

Embodiment 155

(6-((5-Bromo-2-((4-((2S,6S)-2,6-dimethylmorpholinyl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and

(6-((5-bromo-2-((4-((2R,6R)-2,6-dimethylmorpholinyl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0890] Step 1:

##STR00733##

[0891] The racemic compound 135 (trans, 70 mg, 0.1 mmol) was subjected to a chiral resolution (resolution conditions: chiral column (R, R)-Whelk-01, 2.12×25 cm, 5 □m; mobile phase A n-hexane (10 mM ammonia in methanol), mobile phase B ethanol; flow rate of 20 mL/min; gradient of 50% B; detection wavelength of 210/270 nm) to obtain 23 mg of optically pure compound 155a and 11 mg of optically pure compound 155b.

[0892] 155a: MS (ESI, m/z) 692.2, 694.2 [M+H].sup.+.

[0893] [α].sub.D.sup.25=−31.5° (c=0.35, MeOH)

[0894] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.71 (s, 1H), 8.97 (dd, J=9.6, 4.2 Hz, 1H), 8.75 (dd, J=12.9, 1.8 Hz, 2H), 8.28 (s, 1H), 8.17 (s, 1H), 7.64 (s, 2H), 7.60 (s, 1H), 7.54 (s, 1H), 6.72 (s, 1H), 4.13-4.08 (m, 2H), 3.94 (s, 3H), 3.80 (s, 3H), 3.00-2.96 (m, 2H), 2.58-2.52 (m, 2H), 2.15 (d, J=14.4 Hz, 6H), 1.26 (d, J=6.6 Hz, 6H).

[0895] 155b: MS (ESI, m/z) 692.2, 694.2 [M+H].sup.+.

[0896] [α].sub.D.sup.25=+35.8° (c=0.22, MeOH)

[0897] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.73 (s, 1H), 8.97 (dd, J=9.6, 4.2 Hz, 1H), 8.75 (dd, J=13.2, 1.8 Hz, 2H), 8.27 (s, 1H), 8.16 (s, 1H), 7.64-7.54 (m, 4H), 6.72 (s, 1H), 4.13-4.08 (m, 2H), 3.94 (s, 3H), 3.81 (s, 3H), 3.00-2.96 (m, 2H), 2.58-2.52 (m, 2H), 2.15 (d, J=14.1 Hz, 6H), 1.26 (d, J=6.3 Hz, 6H).

Embodiment 164

Preparation of (6-((5-bromo-2-((4-(3-(fluoromethyl)-4-isopropylpiperazin-1-yl)-2-methoxy-5-(1-methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (compound 164)

[0898] Step 1:

##STR00734##

[0899] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with 1-tert-butoxycarbonyl-2-(hydroxymethyl)piperazine (1.1 g, 8 mmol) to obtain 1.7 g of compound 164-1.

[0900] MS (ESI, m/z): 446.1, 448.1 [M+H].sup.+.

[0901] Step 2:

##STR00735##

[0902] Prepared according to the method of step 2 in Embodiment 133, the raw materials were replaced with compound 164-1 (528 mg, 1.2 mmol) to obtain 453 mg of compound 164-2.

[0903] MS (ESI, m/z): 346.1, 348.1 [M+H].sup.+.

[0904] Step 3:

##STR00736##

[0905] Compound 164-2 (409 mg, 1.2 mmol) was dissolved in 1,2-dichloroethane (13 mL). Then, acetone (823 mg, 14.2 mmol) was added to the above reaction solution and the mixture was continued to stir for 30 minutes; then, sodium triacetoxyborohydride (907 mg, 4.3 mmol) was added to the above reaction. The reaction system was continued to stir at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, water (50 mL) was added to the reaction solution. The mixture was extracted with chloroform (100 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 310 mg of compound 164-3.

[0906] MS (ESI, m/z): 388.2, 390.2 [M+H].sup.+.

[0907] Step 4:

##STR00737##

[0908] Prepared according to the method of step 3 in Embodiment 153, the raw materials were replaced with compound 164-3 (284 mg, 0.7 mmol) to obtain 108 mg of compound 164-4.

[0909] MS (ESI, m/z): 390.0, 392.0 [M+H].sup.+.

[0910] Step 5:

##STR00738##

[0911] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 164-4 (108 mg, 0.3 mmol) to obtain 59 mg of compound 164-5.

[0912] MS (ESI, m/z): 392.1 [M+H].sup.+.

[0913] Step 6:

##STR00739##

[0914] Prepared according to the method of step 6 in Embodiment 1, the corresponding raw materials were replaced with compound 164-5 (59 mg, 0.15 mmol) to obtain 59 mg of compound 164-6.

[0915] MS (ESI, m/z): 362.3 [M+H].sup.+.

[0916] Step 7:

##STR00740##

[0917] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 164-6 (59 mg, 0.16 mmol) to obtain 25 mg of compound 164.

[0918] MS (ESI, m/z): 737.2, 739.2 [M+H].sup.+.

[0919] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.86-8.74 (m, 3H), 8.43 (s, 1H), 8.26 (s, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 7.55-7.50 (m, 2H), 6.84 (s, 1H), 4.70 (d, J=3.9 Hz, 1H), 4.54 (d, J=3.9 Hz, 1H), 3.92 (s, 3H), 3.67 (s, 3H), 3.53-3.48 (m, 1H), 3.23-2.96 (m, 4H), 2.91-2.71 (m, 3H), 2.15 (d, J=14.4 Hz, 6H), 1.25 (d, J=6.6 Hz, 3H), 1.15 (d, J=6.6 Hz, 3H).

Embodiment 168

Preparation of (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(1-methyloctahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin yl)dimethylphosphine oxide (compound 168)

[0920] Step 1:

##STR00741##

[0921] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with 7-tert-butoxycarbonyl-4,7-diazabicyclo[4.3.0]nonane (550 mg, 2.43 mmol) to obtain 700 mg of compound 168-1.

[0922] MS (ESI, m/z): 456.0, 458.0 [M+H].sup.+.

[0923] Step 2:

##STR00742##

[0924] Prepared according to the method of step 2 in Embodiment 144, the raw materials were replaced with compound 168-1 (650 mg, 1.42 mmol) to obtain 550 mg of compound 168-2.

[0925] MS (ESI, m/z): 370.1, 372.1 [M+H].sup.+.

[0926] Step 3:

##STR00743##

[0927] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 168-2 (600 mg, 1.62 mmol) to obtain 360 mg of compound 168-3.

[0928] MS (ESI, m/z): 372.3 [M+H].sup.+.

[0929] Step 4:

##STR00744##

[0930] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 168-3 (160 mg, 0.43 mmol) to obtain 130 mg of compound 168-4.

[0931] MS (ESI, m/z): 342.3 [M+H].sup.+.

[0932] Step 5:

##STR00745##

[0933] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 168-4 (87 mg, 0.26 mmol) to obtain 47 mg of compound 168.

[0934] MS (ESI, m/z): 717.2, 719.2 [M+H].

[0935] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.56 (s, 1H), 8.96 (dd, J=9.6, 4.4 Hz, 1H), 8.72 (s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.59 (d, J=10.0 Hz, 1H), 7.38 (s, 1H), 7.34 (s, 1H), 6.74 (s, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 3.46 (s, 1H), 3.11-2.58 (m, 7H), 2.35 (s, 5H), 2.12 (d, J=14.4 Hz, 8H).

Embodiment 171

Preparation of N-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (compound 171)

[0936] Step 1:

##STR00746##

[0937] Compound 171-1 (15 g, 65 mmol) was dissolved in water (800 mL); and then an aqueous solution of glyoxal (40%) (23.6 mL) was added to the above reaction solution. The resulting reaction system was heated to 100° C. and continued to stir for 4 hours.

[0938] After TLC monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature. The precipitated solid was filtered, and the filter cake was washed with water (100 mL×2 times). The filter cake was dried to obtain 18.2 g of compound 171-2.

[0939] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.18 (d, J=1.8 Hz, 1H), 9.10 (d, J=1.8 Hz, 1H), 8.31 (d, J=9.0 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H).

[0940] Step 2:

##STR00747##

[0941] Compound 171-2 (16 g, 63 mmol) was dissolved in ethanol (250 mL). Then, ammonium chloride (50 g, 929 mmol), iron powder (65 g, 1.1 mol) and water (170 mL) were added to the above reaction; The resulting reaction system was heated to 90° C. and continued to stir for 2 hours.

[0942] After the LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (100 mL×2 times) and the filtrate was concentrated under reduced pressure. Water (1 L) was added to the resulting residue, and the mixture was extracted with ethyl acetate (1.5 L×2 times). The organic phases were combined, and the organic phases were washed with saturated brine (1 L×2 times) first, and then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain 6.3 g of compound 171-3.

[0943] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.94 (d, J=1.8 Hz, 1H), 8.82 (d, J=1.8 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 6.21 (br, 2H).

[0944] Step 3:

##STR00748##

[0945] Prepared according to the method of step 4 in Embodiment 80, the raw materials were replaced with compound 171-3 (3 g, 13.4 mmol) to obtain 3.5 g of compound 171-4.

[0946] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.13-9.09 (m, 2H), 8.28 (d, J=9.0 Hz, 1H), 8.22 (d, J=9.0 Hz, 1H), 3.71-3.67 (m, 6H).

[0947] Step 4:

##STR00749##

[0948] Compound 171-4 (8 g, 21 mmol) was dissolved in a mixed solvent of methanol (80 mL) and tetrahydrofuran (80 mL). Then, 50% sodium hydroxide aqueous solution (33.6 g, 420 mmol) was added to the reaction solution at 0° C. The reaction system was heated to room temperature and continued to stir for 1 hour. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was diluted with water (200 mL), and then the pH was adjusted to 6 with concentrated hydrochloric acid. The mixture was extracted with a mixed solvent of chloroform and isopropanol (3:1, 80 mL×3 times). The organic phases were combined, and the organic phases were washed with saturated brine (300 mL×2 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=5/1) to obtain 6 g of compound 171-5.

[0949] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.83 (br, 1H), 9.09-9.01 (m, 2H), 8.15 (d, J=9.0 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 3.31 (s, 3H).

[0950] Step 5:

##STR00750##

[0951] Prepared according to the method of step 2 in Embodiment 147, the raw materials were replaced with compound 171-5 (3 g, 9.9 mmol) to obtain 3 g of compound 171-6.

[0952] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.92-8.90 (m, 2H), 8.06-8.02 (m, 2H), 3.41 (s, 3H), 3.30 (s, 3H).

[0953] Step 6:

##STR00751##

[0954] Prepared according to the method of step 1 in Embodiment 79, the raw materials were replaced with compound 171-6 (2.8 g, 8.8 mmol) to obtain 4 g of compound 171-7.

[0955] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.82 (d, J=9.6 Hz, 1H), 8.79-8.77 (m, 2H), 8.10 (d, J=9.6 Hz, 1H), 7.87 (br, 1H), 3.45 (s, 3H), 3.14 (s, 3H), 1.45 (s, 9H).

[0956] Step 7:

##STR00752##

[0957] Prepared according to the method of step 2 in Embodiment 133, the raw materials were replaced with compound 171-7 (1 g, 2.8 mmol) to obtain 0.68 g of compound 171-8.

[0958] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.67 (d, J=2.1 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.30 (d, J=9.0 Hz, 1H), 4.83 (br, 2H), 3.41 (s, 3H), 3.16 (s, 3H).

[0959] Step 8:

##STR00753##

[0960] Prepared according to the method of step 3 in Embodiment 1, the raw materials were replaced with compound 171-8 (650 mg, 2.6 mmol) to obtain 1 g of compound 171-9.

[0961] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.11 (s, 1H), 9.05-8.97 (m, 2H), 8.66 (s, 1H), 8.56 (d, J=9.6 Hz, 1H), 8.25 (d, J=9.3 Hz, 1H), 3.41 (s, 3H), 3.19 (s, 3H).

[0962] Step 9:

##STR00754##

[0963] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 171-9 (80 mg, 0.18 mmol) to obtain 18 mg of compound 171.

[0964] MS (ESI) m/z: 695.1, 697.1 [M+H].sup.+.

[0965] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.91 (d, J=1.8 Hz, 1H), 8.81 (d, J=1.8 Hz, 1H), 8.73 (d, J=9.3 Hz, 1H), 8.24 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.51 (s, 1H), 7.45 (d, J=9.3 Hz, 1H), 6.83 (s, 1H), 3.91 (s, 3H), 3.82-3.78 (m, 4H), 3.72 (s, 3H), 3.49 (s, 3H), 3.20 (s, 3H), 2.92-2.86 (m, 4H).

Embodiment 183

N-(2-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-)(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl-N-methylcyclopropanesulfonamide (Compound 183)

[0966] Step 1:

##STR00755##

[0967] A tetrahydrofuran solution of triethylamine (2.16 g, 21.3 mmol) and methylamine (22 mL, 43 mmol) was dissolved in dichloromethane (16 mL) at 0° C. Then, cyclopropylsulfonyl chloride (2 g, 14.2 mmol) was added to the above reaction solution. The reaction system was heated to room temperature and continued to stir for 24 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction system was distilled under reduced pressure, and the resulting residue was dissolved in acetonitrile (20 mL). After cesium carbonate (5.8 g, 18 mmol) and 2-nitrofluorobenzene (2.5 g, 18 mmol) were added to the reaction solution, the mixture was continued to stir at room temperature for 24 hours. After TLC monitoring showed that the raw materials disappeared, the reaction system was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain 2.7 g of compound 183-2.

[0968] MS (ESI) m/z: 257.0 [M+H].sup.+.

[0969] Step 2:

##STR00756##

[0970] Prepared according to the method of step 6 in Embodiment 1, the corresponding raw materials were replaced with compound 183-2 (2.4 g, 9.37 mmol) to obtain 2.1 g of compound 183-3.

[0971] MS (ESI, m/z): 227.1 [M+H].sup.+.

[0972] Step 3:

##STR00757##

[0973] Prepared according to the method of step 1 in Embodiment 2, the corresponding raw materials were replaced with compound 183-3 (1 g, 4.6 mmol) to obtain 0.4 g of compound 183-4.

[0974] MS (ESI, m/z): 416.9, 418.9 [M+H].sup.+.

[0975] Step 4:

##STR00758##

[0976] Prepared according to the method of step 7 in Embodiment 1, the corresponding raw materials were replaced with compound 183-4 (100 mg, 0.24 mmol) and compound 101-3 (133 mg, 0.36 mmol) to obtain 36 mg of compound 183.

[0977] MS (ESI, m/z): 750.4, 752.4 [M+H].sup.+.

[0978] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.56 (s, 1H), 8.20-8.15 (m,2H), 7.92 (s, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.61 (dd, J=7.8, 1.5 Hz, 1H), 7.06-7.01 (m, 1H), 6.86-6.78 (m, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.30 (s, 3H), 3.12 (s, 4H), 2.89 (s, 4H), 2.78 (s, 3H), 2.75-2.69 (m, 1H), 1.82-1.70 (m, 8H), 1.11-1.01 (m, 4H).

Embodiment 200

(6-((5-Bromo-2-((5-(1-methyl-1H-pyrazol-4-yl)-3-(4-methylpiperazin-1-yl)benzo[d]isoxazol-7-yl)amino)pyrimidin-4-yl)aminoquinoxalin-5-yl)dimethylphosphine oxide

[0979] Step 1:

##STR00759##

[0980] Methyl 2-hydroxy-3-nitrobenzoate (10.0 g, 50.7 mmol) was dissolved in glacial acetic acid (150 g) at room temperature. Then, bromine (3.9 mL) was added dropwise to the above reaction solution. The reaction system was continued to stir at room temperature for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was poured into water (500 mL). The precipitated solid was filtered and dried to obtain 13 g of compound 200-2.

[0981] MS (ESI) m/z: 274.0, 276.0 [M−H].sup.+.

[0982] Step 2:

##STR00760##

[0983] Compound 200-2 (1 g, 3.6 mmol) and hydroxylamine hydrochloride (1.01 g, 14.49 mmol) were dissolved in methanol (80 mL) at room temperature. Then, potassium hydroxide (1.63 g, 28.98 mmol) was added to the reaction solution. The reaction system was continued to stir at room temperature for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL), and the pH of the mixture was adjusted to 2 with 2N hydrochloric acid. The precipitated solid was filtered and dried to obtain 0.8 g of compound 200-3.

[0984] MS (ESI) m/z: 275.0, 277.0 [M−H].sup.+.

[0985] Step 3:

##STR00761##

[0986] Compound 200-3 (6 g, 21.66 mmol) was dissolved in tetrahydrofuran (80 mL). Then, carbonyldiimidazole (7.02 g, 43.32 mmol) was added to the reaction solution, and the reaction system was heated to 65° C. and continued to stir for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added to the residue, and the pH of the mixture was adjusted to 2 with 2N aqueous hydrochloric acid. The precipitated solid was filtered and dried to obtain 5.5 g of compound 200-4.

[0987] MS (ESI) m/z: 257.0, 259.0 [M−H].sup.+.

[0988] Step 4:

##STR00762##

[0989] Compound 200-4 (1 g, 3.8 mmol) and 1,8-diazabicycloundec-7-ene (1.76 g, 11.7 mmol) were dissolved in N,N-dimethylformamide (20 mL). Then, a BOP reagent (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 3.42 g, 7.8 mmol) was added to the reaction solution at 0° C. The reaction system was heated to 50° C. and continued to stir for 2 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature and directly purified by a C18 reverse-phase column. Purification conditions were as follows: chromatographic column: 80 g C18 reversed-phase column; mobile phase, water (with 10 mM ammonium bicarbonate) and acetonitrile; flow rate, 50 mL/min; gradient, acetonitrile increased from 25% to 50% within 15 minutes; detection wavelength, 254 nm. The product was collected and lyophilized under reduced pressure to obtain 0.7 g of compound 200-5.

[0990] MS (ESI) m/z: 341.0, 343.0 [M+H].sup.+.

[0991] Step 5:

##STR00763##

[0992] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with 200-5 (400 mg, 1.18 mmol) to obtain 350 mg of compound 200-6.

[0993] MS (ESI) m/z: 343.1 [M+H].sup.+.

[0994] Step 6

##STR00764##

[0995] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with 200-6 (400 mg, 1.17 mmol) to obtain 200 mg of compound 200-7.

[0996] MS (ESI) m/z: 313.2 [M+H].sup.+.

[0997] Step 7:

##STR00765##

[0998] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with 200-7 (100 mg, 0.32 mmol) to obtain 45 mg of compound 200.

[0999] MS (ESI) m/z: 688.3, 690.3 [M+H].sup.+.

[1000] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.91 (d, J=1.8 Hz, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.75 (dd, J=9.6, 4.2 Hz, 1H), 8.43 (d, J=6.3 Hz, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.65-7.62 (m, 2H), 3.83 (s, 3H), 3.80-3.71 (m, 4H), 3.04-3.01 (m, 4H), 2.66 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H).

Embodiment 205

(6-((5-Bromo-2-((4-(1-(2-fluoroethyl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1001] Step 1:

##STR00766##

[1002] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 168-1 (600 mg, 1.3 mmol) to obtain 456 mg of compound 205-1.

[1003] MS (ESI) m/z: 457.3 [M+H].sup.+.

[1004] Step 2:

##STR00767##

[1005] Prepared according to the method of step 2 in Embodiment 16, the raw materials were replaced with compound 205-1 (600 mg, 1.3 mmol) to obtain 456 mg of compound 205-2.

[1006] MS (ESI) m/z: 357.1 [M+H].sup.+.

[1007] Step 3:

##STR00768##

[1008] Prepared according to the method of step 3 in Embodiment 133, the raw materials were replaced with compound 205-2 (200 mg, 0.56 mmol) to obtain 70 mg of compound 205-3.

[1009] MS (ESI) m/z: 403.4 [M+H].sup.+.

[1010] Step 4:

##STR00769##

[1011] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 205-3 (70 mg, 0.17 mmol) to obtain 60 mg of compound 205-4.

[1012] MS (ESI) m/z: 373.4 [M+H].sup.+.

[1013] Step 5:

##STR00770##

[1014] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 205-4 (60 mg, 0.1 mmol) to obtain 5 mg of compound 205.

[1015] MS (ESI) m/z: 749.3, 751.3 [M+H].sup.+.

[1016] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.57 (s, 1H), 8.98 (dd, J=9.6, 4.0 Hz, 1H), 8.74-8.67 (m, 2H), 8.29 (s, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.61 (s, 1H), 7.50 (s, 1H), 7.31 (s, 1H), 6.72 (s, 1H), 4.57-4.45 (m, 2H), 3.90 (s, 3H), 3.78 (s, 3H), 3.28-3.62 (m, 9H), 2.27-2.20 (m, 1H), 2.12 (d, J=14.4 Hz, 6H), 1.99-1.91 (m, 1H), 1.72 (s, 3H).

Embodiment 217

(6-((5-Bromo-2-((4-(2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1017] Step 1:

##STR00771##

[1018] tert-Butyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate 217-1 (5 g, 23.44 mmol) was dissolved in ethanol (80 mL) and water (9 mL) at room temperature. Then, methylamine aqueous solution (30%, 73 g, 705.2 mmol) was added to the reaction solution. The reaction system was continued to stir at room temperature for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure to obtain 5.7 g of compound 217-2.

[1019] MS (ESI) m/z: 245.2 [M+H].sup.+.

[1020] Step 2:

##STR00772##

[1021] Compound 217-2 (1 g, 4.1 mmol) and potassium carbonate (1.69 g, 12.2 mmol) were dissolved in dichloromethane (10 mL). Then, a solution of 2-chloropropionyl chloride (769 mg, 6.1 mmol) in dichloromethane (5 mL) was added dropwise to the reaction solution at 0° C. The reaction system was heated to room temperature and continued to stir for 1 hour. After LCMS monitoring showed that the raw materials disappeared, water (100 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (150 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (15 mL). Potassium tert-butoxide (479 mg, 4.27 mmol) was added to the reaction solution at −78° C. under nitrogen atmosphere. The reaction solution was heated to room temperature and continued to stir for 1 hour. After LCMS monitoring showed that the raw materials disappeared, water (100 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (150 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain 1.2 g of racemic compound 217-3.

[1022] MS (ESI) m/z: 299.3 [M+H].sup.+.

[1023] Step 3:

##STR00773##

[1024] Prepared according to the method of step 2 in Embodiment 16, the raw materials were replaced with compound 217-3 (1.1 g, 3.69 mmol) to obtain 0.7 g of compound 217-4.

[1025] MS (ESI) m/z: 199.3 [M+H].sup.+.

[1026] Step 4:

##STR00774##

[1027] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with compound 217-4 (750 mg, 3.78 mmol) to obtain 1.1 g of compound 217-5.

[1028] MS (ESI) m/z: 427.9, 429.9 [M+H].sup.+.

[1029] Step 5:

##STR00775##

[1030] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 217-5 (1 g, 2.335 mmol) to obtain 1 g of compound 217-6.

[1031] MS (ESI) m/z: 430.2 [M+H].sup.+.

[1032] Step 6:

##STR00776##

[1033] Compound 217-6 (200 mg, 0.47 mmol) was dissolved in tetrahydrofuran (3 mL) under nitrogen atmosphere. Then, borane dimethyl sulfide (0.44 mL) was added to the reaction solution at 0° C. The reaction system was heated to room temperature and continued to stir for 16 hours. After LCMS monitoring showed that the raw materials disappeared, methanol (5 mL) was added to the reaction solution at 0° C. and concentrated under reduced pressure. The residue was purified by reversed-phase column, and the purification conditions were as follows: chromatographic column: 40 g C18 reversed-phase column; mobile phase: water (with 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 30 mL/min; gradient: acetonitrile increased from 30% to 50% within 30 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to obtain 80 mg of compound 217-7.

[1034] MS (ESI) m/z: 386.2 [M+H].sup.+.

[1035] Step 7:

##STR00777##

[1036] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 217-7 (60 mg, 0.156 mmol) to obtain 40 mg of racemic compound 217.

[1037] MS (ESI) m/z: 761.4, 763.4 [M+H].sup.+.

[1038] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.87-8.78 (m, 3H), 8.26 (s, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 7.54-7.49 (m, 2H), 6.86 (s, 1H), 3.93 (s, 4H), 3.71 (s, 3H), 3.07-3.00 (m, 1H), 2.91-2.80 (m, 5H), 2.31 (s, 4H), 2.16 (d, J=14.4 Hz, 6H), 1.90-1.63 (m, 5H), 1.17 (d, J=6.3 Hz, 3H).

Embodiment 219

(6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1039] Step 1:

##STR00778##

[1040] Prepared according to the method in Embodiment 148, the raw materials were replaced with compound 150-5 (100 mg, 0.15 mmol) and oxetane-3-carbaldehyde (39 mg, 0.45 mmol) to obtain 50 mg of compound 219.

[1041] MS (ESI, m/z): 733.3, 735.3 [M+H].sup.+.

[1042] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.86-8.79 (m, 3H), 8.26 (s, 1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.53-7.49 (m, 2H), 6.84 (s, 1H), 4.86-4.78 (m, 2H), 4.48 (t, J=6.3 Hz, 2H), 3.92 (s, 3H), 3.69 (s, 3H), 3.40-3.38 (m, 1H), 2.94-2.82 (m, 6H), 2.59 (s, 4H), 2.16 (d, J=14.4 Hz, 6H).

Embodiment 221

(6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(7-methyl-3,7-diazabicyclo[4.2.0]octan-3-yl)phenyl)aminopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1043] Step 1:

##STR00779##

[1044] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with compound tert-butyl 3,7-diazabicyclo[4.2.0]octane-7-carboxylate (cas #: 885271-73-8, 509 mg, 2.4 mmol) to obtain 700 mg of compound 221-1.

[1045] MS (ESI, m/z): 442.1, 444.1 [M+H].sup.+.

[1046] Step 2:

##STR00780##

[1047] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 221-1 (700 mg, 1.58 mmol) to obtain 400 mg of compound 221-2.

[1048] MS (ESI, m/z): 444.2 [M+H].sup.+.

[1049] Step 3:

##STR00781##

[1050] Compound 221-2 (350 mg, 0.8 mmol) was dissolved in tetrahydrofuran (4 mL) under nitrogen atmosphere. Then, lithium aluminum hydride (60 mg, 1.5 mmol) was added to the reaction solution at 0° C. The reaction system was heated to 65° C. and continued to stir for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to 0° C. and sodium hydroxide aqueous solution (1 M, 0.5 mL) was added thereto and filtered. The filtrate was concentrated under reduced pressure to obtain 200 mg of compound 221-3.

[1051] MS (ESI, m/z): 328.2 [M+H].sup.+.

[1052] Step 4:

##STR00782##

[1053] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 221-3 (150 mg, 0.4 mmol) to obtain 24 mg of racemic compound 221.

[1054] MS (ESI, m/z): 703.3, 705.3 [M+H].sup.+.

[1055] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.88-8.78 (m, 3H), 8.28 (s, 1H), 7.95 (s, 1H), 7.79 (s, 1H), 7.55 (d, J=9.6 Hz, 1H), 7.48 (s, 1H), 6.90 (s, 1H), 3.95 (s, 3H), 3.70 (s, 5H), 3.39-3.26 (m, 2H), 3.09-2.89 (m, 3H), 2.72-2.65 (m, 1H), 2.54 (s, 3H), 2.17 (d, J=14.4 Hz, 6H), 1.97-1.85 (m, 2H).

Embodiment 222

(6-((5-Bromo-2-((4-(4-(3,3-difluoropropyl)piperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1056] Step 1:

##STR00783##

[1057] 3,3-Difluoro-1-propanol (200 mg, 2.1 mmol), triethylamine (421 mg, 4.16 mmol) and 4-dimethylaminopyridine (51 mg, 0.42 mmol) were dissolved in dichloromethane (10 mL). Then, p-toluenesulfonyl chloride (600 mg, 3.15 mmol) was added to the reaction solution in batches at 0° C. The reaction system was heated to room temperature and continued to stir for 16 hours. After TLC monitoring showed that the raw materials disappeared, water (30 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain 380 mg of compound 222-2.

[1058] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.80 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.05-5.74 (m, 1H), 4.18 (t, J=6.0 Hz, 2H), 2.46 (s, 3H), 2.27-2.15 (m, 2H).

[1059] .sup.19F NMR (377 MHz, CDCl.sub.3) δ −118.40.

[1060] Step 2:

##STR00784##

[1061] Compound 150-5 (300 mg, 0.43 mmol) and potassium carbonate (250 mg, 1.81 mmol) were dissolved in N,N-dimethylformamide (5 mL). Then, compound 222-2 (136 mg, 0.5 mmol) was added to the reaction solution. The reaction system was heated to 100° C. and continued to stir for 16 hours. After TLC monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature. Water (30 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 38 mg of compound 222.

[1062] MS (ESI, m/z): 741.2, 743.2 [M+H].sup.+.

[1063] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.61 (s, 1H), 8.01 (dd, J=9.6, 4.2 Hz, 1H), 8.76 (d, J=2.1 Hz, 1H), 8.72 (d, J=2.1 Hz, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.66-7.64 (m, 3H), 7.38 (s, 1H), 6.75 (s, 1H), 6.19-5.79 (m, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 3.02 (s, 4H), 2.70 (s, 6H), 2.17-2.13 (m, 8H).

[1064] .sup.19F NMR (282 MHz, CDCl.sub.3) δ −116.99.

Embodiment 223

[1065] (6-((5-Bromo-2-((4-(3-(3-fluoroazetidin-1-yl)pyrrolidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1066] Step 1:

##STR00785##

[1067] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with 3-pyrrolidinol (2.51 g, 28.8 mmol) to obtain 7.5 g of compound 223-1.

[1068] MS (ESI, m/z): 317.0, 319.0 [M+H].sup.+.

[1069] Step 2:

##STR00786##

[1070] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 223-1 (7.5 g, 23.7 mmol) to obtain 4.5 g of compound 223-2.

[1071] MS (ESI, m/z): 319.1 [M+H].sup.+.

[1072] Step 3:

##STR00787##

[1073] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 223-2 (500 mg, 1.57 mmol) to obtain 420 mg of compound 223-3.

[1074] MS (ESI, m/z): 289.1 [M+H].sup.+.

[1075] Step 4:

##STR00788##

[1076] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 223-3 (377 mg, 1.31 mmol) to obtain 470 mg of compound 223-4.

[1077] MS (ESI, m/z): 664.1, 666.1 [M+H].sup.+.

[1078] Step 5:

##STR00789##

[1079] Compound 223-4 (500 mg, 0.75 mmol) was dissolved in dimethyl sulfoxide (5 mL). Then, triethylamine (761 mg, 7.52 mmol) was added to the reaction solution and the mixture was continued to stir for 30 minutes. Sulfur trioxide pyridine complex (1.2 g, 7.52 mmol) was added to the reaction solution in batches at 40° C. The reaction system was continued to stir at 40° C. for 3 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and added with ice water (30 g) to quench. The mixture was extracted with ethyl acetate (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 260 mg of compound 223-5.

[1080] MS (ESI, m/z): 662.3, 664.3 [M+H].sup.+.

[1081] Step 6:

##STR00790##

[1082] Prepared according to the method of step 1 in Embodiment 148, the raw materials were replaced with compound 223-5 (240 mg, 0.36 mmol) and 3-fluoroazetidine hydrochloride (201 mg, 1.81 mmol) to obtain 170 mg of racemic compound 223.

[1083] MS (ESI, m/z): 721.0, 723.0 [M+H].sup.+.

[1084] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.90-8.79 (m, 3H), 8.25 (s, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.56 (d, J=9.6 Hz, 1H), 7.40 (s, 1H), 6.78 (s, 1H), 5.33-5.11 (m, 1H), 3.92 (s, 3H), 3.87-3.82 (m, 2H), 3.76 (s, 3H), 3.59-3.48 (m, 2H), 3.42-3.38 (m, 1H), 3.26-3.19 (m, 1H), 3.10-2.90 (m, 3H), 2.19-2.09 (m, 7H), 1.79-1.70 (m, 1H).

[1085] .sup.19F NMR (282 MHz, CD.sub.3OD) δ −181.14.

Embodiment 224

(6-((5-Bromo-2-((4-(4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro [5.5]undecane-9-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1086] Step 1:

##STR00791##

[1087] Prepared according to the method of step 4 in Embodiment 93, the raw materials were replaced with compound 121-1 (7 g, 18.7 mmol) to obtain 4.64 g of compound 224-1.

[1088] MS (ESI) m/z: 331.1 [M+H].sup.+.

[1089] Step 2:

##STR00792##

[1090] Trimethylsulfonium iodide (1.05 mg, 5.1 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen atmosphere at 0° C. Then, sodium hydride (60%, 206 mg, 5.1 mmol) was added to the reaction solution and the mixture was continued to stir for 30 minutes. A solution of compound 224-1 (850 mg, 2.6 mmol) in dimethyl sulfoxide (10 mL) was added to the reaction solution. The reaction system was continued to stir at 0° C. for 2 hours. After LCMS monitoring showed that the raw materials disappeared, ice water (80 g) was added to the reaction solution. The mixture was extracted with ethyl acetate (80 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 200 mg of compound 224-2.

[1091] MS (ESI, m/z): 345.2 [M+H].sup.+.

[1092] Step 3:

##STR00793##

[1093] Compound 224-2 (320 mg, 0.9 mmol) and 2-methylallylamine (132 mg, 1.9 mmol) were dissolved in ethanol (6 mL). Then, diisopropylethylamine (240 mg, 1.9 mmol) was added to the reaction solution. The reaction system was heated to 70° C. and continued to stir for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 330 mg of compound 224-3.

[1094] MS (ESI, m/z): 416.2 [M+H].sup.+.

[1095] Step 4:

##STR00794##

[1096] Compound 224-3 (245 mg, 0.6 mmol) was dissolved in concentrated sulfuric acid (1.5 mL). The reaction system was continued to stir at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was added to ice water (30 g) to quench, and the mixture of the pH was adjusted to 10 with sodium carbonate. The mixture was extracted with dichloromethane (80 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 95 mg of compound 224-4.

[1097] MS (ESI, m/z): 416.2 [M+H].sup.+.

[1098] Step 5:

##STR00795##

[1099] Prepared according to the method of step 3 in Embodiment 164, the raw materials were replaced with compound 224-4 (95 mg, 0.2 mmol) to obtain 100 mg of compound 224-5.

[1100] MS (ESI) m/z: 458.3 [M+H].sup.+.

[1101] Step 6:

##STR00796##

[1102] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 224-5 (100 mg, 0.2 mmol) to obtain 80 mg of compound 224-6.

[1103] MS (ESI) m/z: 428.3 [M+H].sup.+.

[1104] Step 7:

##STR00797##

[1105] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 224-6 (60 mg, 0.1 mmol) to obtain 20 mg of compound 224.

[1106] MS (ESI) m/z: 803.2, 805.2 [M+H].sup.+.

[1107] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.88-8.78 (m, 3H), 8.27 (s, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.56-7.50 (m, 2H), 6.87 (s, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.05-2.99 (m, 2H), 2.81-2.75 (m, 3H), 2.53 (s, 2H), 2.41 (s, 2H), 2.17 (d, J=14.6 Hz, 6H), 1.90-1.81 (m, 4H), 1.29 (s, 6H), 1.11 (d, J=6.6 Hz, 6H).

Embodiment 229

(6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(1-methylcyclopropyl))piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1108] Step 1:

##STR00798##

[1109] Compound 1-tert-butoxycarbonylpiperazine (5 g, 26.9 mmol) was dissolved in dichloromethane (50 mL). Then, acetic anhydride (2.77 mL, 29.5 mmol) was added to the reaction solution at 0° C. and the mixture was continued to stir at this temperature for 20 minutes. After LCMS monitoring showed that the raw materials disappeared, saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution to quench. The mixture was extracted with dichloromethane (80 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 6 g of compound 229-2 was obtained.

[1110] MS (ESI, m/z): 229.2 [M+H].sup.+.

[1111] Step 2:

##STR00799##

[1112] Compound 229-2 (2 g, 8.76 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen atmosphere. Then, a solution of tetraisopropyl titanate (10.5 mL, 10.5 mmol) and ethylmagnesium bromide (10.3 mL, 35.0 mmol) in tetrahydrofuran was added dropwise to the reaction solution at −78° C. The reaction system was slowly heated to room temperature and continued to stir for 1 hour. After LCMS monitoring showed that the raw materials disappeared, water (10 mL) and sodium potassium tartrate aqueous solution (30 mL) were added to the reaction solution, and the mixture was continued to stir for 30 minutes. The mixture was extracted with ethyl acetate (80 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (150 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/methyl tert-butyl ether=2/1) to obtain 0.85 g of compound 229-3.

[1113] MS (ESI, m/z): 241.4 [M+H].sup.+.

[1114] Step 3:

##STR00800##

[1115] Prepared according to the method of step 2 in Embodiment 133, the raw materials were replaced with compound 229-3 (850 mg, 3.54 mmol) to obtain 430 mg of compound 229-4.

[1116] MS (ESI) m/z: 141.1 [M+H].sup.+.

[1117] Step 4:

##STR00801##

[1118] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with compound 229-4 (430 mg, 3.1 mmol) to obtain 200 mg of compound 229-5.

[1119] MS (ESI) m/z: 370.2. 372.2 [M+H].sup.+.

[1120] Step 5:

##STR00802##

[1121] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with compound 229-5 (200 mg, 0.54 mmol) to obtain 100 mg of compound 229-6.

[1122] MS (ESI) m/z: 372.2 [M+H].sup.+.

[1123] Step 6:

##STR00803##

[1124] Prepared according to the method of step 6 in Embodiment 1, the raw materials were replaced with compound 229-6 (100 mg, 0.3 mmol) to obtain 80 mg of compound 229-7.

[1125] MS (ESI) m/z: 342.1 [M+H].sup.+.

[1126] Step 7:

##STR00804##

[1127] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 229-7 (80 mg, 0.23 mmol) to obtain 15 mg of compound 229.

[1128] MS (ESI) m/z: 717.2, 719.2 [M+H].sup.+.

[1129] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.87-8.78 (m, 3H), 8.26 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.56-7.51 (m, 2H), 6.83 (s, 1H), 3.91 (s, 3H), 3.68 (s, 3H), 2.89-2.82 (m, 8H), 2.18 (s, 3H), 2.13 (s, 3H), 1.19 (s, 3H), 0.65-0.62 (m, 2H), 0.45-0.42 (m, 2H).

Embodiment 232

(6-((5-Bromo-2-((2-methoxy-4-(4-(4-(2-methoxyethyl)piperazin-1-yl)piperidin-1-yl))-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxolin-5-yl)dimethylphosphine sulfide

[1130] Step 1:

##STR00805##

[1131] Compound 1-3 (1 g, 4.52 mmol) was dissolved in toluene (10 mL). Lawesson reagent (2,4-bis(p-methoxyphenyl)-1,3-dithio-diphosphetane-2,4 sulfide, 3.66 g, 9.0 mmol) was then added to the reaction solution. The reaction system was heated to 110° C. and continued to stir for 3 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (50 mL) was added thereto. The mixture was extracted with ethyl acetate (80 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 500 mg of compound 232-1.

[1132] MS (ESI) m/z: 238.2 [M+H].sup.+.

[1133] Step 2:

##STR00806##

[1134] Prepared according to the method of step 3 in Embodiment 1, the raw materials were replaced with compound 232-1 (417 mg, 1.76 mmol) to obtain 470 mg of compound 232-2.

[1135] MS (ESI, m/z): 427.9, 429.9 [M+H].sup.+.

[1136] Step 3:

##STR00807##

[1137] Prepared according to the method of step 5 in Embodiment 93, the raw materials were replaced with compound 224-1 (160 mg, 1.45 mmol) and 1-(2-methoxyethyl)piperazine (210 mg, 1.45 mmol) to obtain 112 mg of compound 232-3.

[1138] MS (ESI, m/z): 459.4 [M+H].sup.+.

[1139] Step 4:

##STR00808##

[1140] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with compound 232-3 (110 mg, 0.24 mmol) to obtain 80 mg of compound 232-4.

[1141] MS (ESI, m/z): 429.3 [M+H].sup.+.

[1142] Step 5:

##STR00809##

[1143] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with compound 232-4 (80 mg, 0.19 mmol) and 232-2 (80 mg, 0.19 mmol) to obtain 14 mg of compound 232.

[1144] MS (ESI, m/z): 820.3, 822.3 [M+H].sup.+.

[1145] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 11.71 (s, 1H), 8.79-8.77 (m, 2H), 8.36-8.31 (m, 2H), 8.20 (s, 1H), 7.72-7.68 (m, 2H), 7.40 (s, 1H), 7.12 (s, 1H), 6.67 (s, 1H), 3.89 (s, 3H), 3.74 (s, 3H), 3.58-3.55 (m, 2H), 3.38 (s, 3H), 3.17-3.14 (m, 2H), 2.81-2.66 (m, 10H), 2.61-2.54 (m, 2H), 2.49 (s 3H), 2.44 (s, 3H), 2.41-2.37 (m, 1H), 2.03-1.99 (m, 2H), 1.72-1.65 (m, 2H).

Embodiment 234

(6-((5-Bromo-2-((4-((3aS,7aS)-1-(cyclopropylmethyl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1146] (6-((5-Bromo-2-((4-(((3aR,7aR)-1-(cyclopropylmethyl)octahydro-6H-pyrrolo[2,3-c]pyridine-6-6yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

##STR00810##

[1147] Compound 227 (100 mg) was subjected to a chiral resolution, and resolution conditions were as follows: chiral column, CHIRALPAK ID 2×25 cm (5 □m); mobile phase A methyl tert-butyl ether (10 mM ammonia methanol), mobile phase B ethanol; flow rate of 20 mL/min; gradient of 50% B; detection wavelength of 210/270 nm; 20 mg of compound 234a was obtained at 9.45 minutes and 20 mg of compound 234b was obtained at 11.8 minutes.

[1148] 234a: MS (ESI) M/Z: 757.3, 759.3 [M+H].sup.+; .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.87-8.77 (m, 3H), 8.25 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.53-7.48 (m, 2H), 6.85 (s, 1H), 3.92 (s, 3H), 3.72 (s, 3H), 3.21-3.16 (m, 1H), 3.08-2.98 (m, 2H), 2.86-2.70 (m, 4H), 2.50-2.24 (m, 3H), 2.16 (dd, J=14.7, 1.8 Hz, 6H), 1.96-1.77 (m, 4H), 0.83-0.78 (m, 1H), 0.47-0.43 (m, 2H), 0.10-0.07 (m, 2H).

[1149] 234b: MS (ESI) M/Z: 757.4, 759.4 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.84-8.75 (m, 3H), 8.23 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.50-7.46 (m, 2H), 6.83 (s, 1H), 3.90 (s, 3H), 3.70 (s, 3H), 3.19-3.13 (m, 1H), 3.05-2.94 (m, 2H), 2.84-2.66 (m, 4H), 2.47-2.23 (m, 3H), 2.14 (dd, J=14.4, 2.8 Hz, 6H), 1.94-1.76 (m, 4H), 0.80-0.77 (m, 1H), 0.44-0.40 (m, 2H), 0.07-0.04 (m, 2H).

Embodiment 237

1-((4-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)cyclopropane-1-carbonitrile

[1150] Step 1:

##STR00811##

[1151] Prepared according to the method of step 1 in Embodiment 222, the raw materials were replaced with compound 237-1 (1 g, 10.3 mmol) to obtain 330 mg of compound 237-2.

[1152] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.84-7.81 (m, 2H), 7.40-7.36 (m, 2H), 4.00 (s, 2H), 2.46 (s, 3H), 1.39-1.35 (m, 2H), 1.09-1.05 (m, 2H).

[1153] Step 2:

##STR00812##

[1154] Prepared according to the method of step 2 in Embodiment 222, the raw materials were replaced with compound 237-2 (57 mg, 0.23 mmol) to obtain 9 mg of compound 237.

[1155] MS (ESI) m/z: 742.4, 744.4 [M+H].sup.+.

[1156] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 8.99 (dd, J=9.6, 4.2 Hz, 1H), 8.73 (d, J=2.1 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.68-7.62 (m, 3H), 7.34 (s, 1H), 6.75 (s, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 2.98-2.95 (m, 4H), 2.72-2.63 (m, 4H), 2.51 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.35-1.28 (m, 2H), 0.93-0.86 (m, 2H).

Embodiment 242

(6-((5-Bromo-2-((4-(9-((1-fluorocyclopropyl)methyl)-3,9-diazaspiro[5.5]undecan-3yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1157] Step 1:

##STR00813##

[1158] 1-Fluorocyclopropanecarboxylic acid (162 mg, 1.56 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (740 mg, 1.95 mmol) was added to the reaction solution, and the mixture was continued to stir at room temperature for 30 minutes. Then, 133-2 (500 mg, 1.3 mmol) and N,N-diisopropylethylamine (838 mg, 6.49 mmol) were added to the reaction solution. The reaction system was continued to stir at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, water (50 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (80 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate=1/1) to obtain 560 mg of compound 242-1.

[1159] MS (ESI) m/z: 472.0 [M+H].sup.+.

[1160] Step 2:

##STR00814##

[1161] Compound 242-1 (250 mg, 0.53 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and borane dimethyl sulfide (5 mL) was added to the reaction solution under nitrogen protection at 0° C. The reaction system was heated to room temperature and continued to stir for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was slowly added dropwise to methanol (5 mL) at 0° C. The reaction solution was heated to 65° C. and continued to stir for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 140 mg of compound 242-2.

[1162] MS (ESI) m/z: 458.1 [M+H].sup.+.

[1163] Step 3:

##STR00815##

[1164] Compound 242-2 (140 mg, 0.31 mmol) was dissolved in ethanol (2.5 mL). Then, ammonium chloride (65 mg, 1.22 mmol), iron powder (85 mg, 1.53 mmol) and water (0.5 mL) were added to the reaction. The resulting reaction system was heated to 90° C. and continued to stir for 2 hours. After the LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethanol (2 mL×2 times) and the filtrate was concentrated under reduced pressure. Water (5 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate (7.5 mL×2 times). The organic phases were combined, and the organic phases were washed with saturated brine (5 mL×2 times) first, and then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 100 mg of compound 242-3.

[1165] MS (ESI) m/z: 428.2 [M+H].sup.+.

[1166] Step 4:

##STR00816##

[1167] Compound 242-3 (93 mg, 0.22 mmol) was dissolved in N-methylpyrrolidone (1 mL), then compound 1-5 (60 mg, 0.15 mmol) and methanesulfonic acid (42 mg, 0.44 mmol) were added to the above solution sequentially. The reaction solution was heated to 95° C. and continued to stir for 16 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature and directly purified by reversed-phase C18 column. Purification conditions were as follows: chromatographic column 80 g C18 reversed-phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate of 50 mL/min; gradient: acetonitrile increased from 10% to 50% within 10 minutes; detection wavelength of 254 nm. The product was collected and lyophilized under reduced pressure to obtain 18 mg of compound 242.

[1168] MS (ESI) m/z: 802.9, 804.9 [M+H].sup.+.

[1169] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.60 (s, 1H), 9.02 (dd, J=9.6, 4.2 Hz, 1H), 8.75 (d, J=2.1 Hz, 1H), 8.71 (d, J=1.8 Hz, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.70 (s, 1H), 7.65 (s, 2H), 7.33 (s, 1H), 6.75 (s, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 2.97-2.78 (m, 10H), 2.17 (s, 3H), 2.12 (s, 3H), 1.76-1.63 (m, 8H), 1.20-1.10 (m, 2H), 0.88-0.80 (m, 2H).

Embodiment 243

[1170] (6-((5-Bromo-2-((4-(9-(1-fluoro-2-methylpropan-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1171] Step 1:

##STR00817##

[1172] Compound 133-2 (9.7 g, 25.16 mmol) was dissolved in N,N-dimethylformamide (100 mL), then anhydrous potassium carbonate (14 g, 100.66 mmol) and ethyl 2-bromoisobutyrate (19.63 g, 100.66 mmol) were added to the reaction solution. The reaction system was heated to 80° C. and continued to stir for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and poured into water (800 mL) to quench. The mixture was extracted with ethyl acetate (300 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (300 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate=1/1) to obtain 8.6 g of compound 243-1.

[1173] MS (ESI) m/z: 500.2 [M+H].sup.+.

[1174] Step 2:

##STR00818##

[1175] Compound 243-1 (500 mg, 1 mmol) was dissolved in dichloromethane (10 mL) under nitrogen atmosphere. Then, the reaction solution was cooled to −78° C., and diisobutylaluminum hydride (1.5 M, 1.67 mL, 2.5 mmol) was added to the reaction solution, and the mixture was continued to stir for 15 minutes. The reaction system was heated to 0° C. and continued to stir for 1 hour. After LCMS monitoring showed that the raw material disappeared, saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 370 mg of compound 243-2.

[1176] MS (ESI) m/z: 458.3 [M+H].sup.+.

[1177] Step 3:

##STR00819##

[1178] Compound 243-2 (500 mg, 1.09 mmol) was dissolved in dichloromethane (20 mL) under nitrogen atmosphere. Then, diethylamino sulfur trifluoride (1057 mg, 6.56 mmol) was slowly added dropwise to the reaction solution at −10° C., and the mixture was continued to stir at this temperature for 30 minutes. The reaction system was heated to room temperature and continued to stir for 1 hour. After LCMS monitoring showed that the raw materials disappeared, water (10 mL) was added to the reaction solution to quench. The mixture was extracted with dichloromethane (50 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 400 mg of compound 243-3.

[1179] MS (ESI) m/z: 460.4 [M+H].sup.+.

[1180] Step 4:

##STR00820##

[1181] Compound 243-3 (100 mg, 0.22 mmol) was dissolved in ethanol (5 mL) and water (1 mL). Iron powder (61 mg, 1.1 mmol) and ammonium chloride (58 mg, 1.1 mmol) were then added to the reaction solution. The reaction system was heated to 80° C. and continued to stir for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 90 mg of compound 243-4.

[1182] MS (ESI) m/z: 430.2 [M+H].sup.+.

[1183] Step 5:

##STR00821##

[1184] Compound 243-4 (50 mg, 0.12 mmol) was dissolved in N-methylpyrrolidone (2 mL), then compound 1-5 (48 mg, 0.12 mmol) and methanesulfonic acid (34 mg, 0.35 mmol) were added to the above solution sequentially. The reaction solution was heated to 95° C. and continued to stir for 16 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature and directly purified by reversed-phase C18 column. Purification conditions were as follows: chromatographic column 40 g C18 reversed-phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate of 35 mL/min; gradient: acetonitrile increased from 10% to 45% within 25 minutes; detection wavelength of 254 nm. The product was collected and lyophilized under reduced pressure to obtain 15 mg of compound 243.

[1185] MS (ESI) m/z: 805.4, 807.4 [M+H].sup.+.

[1186] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 9.04-8.99 (m, 1H), 8.74 (d, J=10.2 Hz, 2H), 8.30 (s, 1H), 8.19 (s, 1H), 7.69-7.65 (m, 3H), 7.40 (s, 1H), 6.74 (s, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 2.86-2.78 (m, 10H), 2.17 (s, 3H), 2.13 (s, 3H), 1.78 (s, 4H), 1.63 (s, 4H), 1.52 (s, 3H), 1.45 (s, 3H).

[1187] .sup.19F NMR (282 MHz, CDCl.sub.3) δ −137.04.

Embodiment 244

1-((9-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropane-1-carbonitrile

[1188] Step 1:

##STR00822##

[1189] Compound 133-1 (15 g, 30.9 mmol) was dissolved in ethanol (80 mL); and then wet palladium on carbon (2 g) was added to the above solution; the reaction system was replaced with hydrogen for 3 times, and then stirred at room temperature for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was filtered through diatomite, and the filter cake was washed with ethanol (50 mL×3 times). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 13.5 g of compound 244-1.

[1190] MS (ESI) m/z: 456.3 [M+H].sup.+.

[1191] Step 2:

##STR00823##

[1192] Compounds 224-1 (2.2 g, 4.83 mmol) and 1-5 (1.79 g, 4.35 mmol) were dissolved in dioxane (30 mL) under nitrogen atmosphere. Then, dichloro-[1,3-bis(diisopropylphenyl)imidazolylidene]-(3-chloropyridyl)palladium (0.33 g, 0.48 mmol) and cesium carbonate (3.15 g, 9.7 mmol) were added to the above reaction solution. The reaction system was heated to 100° C. and continued to stir for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 1.2 g of compound 244-2.

[1193] MS (ESI) m/z: 831.0, 833.0 [M+H].sup.+.

[1194] Step 3:

##STR00824##

[1195] Prepared according to the method of step 2 in Embodiment 133, the raw materials were replaced with compound 244-2 (1.2 g, 1.44 mmol) to obtain 1 g of compound 244-3.

[1196] MS (ESI) m/z: 731.1, 733.1 [M+H].sup.+.

[1197] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.82-8.75 (m, 3H), 8.22 (s, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.48-7.73 (m, 2H), 6.83 (s, 1H), 3.89 (s, 3H), 3.66 (s, 3H), 2.83 (t, J=5.6 Hz, 8H), 2.15 (s, 3H), 2.11 (s, 3H), 1.63 (t, J=5.6 Hz, 4H), 1.57 (t, J=5.6 Hz, 4H).

[1198] Step 4:

##STR00825##

[1199] Prepared according to the method of step 3 in Embodiment 133, the raw materials were replaced with compound 237-2 (74 mg, 0.29 mmol) to obtain 15 mg of compound 244.

[1200] MS (ESI) m/z: 810.2, 812.2 [M+H].sup.+.

[1201] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 12.61 (s, 1H), 9.02 (dd, J=9.6, 4.2 Hz, 1H), 8.75 (d, J=1.8 Hz, 1H), 8.71 (d, J=1.8 Hz, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.72 (s, 1H), 7.64 (s, 2H), 7.33 (s, 1H), 6.75 (s, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 2.87-2.83 (m, 4H), 2.57-2.49 (m, 6H), 2.17 (s, 3H), 2.12 (s, 3H), 1.62-1.60 (m, 8H), 1.32 (s, 2H), 0.90 (s, 2H).

Embodiment 247

(6-((5-Bromo-2-((4-(5-(2-fluoroethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[1202] Step 1:

##STR00826##

[1203] Prepared according to the method of step 4 in Embodiment 1, the raw materials were replaced with tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (5 g, 23.56 mmol) to obtain 6.6 g of compound 247-1.

[1204] MS (ESI) m/z: 442.2, 444.2 [M+H].sup.+.

[1205] Step 2:

##STR00827##

[1206] Prepared according to the method of step 5 in Embodiment 1, the raw materials were replaced with 247-1 (500 mg, 1.1 mmol) to obtain 380 mg of compound 247-2.

[1207] MS (ESI) m/z: 444.1 [M+H].sup.+.

[1208] Step 3:

##STR00828##

[1209] Prepared according to the method of step 2 in Embodiment 133, the raw materials were replaced with 247-2 (380 mg, 0.86 mmol) to obtain 290 mg of compound 247-3.

[1210] MS (ESI) m/z: 344.1 [M+H].sup.+.

[1211] Step 4:

##STR00829##

[1212] Prepared according to the method of step 3 in Embodiment 133, the raw materials were replaced with 247-3 (290 mg, 0.85 mmol) to obtain 280 mg of compound 247-4.

[1213] MS (ESI) m/z: 390.3 [M+H].sup.+.

[1214] Step 5:

##STR00830##

[1215] Prepared according to the method of step 3 in Embodiment 70, the raw materials were replaced with 247-4 (280 mg, 0.72 mmol) to obtain 230 mg of compound 247-5.

[1216] MS (ESI) m/z: 360.3 [M+H].sup.+.

[1217] Step 6:

##STR00831##

[1218] Prepared according to the method of step 7 in Embodiment 1, the raw materials were replaced with 247-5 (60 mg, 0.17 mmol) to obtain 25 mg of compound 247.

[1219] MS (ESI) m/z: 735.3, 737.3 [M+H].sup.+.

[1220] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 8.01 (dd, J=9.6, 4.2 Hz, 1H), 8.74-8.69 (m, 2H), 8.27 (s, 1H), 8.12 (s, 1H), 7.60 (s, 2H), 7.50 (s, 1H), 7.30 (s, 1H), 6.68 (s, 1H), 4.74c4.55 (m, 2H), 3.91 (s, 3H), 3.78 (s, 3H), 3.01-2.84 (m, 10H), 2.44-2.41 (m, 2H), 2.14 (s, 3H), 2.10 (s, 3H).

[1221] The compounds given in Table 1 below were prepared by substantially the same procedure as described in the above embodiments.

TABLE-US-00004 TABLE 1 Compounds MS (ESI) Com- M/Z pound Structural formula .sup.1HNMR [M + H].sup.+  2 [00832] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.96 (s, 1H), 8.35-8.29 (m, 1H), 8.26 (s, 1H), 8.19- 8.18 (m, 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.59 (s, 1H), 7.53-7.47 (m, 1H), 7.01-6.97 (m, 2H), 6.81 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.76-3.73 (m, 4H), 2.86-2.84 (m, 4H), 1.78 (s, 3H), 1.74 (s, 3H).  612.1, 614.1  3 [00833] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.80 (s, 1H), 9.06-9.02 (m, 1H), 8.74 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.68-7.61 (m, 2H), 7.42 (brs, 1H), 7.33-7.29 (m, 2H), 7.28-7.26 (m, 1H), 7.09-7.05 (m, 1H), 6.74 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.86-3.83 (m, 4H), 2.96-2.94 (m, 4H), 1.92 (s, 3H), 1.88 (s, 3H). 584.3  4 [00834] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.51 (s, 1H), 9.18 (dd, J = 9.6, 3.6 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.84-7.75 (m, 2H), 7.55 (d, J = 9.6 Hz, 1H), 6.85 (s, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 3.75 (t, J = 4.4 Hz, 4H), 2.86 (t, J = 4.4 Hz, 4H), 2.15 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H) 600.2  5 [00835] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.70 (s, 1H), 8.99 (dd, J = 9.6, 4.2 Hz, 1H), 8.75 (dd, J = 7.2, 1.8 Hz, 2H), 8.35 (s, 1H), 8.33 (s, 1H), 7.75 (d, J = 9.6 Hz, 2H), 7.35 (s, 2H), 7.12 (dd, J = 8.1, 2.1 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.75 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H).  579.1, 581.1  9 [00836] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 8.86 (dd, J = 9.6, 4.2 Hz, 1H), 8.78 (dd, J = 7.5, 1.8 Hz, 2H), 8.47 (s, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.84 (d, J = 9.6 Hz, 1H), 7.68 (s, 1H), 7.09 (dd, J = 8.1, 2.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 3.96 (s, 3H), 2.20 (s, 3H), 2.15 (s, 3H).  566.0, 568.0  10 [00837] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 9.00 (dd, J = 9.6, 4.2 Hz, 1H), 8.74 (dd, J = 10.8, 1.8 Hz, 2H), 8.35 (s, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.66 (d, J = 9.6 Hz, 1H), 7.50 (s, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 6.67 (s, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 3.61-3.52 (m, 1H), 3.46-3.41 (m, 1H), 3.30-3.23 (m, 2H), 3.08-3.00 (m, 1H), 2.69 (s, 6H), 2.30-2.25 (m, 2H), 2.17 (s, 3H), 2.12 (s, 3H)  691.1, 693.1  11 [00838] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.91-8.75 (m, 3H), 8.42 (s, 1H), 8.25 (s, 2H), 7.72 (s, 2H), 7.50 (s, 1H), 7.27 (s, 1H), 6.64 (s, 1H), 4.10 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.51-3.45 (m, 1H), 2.96- 2.94 (m, 2H), 2.84-2.78 (m, 2H), 2.37-2.29 (m, 3H), 2.04 (s, 3H), 2.00 (s, 3H), 1.88- 1.79 (m, 2H).  689.3, 691.3  12 [00839] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 8.98 (dd, J = 9.6, 4.2 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.49 (s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 7.69 (d, J = 9.6 Hz, 1H), 7.63 (s, 1H), 7.45 (d, J = 3.3 Hz, 2H), 6.74 (s, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 3.41 (m, 2H), 3.30 (m, 2H), 3.17 (m, 2H), 3.15 (d, J = 12.3 Hz, 2H), 2.77 (s, 3H), 2.17 (s, 5H), 2.13 (s, 3H).  691.2, 693.2  14 [00840] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 13.02 (s, 1H), 8.91-8.88 (m, 1H), 8.80 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 7.74 (s, 1H), 7.64-7.57 (m, 2H), 6.69 (s, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 2.76 (s, 2H), 3.56 (s, 2H), 2.95-2.90 (m, 4H), 2.17 (s, 3H), 2.15 (s, 3H), 2.13 (s, 3H).  705.1, 707.1  15 [00841] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.88 (dd, J = 9.6, 4.0 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H), 7.72 (s, 1H), 7.60-7.56 (m, 2H), 7.39 (s, 1H), 6.75 (s, 1H), 3.95-3.84 (m, 5H), 3.75-3.73 (m, 4H), 3.67-3.65 (m, 1H), 3.10-3.02 (m, 4H), 2.17 (s, 3H), 2.14 (s, 3H), 2.06-1.92 (m, 4H).  704.2, 706.2  18 [00842] .sup.1H NMR: (300 MHz, CD.sub.3OD) δ 8.88-8.83 (m, 2H), 8.79 (d, J = 2.1 Hz, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.53-7.51 (m, 2H), 6.84 (s, 1H), 3.92 (s, 3H), 3.69 (s, 3H), 3.24-3.20 (m, 2H), 3.11-2.85 (m, 8H), 2.72-2.60 (m, 6H), 2.19 (s, 3H), 2.14 (s, 3H), 2.04-2.00 (m, 2H), 1.77-1.65 (m, 2H).  760.2, 762.2  19 [00843] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.83 (s, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.76-8.71 (m, 1H), 8.63 (s, 1H), 8.19 (s, 1H), 8.07- 7.95 (m, 1H), 7.72 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 3.97 (s, 3H), 3.85-3.83 (m, 4H), 2.94-2.91 (m, 4H), 2.19 (s, 3H), 2.16 (s, 3H).  651.1, 653.1  20 [00844] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.78 (s, 1H), 8.88 (dd, J = 9.6, 3.9 Hz, 1H), 8.77 (dd, J = 13.5, 1.8 Hz, 2H), 8.62 (s, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.62 (s, 1H), 7.47 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.19 (s, 1H), 3.97 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H).  565.1, 567.1  21 [00845] .sup.1H NMR: (300 MHz, CD.sub.3OD) δ 8.88-8.83 (m, 2H), 8.79 (d, J = 2.1 Hz, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.53-7.51 (m, 2H), 6.84 (s, 1H), 3.92 (s, 3H), 3.69 (s, 3H), 3.24-3.20 (m, 2H), 3.11-2.85 (m, 8H), 2.72-2.60 (m, 6H), 2.19 (s, 3H), 2.14 (s, 3H), 2.04-2.00 (m, 2H), 1.77-1.65 (m, 2H).  679.0, 681.0  23 [00846] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 12.64 (s, 1H), 8.93 (dd, J = 9.6, 4.0 Hz, 1H), 8.80- 8.72 (dd, J = 7.2, 2.0 Hz, 2H), 8.34 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.67 (d, J = 9.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.28 (s, 1H), 4.01 (d, J = 1.2 Hz, 3H), 3.80 (t, J = 4.4 Hz, 4H), 3.77 (s, 3H), 3.13 (s, 4H), 2.17 (s, 3H), 2.14 (s, 3H). .sup.19F NMR: (377 MHz, CDCl.sub.3) δ −137.83.  681.9, 683.9  24 [00847] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.40 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.89-8.78 (m, 3H), 8.38 (s, 1H), 8.10 (s, 1H), 7.67 (s, 1H), 7.58 (d, J = 1.5 Hz, 2H), 4.03-3.91 (m, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.72 (t, J = 4.5 Hz, 4H), 3.03 (s, 4H), 2.07 (d, J = 16.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H). .sup.19F NMR: (282 MHz, CDCl.sub.3) δ −138.08.  712.1, 714.1  25 [00848] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.64 (s, 1H), 8.99 (s, 1H), 8.83 (d, J = 6.9 Hz, 2H), 8.45 (s, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 6.83 (s, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.75 (t, J = 4.5 Hz, 4H), 2.85 (t, J = 4.5 Hz, 4H), 2.03 (s, 3H), 1.98 (s, 3H). 654.2  26 [00849] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.84 (d, J = 6.9 Hz, 3H), 8.41 (s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 6.83 (s, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.29 (s, 3H), 3.08-2.96 (m, 2H), 2.69 (t, J = 10.8 Hz, 2H), 2.04 (s, 3H), 2.00 (s, 3H), 1.97-1.95 (m, 2H), 1.69-1.55 (m, 2H).  692.1, 694.1  28 [00850] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 9.01 (dd, J = 9.6, 4.2 Hz, 1H), 8.73 (d, J = 12 Hz, 2H), 8.31 (s, 1H), 8.26 (s, 1H), 7.87 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 6.78 (s, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.48 (t, J = 6.0 Hz, 2H), 3.33 (s, 3H), 3.12 (t, J = 6.0 Hz, 2H), 2.68 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H).  666.3, 668.3  29 [00851] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.93 (dd, J = 9.6, 4.8 Hz, 1H), 8.80 (d, J = 2.1 Hz, 2H), 8.24 (s, 1H), 7.80 (s, 1H), 7.64 (s, 1H), 7.60 (d, J = 10.5 Hz, 1H), 7.41 (s, 1H), 4.58 (t, J = 8.7 Hz, 2H), 3.76 (s, 3H), 3.45 (t, J = 8.7 Hz, 2H), 2.75 (s, 6H), 2.19 (s, 3H), 2.14 (s, 3H).  633.9, 635.9  30 [00852] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.65 (s, 1H), 8.92 (dd, J = 9.6, 4.2 Hz, 1H), 8.77 (dd, J = 7.8, 1.8 Hz, 2H), 8.65 (d, J = 2.1 Hz, 1H), 8.37 (s, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 9.6 Hz, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 4.07 (s, 3H), 3.82 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H).  580.1, 582.1  32 [00853] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.83 (s, 1H), 8.95 (dd, J = 9.6, 4.2Hz, 1H), 8.77- 8.73 (m, 2H), 8.25 (s, 1H), 8.11 (s, 1H), 7.94-7.71 (m, 2H), 7.62 (d, J = 4.8 Hz, 1H), 7.46 (s, 1H), 6.83 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 2.74 (s, 6H), 2.17 (s, 3H), 2.12 (s, 3H).  622.1, 624.1  34 [00854] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.68 (s, 1H), 8.91 (dd, J = 9.6, 4.2 Hz, 1H), 8.76 (dd, J = 7.5, 1.5 Hz, 2H), 8.46 (s, 1H), 8.32 (s, 1H), 7.72 (d, J = 9.6 Hz, 1H), 7.66 (s, 1H), 7.53 (s, 1H), 7.19 (s, 1H), 4.87 (q, J = 12.6, 6.3 Hz, 2H), 3.81 (m, 7H), 3.10 (t, J = 3.3 Hz, 4H), 2.18 (s, 3H), 2.14 (s, 3H).  733.0, 735.0  35 [00855] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.79 (s, 1H), 8.90 (s, 2H), 8.78 (dd, J = 9.6. 3.9 Hz, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 8.09, (s, 1H), 7.71 (s, 2H), 7.47 (s, 1H), 7.33 (s, 1H), 3.96 (s, 3H), 3.76 (s, 3H), 2.43 (s, 6H), 2.07 (s, 3H), 2.02 (s, 3H).  686.1, 688.1  36 [00856] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.83 (dd, J = 9.0, 1.8 Hz, 2H), 8.74 (s, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.52 (s, 1H), 4.35 (q, J = 14.1, 9.6 Hz, 2H), 3.79 (s, 3H), 3.75 (t, J = 4.5 Hz, 4H), 3.04 (t, J = 4.5 Hz, 4H), 2.05 (s, 3H), 2.00 (s, 3H), 1.26 (t, J = 6.9 Hz, 4H).  679.2, 681.2  37 [00857] 1H NMR (400 MHz, CDCl.sub.3) δ 12.54 (s, 1H), 8.88 (dd, J = 9.2, 4.0 Hz, 1H), 8.76 (dd, J = 18.4, 2.4 Hz, 2H), 8.30 (d, J = 12.0 Hz, 2H), 7.72 (s, 1H), 7.48 (s, 1H), 7.23 (s, 1H), 4.03 (s, 3H), 3.83 (s, 3H), 3.70 (t, J = 4.4 Hz, 4H), 3.08 (t, J = 4.4 Hz, 4H), 2.16 (s, 3H), 2.12 (s, 3H), 2.04 (s, 3H).  678.9, 680.9  38 [00858] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 13.20 (s, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.78-8.70 (m, 2H), 8.14 (s, 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.59 (d, J = 9.3 Hz, 1H), 3.90 (s, 3H), 3.83 (t, J = 4.5 Hz, 4H), 3.20 (t, J = 4.5 Hz,, 4H), 2.49 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H).  649.2, 651.2  39 [00859] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.94 (s, 1H), 8.97 (dd, J = 9.6, 4.2 Hz, 1H), 8.76 (dd, J = 9.3, 2.1 Hz, 2H), 8.17 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.64 (s, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.24 (s, 1H), 4.72 (t, J = 8.7 Hz, 2H), 3.91 (s, 3H), 3.25 (t, J = 8.7 Hz, 2H), 2.18 (s, 3H), 2.13 (s, 3H).  591.1, 593.1  40 [00860] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.73 (s, 1H), 8.85 (dd, J = 9.6, 1.8 Hz, 2H), 8.78 (dd, J = 9.6, 4.2 Hz, 1H), 8.51 (s, 1H), 8.36 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 6.0 Hz, 1H), 7.63 (d, J = 9.6 Hz, 1H), 7.55 (s, 1H), 7.33 (s, 1H), 6.95 (s, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 2.97 (s, 3H), 2.60 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H).  650.0, 652.0  43 [00861] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.87 (d, J = 1.2 Hz, 2H), 8.80 (d, J = 10.2 Hz, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 7.68 (s, 2H), 7.42 (s, 1H), 6.78 (s, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.60 (t, J = 4.8 Hz, 4H), 2.80 (t, J = 4.8 Hz, 4H), 2.05 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H).  678.1, 680.1  44 [00862] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.80 (s, 1H), 8.90 (d, J = 1.2 Hz, 2H), 8.78 (dd, J = 9.6, 3.9 Hz, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.22 (d, J = 5.4 Hz, 1H), 7.81 (s, 1H), 7.68 (d, J = 9.6 Hz, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 3.97 (s, 3H), 3.77 (s, 3H), 2.85 (s, 3H), 2.08 (s, 3H), 2.03 (s, 3H).  657.1, 659.1  45 [00863] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.61 (s, 1H), 8.92 (dd, J = 9.6, 4.2 Hz, 1H), 8.75 (dd, J = 6.6, 1.8 Hz, 2H), 8.51 (d, J = 10.5 Hz, 2H), 8.32 (s, 1H), 7.76 (s, 2H), 7.35 (s, 1H), 7.20 (s, 1H), 4.02 (s, 3H), 3.85 (s, 3H), 3.57 (t, J = 6.9 Hz, 2H), 2.98 (t, J = 6.9 Hz, 2H), 2.71 (s, 3H), 2.62 (s, 6H), 2.18 (s, 3H), 2.13 (s, 3H).  680.2, 682.2  46 [00864] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.72 (s, 1H), 9.65 (s, 1H), 8.89 (dd, J = 7.2, 1.8 Hz,, 3H), 8.41 (s, 1H), 8.11 (s, 1H), 7.92 (d, J = 9.3 Hz, 1H), 7.68 (s, 1H), 7.58-7.43 (m, 2H), 3.81 (s, 3H), 3.70 (d, J = 4.5 Hz, 4H), 2.96 (s, 4H), 2.09 (s, 3H), 2.04 (s, 3H).  652.0, 654.0  47 [00865] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.72 (s, 1H), 8.94 (dd, J = 9.6, 4.2 Hz, 1H), 8.84 (dd, J = 13.8, 1.8 Hz, 2H), 8.29 (d, J = 6.0 Hz, 2H), 7.88 (s, 1H), 7.64 (s, 1H), 7.58 (d, J = 9.3 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 6.74 (d, J = 1.8 Hz, 1H), 4.24 (t, J = 4.2 Hz, 2H), 3.72 (s, 3H), 3.24 (t, J = 4.2 Hz, 2H), 2.93 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H).  620.2, 622.2  48 [00866] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.66 (s, 1H), 9.40 (s, 1H), 8.93-8.85 (m, 3H), 8.35 (s, 1H), 8.09 (s, 1H), 7.75 (s, 2H), 7.68 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 8.4, 1H), 7.05 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.74-3.71 (m, 4H), 2.78-2.75 (m, 4H), 2.08 (s, 3H), 2.03 (s, 3H).  634.3, 636.3  49 [00867] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.62 (s, 1H), 9.05 (dd, J = 9.6, 4.8 Hz, 1H), 8.72 (dd, J = 7.5, 1.8 Hz, 2H), 8.31 (s, 1H), 8.25 (s, 1H), 7.83 (s, 1H), 7.63 (m, 2H), 7.33 (s, 1H), 6.72 (s, 1H), 4.06 (q, J = 14.7, 7.5 Hz, 2H), 3.94 (s, 3H), 3.82 (t, J = 4.5 Hz, 4H), 2.93 (t, J = 4.5 Hz, 4H), 2.17 (s, 3H), 2.12 (s, 3H), 1.41 (t, J = 7.5 Hz, 3H).  678.2, 680.2  50 [00868] 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.85 (dd, J = 16.0, 2.0 Hz, 2H), 8.80-8.75 (m, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 8.09 (d, J = 2.8 Hz, 1H), 8.04 (s, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.34 (dd, J = 8.8, 2.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 6.90 (s, 1H), 3.88 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H).  565.0, 567.0  51 [00869] 1H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 8.88 (m, 3H), 8.30 (s, 1H), 8.11 (s, 1H), 7.66 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 4.5 (t, J = 4.8 Hz, 2H), 3.82 (s, 3H), 3.60 (m, 4H), 2.87-2.75 (m, 6H), 2.05 (s, 3H), 2.02 (s, 3H), 1.89 (t, J = 5.6 Hz, 2H).  690.3, 692.3  52 [00870] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.45 (s, 1H), 8.71 (m, 1H), 8.50 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.68-7.66 (m, 1H), 7.62 (d, J = 7.2 Hz, 1H), 6.97 (q, J = 17.6, 10.4 Hz, 2H), 6.82 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.75 (t, J = 4.8 Hz, 4H), 2.86 (t, J = 4.8 Hz, 4H), 2.79 (d, J = 4.4 Hz, 3H).  593.1, 595.1  53 [00871] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.67 (s, 1H), 9.23 (dd, J = 9.6, 4.0 Hz, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 3.2 Hz, 1H), 8.20 (d, J = 1.2 Hz, 2H), 8.18 (s, 1H), 8.10 (s, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J = 1.2 Hz, 1H), 3.97 (s, 3H), 3.66 (s, 3H), 2.23 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H). 516.2  54 [00872] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.40 (s, 1H), 8.48 (s, 2H), 8.8 (s, 1H), 8.04 (s, 1H), 7.82-7.73 (m, 2H), 7.60 (d, J = 4.5 Hz, 1H), 7.19 (m, 2H), 6.81 (s, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.75 (t, J = 4.5 Hz, 5H), 3.44 (m, 1H), 2.85 (t, J = 4.5 Hz, 4H), 1.18 (d, J = 6.9 Hz, 6H).  642.2, 644.2  55 [00873] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.77 (s, 1H), 8.89 (s, 2H), 8.82-8.78 (m, 1H), 8.41 (s, 1H), 8.40 (s, 1H), 8.00 (d, J = 4.5 Hz, 1H), 7.92 (s, 1H), 7.65 (d, J = 9.6 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J = 13.5 Hz, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 2.04 (d, J = 14.4 Hz, 6H), 1.48 (d, J = 13.2 Hz, 6H).  655.1, 657.1  59 [00874] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.69 (s, 1H), 8.95-8.81 (m, 2H), 8.75 (d, J = 1.8 Hz, 1H), 8.55 (s, 1H), 8.41-8.23 (m, 2H), 7.65 (s, 1H), 6.55 (s, 1H), 4.03-3.88 (m, 7H), 3.24-3.14 (m, 4H), 2.16 (d, J = 14.4 Hz, 6H).  608.8, 610.8  60 [00875] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.51 (s, 1H), 9.16-9.07 (m, 1H), 8.96 (s, 1H), 8.92 (s, 2H), 8.83 (dd, J = 10.5, 1.8 Hz, 2H), 8.03 (s, 1H), 7.96 (d, J = 2.7 Hz, 2H), 7.59 (d, J = 9.6 Hz, 1H), 6.98 (s, 1H), 3.94 (s, 3H), 3.53 (t, J = 4.5 Hz, 4H), 2.79 (t, J = 4.5 Hz, 4H), 2.15 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H). 597.2  61 [00876] 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.87-8.85 (m, 3H), 8.45 (s, 1H), 8.31 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.84-7.82 (m, 1H), 7.70 (s, 1H), 7.55 (s, 1H), 6.85 (s, 1H), 6.43 (dd, J = 2.4, 2.4 Hz, 1H), 3.89 (s, 3H), 3.59-3.57 (m, 4H), 2.67- 2.64 (m, 4H), 2.02 (d, J = 14.4 Hz, 6H).  650.2, 652.2  62 [00877] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.60 (s, 1H), 8.94 (dd, J = 9.7, 4.2 Hz, 1H), 8.70 (dd, J = 11.4, 1.8 Hz, 2H), 8.25 (s, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7.78 (d, J = 2.7 Hz, 1H), 7.61 (d, J = 9.9 Hz, 1H), 6.50 (d, J = 1.5 Hz, 1H), 6.39 (s, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.81 (t, J = 4.5 Hz, 4H), 2.97 (t, J = 4.5 Hz, 4H), 2.12 (s, 3H), 2.08 (s, 3H). .sup.19F NMR: (282 MHz, CDCl.sub.3) δ −117.00.  681.8, 683.8  63 [00878] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.47 (m, 1H), 9.26-9.22 (m, 1H), 8.74-8.71 (m, 2H), 8.45 (s, 1H), 8.00 (s, 1H), 7.71-7.66 (m, 3H), 4.04 (s, 3H), 3.83-3.81 (m, 7H), 3.16-3.13 (m, 4H), 2.31 (s, 3H), 2.14 (d, J = 14.4 Hz, 6H). 601.3  65 [00879] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.69 (s, 1H), 8.85-8.75 (m, 3H), 8.63 (s, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.56 (s, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.14-3.04 (m, 4H), 2.47-2.41 (m, 4H), 2.25 (s, 3H), 2.02 (d, J = 14.4 Hz, 6H).  678.3, 680.3  66 [00880] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.85-8.82 (m, 3H), 8.42 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.58 (s, 2H), 6.83 (s, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 2.83-2.80 (m, 4H), 2.02 (d, J = 14.4 Hz, 6H), 1.66-1.50 (m, 6H).  662.1, 664.1  67 [00881] .sup.1H NMR (300 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.86-8.82 (m, 3H), 8.54 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.47-7.45 (m, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.81-3.71 (m, 2H), 3.59-3.54 (m, 2H), 3.32-3.20 (m, 4H), 2.02 (d, J = 14.4 Hz, 6H), 1.91-1.84 (m, 4H).  705.2, 707.2  71 [00882] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.50 (s, 1H), 9.26 (dd, J = 9.6, 4.2 Hz, 1H), 8.76 (dd, J = 11.7, 2.1 Hz, 2H), 8.22 (s, 1H), 8.13 (s, 1H), 8.08-7.91 (m, 2H), 7.44 (d, J = 9.6 Hz, 1H), 7.35 (s, 1H), 4.00-3.70 (m, 10H), 2.98-2.95 (m, 4H), 2.28-2.12 (m, 3H), 2.02 (d, J = 14.4 Hz, 6H). 601.3  72 [00883] .sup.1H NMR (300 MHz, DMSO-d6) δ 12.90 (s, 1H), 9.01-8.94 (m, 1H), 8.86-8.82 (m, 2H), 8.47 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.62-7.51 (m, 2H), 6.86 (s, 1H), 3.97-3.75 (m, 10H), 2.89-2.86 (m, 4H), 2.02 (d, J = 14.4 Hz, 6H).  620.3, 622.3  73 [00884] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.71 (s, 1H), 8.87-8.81 (m, 3H), 8.41 (s, 1H), 8.30 (s, 1H), 7.95 (s, 1H), 7.77-7.70 (m, 2H), 7.32 (s, 1H), 6.81 (s, 1H), 3.88 (s, 3H), 3.6-3.59 (m, 4H), 2.67-2.64 (m, 4H), 2.10 (s, 3H), 2.02 (d, J = 14.4 Hz, 6H).  664.2, 666.2  76 [00885] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.69 (s, 1H), 9.35 (s, 1H), 8.97-8.85 (m, 3H), 8.34 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.78 (s, 2H), 7.65 (d, J = 2.8 Hz, 1H), 7.34 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 3.76 (s, 3H), 2.74-2.72 (m, 4H), 2.39 (s, 4H), 2.23 (s, 3H), 2.05 (d, J = 14.4 Hz, 6H), 1.54 (s, 8H).  715.3, 717.3  77 [00886] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 12.62 (s, 1H), 8.95 (s, 1H), 8.74 (s, 2H), 8.31 (s,, 1H), 8.21 (s, 1H), 7.63 (s, 2H), 7.54 (s, 1H), 7.36 (s, 1H), 6.92 (s, 1H), 3.96-3.89 (m, 8H), 3.51-3.48 (m, 1H), 3.21 (s, 1H), 2.16-2.05 (m, 7H), 1.89-1.86 (m, 1H), 1.17 (s, 1H), 0.98-0.96 (m, 1H), 0.86-0.83 (m, 1H).  675.1, 677.1  78 [00887] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.85-8.77 (m, 3H), 8.56 (s, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.77 (dd, J = 59.2, 59.2 Hz, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 6.92 (s, 1H), 3.85 (s, 3H), 3.77- 3.74 (m, 4H), 2.88-2.86 (m, 4H), 2.02 (d, J = 14.4 Hz, 6H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) δ −94.01.  700.1, 702.1  81 [00888] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 13.15 (s, 1H), 9.40 (dd, J = 9.6, 4.0 Hz, 1H), 8.74 (dd, J = 15.2, 2.0 Hz, 2H), 8.26 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.56 (d, J = 9.6 Hz, 1H), 7.47-7.38 (m, 1H), 6.75 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.84 (s, 4H), 2.96 (s, 4H), 2.14 (d, J = 14.4 Hz, 6H). .sup.19F NMR (377 MHz, CDCl.sub.3) δ −162.16. 604.3  83 [00889] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.57 (s, 1H), 8.86 (dd, J = 9.6, 4.4 Hz, 1H), 8.74 (dd, J = 11.6, 2.0 Hz, 2H), 8.48-8.38 (m, 1H), 8.31 (s, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.54 (s, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.99 (s, 1H), 6.75 (s, 1H), 6.50 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H), 3.92-3.85 (m, 4H), 2.97- 2.90 (m, 4H), 2.17 (s, 3H), 2.14 (s, 3H).  666.1, 668.1  84 [00890] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 13.00 (s, 1H), 8.89-8.79 (m, 1H), 8.79-8.71 (m, 2H), 8.23 (s, 1H), 8.18 (s, 1H), 7.72-7.61 (m, 2H), 7.26-7.24 (m, 1H), 6.76 (d, J = 11.9 Hz, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H). .sup.19F NMR (282 MHz, DMSO-d.sub.6) δ −116.7.  597.1, 599.1  85 [00891] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.17 (s, 1H), 7.96-7.93 (m, 2H), 7.92 (s, 1H), 7.52 (s, 1H), 6.82 (s, 1H), 6.72-6.67 (m, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.83-3.79 (m, 4H), 3.36-3.33 (m, 2H), 3.12-3.08 (m, 2H), 2.91-2.87 (m, 4H), 1.83 (d, J = 13.2 Hz, 6H).  638.1, 640.1  86 [00892] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.67 (s, 1H), 8.84 (dd, J = 11.2, 2.0 Hz, 3H), 8.45 (s, 1H), 8.28 (s, 1H), 7.68-7.52 (m, 4H), 7.47-7.45 (m, 1H), 6.81 (s, 1H), 3.85 (s, 3H), 3.66 (t, J = 4.4 Hz, 4H), 2.83 (t, J = 4.4 Hz, 4H), 2.02 (d, J = 14.4 Hz, 6H).  666.1, 668.1  87 [00893] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.66 (s, 1H), 8.84 (d, J = 1.6 Hz, 1H), 8.79 (d, J = 1.6 Hz, 1H), 8.77 (s, 1H), 8.65 (s, 1H) 8.28 (s, 1H), 8.02 (s, 1H), 7.82-7.08 (m, 2H), 7.56 (s, 1H), 4.92 (q, J = 9.2 Hz, 2H), 3.81 (s, 3H), 3.07-3.04 (m, 4H), 2.35-2.32 (m, 4H), 2.19 (s, 3H), 2.01 (d, J = 14.0 Hz, 6H), 1.59-1.51 (m, 8H).  814.3, 816.3  89 [00894] .sup.1H NMR (300 MHz, D.sub.2O) δ 8.61 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 7.24 (s, 1H), 6.87 (s, 1H), 6.32-6.07 (m, 2H), 5.96 (s, 1H), 3.52 (s, 3H), 3.23-2.97 (m, 4H), 2.88 (s, 3H), 2.76- 2.57 (m, 2H), 2.52-2.04 (m, 4H), 1.66-1.46 (m, 6H), 1.15 (t, J = 7.2 Hz, 3H).  691.2, 693.2  90 [00895] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.48 (s, 1H), 8.82 (dd, J = 9.2, 3.2 Hz, 2H), 8.73 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.77 (d, J = 9.6 Hz, 1H), 7.42 (s, 1H), 6.66 (s, 1H), 6.09 (s, 1H), 3.97 (s, 3H), 3.74 (s, 3H), 3.63 (t, J = 4.8 Hz, 4H), 2.81 (t, J = 4.8 Hz, 4H), 2.15 (s, 3H), 2.11 (s, 3H).  664.2, 666.2  91 [00896] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.50 (s, 1H), 8.87-8.72 (m, 3H), 8.29 (s, 1H), 8.19 (s, 1H), 7.66 (s, 2H), 7.45 (s, 1H), 6.80 (s, 1H), 6.69 (s, 1H), 3.98 (s, 3H), 3.64 (s, 7H), 2.83 (t, J = 4.8 Hz, 4H), 2.14 (d, J = 14.4 Hz, 6H).  664.2, 666.2  92 [00897] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 9.01 (dd, J = 9.6, 4.4 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.68-7.62 (m, 3H), 7.38 (s, 1H), 6.76 (s, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.65 (t, J = 5.2 Hz, 2H), 3.39 (s, 3H), 3.07-3.03 (m, 4H), 2.85-2.76 (m, 6H), 2.17 (s, 3H), 2.13 (s, 3H).  721.2, 723.2  94 [00898] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.72 (s, 1H), 8.93 (s, 1H), 8.81-8.73 (m, 2H), 8.29-8.22 (m, 2H), 7.63 (s, 1H), 7.57 (s, 2H), 6.74 (s, 1H), 3.94 (s, 3H), 3.79 (s, 3H), 3.44 (s, 4H), 3.16 (s, 4H), 2.18 (s, 3H), 2.13 (s, 3H).  712.3, 714.3  95 [00899] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.70 (s, 1H), 8.89-8.73 (m, 4H), 8.34 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.52-7.50 (m, 1H), 3.79(s, 3H), 3.75 (s, 3H), 3.12-3.98 (m, 4H), 2.25 (s, 7H), 2.03 (d, J = 14.4 Hz, 6H), 1.82-1.78 (m, 2H), 1.59-1.48 (m, 2H). .sup.19F NMR (282 MHz, DMSO-d.sub.6) δ −137.81.  723.2, 725.2  96 [00900] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.90-8.79 (m, 3H), 8.41 (s, 1H), 8.28 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 6.82 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.15-3.12 (m, 2H), 2.66-2.57 (m, 2H), 2.34 (d, 7H), 2.02 (d, J = 14.4 Hz, 6H), 1.89-1.86 (m, 2H), 1.66-1.58 (m, 2H).  705.2, 707.2  97 [00901] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.55 (s, 1H), 9.21 (dd, J = 9.6, 4.2 Hz, 1H), 8.76- 8.67 (m, 2H), 8.21 (s, 1H), 7.96-7.82 (m, 3H), 7.53 (d, J = 9.6 Hz, 1H), 6.75 (s, 1H), 3.95 (s, 3H), 3.82 (t, J = 4.5 Hz, 4H), 2.94 (t, J = 4.5 Hz, 4H), 2.31 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H). 586.3  98 [00902] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.57 (s, 1H), 8.86 (dd, J = 9.5, 4.4 Hz, 1H), 8.74- 8.69 (m, 3H), 8.42 (s, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 6.73 (s, 1H), 3.94 (s, 3H), 3.23-3.20 (m, 2H), 3.05-2.98 (m, 8H), 2.70-2.56 (m, 6H), 2.13 (d, J = 14.0 Hz, 6H), 1.99-1.95 (m, 2H), 1.73-1.65 (m, 2H).  763.3, 765.3  99 [00903] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.66 (s, 1H), 8.84-8.80 (m, 3H), 8.47 (s, 1H), 8.34 (s, 2H), 8.26 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 6.86 (s, 1H), 4.25 (t, J = 5.6 Hz, 2H), 3.83 (s, 3H), 3.79(s, 3H), 2.90-2.88 (m, 4H), 2.84 (t, J = 5.6 Hz, 2H), 2.58 (s, 4H), 2.01 (d, J = 14.4 Hz, 6H).  707.2, 709.2 101 [00904] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 9.01 (dd, J = 5.2, 4.0 Hz, 1H), 8.74 (dd, J = 9.6, 2.0 Hz, 2H), 8.42 (s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.69-7.61 (m, 3H), 7.38 (s, 1H), 6.72 (s, 1H), 3.93 (s, 3H), 3.74 (s, 3H), 3.05 (s, 3H), 2.87 (s, 5H), 2.72 (s, 3H), 2.15 (d, J = 14.4 Hz, 6H), 1.94 (s, 4H), 1.67 (s, 4H).  745.3, 747.3 102 [00905] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.86-8.83 (m, 2H), 8.80 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 6.84 (s, 1H), 3.93 (s, 3H), 3.71 (s, 3H), 2.92 (s, 4H), 2.80 (s, 4H), 2.17 (d, J = 14.4 Hz, 6H), 1.83-1.78 (m, 1H), 0.58-0.46 (m, 4H).  703.2, 705.2 103 [00906] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.60 (s, 1H), 9.01 (dd, J = 9.6, 4.2Hz, 1H), 8.74 (dd, J = 9.9, 1.8 Hz, 2H), 8.31 (s, 1H), 8.25 s, 1H), 7.67-7.63 (m, 3H), 7.34 (s, 1H), 6.76 (s, 1H), 4.79-4.64 (m, 2H), 3.92 (s, 3H), 3.74 (s, 3H), 3.04-2.80 (m, 10H), 2.15 (d, J = 14.1 Hz, 6H).  709.2, 711.2 104 [00907] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.63 (s, 1H), 9.00 (dd, J = 9.6, 4.2 Hz, 1H), 8.74 (dd, J = 7.8, 2.1 Hz, 2H), 8.35 (s, 1H), 8.33 (s, 1H), 7.82 (s, 1H), 7.65 (d, J = 9.6 Hz, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 6.81 (s, 1H), 3.93 (s, 3H), 3.91-3.85 (m, 2H), 3.77- 3.69 (m, 4H), 3.45-3.38 (m, 1H), 3.25-3.20 (m, 1H), 2.91-2.78 (m, 2H), 2.16 (dd, J = 14.1, 2.7 Hz, 6H), 0.88 (d, J = 6.3 Hz, 3H). [α].sub.D.sup.25 = −20.9° (c = 0.3, MeOH)  678.2, 680.2 105 [00908] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 8.97 (dd, J = 9.6, 4.2 Hz, 1H), 8.78- 8.70 (m, 2H), 8.30 (d, J = 12.0 Hz, 2H), 8.10 (s, 1H), 7.64 (d, J = 7.8 Hz, 2H), 7.51 (s, 1H), 7.43 (s, 1H), 6.68 (s, 1H), 6.18 (s, 1H), 3.94 (s, 3H), 3.78 (s, 3H), 3.68 (s, 2H), 3.38 (s, 2H), 3.13 (t, J = 5.4 Hz, 2H), 2.17 (s, 3H), 2.13 (s, 3H).  677.0, 679.0 107 [00909] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.66 (s, 1H), 9.03 (dd, J = 9.6, 4.0 Hz, 1H), 8.74 (dd, 17.6, 2.0 Hz, 2H), 8.27 (s, 1H), 8.04 (s, 1H), 7.65 (s, 1H), 7.47 (s, 3H), 6.59 (s, 1H), 4.54 (s, 1H), 4.14-4.01 (m, 2H), 3.92 (s, 3H), 3.81 (s, 4H), 3.13 (s, 2H), 2.14 (dd, J = 14.0, 2.0 Hz, 6H), 1.99-1.82 (m, 2H). [α].sub.D.sup.25 = −1.7° (c = 0.26, MeOH)  676.2, 678.2 108 [00910] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.60 (s, 1H), 8.99 (dd, J = 9.6, 4.4 Hz, 1H), 8.75 (dd, J = 17.6, 2.0 Hz, 2H), 8.57 (s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 7.67 (d, J = 9.6 Hz, 1H) 7.60 (s, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 6.74 (s, 1H), 3.94 (s, 3H), 3.77 (s, 3H), 2.99-2.83 (m, 6H), 2.49 (s, 3H), 2.15 (d, J = 14.4 Hz, 6H), 1.28 (s, 6H).  705.3, 707.3 109 [00911] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.57 (s, 1H), 9.00 (dd, J = 9.6, 4.4 Hz, 1H), 8.74 (dd, J = 19.6, 2.0 Hz, 2H), 8.26 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.42 (s, 1H) 7.34 (s, 1H), 7.21 (s, 1H), 6.18 (s, 1H), 4.77 (s, 4H), 3.92 (s, 3H), 3.87 (s, 3H), 3.74 (s, 4H), 2.13 (d, J = 14.4 Hz, 6H).  676.3, 678.3 110 [00912] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.94-8.77 (m, 3H), 8.46 (s, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.62 (s, 1H) 7.55 (s, 1H), 6.90 (s, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.30-3.27 (m, 4H), 3.00 (s, 3H), 2.98-2.95 (m, 4H), 2.02 (d, J = 14.7 Hz, 6H).  740.9, 742.9 112 [00913] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.88-8.77 (m, 3H), 8.43 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.76 (s, 1H), 7.61- 7.54 (m, 2H), 6.84 (s, 1H), 6.05 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.45 (s, 4H), 2.80 (s, 4H), 2.02 (d, J = 14.4 Hz, 6H).  706.1, 708.1 113 [00914] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 8.99 (dd, J = 9.6, 4.2 Hz, 1H), 8.77- 8.67 (m, 2H), 8.55 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 7.75 (s, 1H), 7.58 (s, 2H), 7.41 (s, 1H), 6.79 (s, 1H), 3.92 (s, 3H), 3.77 (s, 3H), 3.12 (d, J = 12.3 Hz, 2H), 2.84 (t, J = 9.9 Hz, 2H), 2.14 (d, J = 14.4 Hz, 8H), 1.90 (s, 2H), 1.52 (s, 3H).  691.4, 693.4 114 [00915] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.68 (s, 1H), 8.91-8.83 (m, 3H), 8.41 (s, 1H), 8.25 (s, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.50 (s, 1H), 7.32 (s, 1H), 6.65 (s, 1H), 4.48 (s, 1H), 4.29 (s, 1H), 3.91-3.88 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.71-3.68 (m, 1H), 3.10-3.07 (m, 1H), 2.79-2.76 (m, 1H), 2.02 (d, J = 14.4 Hz, 6H), 1.93-1.90 (m, 1H), 1.78-1.75 (m, 1H). [α].sub.D.sup.25 = +3.9° (c = 0.45, MeOH)  676.3, 678.3 115 [00916] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.67 (s, 1H), 8.85-8.76 (m, 3H), 8.43 (s, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.56 (s, 1H), 6.85 (s, 1H), 4.72 (s, 1H), 3.87-3.67 (m, 9H), 3.49-3.45 (m, 1H), 3.38-3.34 (m, 1H), 3.04-3.01 (m, 1H), 2.90-2.87 (m, 1H), 2.76-2.69 (m, 1H), 2.57-2.53 (m, 1H), 2.02 (d, J = 14.4 Hz, 6H).  694.2, 696.2 116 [00917] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.85-8.77 (m, 3H), 8.43 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 6.87 (s, 1H), 3.86 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.66 (s, 2H), 3.89-3.83 (m, 4H), 2.02 (d, J = 14.4 Hz, 7H), 0.81-0.71 (m, 4H).  731.4, 733.4 117 [00918] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.69 (s, 1H), 8.87-8.79 (m, 3H), 8.43 (s, 1H), 8.30 (s, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 7.54 (s, 1H), 6.80 (s, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.97 (s, 4H), 2.86 (s, 4H), 2.02 (d, J = 14.4 Hz, 6H).  663.4, 665.4 119 [00919] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 9.25 (dd, J = 9.6, 4.0 Hz, 1H), 8.80 (dd, J = 17.6, 2.0 Hz, 2H), 8.08 (d, J = 3.6 Hz, 1H), 8.00 (s, 2H), 7.68 (s, 1H), 7.47 (d, J = 9.6 Hz, 1H), 6.85 (s, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 3.23-3.20 (m, 2H), 2.74-2.47 (m, 10H), 2.33 (s, 4H), 2.15 (d, J = 14.4 Hz, 6H), 2.02-1.99 (m, 2H), 1.72-1.60 (m, 2H). .sup.19F NMR (377 MHz, CDCl.sub.3) δ −165.77. 700.3 120 [00920] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.86-8.76 (m, 3H), 8.44 (s, 1H), 8.28 (s, 1H), 7.89 (s, 1H), 7.70 (s, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.52 (s, 1H), 6.83 (s, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.71-3.67 (m, 2H), 2.74 (s, 2H), 2.72-2.69 (m, 2H), 2.02 (d, J = 14.4 Hz, 6H), 1.26 (s, 6H).  692.1, 694.1 121 [00921] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.64 (s, 1H), 9.00 (dd, J = 9.6, 3.2 Hz, 1H), 8.74 (dd, J = 9.0, 1.8 Hz, 2H), 8.30 (s, 1H), 8.22 (s, 1H), 7.81 (s, 1H), 7.63-7.43 (m, 3H), 6.75 (s, 1H), 3.92-3.80 (m, 7H), 3.16-3.12 (m, 2H), 2.75-2.68 (m, 2H), 2.15 (d, J = 14.4 Hz, 6H), 2.02-1.98 (m, 2H), 1.76-1.68 (m, 3H).  678.4, 680.4 122 [00922] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.60 (s, 1H), 9.05 (dd, J = 9.6, 4.0 Hz, 1H), 8.79- 8.68 (m, 2H), 8.45 (s, 1H), 8.32 (s, 1H), 7.84-7.73 (m, 2H), 7.46 (d, J = 10.0 Hz, 2H), 7.34 (s, 1H), 6.58 (d, J = 2.0 Hz, 1H), 4.36-4.30 (m, 2H), 3.76 (s, 3H), 3.64 (t, J = 7.2 Hz, 2H), 3.46 (t, J = 4.4 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.57 (s, 6H), 2.18 (s, 3H), 2.14 (s, 3H).  677.4, 679.4 123 [00923] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 10.97 (s, 1H), 8.60 (s, 1H), 8.19 (s, 2H), 8.05 (s, 1H), 7.86 (s, 2H), 7.55-7.43 (m, 1H), 7.04- 6.92 (m, 2H), 4.92 (q, J = 9.0 Hz, 2H), 3.86 (s, 3H), 3.80-3.69 (m, 4H), 3.06 (t, J = 4.5 Hz, 4H), 1.78 (s, 3H), 1.73 (s, 3H).  681.0, 683.0 124 [00924] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.62 (s, 1H), 9.01 (dd, J = 9.3, 1.2 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.73 (s, 1H), 7.64-7.57 (m, 2H), 7.40 (s, 1H), 6.75 (s, 1H), 4.90-4.73 (m, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 3.09-3.05 (m, 2H), 2.86-2.80 (s, 2H), 2.15 (d, J = 14.1 Hz, 6H), 2.05-1.95 (m, 4H).  680.1, 682.1 125 [00925] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 8.40 (s, 1H), 8.20 (s, 2H), 8.06 (d, J = 8.1 Hz, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.32 (dd, J = 7.8, 1.5 Hz, 1H), 7.02-7.00 (m, 1H), 6.79 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.75-3.72 (m, 4H), 2.85- 2.82 (m, 4H), 2.62-2.56 (m, 1H), 0.99-0.90 (m, 2H), 0.87-0.84 (m, 2H).  655.2, 657.2 126 [00926] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.01 (s, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.89-8.85 (m, 2H), 8.68 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.46 (s, 1H), 6.83 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78-3.73 (m, 4H), 3.01 (s, 3H), 2.88-2.83 (m, 4H).  681.0, 683.0 127 [00927] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 12.68 (s, 1H), 8.98 (dd, J = 9.6, 4.4 Hz, 1H), 8.74 (dd, J = 12.8, 2.0 Hz, 2H), 8.29 (s, 1H), 8.22 (s, 1H), 7.76 (s, 1H), 7.65-7.58 (m, 1H), 7.55 (s, 2H), 6.72 (s, 1H), 4.02-3.95 (m, 1H), 3.94 (s, 3H), 3.91-3.84 (m, 1H), 3.83-3.73 (1H, 4H), 3.53-3.40 (m, 2H), 3.41 (s, 3H), 3.05-2.91 (m, 2H), 2.86-2.75 (m, 1H), 2.67 (t, J = 10.8 Hz, 1H), 2.15 (d, J = 14.0 Hz, 6H). [α].sub.D.sup.25 = +3.5° (c = 0.33, MeOH)  708.1, 710   128 [00928] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.87-8.77 (m, 3H), 8.41 (s, 1H), 8.26 (s, 1H), 7.82 (s, 1H), 7.60 (s, 2H), 7.43 (s, 1H), 6.72 (s, 1H), 4.02-3.98 (m, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.23 (m, 3H), 3.16- 3.08 (m, 2H), 3.02-2.94 (m, 2H), 2.17-2.08 (m, 1H), 2.04 (s, 3H), 1.99 (s, 3H), 1.88- 1.83 (m, 1H).  678.2, 680.2 129 [00929] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 8.99 (dd, J = 9.6, 4.2 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.61 (d, J = 9.3 Hz, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 6.70 (s, 1H), 3.95-3.92 (m, 7H), 3.83 (s, 3H), 3.29-3.25 (m, 2H), 2.86 (s, 4H), 2.66-2.59 (m, 4H), 2.15 (d, J = 14.1 Hz, 6H), 2.09-2.05 (m, 3H).  747.4, 749.4 130 [00930] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.85-8.77 (m, 3H), 8.43 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.58 (s, 2H), 6.87 (s, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.16-3.13 (m, 1H), 3.05-2.96 (m, 3H), 2.78-2.72 (m, 1H), 2.59-2.54 (m, 1H), 2.35-2.29 (m, 1H), 2.23-2.13 (m, 2H), 2.02 (d, J = 14.4 Hz, 6H), 1.79-1.68 (m, 3H), 1.41-1.32 (m, 1H).  703.2, 705.2 131 [00931] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.89-8.74 (m, 3H), 8.49 (s, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.53-7.50 (m, 2H), 6.85 (s, 1H), 3.95 (s, 3H), 3.71 (s, 3H), 3.26-3.12 (m, 4H), 3.00-2.88 (m, 3H), 2.76-2.71 (m, 2H), 2.17 (d, J = 14.4 Hz, 6H), 1.92-1.89 (m, 2H), 1.77-1.74 (m, 2H), 1.59-1.45 (m, 2H).  717.3, 719.3 132 [00932] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.21 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.68-7.65 (m, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 7.13-7.09 (m, 2H), 6.69 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.68 (s, 2H), 3.39 (s, 3H), 3.03 (s, 5H), 2.90 (s, 3H), 2.84 (s, 5H).  686.1, 688.1 134 [00933] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.60 (s, 1H), 9.00 (dd, J = 9.6, 4.2 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 8.30 (s, 1H), 8.24 (d, J = 2.7 Hz, 1H), 7.75 (s, 1H), 7.64-7.58 (m, 2H), 7.44 (s, 1H), 6.72 (s, 1H), 3.94 (s, 4H), 3.83-3.72 (m, 5H), 3.01-2.92 (m, 2H), 2.77 (m, 1H), 2.56-2.44 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 1.20 (d, J = 6.3 Hz, 3H).  677.9, 679.9 135 [00934] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.67 (s, 1H), 8.87-8.80 (m, 2H), 8.76 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.59-7.53 (m, 2H), 6.84 (s, 1H), 4.07- 4.02 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.32 (s, 2H), 2.98-2.93 (m, 2H), 2.02 (d, J = 14.4 Hz, 6H), 1.18 (d, J = 6.3 Hz, 6H).  692.1, 694.1 136 [00935] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 10.70 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.76-7.50 (m, 3H), 7.04 (d, J = 12.9 Hz, 1H), 6.71 (s, 1H), 3.93-3.70 (m, 8H), 3.06 (s, 2H), 2.94 (s, 2H), 2.80 (s, 2H), 2.41 (s, 2H), 1.88 (s, 3H), 1.84 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H).  665.9, 667.9 137 [00936] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.56 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.59-7.57 (m, 3H), 7.01 (d, J = 13.2 Hz, 1H), 6.69 (s, 1H), 4.15-4.11 (m, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.06 (t, J = 4.4 Hz, 2H), 2.96 (dd, J = 11.2, 3.2 Hz, 2H), 2.86 (s, 2H), 2.50 (dd, J = 11.2, 5.6 Hz, 2H), 1.83 (d, J = 13.2 Hz, 6H), 1.25 (d, J = 6.4 Hz, 6H).  666.2, 668.2 138 [00937] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.43 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.02 (d, J = 3.6 Hz, 1H), 7.72 (s, 1H), 7.53-7.51 (m, 2H), 7.04 (d, J = 13.6 Hz, 1H), 6.75 (s, 1H), 4.88 (s, 1H), 4.76 (s, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.14-3.05 (m, 8H), 3.00 (s, 4H), 2.86 (s, 2H), 1.86 (d, J = 13.2 Hz, 6H).  683.2, 685.2 139 [00938] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.60 (s, 1H), 9.02 (dd, J = 9.6, 4.2 Hz, 1H), 8.79- 8.69 (m, 2H), 8.31 (s, 1H), 8.21 (s, 1H), 7.66 (s, 3H), 7.33 (s, 1H), 6.73 (s, 1H), 3.93 (s, 3H), 3.75 (s, 5H), 3.38 (s, 3H), 2.95-2.84 (m, 10H), 2.15 (d, J = 14.4 Hz, 6H), 1.87-1.83 (m, 4H), 1.65-1.62 (m, 4H).  789.4, 791.4 140 [00939] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 12.67 (s, 1H), 9.05 (dd, J = 9.2, 4.0 Hz, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.47 (s, 1H), 8.27 (s, 1H), 7.49 (s, 2H), 7.30 (d, J = 2.0 Hz, 1H), 6.96 (s, 1H), 6.70 (s, 1H), 3.94 (s, 3H), 3.83-3.81 (m, 4H), 3.54 (s, 3H), 2.95 (s, 4H), 2.12 (d, J = 14.4 Hz, 6H).  664.2, 666.2 141 [00940] .sup.1H NMR (300 MHz, CDCl.sub.3): δ 12.35 (s, 1H), 9.32 (dd, J = 9.6, 4.5 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 8.69 (d, J = 1.8 Hz, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.59 (d, J = 9.6 Hz, 1H), 6.73 (s, 1H), 3.95 (s, 3H), 3.79 (s, 3H), 2.30 (s, 3H), 2.13 (d, J = 14.1Hz, 6H). 608.3 142 [00941] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.61 (s, 1H), 9.02 (dd, J = 9.6, 4.2 Hz, 1H), 8.79- 8.66 (m, 2H), 8.30 (s, 1H), 8.21 (s, 1H), 7.71 (s, 1H), 7.63 (s, 2H), 7.38 (s, 1H), 6.80 (s, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 3.06-2.82 (m, 4H), 2.17 (s, 3H), 2.12 (s, 3H), 1.84-1.67 (m, 5H), 1.35 (s, 3H).  692.2, 694.2 143 [00942] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ 12.50 (s, 1H), 9.23-9.12 (m, 1H), 8.81 (dd, J = 13.8, 1.8 Hz, 2H), 8.17 (s, 1H), 7.98 (d, J = 10.2 Hz, 2H), 7.89 (s, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.55 (d, J = 9.6 Hz, 1H), 6.84 (s, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 2.14 (s, 3H), 2.03 (d, J = 14.4 Hz, 6H). 564.3 145 [00943] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 12.70 (s, 1H), 8.85-8.76 (m, 3H), 8.46 (s, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.70 (s, 1H), 7.58 (s, 2H), 6.85 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 2.02 (d, J = 14.4 Hz, 6H).  628.2, 630.2 146 [00944] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.88 (dd, J = 9.6, 1.2 Hz, 1H), 8.83 (d, J = 2.1 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 9.6 Hz, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 3.92 (s, 3H), 3.88-3.82 (m, 1H), 3.80-3.74 (m, 1H), 3.72 (s, 3H), 3.24-3.19 (m, 2H), 3.12-3.00 (m, 2H), 2.80-2.76 (m, 1H), 2.70-2.66 (m, 3H), 2.49 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H), 2.11-1.98 (m, 2H).  733.2, 735.2 149 [00945] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.87-8.82 (m, 2H), 8.79 (d, J = 1.8 Hz, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.56-7.50 (m, 2H), 6.88 (s, 1H), 6.22-5.79 (m, 1H), 3.92 (s, 3H), 3.69 (s, 3H), 2.91-2.85 (m, 4H), 2.83-2.72 (m, 2H), 2.66-2.58 (m, 4H), 2.19 (s, 3H), 2.14 (s, 3H), 1.69-1.61 (m, 8H). .sup.19F NMR (300 MHz, CD.sub.3OD) δ −120.23.  795.0, 797.0 151 [00946] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 12.67 (s, 1H), 8.84-8.81 (m, 3H), 8.38 (s, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.66- 7.45 (m, 2H), 6.82 (s, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.76-3.70 (m, 1H), 3.55-3.45 (m, 1H), 3.07-2.97 (m, 2H), 2.76-2.64 (m, 2H), 2.01 (d, J = 14.4 Hz, 6H), 1.94-1.84 (m, 2H), 1.63-1.50 (m, 2H), 1.11 (d, J = 6.0 Hz, 6H).  720.2, 722.2 152 [00947] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.91-8.88 (m, 2H), 8.75 (s, 1H), 8.30 (s, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.65-7.61 (m, 2H), 6.89 (s, 1H), 3.97-3.80 (m, 8H), 3.52-3.42 (m, 2H), 3.37 (s, 3H), 3.12-2.99 (m, 2H), 2.87- 2.76 (m, 2H), 2.67-2.59 (m, 1H), 2.20 (s, 3H), 2.16 (s, 3H). [α].sub.D.sup.25 = −19.9° (c = 0.34, MeOH)  708.2, 710.2 154 [00948] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.67 (s, 1H), 8.93 (dd, J = 9.6, 4.0 Hz, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 7.59 (s, 1H), 7.40 (d, J = 4.4 Hz, 2H), 6.37 (s, 1H), 4.00 (s, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.11 (dd, J = 14.4, 2.0 Hz, 6H), 1.36 (d, J = 6.4 Hz, 3H).  690.2, 692.2 156 [00949] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.64 (s, 1H), 9.00 (dd, J = 9.6, 4.2 Hz, 1H), 8.78- 8.68 (m, 2H), 8.29 (s, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.59 (d, J = 9.6 Hz, 1H), 7.43 (s, 2H), 6.74 (s, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.50-3.38 (m, 1H), 3.35 (d, J = 6.9 Hz, 2H), 3.16-3.12 (m, 2H), 2.67 (t, J = 10.8 Hz, 2H), 2.14 (d, J = 14.4 Hz, 6H), 2.03- 1.99 (m, 2H), 1.75-1.66 (m, 2H), 1.14-1.07 (m, 1H), 0.62-0.56 (m, 2H), 0.27-0.22 (m, 2H).  732.3, 734.3 157 [00950] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.84-8.80 (m, 2H), 8.77 (d, J = 2.0 Hz, 1H), 8.48 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.51-7.48 (m, 2H), 6.85 (s, 1H), 3.93 (s, 3H), 3.68 (s, 3H), 3.20 (s, 3H), 3.11 (s, 5H), 2.88 (d, J = 6.8 Hz, 2H), 2.14 (d, J = 14.4 Hz, 6H), 1.11-1.06 (m, 1H), 0.76-0.71 (m, 2H), 0.40-0.36 (m, 2H).  716.9, 718.9 158 [00951] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.44 (s, 1H), 8.28 (d, J = 8.1 Hz, 2H), 8.19 (s, 1H), 7.99 (s, 1H), 7.67 (d, J = 12.9 Hz, 2H), 7.37 (s, 1H), 7.07 (s, 1H), 6.69 (s, 1H), 3.91 (s, 6H), 3.31 (s, 3H), 3.21 (s, 2H), 3.05 (d, J = 7.9 Hz, 6H), 2.96 (s, 6H), 2.87 (s, 1H), 2.76 (s, 1H), 2.62 (s, 3H), 2.55 (s, 4H), 2.00 (d, J = 11.8 Hz, 2H), 1.78 (d, J = 12.4 Hz, 2H).  765.2, 767.2 159 [00952] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.87-8.81 (m, 2H), 8.79 (d, J = 2.1 Hz, 1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.50 (d, J = 9.6 Hz, 1H), 7.46 (s, 1H), 6.85 (s, 1H), 5.42 (s, 0.5H), 5.24 (s, 0.5H), 4.26-4.16 (m, 2H), 3.98-3.87 (m, 5H), 3.70 (s, 3H), 3.21-3.18 (m, 2H), 2.93-2.84 (m, 1H), 2.74-2.66 (m, 2H), 2.17 (d, J = 14.4 Hz, 6H), 2.01-1.97 (m, 2H), 1.61-1.49 (m, 2H). .sup.19F NMR (282 MHz, CD.sub.3OD) δ −181.60.  735.1, 737.1 160 [00953] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.40 (s, 1H), 8.84 (d, J = 4.0 Hz, 1H), 8.73 (dd, J = 9.6, 4.4 Hz, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.44 (dd, J = 8.8, 4.4 Hz, 1H), 6.69 (s, 1H), 3.91 (s, 3H), 3.83- 3.75 (m, 4H), 3.71 (s, 3H), 2.89 (t, J = 4.6 Hz, 4H), 2.14 (d, J = 12.8 Hz, 6H).  663.4, 665.4 161 [00954] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 8.99 (dd, J = 9.6, 4.2 Hz, 1H), 8.78- 8.67 (m, 2H), 8.29 (s, 1H), 8.23 (s, 1H), 7.75-7.54 (m, 3H), 7.38 (s, 1H), 6.74 (s, 1H), 3.96-3.70(m, 9H), 3.43 (s, 1H), 3.16- 2.77 (m, 5H), 2.57 (s, 4H), 2.17 (s, 3H), 2.13 (s, 3H).  719.2, 721.2 162 [00955] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.84-8.77 (m, 3H), 8.24 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.50 (d, J = 9.6 Hz, 1H), 7.44 (s, 1H), 6.81 (s, 1H), 3.91 (s, 3H), 3.70 (s, 3H), 3.31-3.24 (m, 5H), 3.19-3.11 (m, 1H), 3.06-2.97 (m, 1H), 2.61-2.49 (m, 1H), 2.41-2.29 (m, 1H), 2.18 (s, 3H), 2.13 (s, 3H), 2.09-1.99 (m, 1H), 1.87-1.66 (m, 3H), 1.20-1.04 (m, 1H).  705.9, 707.9 163 [00956] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.89-8.82 (m, 2H), 8.79 (d, J = 1.8 Hz, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.52 (d, J = 10.8 Hz, 2H), 6.85 (s, 1H), 4.05-4.00 (m, 1H), 3.93 (s, 3H), 3.83- 3.72 (m, 2H), 3.70 (s, 3H), 3.26-3.22 (m, 4H), 2.73-2.66 (m, 4H), 2.41-2.36 (m, 1H), 2.19 (s, 3H), 2.17-2.14 (m, 5H), 1.80- 1.69 (m, 2H), 1.23 (d, J = 6.3 Hz, 3H). [α].sub.D.sup.25 = +6.4° (c = 0.31, MeOH)  761.3, 763.3 165 [00957] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.89-8.82 (m, 2H), 8.79 (d, J = 1.8 Hz, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.55-7.51 (m, 2H), 6.85 (s, 1H), 4.05- 4.00 (m, 1H), 3.93 (s, 3H), 3.83-3.72 (m, 2H), 3.70 (s, 3H), 3.29-3.20 (m, 4H), 2.74- 2.67 (1H, 4H), 2.40-2.33 (m, 1H), 2.19 (s, 3H), 2.17-2.14 (m, 5H), 1.80-1.69 (m, 2H), 1.23 (d, J = 6.3 Hz, 3H). [α].sub.D.sup.25 = −5.6° (c = 0.36, MeOH)  761.3, 763.3 166 [00958] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.86-8.78 (m, 3H), 8.50 (s, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.54-7.50 (m, 2H), 6.85 (s, 1H), 3.95 (s, 3H), 3.70 (s, 3H), 3.27-3.10 (m, 4H), 3.04-2.83 (m, 3H), 2.78-2.68 (m, 2H), 2.17 (d, J = 14.4 Hz, 6H), 1.92-1.88 (m, 2H), 1.78-1.73 (m, 2H), 1.59-1.44 (m, 2H). [α].sub.D.sup.25 = −19.4° (c = 0.27, MeOH)  717.2, 719.2 167 [00959] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 9.00 (dd, J = 9.6, 4.0 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 7.65-7.63 (m, 3H), 7.31 (s, 1H), 6.71 (s, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 2.93 (brs, 3H), 2.84 (t, J = 5.6 Hz, 5H), 2.65 (d, J = 6.8 Hz, 2H), 2.12 (d, J = 14.4 Hz, 6H), 1.86 (brs, 4H), 1.63 (t, J = 5.2 Hz, 4H), 1.10 (brs, 1H), 0.75-0.65 (m, 2H), 0.30-0.26 (m, 2H).  785.4, 787.4 169 [00960] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.64 (s, 1H), 9.00 (dd, J = 9.6, 4.2 Hz, 1H), 8.79- 8.67 (m, 2H), 8.31 (s, 1H), 8.24 (s, 1H), 7.74 (s, 1H), 7.65-7.59 (m, 2H), 7.44 (s, 1H), 6.72 (s, 1H), 3.94 (s, 3H), 3.91 (s, 1H), 3.82-3.75 (m, 5H), 3.01-2.93 (s, 2H), 2.82-2.74 (m, 1H), 2.57-2.45 (m, 1H), 2.15 (d, J = 14.4 Hz, 6H), 1.20 (d, J = 6.3 Hz, 3H). [α].sub.D.sup.25 = +18.2° (c = 0.26, MeOH)  678.3, 680.3 170 [00961] [α].sub.D.sup.25 = −16.6° (c = 0.29 , MeOH) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.68 (s, 1H), 8.96 (dd, J = 9.6, 4.4 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.73 (s, 1H), 7.61-7.58 (m, 3H), 6.70 (s, 1H), 3.92 (s, 3H), 3.89 (s, 1H), 3.79-3.73 (m, 5H), 2.99- 2.91 (m, 2H), 2.79-2.73 (m, 1H), 2.56-2.44 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 1.20 (d, J = 6.4 Hz, 3H).  678.3, 680.3 172 [00962] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.89-8.81 (m, 2H), 8.78 (d, J = 1.8 Hz, 1H), 8.49 (s, 1H), 8.27 (s, 1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.52 (d, J = 9.6 Hz, 1H), 7.45 (s, 1H), 6.84 (s, 1H), 4.09 (s, 4H), 3.92 (s, 3H), 3.69 (s, 3H), 3.63 (s, 4H), 3.16-3.12 (m, 2H), 2.78 (s, 3H), 2.69-2.62 (m, 2H), 2.44- 2.37 (m, 1H), 2.16 (d, J = 14.4 Hz, 6H), 1.88-1.84 (m, 2H), 1.51-1.35 (m, 2H).  772.4, 774.4 173 [00963] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.88-8.79 (m, 3H), 8.27 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.54 (s, 2H), 6.85 (s, 1H), 3.92 (s, 3H), 3.70 (s, 3H), 3.61-3.58 (m, 1H), 3.21- 3.17 (m, 2H), 2.69-2.62 (m, 3H), 2.46 (s, 3H), 2.17 (d, J = 14.4 Hz, 6H), 1.97-1.91 (m, 1H), 1.82-1.65 (m, 3H), 1.30 (d, J = 6.9 Hz, 3H). .sup.19F NMR (282 MHz, MeOD) δ −76.05.  787.4, 789.4 174 [00964] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.85-8.81 (m, 3H), 8.39 (s, 1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 7.56 (s, 2H), 6.82 (s, 1H), 3.93-3.87 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.13-3.11 (m, 2H), 2.64-2.54 (m, 4H), 2.27-2.17 (m, 3H), 2.01 (d, J = 14.4 Hz, 6H), 1.84-1.80 (m, 2H), 1.59-1.52 (m, 2H), 1.15 (d, J = 6.4 Hz, 6H).  775.1, 777.1 175 [00965] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.85-8.79 (m, 3H), 8.49 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.55-7.51 (m, 2H), 6.86 (s, 1H), 3.95 (s, 3H), 3.70 (s, 3H), 3.18- 3.06 (m, 4H), 2.99-2.91 (m, 1H), 2.85-2.60 (s, 4H), 2.20 (s, 3H), 2.15 (s, 3H), 1.90- 1.68 (m, 4H), 1.55-1.39 (m, 2H). [α].sub.D.sup.25 = +24.5 (c = 0.35, MeOH)  717.3, 719.3 176 [00966] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.85-8.79 (m, 3H), 8.45 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.83 (s, 1H), 7.54 (d, J = 9.3 Hz, 1H), 7.48 (s, 1H), 6.90 (s, 1H), 3.96 (s, 3H), 3.71 (s, 3H), 3.52-3.40 (m, 3H), 3.24-3.17 (m, 2H), 3.06-3.00 (m, 3H), 2.91-2.84 (s, 1H), 2.19-2.12 (m, 9H) 1.83-1.73 (m, 1H). [α].sub.D.sup.25 = +5.5° (c = 0.4 , MeOH)  703.2, 705.2 177 [00967] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.61 (s, 1H), 8.94 (dd, J = 9.6, 4.0 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.33 (s, 2H), 7.64 (d, J = 9.6 Hz, 1H), 7.58 (s, 1H), 7.46 s, 1H), 6.74 (s, 1H), 5.73 (s, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 3.62 (s, 2H), 3.05 (s, 2H), 2.75 (s, 3H), 2.48 (s, 2H), 2.15 (d, J = 14.4 Hz, 6H).  674.4, 676.4 178 [00968] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 13.42 (s, 1H), 8.81-8.75 (m, 3H), 8.07 (s, 1H), 7.71 (s, 2H), 7.59-7.54 (m, 2H), 6.71 (s, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 3.43 (s, 4H), 3.04 (s, 4H), 2.34 (s, 1H), 2.13 (d, J = 14.0 Hz, 6H), 1.26-1.21 (m, 2H), 1.08-1.03 (m, 2H).  767.1, 769.1 179 [00969] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.82 (p, J = 4.0 Hz, 2H), 8.77 (d, J = 2.0 Hz, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 6.82 (s, 1H), 3.90 (s, 3H), 3.68 (s, 3H), 3.43 (s, 1H), 3.37 (s, 3H), 3.21 (d, J = 11.6 Hz, 2H), 3.13 (s, 2H), 2.79 (s, 3H), 2.71- 2.62 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 2.06-2.00 (m, 4H), 1.85-1.68 (m, 4H).  775.5, 777.5 180 [00970] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.89-8.83 (m, 2H), 8.79 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 8.28 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 6.86 (s, 1H), 4.71-4.61 (m, 1H), 3.93 (s, 3H), 3.71 (s, 3H), 3.24 (d, J = 12.3 Hz, 2H), 3.03- 2.92 (m, 4H), 2.74-2.66 (m, 3H), 2.17 (d, J = 14.4 Hz, 6H), 2.12-1.92 (m, 6H), 1.79- 1.75 (m, 2H).  763.4, 765.4 181 [00971] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.60 (s, 1H), 9.01 (dd, J = 9.6, 4.2 Hz, 1H), 8.78- 8.66 (m, 2H), 8.31 (s, 1H), 8.24 (s, 1H), 7.65 (d, J = 6.6 Hz, 3H), 7.38 (s, 1H), 6.76 (s, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 3.67 (t, J = 5.4 Hz, 2H), 3.06 (d, J = 5.1 Hz, 4H), 2.84 (d, J = 6.6 Hz, 6H), 2.17 (s, 3H), 2.12 (s, 3H).  723.9, 725.9 182 [00972] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 8.97 (dd, J = 9.6, 4.4 Hz, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 8.23 (s, 1H), 7.77 (s, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 6.70 (s, 1H), 3.96-3.82 (m, 4H), 3.85-3.74 (m, 5H), 3.62-3.56 (m, 1H), 3.53-3.49 (m, 1H), 3.43-3.93 (m, 1H), 3.06-3.02 (m, 1H), 2.93-2.90 (m, 1H), 2.81-2.75 (m, 1H), 2.62-2.57 (m, 1H), 2.13 (d, J = 14.4 Hz, 6H), 1.17 (s, 3H), 1.16 (s, 3H).  736.1, 737.9 184 [00973] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.82 (dd, J = 8.8, 3.2 Hz, 2H), 8.76 (d, J = 2.0 Hz, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.51 (s, 2H), 6.85 (s, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.28 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.65 (s, 3H), 2.99-2.92 (m, 4H), 2.57-2.51 (m, 4H), 2.16 (s, 3H), 2.12 (s, 3H), 1.47 (s, 3H).  733.4, 735.4 185 [00974] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 9.00 (dd, J = 9.6, 4.2 Hz, 1H), 8.77- 8.69 (m, 2H), 8.31 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.56 (s, 1H), 7.36 (s, 1H), 6.71 (s, 1H), 4.92-4.74 (m, 1H), 3.92 (s, 3H), 3.78 (s, 3H), 3.48 (s, 4H), 3.24 (d, J = 11.1 Hz, 2H), 3.07 (s, 1H), 2.83 (s, 2H), 2.61 (t, J = 11.4 Hz, 4H), 2.17 (s, 3H), 2.13 (s, 3H), 1.96 (s, 4H), 1.73 (s, 2H). [α].sub.D.sup.25 = +1.6° (c = 0.29, MeOH)  793.0, 795.0 186 [00975] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.89-8.78 (m, 3H), 8.27 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.53 (d, J = 9.9 Hz, 1H), 7.45 (s, 1H), 6.85 (s, 1H), 6.00 (t, J = 55.8 Hz, 1H), 3.92 (s, 3H), 3.72 (s, 3H), 3.19 (d, J = 11.7 Hz, 2H), 2.87-2.59 (m, 12H), 2.33 (s, 1H), 2.17 (d, J = 14.4 Hz, 6H), 2.01 (d, J = 10.5 Hz, 2H), 1.70-1.58 (m, 2H).  810.4, 812.4 187 [00976] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.83 (s, 1H), 8.94 (dd, J = 9.6, 4.2 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.56 (d, J = 9.3 Hz, 1H), 7.32 (s, 1H), 6.73 (s, 1H), 4.98-4.82 (m, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.51 (s, 3H), 3.48-3.42 (m, 2H), 3.11-3.07 (m, 1H), 2.99-2.86 (m, 1H), 2.76-2.69 (m, 1H), 2.15 (d, J = 14.1 Hz, 6H), 2.06-1.99 (m, 1H), 1.91-1.83 (m, 1H). [α].sub.D.sup.25 = 7.0° (c = 0.38 , MeOH)  709.9, 711.9 188 [00977] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 12.63 (s, 1H), 8.98 (dd, J = 9.6, 4.4 Hz, 1H), 8.71 (dd, J = 14.4, 2.0 Hz, 2H), 8.27 (s, 1H), 8.16 (s, 1H), 7.70 (s, 1H), 7.60 (s, 2H), 7.46 (s, 1H), 6.76 (s, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.23 (s, 3H), 2.97-2.77 (m, 4H), 2.12 (d, J = 14.4 Hz, 6H), 1.85-1.64 (m, 4H), 1.22 (s, 3H).  706.4, 708.4 189 [00978] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 8.98 (dd, J = 9.6, 4.2 Hz, 1H), 8.75- 8.70 (m, 2H), 8.32-8.27 (m, 2H), 8.06 (s, 1H), 7.59 (d, J = 9.6 Hz, 1H), 7.39-7.32 (m, 2H), 6.70 (s, 1H), 5.13-4.91 (m, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.57-3.43 (m, 1H), 3.29-3.18 (m, 1H), 2.88-2.69 (m, 9H), 2.47 (s, 3H), 2.43-2.39 (m, 1H), 2.38- 2.35 (m, 1H), 2.17 (s, 3H), 2.12 (s, 3H), 2.10-2.03 (m, 1H), 1.87-1.79 (m, 1H). .sup.19F NMR: (282 MHz, CDCl.sub.3) δ −198.58.  778.4, 780.4 190 [00979] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.45-8.33 (m, 2H), 8.20 (d, J = 2.1 Hz, 2H), 7.80 (s, 1H), 7.61 (s, 1H), 7.53-7.37 (m, 1H), 7.31 (s, 1H), 7.04-6.86 (m, 1H), 6.87 (s, 1H), 6.70 (s, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.34 (s, 3H), 3.23 (d, J = 11.4 Hz, 2H), 2.94-2.59 (m, 9H), 2.60-2.44 (m, 2H), 2.42 (s, 3H), 2.38 (s, 1H), 1.97 (d, J = 12.0 Hz, 2H), 1.76-1.60 (m, 2H), 1.19 (s, 2H), 1.05 (s, 2H).  765.4, 767.4 191 [00980] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.81-8.76 (m, 3H), 8.25 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 6.84 (s, 1H), 3.92 (s, 3H), 3.73 (t, J = 4.8 Hz, 4H), 3.67 (s, 3H), 2.98 (t, J = 4.8 Hz, 4H), 2.81- 2.77 (m, 6H), 2.68-2.65 (m, 2H), 2.60-2.58 (m, 4H), 2.15 (d, J = 14.4 Hz, 6H).  776.4, 778.4 193 [00981] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 8.99 (dd, J = 9.6, 3.9 Hz, 1H), 8.76- 8.82 (m, 2H), 8.31 (s, 1H), 8.22 (s, 1H), 7.69-7.59 (m, 3H), 7.36 (s, 1H), 6.69 (s, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.27-3.15 (m, 5H), 2.99 (s, 3H), 2.66-2.57 (m, 7H), 2.15 (d, J = 14.1 Hz, 6H), 2.01 (s, 4H), 1.37 (s, 3H).  774.4, 776.4 194 [00982] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.87-8.79 (m, 3H), 8.27 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.52 (s, 1H), 6.90 (s, 1H), 3.94 (s, 3H), 3.70 (s, 3H), 3.08-3.04 (m, 4H), 2.90-2.83 (m, 3H), 2.66 (s, 6H), 2.40 (s, 3H), 2.16 (d, J = 14.4 Hz, 6H), 2.07-2.03 (m, 2H), 1.92-1.85 (s, 2H).  760.2, 762.2 195 [00983] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.29-8.25 (m, 2H), 8.18 (s, 1H), 8.01 (s, 1H), 7.74 (s, 1H), 7.63 (s, 1H), 7.37 (s, 1H), 7.07 (s, 1H), 6.77 (s, 1H), 3.91-3.83 (m, 8H), 3.31 (s, 3H), 3.08-2.77 (m, 11H), 2.55-2.38 (m, 7H), 2.10-2.05 (m, 2H), 1.77-1.70 (m, 2H).  751.9, 753.9 196 [00984] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.27-8.26 (m, 2H), 8.19 (s, 1H), 8.01 (s, 1H), 7.85 (s, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 7.07 (s, 1H), 6.71 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.31 (s, 3H), 3.07-3.04 (m, 8H), 2.87- 2.84 (m, 7H), 2.75 (s, 3H), 1.95 (s, 4H). 1.71-1.67 (m, 4H).  750.1, 752.1 197 [00985] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.86-8.76 (m, 3H), 8.25 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.55-7.51 (m, 2H), 6.83 (s, 1H), 3.90 (s, 3H), 3.66 (s, 3H), 3.27-3.18 (m, 4H), 3.11-3.08 (m, 2H), 2.75 (s, 3H), 2.69-2.63 (m, 2H), 2.58-2.52 (m, 1H), 2.44-2.38 (m, 2H), 2.16 (s, 3H), 2.13 (s, 3H), 1.98-1.95 (m, 2H), 1.72-1.64 (m, 2H), 1.36 (s, 3H), 1.35 (s, 3H).  788.4, 790.4 198 [00986] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.89-8.78 (m, 3H), 8.27 (s, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 6.85 (s, 1H), 3.92 (s, 3H), 3.86-3.80 (m, 2H), 3.68 (s, 3H), 3.64-3.52 (m, 1H), 3.29-3.26 (m, 2H), 3.15-3.11 (m, 2H), 2.86 (s, 6H), 2.79- 2.72 (m, 2H), 2.17 (d, J = 14.4 Hz, 6H), 2.09-2.05 (m, 2H), 1.79-1.70 (m, 2H).  748.9, 750.9 199 [00987] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.82-8.81 (m, 1H), 8.67 (d, J = 8.7 Hz, 1H), 8.48 (dd, J = 9.3, 4.2 Hz, 1H), 8.24 (s, 1H), 7.87 (s, 1H), 7.70-7.60 (m, 3H), 7.48 (s, 1H), 6.81 (s, 1H), 3.91-3.87 (m, 7H), 3.64 (s, 3H), 3.23-3.19 (m, 2H), 3.09 (s, 4H), 2.90-2.79 (m, 1H), 2.71-2.64 (m, 2H), 2.18-2.11 (m, 8H), 1.79-1.68 (m, 2H).  746.3, 748.3 201 [00988] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.93-8.85 (m, 3H), 8.33 (s, 1H), 7.97 (s, 1H), 7.90 (s, 1H), 7.60 (s, 2H), 6.90 (s, 1H), 4.44- 4.35 (m, 1H), 4.08-4.05 (m, 1H), 3.99 (s, 3H), 3.97-3.94 (m, 1H), 3.76 (s, 3H), 3.14- 3.07 (m, 2H), 2.83-2.80 (m, 2H), 2.74 (s, 6H), 2.70-2.64 (m, 1H), 2.26 (s, 3H), 2.21 (s, 3H), 2.16-2.07 (m, 2H), 1.90-1.85 (m, 1H), 1.74-1.70 (m, 1H), 1.44 (d, J = 6.6 Hz, 3H). [α].sub.D.sup.25 = −7.5° (c = 0.18 , CHCl.sub.3).  775.4, 777.4 202 [00989] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.57 (s, 1H), 9.01 (dd, J = 9.6, 4.2 Hz, 1H), 8.78- 8.68 (m, 2H), 8.30 (s, 1H), 8.20 (s, 1H), 7.70 (s, 1H), 7.63 (s, 2H), 7.37 (s, 1H), 6.78 (s, 1H), 3.92 (s, 3H), 3.88-3.83 (m, 2H), 3.76 (s, 3H), 2.98-2.83 (m, 7H), 2.67- 2.64 (m, 2H), 2.17 (s, 3H), 2.12-2.07 (m, 5H), 1.74-1.66 (m, 2H), 1.13 (d, J = 6.5 Hz, 6H).  774.9, 776.9 203 [00990] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.69 (s, 1H), 8.85-8.82 (m, 3H), 8.42 (s, 1H), 8.25 (s, 1H), 7.75 (s, 1H), 7.55 (s, 2H), 7.36 (s, 1H), 6.70 (s, 1H), 3.84-3.71 (m, 8H), 3.64-3.56 (m, 2H), 3.08-2.97 (m, 4H), 2.02 (d, J = 14.4 Hz, 6H), 1.96-1.86 (m, 4H).  704.4, 706.4 204 [00991] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.87-8.74 (m, 3H), 8.27 (s, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.57 (s, 2H), 6.82 (s, 1H), 4.59 (d, J = 6.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.31-3.28 (m, 2H), 3.05-2.94 (m, 4H), 2.77-2.58 (m, 3H), 2.19-2.13 (m, 1H), 2.01 (d, J = 14.4 Hz, 6H), 1.73-1.70 (m, 2H), 1.37-1.30 (m, 2H).  749.4, 751.4 206 [00992] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.89-8.80 (m, 3H), 8.28 (s, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.55 (s, 2H), 6.90 (s, 1H), 3.95 (s, 3H), 3.72 (s, 3H), 3.60-3.54 (m, 3H), 3.47- 3.40 (m, 2H), 3.17-3.05 (m, 3H), 2.95-2.80 (m, 4H), 2.55-2.48 (m, 1H), 2.17 (d, J = 14.4 Hz, 6H), 2.06-1.93 (m, 3H), 1.82- 1.75 (m, 1H), 1.11 (t, J = 6.6 Hz, 6H).  789.4, 791.4 207 [00993] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.31 (s, 1H), 8.86 (dd, J = 4.2, 1.5 Hz, 1H), 8.79 (dd, J = 9.6, 4.2 Hz, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.45 (dd, J = 9.0, 4.2 Hz, 1H), 7.35 (s, 1H), 6.72 (s, 1H), 6.15-5.86 (m, 1H), 3.92 (s, 3H), 3.70 (s, 3H), 2.84-2.66 (m, 10H), 2.18 (s, 3H), 2.13 (s, 3H), 1.66-1.62 (m, 8H). .sup.19F NMR (282 MHz, CDCl.sub.3) δ −118.13.  794.0, 796.0 208 [00994] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.26 (s, 2H), 8.17 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.33 (s, 1H), 7.06 (s, 1H), 6.68 (s, 1H), 3.89-3.85 (m, 9H), 3.29 (s, 3H), 3.10-3.02 (m, 8H), 2.85- 2.56 (m, 8H), 2.15-2.03 (m, 3H), 1.73- 1.67 (m, 2H).  752.4, 754.4 209 [00995] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.40-8.35 (m, 2H), 8.20 (s, 2H), 7.77 (s, 1H), 7.66 (s, 1H), 7.47 (dd, J = 8.1, 1.5 Hz, 1H), 7.30 (s, 1H), 7.04-6.99 (m, 1H), 6.91-6.84 (m, 1H), 6.70 (s, 1H), 4.69 (t, J = 4.8 Hz, 1H), 4.53 (t, J = 4.8 Hz, 1H), 3.91 (s, 6H), 3.34 (s, 3H), 3.27-3.23 (m, 2H), 2.81-2.42 (m, 13H), 2.35-2.27 (m, 1H), 2.05-1.95 (m, 2H), 1.69-1.64 (m, 2H), 1.20-1.04 (m, 4H).  797.4, 799.4 210 [00996] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 9.07 (dd, J = 9.6, 4.2 Hz, 1H), 8.71- 8.69 (m, 2H), 8.64 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.71 (s, 1H), 7.43 (dd, J = 9.6 Hz, 1H), 7.15 (s, 1H), 6.75 (s, 1H), 3.91 (s, 7H), 3.78 (s, 3H), 3.32-3.28 (m, 2H), 2.84-2.67 (m, 7H), 2.15-2.10 (m, 8H), 1.92-1.85 (m, 2H).  747.0, 749.0 211 [00997] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.42 (s, 1H), 8.37-8.34 (m, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.49- 7.46 (m, 1H), 7.33 (s, 1H), 7.05-7.00 (m, 1H), 6.93-6.90 (m, 1H), 6.67 (s, 1H), 5.09- 4.92 (m, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.56-3.46 (m, 1H), 3.34 (s, 3H), 3.26-3.22 (s, 1H), 3.10-2.86 (m, 8H), 2.78-2.50 (m, 7H), 2.11-2.05 (m, 2H), 1.20-1.05 (m, 4H).  783.0, 785.0 212 [00998] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 12.50 (s, 1H), 8.86 (dd, J = 9.6, 4.2 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.74 (d, J = 1.8 Hz, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 8.32-8.28 (m, 2H), 7.69 (d, J = 9.6 Hz, 1H), 7.47 (s, 1H), 6.72 (s, 1H), 3.96 (s, 3H), 3.91-3.86 (m, 4H), 3.16-3.12 (m, 2H), 2.83-2.76 (m, 4H), 2.71-2.59 (m, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 2.02-1.93 (m, 2H), 1.72-1.55 (m, 2H).  749.9, 751.9 213 [00999] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.27 (s, 1H), 8.85 (dd, J = 4.2, 1.5 Hz, 1H), 8.78 (dd, J = 9.6, 4.2 Hz, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.65 (s, 1H), 7.61 (s, 1H), 7.44 (dd, J = 8.7, 4.2 Hz, 1H), 7.33 (s, 1H), 6.76 (s, 1H), 3.91 (s, 3H), 3.83-3.79 (m, 2H), 3.71 (s, 3H), 2.98- 2.82 (m, 4H), 2.44 (s, 2H), 2.34-2.31 (m, 5H), 2.15 (d, J = 12.9 Hz, 6H), 2.06-2.01 (m, 2H), 1.74-1.64 (m, 2H).  745.9, 747.9 214 [01000] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.85-8.78 (m, 3H), 8.41 (s, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.64 (s, 1H), 7.58-7.54 (m, 1H), 6.87 (s, 1H), 5.20-5.04 (m, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.62 (s, 4H), 3.08-2.91 (m, 2H), 2.70-2.62 (m, 4H), 2.47-2.40 (m, 2H), 2.05-1.88 (m, 8H), 1.74-1.70 (m, 1H). .sup.19F NMR (282 MHz, DMSO-d.sub.6) δ −199.90.  765.3, 767.3 215 [01001] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.86-8.78 (m, 3H), 8.26 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.55-7.52 (m, 2H), 6.87 (s, 1H), 3.92 (s, 3H), 3.74-3.69 (m, 7H), 2.90-2.86 (m, 4H), 2.16 (d, J = 14.4 Hz, 6H), 1.72-1.60 (m, 8H).  732.3, 734.3 216 [01002] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.88-8.78 (m, 3H), 8.28 (s, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.52 (d, J = 9.6 Hz, 1H), 7.35 (s, 1H), 6.87 (s, 1H), 5.19-5.03 (m, 1H), 3.93 (s, 3H), 3.71 (s, 3H), 3.47-3.39 (m, 1H), 3.17-3.13 (m, 1H), 3.03-2.87 (m, 1H), 2.76-2.68 (m, 1H), 2.45 (s, 6H), 2.41-2.26 (m, 1H), 2.20-2.15 (m, 6H), 2.04-1.84 (m, 2H). .sup.19F NMR (282 MHz, CD.sub.3OD) δ −200.84.  723.3, 725.3 218 [01003] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.37 (s, 1H), 9.28 (dd, J = 9.6, 4.5 Hz, 1H), 8.73- 8.69 (m, 2H), 8.29 (s, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.64-7.57 (m, 3H), 6.77 (s, 1H), 3.94 (s, 3H), 3.74 (s, 3H), 3.23-2.90 (m, 6H), 2.44-2.36 (m, 3H), 2.29 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 1.92-1.77 (m, 3H), 1.66-1.63 (m, 2H), 1.50-1.39 (m, 1H). [α].sub.D.sup.25 = +20.2° (c = 0.17 , CHCl.sub.3). 653.3 220 [01004] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.81 (dd, J = 4.5, 1.5 Hz, 1H), 8.66 (d, J = 8.7 Hz, 1H), 8.47 (dd, J = 9.3, 4.2 Hz, 1H), 8.23 (s, 1H), 7.87 (s, 1H), 7.68-7.59 (m, 3H), 7.45 (s, 1H), 6.79 (s, 1H), 4.86-4.75 (m, 2H), 4.48 (t, J = 6.3 Hz, 2H), 3.90 (s, 3H), 3.63 (s, 3H), 3.39-3.30 (m, 1H), 2.90-2.81 (m, 6H), 2.57 (s, 4H), 2.16 (d, J = 13.2 Hz, 6H).  732.3, 734.3 225 [01005] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.25 (s, 1H), 8.83-8.80 (m, 1H), 8.74 (dd, J = 9.6, 4.2 Hz, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.79-7.83 (m, 2H), 7.45-7.40 (m, 2H), 7.32 (s, 1H), 6.70 (s, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 3.44- 3.77 (m, 1H), 3.33 (d, J = 6.6 Hz, 2H), 3.12-3.08 (m, 2H), 2.67-2.59 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.99-1.95 (m, 2H), 1.72-1.63 (m, 2H), 1.26-1.04 (m, 1H), 0.59-0.53 (m, 2H), 0.23-0.20 (m, 2H).  731.3, 733.3 226 [01006] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.58 (s, 1H), 9.01 (dd, J = 9.3, 4.2 Hz, 1H), 8.74- 8.70 (m, 2H), 8.29 (s, 1H), 8.19 (s, 1H), 7.65-7.60 (m, 3H), 7.32 (s, 1H), 6.70 (s, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 2.97-2.82 (m, 10H), 2.14 (s, 3H), 2.01 (s, 3H), 1.93- 1.89 (m, 4H), 1.65-1.62 (m, 4H), 1.34 (t, J = 7.5 Hz, 3H).  759.4, 761.4 227 [01007] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.89-8.70 (m, 3H), 8.54 (s, 1H), 8.29 (s, 1H), 7.96 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 6.92 (s, 1H), 3.96 (s, 3H), 3.82-3.66 (m, 5H), 3.25-3.19 (m, 1H), 2.96-2.69 (m, 6H), 2.19-2.06 (m, 9H), 1.87-1.84 (m, 1H), 0.97-0.88 (m, 1H), 0.68-0.64 (s, 2H), 0.38- 0.34 (m, 2H).  757.3, 579.3 228 [01008] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 9.01 (dd, J = 9.6, 4.2 Hz, 1H), 8.74- 8.70 (m, 2H), 8.29 (s, 1H), 8.19 (s, 1H), 7.65-7.60 (m, 3H), 7.31 (s, 1H), 6.70 (s, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 3.39-3.35 (m, 1H), 2.97 (s, 4H), 2.85-2.82 (m, 4H), 2.15 (s, 3H), 2.10 (s, 3H), 1.97 (s, 4H), 1.65-1.61 (m, 4H), 1.34 (s, 3H), 1.32 (s, 3H).  773.4, 775.4 229 [01009] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.66 (s, 1H), 8.48 (dd, J = 9.2, 4.4 Hz, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 7.81 (s, 1H), 7.53 (s, 1H), 7.31 (s, 1H), 7.29-7.23 (m, 1H), 6.99-6.95 (m, 2H), 6.70 (s, 1H), 4.73 (t, J = 4.8 Hz, 1H), 4.62 (t, J = 4.8 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 2.95-2.72 (m, 10H), 1.86 (s, 3H), 1.83 (s, 3H), 1.71 (t, J = 5.6 Hz, 4H), 1.61 (t, J = 5.6 Hz, 4H). .sup.19FNMR (377 MHz, CDCl.sub.3) δ −217.12  725.4, 727.4 230 [01010] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.66 (s, 1H), 8.48 (dd, J = 9.2, 4.4 Hz, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 7.81 (s, 1H), 7.53 (s, 1H), 7.31 (s, 1H), 7.29-7.23 (m, 1H), 6.99- 6.95 (m, 2H), 6.70 (s, 1H), 4.73 (t, J = 4.8 Hz, 1H), 4.62 (t, J = 4.8 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 2.95-2.72 (m, 10H), 1.86 (s, 3H), 1.83 (s, 3H), 1.71 (t, J = 5.6 Hz, 4H), 1.61 (t, J = 5.6 Hz, 4H). .sup.19FNMR (377 MHz, CDCl.sub.3) δ −217.12  725.4, 727.4 231 [01011] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.52 (s, 1H), 8.92 (dd, J = 9.3, 4.2 Hz, 1H), 8.75- 8.73 (m, 2H), 8.35 (s, 1H), 8.30 (s, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 9.3 Hz, 1H), 7.46 (s, 1H), 6.73 (s, 1H), 4.90- 4.87 (m, 1H), 4.74-4.72 (m, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.19-3.16 (m, 1H), 3.09- 3.06 (m, 1H), 2.97-2.95 (m, 4H), 2.85- 2.82 (m, 4H), 2.18 (s, 3H), 2.13 (s, 3H), 1.85-1.81 (m, 4H), 1.62-1.60 (m, 4H). .sup.19F NMR (282 MHz, CDCl.sub.3) δ −216.32, −131.24.  795.2, 797.2 233 [01012] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.78 (s, 1H), 9.16 (dd, J = 9.3, 4.2 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.30 (s, 1H), 6.73 (s, 1H), 4.80-4.64 (m, 2H), 3.91 (s, 3H), 3.76 (s, 3H), 2.94-2.73 (m, 10H), 2.14 (s, 3H), 2.10 (s, 3H), 1.78- 1.73 (m, 4H), 1.63-1.60 (m, 4H).  733.4, 735.4 235 [01013] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 9.96 (s, 1H), 9.23 (s, 1H), 8.52-8.48 (m, 1H), 8.27 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.34 (s, 1H), 6.82 (s, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 2.96-2.86 (m, 8H), 2.53 (d, J = 3.6 Hz, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 1.00-0.95 (m, 1H). 0.67-0.62 (m, 2H), 0.29-0.24 (m, 2H).  717.3, 719.3 236 [01014] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 9.20 (s, 1H), 9.08 (s, 1H), 8.72 (dd, J = 9.3, 3.6 Hz, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.73 (s, 1H), 7.62 (s, 1H), 7.48 (d, J = 9.6 Hz, 1H), 6.88 (s, 1H), 3.98 (s, 3H), 3.60 (s, 3H), 3.23-3.12 (m, 8H), 2.93-2.91 (d, J = 7.2 Hz, 2H), 2.23 (s, 3H), 2.18 (s, 3H), 1.15- 1.06 (m, 1H), 0.79-0.73 (m, 2H), 0.43- 0.40 (m, 2H).  717.2, 719.2 238 [01015] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.26 (s, 1H), 8.84-8.82 (m, 1H), 8.79-8.84 (m, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 9.3 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.45-7.41 (m, 1H), 7.30 (s, 1H), 6.70 (s, 1H), 4.80-4.63 (m, 2H), 3.90 (s, 3H), 3.68 (s, 3H), 2.96-2.74 (m, 10H), 2.16 (s, 3H), 2.11 (s, 3H), 1.77-1.74 (m, 4H), 1.62-1.58 (m, 4H).  776.3, 778.3 239 [01016] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.90 (s, 1H), 9.13-9.08 (m, 1H), 8.74 (s, 1H), 8.70 (s, 1H), 8.14 (s, 2H), 7.76 (s, 1H), 7.65- 7.50 (m, 2H), 7.26-7.23 (m, 1H), 6.77 (s, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.23 (s, 3H), 2.97-2.83 (m, 4H), 2.14 (s, 3H), 2.10 (s, 3H), 1.86-1.82 (m, 2H), 1.72-1.66 (m, 2H), 1.22 (s, 3H).  662.4, 666.4 240 [01017] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 10.63 (s, 1H), 8.45 (dd, J = 8.8, 4.4 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 7.26-7.23 (m, 1H), 6.99-6.95 (m, 2H), 6.75 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.23 (s, 3H), 2.93-2.81 (m, 5H), 1.86-1.81 (m, 7H), 1.67-1.60 (m, 2H), 1.22 (s, 3H).  654.3, 656.3 241 [01018] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 15.33 (s, 1H), 12.65 (s, 1H), 8.96 (dd, J = 9.6, 4.5 Hz, 1H), 8.75 (d, J = 5.7 Hz, 2H), 8.39 (s, 1H), 8.34 (s, 1H), 7.71 (d, J = 9.6 Hz, 1H), 7.48 (s, 1H), 7.00 (s, 1H), 6.85 (s, 1H), 3.96 (s, 3H), 3.68 (s, 3H), 3.27 (s, 3H), 3.17 (s, 2H), 3.06-3.03 (m, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 1.95 (s, 4H), 1.30 (s, 3H).  722.3, 724.3 245 [01019] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 12.64 (s, 1H), 8.98 (dd, J = 9.6, 4.2 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.69 (s, 1H), 7.62 (s, 2H), 7.44 (s, 1H), 6.73 (s, 1H), 3.91 (s, 3H), 3.74 (s, 3H), 3.03-2.94 (m, 2H), 2.85-2.81 (m, 4H), 2.67-2.64 (m, 4H), 2.15 (s, 3H), 2.10 (s, 3H), 1.62-1.59 (m, 8H). .sup.19F NMR: (282 MHz, CDCl.sub.3) δ −68.76.  813.2, 815.2 246 [01020] .sup.1H NMR: (300 MHz, CDCl.sub.3) δ 12.56 (s, 1H), 8.98 (dd, J = 9.3, 4.2 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.64-7.62 (m, 3H), 7.38 (s, 1H), 6.70 (s, 1H), 4.90- 4.48 (m, 2H), 3.91 (s, 3H), 3.73 (s, 3H), 3.55-3.46 (m, 1H), 3.07-3.03 (m, 4H), 2.86-2.83 (m, 4H), 2.15 (s, 3H), 2.11 (s, 3H), 1.89-1.86 (m, 4H), 1.64-1.61 (m, 4H), 1.34 (d, J = 6.9 Hz, 3H).  791.2, 793.2 248 [01021] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.66 (s, 1H), 8.84-8.77 (m, 3H), 8.41 (s, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.55 (s, 2H), 6.88 (s, 1H), 4.55-4.40 (m, 4H), 3.81 (s, 3H), 3.76 (s, 3H), 3.43-3.39 (m, 1H), 2.83-2.80 (m, 4H), 2.22-2.19 (m, 4H), 2.04 (s, 3H), 1.99 (s, 3H), 1.58-1.54 (m, 8H).  787.0, 789.0 249 [01022] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.59 (s, 1H), 8.97 (dd, J = 9.6, 4.2 Hz, 1H), 8.76- 8.73 (m, 2H), 8.34 (s, 1H), 8.30 (s, 1H), 7.74 (d, J = 9.6 Hz, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.17 (s, 1H), 4.86-4.83 (m, 1H), 4.70-4.67 (m, 1H), 4.02 (s, 3H), 3.80 (s, 3H), 3.09-3.06 (m, 5H), 3.01-3.29 (m, 1H), 2.92-2.82 (m, 4H), 2.18 (s, 3H), 2.13 (s, 3H), 1.81-1.77 (m, 4H), 1.63-1.60 (m, 4H). .sup.19F NMR (282 MHz, CDCl.sub.3) δ −216.61.  778.2, 780.2

[1222] Biological Test Evaluation:

[1223] (I) Enzymology Experiments In Vitro

[1224] In this experiment, the method of fluorescence resonance energy transfer was used to test the inhibitory effect of the compounds on the kinase activity of wild-type EGFR and L858R/T790M/C797S triple mutant EGFR, and the half inhibitory concentration IC.sub.50 of the compounds on the kinase activity of the wild-type EGFR and the L858R/T790M/C797S triple mutant EGFR were obtained.

[1225] 1. Experimental Materials

[1226] Wild-type EGFR and L858R/T790M/C797S triple mutant EGFR recombinase, purchased from Signalchem.

[1227] HTRF KinEASE-TK kit detection reagent, purchased from Cisbio

[1228] Brigatinib, purchased from Selleck.

[1229] 2. Experimental Methods

[1230] 1) 10 nL of gradient diluted compound was transferred into a 384-well experimental plate using Echo 550 (Labcyte).

[1231] 2) 5 μL of 2×EGFR enzyme solution was added to the 384-well experimental plate and incubated at room temperature for 10 minutes.

[1232] 3) 5 μL of 2× substrate solution containing polypeptide and ATP was added to the 384-well experimental plate and incubated at room temperature for 40 minutes.

[1233] 4) 10 μL of detection solution containing EDTA, XL665-labeled streptavidin and Eu.sup.3+-labeled antibody was added thereto and incubated at room temperature for 1 hour.

[1234] 5) Envision microplate reader (PerkinElmer) detected the fluorescence signal values at 615 nm and 665 nm of each well.

[1235] 6) The ratio of fluorescence signal 665 nm/615 nm per well was calculated.

[1236] 7) GraphPad Prism 8 software was used for data analysis to obtain the IC.sub.50 of the compounds of the present disclosure and the comparative embodiment Brigatinib.

[1237] The results of kinase activity inhibition of wild-type EGFR and L858R/T790M/C797S triple mutant EGFR are shown in Table 2.

[1238] It can be seen from Table 2 that the compounds of the present disclosure have a good inhibitory effect on EGFR (L858R/T790M/C797S) kinase, a weak inhibitory effect on wild-type EGFR, and good selectivity.

TABLE-US-00005 TABLE 2 Enzymology inhibition results EGFR (WT) EGFR (L858R/T790M/C797S) Compound IC.sub.50(nM) IC.sub.50(nM)  1 0.94 0.12  2 17.98 0.09  3 1252 21.96   4 1.41 0.28  5 8.13 0.03  6 0.17 <0.05   7 9.88 0.23  8 357.60 3.19  9 75.73 0.88  10 4.55 0.10  11 12.09 0.07  12 1.59 0.05  13 7.62  0.890  14 1.060 0.15  15 12.15 <0.05   16 0.51 0.05  17 3.61 0.08  18 1.26 0.08  19 39.34 0.17  20 178.70 9.21  21 1.57 0.06  23 40.34 1.92  24 346.30 11.38   25 18.67 0.19  26 5.75 0.49  28 15.41 0.13  29 3.37 0.06  30 55.73 1.01  31 0.38 0.25  32 3.07 0.22  33 50.19 0.26  34 15.16 0.27  35 383.90 11.88   36 21.91 0.54  37 268.20 3.18  38 17.77 0.23  39 7.45 0.06  40 55.26 2.85  41 21.12 0.31  42 165.7  1.242  43 95.29 0.47  44 1558 22.0   45 n.d. n.d.  46 n.d. n.d.  47 20.46 0.37  48 n.d. n.d.  49 21.47 0.12  50 n.d. n.d.  51 111.10 0.11  52 n.d. n.d.  53 87.03 3.60  54 n.d. n.d.  55 n.d. n.d.  59 n.d. n.d.  60 n.d. n.d.  61 n.d. n.d.  62 n.d. n.d.  63 n.d. n.d.  65 n.d. n.d.  66 n.d. n.d.  67 n.d. n.d.  68 n.d. n.d.  69 17.36 0.17  70 n.d. n.d.  71 38.86 1.70  72 4.69 0.20  73 n.d. n.d.  76 n.d. n.d.  77 113.70 1.24  78 45.53 0.53  79 29.85 0.45  80 8.85 0.01  81 7.68 0.34  82 18.19 0.28  83 1000.00 3.95  84 16.56 0.33  85 9.06 0.11  86 344.60 15.62   87 3.47 0.35  88 4.26 0.09  89 2.11 0.11  90 n.d. n.d.  91 n.d. n.d.  92 2.34 0.03  93 23.11 0.18  94 2.78 0.15  95 n.d. n.d.  96 n.d. n.d.  97 1.02 0.15  98 16.21 0.82  99 n.d. n.d. 100 n.d. n.d. 101 0.41 0.18 102 1.49 0.23 103 1.57 0.13 104 27.21 0.95 105 5.62 0.16 107 26.37 1.30 108 n.d. n.d. 109 n.d. n.d. 110 1.54 0.57 111 5.65 1.38 112 0.92 0.26 113 n.d. n.d. 114 5.41 0.56 115 1.65 0.40 116 3.13 1.31 117 n.d. n.d. 119 4.07 1.30 120 9.84 1.17 121 0.67 0.25 122 3.42 0.62 123 120.70 1.12 124 8.35 1.20 125 23.77 0.53 126 1.55 0.15 127 2.83 0.24 128 6.83 0.53 129 1.11 0.27 130 1.44 0.05 131 2.57 0.12 132 5.71 0.07 133 0.78 0.15 134 3.57 0.21 135 15.58 0.47 136 99.50 5.3  137 170.40 9.81 138 30.70 0.53 139 0.57 0.24 140 94.56 5.44 141 1.14 0.18 142 1.16 0.25 143 1.75 0.41 144 2.77 0.66 145 3.48 0.31 146 8.43 0.38 147 53.02 1.16 148 5.04 0.64 149 78.50 3.36 150 2.45 0.29 151 38.16 2.20 152 4.24 0.35 153 3.02 0.22 154 36.87 0.86 155a 27.73 0.67 155b 21.63 0.80 156 33.49 3.81 157 3.60 0.33 158 2.48 0.81 159 1.54 0.70 160 2.32 0.26 161 2.71 0.39 162 20.55 2.28 163 1.89 0.28 164 5.30 0.73 165 1.36 0.69 166 3.81 0.48 167 1.95 0.79 168 2.57 0.35 169 4.39 0.73 170 4.94 0.45 171 4.59 0.29 172 0.69 0.14 173 50.66 6.00 174 2.39 0.60 175 3.10 0.33 176 3.26 0.34 177 n.d. n.d. 178 7.68 1.29 179 1.48 0.40 180 1.40 0.36 181 3.53 0.16 182 8.49 0.40 183 12.19 1.12 184 2.23 0.24 185 2.42 0.36 186 1.19 0.37 187 5.73 0.04 188 5.62 0.43 189 1.08 0.16 190 4.37 0.53 191 2.44 0.23 193 0.99 0.27 194 2.85 0.17 195 8.52 2.33 196 3.35 0.59 197 0.62 0.25 198 0.62 0.22 199 2.57 0.20 200 7.56 0.19 201 6.92 0.74 202 3.74 0.59 203 21.21 0.47 204 1.57 0.25 205 3.08 0.35 206 8.46 0.62 207 8.43 1.14 208 5.79 0.57 209 9.74 0.73 210 8.41 0.11 211 10.93 0.61 212 18.95 0.33 213 1.02 0.18 214 1.86 0.36 215 7.3 0.25 216 1.71 0.29 217 3.87 0.95 218 1.82 0.29 219 1.66 0.12 220 2.29 0.12 221 1.37 0.09 222 4.22 0.30 223 7 0.17 224 10.66 4.31 225 10.77 1.96 226 1.40 0.19 227 2.69 0.59 228 1.04 0.48 229 8.53 0.42 230 12 0.29 231 1.12 0.37 232 4.11 0.58 233 2.49 0.26 234a 5.04 0.32 234b 5.44 0.37 235 10.49 0.27 236 10.95 0.21 237 5.20 0.52 238 3.02 0.30 239 7.57 1.60 240 29.93 0.51 241 30.06 0.13 242 2.40 0.40 243 4.91 0.54 244 2.74 0.78 245 105.4 2.80 246 1.05 0.40 247 5.81 0.12 248 1.91 0.29 249 3.31 0.40 Brigatinib 166.3 11.5  n.d. stands for not determined.

[1239] (II) Cell Proliferation Inhibition Experiment

[1240] In this experiment, the method of CellTiter-Glo was used to test the inhibitory effect of compounds on cell proliferation of EGFR wild-type cell line A431 and Ba/F3 De119/T790M/C797S EGFR triple mutant cell line and Ba/F3 L858R/T790M/C797S EGFR triple mutant cell line, and the half concentration IC.sub.50 of the compounds inhibiting cell growth were obtained.

[1241] 1 Experimental Materials

[1242] A431 cells, purchased from ATCC.

[1243] Ba/F3 De119/T790M/C797S EGFR triple mutant cells, purchased from KYinno Biotechnology (Beijing) Co., Ltd.;

[1244] Ba/F3 L858R/T790M/C797S EGFR triple mutant cells, purchased from Pharmaron (Beijing) New Drug Technology Co., Ltd.;

[1245] DMEM medium, purchased from Thermo Fisher.

[1246] RPMI 1640 medium, purchased from Thermo Fisher.

[1247] Fetal bovine serum (FBS), purchased from Thermo Fisher.

[1248] CellTiter-Glo reagent, purchased from Promega.

[1249] Brigatinib, purchased from Selleck.

[1250] 2 Experimental Methods

[1251] 1) A431 cells were inoculated in a 384-well culture plate at a density of 800 cells per well, 30 μL per well, placed in a cell incubator, and cultured for 24 hours (37° C., 5% CO.sub.2).

[1252] 2) Ba/F3 De119/T790M/C797S EGFR triple mutant cells and Ba/F3 L858R/T790M/C797S EGFR triple mutant cells were inoculated in the 384-well culture plate at a density of 700 cells per well, 30 μL per well, and placed in a cell incubator.

[1253] 3) 30 nL of gradient diluted compound was transferred into the 384-well experimental plate using Echo 550 (Labcyte) at a DMSO final concentration of 0.1%, and the culture plate was incubated in a cell incubator for 72 hours (37° C., 5% CO.sub.2).

[1254] 4) 30 μL of Cell Titer-Glo reagent was added to each well and left for 30 minutes at room temperature and protected from light.

[1255] 5) Envision microplate reader (PerkinElmer) detected chemiluminescence signals.

[1256] 6) GraphPad Prism 8 software was used for data analysis to obtain the IC.sub.50 of the compounds of the present disclosure and the positive control.

[1257] The cell viability inhibition results are shown in Table 3.

[1258] It can be seen from the experimental results in Table 3 that, compared with the comparative embodiment Brigatinib, the compounds of the present disclosure have a good inhibitory effect on the cell proliferation of Ba/F3 De119/T790M/C797S EGFR triple mutant cell line and Ba/F3 L858R/T790M/C797S EGFR triple mutant cell line, and the IC.sub.50 of some compounds are lower than 1.0 nM, showing a very good inhibitory effect; showing a weak inhibitory effect on EGFR wild-type cell line A431, and good selectivity.

TABLE-US-00006 TABLE 3 Results of cell proliferation inhibition test data Ba/F3 Ba/F3 (Del19/T790M/ (L858R/T790M/ A431 EGFR C797S) C797S) Compound WT IC.sub.50(nM) IC.sub.50(nM) IC.sub.50(nM)  1 136.70 0.58 5.61  2 315.50 4.21 17.49  3 2236 281.1 443.6  4 193.50 2.38 13.58  5 140.00 3.71 12.66  6 24.51 1.99 5.96  7 158.90 4.43 14.77  8 769.20 68.95 136.70  9 450.30 55.04 110.00  10 47.03 6.06 10.71  11 159.25 83.42 223.6  12 76.14 6.32 45.85  13 398.40 43.35 84.28  14 150.10 5.98 13.61  15 177.00 4.62 15.59  16 51.32 13.18 23.46  17 67.82 1.28 2.13  18 45.44 2.87 20.91  19 488.00 6.71 68.85  20 1586.27 276.7 629.09  21 63.91 4.03 18.07  23 194.80 8.67 30.30  24 567.20 45.24 139.20  25 159.00 2.41 8.64  26 152.10 1.22 4.25  28 361.50 4.73 13.73  29 121.30 1.29 4.25  30 284.50 12.12 62.60  31 194.30 4.58 12.81  32 208.10 0.98 5.45  33 1424.00 10.10 32.45  34 462.50 2.04 8.94  35 752.1 93.23 326.8  36 320.30 2.63 17.73  37 1141.00 32.61 65.56  38 295.40 10.21 32.60  39 41.27 4.07 9.69  40 1180 1131.1 542.4  41 371.00 8.64 34.48  42 5000.00 6.76 69.16  43 880.20 16.42 29.70  44 5000 93.45 n.d.  45 102.40 7.65 n.d.  46 67.2 6.71 11.68  47 126.40 4.31 n.d.  48 51.07 3.0235 6.03  49 233.60 4.88 n.d.  50 507.70 34.13 n.d.  51 292.10 911.56 36.84  52 158.40 26.73 n.d.  53 293.60 62.24 n.d.  54 638.1 102.6 n.d.  55 5000 1228 n.d.  59 345.00 26.24 n.d.  60 658.2 89.35 n.d.  61 6580.5 312.05 794.15  62 3380.00 73.60 195.10  63 331.30 14.30 24.95  65 72.44 6.68 17.32  66 575 3.04 10.78  67 622.05 42.26 59.16  68 1393.00 113.90 372.50  69 303.30 5.91 19.18  70 156.85 116.80 348.40  71 >10000.00 99.38 316.20  72 369.50 4.54 13.47  73 3255.00 326.20 536.40  76 20.71 5.40 9.96  77 479.50 14.42 26.39  78 549.60 6.76 14.44  79 632.90 9.89 13.53  80 414.90 5.37 10.13  81 10000.00 19.12 32.35  82 179.90 7.85 21.72  83 2418.00 34.05 58.88  84 392.10 12.54 20.74  85 380.80 6.15 9.29  86 3065.00 87.77 136.10  87 178.10 5.89 14.25  88 40.85 2.18 4.45  89 40.88 2.33 4.16  90 4389.00 250.70 446.10  91 3549.00 278.20 430.10  92 31.84 0.54 2.85  93 178.20 12.49 27.03  94 167.70 6.99 28.82  95 96.72 15.70 40.93  96 44.21 3.52 9.39  97 405.50 6.64 25.48  98 177.10 10.95 27.75  99 208.80 40.61 103.50 100 29.06 2.87 6.20 101 46.11 2.87 4.53 102 107.80 0.76 2.02 103 152.40 0.51 5.02 104 191.90 4.07 17.71 105 1187.00 20.91 61.88 107 380.10 11.20 30.92 108 92.75 12.48 24.48 109 546.90 46.28 62.79 110 161.80 3.70 10.88 111 209.60 3.22 4.79 112 1096.00 57.03 161.00 113 189.20 74.47 175.70 114 270.60 5.86 11.20 115 159.00 6.53 16.06 116 169.40 2.25 8.15 117 157.10 41.00 120.40 119 639.10 36.56 239.40 120 196.80 2.62 8.67 121 150.50 1.61 6.16 122 37.22 2.07 9.96 123 8835.00 24.32 82.00 124 515.70 3.93 7.93 125 489.50 5.87 14.45 126 285.90 0.93 3.81 127 170.30 0.59 4.18 128 397.40 2.86 11.88 129 86.24 0.72 2.71 130 73.46 1.00 9.00 131 67.77 0.60 7.17 132 270.40 2.45 30.03 133 82.75 0.64 2.85 134 315.90 1.02 7.82 135 402.00 3.68 13.34 136 1748.00 13.67 57.09 137 1495.00 27.09 77.82 138 629.50 9.31 11.90 139 61.00 1.59 2.33 140 3670.00 29.76 61.99 141 194.00 2.26 5.16 142 196.40 0.34 2.89 143 420.40 3.23 10.16 144 84.04 0.35 1.91 145 202.70 1.70 2.41 146 178.80 1.44 5.47 147 475.30 1.30 2.93 148 123.80 0.70 2.78 149 376.40 1.62 3.21 150 138.60 1.57 3.34 151 318.40 1.84 7.47 152 133.30 1.06 4.59 153 61.85 1.03 2.89 154 469.20 5.26 15.39 155a 320.20 2.98 15.56 155b 212.80 1.63 7.55 156 372.00 1.05 7.29 157 49.38 1.28 7.05 158 165.50 3.28 6.76 159 113.90 0.93 4.11 160 207.90 1.56 9.04 161 153.70 2.36 6.39 162 517.90 6.20 17.96 163 71.81 0.62 1.97 164 195.00 3.22 8.26 165 70.17 0.80 2.62 166 92.07 1.58 5.05 167 47.44 2.97 4.34 168 67.39 0.71 4.20 169 175.00 2.36 4.24 170 280.30 1.80 8.14 171 622.60 2.13 7.23 172 329.10 101.70 328.10 173 737.70 11.20 24.52 174 307.40 4.63 7.85 175 41.28 1.70 5.38 176 61.85 2.97 5.96 177 59.26 25.62 35 178 168.50 2.86 13.02 179 54.33 1.37 6.84 180 64.75 4.13 6.53 181 88.93 3.52 9.67 182 100.60 1.71 4.43 183 246.40 14.41 27.05 184 218.10 2.28 5.67 185 127.00 1.77 4.02 186 61.99 1.39 3.47 187 245.30 2.11 8.73 188 56.60 0.61 0.87 189 128.10 9.18 23.62 190 193.70 4.16 8.69 191 70.02 3.47 11.37 193 59.93 4.48 9.83 194 79.47 5.56 16.36 195 415.10 7.70 12.46 196 355.60 12.32 20.80 197 95.59 7.70 14.29 198 37.99 4.26 9.49 199 154.10 7.08 18.43 200 69.61 7.47 21.99 201 120.20 2.22 3.70 202 91.26 2.93 3.75 203 351.40 10.56 19.98 204 66.88 5.19 11.18 205 116.30 3.20 8.90 206 297.70 7.62 30.22 207 435.80 12.34 37.50 208 348.00 9.45 14.57 209 171.40 7.18 12.57 210 274.60 4.42 7.23 211 354.10 14.26 24.85 212 179.20 9.29 25.05 213 162.90 3.36 8.39 214 138.60 1.47 4.87 215 226.80 2.23 5.58 216 45.67 2.06 7.32 217 60.55 0.94 3.29 218 69.22 5.20 20.12 219 32.07 1.10 1.08 220 77.68 4.04 4.37 221 26.21 2.41 2.79 222 70.41 1.22 2.02 223 76.90 2.88 3.56 224 336.00 8.88 13.18 225 370.20 3.54 11.32 226 47.36 1.55 4.34 227 34.70 2.78 6.64 228 44.84 4.58 8.50 229 163.80 3.76 12.11 230 126.20 4.47 10.14 231 40.13 1.08 1.12 232 126.20 3.16 8.59 233 79.55 1.74 3.54 234a 42.36 2.05 3.91 234b 38.37 2.52 5.65 235 88.97 8.53 24.80 236 91.49 5.45 12.72 237 128.80 1.26 3.05 238 61.91 1.83 3.59 239 141.10 2.10 4.61 240 303.60 8.20 19.19 241 181.80 2.92 12.34 242 75.72 1.36 3.07 243 140.90 1.73 3.95 244 124.80 1.19 2.43 245 747.30 5.35 11.59 246 128.30 2.59 3.64 247 66.41 3.76 7.76 248 84.71 1.17 2.37 249 84.97 2.55 8.95 Brigatinib 771.10 103.00 319.80

[1259] (III) In Vivo Efficacy Research Experiment A

[1260] 1. Experimental Objectives

[1261] To evaluate the antitumor activity and toxic side effects of compound 242 orally administered for 21 days in PC9 (De119/T790M/C797S) nude mice xenograft model.

[1262] 2. Experimental Materials

[1263] BALB/c-nu mice, female, SPF grade, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[1264] PC9 (De119/T790M/C797S) cells, constructed by Qilu Pharmaceutical Co., Ltd.

[1265] 3. Experimental Steps

[1266] 3.1 Cell Culture

[1267] PC9 (De119/T790M/C797S) cells were cultured in RPMI 1640 medium containing 10% FBS at 37° C. in a 5% carbon dioxide incubator; cells in exponential growth phase were collected and inoculated.

[1268] 3.2 Cell Inoculation

[1269] Under sterile conditions, PC9 (De119/T790M/C797S) cell suspension cultured in vitro was taken, the cell concentration was adjusted to 5×10.sup.7 cells /mL after centrifugation, and subcutaneously inoculated under the right armpit of mice (0.1 mL/ mouse). The day of inoculation was set as day 0.

[1270] 3.3 Tumor Grouping, Administration and Measurement

[1271] a, When the average tumor volume was about 180 mm.sup.3, 24 mice with moderate tumor volume were selected and randomly divided into 3 groups according to the tumor volume: G1: solvent control group, G2: compound 242 (25 mg/kg) and G3: compound 242 (75/50 mg/kg), 8 mice/group.

[1272] b, After animals were grouped, administration was started, and the administration volume was 10 mL/kg, administered orally (po); administered by weight once a day for 21 consecutive days; tumor diameter was measured twice a week.

[1273] c, Tumor volume (TV): the tumor volume was measured twice a week to observe the volume change and growth rate of the tumor. Tumor volume V=½×a×b.sup.2, where a and b represent the long and short diameters of the tumor, respectively. The growth inhibition effect of the compounds on tumor tissue was evaluated by tumor growth inhibition rate TGI (%). TGI (%)=[1−(average tumor volume of a certain administration group−average tumor volume of the administration group on the day of grouping)/(average tumor volume of a negative control group−average tumor volume of the negative control group on the day of grouping)]×100%. The data of the administration group and the negative control group were taken on the same day.

[1274] d, During the experiment, the living conditions of the mice, including appearance signs, general behavior, mental state, food intake, respiratory state, feces and urine characteristics, local injection site and other toxicity manifestations, were closely observed.

[1275] e, After the experiment reached the end point, the mice were euthanized, and the animal carcasses were frozen in a freezer and handed over to a qualified medical waste disposal unit for disposal.

[1276] 4 Experimental Results

TABLE-US-00007 TABLE 4 Tumor inhibition experiment results of compound 242 Tumor Weight Dose volume.sup.a TGI change Grouping (mg/kg) (mm.sup.3) (%) (%) G1: solvent control — 2489.2 ± 314.0  — 11.7 group G2: Compound 242 25 139.8 ± 13.7** 102 2.4 G3: Compound 242 75 (D1-D6),  64.0 ± 11.9** 105 −3.4 50(D7-D21) .sup.amean ± standard error; b, P value was statistically analyzed according to tumor volume, compared with G1 group, *P < 0.05; **P < 0.01.

[1277] The graph of tumor growth curves of animals in each group is shown in FIG. 1, and the graph of weight curves of animals in each group is shown in FIG. 2.

[1278] 5 Experimental Conclusions

[1279] It can be seen from the above results that compound 242 (25, 75/50 mg/kg) can significantly inhibit tumor growth, showing good anti-tumor efficacy. The mice are well tolerated at 25 mg/kg and 50 mg/kg doses.

[1280] (1V) In Vivo Efficacy Research Experiment B

[1281] 1. Experimental Objectives

[1282] To evaluate the antitumor activity and toxic side effects of compound 243 orally administered for 21 days in PC9 (De119/T790M/C797S) nude mice xenograft model.

[1283] 2. Experimental Materials

[1284] BALB/c-nu mice, female, SPF grade, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[1285] PC9 (De119/T790M/C797S) cells, constructed by Qilu Pharmaceutical Co., Ltd.

[1286] 3. Experimental Steps

[1287] 3.1 Cell Culture

[1288] PC9 (De119/T790M/C797S) cells were cultured in RPMI 1640 medium containing 10% FBS at 37° C. in a 5% carbon dioxide incubator; cells in exponential growth phase were collected and inoculated.

[1289] 3.2 Cell Inoculation

[1290] Under sterile conditions, PC9 (De119/T790M/C797S) cell suspension cultured in vitro was taken, the cell concentration was adjusted to 3×10.sup.7 cells/mL after centrifugation, and subcutaneously inoculated under the right armpit of mice (0.1 mL/ mouse). The day of inoculation was set as day 0.

[1291] 3.3 Tumor Grouping, Administration and Measurement

[1292] a, When the average tumor volume was about 140 mm.sup.3, 21 mice with moderate tumor volume were selected and randomly divided into 5 groups according to the tumor volume: G1: solvent control group, G2: compound 243 (15 mg/kg) and G3: compound 243 (40 mg/kg), 7 mice/group.

[1293] b, After animals were grouped, administration was started, and the administration volume was 10 mL/kg, administered orally (po); administered by weight once a day for 21 consecutive days; tumor diameter was measured twice a week.

[1294] c, Tumor volume (TV): the tumor volume was measured twice a week to observe the volume change and growth rate of the tumor. Tumor volume V=½×a×b.sup.2, where a and b represent the long and short diameters of the tumor, respectively. The growth inhibition effect of the compounds on tumor tissue was evaluated by tumor growth inhibition rate TGI (%). TGI (%)=[1−(average tumor volume of a certain administration group−average tumor volume of the administration group on the day of grouping)/(average tumor volume of a negative control group−average tumor volume of the negative control group on the day of grouping)]×100%. The data of the administration group and the negative control group were taken on the same day.

[1295] d, During the experiment, the living conditions of the mice, including appearance signs, general behavior, mental state, food intake, respiratory state, feces and urine characteristics, local injection site and other toxicity manifestations, were closely observed.

[1296] e, After the experiment reached the end point, the mice were euthanized, and the animal carcasses were frozen in a freezer and handed over to a qualified medical waste disposal unit for disposal.

[1297] 4 Experimental Results

TABLE-US-00008 TABLE 5 Tumor inhibition experimental data of compound 243 Tumor Weight Dose volume.sup.a TGI change Grouping (mg/kg) (mm.sup.3) (%) (%) G1: solvent control — 1110 ± 235.7.sup.  — 5.3 group G2: Compound 243 15 318.6 ± 38.63** 81.4 −0.4 G3: Compound 243 40 38.6 ± 5.19** 110.1 −6.1 .sup.amean ± standard error; b, P value was statistically analyzed according to tumor volume, compared with G1 group, *P < 0.05; **P < 0.01.

[1298] The graph of tumor growth curves of animals in each group is shown in FIG. 3, and the graph of weight curves of animals in each group is shown in FIG. 4.

[1299] 5 Experimental Conclusions

[1300] It can be seen from the above results that compound 243 (15, 40 mg/kg) can significantly inhibit tumor growth, and shows a significant dose-effect relationship, showing good anti-tumor efficacy. Mice are well tolerated.