Applications of Substituent Benzyloxy Group Containing Ether Compounds for Preparing Antitumor Drugs

Abstract

Disclosed are applications of substituent benzyloxy group containing ether compounds represented by general formula I for preparing antitumor drugs.

##STR00001##

The definition of the substituent groups in the formula I are provided in the specification.

The compounds having general formula I have desirable antitumor activity, particularly, and have excellent activity against leukemia strain HL-60, lung cancer A549, H157, H460, H520, bladder cancer T24, J82, prostate cancer LNCap, PC-3, rectal cancer HCT8, HCT116, RkO and the like.

Claims

1. A method of treating a subject having a cancer, which comprises administering to the subject a substituent benzyloxy group containing ether compound as an antitumor agent, said substituent benzyloxy group containing either compound having general formula I: ##STR00022## wherein: Ar is selected from one of the following groups, Ar1 to Ar16: ##STR00023## ##STR00024## Q is selected from one of the following groups, Q1 to Q22: ##STR00025## ##STR00026## R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6, are each independently H, halo, CN, NO.sub.2, OH, NH.sub.2, CHO, CO.sub.2H, CO.sub.2Na, CO.sub.2NH.sub.4, C.sub.1-C.sub.12alkyl, C.sub.1-C.sub.12haloalkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.1-C.sub.12alkoxy, C.sub.1-C.sub.12haloalkoxy, C.sub.1-C.sub.12alkylthio, C.sub.1-C.sub.12haloalkylthio, C.sub.1-C.sub.12alkoxyC.sub.1-C.sub.12alkyl, haloC.sub.1-C.sub.12alkoxyC.sub.1-C.sub.12alkyl, C.sub.1-C.sub.12alkoxyC.sub.1-C.sub.12alkoxy, haloC.sub.1-C.sub.12alkoxyC.sub.1-C.sub.12alkoxy, C.sub.1-C.sub.12alkylthioC.sub.1-C.sub.12alkyl, haloC.sub.1-C.sub.12alkylthioC.sub.1-C.sub.12alkyl, C.sub.1-C.sub.12alkylamino, C.sub.1-C.sub.12haloalkylamino, C.sub.2-C.sub.12dialkylamino, C.sub.2-C.sub.12halodialkylamino, piperidinyl, pyrrolidinyl, N-methylpiperidinyl, morpholinyl, C.sub.2-C.sub.12alkenyl, C.sub.2-C.sub.12haloalkenyl, C.sub.2-C.sub.12alkynyl, C.sub.2-C.sub.12haloalkynyl, C.sub.2-C.sub.12alkenyloxy, C.sub.2-C.sub.12haloalkenyloxy, C.sub.2-C.sub.12alkynyloxy, C.sub.2-C.sub.12haloalkynyloxy, C.sub.1-C.sub.12alkylsulfonyl, C.sub.1-C.sub.12haloalkylsulfonyl, C.sub.1-C.sub.12alkylsulfinyl, C.sub.1-C.sub.12haloalkylsulfinyl, C.sub.1-C.sub.12alkylcarbonyl, C.sub.1-C.sub.12haloalkylcarbonyl, C.sub.1-C.sub.12alkylcarbonyloxy, C.sub.1-C.sub.12alkylcarbonylamino, C.sub.1-C.sub.12alkylsulfonyloxy, C.sub.1-C.sub.12alkoxycarbonyl, C.sub.1-C.sub.12haloalkoxycarbonyl, C.sub.1-C.sub.12alkylaminosulfonyl, C.sub.1-C.sub.12alkoxycarbonylamino, C.sub.1-C.sub.12alkoxycarbonylC.sub.1-C.sub.12alkyl, C.sub.1-C.sub.12alkoxycarbonylC.sub.1-C.sub.12alkoxy, aminoC.sub.1-C.sub.12alkyl, C.sub.1-C.sub.12alkylaminoC.sub.1-C.sub.12alkyl, C.sub.2-C.sub.12dialkylaminoC.sub.1-C.sub.12alkyl, C(═O)NR.sub.10R.sub.11, OC(═O)NR.sub.10R.sub.11, C(═S)NR.sub.10R.sub.11, SO.sub.2NR.sub.10R.sub.11, C(═NOR.sub.9)R.sub.8, or R.sub.7; or R.sub.1 and R.sub.2 are linked with a carbon atom to form a five, six, or seven-membered ring; R.sub.7 is unsubstituted or substituted phenyl, phenyloxy, phenyloxy C.sub.1-C.sub.12alkyl, phenylcarbonyl, phenyloxycarbonyl, phenylaminocarbonyl, phenylC.sub.1-C.sub.12alkyl, phenylC.sub.1-C.sub.12alkoxy, phenylC.sub.1-C.sub.12alkoxyC.sub.1-C.sub.12alkyl, naphthyl, naphthyloxy, naphthyloxy C.sub.1-C.sub.12alkyl, naphthylcarbonyl, naphthyl C.sub.1-C.sub.12alkyl, naphthyl C.sub.1-C.sub.12alkoxy, naphthyl C.sub.1-C.sub.12alkoxyC.sub.1-C.sub.12alkyl, heteroaryl, heteroaryloxy, heteroarylC.sub.1-C.sub.12alkoxyC.sub.1-C.sub.12alkyl, heteroaryloxyC.sub.1-C.sub.12alkyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroarylC.sub.1-C.sub.12alkyl or heteroarylC.sub.1-C.sub.12alkoxy, which may be optionally substituted by 1 to 5 substituents selected from the group consisting of: halo, NO.sub.2, CN, SH, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6 halo alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6 halo alkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6 halo alkylthio, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 halo alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6 halo alkynyl, C.sub.3-C.sub.6alkenyloxy, C.sub.3-C.sub.6 halo alkenyloxy, C.sub.3-C.sub.6alkynyloxy, C.sub.3-C.sub.6 halo alkynyloxy, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6 halo alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.1-C.sub.6 halo alkylsulfonyl, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6 halo alkylcarbonyl, C.sub.1-C.sub.6alkylcarbonyloxy, C.sub.1-C.sub.6alkylcarbonylamino, C.sub.1-C.sub.6alkylsulfonyloxy, C.sub.1-C.sub.6alkoxycarbonyl, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkoxycarbonylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxycarbonylamino, C.sub.1-C.sub.6alkoxycarbonylC.sub.1-C.sub.6alkoxy, CHO, CO.sub.2H, CO.sub.2Na, CO.sub.2NH.sub.4, NR.sub.10R.sub.11, C(═O)NR.sub.10R.sub.11, OC(═O)NR.sub.10R.sub.11, C(═S)NR.sub.10R.sub.11, and SO.sub.2NR.sub.10R.sub.11; R.sub.8 and R.sub.9 are each independently H, C.sub.1-C.sub.6alkyl, aryl, or aryl C.sub.1-C.sub.6alkyl; R.sub.10 and R.sub.11 are each independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6 halo alkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6 halo alkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6 halo alkylthio, or C.sub.3-C.sub.8cycloalkyl; and stereoisomers thereof.

2. The method according to claim 1, wherein Ar is Ar1, Ar2, Ar3, Ar4, or Ar16; Q is Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, Q.sub.5, Q.sub.6, Q.sub.7, Q.sub.8, Q.sub.9, Q.sub.19, Q.sub.20, Q.sub.21, or Q.sub.22; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are each independently H, halo, CN, NO.sub.2, OH, NH.sub.2, CHO, CO2H, CO.sub.2Na, CO.sub.2NH.sub.4, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6haloalkylthio, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6alkoxy, haloC.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkylthioC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkylthioC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkylamino, C.sub.1-C.sub.6haloalkylamino, C.sub.2-C.sub.8dialkylamino, C.sub.2-C.sub.8halodialkylamino, piperidinyl, pyrrolidinyl, N-methylpiperidinyl, morpholinyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6haloalkynyl, C.sub.2-C.sub.6alkenyloxy, C.sub.2-C.sub.6haloalkenyloxy, C.sub.2-C.sub.6alkynyloxy, C.sub.2-C.sub.6haloalkynyloxy, C.sub.1-C.sub.6alkylsulfonyl, C.sub.1-C.sub.6haloalkylsulfonyl, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.8haloalkylsulfinyl, C.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6haloalkylcarbonyl, C.sub.1-C.sub.6alkylcarbonyloxy, C.sub.1-C.sub.6alkylcarbonylamino, C.sub.1-C.sub.6alkylsulfonyloxy, C.sub.1-C.sub.6alkoxycarbonyl, C.sub.1-C.sub.6haloalkoxycarbonyl, C.sub.1-C.sub.6alkylaminosulfonyl, C.sub.1-C.sub.6alkoxycarbonylamino, C.sub.1-C.sub.6alkoxycarbonylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxycarbonylC.sub.1-C.sub.6alkoxy, aminoC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkylaminoC.sub.1-C.sub.6alkyl, C.sub.2-C.sub.8dialkylaminoC.sub.1-C.sub.6alkyl, C(═O)NR.sub.10R.sub.11, OC(═O)NR.sub.10R.sub.11, C(═S)NR.sub.10R.sub.11, SO.sub.2NR.sub.10R.sub.11, C(═NOR.sub.9)R.sub.8, or R.sub.7; or R.sub.1 and R.sub.2 are linked with a carbon atom to form a five or six-membered ring; R.sub.7 is selected from unsubstituted or substituted phenyl, phenyloxy, phenyloxy C.sub.1-C.sub.6alkyl, phenylcarbonyl, phenyloxycarbonyl, phenylaminocarbonyl, phenylC.sub.1-C.sub.6alkyl, phenylC.sub.1-C.sub.6alkoxy, phenylC.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6alkyl, naphthyl, naphthyloxy, naphthyloxy C.sub.1-C.sub.6alkyl, naphthyl carbonyl, naphthyl C.sub.1-C.sub.6alkyl, naphthyl C.sub.1-C.sub.6alkoxy, naphthylC.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6alkyl, heteroaryl, heteroaryloxy, heteroarylC.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6alkyl, heteroaryloxyC.sub.1-C.sub.6alkyl, heteroaryl carbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroarylC.sub.1-C.sub.6alkyl or heteroarylC.sub.1-C.sub.6alkoxy, which is further mutually independently may be optionally substituted by 1 to 5 substituents selected from the group consisting of: halo, NO.sub.2, CN, SH, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4 halo alkoxy, C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4 halo alkylthio, C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4 halo alkenyl, C.sub.2-C.sub.4alkynyl, C.sub.2-C.sub.4 halo alkynyl, C.sub.3-C.sub.4alkenyloxy, C.sub.3-C.sub.4halo alkenyloxy, C.sub.3-C.sub.4alkynyloxy, C.sub.3-C.sub.4 halo alkynyloxy, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4 halo alkylsulfinyl, C.sub.1-C.sub.4alkylsulfonyl, C.sub.1-C.sub.4 halo alkylsulfonyl, C.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4 halo alkylcarbonyl, C.sub.1-C.sub.4alkylcarbonyloxy, C.sub.1-C.sub.4alkylcarbonylamino, C.sub.1-C.sub.4alkylsulfonyloxy, C.sub.1-C.sub.4alkoxycarbonyl, C.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkoxycarbonylC.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxycarbonylamino, C.sub.1-C.sub.4alkoxycarbonylC.sub.1-C.sub.4alkoxy, CHO, CO.sub.2H, CO.sub.2Na, CO.sub.2NH.sub.4, NR.sub.10R.sub.11, C(═O)NR.sub.10R.sub.11, OC(═O)NR.sub.10R.sub.11, C(═S)NR.sub.10R.sub.11, and SO.sub.2NR.sub.10R.sub.11; R.sub.8 and R.sub.9 are each independently H, C.sub.1-C.sub.4alkyl, aryl, or aryl C.sub.1-C.sub.4alkyl; R.sub.10 and R.sub.11 are each independently H, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4 halo alkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4 halo alkoxy, C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4 halo alkylthio, or C.sub.3-C.sub.6cycloalkyl.

3. The method according to claim 2, wherein Ar is Ar1, Ar2, Ar3, Ar4, or Ar16; Q is Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, Q.sub.5, Q.sub.6, Q.sub.7, Q.sub.8, Q.sub.9, Q.sub.19, Q.sub.20, Q.sub.21, or Q.sub.22; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are each independently H, halo, CN, NO.sub.2, OH, NH.sub.2, CHO, CO.sub.2H, CO.sub.2Na, CO.sub.2NH.sub.4, C.sub.1-.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4haloalkylthio, C.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkyl, haloC.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkoxy, haloC.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylthioC.sub.1-C.sub.4alkyl, haloC.sub.1-C.sub.4alkylthioC.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkylamino, C.sub.1-C.sub.4haloalkylamino, C.sub.2-C.sub.6dialkylamino, C.sub.2-C.sub.6halodialkylamino, piperidinyl, pyrrolidinyl, N-methylpiperidinyl, morpholinyl, C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4haloalkenyl, C.sub.2-C.sub.4alkynyl, C.sub.2-C.sub.4haloalkynyl, C.sub.2-C.sub.4alkenyloxy, C.sub.2-C.sub.4haloalkenyloxy, C.sub.2-C.sub.4alkynyloxy, C.sub.2-C.sub.4haloalkynyloxy, C.sub.1-C.sub.4alkylsulfonyl, C.sub.1-C.sub.4haloalkylsulfonyl, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4haloalkylcarbonyl, C.sub.1-C.sub.4alkylcarbonyloxy, C.sub.1-C.sub.4alkylcarbonylamino, C.sub.1-C.sub.4alkylsulfonyloxy, C.sub.1-C.sub.4alkoxycarbonyl, C.sub.1-C.sub.4haloalkoxycarbonyl, C.sub.1-C.sub.4alkylaminosulfonyl, C.sub.1-C.sub.4alkoxycarbonylamino, C.sub.1-C.sub.4alkoxycarbonylC.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxycarbonylC.sub.1-C.sub.4alkoxy, aminoC.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkylaminoC.sub.1-C.sub.4alkyl, C.sub.2-C.sub.6dialkylaminoC.sub.1-C.sub.4alkyl, C(═O)NR.sub.10R.sub.11, OC(═O)NR.sub.10R.sub.11, C(═S)NR.sub.10R.sub.11, SO.sub.2NR.sub.10R.sub.11, C(═NOR.sub.9)R.sub.8, or R.sub.7; or R.sub.1 and R.sub.2 are linked with a carbon atom to form a saturated five or six-membered ring; R.sub.7 is unsubstituted or substituted phenyl, phenyloxy, phenyloxy C.sub.1-C.sub.4alkyl, phenylcarbonyl, phenyloxycarbonyl, phenylaminocarbonyl, phenylC.sub.1-C.sub.4alkyl, phenylC.sub.1-C.sub.4alkoxy, phenylC.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkyl, naphthyl, naphthyloxy, naphthyloxy C.sub.1-C.sub.4alkyl, naphthyl carbonyl, naphthyl C.sub.1-C.sub.4alkyl, naphthyl C.sub.1-C.sub.4alkoxy, naphthylC.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkyl, heteroaryl, heteroaryloxy, heteroarylC.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkyl, heteroaryloxyC.sub.1-C.sub.4alkyl, heteroaryl carbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C.sub.1-C.sub.4alkyl, or heteroarylC.sub.1-C.sub.4alkoxy, which may be optionally substituted by 1 to 5 substituents selected from the group consisting of: halo, NO.sub.2, CN, SH, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4 halo alkylthio, C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4 halo alkenyl, C.sub.2-C.sub.4alkynyl, C.sub.2-C.sub.4 halo alkynyl, C.sub.3-C.sub.4alkenyloxy, C.sub.3-C.sub.4halo alkenyloxy, C.sub.3-C.sub.4alkynyloxy, C.sub.3-C.sub.4 haloalkynyloxy, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4 halo alkylsulfinyl, C.sub.1-C.sub.4alkylsulfonyl, C.sub.1-C.sub.4 halo alkylsulfonyl, C.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4 halo alkylcarbonyl, C.sub.1-C.sub.4alkylcarbonyloxy, C.sub.1-C.sub.4alkylcarbonylamino, C.sub.1-C.sub.4alkylsulfonyloxy, C.sub.1-C.sub.4alkoxycarbonyl, C.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkoxycarbonylC.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxycarbonylamino, C.sub.1-C.sub.4alkoxycarbonylC.sub.1-C.sub.4alkoxy, CHO, CO.sub.2H, CO.sub.2Na, CO.sub.2NH.sub.4, NR.sub.10R.sub.11, C(═O)NR.sub.10R.sub.11, OC(═O)NR.sub.10R.sub.11, C(═S)NR.sub.10R.sub.11, and SO.sub.2NR.sub.10R.sub.11; R.sub.8 and R.sub.9 is are each independently H, C.sub.1-C.sub.4alkyl, aryl, or aryl C.sub.1-C.sub.4alkyl; R.sub.10 and R.sub.11 are each independently H, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4 haloalkylthio, or C.sub.3-C.sub.6cycloalkyl.

4. The method according to claim 3, wherein Ar is Ar1, Ar2, Ar3, or Ar16; Q is Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, Q.sub.5, Q.sub.6, Q.sub.7, or Q.sub.8; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are each independently H, halo, CN, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4alkoxyC.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkylamino, C.sub.2-C.sub.6dialkylamino, C.sub.1-C.sub.4alkylsulfonyl, or R.sub.7; or R.sub.1 and R.sub.2 are linked with a carbon atom to form a saturated five or six-membered ring; R.sub.7 is unsubstituted or substituted phenyl, benzyl, phenylethyl or heteroaryl, which may be optionally substituted by 1 to 5 substituents selected from the group consisting of: halo, NO.sub.2, CN, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4alkoxy, and C.sub.1-C.sub.4 haloalkoxy.

5. The method according to claim 4, wherein Ar is Ar1, Ar2, Ar3, or Ar16; Q is Q.sub.1; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are each independently H, halo, CN, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.4haloalkyl, or R.sub.7; or R.sub.1 and R.sub.2 are linked with a carbon atom to form a saturated five or six-membered ring; R.sub.7 is unsubstituted or substituted phenyl, benzyl, or heteroaryl, which may be optionally substituted by 1 to 5 substituents selected from the group consisting of: halo, NO.sub.2, CN, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4alkoxy, and C.sub.1-C.sub.4 haloalkoxy.

6. The method according to claim 5, wherein Ar is Ar3 or Ar16; Q is Q.sub.1; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are each independently H, halo, CN, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, or R.sub.7; or R.sub.1 and R.sub.2 are linked with a carbon atom to form a saturated five or six-membered ring; R.sub.7 is unsubstituted or substituted phenyl, benzyl, or heteroaryl, which may be optionally substituted by 1 to 5 substituents selected from the group consisting of: halo, NO.sub.2, CN, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4alkoxy, and C.sub.1-C.sub.4 haloalkoxy.

7. The method according to claim 6, wherein Ar is Ar3 or Ar16; Q is Q.sub.1; R.sub.1 is H, halo, or C.sub.1-C.sub.6alkyl; R.sub.2 is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, or R.sub.7; or R.sub.1 and R.sub.2 are linked with a carbon atom to form a saturated five or six-membered ring; R.sub.3 and R.sub.4 are H; R.sub.6 is selected from H or C.sub.1-C.sub.4alkyl; R.sub.7 is selected from unsubstituted or substituted phenyl, which may be optionally substituted by 1 to 3 substituents selected from the group consisting of: halo, CN, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4alkoxy, and C.sub.1-C.sub.4 haloalkoxy.

8. The method according to claim 7, wherein Ar is selected from Ar3 or Ar16; Q is Q.sub.1; R.sub.1 is H, halo, or C.sub.1-C.sub.6alkyl; R.sub.2 is C.sub.1-C.sub.4alkyl or R.sub.7; or R.sub.1 and R.sub.2 are linked with a carbon atom to form a saturated five or six-membered ring; R.sub.3 and R.sub.4 are H; R.sub.6 is H or C.sub.1-C.sub.4alkyl; R.sub.7 is unsubstituted or substituted phenyl, which may be optionally substituted by 1 to 2 substituents selected from the group consisting of: halo, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, and C.sub.1-C.sub.4 haloalkoxy.

9. The method according to claim 8, wherein Ar is selected from Ar3 or Ar16; Q is Q.sub.1; R.sub.1 is H, F, or C.sub.1-C.sub.4alkyl; R.sub.2 is C.sub.1-C.sub.4alkyl or phenyl; or R.sub.1 and R.sub.2 are linked with a carbon atom to form a saturated six-membered ring; R.sub.3 and R.sub.4 are H; R.sub.6 is H or CH.sub.3.

10. The method according to claim 9, wherein Ar is selected from Ar3 or Ar16; Q is Q.sub.1; R.sub.1 is H or C.sub.1-C.sub.4alkyl; R.sub.2 is CH.sub.3 or phenyl; or R.sub.1 and R.sub.2 are linked with a carbon atom to form a saturated six-membered ring; R.sub.3, R.sub.4, R.sub.6 are H.

11. The method according to claim 1, wherein the substituent benzyloxy group containing ether compound is administered, as an active ingredient orally or parentally, or by implantable medication pump administration.

12. The method according to claim 11, wherein the substituent benzyloxy group containing ether compound is administered as an active ingredient in the form of a tablet, a pill, a capsule, a granule, a syrup, an injection, or a freeze-dried powder injection.

13. The method according to claim 12, two of two or more of the substituted benzyloxy group containing ether compounds is provided as the active ingredient.

14. The method according to claim 1, wherein the cancer is selected from the group consisting of colon cancer, liver cancer, lymph cancer, lung cancer, esophageal cancer, breast cancer, central nervous system cancer, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostatic cancer, pancreatic cancer, bladder cancer, rectal cancer, and stomach cancer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0173] The present invention is illustrated by the following examples, but without being restricted thereby. (All raw materials are commercially available unless otherwise specified.)

Antitumor Activity Bioassay

[0174] In vitro Cell inhibition assay is as follows:

[0175] The human cancer cell lines used for this assay were bladder cancer J82, T24, prostate cancer LNCap, PC-3, lung cancer A549, H157, H460, H520, colon cancer HCT8, HCT116, RkO, and leukemia HL-60, etc.

Example 1

[0176] In vitro cell culture technology was selected for the determination of inhibition rate bladder cancer cell lines J82 and T24, prostate cancer cell lines LNCap and PC-3, lung cancer cell lines A549, H157, H460 and H520. 1000 to 3000 cells were inoculated to 24-well plate, followed by addition of 1 mL culture medium well known to researchers in this field to each well, the cells were cultured in 5% incubator for 24 hours at 37° C., then the different concentration compounds and controls were added to each well. It should be noted that the added volume is not more than 0.5% of total volume. After completion of addition, the cells continued being cultured in incubator for one week, the culture medium was removed and washed by cold PBS of 1 mL once, and then fixed for 10 minutes at room temperature with 1% formalin, followed by wash with PBS of 1 mL. After fixation, stain was carried out with 0.1% crystal violet for 30 minutes. 0.1% crystal violet was recycled. The stained cells were washed gently with deionized water, dried at room temperature and kepted. The inhibition rate was calculated according to the foiling equation. The controls are Selumetinib (AZD6244), Gefitinib, Cisplatin.

[0177] Inhibition rate=number of left cells each treatment/number of left cells of untreated control×100%

[0178] At the concentration of 10 μM, the inhibition rate of compounds of this invention against all tested cell lines attached 90%-100%, some of them were further tested at lower concentration and the comparative bioassay was conducted with the controls selumetinib (AZD6244), gefitinib, Cisplatin at the same time, part of test results are listed in Table 55:

TABLE-US-00007 TABLE 55 Inhibition rate on human cancer cells Concentration (μM)/Inhibition (%) Cell line Compound No 5.0 2.5 1.0 0.5 0.25 J82 28-5 100 100 80 / / 28-72 100 100 95 90 70 Pyraoxystrobin 100 100 100 100 70 selumetinib 70 / / / / Cisplatin 20 5 0 0 0 Compound A 100 100 95 50 0 Compound B 100 95 90 50 0 Flufenoxystrobin Azoxystrobin 0 / / / / T24 28-5 100 100 100 100 100 28-72 100 100 100 100 100 Pyraoxystrobin 100 100 100 100 100 Selumetinib 70 / / / / Cisplatin 20 5 0 0 0 Compound A 100 100 100 0 / Compourtd B 100 100 100 5 0 Flufenoxystrobin Azoxystrobin 0 / / / / LNCap 28-5 100 100 100 / / 28-72 100 100 100 100 100 Pyraoxystrobin 100 100 100 100 100 selumetinib 20 / / / / Compound A 100 100 100 0 / Compourtd B 100 50 0 / / Flufenoxystrobin Azoxystrobin 0 / / / / PC-3 28-5 100 100 100 / / 28-72 100 100 100 100 100 Pyraoxystrobin 100 100 100 100 100 Selumetinib 0 / / / / Compound A 100 100 85 0 / Compourtd B 100 100 50 / / Flufenoxystrobin Azoxystrobin 0 / / / / A549 28-5 100 100 80 / / 28-7 90 70 / / / 28-12 100 95 80 / / 28-18 100 100 100 90 / 28-27 95 90 80 / / 28-29 95 / / / / 28-33 99 95 80 / / 28-34 100 95 90 / / 28-50 90 / / / / 28-52 100 100 95 90 / 28-72 100 100 95 90 / 28-75 90 / / / / 28-126 90 85 / / / 28-128 100 100 100 100 70 28-129 100 100 100 95 90 28-132 90 / / / / 28-133 100 100 / / / 28-134 100 100 28-135 80 / / / / 28-136 100 100 / / / 28-137 100 100 / / / 28-137 100 100 / / / Selumetinib 10 0 0 0 0 Gefitinib 20 10 0 0 0 Cisplatin 80 30 5 0 0 H157 28-5 100 100 100 100 / 28-72 100 100 100 100 >90 AZD6244 20 / / / / H460 28-2 95 / / / / 28-5 100 100 100 100 / 28-7 95 80 / / / 28-12 95 90 75 / / 28-18 95 95 95 90 80 28-27 95 95 80 / / 28-29 95 90 70 / / 28-33 95 95 90 / / 28-34 95 95 93 / / 28-41 85 75 / / / 28-50 95 90 70 / / 28-52 100 100 100 90 60 28-72 100 100 100 100 95 28-75 95 90 70 / / 28-124 75 / / / / 28-126 95 90 / / / 28-128 100 100 100 100 80 28-129 100 100 95 70 / 32-5 95 / / / / 32-6 85 / / / / Selumetinib 60 0 0 0 0 Gefitinib 95 0 0 0 0 Cisplatin 90 30 5 0 0 H520 28-5 100 100 90 80 70 28-7 100 80 / / / 28-12 100 100 50 / / 28-18 100 100 100 95 50 28-27 100 100 100 95 / 28-29 100 70 70 40 30 28-33 100 90 / / / 28-34 100 100 99 70 / 28-41 70 / / / / 28-50 100 80 60 50 30 28-52 100 100 100 100 70 28-72 100 100 100 100 >90 28-75 100 80 / / / 28-124 70 / / / / 28-126 95 90 70 / / 28-128 100 100 100 100 70 28-129 100 100 100 95 85 Selumetinib 20 / / / / Gefitinib 5 0 0 0 0 Cisplatin 50 30 20 5 0 HCT 8 28-72 100 100 100 95 / 28-128 100 100 100 100 95 28-129 100 100 100 95 80 Selumetinib 50 40 20 / / Gefitinib / 10 5 0 / Cisplatin 90 70 50 10 5 HCT 116 28-72 100 100 99 95 80 28-128 100 100 100 100 95 28-129 100 100 100 95 90 Selumetinib 90 85 80 75 50 Gefitinib 30 5 0 0 0 Cisplatin 50 20 5 0 0 RkO 28-72 100 100 100 100 95 28-128 100 100 100 100 99 28-129 100 100 100 99 85 Selumetinib 95 90 85 80 30 Gefitinib / 80 75 70 50 Cisplatin 70 50 10 5 0 Note: 1.“/” stands for no data. 2.bladder cancer cell lines J82    T24, prostate cancer cell lines LNCap    PC-3, lung cancer cell lines A549, H157    H460    H520, clon cancer cell lines HCT8, HCT116, RkO, the culture medium for all cell lines is RMPI-1640.

Example 2

[0179] The inhibition rate of human leukemia HL-60 cells was evaluated by regular MTT method. The human leukemia HL-60 cells were picked up from cell incubator, after washed for twice using PBS, cells were digested by 0.25% trypsin, and then add medium to terminate the digestion. After cells were collected using centrifuge and re-suspended, counting cells under inverted microscope and adding medium to make a density which was 5×10.sup.4 cells/mL. After 100 μL aliquots were added to each well of 96-well microtiter plates, cells were cultured in 5% incubator for overnight at 37° C., then the different concentration compounds were added to each well. After incubation for 48 h, MTT solution was added to each well and plates were then incubated for 4 h. The MTT tetrazolium was reduced to formazan by living cells. Then the formazan crystals were dissolved though adding DMSO to each well. The absorbance was read at 570 nm with a microplate reader.

[0180] Part of the test results are listed in Table 56:

TABLE-US-00008 TABLE 56 Proliferation inhibitory effect on human leukemia HL-60 cell (%) Concentration (μM) Compound No. 100 10 1  2-1 48.8 0 0 28-2 71.3 49.2 6.0 28-3 58.8 33.4 4.1 28-5 73.8 59.3 31.7  28-6 52.0 53.0 48.2 28-7 83.9 71.0 42.3 28-24 86.7 44.5 10.8 28-27 83.9 79.9 59.0 28-38 63.7 72.9 77.5 28-50 84.8 83.1 47.1 28-68 84.4 62.0 54.6 28-71 50.3 48.2 40.9 28-72 54.4 47.9 45.3 28-79 71.2 53.1 28.8 28-124 27.8 29.3 0.5 28-125 85.0 73.8 47.0 15-22 86.8 51.8 50.3 Note: the culture medium for human leukemia HL-60 is OPTI-MEM.