EGFR Degraders and Associated Methods of Use

Abstract

Provided herein are novel bifunctional compounds formed by conjugating EGFR inhibitor moieties with E3 ligase Ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation. The disclosure also provides pharmaceutically acceptable compositions comprising compounds and methods for the treatment of EGFR mutant-related cancers.

Claims

1. A compound of Formula (X): ##STR00199## or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, wherein: Cy1 is a 4- to 7-membered saturated or partially unsaturated ring including P?O shown in Formula (X), said ring comprising 0-3 additional heteroatoms independently selected from nitrogen, oxygen or sulfur in addition to P?O; said ring is optionally substituted with at least one substituent R.sup.1c; R.sup.1c is selected from hydrogen, halogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, CN, OR.sup.1d, COR.sup.1d, CO.sub.2R.sup.1d, CONR.sup.1dR.sup.1e, NR.sup.1dR.sup.1e, NR.sup.1dCOR.sup.1e or NR.sup.1dCO.sub.2R.sup.1e, wherein each of C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.1f; R.sup.1d, R.sup.1e and R.sup.1f are each independently selected from hydrogen, hydroxy, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, or C.sub.3-C.sub.8cycloalkyl; Z.sup.5 is selected from CR.sup.2, or N; Z.sup.6 is selected from CR.sup.3, or N; Z.sup.7 is selected from CR.sup.9, or N; Z.sup.8 is selected from CR.sup.10, or N; R.sup.2 and R.sup.3 are each independently selected from hydrogen, halogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, CN, OR.sup.2a, SO.sub.2R.sup.2a, SO.sub.2NR.sup.2aR.sup.2b, COR.sup.2a, CO.sub.2R.sup.2a, CONR.sup.2aR.sup.2b, NR.sup.2aR.sup.2b, NR.sup.2aCOR.sup.2b, NR.sup.2aCO.sub.2R.sup.2b, or NR.sup.2aSO.sub.2R.sup.2b, wherein each of C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.2d; or R.sup.2 and R.sup.3 together with the carbon atoms to which they are attached, form a 5-6 membered saturated or partially or completely unsaturated (preferably completely unsaturated, i.e., aromatic) ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R.sup.2e; R.sup.2e, at each of its occurrences, is independently hydrogen, halogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy, C.sub.3-C.sub.8cycloalkyl, oxo, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, CN, SO.sub.2R.sup.2a, SO.sub.2NR.sup.2aR.sup.2b, COR.sup.2a, CO.sub.2R.sup.2a, CONR.sup.2aR.sup.2b, NR.sup.2aR.sup.2b, NR.sup.2aCOR.sup.2b, NR.sup.2aCO.sub.2R.sup.2b or NR.sup.2aSO.sub.2R.sup.2b, wherein each of C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.2d; R.sup.2a and R.sup.2b are each independently selected from hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl; or R.sup.2a and R.sup.2b together with the carbon atoms to which they are attached, form a 5-6 membered saturated or partially or completely unsaturated (preferably completely unsaturated, i.e., aromatic) ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R.sup.2d; R.sup.2d, at each of its occurrences, is independently halogen, OH, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-, oxo, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, or 5- to 12-membered heteroaryl; R.sup.4 is selected from hydrogen, halogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, CN, SO.sub.2R.sup.4a, SO.sub.2NR.sup.4aR.sup.4b, COR.sup.4a, CO.sub.2R.sup.4a, CONR.sup.4aR.sup.4b, NR.sup.4aR.sup.4b, NR.sup.4aCOR.sup.4b, NR.sup.4aCO.sub.2R.sup.4b, or NR.sup.4aSO.sub.2R.sup.4b, wherein each of C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with halogen, C.sub.1-8alkoxy, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, oxo, CN, OR.sup.4c, SO.sub.2R.sup.4c, SO.sub.2NR.sup.4cR.sup.4d, COR.sup.4c, CO.sub.2R.sup.4c, CONR.sup.4cR.sup.4d, NR.sup.4cR.sup.4d, NR.sup.4cCOR.sup.4d, NR.sup.4cCO.sub.2R.sup.4d, or NR.sup.4cSO.sub.2R.sup.4d; R.sup.4a, R.sup.4b, R.sup.4c and R.sup.4d are each independently hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, or 5- to 12-membered heteroaryl; or R.sup.4 and R.sup.11 together with the carbon atoms to which they are attached, form a 5-6 membered saturated or partially or completely unsaturated (preferably completely unsaturated, i.e., aromatic) ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R.sup.4e; R.sup.4e, at each of its occurrences, is independently hydrogen, halogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy, C.sub.3-C.sub.8cycloalkyl, oxo, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, CN, SO.sub.2R.sup.4f, SO.sub.2NR.sup.4fR.sup.4g, COR.sup.4f, CO.sub.2R.sup.4f, CONR.sup.4fR.sup.4g, NR.sup.4fR.sup.4g, NR.sup.4fCOR.sup.4g, NR.sup.4fCO.sub.2R.sup.4g or NR.sup.4fSO.sub.2R.sup.4g, wherein each of C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.4h; R.sup.4f and R.sup.4g are each independently selected from hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl; R.sup.4h, at each of its occurrences, is independently halogen, OH, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, or 5- to 12-membered heteroaryl; R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each independently selected from hydrogen, halogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, NR.sup.9aR.sup.9b, OR.sup.9a, oxo, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, or CN, wherein each of C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.9c; or two R.sup.12 together with the carbon atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring is optionally substituted with at least one substituent R.sup.9c; R.sup.9a and R.sup.9b are each independently selected from hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl, wherein each of said C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.9d; or R.sup.9c and R.sup.9d are each independently halogen, hydroxy, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, CN or NR.sup.9aaR.sup.9bb, wherein each of said C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl is optionally substituted with at least one hydrogen, halogen, hydroxy, C.sub.1-8alkyl, C.sub.1-8alkoxy, CN, NH.sub.2 or oxo, and R.sup.9aa and R.sup.9bb are each independently hydrogen or C.sub.1-8alkyl; Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 are each independently selected from CR.sup.z, or N; R.sup.Z, at each of its occurrences, is independently selected from hydrogen, halogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, NR.sup.ZaR.sup.Zb, OR.sup.Za, SR.sup.Za, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, or CN, wherein each of C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one R.sup.Zc; or when adjacent two R.sup.z together with the carbon atoms to which they are attached, form a 5-6 membered saturated or partially or completely unsaturated (preferably completely unsaturated, i.e., aromatic) ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R.sup.Zc; R.sup.Za and R.sup.Zb are each independently selected from hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, or 5- to 12-membered heteroaryl, wherein each of said C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.Zd; R.sup.Zc and R.sup.Zd are each independently halogen, hydroxy, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, or 5- to 12-membered heteroaryl; L.sup.1 is selected from a single bond, O, SO.sub.2, C(O), NR.sup.L1a, C.sub.3-C.sub.8cycloalkylene-, *.sup.L1OC.sub.1-8alkylene-**.sup.L1, .sup.L1C.sub.1-8alkylene-O**.sup.L1, *.sup.L1SO.sub.2-C.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-SO.sub.2**.sup.L1, *.sup.L1COC.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alklylene-CO**.sup.L1, *.sup.L1NR.sup.L1aC.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-NR.sup.L1a**.sup.L1, *.sup.L1NR.sup.L1aC(O)**.sup.L1, *.sup.L1C(O)NR.sup.L1a**.sup.L1, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, [O(CR.sup.L1aR.sup.L1b).sub.m4].sub.m5, ##STR00200## wherein each of said C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L1OC.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-O**.sup.L1, *.sup.L1SO.sub.2C.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-SO.sub.2**.sup.L1, *.sup.L1COC.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-CO**.sup.L1, *.sup.L1NR.sup.L1aC.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-NR.sup.L1a**.sup.L1, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, ##STR00201## is optionally substituted with at least one R.sup.L1c; wherein *.sup.L1 refers to the position attached to ##STR00202## moiety, and **.sup.L1 refers to the position attached to the ##STR00203## moiety; R.sup.L1a and R.sup.L1b are each independently selected from hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl, wherein each of said C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.L1d; each of said R.sup.L1c and R.sup.L1d are independently halogen, hydroxy, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl or oxo; L.sup.2 is selected from a single bond, O, SO.sub.2, C(O), NR.sup.L2a, C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L2OC.sub.1-8alkylene-**.sup.L2, .sup.L2C.sub.1-8alkylene-O**.sup.L2, *.sup.L2SO.sub.2C.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-SO.sub.2**.sup.L2, *.sup.L2COC.sub.1- 8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alklylene-CO**.sup.L2, *.sup.L2NR.sup.L2aC.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-NR.sup.L2a**.sup.L2, *.sup.L2NR.sup.L2aC(O)**.sup.L2, *.sup.L2C(O)NR.sup.L2a**.sup.L2, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, [O(CR.sup.L2aR.sup.L2b).sub.m4].sub.m5, ##STR00204## wherein each of said C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L2OC.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-O**.sup.L2, *.sup.L2SO.sub.2C.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-SO.sub.2**.sup.L2, *.sup.L2COC.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-CO**.sup.L2, *.sup.L2NR.sup.L2aC.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-NR.sup.L2a**.sup.L2, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, ##STR00205## is optionally substituted with at least one substituent R.sup.L2c; wherein *.sup.L2 refers to the position attached to ##STR00206## moiety, and **.sup.L2 refers to the position attached to the ##STR00207## moiety; R.sup.L2a and R.sup.L2b are each independently selected from hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl, wherein each of said C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.L2d; each of said R.sup.L2c and R.sup.L2d are independently halogen, hydroxy, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl or oxo; L.sup.3 is selected from a single bond, O, SO.sub.2, C(O), NR.sup.L3a, C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L3OC.sub.1-8alkylene-**.sup.L3, .sup.L3C.sub.1-8alkylene-O**.sup.L3, *.sup.L3SO.sub.2C.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-SO.sub.2**.sup.L3, *.sup.L3COC.sub.1- 8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alklylene-CO**.sup.L3, *.sup.L3NR.sup.L3aC.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-NR.sup.L3a**.sup.L3, *.sup.L3NR.sup.L3aC(O)**.sup.L3, *.sup.L3C(O)NR.sup.L3a**.sup.L3, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, [O(CR.sup.L3aR.sup.L3b).sub.m4].sub.m5, ##STR00208## wherein each of said C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L3OC.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-O**.sup.L3, *.sup.L3SO.sub.2C.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-SO.sub.2**.sup.L3, *.sup.L3COC.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-CO**.sup.L3, *.sup.L3NR.sup.L3aC.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-NR.sup.L3a**.sup.L3, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, ##STR00209## is optionally substituted with at least one substituent R.sup.L3c; wherein *.sup.L3 refers to the position attached to ##STR00210## moiety, and **.sup.L3 refers to the position attached to the ##STR00211## moiety; R.sup.L3a and R.sup.L3b are each independently selected from hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl, wherein each of said C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.L3d; each of said R.sup.L3c and R.sup.L3d are independently halogen, hydroxy, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl or oxo; ##STR00212## is selected from ##STR00213## ##STR00214## ##STR00215## ##STR00216## Ring A is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, aryl, or heteroaryl; said Ring A is optionally substituted with at least one halogen, oxo, C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-, C.sub.2-8alkenyl, C.sub.3-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl; R.sup.13 and R.sup.14 are independently selected from hydrogen, halogen, CN, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl; said each C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl; X.sup.1, X.sup.2, X.sup.3, X.sup.4 and X.sup.8 are each independently selected from CR.sup.a, or N; X.sup.5, X.sup.6, X.sup.7 and X.sup.9 are each independently selected from NR.sup.a, O, S and CR.sup.aR.sup.b; X.sup.12 and X.sup.13 are each independently selected from NR.sup.a and O; L.sup.4, L.sup.5 and L.sup.6 are each independently selected from a single bond, O, NR.sup.a, (CR.sup.aR.sup.b).sub.n8, O(CR.sup.aR.sup.b).sub.n8, NR.sup.a(CR.sup.aR.sup.b).sub.n8 or C(O); Y.sup.1, Y.sup.2 and Y.sup.3 are each independently selected from CR.sup.a or N; R.sup.a and R.sup.b are each independently selected from hydrogen (H, D or T), halogen, CN, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl, wherein each of said C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, halogen, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl; or R.sup.a and R.sup.b together with the carbon atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring is optionally substituted with at least one substituent halogen, hydroxy, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkoxy, C.sub.2-8-alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl; m.sub.1 is 0 or 1; m.sub.2 and m.sub.3 are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; m.sub.4 and m.sub.5 are each independently 0, 1, 2 or 3; n, n.sub.1, n.sub.2, n.sub.3, n.sub.4 and n.sub.5 are each independently 0, 1, 2 or 3; and n.sub.6 is 0, 1, 2, 3 or 4 n.sub.7 is 0, 1, 2 or 3; n.sub.8 is 0, 1, 2, 3, 4, 5, 6.7 or 8.

2. The compound of claim 1, wherein Cy1 is a 4-, 5-, 6- or 7-membered saturated or partially unsaturated ring including P?O, said ring comprising 0 or 1 additional heteroatom independently selected from nitrogen, oxygen or sulfur in addition to P?O; said ring is optionally substituted with at least one substituent R.sup.1c; R.sup.1c is selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, CN, OR.sup.1d, COR.sup.1d, CO.sub.2R.sup.1d, CONR.sup.1dR.sup.1e, NR.sup.1dR.sup.1e, NR.sup.1dCOR.sup.1e or NR.sup.1dCO.sub.2R.sup.1e, wherein each of C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.1f; R.sup.1d, R.sup.1e and R.sup.1f are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

3. The compound of any one of claims 1-2, wherein the ##STR00217## moiety is selected from ##STR00218## wherein is a single or double bond; R.sup.1c, at each of its occurrences, has the same definition with claim 1 or 2.

4. The compound of any one of claims 1-3, wherein the ##STR00219## moiety is selected from ##STR00220##

5. The compound of any one of claims 1-4, wherein R.sup.2 and R.sup.3 are each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, CN, OR.sup.2a, SO.sub.2R.sup.2a, SO.sub.2NR.sup.2aR.sup.2b, COR.sup.2a, CO.sub.2R.sup.2a, CONR.sup.2aR.sup.2b, NR.sup.2aR.sup.2b, NR.sup.2aCOR.sup.2b, NR.sup.2aCO.sub.2R.sup.2b, or NR.sup.2aSO.sub.2R.sup.2b, wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.2d, R.sup.2a and R.sup.2b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; R.sup.2d, at each of its occurrences, is independently halogen, OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

6. The compound of any one of claims 1-5, wherein R.sup.2 and R.sup.3 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl, preferable selected from H, F, Cl, Br, I, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, or C(CH.sub.3).sub.3.

7. The compound of any one of claims 1-4, wherein Z.sup.5 is CR.sup.2 and Z.sup.6 is CR.sup.3, wherein R.sup.2 and R.sup.3 together with the carbon atoms to which they are attached, form a 5 or 6 membered unsaturated (preferred aromatic) ring, said ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R.sup.2e; R.sup.2e, at each of its occurrences, is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or oxo, wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with at least one substituent R.sup.2d; R.sup.2d, at each of its occurrences, is independently F, Cl, Br, I, OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or phenyl.

8. The compound of any one of claims 1-7, wherein the ##STR00221## moiety is ##STR00222## wherein Cy2 is a 5-6 membered unsaturated (preferred aromatic) or saturated ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; preferable, the ##STR00223## moiety is ##STR00224## wherein R.sup.2e, Z.sup.7, and Z.sup.8 are defined as in claim 1.

9. The compound any of claims 1-8, wherein R.sup.2e at each of its occurrences, is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or oxo, wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with at least one substituent R.sup.2d; R.sup.2d, at each of its occurrences, is independently F, Cl, Br, I, OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or phenyl.

10. The compound any one of claims 1-9, wherein R.sup.2e at each of its occurrences, is independently hydrogen, F, Cl, Br, I, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3, ##STR00225##

11. The compound of one of claims 1-10, wherein the ##STR00226## moiety is ##STR00227## ##STR00228##

12. The compound of any one of claims 1-11, wherein R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, NH.sub.2 or oxo, wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted with at least one substituent R.sup.9c; or two R.sup.12 together with the carbon atoms to which they are attached, form a 3, 4, 5, 6, 7 or 8-membered ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R.sup.9c; R.sup.9c is independently F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, NH.sub.2, or NHCH.sub.3.

13. The compound of any one of claims 1-12, wherein R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each independently selected from hydrogen, F, Cl, Br, NH.sub.2, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.4H.sub.9, C.sub.5H.sub.11, OCH.sub.3, OC.sub.2H.sub.5, OC.sub.3H.sub.7, OC.sub.4H.sub.9, OC.sub.5H.sub.11, CN, cyclopropyl or oxo; or two R.sup.12 together with the carbon atoms to which they are attached, form a 3, 4, 5, 6, 7 or 8-membered ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent H, F, Cl, Br, I, methyl, ethyl, propyl, butyl, NH.sub.2, NHCH.sub.3, OH, OCH.sub.3, OC.sub.2H.sub.5, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

14. The compound of any one of claims 1-13, wherein R.sup.4 is selected from H, F, Cl, Br, I, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, C.sub.5H.sub.11, OCH.sub.3, OC.sub.2H.sub.5, OC.sub.3H.sub.7, OC.sub.4H.sub.9, OC.sub.5H.sub.11, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl or CN, wherein each of CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, C.sub.5H.sub.11, OCH.sub.3, OC.sub.2H.sub.5, OC.sub.3H.sub.7, OC.sub.4H.sub.9, OC.sub.5H.sub.11, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or phenyl is optionally substituted with F, Cl, Br, I, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, 5- to 12-membered heteroaryl, oxo, CN, OR.sup.4c, SO.sub.2R.sup.4c, SO.sub.2NR.sup.4cR.sup.4d, COR.sup.4c, CO.sub.2R.sup.4c, CONR.sup.4cR.sup.4d, NR.sup.4cR.sup.4d, NR.sup.4cCOR.sup.4d, NR.sup.4cCO.sub.2R.sup.4d, or NR.sup.4cSO.sub.2R.sup.4d; R.sup.4c and R.sup.4d are each independently hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-C.sub.8cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-C.sub.12aryl, or 5- to 12-membered heteroaryl.

15. The compound of any one of claims 1-14, wherein R.sup.4 is selected from F, Cl, Br, I, CH.sub.3, CF.sub.3, CH.sub.2F, or CHF.sub.2.

16. The compound of any one of claims 1-15, wherein L.sup.1 is selected from a single bond, O, SO.sub.2, C(O), NR.sup.L1a, C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L1OC.sub.1-8alkylene-**.sup.L1, .sup.L1C.sub.1-8alkylene-O**.sup.L1, *.sup.L1SO.sub.2C.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-SO.sub.2**.sup.L1, *.sup.L1COC.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alklylene-CO**.sup.L1, *.sup.L1NR.sup.L1aC.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-NR.sup.L1a**.sup.L1, *.sup.L1NR.sup.L1aC(O)**.sup.L1, *.sup.L1C(O)NR.sup.L1a**.sup.L1, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, [O(CR.sup.L1aR.sup.L1b).sub.m4].sub.m5, ##STR00229## ##STR00230## wherein each of said C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L1OC.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-O**.sup.L1, *.sup.L1SO.sub.2C.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-SO.sub.2**.sup.L1, *.sup.L1COC.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-CO**.sup.L1, *.sup.L1NR.sup.L1aC.sub.1-8alkylene-**.sup.L1, *.sup.L1C.sub.1-8alkylene-NR.sup.L1a**.sup.L1, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, ##STR00231## ##STR00232## is optionally substituted with at least one R.sup.Lc; R.sup.L1a and R.sup.L1b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with at least one substituent R.sup.L1d; each of said R.sup.L1c and R.sup.L1d are independently F, Cl, Br, I, OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, hexoxyl, heptyloxyl, octyloxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl or oxo.

17. The compound of any one of claims 1-16, wherein L.sup.1 is selected from a single bond, C.sub.1-8alkylene- (preferably CH.sub.2, C.sub.2H.sub.4, C.sub.3H.sub.6), CO, O, N(CH.sub.3), NH, ##STR00233## ##STR00234## ##STR00235##

18. The compound of any one of claims 1-17, wherein X.sup.1 and X.sup.2 are each independently selected from CR.sup.a or N; wherein R.sup.a is selected from hydrogen, F, Cl, Br, I, CN, methyl, ethyl, methoxy, ethoxy, or cyclopropyl, wherein each of said methyl, ethyl, methoxy, ethoxy, or cyclopropyl is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, or ethyl, (preferably, X.sup.1 and X.sup.2 are each independently selected from CH, C(F), C(CH.sub.3) or N); m1=1 or 0; R.sup.12 is hydrogen, oxo, methoxymethyl, hydroxymethyl, CN or CH.sub.3.

19. The compound of any one of claims 1-18, wherein m1 is 1; preferably, ##STR00236## moiety is ##STR00237## wherein *.sup.X refers to the position attached to ##STR00238## moiety, and **.sup.X refers to the position attached to the ##STR00239## moiety.

20. The compound of any one of claims 1-19, wherein m1 is 0.

21. The compound of any one of claims 1-20, wherein ##STR00240## moiety is ##STR00241##

22. The compound of any one of claims 1-21, wherein m2 is selected from 0, 1, 2, 3, 4 or 5.

23. The compound of any one of claims 1-24, wherein L.sup.2 is selected from a single bond, O, SO.sub.2, CO, NR.sup.L2a, C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L2OC.sub.1-8alkylene-**.sup.L2, .sup.L2C.sub.1-8alkylene-O**.sup.L2, *.sup.L2SO.sub.2C.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-SO.sub.2**.sup.L2, *.sup.L2COC.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alklylene-CO**.sup.L2, *.sup.L2NR.sup.L2aC.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-NR.sup.L2a**.sup.L2, *.sup.L2NR.sup.L2aC(O)**.sup.L2, *.sup.L2C(O)NR.sup.L2a**.sup.L2, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, [O(CR.sup.L2aR.sup.L2b).sub.m4].sub.m5, ##STR00242## ##STR00243## wherein each of said C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L2OC.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-O**.sup.L2, *.sup.L2SO.sub.2C.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-SO.sub.2**.sup.L2, *.sup.L2COC.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-CO**.sup.L2, *.sup.L2NR.sup.L2aC.sub.1-8alkylene-**.sup.L2, *.sup.L2C.sub.1-8alkylene-NR.sup.L2a**.sup.L2, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, ##STR00244## ##STR00245## is optionally substituted with at least one substituent R.sup.L2c; R.sup.L2a and R.sup.L2b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazoyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with at least one substituent R.sup.L2d; each of said R.sup.L2c and R.sup.L2d are independently F, Cl, Br, I, OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl or oxo;

24. The compound of any one of claims 1-23, wherein L.sup.2 is selected from a single bond, C.sub.1-8alkylene- (preferably CH.sub.2, C.sub.2H.sub.4, C.sub.3H.sub.6), CO, O, N(CH.sub.3), NH, ##STR00246## ##STR00247## ##STR00248##

25. The compound of any one of claims 1-24, wherein m3 is 0, 1, 2, 3, 4, 5 or 6.

26. The compound of any one of claims 1-25, wherein L.sup.3 is selected from a single bond, O, SO.sub.2, CO, NR.sup.L3a, C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L3OC.sub.1-8alkylene-**.sup.L3, .sup.L3C.sub.1-8alkylene-O**.sup.L3, *.sup.L3SO.sub.2C.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-SO.sub.2**.sup.L3, *.sup.L3COC.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alklylene-CO**.sup.L3, *.sup.L3NR.sup.L3aC.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-NR.sup.L3a**.sup.L3, *.sup.L3NR.sup.L3aC(O)**.sup.L3, *.sup.L3C(O)NR.sup.L3a**.sup.L3, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, [O(CR.sup.L3aR.sup.L3b).sub.m4].sub.m5, ##STR00249## ##STR00250## wherein each of said C.sub.1-8alkylene, C.sub.3-C.sub.8cycloalkylene-, *.sup.L3OC.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-O**.sup.L3, *.sup.L3SO.sub.2C.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-SO.sub.2**.sup.L3, *.sup.L3COC.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-CO**.sup.L3, *.sup.L3NR.sup.L3aC.sub.1-8alkylene-**.sup.L3, *.sup.L3C.sub.1-8alkylene-NR.sup.L3a**.sup.L3, C.sub.1-8alkylene-, C.sub.2-8alkenylene-, C.sub.2-8alkynylene-, ##STR00251## ##STR00252## ##STR00253## is optionally substituted with at least one substituent R.sup.L3c; R.sup.L3a and R.sup.L3b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with at least one substituent R.sup.L3d; each of said R.sup.L3c and R.sup.L3d are independently F, Cl, Br, I, OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl or oxo.

27. The compound of any one of claims 1-26, wherein L.sup.3 is selected from single bond, C.sub.1-8alkylene- (preferably CH.sub.2, C.sub.2H.sub.4, C.sub.3H.sub.6), CO, O, N(CH.sub.3), NH, ##STR00254## ##STR00255## ##STR00256##

28. The compound of any one of claims 1-27, wherein ##STR00257## is selected from CH.sub.2CH.sub.2, ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## wherein * refers to the position attached to ##STR00266## moiety, and ** refers to the position attached to the ##STR00267## moiety.

29. The compound of any one of claims 1-28, wherein ##STR00268## is selected from ##STR00269## ##STR00270## R.sup.14 is independently selected from hydrogen, halogen, C.sub.1-8alkyl, C.sub.1-8alkoxy, or CN; said each C.sub.1-8alkyl, or C.sub.1-8alkoxy is optionally substituted by one or more halogen or C.sub.1-8alkyl, preferably R.sup.14 is independently selected from H, F, Cl, Br, I, CH.sub.3, OCH.sub.3, CH.sub.2F, CN, CHF.sub.2, or CF.sub.3; X.sup.8 is independently selected from CH, CD, C(CH.sub.3), C(C.sub.2H.sub.5), C(C.sub.3H.sub.7), C(CN) or N; L.sup.4 is independently selected from a single bond, ##STR00271## O, NH, CH.sub.2, CHF, or CF.sub.2; Y.sup.1, Y.sup.2, and Y.sup.3 are each independently selected from CR.sup.a or N; X.sup.9 is CH.sub.2; R.sup.a is each independently selected from hydrogen, halogen, C.sub.1-8alkyl, or C.sub.1-8alkoxy, wherein each of said C.sub.1-8alkyl or C.sub.1-8alkoxy is optionally substituted with at least one or more halogen, hydroxy, halogen, C.sub.1-8alkyl, or C.sub.1-8alkoxy; and n6 is independently 0, 1 or 2.

30. The compound of any one of claims 1-29, wherein ##STR00272## is ##STR00273## ##STR00274## Wherein L.sup.5 and L.sup.6 is independently selected from a single bond, ##STR00275## O, NH, NMe-, N(CH.sub.2CH.sub.3), CH.sub.2, CHF, CF.sub.2, C(CH.sub.3).sub.2 or CO (preferably L.sup.5 is CO or CH.sub.2, and L.sup.6 is ##STR00276## O, NH, NMe-, N(CH.sub.2CH.sub.3), CH.sub.2, CHF, CF.sub.2, C(CH.sub.3).sub.2 or CO); X.sup.9 is CH.sub.2; each R.sup.13 is independently selected from hydrogen, F, Cl, Br, I, CN, C.sub.1-8alkyl, or C.sub.1-8alkoxy; n.sub.6 is 0 or 1; and n.sub.7 is 0, 1 2.

31. The compound of any one of claims 1-30, wherein ##STR00277## is selected from ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287##

32. The compound of any one of claims 1-31, wherein Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 are each independently CR.sup.z; R.sup.Z, at each of its occurrences, is independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, NR.sup.ZaR.sup.Zb, OR.sup.Za, SR.sup.Za, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN, wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one R.sup.Ze; R.sup.Za and R.sup.Zb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, wherein each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R.sup.Zd; R.sup.Zc and R.sup.Zd are each independently F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, C.sub.1-8alkoxy, C.sub.2-8alkenyl, C.sub.2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

33. The compound of any one of claims 1-32, wherein R.sup.z is independently selected from H, CH.sub.3, C.sub.2H.sub.5, F, CH.sub.2F, CHF.sub.2, CF.sub.3, OCH.sub.3, OC.sub.2H.sub.5, C.sub.3H.sub.7, OCH.sub.2F, OCHF.sub.2, OCH.sub.2CF.sub.3, OCF.sub.3, SCF.sub.3, CF.sub.3, cyclopropyl or CH(OH)CH.sub.3.

34. The compound of any one of claims 1-33, wherein the deuterium substitution is on degron, preferable, deuterium substitution is on X.sup.8.

35. The compound of any one of claims 1-34, wherein the compound is selected from ##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317## ##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331##

36. A pharmaceutical composition comprising a compound of any one of claims 1-35 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, together with a pharmaceutically acceptable excipient.

37. A method of decreasing EGFR activity by inhibition and/or degradation, which comprises administering to an individual the compound according to any one of claims 1-35, or a pharmaceutically acceptable salt thereof, including the compound of formula (I) or the specific compounds exemplified herein.

38. The method of claim 37, wherein the disease is selected from cancer, preferred pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

39. Use of a compound of any one of claims 1-35 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof in the preparation of a medicament for treating a disease that can be affected by EGFR modulation.

40. The use of claim 39, wherein the disease is cancer, preferred pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

41. A method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of the compound any one of claims 1-35, or a pharmaceutically acceptable salt thereof as a EGFR kinase inhibitor and/or degrader, wherein the disease or disorder is associated with inhibition of EGFR.

42. The method of claim 41, wherein the disease is selected from cancer, preferred pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0153] The following terms have the indicated meanings throughout the specification:

[0154] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0155] The following terms have the indicated meanings throughout the specification:

[0156] As used herein, including the appended claims, the singular forms of words such as a. an, and the, include their corresponding plural references unless the context clearly indicates otherwise.

[0157] The term or is used to mean, and is used interchangeably with, the term and/or unless the context clearly dictates otherwise.

[0158] The term alkyl includes a hydrocarbon group selected from linear and branched, saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms. Examples of alkyl groups comprising from 1 to 6 carbon atoms (i.e., C.sub.1a alkyl) include, but not limited to, methyl, ethyl, 1-propyl or n-propyl (n-Pr), 2-propyl or isopropyl (i-Pr), 1-butyl or n-butyl (n-Bu), 2-methyl-1-propyl or isobutyl (i-Bu), 1-methylpropyl or s-butyl (s-Bu), 1,1-dimethylethyl or t-butyl (t-Bu), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups.

[0159] The term propyl includes 1-propyl or n-propyl (n-Pr), 2-propyl or isopropyl (i-Pr).

[0160] The term butyl includes 1-butyl or n-butyl (n-Bu), 2-methyl-1-propyl or isobutyl (i-Bu), 1-methylpropyl or s-butyl (s-Bu), 1,1-dimethylethyl or t-butyl (t-Bu).

[0161] The term pentyl includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.

[0162] The term hexyl includes 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl.

[0163] The term alkylene refers to a divalent alkyl group by removing two hydrogen from alkane. Alkylene includes but not limited to methylene, ethylene, propylene, and so on.

[0164] The term halogen includes fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

[0165] The term alkenyl includes a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one C?C double bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkenyl group, e.g., C.sub.2-6, alkenyl, include, but not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0166] The term alkenylene refers to a divalent alkenyl group by removing two hydrogen from alkene.

[0167] Alkenylene includes but not limited to, vinylidene, butenylene, and so on.

[0168] The term alkynyl includes a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C?C triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkynyl group, e.g., C.sub.2-6 alkynyl, include, but not limited to ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0169] The term alkynylene refers to a divalent alkynyl group by removing two hydrogen from alkyne. Alkenylene includes but not limited to ethynylene and so on.

[0170] The term cycloalkyl includes a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl.

[0171] For example, the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, examples of the saturated monocyclic cycloalkyl group, e.g., C.sub.3-8cycloalkyl, include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C.sub.3-6 cycloalkyl), including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further Examples of the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0172] The term spiro cycloalkyl includes a cyclic structure which contains carbon atoms and is formed by at least two rings sharing one atom.

[0173] The term fused cycloalkyl includes a bicyclic cycloalkyl group as defined herein which is saturated and is formed by two or more rings sharing two adjacent atoms.

[0174] The term bridged cycloalkyl includes a cyclic structure which contains carbon atoms and is formed by two rings sharing two atoms which are not adjacent to each other. The term 7 to 10 membered bridged cycloalkyl includes a cyclic structure which contains 7 to 12 carbon atoms and is formed by two rings sharing two atoms which are not adjacent to each other.

[0175] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include but are not limited to bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, as well as benzo 3 to 8 membered cycloalkyl, benzo C.sub.4-6 cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1, 2, 3, 4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8 to 9 membered fused rings, which refer to cyclic structures containing 8 to 9 ring atoms within the above examples.

[0176] The term aryl used alone or in combination with other terms includes a group selected from: [0177] 5- and 6-membered carbocyclic aromatic rings, e.g., phenyl; [0178] bicyclic ring systems such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and, [0179] tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, e.g., fluorenyl.

[0180] The terms aromatic hydrocarbon ring and aryl are used interchangeably throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C.sub.5-10 aryl). Examples of a monocyclic or bicyclic aromatic hydrocarbon ring includes, but not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0181] Specifically, the term bicyclic fused aryl includes a bicyclic aryl ring as defined herein. The typical bicyclic fused aryl is naphthalene.

[0182] The term heteroaryl includes a group selected from: [0183] 5-, 6- or 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N), sulfur (S) and oxygen (O), with the remaining ring atoms being carbon; [0184] 7- to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and [0185] 11- to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N. O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

[0186] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.

[0187] Specifically, the term bicyclic fused heteroaryl includes a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl ring as defined herein. Typically, a bicyclic fused heteroaryl is 5-membered/5-membered, 5-membered/6-membered, 6-membered/6-membered, or 6-membered/7-membered bicyclic. The group can be attached to the remainder of the molecule through either ring.

[0188] Heterocyclyl, heterocycle or heterocyclic are interchangeable and include a non-aromatic heterocyclyl group comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.

[0189] The term at least one substituent disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents, provided that the theory of valence is met. For example. at least one substituent F disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents F.

[0190] The term divalent refers to a linking group capable of forming covalent bonds with two other moieties. For example, a divalent cycloalkyl group refers to a cycloalkyl group obtained by removing two hydrogen from the corresponding cycloalkane to form a linking group, the term divalent aryl group, divalent heterocycyl group or divalent heteroaryl group should be understood in a similar manner.

[0191] Compounds disclosed herein may contain an asymmetric center and may thus exist as enantiomers. Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

[0192] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are meant to include both E and Z geometric isomers.

[0193] When compounds disclosed herein contain a di-substituted cyclic ring system, substituents found on such ring system may adopt cis and trans formations. Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides. For example, the di-substituted cyclic ring system may be cyclohexyl or cyclobutyl ring.

[0194] It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art could select and apply the techniques most likely to achieve the desired separation.

[0195] Diastereomers refer to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0196] A single stereoisomer, e.g., a substantially pure enantiomer, may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E and Wilen, S Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. Chromatographic resolution of enantiomers: Selective review. J. Chromatogr., 113(3) (1975): pp, 283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0197] Some of the compounds disclosed herein may exist with different points of attachment of hydrogen, referred to as tautomers. For example, compounds including carbonyl CH.sub.2C(O) groups (keto forms) may undergo tautomerism to form hydroxyl CH?C(OH) groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.

[0198] Prodrug refers to a derivative of an active agent that requires a transformation within the body to release the active agent. In some embodiments, the transformation is an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.

[0199] Pharmaceutically acceptable salts refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base. The term also includes salts of the stereoisomers (such as enantiomers and/or diastereomers), tautomers and prodrugs of the compound of the invention.

[0200] In addition, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0201] The terms administration, administering, treating and treatment herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell. The term administration and treatment also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell. The term subject herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.

[0202] The term effective amount or therapeutically effective amount refers to an amount of the active ingredient, such as compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The term therapeutically effective amount can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments. In some embodiments, therapeutically effective amount is an amount of at least one compound and/or at least one stereoisomer, tautomer or prodrug thereof, and/or at least one pharmaceutically acceptable salt thereof disclosed herein effective to treat as defined herein, a disease or disorder in a subject. In the case of combination therapy, the term therapeutically effective amount refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.

[0203] The term disease refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term disorder or condition.

[0204] Throughout this specification and the claims which follow, unless the context requires otherwise, the term comprise, and variations such as comprises and comprising are intended to specify the presence of the features thereafter, but do not exclude the presence or addition of one or more other features. When used herein the term comprising can be substituted with the term containing, including or sometimes having.

[0205] Throughout this specification and the claims which follow, the term C.sub.n-m? indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C.sub.1-8, C.sub.1-6, and the like.

[0206] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

EXAMPLES

[0207] The examples below are intended to be purely exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc.), but some experimental errors and deviations should be accounted for. Unless indicated otherwise, temperature is in degrees Centigrade. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless indicated otherwise. Unless indicated otherwise, the reactions set forth below were performed under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents; the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven dried and/or heat dried.

[0208] .sup.1H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. .sup.1HNMR spectra were obtained using CDCl.sub.3, CD.sub.2Cl.sub.2, CD.sub.3OD, D.sub.2O, d.sub.6-DMSO, d.sub.6-acetone or (CD.sub.3).sub.2CO as solvent and tetramethylsilane (0.00 ppm) or residual solvent (CDCl.sub.3: 7.25 ppm; CD.sub.3OD: 3.31 ppm; D.sub.2O: 4.79 ppm; d.sub.6-DMSO: 2.50 ppm; d.sub.6-acetone: 2.05; (CD.sub.3).sub.3CO: 2.05) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintuplet), sx (sextuplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

[0209] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190-400 nm), Mass detector: 6120 SQ Mobile phase: A: water with 0.1% Formic acid, B: acetonitrile with 0.1% Formic acid Column: Poroshell 120 EC-C18, 4.6?50 mm, 2.7 pm Gradient method: Flow: 1.8 mL/min Time (min) A (%) B (%)

TABLE-US-00001 Time (min) A(%) B(%) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0210] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190400 nm). Mass detector: G6125C SQ Mobile phase: A: water with 0.1% Formic acid, B: acetonitrile with 0.1% Formic acid Column: Poroshell 120 EC-C18, 4.6?50 mm, 2.7 pm Gradient method: Flow: 1.8 mL/min Time (min) A (%) B (%)

TABLE-US-00002 Time (min) A(%) B(%) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0211] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II) Detector: MWD (190-400 nm). Mass detector: G6125C SQ Mobile phase: A: water with 0.1% Formic acid, B: acetonitrile with 0.1% Formic acid Column: Poroshell 120 EC-C18, 4.6?50 mm, 2.7 pm Gradient method: Flow: 1.2 mL/min Time (min) A (%) B (%)

TABLE-US-00003 Time (min) A(%) B(%) 0.00 90 10 1.5 5 95 2.0 5 95 2.1 90 10 3.0 90 10

[0212] Preparative HPLC was conducted on a column (150?21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml/min, injection volume 2 ml, at room temperature and UV Detection at 214 nm and 254 nm.

[0213] In the following examples, the abbreviations below are used:

TABLE-US-00004 (BPin).sub.2 4,4,4,4,5,5,5,5-Octamethyl-2,2-bi-1,3,2-dioxaborolane Ac.sub.2O acetic anhydride AcCl Acetyl chloride ACN or MeCN Acetonitrile AcOH or HOAc Acetic acid AcONa or NaOAc Sodium acetate Aq Aqueous BINAP (?)-2,2-Bis(diphenylphosphino)-1,1-BINAPhthyl Bn benzyl BnBr Benzyl Bromide Boc t-Butyloxy carbonyl C: 40691-33-6 dichlorobis(tri-o-tolylphosphine)palladium(II) Cbz Benzyloxycarbonyl CDI 1,1-Carbonyldiimidazole DCM Dichloromethane Con. Concentrated DavePhos 2-(Dicyclohexylphosphino)-N,N-dimethyl-2-biphenylamine DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE dichloroethane DHP 3,4-Dihydro-2H-pyran DIBAL-H Diisobutylaluminium hydride DIEA or DIPEA N,N-diisopropylethylamine DMAc N,N-Dimethylacetamide DMAP 4-N,N-dimethylaminopyridine DMP Dess-Martin periodinane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide Dppf 1,1-bis(diphenylphosphino)ferrocene EA or EtOAc Ethyl acetate EtOH ethanol FA Formic acid h or hr Hour HATU 2-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate HBTU O-(7-Benzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate Hex Hexane HPLC High Performance Liquid Chromatography HOVEYDA-Grubbs (1,3-Bis-(2,4,6-trimethylpheny1)-2-imidazolidinylidene)dichloro(o- catalyst isopropylphenylMethylene)ruthenium hrs hours IBX 2-lodoxybenzoic acid IPA 2-propanol i-PrOH Isopropyl alcohol KHMDS Potassium bis(trimethylsilyl)amide LiHMDS Lithium bis(trimethylsilyl)amide KOAc or AcOK Potassium Acetate MeCN or ACN Acetonitrile MeOH Methanol Min Minutes ms or MS Mass spectrum MsCl Methanesulfonyl chloride MsOH Methanesulfonic acid MTBE Methyl tert-butyl ether NMP 1-Methyl-2-pyrrolidinone o/n overnight Pd(dppf)Cl.sub.2 [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd.sub.2(dba).sub.3 Tris(dibenzylideneacetone)dipalladium PE Petroleum ether PhMe Toluene PMB 4-Methoxybenzyl PPA Polyphosphoric acid R.T. or r.t. Room temperature Rt Retention time SEMCl 2-(TrimethylsilyD)ethoxymethyl chloride STAB Sodium Triacetoxyborohydride;Sodium triacetoborohydride Sat. saturated TBAF Tetra-butyl ammonium fluoride TBDPS tert-Butyldiphenylsilyl TBS tert-Butyldimethylsilyl TBSCl tert-Butyldimethylsilyl chloride Ti(OiPr).sub.4 Titanium tetraisopropanolate T3P Propylphosphonic anhydride t-Bu tert-butyl t-BuOH tert-Butanol t-BuONa Sodium tert-butoxide t-BuOK Potassium tert-butoxide TEA Triethy lamine Tf.sub.2O Triflic anhydride TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMSOK Potassium trimethylsilanolate Ts para-Toluenesulfonyl TsCl 4-Toluenesulfonyl chloride TsOH p-toluenesulfonic acid TsOH,Py Pyridinium toluene-4-sulphonate Xphos or X-phos 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene RBF round-bottomed flask

Example 77: 3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1l-carbonyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

Step 1: 1-(6-amino-2-methylquinolin-5 yl)phospholane 1-oxide

[0214] ##STR00132##

[0215] To a solution of 1-((6-amino-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide (800 mg, 3.1 mmol) in MeOH (20 mL) was added Pd/C (10%, wet, 100 mg). The resulting solution was stirred for 12 h at room temperature under H.sub.2 atmosphere (1-2 atm). Pd/C was filtered out, the filtrate was evaporated to dryness. 1-(6-amino-2-methylquinolin-5-yl)phospholane 1-oxide (720 mg, 89.3%) was obtained and used to the next step without further purification. [M+H].sup.+=261.1.

Step 2: 1-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide

[0216] ##STR00133##

[0217] To a solution of 1-(6-amino-2-methylquinolin-5-yl)phospholane 1-oxide (720 mg, 2.8 mmol) in THF (20 mL) was added 5-bromo-2,4-dichloropyrimidine (1.6 g, 6.9 mmol) at 0? C. And then LiHMDS (1 M, 5.5 mL, 5.5 mmol) was added to the reaction mixture at 0? C. The mixture was stirred at 20? C., for 3 hrs. Water (10 mL) was poured into the mixture, which was further extracted with DCM (20 mL?3). The combined organic phase was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1) to afford 1-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide (680 mg, 54.4%). [M+H].sup.+=451.0.

Step 3: tert-butyl 4-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate

[0218] ##STR00134##

[0219] A mixture of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (4 g, 16 mmol), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (6.4 g, 24 mmol), K.sub.2CO.sub.3 (4.4 g, 32 mmol) in DMF (50 mL) was stirred in a flask at 80? C. overnight. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3?500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (7 g, 90%). [M+H].sup.+=499.1.

[0220] Step 4: tert-butyl 4-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate

##STR00135##

[0221] A mixture of tert-butyl 4-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (7 g, 14 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.3 g, 28 mmol), Pd(dppf)Cl.sub.2 (1.1 g, 1.4 mmol) and K.sub.3PO.sub.4 (8.9 g, 42 mmol) in DMF (160 mL) and water (20 mL) was stirred in a flask at 90? C. under nitrogen atmosphere for 16 hrs. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3?1000 mL). The combined organic layers were washed with brine (50) mL), dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (5 g, 80%). [M+H].sup.+=447.0.

Step 5: tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate

[0222] ##STR00136##

[0223] To a stirred solution of tert-butyl 4-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate (5 g, 11.2 mmol) in MeOH (100 mL) and DCM (20.00 mL) was added Pd/C (wet, 10%) (1 g) under nitrogen atmosphere. The resulting mixture was stirred for 16 hrs at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM/CH.sub.3OH (10:1, 200 mL). The filtrate was concentrated under reduced pressure to afford the product (4.0 g, 85.3%). [M+H].sup.+=419.1.

Step 6: 1-(6-(5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide

[0224] ##STR00137##

[0225] To a solution of 1-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide (680 mg, 1.5 mmol) in n-BuOH (20 mL) was added tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (633 mg, 1.5 mmol) at 20? C. 4-methylbenzenesulfonic acid (774 mg, 4.5 mmol) was added to the reaction mixture at 20? C. Then the mixture was stirred at 90? C. for 15 hrs. The reaction mixture was evaporated to dryness, water (20 mL) was poured into the mixture. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO.sub.3 solution and extracted with DCM (20 mL?3). The organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1) to afford 1-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide (580 mg, 52.3%). [M+H].sup.+=733.3.

Step 7: 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0226] ##STR00138##

[0227] A mixture of 2,6-bis(benzyloxy)-3-bromopyridine (15 g, 40.65 mmol) and 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (12.6 g, 49.61 mmol), Pd(dppf)Cl.sub.2 (3.32 g, 4.07 mmol), KOAc (12 g, 122.45 mmol) in dioxane (200 mL) was stirred overnight at 100? C. under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH and DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (8:1) to afford the product (9.00 g, 53%). [M+H].sup.+=418.3.

Step 8: 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine

[0228] ##STR00139##

[0229] A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9.00 g, 21.56 mmol) and 5-bromo-1,3-difluoro-2-iodobenzene (6.88 g, 21.57 mmol), K.sub.2CO.sub.3 (10.43 g, 75.48 mmol), Pd(dppf)Cl.sub.2 (789 mg, 1.078 mmol) in dioxane (90 mL) and H.sub.2O (30 mL) was stirred for 16 h at 100? C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (50 mL?3). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford the product (4 g, 38%). [M+H].sup.+=482.4.

Step 9: methyl (R)-1-(4-(2,6-bis(benzyloxyl)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylate

[0230] ##STR00140##

[0231] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (1 g, 2.07 mmol), methyl (R)-pyrrolidine-3-carboxylate hydrochloride (495 mg, 3 mmol) and Cs.sub.2CO.sub.3 (1.95 g, 6 mmol) in 10 mL DMSO, Pd.sub.2(dba).sub.3 (183 mg, 0.2 mmol) and Xantphos (231 mg, 0.4 mmol) was added wider N.sub.2 atmosphere. The mixture was stirred at 90? C. for 16 hours under N.sub.2 atmosphere. After LCMS showed the reaction was completed. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL?2). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica column chromatography (PE:EA=10:1) to afford product (740 mg, 67.4% yield). [M+H].sup.+=530.8.

Step 10: (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid

[0232] ##STR00141##

[0233] To a solution of methyl (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylate (740 mg, 1.4 mmol) in 10 mL THF. LiOH.Math.H.sub.2O (84 mg, 2 mmol) in 2 mL water was added. The mixture was stirred at 25? C. for 2 hours. After LCMS showed the reaction was completed. The mixture was concentrated in vacuum. The residue was adjust pH<5 with 1 N HCl and extracted with 50 mL EtOAc. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford product (700 mg, 96.9% yield). [M+H].sup.+=516.8.

Step 11: (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid

[0234] ##STR00142##

[0235] To a solution of (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (700 mg, 1.35 mmol) in 5 mL DCM and 30 mL MeOH, 350 mg Pd/C was added. The mixture was stirred at 30? C. for 16 hours under H.sub.2 atmosphere. After LCMS showed the reaction was completed and the mixture was filtered. The organic phase was concentrated in vacuum to afford product (350 mg, 76.7% yield). [M+H].sup.+=338.8.

Step 12: 3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0236] ##STR00143##

[0237] To a solution of 1-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane-1-oxide (50 mg, 0.07 mmol), (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (35 mg, 0.1 mmol) and DIEA (26 mg, 0.2 mmol) in 10 mL DCM, 50% w.t. T.sub.3P in EtOAc solution (64 mg, 0.1 mmol) was added. The mixture was stirred at 25? C. for 16 hours. When LCMS showed the reaction was completed, the mixture was quenched with water (10 mL). The organic phase was concentrated in vacuum and purified by prep-HPLC with C-18 column chromatography (0.1% FA in water:acetonitrile=90:10?50:50 gradient elution) to afford product (18.2 mg, 25.3% yield). .sup.1H NMR (500 MHz, DMSO) ? 11.31 (s, 1H), 10.84 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.94 (dd, J=13.9, 9.3 Hz, 2H), 7.29-7.47 (m, 2H), 6.75 (s, 1H), 6.18 (dd, J=44.0, 21.4 Hz, 4H), 4.02 (dd, J=12.5, 4.9 Hz, 1H), 3.78 (s, 3H), 3.43-3.56 (m, 7H), 3.24-3.28 (m, 4H), 2.94-3.04 (m, 4H), 2.73-2.88 (m, 3H), 2.52-2.71 (m, 9H), 2.47-2.49 (m, 1H), 2.23-2.43 (m, 3H), 2.02-2.21 (m, 3H), 1.89-2.00 (m, 1H), 1.83 (d, J=10.4 Hz, 2H), 1.49-1.63 (m, 2H), 0.78 (s, 3H). [M+H].sup.+=1053.4.

Example 147: 3-(4-(2-(4-(1-(4-((5-bromo-4-((2-(1-oxidophospholan-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione

Step 1: diallylphosphine oxide

[0238] ##STR00144##

[0239] To a solution of allylmagnesium bromide (310 mL, 1M in Et.sub.2O, 0.35 mol) in Et.sub.2O (200 mL) was added diethyl phosphonate (12 g dissolved in Et.sub.2O, 87 mmol) dropwise in 30 min at ?20 degrees C. the reaction solution was stirred for 30 min at this temperature, then allowed the temperature rise to room temperature naturally. Then the mixture was stirred at 100? C. for 14 hrs. The reaction was quenched by the addition of Sat.NH.sub.4Cl, extracted with Et.sub.2O (100 mL?2), combined the organic layer and washed with brine, dried over anhydrous Na.sub.2SO.sub.4, after filtration, the filtrate was concentrated under reduced pressure to afford the product (3.1 g, 27.2%). [M+H].sup.+=131.1.

Step 2: diallyl(2-aminophenyl)phosphine oxide

[0240] ##STR00145##

[0241] To a solution of 2-iodoaniline (2 g, 9.1 mmol) and diallylphosphine oxide (2.4 g, 18.3 mmol) in dioxane (50 mL) was added K.sub.3PO.sub.4 (4.8 g, 22.7 mmol), then Pd(OAc).sub.2 (205 mg, 0.91 mmol) and Xantphos (528 mg, 0.91 mmol) were added to the mixture at 20? C. The suspension was degassed under vacuum and purged with N.sub.2 three times. Then the mixture was stirred at 100? C. for 4 hrs. The mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=20/1 to 10/1) to afford diallyl(2-aminophenyl)phosphine oxide (1.2 g, 60%). [M+H].sup.+=222.1.

Step 3: 1-(2-aminophenyl)-2,5-dihydrophosphole 1-oxide

[0242] ##STR00146##

[0243] To a solution of diallyl(2-aminophenyl)phosphine oxide (1.2 g, 5.4 mmol) in DCM (200 mL) was added Grubbs 2.sup.nd generation catalyst (918 mg, 1.1 mmol). The reaction mixture was stirred for 16 h at room temperature. The mixture was concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=20/1 to 10/1) to afford 1-(2-aminophenyl)-2,5-dihydrophosphole 1-oxide (750 mg, 71.4%). m/z [M+H].sup.+=194.1.

Step 4: 1-(2-aminophenyl)phospholane 1-oxide

[0244] ##STR00147##

[0245] To a solution of 1-(2-aminophenyl)-2,5-dihydrophosphole 1-oxide (750 mg, 3.9 mmol) in MeOH (20 mL) was added Pd/C (10%, wet, 100 mg). The resulting solution was stirred for 12 h at room temperature under H.sub.2 atmosphere (1-2 atm). Pd/C was filtered out, the filtrate was evaporated to dryness, 1-(2-aminophenyl)phospholane 1-oxide (720 mg, 95%) was obtained and used to the next step without further purification. m/z [M+H].sup.+=196.1.

Step 5: 1-(2-(5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)phospholane 1-oxide

[0246] ##STR00148##

[0247] To a solution of 1-(2-aminophenyl)phospholane 1-oxide (720 mg, 3.7 mmol) in THF (15 mL) was added 5-bromo-2,4-dichloropyrimidine (2.1 g, 9.2 mmol) at 0? C. And then LiHMDS (1 M, 7.4 mL, 7.4 mmol) was added to the reaction mixture at 0? C. The mixture was stirred at 20? C. for 3 hrs. Water (10 mL) was poured into the mixture, which was further extracted with DCM (20 mL?3). The combined organic phase was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1) to afford 1-(2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)phospholane 1-oxide (620 mg, 43%). [M+H].sup.+=386.0.

Step 6: 1-(2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl amino)phenyl)phospholane 1-oxide

[0248] ##STR00149##

[0249] To a solution of 1-(2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)phospholane 1-oxide (620 mg, 1.6 mmol) in n-BuOH (20 mL) was added tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (671 mg, 1.6 mmol) at 20? C. 4-methylbenzenesulfonic acid (826 mg, 4.8 mmol) was added to the reaction mixture at 20? C. Then the mixture was stirred at 90? C. for 15 hrs. The reaction mixture was evaporated to dryness, water (20 mL) was poured into the mixture. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO.sub.3 solution and extracted with DCM (20 mL?3). The organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1) to afford 1-(2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phospholane 1-oxide (510 mg, 47.7%). [M+H]+=668.2.

Step 7: ethyl 2-(3,5-difluoro-4-nitrophenyl)acetate

[0250] ##STR00150##

[0251] A solution of 1,3-difluoro-2-nitrobenzene (50.0 g, 314.4 mmol) in NMP (300 mL) were cooled to ?20? C. under N.sub.2 atmosphere. Then a mixture of ethyl 2-chloroacetate (65.5 g, 534.7 mmol) and t-BuOK (121.0 g, 1.08 mol) in NMP (50 mL) was added slowly at ?10? C. to ?20? C. over 2 h. After being stirred for 2 h, the reaction was quenched by pouring into 1M HCl (200 mL) and ice-water. The mixture was extracted with EA (300 mL?3). The combined organic layer was washed by brine, dried with Na.sub.2SO.sub.4. The solution was concentrated in vacuum and the residue was purified by silica gel column chromatography (PE/EA=200/1 to 100/1) to provide product (13.7 g, 18%). .sup.1H NMR (400 MHz, CDCl.sub.3) ?.sub.H 7.06 (d, J=8.4 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.65 (s, 2H), 1.28 (t, J=7.2 Hz, 3H).

Step 8: ethyl 2-(4-amino-3,5-difluorophenyl)acetate

[0252] ##STR00151##

[0253] To a solution of ethyl 2-(3,5-difluoro-4-nitrophenyl)acetate (13.7 g, 56 mmol) in MeOH (150 mL) was added 10% Pd/C (1.5 g) at r.t. The mixture was stirred at r.t under H.sub.2 atmosphere for 5 h. Filtrated on vacuum to remove Pd/C and concentrated in vacuum to provide the product (12.2 g), which was used in next step without further purification. .sup.1H NMR (400 MHz, DMSO_d.sub.6) ?.sub.H 6.82 (d, J=8.0 Hz, 2H), 5.69 (s, 2H), 4.06 (q, J=7.2 Hz, 2H), 3.52 (s, 2H), 1.17 (t, J=7.2 Hz, 3H). [M+H].sup.+=216.4.

Step 9: ethyl 2-(3,5-difluoro-4-iodophenyl)acetate

[0254] ##STR00152##

[0255] A solution of ethyl 2-(4-amino-3,5-difluorophenyl)acetate (12.2 g, 56 mmol) in MeCN (150 mL) was cooled to 0? C. under N.sub.2 atmosphere and CuI (21.2 g, 112 mmol) was added. After stirring for 10 min, tert-butylnitrite (11.5 g, 112 mmol) was added dropwise over 30 min. Then the mixture was stirred at r.t for overnight. The reaction was quenched by pouring into water and extracted with EA (300 mL?3). All organic layers were combined and washed by brine, dried with Na.sub.2SO.sub.4. The solution was concentrated in vacuum and the residue was purified by silica gel column chromatography (PE/EA=500/1 to 100/1) to provide the product (8.8 g, 48%). [M+H].sup.+=326.5.

Step 10: ethyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)acetate

[0256] ##STR00153##

[0257] To a solution of ethyl 2-(3,5-difluoro-4-iodophenyl)acetate (8.8 g, 27.0 mmol) in a mixed solvent of 1,4-dioxane/H.sub.2O (100 mL/20 mL) were added K.sub.2CO.sub.3 (9.3 g, 67.4 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (14.6 g, 35.0 mol) and Pd(dppf)Cl.sub.2 (2.9 g, 4.0 mmol) under N.sub.2 atmosphere. The resulting solution was stirred for 6 h at 100? C. The mixture was diluted with water (300 mL) and extracted with EA (300 mL?3). All organic layers were combined and washed with brine (300 mL), dried over Na.sub.2SO.sub.4. The solution was concentrated in vacuum and the residue was purified by silica gel column chromatography (PE/EA=200/1) to give the product (8.2 g, 62%). .sup.1H NMR (40) MHz, CDCl.sub.3) &a 7.49 (d, J=8.0 Hz, 1H), 7.40-7.24 (m, 10H), 6.90 (d, J=8.0 Hz, 2H), 6.47 (d, J=8.0 Hz, 1H), 5.38 (s, 2H), 5.33 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 3.61 (s, 2H), 1.28 (t, J=7.2 Hz, 3H).

Step 11: 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)ethanol

[0258] ##STR00154##

[0259] A solution of ethyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)acetate (8.2 g, 16.7 mol) in THF (100 mL) was cooled to 0? C. under N.sub.2 atmosphere and 1.5 M DIBAL-H (45 mL, 67.5 mol) in THF was added dropwise over 30 min. Then the mixture was stirred at r.t for 2 h. The reaction was quenched by pouring into water and extracted with EA (300 mL?3). All organic layers were combined and washed by brine, dried with Na.sub.2SO.sub.4. The solution was concentrated in vacuum and the residue was purified by column chromatography (PE/EA=10/1 to 3/1) to provide the product (6.6 g, 88%). .sup.1H NMR (400 MHz, CDCl.sub.3) ?.sub.H 7.49 (d, J=8.0 Hz, 1H), 7.42-7.25 (m, 9H), 6.84 (d, J=8.0 Hz, 2H), 6.47 (d, J=8.0 Hz, 1H), 5.38 (s, 2H), 5.33 (s, 2H), 3.90 (m, 2H), 2.87 (t, J=6.4 Hz, 2H). [M+H].sup.+=448.3.

Step 12: 3-(2,6-difluoro-4-(2-hydroxyethyl phenyl)piperidine-2,6-dione

[0260] ##STR00155##

[0261] To a solution of 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)ethanol (6.6 g, 14.7 mmol) in DCM (150 mL) was added TFA (50 mL). After stirred overnight, the mixture was concentrated in vacuo. The residue was dissolved in MeOH (200 mL) and 10% Pd/C (1.0 g) was added. The resulted mixture was stirred for 2 days at r.t under H.sub.2 atmosphere. The mixture was filtered and the filtrate was concentrated to give a residue which was purified by reversed flash C18 chromatography (ACN/water=0% to 30%) to give the title compound (2.1 g, 53%). [M+H].sup.+=270.1.

Step 13: 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde

[0262] ##STR00156##

[0263] A mixture of 3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (86.4 mg, 0.32 mmol) and IBX (132 mg, 0.47 mmol) in DMSO (10 mL) was stirred in a flask at room temperature overnight. The reaction was quenched with water and the mixture was extracted with EtOAc, washed three times with saturated aqueous NaCl and twice with saturated aqueous NaHCO.sub.3. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuum to afford the product (61 mg, 71%). [M+H].sup.+=268.1.

Step 14: 3-(4-(2-(4-(1-(4-((5-bromo-4-((2-(1-oxidophospholan-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione

[0264] ##STR00157##

[0265] To a solution of 1-(2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phospholane 1-oxide (50 mg, 0.075 mmol) in DCM (3 mL) was added 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (40 mg, 0.15 mmol) at 20? C. The mixture was stirred at 20? C. for 1 hr and STAB (32 mg, 0.15 mmol) was added. Then the mixture was stirred at 20? C. for 2 hrs. Water (10 mL) was poured into the mixture. Then the mixture was extracted with DCM (20 mL). The organic phase was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (C-18 column chromatography (0.1% FA in water:acetonitrile=90:10?60:40 gradient elution) to afford the product (17.7 mg, 17.6%). .sup.1H NMR (500 MHz, DMSO) ? 10.88 (s, 1H), 10.50 (s, 1H), 8.15 (d, J=27.9 Hz, 2H), 7.98 (s, 1H), 7.42 (dd, J=13.4, 7.7 Hz, 1H), 7.36 (s, 1H), 7.30 (t, J=7.6 Hz, 1H), 7.10 (t, J=7.4 Hz, 1H), 6.96 (d, J=10.2 Hz, 2H), 6.69 (s, 1H), 4.13 (dd, J=12.6, 5.0 Hz, 1H), 3.69 (s, 3H), 2.92 (d, J=10.8 Hz, 2H), 2.65-2.80 (m, 6H), 2.46-2.60 (m, 6H), 2.21-2.41 (m, 6H), 1.73-2.10 (m, 13H), 1.39-1.60 (m, 2H), 0.85-1.02 (m, 3H). [M+H].sup.+=919.3.

Example 62: 3-(4-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione

Step 1: 4-ethoxy-1-ethyl-2-fluorobenzene

[0266] ##STR00158##

[0267] To a solution of 4-ethyl-3-fluorophenol (35 g, 0.25 mol) in DMF (200 mL) was added K.sub.2CO.sub.3 (69, 0.5 mol). EtI (50.7 g, 0.32 mol). The mixture was stirred at 20-30? C. for 18 hours. The reaction was quenched by H.sub.2O (200 mL) and extracted with EA (150 mL*2). The organic phase was combined and washed with brine (300 mL*3). The organic phase was concentrated and purified by a silica gel column, eluted with PE (100%) to give product (35 g, yield: 83.3%). [M+H].sup.+=169.2.

Step 2: 1-ethoxy-7-ethyl-5-fluoro-2-nitrobenzene

[0268] ##STR00159##

[0269] To a solution of 4-ethoxy-1-ethyl-2-fluorobenzene (35 g, 0.2 mol) in Ac.sub.2O (100 mL) was added conc. HNO.sub.3 (25.2 g, 0.26 mol, 65%) dropwise at 0? C. The mixture was stirred at r.t. for 2 hs. The reaction was quenched with Na.sub.2CO.sub.3 solution (500 mL). Product was isolated by filtration. (25 g, yield: 58.7%). .sup.1H NMR (500 MHz, d-DMSO) ? 7.90 (d, J=8.0 Hz, 1H), 7.26 (d, J=12.0 Hz, 1H), 4.2 (q, J=7.0 Hz, 2H), 2.60 (q, J=7.5 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H), 1.15 (t, J=7.5 Hz, 3H).

Step 3: tert-butyl 4-(1-(5-ethoxy-2-ethyl-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate

[0270] ##STR00160##

[0271] To a solution of 1-ethoxy-4-ethyl-5-fluoro-2-nitrobenzene (20 g, 94 mmol) in DMF (300 mL) was added tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (30 g, 112 mmoL), K.sub.2CO.sub.3 (32 g, 235 mmol). The mixture was stirred at 120? C. for 28 hours. The mixture was poured into ice water. The product was isolated by filtration. (20 g, yield: 46.1%). [M+H].sup.+=: 463.2. .sup.1H NMR (500 MHz, d-DMSO) ? 7.74 (s, 1H), 6.73 (s, 1H), 4.19 (q, J=7.0 Hz, 2H), 3.30 (br, 4H), 3.23 (d, J=11.0 Hz, 2H), 2.71 (t, J=11.5 Hz, 2H), 2.57 (q, J=7.5 Hz, 2H), 2.47 (br, 4H), 2.39 (t, J=11.0 Hz, 1H), 1.84 (d, J=11.5 Hz, 2H), 1.58 (q, J=10.5 Hz, 2H), 1.39 (s, 9H), 1.34 (t, J=7.5 Hz, 3H), 1.19 (t, J=7.5 Hz, 3H).

Step 4: tert-butyl 4-(1-(4-amino-5-ethoxy-2-ethylphenyl piperidin-4-yl)piperazine-1-carboxylate

[0272] ##STR00161##

[0273] To a solution of tert-butyl 4-(1-(5-ethoxy-2-ethyl-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (20 g, 94 mmol) in THF (150 mL) was added Pd/C (2 g). The mixture was stirred at r.t. under H.sub.2 (1 atm) for 48 hs. The solid was filtered off. The filtrate was concentrated for next step directly without further operation. [M+H].sup.+=433.4.

Step 5: 1-(6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide

[0274] ##STR00162##

[0275] The titled compound was synthesized in a manner similar to that in Example 77 Step 6 from 1-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide and tert-butyl 4-(1-(4-amino-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate. [M+H].sup.+=747.2.

Step 6: 3-(4-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione

[0276] ##STR00163##

[0277] The titled compound was synthesized in a manner similar to that in Example 147 Step 14 from 1-(6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide and 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde. .sup.1H NMR (500 MHz, DMSO) ? 10.88 (s, 1H), 10.48 (s, 1H), 8.65 (d, J=8.7 Hz, 1H), 8.17 (s, 1H), 7.89-7.94 (m, 2H), 7.74 (s, 1H), 7.42 (dd, J=13.2, 8.5 Hz, 1H), 7.32 (s, 11H), 6.95 (d, J=10.0 Hz, 2H), 6.59 (s, 1H), 4.13 (dd, J=12.6, 5.0 Hz, 1H), 3.93 (q, J=7.0 Hz, 2H), 2.64-2.83 (m, 5H), 2.60 (s, 3H), 2.44-2.55 (m, 8H), 2.28-2.40 (m, 4H), 1.80-2.21 (m, 14H), 1.73 (d, J=10.9 Hz, 2H), 1.32-1.48 (m, 2H), 1.21 (t, J=6.9 Hz, 3H), 0.47 (s, 3H). [M+H].sup.+=998.4.

Example 68: 3-(4-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

Step 1: 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0278] ##STR00164##

[0279] To a solution of 6-bromo-N1-methylbenzene-1,2-diamine (4 g, 19.9 mmol) in CH.sub.3CN (50 mL) was added CDI (6.4 g, 39.8 mmol). The resulting solution was stirred for 6 h at 90? C. under nitrogen atmosphere. The solid was collected by filtration. This was resulted in 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.1 g, 90.7%). [M+H].sup.+=227.0.

Step 2: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

[0280] ##STR00165##

[0281] To a solution of 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (600 mg, 2.6 mmol) in THF (10 mL) was added t-BuOK (1M in THF, 3.2 mL, 3.1 mmol) dropwise in 10 min at 0? C., the reaction solution was stirred for 30 min at this temperature, then to this was added 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.1 g, 2.9 mmol) in THF (5 mL) dropwise in 10 min. The resulting solution was stirred for 2 h at 0-10? C. The reaction was quenched by the addition of sat.aq. NH.sub.4Cl solution, extracted with EtOAc (10 mL?3), combined the organic layer, and washed with brine, dried over anhydrous Na.sub.2SO.sub.4, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column, eluted with PE/EtOAc (1:1) to afford product (910 mg, 75.2%). [M+H].sup.+=458.1.

Step 3: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0282] ##STR00166##

[0283] 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (800 mg, 1.75 mmol) was dissolved in MeSO.sub.2H/toluene (2 mL/6 mL). The resulting mixture was stirred for 3 h at 100? C. Solvent was removed and the residue was poured into ice/water. The solid was collected by filtration. 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione was obtained (510 mg, 86.4%). [M+H].sup.+=338.1.

Step 4: (E)-3-(4-(2-ethoxyvinyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0284] ##STR00167##

[0285] To a stirred solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (250 mg, 0.74 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (176 mg, 0.89 mmol) in DMF/H.sub.2O (8 mL/2 mL) were added Pd(dtbpf)Cl.sub.2 (48 mg, 0.074 mmol) and CsF (225 mg, 1.48 mmol). The resulting mixture was stirred for 2 h at 80? C. under nitrogen atmosphere. The reaction solution was diluted with water, extracted with EtOAc (10 mL?3). The organic layer was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4 which was evaporated to dryness. The residue was purified by a silica gel column, eluted with PE/EtOAc=1:1 to afford the product. (180 mg, 73.8%). m/z [M+H].sup.+=330.2.

Step 5: 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde

[0286] ##STR00168##

[0287] (E)-3-(4-(2-ethoxyvinyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (180 mg, 0.55 mmol) was dissolved in HCOOH (2 mL). The resulting solution was stirred for 2 h at room temperature. The reaction solution was evaporated to dryness to afford product (125 mg, 75.3%) which was used directly in the next step. m/z [M+H].sup.+=302.1.

Step 6: 3-(4-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0288] ##STR00169##

[0289] The titled compound was synthesized in a manner similar to that in Example 147 Step 14 from 1-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide and 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde. .sup.1H NMR (500 MHz, DMSO) ? 11.02 (s, 1H), 10.60 (s, 1H), 8.58 (d, J=8.0 Hz, 11H), 8.16-8.24 (m, 11H), 7.97 (s, 1H), 7.89 (d, J=9.1 Hz, 11H), 7.80 (s, 11H), 7.42 (d, J=8.9 Hz, 1H), 7.29 (s, 1H), 6.94-6.78 (m, 3H), 6.63 (s, 1H), 5.30 (dd, J=12.7, 5.4 Hz, 1H), 3.69 (s, 3H), 3.51 (s, 3H), 2.94-3.04 (m, 3H), 2.80-2.85 (m, 4H), 2.45-2.70 (m, 15H), 1.82-2.31 (m, 12H), 1.74-1.76 (m, 2H), 1.41-1.47 (m, 2H), 0.54 (s, 3H). [M+H].sup.+=1018.4.

Example 71: 3-(6-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione

[0290] ##STR00170##

[0291] To a solution of 6-bromobenzo[d]oxazol-2(3H)-one (30.0 g, 140 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (61 g, 147 mml), and Cu(OAc).sub.2 (25.5 g, 140 mmol) in dry 1,4-dioxane (500 ml), were added pyridine (33.3 mL, 420 mmol), and activated 4 ? molecular sieve (20 g).

[0292] The mixture was stirred at 80? C. under the atmosphere of oxygen for 48 hours. After being cooled to rt, the mixture was diluted with ethyl acetate (1500 mL), and filtered through a pad of celite. The filtrate was washed with water (500 mL), and brine (3?500 mL), then dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by silica column chromatography (PE/DCM, 30%-50%) to afford crude product, which is further purified by trituration with PE to afford the target product (25.3 g, 35.8%). [M+H].sup.+=503.1.

Step 2: 6-(2-(benzyloxy)ethyl)-3-(2,6-bis(benzyloxy)pyridin-3-yl)benzo[d]oxazol-2(3H)-one

[0293] ##STR00171##

[0294] A 500 mL three-neck round-bottomed flask equipped with a magnetic stirrer, were charged with 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromobenzo[d]oxazol-2(3H)-one (20 g, 39.7 mmol), ((2-bromoethoxy)methyl)benzene (15.4 g, 71.5 mmol). NiI.sub.2 (2.48 g, 7.94 mmol), picolinimidamide hydrochloride (1.23 g, 7.94 mmol). NaI (2.98 g, 19.8 mmol), and Mn (6.55 g, 119 mmol). The mixture was degassed under vacuum and purged with N.sub.2 for three times. Dry DMAc (300 mL) was added into the round-bottomed flask by a syringe, the mixture was degassed under vacuum and purged with N.sub.2 once more. A solution of TFA (0.89 mL, 11.9 mmol) in DMAc (5 mL) was added into the round-bottomed flask by a syringe. The resulting mixture was stirred at 100? C. till complete conversion (confirmed by LCMS, ?5 hours). After being cooled to rt, the mixture was diluted with ethyl acetate (1.5 L), then filtered through a pad of celite. The filtrate was washed with brine (5?500 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica column chromatography (PE/EA, 10%-20%) to afford crude product (8.00 g, 36.1%). [M+H].sup.+=559.4.

Step 3: 3-(6-(2-hydroxyethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione

[0295] ##STR00172##

[0296] To a solution of 6-(2-(benzyloxy)ethyl)-3-(2,6-bis(benzyloxy)pyridin-3-yl)benzo[d]oxazol-2(3H)-one (8.00 g, 14.3 mmol) in THF/EtOH (200 mL/200 mL), was added Pd/C (10 wt %, 5.00 g). The mixture was degassed under reduced pressure and purged with H.sub.2 for five times, and stirred under H.sub.2 at 50? C. overnight. After being cooled to rt, the mixture was diluted with EtOH/DCM (200 ml/400 mL), and sonicated in an ultrasonic washer for 5 minutes, then filtered through a pad of celite. The filtrate was concentrated under reduced pressure. Precipitate was observed during evaporation, then it was collected by filtration, and dried under vacuum to afford the first part of product (2.50 g). The filtrate was concentrated under reduced pressure and purified by silica column chromatography (PE/EA=1:1) to afford the other part of target product (0.80 g). Totally 3.30 g product was obtained (79.7%). [M+H].sup.+=291.2.

Step 3: 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde

[0297] ##STR00173##

[0298] The titled compound was synthesized in a manner similar to that in Example 147 Step 13 from 3-(6-(2-hydroxyethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione and IBX. [M+H].sup.+=289.1.

Step 4: 3-(6-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione

[0299] ##STR00174##

[0300] The titled compound was synthesized in a manner similar to that in Example 147 Step 14 from 1-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide and 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde. .sup.1H NMR (500 MHz, DMSO) ? 11.14 (s, 1H), 10.60 (s, 1H), 8.57 (d, J=8.8 Hz, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.89 (d, J=9.1 Hz, 1H), 7.80 (s, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.29 (s, 1H), 7.22 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 6.62 (s, 1H), 5.28 (dd, J=12.9, 5.2 Hz, 1H), 3.68 (s, 3H), 2.74-2.89 (m, 3H), 2.47-2.72 (m, 13H), 2.30-2.42 (m, 5H), 1.87-2.17 (m, 13H), 1.72-1.74 (m, 2H), 1.40-1.46 (m, 2H), 0.54 (s, 3H). [M+H].sup.+=1005.4.

Example 73: 3-(4-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione

Step 1: N-(2,6-bis(benzyloxy)pyridin-3-yl)-2-(2,6-dibromophenyl)acetamide

[0301] ##STR00175##

[0302] Into a 100-mL round-bottom flask, (2,6-dibromophenyl)acetic acid (0.85 g, 2.892 mmol). DMF (35 mL), 2,6-bis(benzyloxy)pyridin-3-amine hydrochloride (1.0 g, 2.916 mmol), DIEA (2.0 mL, 11.654 mmol) and HATU (1.3 g, 3.499 mmol) were added. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with H.sub.2O The solids were collected by filtration. The solid was washed with MeOH to afford 1.5 g (89.08%) product which was used in next step without further purification. [M+H].sup.+=581.1.

Step 2: 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromoindolin-2-one

[0303] ##STR00176##

[0304] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added N-[2,6-bis(benzyloxy)pyridin-3-yl]-2-(2,6-dibromophenyl) acetamide (580 mg, 0.996 mmol), NMP (15 mL). K.sub.2CO.sub.3 (688 mg, 4.978 mmol), acetylacetone (200 mg, 1.998 mmol) and CuCl (99 mg, 1.000 mmol). The resulting solution was stirred for 1.5 hr at 85? C. The reaction mixture was cooled to room temperature. The resulting solution was diluted with EtOAc. The resulting solution was extracted with brine and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/EA (6:1) to afford 403 mg (80.1%) of desired product. [M+H].sup.+=501.2.

Step 3: 1-(2,6-bis(benzyloxyl)pyridin-3-yl)-4-bromo-3,3-dimethylindolin-2-one

[0305] ##STR00177##

[0306] Into a 50-mL round-bottom flask, was added 1-[2,6-bis(benzyloxy)pyridin-3-yl]-4-bromo-3H-indol-2-one (500 mg, 0.997 mmol). DMF (15 mL), NaH (189 mg, 5.0 mol). The resulting solution was stirred for 0.5 hr at room temperature. And then CH.sub.3I (850 mg, 5.988 mmol) was added to the mixture at room temperature. The reaction was stirred overnight at room temperature. The resulting solution was diluted with EA. The pH value of the solution was adjusted to <7 with 2N HCl. The resulting mixture was extracted with ethyl acetate and the organic layers combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/PE (3:1) to afford 401 mg (75%) of desired product. [M+H].sup.+=529.2.

Step 4: ethyl 2-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3,3-dimethyl-2-oxoindolin-4-yl) acetate

[0307] ##STR00178##

[0308] Into a 30-mL microwave vial #1 purged and maintained with an inert atmosphere of nitrogen, was placed zinc powder (490 mg, 7.555 mmol), THF (8 mL), TMSCI (41 mg, 0.377 mmol). The resulting solution was stirred for 10 min at room temperature. And then ethyl bromoacetate (630 mg, 3.778 mmol) was added to the mixture. The resulting solution was stirred for 1.5 hrs at 60? C. Into a 100-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 1-[2,6-bis(benzyloxy)pyridin-3-yl]-4-bromo-3,3-dimethylindol-2-one (1 g, 1.889 mmol), THF (17 mL), Xphos (180 mg, 0.378 mmol), Pd.sub.2(dba).sub.3 (170 mg, 0.189 mmol). To the above mixture was added the solution in vial #1 by a syringe through a millipore filter. The resulting solution was allowed to react for an additional 3 hrs at 60? C. The resulting solution was diluted with EtOAc. The pH value of the solution was adjusted to <7 with 2N HCl. The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA/PE (1:2) to afford 810 mg (78.9%) of desired product. [M+H].sup.+=537.2.

Step 5: [1-[2,6-bis(benzyloxy)pyridin-3]-yl-3,3-dimethyl-2-oxoindol-4-yl]acetic acid

[0309] ##STR00179##

[0310] Into a 50-mL round-bottom flask, was placed ethyl 2-[1-[2,6-bis(benzyloxy)pyridine-3-yl]-3,3-dimethyl-2-oxoindol-4-yl]acetate (740 mg, 1.379 mmol), THF (10 mL), H.sub.2O (1 mL), NaOH (276 mg, 6.901 mmol). The resulting solution was stirred for 3 hr at 65? C. The pH value of the solution was adjusted to <7 with 2N HCl (1 mL). The resulting solution was extracted with ethyl acetate and the organic layers combined and concentrated under vacuum to afford 502 mg (71.29%) of desired product which was used in next step without further purification. [M+H].sup.+=509.2.

Step 6: 1-[2,6-bis(benzyloxy)pyridin-3-yl]-4-(2-hydroxyethyl)-3,3-dimethylindol-2-one

[0311] ##STR00180##

[0312] Into a 50-mL round-bottom flask, was placed [1-[2,6-bis(benzyloxy)pyridin-3-yl]-3,3-dimethyl-2-oxoindol-4-yl] acetic acid (600 mg, 1.180 mmol), THF (15 mL). And then BH.sub.3 (1M in THF, 6 mL) was added dropwise to the mixture at room temperature. The resulting solution was stirred for 5 hr at room temperature. The reaction was then quenched by the addition of MeOH (10 mL). The resulting mixture was concentrated under vacuum to afford the crude residue which was purified with EA/PE (1:1) to afford 400 mg (68.5%) of desired product. [M+H].sup.+=495.2.

Step 7: 3-[4-(2-hydroxyethyl)-3,3-dimethyl-2-oxoindol-1-yl]piperidine-2,6-dione

[0313] ##STR00181##

[0314] Into a 100-mL round-bottom flask, was placed 1-[2,6-bis(benzyloxy)pyridin-3-yl]-4-(2-hydroxyethyl)-3,3-dimethylindol-2-one (400 mg, 0.809 mmol). EtOH (15 mL), THF (15 mL), AcOH (0.50 mL), Pd/C (400 mg, 10% wt) at hydrogen atmosphere. The resulting solution was stirred overnight at 50? C. and the solids were filtered out. The organic phase was concentrated under vacuum to afford 213 mg (83.37%) of desired product [M+H].sup.+=317.1.

Step 8: 2-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-4-yl)acetaldehyde

[0315] ##STR00182##

[0316] The titled compound was synthesized in a manner similar to that in Example 147 Step 13 from 3-[4-(2-hydroxyethyl)-3,3-dimethyl-2-oxoindol-1-yl]piperidine-2,6-dione and IBX. [M+H].sup.+=315.2.

Step 9: 3-(4-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione

[0317] ##STR00183##

[0318] The titled compound was synthesized in a manner similar to that in Example 147 Step 14 from 1-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide and 2-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-4-yl)acetaldehyde. .sup.1H NMR (500 MHz, DMSO) ? 11.07 (s, 1H), 10.68 (s, 1H), 8.64 (d, J=8.8 Hz, 1H), 8.29 (s, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.96 (d, J=9.1 Hz, 1H), 7.87 (s, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.36 (s, 1H), 7.17 (t, J=7.8 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.83 (s, 1H), 6.69 (s, 1H), 5.21 (s, 1H), 3.75 (s, 3H), 2.75-2.94 (m, 6H), 2.51-2.74 (m, 14H), 1.89-2.32 (m, 13H), 1.81 (d, J=10.9 Hz, 2H), 1.51 (dd, J=20.3, 11.3 Hz, 2H), 1.38 (d, J=4.1 Hz, 6H), 0.61 (s, 3H). [M+H].sup.+=1031.4.

Example 75: 3-(4-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione

[0319] ##STR00184##

[0320] The titled compound was synthesized in a manner similar to that in Example 147 Step 14 from 1-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)phospholane 1-oxide and 3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione.

[0321] .sup.1H NMR (500 MHz, DMSO) ? 10.95 (s, 1H), 10.67 (s, 1H), 8.64 (d, J=8.7 Hz, 1H), 8.24 (d, J=11.0 Hz, 1H), 8.04 (s, 1H), 7.96 (d, J=9.1 Hz, 1H), 7.87 (s, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.36 (s, 1H), 7.02 (d, J=10.1 Hz, 2H), 6.69 (s, 1H), 4.20 (dd, J=12.6, 5.0 Hz, 1H), 3.75 (s, 3H), 2.51-2.92 (m, 16H), 2.36-2.48 (m, 4H), 1.88-2.30 (m, 14H), 1.80 (d, J=10.9 Hz, 2H), 1.50 (dd, J=20.2, 11.3 Hz, 2H), 0.61 (s, 3H). [M+H].sup.+=984.3.

Example 76: 3-(4-(3-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxidophospholan-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0322] ##STR00185##

[0323] The titled compound was synthesized in a procedure similar to Example 77.

[0324] .sup.1H NMR (500 MHz, DMSO) ? 10.86 (s, 1H), 10.67 (s, 1H), 8.65 (s, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.86 (s, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 6.69 (s, 1H), 6.17 (d, J=11.1 Hz, 2H), 4.03 (t, J=7.4 Hz, 3H), 3.91 (t, J=6.1 Hz, 2H), 3.79-3.86 (m, 1H), 3.75 (s, 3H), 3.48 (s, 2H), 2.87-2.89 (m, 2H), 2.72-2.82 (m, 1H), 2.56-2.71 (m, 5H), 2.51-2.54 (m, 4H), 2.45-2.49 (m, 3H), 2.31-2.39 (m, 1H), 2.17-2.26 (m, 2H), 1.87-2.16 (m, 10H), 1.79 (d, J=10.8 Hz, 2H), 1.53 (dd, J=20.4, 11.3 Hz, 2H), 0.61 (s, 3H). [M+H].sup.+=1039.4.

Example 111: 3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((2-(1-oxidophospholan-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0325] ##STR00186##

[0326] The titled compound was synthesized in a manner similar to that in Example 77 Step 12 from 1-(2-(5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phospholane 1-oxide and (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid. .sup.1H NMR (500 MHz, DMSO) ? 10.78 (s, 1H), 10.50 (s, 11H), 8.19 (d, J=12.7 Hz, 11H), 8.12 (s, 11H), 7.99 (s, 11H), 7.29-7.39 (m, 3H), 7.10 (t, J=7.3 Hz, 11H), 6.69 (s, 1H), 6.16 (d, J=12.2 Hz, 2H), 3.95 (dd, J=12.5, 4.9 Hz, 1H), 3.69 (s, 3H), 3.37-3.49 (m, 7H), 3.16-3.27 (in, 6H), 2.93-2.95 (m, 2H), 2.47-2.76 (m, 5H), 2.19-2.36 (m, 2H), 1.78-2.13 (m, 14H), 1.50-1.56 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). [M+H].sup.+=988.3.

Example 143: 3-(4-(R)-3-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxido-2,5-dihydrophosphol-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

Step 1: 5-iodo-2-methylquinolin-6-amine

[0327] ##STR00187##

[0328] To a solution of 2-methylquinolin-6-amine (5.3 g, 33.5 mmol) in HOAc (60 mL) was added IC1 (6.5 g, 40.3 mmol) at 20? C. Then the mixture was stirred at 20? C. for 1 hr. The reaction solution was concentrated under vacuum. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO.sub.3 solution and extracted with DCM (150 mL). The organic phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum, 5-iodo-2-methylquinolin-6-amine (8 g, 83.7%) was obtained. [M+H].sup.+=285.0.

Step 2: diallyl(6-amino-2-methylquinolin-5-yl)phosphine oxide

[0329] ##STR00188##

[0330] To a solution of 5-iodo-2-methylquinolin-6-amine (4 g, 14 mmol) and diallylphosphine oxide (3.6 g, 28 mmol) in dioxane (80 mL) was added K.sub.3PO.sub.4 (7.4 g, 35 mmol), then Pd(OAc).sub.2 (316 mg, 1.4 mmol) and Xantphos (813 mg, 1.4 mmol) were added to the mixture at 20? C. The suspension was degassed under vacuum and purged with N.sub.2 three times. Then the mixture was stirred at 100? C. for 15 hrs. The mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=20/1 to 10/1) to afford diallyl(6-amino-2-methylquinolin-5-yl)phosphine oxide (2.1 g, 52.2%) as a brown solid. [M+H].sup.+=287.1.

[0331] Step 3: N-(5-(diallylphosphoryl)-2-methylquinolin-6-yl)pivalamide

##STR00189##

[0332] To a solution of diallyl(6-amino-2-methylquinolin-5-yl)phosphine oxide (2.1 g, 7.3 mmol) in DCM (50 mL) was added TEA (1.85 g, 18.3 mmol), then pivaloyl chloride (1.06 g, 8.8 mmol) was added dropwise in 5 min. The resulting solution was stirred at rt for 3 h. The reaction mixture was diluted with DCM, washed water and brine, dried over anhydrous Na.sub.2SO.sub.4. The organic phase was evaporated to dryness to afford N-(5-(diallylphosphoryl)-2-methylquinolin-6-yl)pivalamide. (2.6 g, 95.9%). [M+H].sup.+=371.2.

Step 4: N-(2-methyl-5-(1-oxido-2,5-dihydrophosphol-1-yl)quinolin-6-yl)pivalamide

[0333] ##STR00190##

[0334] To a solution of N-(5-(diallylphosphoryl)-2-methylquinolin-6-yl)pivalamide (2.6 g, 7.0 mmol) in DCM (200 mL) was added HOVEYDA-Grubbs catalyst (878 mg, 1.4 mmol). The reaction mixture was stirred for 16 h at room temperature. The mixture was concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=20/1 to 10/1) to afford N-(2-methyl-5-(l-oxido-2,5-dihydrophosphol-1-yl)quinolin-6-yl)pivalamide (2 g, 83.3%) as a dark-brown solid. [M+H].sup.+=343.2.

Step 5: 1-(6-amino-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide

[0335] ##STR00191##

[0336] N-(2-methyl-5-(1-oxido-2,5-dihydrophosphol-1-yl)quinolin-6-yl)pivalamide (2 g, 5.8 mmol) was dissolved in dioxane (15 mL). HCl (2 M, 15 mL) was added to the reaction mixture. The resulting solution was stirred for 15 h at 100? C. The reaction solution was evaporated to dryness, the reside was dissolved in water, the pH value was adjusted to 8-9 with NaOH (1M), extracted with DCM, then the organic phase was concentrated under vacuum to afford 1-(6-amino-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide (1.3 g, 86.1%) and used directly to the next step without further purification. [M+H].sup.+=259.1.

Step 6: 1-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide

[0337] ##STR00192##

[0338] To a solution of 1-(6-amino-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide (500 mg, 1.9 mmol) in THF (15 mL) was added 5-bromo-2,4-dichloropyrimidine (1.1 g, 4.8 mmol) at 0? C. And then LiHMDS (1 M, 3.8 mL, 3.8 mmol) was added to the reaction mixture at 0? C. The mixture was stirred at 20? C. for 3 hrs. Water (10 mL) was poured into the mixture, which was further extracted with DCM (20 mL?3). The combined organic phase was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1) to afford 1-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide (505 mg, 58.2%). [M+H].sup.+=449.0.

Step 7: 1-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide

[0339] ##STR00193##

[0340] To a solution of 1-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide (505 mg, 1.1 mmol) in n-BuOH (20 mL) was added tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (472 mg, 1.1 mmol) at 20? C. 4-methylbenzenesulfonic acid (568 mg, 3.3 mmol) was added to the reaction mixture at 20? C. Then the mixture was stirred at 90? C. for 15 hrs. The reaction mixture was evaporated to dryness, water (20 mL) was poured into the mixture. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO.sub.3 solution and extracted with DCM (20 mL?3). The organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1) to afford the product (485 mg, 58.9%). [M+H].sup.+=731.3.

Step 8: 3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxido-2,5-dihydrophosphol-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl-2,6-difluorophenyl)piperidine-2,6-dione

[0341] ##STR00194##

[0342] To a solution of 1-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide (50 mg, 0.07 mmol). (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (35 mg, 0.1 mmol) and DIEA (26 mg, 0.2 mmol) in 10 mL DCM, 50% w.t. T.sub.3P in EtOAc solution (64 mg, 0.1 mmol) was added. The mixture was stirred at 25? C. for 16 hours. After LCMS showed the reaction was completed. The mixture was quenched with water (10 mL). The organic phase was concentrated in vacuum and purified by prep-HPLC with C-18 column chromatography (0.1% FA in water:acetonitrile=90:10?50:50 gradient elution) to afford product (20.5 mg, 27.8% yield). .sup.1H NMR (500 MHz, DMSO) ? 11.31 (s, 1H), 10.84 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.94 (dd, J=13.9, 9.3 Hz, 2H), 7.29-7.47 (m, 2H), 6.75 (s, 1H), 6.11-6.24 (m, 4H), 4.02 (dd, J=12.5, 4.9 Hz, 1H), 3.78 (s, 3H), 3.43-3.56 (m, 7H), 3.23-3.42 (m, 5H), 2.94-3.04 (m, 4H), 2.73-2.88 (m, 3H), 2.53-2.71 (m, 7H), 2.23-2.43 (m, 3H), 2.02-2.21 (m, 3H), 1.89-2.00 (m, 1H), 1.83 (d, J=10.4 Hz, 2H), 1.49-1.63 (m, 2H), 0.78 (s, 3H). [M+H].sup.+=1051.4.

Example 144: 3-(4-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxido-2,5-dihydrophosphol-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione

[0343] ##STR00195##

[0344] The titled compound was synthesized in a manner similar to that in Example 147 Step 14 from 1-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide and 3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione. .sup.1H NMR (500 MHz, DMSO) ? 11.25 (s, 1H), 10.88 (s, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.79-7.91 (m, 2H), 7.18-7.43 (m, 2H), 6.95 (d, J=10.1 Hz, 2H), 6.67 (s, 1H), 6.07 (d, J=30.6 Hz, 2H), 4.13 (dd, J=12.6, 5.0 Hz, 1H), 3.69 (s, 3H), 2.85-2.97 (m, 4H), 2.67-2.74 (m, 5H), 2.45-2.63 (m, 10H), 2.21-2.30 (m, 9H), 1.99-2.13 (m, 1H), 1.92-1.94 (m, 1H), 1.76 (d, J=10.9 Hz, 2H), 1.47 (dd, J=20.4, 11.4 Hz, 2H), 0.71 (s, 3H). [M+H].sup.+=982.3.

Example 145: 3-(6-(2-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxido-2,5-dihydrophosphol-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione

[0345] ##STR00196##

[0346] The titled compound was synthesized in a manner similar to that in Example 147 Step 14 from 1-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)-2,5-dihydrophosphole 1-oxide and 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde. .sup.1H NMR (500 MHz, DMSO) ? 11.19 (d, J=54.9 Hz, 2H), 8.25 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.86 (t, J=9.8 Hz, 2H), 7.31 (dd, J=44.2, 23.7 Hz, 3H), 7.09 (d, J=8.1 Hz, 11H), 7.00 (d, J=8.1 Hz, 11H), 6.67 (s, 1H), 6.07 (d, J=30.6 Hz, 2H), 5.28 (dd, J=12.9, 5.2 Hz, 1H), 3.69 (s, 3H), 2.44-3.02 (m, 23H), 2.21-2.30 (m, 6H), 2.2.01-2.09 (m, 1H), 1.75-1.77 (m, 2H), 1.43-1.50 (m, 2H), 0.71 (s, 3H). [M+H].sup.+=1003.3.

Example 146: 3-(4-(3-(4-(1-(4-((5-bromo-4-((2-methyl-5-(1-oxido-2,5-dihydrophosphol-1-yl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0347] ##STR00197##

[0348] The titled compound was synthesized in a procedure similar to Example 77. .sup.1H NMR (500 MHz, DMSO) ? 11.24 (s, 1H), 10.79 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.87 (dd, J=13.0, 9.4 Hz, 2H), 7.40-7.25 (m, 2H), 6.68 (s, 1H), 6.09 (dd, J=20.9, 14.5 Hz, 4H), 3.97 (t, J=7.6 Hz, 3H), 3.85 (t, J=6.3 Hz, 2H), 3.65-3.79 (m, 4H), 3.42 (s, 2H), 2.86-2.97 (m, 4H), 2.67-2.77 (m, 3H), 2.57-2.62 (m, 5H), 2.43-2.45 (m, 7H), 2.13-2.36 (m, 3H), 2.00-2.04 (m, 11H), 1.83-1.93 (m, 1H), 1.74-1.76 (m, 2H), 1.47-1.53 (m, 2H), 0.71 (s, 3H). [M+H].sup.+=1037.3.

Example 148: 3-(4-(3-(4-(1-(4-((5-bromo-4-((2-(1-oxidophospholan-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0349] ##STR00198##

[0350] To a solution of 1-(2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phospholane 1-oxide (50 mg, 0.07 mmol), 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (synthesized by the similar method of example 77)(33 mg, 0.1 mmol) and DIEA (26 mg, 0.2 mmol) in 10 mL DCM, 50% w.t. T.sub.3P in EtOAc solution (64 mg, 0.1 mmol) was added. The mixture was stirred at 25? C. for 16 hours. After LCMS showed the reaction was completed. The mixture was quenched with water (10 mL). The organic phase was concentrated in vacuum and purified by prep-HPLC with C-18 column chromatography (0.1% FA in water:acetonitrile=90:10-50:50 gradient elution) to afford product (13.9 mg, 19.3% yield). .sup.1H NMR (500 MHz, DMSO) ? 10.84 (s 11H), 10.57 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.37-7.51 (m, 3H), 7.17 (t, J=7.3 Hz, 1H), 6.76 (s, 2H), 6.17 (d, J=11.1 Hz, 2H), 4.02-4.05 (m, 3H), 3.80-3.93 (m, 3H), 3.76 (s, 3H), 3.50 (s, 3H), 2.99-3.02 (m, 2H), 2.63-2.81 (m, 3H), 2.54-2.55 (m, 4H), 2.38-2.48 (m, 4H), 1.84-2.13 (m, 12H), 1.56-1.63 (m, 2H), 1.01 (t, J=7.4 Hz, 3H). [M+H].sup.+=974.3.

[0351] Cell Degradation

[0352] Cell Treatment

[0353] 1a). BaF3-LTC (L858R/T790M/C797S) cells are seeded at 100000 cells/well in cell culture medium [RPMI1640 (Gibco, phenol red free, Cat #11835-030), 10% heat-inactive FBS, 1% PS (Gibco, Cat #10378)] in Corning 96 well plate (Cat #3799).

[0354] 1b). On day 1, H1975-clone #28 (Del19/T790M/C797S, homozygous) cells are seeded at 20000 cells/well and 30000 cells/well correspondingly in cell culture medium [RPMI1640 (Gibco, Cat #72400-047), 10% heat-inactive FBS, 1% PS (Gibco, Cat #10378)] in Corning 96 well plate (Cat #3599).

[0355] BaF3-LTC (L858R/T790M/C797S) cells are treated with compounds diluted in 0.2% DMSO cell culture medium and incubate for 16 h, 37? C., 5% CO.sub.2. H1975-#28 cells are treated with compounds diluted in 0.2% DMSO cell culture medium on day 2, incubate for 16 h, 37? C., 5% CO.sub.2, the final concentration of compounds in all assay is start with 10 uM, 4-fold dilution, total 8 doses were included.

[0356] HTRF Assay

[0357] After 16 h treatment, add HTRF lysis buffer to each well; seal the plate and incubate 1 hour at room temperature on a plate shaker. Once the cells are lysed, 16 ?L of cell lysate are transferred to a PE 384-well HTRF detection plate: 4 ?L of pre-mixed HTRF antibodies are added to each well; Cover the plate with a plate sealer, spin 1000 rpm for 1 min, Incubate overnight at room temperature; Read on BMG PheraStar with HTRF protocol (337 nm-665 nm-620 nm).

[0358] The inhibition (degradation) percentage of the compound was calculated by the following equation:

Inhibition percentage of Compound=100?100?(Signal?low control)/(High control?low control), [0359] wherein signal=each test compound group [0360] Low control=only lysis buffer without cells, indicating that EGFR is completely degraded; [0361] High control=Cell group with added DMSO and without compound, indicating microplate readings without EGFR degradation; [0362] Dmax is the maximum percentage of inhibition (degradation).

[0363] The IC.sub.50 (DC.sub.50) value of a compound can be obtained by fitting the following equation

Y=Bottom+(TOP?Bottom)/(1+((IC.sub.50/X){circumflex over ()}hillslope))

[0364] Wherein, X and Y are known values, and IC.sub.50. Hillslope, Top and Bottom are the parameters obtained by fitting with software. Y is the inhibition percentage (calculated from the equation), X is the concentration of the compound; IC.sub.50 is the concentration of the compound when the 50% inhibition is reached. The smaller the IC.sub.50 value is, the stronger the inhibitory ability of the compound is. Vice versa, the higher the IC.sub.50 value is, the weaker the ability the inhibitory ability of the compound is; Hillslope represents the slope of the fitted curve, generally around 1*; Bottom represents the minimum value of the curve obtained by data fitting, which is generally 0%?20%. Top represents the maximum value of the curve obtained by data fitting, which is generally 100%?20%. The experimental data were fitted by calculating and analyzing with Dotmatics data analysis software.

TABLE-US-00005 TABLE 1 Degradation (BaF3 and H1975 #28) result for Example 68 to Example 148 H1975 #28 BaF3 Example DC.sub.50(n.M) Dmax (%) DC.sub.50(nM) Dmax (%) 68 1.34 85.88 3.46 90.83 71 1.38 72.97 2.51 88.59 73 0.66 78.13 7.52 89.91 111 4.31 87.16 26.82 90.26 145 0.77 75.97 1.82 91.76 147 3.15 82.21 75.06 86.63 148 2.99 78.19 19.8 90.18

[0365] The foregoing examples and description of certain embodiments should be taken as illustrating, rather than as limiting the present invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims. All such variations are intended to be included within the scope of the present invention. All references cited are incorporated herein by reference in their entireties.

[0366] It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country.