COMPOUND FOR INHIBITING AND INDUCING DEGRADATION OF EGFR KINASE

Abstract

Provided is an EGFR kinase inhibitor according to general formula (I) and a pharmaceutical composition containing the inhibitor. The invention can be used to treat diseases related to EGFR kinase, such as cancer. Also provided is a preparation and use of the above inhibitor.

##STR00001##

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof: ##STR00333## wherein ----- represents single bond or double bond; ----- represents that the point of attachment to the rest of the molecule can be located at an available point of a ring; Z.sub.1 is O, S, N or C atom, which is optionally substituted with one or two R.sub.Z1; Z.sub.2 is O, S, N or C atom, which is optionally substituted with one or two R.sub.Z2; Z.sub.3 is O, S, N or C atom, which is optionally substituted with one or two R.sub.Z3; with the proviso that when ----- represents double bond, Z.sub.2 is N or C atom, and Z.sub.3 is N or C atom; Z.sub.4 is N or CR.sub.Z4; Z.sub.5 is N or CRzs; R.sub.a, R.sub.b and R.sub.c are independently H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.N1 is H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.Z1 is absent, H, CN, halogen, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl; or two R.sub.Z1 are taken together with Z.sub.1 to form C=O; R.sub.Z2 is absent, H, CN, halogen, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl; R.sub.Z3 is absent, H, CN, halogen, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl; or two R.sub.Z3 are taken together with Z.sub.3 to form C=O; R.sub.Z4 is H, CN, halogen, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl; R.sub.Z5 is H, CN, halogen, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl; L.sub.1 is selected from bond, -O-, -S(O).sub.p-, -NR.sup.#-, -CR.sup.#R.sup.#′- or -C.sub.aR#R#′ -C.sub.bR#R#′-; L.sub.2 is selected from bond, -O-, -S(O).sub.p-, -NR.sup.#-, -CR.sup.#R.sup.#′- or -C.sub.aR#R#′-C.sub.bR#R#′-; wherein any one of C.sub.aR.sup.#R.sup.#′ or C.sub.bR.sup.#R.sup.#′ can be replaced by O, S(O).sub.p or NR.sup.#, and when any one of C.sub.aR#R#′ or C.sub.bR.sup.#R.sup.#′ is replaced by O, S or NR.sup.#, the other of C.sub.aR#R#′ or C.sub.bR.sup.#R.sup.#′ can further be replaced by S(O).sub.q; E is independently selected from: -C.sub.cR.sup.#R.sup.#′-C.sub.dR.sup.#R.sup.#′-C.sub.eR.sup.#R.sup.#′ or ##STR00334## wherein any one of CcR.sup.#R.sup.#′, C.sub.aR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′, or both of C.sub.cR.sup.#R.sup.#′ and CeR.sup.#R.sup.#′ can be replaced by O, S(O).sub.p or NR.sup.#, and when any one of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′ is replaced by O, S or NR.sup.#, the other one or two of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′ adjacent to it can further be replaced by S(O).sub.q; H.sub.4 and H.sub.5 are N or C atom; p is 0, 1 or 2; q is 1 or 2; R.sup.# is H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; R.sup.#′ is H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; or, R.sup.# and R.sup.# on adjacent atoms can be taken together to form bond, and R.sup.#′ and R.sup.#′ on adjacent atoms can be taken together to form bond; or, R.sup.# and R.sup.#′ on the same or different atoms can be taken together to form =O; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; X.sub.1 is C or N atom; X.sub.2 is C or N atom; X.sub.3 is C or N atom; X.sub.4 is O, S, C or N atom, which is optionally substituted with one or two R.sub.2; X.sub.5 is O, S, C or N atom; X.sub.6 is C or N atom; X.sub.7 is O, S, C or N atom; R.sub.1 is H, CN, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; R.sub.2 is H, CN, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; R.sub.N2 is H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; the definition of L.sub.1′ is the same as that of L.sub.1; the definition of L.sub.2′ is the same as that of L.sub.2; the definition of E′ is the same as that of E; the definition of m′ is the same as that of m; R.sub.s1 is selected from H, CN, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.s2 is selected from H, CN, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; R.sub.s3 is selected from H, CN, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.s4 is selected from H, CN, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; s1 is 0, 1, 2 or 3; s2 is 0, 1, 2 or 3; s3 is 0, 1 or 2; s4 is 0, 1, 2, 3, 4 or 5.

2. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1, wherein Z.sub.4 and Z.sub.2 are connected to form a compound of formula (II) below: ##STR00335## wherein all the groups are as defined in claim 1; alternatively, custom-character represents single bond or double bond; ----- represents that the point of attachment to the rest of the molecule can be located at an available point of a ring; Z.sub.1 is N or C atom, which is optionally substituted with one or two R.sub.z1; Z.sub.2 is N or C atom, which is optionally substituted with R.sub.Z2; Z.sub.3 is N or C atom, which is optionally substituted with one or two R.sub.Z3; and other groups are as defined in claim 1.

3. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1 , which is a compound of general formula (VI) or (VI′) below: ##STR00336## ##STR00337## wherein all the groups are as defined in claim 1.

4. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1, wherein ##STR00338## is selected from: ##STR00339## ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## .

5. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1 , wherein L.sub.1, L.sub.2, L.sub.1′ and L.sub.2′ are each independently selected from bond, —O—, —S—, —S(O)—, —S(O).sub.2—, —NH—, —N (Me)—, —N(CF.sub.3)—, —CH.sub.2—, —CH(C1)—, —CH(F)—, —CF.sub.2—, —CH (CF.sub.3)—, —C(O)—, —CH.sub.2CH.sub.2—, —CH═CH—, —C═C—, —OCH.sub.2—, —CH.sub.2O—, —SCH.sub.2—, —CH.sub.2S—, —S(O)CH.sub.2—, —CH.sub.2S(O)—, —S(O).sub.2CH.sub.2—, —CH.sub.2S(O).sub.2—, —NHCH.sub.2—, —N (Me)CH.sub.2—, —CH.sub.2NH—, —CH.sub.2N (Me)—, —C(O)CH.sub.2—, —CH.sub.2C(O)—, —C(O)CMe.sub.2—, —CMe.sub.2C(O)—, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —NHC(O)—, —N (Me)C(O)—, —C(O)NH— or —C(O)N (Me)—.

6. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1 , wherein E and E′ are independently selected from bond, —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH═CH—, —CH═CHCH.sub.2—, —CH.sub.2C≡C—, —C≡CCH.sub.2—,—CH.sub.2CH.sub.2C(O)—, —CH.sub.2C(O)CH.sub.2—, —C(O)CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2S(O).sub.2—, —CH.sub.2S(O).sub.2CH.sub.2—, —S(O).sub.2CH.sub.2CH.sub.2—, —C(O)CH═CH—, —C(O)C═C—, —CH.sub.2CH.sub.2O—, —CH.sub.2OCH.sub.2—, —OCH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2S—, —CH.sub.2SCH.sub.2—, —SCH.sub.2CH.sub.2—, —C(O)CH.sub.2O—, —OCH.sub.2C(O)—, —CH.sub.2C(O)O—, —C(O)CH.sub.2S—, —SCH.sub.2C(O)—, —CH.sub.2C(O)S—, —OC(O)CH.sub.2—, —C(O)OCH.sub.2—, —CH.sub.2OC(O)—, —SC(O)CH.sub.2—, —C(O)SCH.sub.2—, —CH.sub.2SC(O)—, —CH.sub.2CH.sub.2NH—, —CH.sub.2NHCH.sub.2—, —NHCH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2NMe—, —CH.sub.2NMeCH.sub.2—, —NMeCH.sub.2CH.sub.2—, —C(O)CH.sub.2NH—, —NHCH.sub.2C(O)—, —CH.sub.2C(O)NH—, —NHC(O)CH.sub.2—, —C(O)NHCH.sub.2—, —CH.sub.2NHC(O)—, ##STR00368## ##STR00369## ##STR00370## .

7. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1 , wherein the ring where X.sub.4, X.sub.5, X.sub.6 and X.sub.7 are located is ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## .

8. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1, wherein ##STR00386## is selected from: ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407## ##STR00408## ##STR00409## ##STR00410## .

9. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1 , which is a compound of general formula (VIII) below: wherein ##STR00411## Z.sub.1 is O, S, N or C atom, which is optionally substituted with one or two R.sub.Z1; wherein R.sub.Z1 is H, CN, halogen, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl; or two R.sub.Z1 are taken together with Z.sub.1 to form C=O; L.sub.1 is selected from bond, -O-, -NR.sup.#-, -CR.sup.#R.sup.#’- or -C.sub.aR.sup.#R.sup.#′C.sub.bR.sup.#R.sup.#′-; L.sub.3 is selected from bond, -O-, -NR.sup.#-, -CR.sup.#R.sup.#′- or -C.sub.aR.sup.#R.sup.#′C.sub.bR.sup.#R.sup.#′-; wherein any one of C.sub.aR.sup.#R.sup.#′ or C.sub.bR.sup.#R.sup.#′ can be replaced by O, S(O).sub.p or NR.sup.#, and when any one of C.sub.aR.sup.#R.sup.#′ or C.sub.bR.sup.#R.sup.#′ is replaced by O, S or NR.sup.#, the other of C.sub.aR#R#′ or C.sub.bR.sup.#R.sup.#′ can further be replaced by S(O).sub.q; E is independently -C.sub.cR.sup.#R.sup.#′-C.sub.dR.sup.#R.sup.#′-C.sub.eR.sup.#R.sup.#′; wherein any one of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′, or both of C.sub.cR.sup.#R.sup.#′ and C.sub.eR.sup.#R.sup.#′ can be replaced by O, S(O).sub.p or NR.sup.#, and when any one of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′ is replaced by O, S or NR.sup.#, the other one or two of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′ adjacent to it can further be replaced by S(O).sub.q; p is 0, 1 or 2; q is 1 or 2; R.sup.# is H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; R.sup.#′ is H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; or, R.sup.# and R.sup.# on adjacent atoms can be taken together to form bond, and R.sup.#′ and R.sup.#′ on adjacent atoms can be taken together to form bond; or, R.sup.# and R.sup.#′ on the same atom can be taken together to form =O; m is 1, 2 or 3.

10. The compound of general formula (VIII), or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 9, wherein Z.sub.1 is —CH.sub.2— or —C(O)—; L.sub.1 is selected from bond, —O—, —NH—, —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH═CH— or —C═C—; E is independently —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH═CH—, —CH═CHCH.sub.2—, —CH.sub.2C≡C—, —C≡CCH.sub.2-,—CH.sub.2CH.sub.2O—, —CH.sub.2OCH.sub.2—, —OCH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2NH—, —CH.sub.2NHCH.sub.2—, —NHCH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2C(O)—, —CH.sub.2C(O)CH.sub.2—, —C(O)CH.sub.2CH.sub.2—, —CH.sub.2OC(O)—, —CH.sub.2C(O)O—, —OC(O)CH.sub.2—, —C(O)OCH.sub.2—, —CH.sub.2NHC(O)—, —CH.sub.2C(O)NH—, —NHC(O)CH.sub.2—, —C(O)NHCH.sub.2—, —OCH.sub.2C(O)—, —C(O)CH.sub.2O—, —NHCH.sub.2C(O)— or —C(O)CH.sub.2NH—; L.sub.3 is selected from bond, —O—, —NH—, —CH.sub.2—, —C(O)—, —CH.sub.2CH.sub.2—, —C(O)CH.sub.2— or —CH.sub.2C(O)—; m is 1, 2 or 3.

11. The compound of general formula (VIII), or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 9, wherein Z.sub.1 is —CH.sub.2— or —C(O)—; L.sub.1 is selected from bond, —O—, —NH—, —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH═CH— or —C═C—; E is independently —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH═CH—, —CH═CHCH.sub.2—, —CH.sub.2C≡C— or —C≡CCH.sub.2-; L.sub.3 is selected from bond, -O-, -NH-, -CH.sub.2- or -C(O)-; m is 1, 2 or 3.

12. The compound of general formula (VIII), or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 9, wherein Z.sub.1 is —CH.sub.2— or —C(O)—; L.sub.1 is selected from bond, -O-, -NH-, -CH.sub.2-, -CH.sub.2CH.sub.2- or -C=C-; E is independently —CH.sub.2CH.sub.2CH.sub.2—; L.sub.3 is selected from bond, —CH.sub.2— or —C(O)—; m is 1 or 2.

13. The compound of general formula (VIII), or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 9, wherein Z.sub.1 is —CH.sub.2—; L.sub.1 is selected from bond, —CH.sub.2—, —CH.sub.2CH.sub.2— or —C═C—; E is independently —CH.sub.2CH.sub.2CH.sub.2—; L.sub.3 is selected from bond or —CH.sub.2—; m is 1 or 2.

14. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1 , which is a compound of general formula (VIII) below: wherein ##STR00412## Z.sub.1 is O, S, N or C atom, which is optionally substituted with one or two R.sub.Z1; R.sub.Z1 is H, CN, halogen, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl; or two R.sub.Z1 are taken together with Z.sub.1 to form C=O; L.sub.1 is selected from bond, -O-, -NR.sup.#-, -CR.sup.#R.sup.#′- or -C.sub.aR.sup.#R.sup.#′C.sub.bR.sup.#R.sup.#′-; L.sub.3 is selected from bond, -O-, -NR.sup.#-, -CR.sup.#R.sup.#′- or -C.sub.aR.sup.#R.sup.#′C.sub.bR.sup.#R.sup.#′-; E is -C.sub.cR.sup.#R.sup.#′-C.sub.dR.sup.#R.sup.#′-C.sub.eR.sup.#R.sup.#′; wherein any one of C.sub.cR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′ can be replaced by O, S(O).sub.p or NR.sup.#; p is 0, 1 or 2; R.sup.# is H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; R.sup.#′ is H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; or, R.sup.# and R.sup.# on adjacent atoms can be taken together to form bond, and R.sup.#′ and R.sup.#′ on adjacent atoms can be taken together to form bond; or, R.sup.# and R.sup.#′ on the same atom can be taken together to form =O; m is 1; alternatively, wherein Z.sub.1 is -CH.sub.2- or -C(O)-; L.sub.1 is selected from bond, -O-, -NH-, -CH.sub.2-, -CH.sub.2CH.sub.2-, -CH=CH- or -C≡C-; E is —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH═CH—, —CH═CHCH.sub.2—, —CH.sub.2C≡C-; —C≡CCH.sub.2-;—CH.sub.2CH.sub.2C(O)—, —CH.sub.2C(O)CH.sub.2—, —C(O)CH.sub.2CH.sub.2—, —OCH.sub.2C(O)—, —C(O)CH.sub.2O—, —NHCH.sub.2C(O)— or —C(O)CH.sub.2NH—; L.sub.3 is selected from bond, —O—, —NH—, —CH.sub.2—, —C(O)—, —CH.sub.2CH.sub.2—, —C(O)CH.sub.2— or —CH.sub.2C(O)—; m is 1; alternatively, wherein Z.sub.1 is —CH.sub.2— or —C(O)—; L.sub.1 is selected from bond, —O—, —NH—, —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH═CH— or —C≡C-; E is —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH═CH—, —CH═CHCH.sub.2—, —CH.sub.2C≡C- or —C≡CCH.sub.2-; L.sub.3 is selected from bond, —O—, —NH—, —CH.sub.2— or —C(O)—; m is 1; alternatively, wherein Z.sub.1 is —CH.sub.2— or —C(O)—; L.sub.1 is selected from bond, —O—, —NH—, —CH.sub.2—, —CH.sub.2CH.sub.2— or —C═C—; E is —CH.sub.2CH.sub.2CH.sub.2—; L.sub.3 is selected from bond, —CH.sub.2— or —C(O)—; m is 1; alternatively, wherein Z.sub.1 is —CH.sub.2—, L.sub.1 is selected from bond, —CH.sub.2—, —CH.sub.2CH.sub.2— or —C≡C-; E is —CH.sub.2CH.sub.2CH.sub.2—; L.sub.3 is selected from bond or —CH.sub.2—; m is 1.

15-18. (canceled)

19. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1, wherein the compound is selected from: ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430## ##STR00431## ##STR00432## ##STR00433## ##STR00434## ##STR00435## .

20. A pharmaceutical composition, comprising: the compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1 ; and pharmaceutically acceptable excipient (s); alternatively, wherein the pharmaceutical composition further comprises other therapeutic agent (s).

21. (canceled)

22. A method of treating and/or preventing diseases mediated by EGFR kinase in a subject, comprising administering to the subj ect the compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or the mixture thereof according to claim 1.

23. (canceled)

24. The method according to claim 22, wherein the diseases mediated by EGFR kinase include cancer, such as ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin’s lymphoma, gastric cancer, lung cancer, hepatocellular cancer, stomach cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cancer of bile duct, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, and mesothelioma.

25. A method of treating and/or preventing diseases mediated by EGFR kinase in a subject, comprising administering to the subject the pharmaceutical composition according to claim 20.

26. The method according to claim 25, wherein the diseases mediated by EGFR kinase include cancer, such as ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, custom-character non-Hodgkins lymphoma, gastric cancer, lung cancer, hepatocellular cancer, stomach cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cancer of bile duct, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, and mesothelioma.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0078] FIG. 1 shows the effect of compound D3 disclosed herein on the protein level of mutant EGFR.sup.L858R/T790M/C797S.

Definition

Chemical Definitions

[0079] Definitions of specific functional groups and chemical terms are described in more detail below.

[0080] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C.sub.1-6 alkyl” is intended to include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5, C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4, C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5 and C.sub.5-6 alkyl.

[0081] “C.sub.1-6 alkyl” refers to a radical of a straight or branched, saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C.sub.1-4 alkyl is alternative. Examples of C.sub.1-6 alkyl include methyl (C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), iso-propyl (C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl (C.sub.4), isobutyl (C.sub.4), n-pentyl (C.sub.5), 3-pentyl (C.sub.5), pentyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butyl (C.sub.5), tert-pentyl (C.sub.5) and n-hexyl (C.sub.6). The term “C.sub.1-6 alkyl” also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are subsituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent. Conventional abbreviations of alkyl include Me (-CH.sub.3), Et (-CH.sub.2CH.sub.3), iPr (-CH (CH.sub.3).sub.2), nPr (-CH.sub.2CH.sub.2CH.sub.3), n-Bu (-CH.sub.2CH.sub.2CH.sub.2CH.sub.3) or i-Bu (-CH.sub.2CH (CH.sub.3).sub.2).

[0082] “C.sub.2-6 alkenyl” refers to a radical of a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C.sub.2-4 alkenyl is alternative. Examples of C.sub.2-6 alkenyl include vinyl (C.sub.2), 1-propenyl (C.sub.3), 2-propenyl (C.sub.3), 1-butenyl (C.sub.4), 2-butenyl (C.sub.4), butadienyl (C.sub.4), pentenyl (C.sub.5), pentadienyl (C.sub.5), hexenyl (C.sub.6), etc. The term “C.sub.2-.sub.6 alkenyl” also includes heteroalkenyl, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0083] “C.sub.2-6 alkynyl” refers to a radical of a straight or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond and optionally one or more carbon-carbon double bonds. In some embodiments, C.sub.2-4 alkynyl is alternative. Examples of C.sub.2-6 alkynyl include, but are not limited to, ethynyl (C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3), 1-butynyl (C.sub.4), 2-butynyl (C.sub.4), pentynyl (C.sub.5), hexynyl (C.sub.6), etc. The term “C.sub.2-6 alkynyl” also includes heteroalkynyl, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl groups can be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0084] “Halo” or “halogen” refers to fluorine (F), chlorine (C1), bromine (Br) and iodine (I).

[0085] Thus, “C.sub.1-6 haloalkyl” refers to the above “C.sub.1-6 alkyl”, which is substituted with one or more halogen. In some embodiments, C.sub.1-4 haloalkyl is yet alternative, and still alternatively C.sub.1-2 haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF.sub.3, -CH.sub.2F, -CHF.sub.2, -CHFCH.sub.2F, -CH.sub.2CHF.sub.2, -CF.sub.2CF.sub.3, -CCl.sub.3, -CH.sub.2Cl, -CHCl.sub.2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0086] “C.sub.3-10 cycloalkyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C.sub.3-7 cycloalkyl and C.sub.3-6 cycloalkyl are yet alternative, and still alternatively C.sub.5-6 cycloalkyl. The cycloalkyl also includes a ring system in which the cycloalkyl described herein is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such case, the number of carbon atoms continues to represent the number of carbon atoms in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C.sub.3), cyclopropenyl (C.sub.3), cyclobutyl (C.sub.4), cyclobutenyl (C.sub.4), cyclopentyl (C.sub.5), cyclopentenyl (C.sub.5), cyclohexyl (C.sub.6), cyclohexenyl (C.sub.6), cyclohexadienyl (C.sub.6), cycloheptyl (C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl (C.sub.7), cycloheptatrienyl (C.sub.7), etc. The cycloalkyl can be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0087] “C.sub.3-10 halocycloalkyl” refers to the above “C.sub.3-10 cycloalkyl”, which is substituted with one or more halogen.

[0088] “3- to 12-membered heterocyclyl” refers to a radical of 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each of the heteroatoms is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In the heterocyclyl containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. In some embodiments, 4- to 12-membered heterocyclyl is alternative, which is a radical of 4- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms. In some embodiments, 3- to 10-membered heterocyclyl is alternative, which is a radical of 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms. In some embodiments, 3- to 8-membered heterocyclyl is alternative, which is a radical of 3- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms. 3- to 6-membered heterocyclyl is alternative, which is a radical of 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. 4- to 8-membered heterocyclyl is alternative, which is a radical of 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. 5- to 6-membered heterocyclyl is more alternative, which is a radical of 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. The heterocyclyl also includes a ring system wherein the heterocyclyl described above is fused with one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or the heterocyclyl described above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocycly groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl and thiepanyl. Exemplary 5-membered heterocyclyl groups fused with a C.sub.6 aryl (also referred as 5,6-bicyclic heterocyclyl herein) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused with a C.sub.6 aryl (also referred as 6,6-bicyclic heterocyclyl herein) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclyl can be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0089] “4- to 12-membered heterocyclylene” and “5- to 6-membered heterocyclylene” refer to the above “4- to 12-membered heterocyclyl” and “5- to 6-membered heterocyclyl”, respectively, wherein another hydrogen is removed and formed divalent groups, and can be substituted or unsubstituted.

[0090] “C.sub.6-10 aryl” refers to a radical of monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (e.g., having 6 or 10 shared π electrons in a cyclic array). In some embodiments, the aryl group has six ring carbon atoms (“C.sub.6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C.sub.10 aryl”; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). The aryl group also includes a ring system in which the aryl ring described above is fused with one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl can be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0091] “C.sub.6-12 aralkyl ” refers to the group -R-R′, wherein R is alkyl, R′ is aryl, and alkyl and aryl have a total of 6-12 carbon atoms.

[0092] “5- to 14-membered heteroaryl” refers to a radical of 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10 or 14 shared π electrons in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In the heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic systems may include one or more heteroatoms in one or two rings. Heteroaryl also includes ring systems wherein the heteroaryl ring described above is fused with one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring. In such case, the number the carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 10-membered heteroaryl groups are alternative, which are radicals of 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryl groups are yet alternative, which are radicals of 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (such as, 1,2,4- oxadiazoly), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. The heteroaryl can be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0093] “Oxo” represents =O.

[0094] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl as defined herein are optionally substituted groups.

[0095] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO.sub.2, -N.sub.3, -SO.sub.2H, -SO.sub.3H, -OH, -OR.sup.aa, -ON (R.sup.bb).sub.2, -N (R.sup.bb).sub.2, -N (Rbb)3.sup.+X.sup.-, -N (OR.sup.cc)R.sup.bb, -SH, -SR.sup.aa, -SSR.sup.cc, -C(=O)R.sup.aa, -CO.sub.2H, -CHO, -C(OR.sup.cc).sub.2, -CO.sub.2R.sup.aa, -OC(=O)R.sup.aa, -OCO.sub.2R.sup.aa, -C(=O)N (R.sup.bb).sub.2, -OC(=O)N (R.sup.bb).sub.2, -NR.sup.bbC(=O)R.sup.aa, -NR.sup.bbCO.sub.2Raa, -NR.sup.bbC(=O)N (R.sup.bb).sub.2, -C(=NR.sup.bb)Raa, -C(=NR.sup.bb)ORaa, _ OC(=NR.sup.bb)R.sup.aa, -OC(=NR.sup.bb)OR.sup.aa, -C(=NR.sup.bb)N (R.sup.bb).sub.2, -OC(=NR.sup.bb)N (R.sup.bb).sub.2, -NR.sup.bbC(=NR.sup.bb)N (R.sup.bb).sub.2, -C(=O)NR.sup.bb SO.sub.2R.sup.aa, -NR.sup.bbSO.sub.2R.sup.aa, -SO.sub.2N (R.sup.bb).sub.2, -SO.sub.2R.sup.aa, -SO.sub.2OR.sup.aa, -OSO.sub.2R.sup.aa, -S(=O)R.sup.aa, -OS(=O)R.sup.aa, -Si (R.sup.aa ).sub.3, -OSi (R.sup.aa).sub.3, -C(=S)N (R.sup.bb).sub.2, -C(=O)SR.sup.aa, -C(=S)SR.sup.aa, -SC(=S)SR.sup.aa, -SC(=O)SR.sup.aa, -OC(=O)SR.sup.aa, -SC(=O)OR.sup.aa, -SC(=O)R.sup.aa, -P (=O).sub.2R.sup.aa, -OP (=O).sub.2R.sup.aa, -P (=O)(R.sup.aa ).sub.2, -OP (=O)(R.sup.aa ).sub.2, -OP (=O)(OR.sup.cc)2, -P (=O).sub.2N (Rbb)2, -OP (=O).sub.2N (Rbb)2, -P (=O)(NR.sup.bb)2, -OP (=O)(NR.sup.bb)2, -NR.sup.bbP (=O)(OR.sup.cc).sub.2, -NR.sup.bbP (=O)(NR.sup.bb)2, -P (R.sup.cc).sub.2, -P (R.sup.cc).sub.3, -OP (R.sup.cc).sub.2, -OP (R.sup.cc).sub.3, -B (R.sup.aa).sub.2, -B (OR.sup.cc).sub.2, -BR.sup.aa (OR.sup.cc), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R.sup.dd groups; [0096] or two geminal hydrogen on a carbon atom are replaced with =O, =S, =NN (R.sup.bb).sub.2, =NNR.sup.bbC(=O)R.sup.aa, =NNR.sup.bbC(=O)OR.sup.aa, =NNR.sup.bbS(=O).sub.2R.sup.aa, =NR.sup.bb or =NOR.sup.cc groups; [0097] each of the R.sup.aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two of the R.sup.aa groups are combined to form a heterocyclyl or heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R.sup.dd groups; [0098] each of the R.sup.bb is independently selected from hydrogen, -OH, -OR.sup.aa, -N (R.sup.cc).sub.2, -CN, -C(=O)R.sup.aa.sub., -C(=O)N (R.sup.cc).sub.2,.sup._CO.sub.2R.sup.aa, -SO.sub.2R.sup.aa, -C(=NR.sup.cc)OR.sup.aa,) -C(=NR.sup.cc)N (R.sup.cc).sub.2, -SO.sub.2N (R.sup.cc).sub.2, -SO.sub.2R.sup.cc, -SO.sub.2OR.sup.cc, -SOR.sup.aa, -C(=S)N (R.sup.cc).sub.2, -C(=O)SR.sup.cc, -C(=S)SR.sup.cc, -P (=O).sub.2R.sup.aa, -P (=O)(R.sup.aa ).sub.2, -P (=O).sub.2N (R.sup.cc).sub.2, -P (=O)(NR.sup.cc)2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R.sup.bb groups are combined to form a heterocyclyl or a heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R.sup.dd groups; [0099] each of the R.sup.cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R.sup.cc groups are combined to form a heterocyclyl or a heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R.sup.dd groups; [0100] each of the R.sup.dd is independently selected from halogen, -CN, -NO.sub.2, -N.sub.3, -SO.sub.2H, -SO.sub.3H, -OH, -OR.sup.ee, -ON (R.sup.ff).sub.2, -N (R.sup.ff).sub.2, -N (R.sup.ff)3.sup.+X.sup.-, -N (OR.sup.ee)R.sup.ff, -SH, -SR.sup.ee, -SSR.sup.ee, -C(=O)R.sup.ee, -CO.sub.2H, -CO.sub.2R.sup.ee, -OC(=O)R.sup.ee, -OCO.sub.2R.sup.ee, -C(=O)N (R.sup.ff).sub.2, -OC(=O)N (R.sup.ff).sub.2, -NR.sup.ffC(=O)R.sup.ee, -NR.sup.ffCO.sub.2R.sup.ee, -NR.sup.ffC(=O)N (R.sup.ff).sub.2, -C(=NR.sup.ff)OR.sup.ee, -OC(=NR.sup.ff)R.sup.ee, -OC(=NR.sup.ff)OR.sup.ee, -C(=NR.sup.ff)N (R.sup.ff).sub.2, -OC(=NR.sup.ffN (R.sup.ff).sub.2, -NR.sup.ffC(=NR.sup.ff)N (R.sup.ff).sub.2, -NR.sup.ffSO.sub.2R.sup.ee, -SO.sub.2N (R.sup.ff).sub.2, -SO.sub.2R.sup.ee, -SO.sub.2OR.sup.ee, -OSO.sub.2R.sup.ee, -S(=O)R.sup.ee, -Si (R.sup.ee).sub.3, -OSi (R.sup.ee).sub.3, -C(=S)N (R.sup.ff).sub.2, -C(=O)SR.sup.ee, -C(=S)SR.sup.ee, -SC(=S)SR.sup.ee, -P (=O).sub.2R.sup.ee, -P (=O)(R.sup.ee).sub.2, -OP (=O)(R.sup.ee).sub.2, -OP (=O)(OR.sup.ee).sub.2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R.sup.gg groups, or two geminal R.sup.dd substituents can be combined to form =O or =S; [0101] each of the R.sup.ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R.sup.gg groups; [0102] each of the R.sup.ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R.sup.ff groups are combined to form a heterocyclyl or a heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R.sup.gg groups; [0103] each of the R.sup.gg is independently selected from halogen, -CN, -NO.sub.2, -N.sub.3, -SO.sub.2H, -SO.sub.3H, -OH, -OC.sub.1-6 alkyl, -ON (C.sub.1-6 alkyl).sub.2, -N (C.sub.1-6 alkyl).sub.2, -N (C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, -NH (C.sub.1-6 alkyl).sub.2.sup.+X.sup.-, -NH.sub.2 (C.sub.1-6 alkyl).sup.+X.sup.-, -NH.sub.3.sup.+X.sup.-, -N (OC.sub.1-6 alkyl)(C.sub.1-6 alkyl), -N (OH)(C.sub.1-6 alkyl), -NH (OH), -SH, -SC.sub.1-6 alkyl, -SS(C.sub.1-6 alkyl), -C(=O)(C.sub.1-6 alkyl), -CO.sub.2H, -CO.sub.2 (C.sub.1-6 alkyl), -OC(=O)(C.sub.1-6 alkyl), -OCO.sub.2 (C.sub.1-6 alkyl), -C(=O)NH.sub.2, -C(=O)N (C.sub.1-6 alkyl).sub.2, -OC(=O)NH (C.sub.1-6 alkyl), -NHC(=O)(C.sub.1-6 alkyl), -N (C.sub.1-6 alkyl)C(=O)(C.sub.1-6 alkyl), -NHCO.sub.2 (C.sub.1-6 alkyl), -NHC(=O)N (C.sub.1-6 alkyl).sub.2, -NHC(=O)NH (C.sub.1-6 alkyl), -NHC(=O)NH.sub.2, -C(=NH)O(C.sub.1-6 alkyl), -OC(=NH)(C.sub.1-6 alkyl), -OC(=NH)OC.sub.1-6 alkyl, -C(=NH)N (C.sub.1-.sub.6 alkyl).sub.2, -C(=NH)NH (C.sub.1-6 alkyl), -C(=NH)NH.sub.2, -OC(=NH)N (C.sub.1-6 alkyl).sub.2, -OC(NH)NH (C.sub.1-6 alkyl), -OC(NH)NH.sub.2, -NHC(NH)N (C.sub.1-.sub.6 alkyl).sub.2, -NHC(=NH)NH.sub.2, -NHSO.sub.2 (C.sub.1-.sub.6 alkyl), -SO.sub.2N (C.sub.1-.sub.6 alkyl).sub.2, -SO.sub.2NH (C.sub.1-6 alkyl), -SO.sub.2NH.sub.2, -SO.sub.2C.sub.1.sub.-6 alkyl, -SO.sub.2OC.sub.1-6 alkyl, -OSO.sub.2C.sub.1.sub.-6 alkyl, -SOC.sub.1-6 alkyl, -Si (C.sub.1-6 alkyl).sub.3, -OSi (C.sub.1-6 alkyl).sub.3, -C(=S)N (C.sub.1-6 alkyl).sub.2, C(=S)NH (C.sub.1-6 alkyl), C(=S)NH.sub.2, -C(=O)S(C.sub.1-.sub.6 alkyl), -C(=S)SC.sub.1-6 alkyl, -SC(=S)SC.sub.1-6 alkyl, -P (=O).sub.2 (C.sub.1-6 alkyl), -P (=O)(C.sub.1-6 alkyl).sub.2, -OP (=O)(C.sub.1-.sub.6 alkyl).sub.2, -OP (=O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.7 heterocyclyl, C.sub.5-C.sub.10 heteroaryl; or two geminal R.sup.gg substituents may combine to form =O or =S; wherein X.sup.- is a counter-ion.

[0104] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR.sup.aa, -N (R.sup.cc).sub.2, -CN, -C(=O)R.sup.aa, -C(=O)N (R.sup.cc).sub.2,.sup._CO.sub.2R.sup.aa, -SO.sub.2R.sup.aa, -C(=NR.sup.bb)R.sup.aa, -C(=NR.sup.cc)OR.sup.aa, -C(=NR.sup.cc)N (R.sup.cc).sub.2, -SO.sub.2N (R.sup.cc).sub.2, -SO.sub.2R.sup.cc, -SO.sub.2OR.sup.cc, -SOR.sup.aa, -C(=S)N (R.sup.cc).sub.2, -C(=O)SR.sup.cc, -C(=S)SR.sup.cc, -P (=O).sub.2R.sup.aa, -P (=O)(R.sup.aa ).sub.2, -P (=O).sub.2N (R.sup.cc).sub.2, -P (=O)(NR.sup.cc).sub.2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R.sup.cc groups attached to a nitrogen atom combine to form a heterocyclyl or a heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R.sup.dd groups, and wherein R.sup.aa, R.sup.bb, R.sup.cc and R.sup.dd are as described herein.

Other Definitions

[0105] The term “cancer” includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lips, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, cancer of brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorder, lymphatic disorder, Hodgkin’s disease, hairy cell carcinoma and leukemia.

[0106] The term “treating” as used herein relates to reversing, alleviating or inhibiting the progression or prevention of the disorders or conditions to which the term applies, or of one or more symptoms of such disorders or conditions. The noun “treatment” as used herein relates to the action of treating, which is a verb, and the latter is as just defined.

[0107] The term “pharmaceutically acceptable salt” as used herein refers to those carboxylate and amino acid addition salts of the compounds of the present disclosure, which are suitable for the contact with patients′ tissues within a reliable medical judgment, and do not produce inappropriate toxicity, irritation, allergy, etc. They are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term includes, if possible, the zwitterionic form of the compounds of the disclosure.

[0108] The pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of the metals used as cations include sodium, potassium, magnesium, calcium, etc. Examples of suitable amines are N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

[0109] The base addition salt of the acidic compound can be prepared by contacting the free acid form with a sufficient amount of the required base to form a salt in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then isolating the free acid. The free acid forms are somewhat different from their respective salt forms in their physical properties, such as solubility in polar solvents. But for the purposes of the present disclosure, the salts are still equivalent to their respective free acids.

[0110] The salts can be prepared from the inorganic acids, which include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides and iodides. Examples of the acids include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. The representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, glucoheptanate, lactobionate, lauryl sulfonate, isethionate, etc. The salts can also be prepared from the organic acids, which include aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acid, aromatic acids, aliphatic and aromatic sulfonic acids, etc. The representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, naphthoate, besylate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, etc. The pharmaceutically acceptable salts can include cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Salts of amino acids are also included, such as arginine salts, gluconates, galacturonates, etc. (for example, see Berge S. M. et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1- 19 for reference).

[0111] “Subjects” to which administration is contemplated include, but are not limited to, humans (e.g., males or females of any age group, e.g., paediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or older adults) and/or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms “humam”, “patient” and “subject” can be used interchangeably herein.

[0112] “Disease,” “disorder,” and “condition” can be used interchangeably herein.

[0113] Unless indicated, otherwise the term “treatment” as used herein includes the effect on a subject who is suffering from a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder or condition (“therapeutic treatment”). The term also includes the effect that occurs before the subject begins to suffer from a specific disease, disorder or condition (“prophylactic treatment”).

[0114] Generally, the “effective amount” of a compound refers to an amount sufficient to elicit a target biological response. As understood by those skilled in the art, the effective amount of the compound of the disclosure can vary depending on the following factors, such as the desired biological endpoint, the pharmacokinetics of the compound, the diseases being treated, the mode of administration, and the age, health status and symptoms of the subjects. The effective amount includes therapeutically effective amount and prophylactically effective amount.

[0115] Unless indicated, otherwise the “therapeutically effective amount” of the compound as used herein is an amount sufficient to provide therapeutic benefits in the course of treating a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. The therapeutically effective amount of a compound refers to the amount of the therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term “therapeutically effective amount” can include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of the disease or condition, or enhances the therapeutic effect of other therapeutic agents.

[0116] Unless indicated, otherwise the “prophylactically effective amount” of the compound as used herein is an amount sufficient to prevent a disease, disorder or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder or condition, or an amount sufficient to prevent the recurrence of a disease, disorder or condition. The prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term “prophylactically effective amount” can include an amount that improves the overall prevention, or an amount that enhances the prophylactic effect of other preventive agents.

[0117] “Combination” and related terms refer to the simultaneous or sequential administration of the compounds of the present disclosure and other therapeutic agents. For example, the compounds of the present disclosure can be administered simultaneously or sequentially in separate unit dosage with other therapeutic agents, or simultaneously in a single unit dosage with other therapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION

[0118] As used herein, the term “compound disclosed herein” refers to the following compounds of formula (I)(including sub general formulas, such as formula (II′) etc), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof.

[0119] In the present disclosure, compounds are named using standard nomenclature. For compounds having an asymmetric center, it should be understood, unless otherwise stated, that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomer compounds and carbon-carbon double bonds included in the present disclosure may occur in the form of Z and E. Compounds which exist in different tautomeric forms, one of which is not limited to any particular tautomer, but is intended to cover all tautomeric forms.

[0120] In one embodiment, the present disclosure relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof:

##STR00014##

[0121] wherein [0122] custom-character represents single bond or double bond; [0123] ----- represents that the point of attachment to the rest of the molecule can be located at an available point of a ring; [0124] Z.sub.1 is O, S, N or C atom, which is optionally substituted with one or two R.sub.Z1; or Z.sub.1 is absent, and thus Z.sub.4 is connected to Z.sub.2, Z.sub.3 or the C atom connected to Z.sub.1 on the aromatic ring, and the Z.sub.2 and the C atom on the aromatic ring that are connected to Z.sub.1 are connected to R respectively; or Z.sub.1, Z.sub.2 and Z.sub.3 are all absent, and thus Z.sub.4 is connected to one of the C atoms connected to Z.sub.1 or Z.sub.3 on the aromatic ring, and the other C atom on the aromatic ring is connected to R; [0125] Z.sub.2 is O, S, N or C atom, which is optionally substituted with one or two R.sub.z2; [0126] Z.sub.3 is O, S, N or C atom, which is optionally substituted with one or two R.sub.z3; with the proviso that when custom-character represents double bond, Z.sub.2 is N or C atom, and Z.sub.3 is N or C atom; [0127] Z.sub.4 is N or CR.sub.Z4; [0128] Z.sub.5 is N or CR.sub.z5; [0129] R.sub.a, R.sub.b and R.sub.c are independently H, halogen, OR′, NR’R″, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; or R.sub.a and R.sub.b are taken together with the carbon atom to which they are attached to form C=O, C.sub.3-7 cycloalkyl or 4- to 8-membered heterocyclyl; or, R.sub.a and R.sub.c are taken together with the carbon atoms to which they are attached to form C.sub.3-7 cycloalkyl or 4- to 8-membered heterocyclyl; or R.sub.a and R.sub.c are taken together to form bond; [0130] R.sub.N1 is H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; [0131] R.sub.z1 is absent, H, CN, halogen, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -(CH.sub.2).sub.0-5-C.sub.3-7 cycloalkyl or -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl; or two R.sub.Z1 are taken together with Z.sub.1 to form C=O, C.sub.3-7 cycloalkyl or 4- to 8-membered heterocyclyl; [0132] R.sub.Z2 is absent, H, CN, halogen, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -(CH.sub.2).sub.0-5-C.sub.3-7 cycloalkyl or -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl; or two R.sub.Z2 are taken together with Z.sub.2 to form C=O, C.sub.3-7 cycloalkyl or 4- to 8-membered heterocyclyl; [0133] R.sub.z3 is absent, H, CN, halogen, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, C.sub.1-6 alkyl, C.sub.1-.sub.6 haloalkyl, -(CH.sub.2).sub.0-5-C.sub.3-7 cycloalkyl or -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl; or two R.sub.z3 are taken together with Z.sub.3 to form C=O, C.sub.3-7 cycloalkyl or 4- to 8-membered heterocyclyl; [0134] R.sub.z4 is H, CN, halogen, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; [0135] R.sub.z5 is H, CN, halogen, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -(CH.sub.2).sub.0-5-C.sub.3-7 cycloalkyl or -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl; [0136] or the ring where Z.sub.4 is located is absent; [0137] wherein R is H, CN, halogen, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, -C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -(CH.sub.2).sub.0-5-C.sub.3-7 cycloalkyl, -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -(CH.sub.2).sub.0-.sub.5-C.sub.3-10 halocycloalkyl, -(CH.sub.2).sub.0-5-C.sub.6-10 aryl or -(CH.sub.2).sub.0-5-5- to 14-membered heteroaryl; [0138] R′ is H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or -(CH.sub.2).sub.0-5-C.sub.3-7 cycloalkyl; [0139] R″ is H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; [0140] L.sub.1 is selected from bond, -O-, -S(O).sub.p-, -S(O)(=NR*)-, -NR.sup.#-, -CR.sup.#R.sup.#′-, -C.sub.aR.sup.#R.sup.#′-C.sub.bR.sup.#R.sup.#′-, -N=S(O)(R*)- or -S(O)(R*)=N-; [0141] L.sub.2 is selected from bond, -O-, -S(O).sub.p-, -S(O)(=NR*)-, -NR.sup.#-, -CR.sup.#R.sup.#′-, -C.sub.aR.sup.#R.sup.#′-C.sub.bR.sup.#R.sup.#′-, -N=S(O)(R*)- or -S(O)(R*)=N-; [0142] wherein one of C.sub.aR.sup.#R.sup.#′ and C.sub.bR.sup.#R.sup.#′ can be replaced by O, S(O).sub.p, S(O)(=NR*) or NR.sup.#, and when one of C.sub.aR.sup.#R.sup.#′ and C.sub.bR.sup.#R.sup.#′ is replaced by O, S or NR.sup.#, the other of C.sub.aR.sup.#R.sup.#′ and C.sub.bR.sup.#R.sup.#′ can further be replaced by S(O).sub.q; [0143] E is independently selected from: bond, -C.sub.cR.sup.#R.sup.#′-C.sub.dR.sup.#R.sup.#′-C.sub.eR.sup.#R.sup.#′, [0144] wherein one of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′, or both of C.sub.cR.sup.#R.sup.#′ and C.sub.eR.sup.#R.sup.#′ can be replaced by O, S(O).sub.p, S(O)(=NR*) or NR.sup.#, and when one of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′ is replaced by O, S or NR.sup.#, the other one or two of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′ adjacent to it can further be replaced by S(O).sub.q; [0145] or two E moieties can be taken together to form -CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-, -OCH.sub.2CH.sub.2CH.sub.2CH.sub.2-, -CH.sub.2CH.sub.2CH.sub.2CH.sub.2O-, [0146] wherein 〰 represents the point of attachment to L.sub.1 or L.sub.2; [0147] H.sub.1 and H.sub.2 are N or C atom, H.sub.3 is O, S, N or C atom, and H.sub.1 and H.sub.3, H.sub.2 and H.sub.3 are not heteroatoms at the same time; [0148] H.sub.4 and H.sub.5 are N or C atom; [0149] H.sub.6, H.sub.7, H.sub.8 and H.sub.9 are C or N atom; [0150] p is 0, 1 or 2; [0151] q is 1 or 2; [0152] R* is H, C.sub.1-.sub.6 alkyl, C.sub.1-.sub.6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-.sub.10 cycloalkyl, C.sub.3-.sub.10 halocycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl or 5- to 14-membered heteroaryl; [0153] R.sup.# is H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-.sub.10 cycloalkyl, C.sub.3-.sub.10 halocycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl or 5- to 14-membered heteroaryl; [0154] R.sup.#′ is H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-.sub.10 cycloalkyl, C.sub.3-.sub.10 halocycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl or 5- to 14-membered heteroaryl; [0155] or, R.sup.# and R.sup.# on adjacent atoms can be taken together to form bond, and R.sup.#′ and R.sup.#′ on adjacent atoms can be taken together to form bond; [0156] or, R.sup.# and R.sup.#′ on the same or different atoms can be taken together to form =O, or C.sub.3-7 cycloalkyl, 4- to 8-membered heterocyclyl, C.sub.6-10 aryl or 5- to 6-membered heteroaryl, wherein the C.sub.3-.sub.7 cycloalkyl, 4- to 8-membered heterocyclyl, C.sub.6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with R.sub.x, and the R.sub.x is H, CN, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; [0157] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; [0158] X.sub.1 is C or N atom; [0159] X.sub.2 is C or N atom; [0160] X.sub.3 is C or N atom; [0161] X.sub.4 is O, S, C or N atom, which is optionally substituted with one or two R.sub.2; [0162] X.sub.5 is O, S, C or N atom; [0163] X.sub.6 is C or N atom; [0164] X.sub.7 is O, S, C or N atom; [0165] R.sub.1 is H, CN, halogen, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -(CH.sub.2).sub.0-5-C.sub.3-7 cycloalkyl, -(CH.sub.2).sub.0-5-C.sub.3-10 halocycloalkyl, -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl, -(CH.sub.2).sub.0-5-C.sub.6-10 aryl, -(CH.sub.2).sub.0-5-5- to 14-membered heteroaryl, -C(O)R, -S(O)R or -S(O).sub.2R; [0166] R.sub.2 is H, CN, halogen, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -(CH.sub.2).sub.0-5-C.sub.3-7 cycloalkyl, -(CH.sub.2).sub.0-5-C.sub.3-10 halocycloalkyl, -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl, -(CH.sub.2).sub.0-5-C.sub.6-10 aryl, -(CH.sub.2).sub.0-5-5- to 14-membered heteroaryl, -C(O)R, -S(O)R or -S(O).sub.2R; [0167] R.sub.N2 is H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; [0168] the definition of L.sub.1′ is the same as that of L.sub.1; [0169] the definition of L.sub.2′ is the same as that of L.sub.2; [0170] the definition of E′ is the same as that of E; [0171] the definition of m′ is the same as that of m; [0172] R.sub.s1 is selected from H, CN, halogen, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -(CH.sub.2).sub.0-5-C.sub.3-7 cycloalkyl, -(CH.sub.2).sub.0-5-C.sub.3-10 halocycloalkyl, -(CH.sub.2).sub.0-5-C.sub.6-10 aryl, -(CH.sub.2).sub.0-5-5- to 14-membered heteroaryl, -C(O)R, -S(O)R or -S(O).sub.2R; [0173] R.sub.s2 is selected from H, CN, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, -(CH.sub.2).sub.0-5-C.sub.3-7cycloalkyl, -(CH.sub.2).sub.0-5-C.sub.3-10 halocycloalkyl, -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl, -(CH.sub.2).sub.0-5-C.sub.6-10 aryl, -(CH.sub.2).sub.0-5-5- to 14-membered heteroaryl, -C(O)R, -S(O)R or -S(O).sub.2R; [0174] R.sub.s3 is selected from H, CN, halogen, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -(CH.sub.2).sub.0-5-C.sub.3-7cycloalkyl, -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -(CH.sub.2).sub.0-5-C.sub.3-10 halocycloalkyl, -(CH.sub.2).sub.0-5-C.sub.6-10 aryl, -(CH.sub.2).sub.0-5-5- to 14-membered heteroaryl, -C(O)R, -S(O)R or -S(O).sub.2R; [0175] R.sub.s4 is selected from H, CN, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -(CH.sub.2).sub.0-5-OR′, -(CH.sub.2).sub.0-5-NR’R″, -(CH.sub.2).sub.0-5-C.sub.3-7cycloalkyl, -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl, -(CH.sub.2).sub.0-5-C.sub.3-10 halocycloalkyl, -(CH.sub.2).sub.0-5-C.sub.6-10 aryl, -(CH.sub.2).sub.0-5-5- to 14-membered heteroaryl, -C(O)R, -S(O)R or -S(O).sub.2R; [0176] s1 is 0, 1, 2 or 3; [0177] s2 is 0, 1, 2 or 3; [0178] s3 is 0, 1 or 2; [0179] s4 is 0, 1, 2, 3, 4 or 5; [0180] the groups containing OH, NH, NH.sub.2, CH, CH.sub.2, or CH.sub.3 in L.sub.1, E, L.sub.2, L.sub.1′, E′, L.sub.2′, or the above alkyl, alkylene, haloalkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with 1, 2, 3 or more R.sup.S at each occurrence, wherein the R.sup.S is independently selected from the following groups at each occurrence: halogen, hydroxyl, amino, cyano, nitro, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 halocycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl, 5- to 14-membered heteroaryl, C.sub.6-12 aralkyl, -OR.sup.a′, -OC(O)R.sup.a′, -C(O)R.sup.a′, -C(O)OR.sup.a′, -C(O)NR.sup.a′R.sup.b′, -S(O)nR.sup.a′, -S(O).sub.nOR.sup.a′, -S(O).sub.nNR.sup.a′R.sup.b′, -NR.sup.a′R.sup.b′, -NR.sup.a′C(O)R.sup.b′, -NR.sup.a′-C(O)OR.sup.b′, -NR.sup.a′-S(O)n-R.sup.b′, -NR.sup.a′C(O)NR.sup.a′R.sup.b′, -C.sub.1-.sub.6 alkylene-R.sup.a′, -C.sub.1-.sub.6 alkylene-OR.sup.a′, -C.sub.1-.sub.6 alkylene-OC(O)R.sup.a′, -C.sub.1-.sub.6 alkylene-C(O)OR.sup.a′, -C.sub.1-.sub.6 alkylene-S(O).sub.nR.sup.a′, -C.sub.1-.sub.6 alkylene-S(O).sub.nOR.sup.a′, -C.sub.1-.sub.6 alkylene-OC(O)NR.sup.a′R.sup.b′, -C.sub.1-.sub.6 alkylene-C(O)NR.sup.a′R.sup.b′, -C.sub.1-.sub.6 alkylene-NR.sup.a′-C(O)NR.sup.a′R.sup.b′, -C.sub.1-.sub.6 alkylene-OS(O).sub.nR.sup.a′, -C.sub.1-.sub.6 alkylene-S(O).sub.nNR.sup.a′R.sup.b′, -C.sub.1-.sub.6 alkylene-NR.sup.a′-S(O).sub.nNR.sup.a′R.sup.b′, -C.sub.1-.sub.6 alkylene-NR.sup.a′R.sup.b′ and -O-C.sub.1-6 alkylene-NR.sup.a′R.sup.b′, and wherein the hydroxyl, amino, alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl described with respect to the substituent R.sup.S are further optionally substituted with 1, 2, 3 or more substituents independently selected from: halogen, OH, amino, cyano, nitro, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkyl hydroxyl, C.sub.3-6 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl, 5- to 14-membered heteroaryl and C.sub.6-12 aralkyl; [0181] n is independently 1 or 2 at each occurrence; [0182] each of R.sup.a′ and R.sup.b′ is independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-.sub.6 alkyl-O-, C.sub.1-6 alkyl-S-, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl, 5- to 14-membered heteroaryl and C.sub.6-12 aralkyl at each occurrence.[0186] custom-character

[0183] In a specific embodiment, custom-character represents single bond; in another specific embodiment, represents double bond.

Z.SUB.1

[0184] In a specific embodiment, Z.sub.1 is O atom; in another specific embodiment, Z.sub.1 is S atom; in another specific embodiment, Z.sub.1 is N atom; in another specific embodiment, Z.sub.1 is C atom; in another specific embodiment, Z.sub.1 is substituted with one R.sub.Z1; in another specific embodiment, Z.sub.1 is substituted with two R.sub.Z1; in another specific embodiment, Z.sub.1 is absent.

Z.SUB.2

[0185] In a specific embodiment, Z.sub.2 is O atom; in another specific embodiment, Z.sub.2 is S atom; in another specific embodiment, Z.sub.2 is N atom; in another specific embodiment, Z.sub.2 is C atom; in another specific embodiment, Z.sub.2 is substituted with one R.sub.Z2; in another specific embodiment, Z.sub.2 is substituted with two R.sub.z2.

Z.SUB.3

[0186] In a specific embodiment, Z.sub.3 is O atom; in another specific embodiment, Z.sub.3 is S atom; in another specific embodiment, Z.sub.3 is N atom; in another specific embodiment, Z.sub.3 is C atom; in another specific embodiment, Z.sub.3 is substituted with one R.sub.Z3; in another specific embodiment, Z.sub.3 is substituted with two R.sub.Z3.

[0187] In a specific embodiment, Z.sub.1, Z.sub.2 and Z.sub.3 are all absent.

Z.SUB.4

[0188] In a specific embodiment, Z.sub.4 is N; in another specific embodiment, Z.sub.4 is CR.sub.Z4.

Z.SUB.5

[0189] In a specific embodiment, Z.sub.5is N; in another specific embodiment, Z.sub.5is CRzs.

R.SUB.a., R.SUB.b and R.SUB.c

[0190] In a specific embodiment, R.sub.a is H; in another specific embodiment, R.sub.a is halogen; in another specific embodiment, R.sub.a is OR′; in another specific embodiment, R.sub.a is NR’R″; in another specific embodiment, R.sub.a is C.sub.1-6 alkyl; in another specific embodiment, R.sub.a is C.sub.1-6 haloalkyl.

[0191] In a specific embodiment, R.sub.b is H; in another specific embodiment, R.sub.b is halogen; in another specific embodiment, R.sub.b is OR′; in another specific embodiment, R.sub.b is NR’R″; in another specific embodiment, R.sub.b is C.sub.1-.sub.6 alkyl; in another specific embodiment, R.sub.b is C.sub.1-6 haloalkyl.

[0192] In a specific embodiment, R.sub.c is H; in another specific embodiment, R.sub.c is halogen; in another specific embodiment, R.sub.c is OR′; in another specific embodiment, R.sub.c is NR’R″; in another specific embodiment, R.sub.c is C.sub.1-6 alkyl; in another specific embodiment, R.sub.c is C.sub.1-6 haloalkyl.

[0193] In a specific embodiment, R.sub.a and R.sub.b are taken together with the carbon atom to which they are attached to form C=O; in another specific embodiment, R.sub.a and R.sub.b are taken together with the carbon atom to which they are attached to form C.sub.3-7 cycloalkyl; in another specific embodiment, R.sub.a and R.sub.b are taken together with the carbon atom to which they are attached to form 4- to 8-membered heterocyclyl; in another specific embodiment, R.sub.a and R.sub.c are taken together to form bond; in another specific embodiment, R.sub.a and R.sub.c are taken together with the carbon atoms to which they are attached to form C.sub.3-7 cycloalkyl or 4- to 8-membered heterocyclyl.

R.SUB.Z1

[0194] In a specific embodiment, R.sub.Z1 is absent; in another specific embodiment, R.sub.Z1 is H; in another specific embodiment, R.sub.Z1 is CN; in another specific embodiment, R.sub.Z1 is halogen; in another specific embodiment, R.sub.Z1 is -(CH.sub.2).sub.0-5-OR′; in another specific embodiment, R.sub.Z1 is -(CH.sub.2).sub.0-5-NR’R″; in another specific embodiment, R.sub.Z1 is C.sub.1-6 alkyl; in another specific embodiment, R.sub.Z1 is C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.Z1 is -(CH.sub.2).sub.0-5-C.sub.3-7cycloalkyl; in another specific embodiment, R.sub.Z1 is -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl; in another specific embodiment, two R.sub.Z1 are taken together with Z.sub.1 to form C=O; in another specific embodiment, two R.sub.Z1 are taken together with Z.sub.1 to form C.sub.3-7 cycloalkyl; in another specific embodiment, two R.sub.Z1 are taken together with Z.sub.1 to form 4- to 8-membered heterocyclyl.

R.SUB.z2

[0195] In a specific embodiment, R.sub.Z2 is absent; in another specific embodiment, R.sub.Z2 is H; in another specific embodiment, R.sub.Z2 is CN; in another specific embodiment, R.sub.Z2 is halogen; in another specific embodiment, R.sub.Z2 is -(CH.sub.2).sub.0-5-OR′; in another specific embodiment, R.sub.Z2 is -(CH.sub.2).sub.0-5-NR’R″; in another specific embodiment, R.sub.Z2 is C.sub.1-6 alkyl; in another specific embodiment, R.sub.Z2 is C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.Z2 is -(CH.sub.2).sub.0-5-C.sub.3-7cycloalkyl; in another specific embodiment, R.sub.Z2 is -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl; in another specific embodiment, two R.sub.Z2 are taken together with Z.sub.2 to form C=O; in another specific embodiment, two R.sub.Z2 are taken together with Z.sub.2 to form C.sub.3-7 cycloalkyl; in another specific embodiment, two R.sub.Z2 are taken together with Z.sub.2 to form 4- to 8-membered heterocyclyl.

R.SUB.z3

[0196] In a specific embodiment, R.sub.Z3 is absent; in another specific embodiment, R.sub.Z3is H; in another specific embodiment, R.sub.Z3is CN; in another specific embodiment, R.sub.Z3is halogen; in another specific embodiment, R.sub.Z3is -(CH.sub.2).sub.0-5-OR′; in another specific embodiment, R.sub.Z3is -(CH.sub.2).sub.0-5-NR’R″; in another specific embodiment, R.sub.Z3is C.sub.1-6 alkyl; in another specific embodiment, R.sub.Z3is C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.Z3is -(CH.sub.2).sub.0-5-C.sub.3-7cycloalkyl; in another specific embodiment, R.sub.Z3 is -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl; in another specific embodiment, two R.sub.Z3 are taken together with Z.sub.3 to form C=O; in another specific embodiment, two R.sub.Z3are taken together with Z.sub.3 to form C.sub.3-7 cycloalkyl; in another specific embodiment, two R.sub.Z3are taken together with Z.sub.3 to form 4- to 8-membered heterocyclyl.

R.SUB.z4

[0197] In a specific embodiment, R.sub.Z4 is H; in another specific embodiment, R.sub.Z4 is CN; in another specific embodiment, R.sub.Z4 is halogen; in another specific embodiment, R.sub.Z4 is -(CH.sub.2).sub.0-5-OR′; in another specific embodiment, R.sub.Z4 is -(CH.sub.2).sub.0-5-NR’R″; in another specific embodiment, R.sub.Z4 is C.sub.1-6 alkyl; in another specific embodiment, R.sub.Z4 is C.sub.1-6 haloalkyl.

R.SUB.z5

[0198] In a specific embodiment, R.sub.Z5 is H; in another specific embodiment, R.sub.Z5 is CN; in another specific embodiment, R.sub.Z5 is halogen; in another specific embodiment, Rzs is -(CH.sub.2).sub.0-5-OR′; in another specific embodiment, Rzs is -(CH.sub.2).sub.0-5-NR’R″; in another specific embodiment, R.sub.Z5 is C.sub.1-6 alkyl; in another specific embodiment, R.sub.Z5 is C.sub.1-6 haloalkyl; in another specific embodiment, Rzs is -(CH.sub.2).sub.0-5-C.sub.3-7 cycloalkyl; in another specific embodiment, Rzs is -(CH.sub.2).sub.0-5-4- to 8-membered heterocyclyl.

[0199] In a specific embodiment, the ring in which Z.sub.4 is located is absent.

L.SUB.1

[0200] In a specific embodiment, L.sub.1 is bond; in another specific embodiment, L.sub.1 is -O-; in another specific embodiment, L.sub.1 is -S(O).sub.p-; in another specific embodiment, L.sub.1 is -S(O)(=NR*)-; in another specific embodiment, L.sub.1 is -NR.sup.#-; in another specific embodiment, L.sub.1 is -CR.sup.#R.sup.#′-; in another specific embodiment, L.sub.1 is -C.sub.aR.sup.#R.sup.#′-C.sub.bR.sup.#R.sup.#′-; in another specific embodiment, L.sub.1 is -N=S(O)(R*)-; in another specific embodiment, L.sub.1 is -S(O)(R*)=N-.

L.SUB.2

[0201] In a specific embodiment, L.sub.2 is bond; in another specific embodiment, L.sub.2 is -O-; in another specific embodiment, L.sub.2 is -S(O).sub.p-; in another specific embodiment, L.sub.2 is -S(O)(=NR*)-; in another specific embodiment, L.sub.2 is -NR.sup.#-; in another specific embodiment, L.sub.2 is -CR.sup.#R.sup.#′-; in another specific embodiment, L.sub.2 is -C.sub.aR.sup.#R.sup.#′-C.sub.bR.sup.#R.sup.#′-; in another specific embodiment, L.sub.2 is -N=S(O)(R*)-; in another specific embodiment, L.sub.2 is -S(O)(R*)=N-.

[0202] In another specific embodiment, one of C.sub.aR.sup.#R.sup.#′ and C.sub.bR.sup.#R.sup.#′ in L.sub.1 or L.sub.2 can be replaced by O, S(O).sub.p, S(O)(=NR*) or NR.sup.#, and when one of C.sub.aR.sup.#R.sup.#′ and C.sub.bR.sup.#R.sup.#′ is replaced by O, S or NR.sup.#, the other of C.sub.aR.sup.#R.sup.#′ and C.sub.bR.sup.#R.sup.#′ can further be replaced by S(O).sub.q;

[0203] In a specific embodiment, E is bond; in another specific embodiment, E is -C.sub.cR.sup.#R.sup.#′-C.sub.dR.sup.#R.sup.#′-C.sub.eR.sup.#R.sup.#′; in another specific embodiment, E is

##STR00026##

in another specific embodiment, E is

##STR00027##

in another specific embodiment, E is

##STR00028##

in another specific embodiment, E is

##STR00029##

in another specific embodiment, E is

##STR00030##

[0204] In another specific embodiment, one of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′, or both of C.sub.cR.sup.#R.sup.#′ and C.sub.eR.sup.#R.sup.#′ can be replaced by O, S(O).sub.p, S(O)(=NR*) or NR.sup.#, and when one of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′ is replaced by O, S or NR.sup.#, the other one or two of C.sub.cR.sup.#R.sup.#′, C.sub.dR.sup.#R.sup.#′ or C.sub.eR.sup.#R.sup.#′ adjacent to it can further be replaced by S(O).sub.q;

[0205] In another specific embodiment, two E moieties can be taken together to form -CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-; in another specific embodiment, two E moieties can be taken together to form -OCH.sub.2CH.sub.2CH.sub.2CH.sub.2-; in another specific embodiment, two E moieties can be taken together to form -CH.sub.2CH.sub.2CH.sub.2CH.sub.2O-; in another specific embodiment, two E moieties can be taken together to form

##STR00031##

in another specific embodiment, two E moieties can be taken together to form

##STR00032##

in another specific embodiment, two E moieties can be taken together to form

##STR00033##

in another specific embodiment, two E moieties can be taken together to form

##STR00034##

in another specific embodiment, two E moieties can be taken together to form

##STR00035##

in another specific embodiment, two E moieties can be taken together to form

##STR00036##

[0206] In another specific embodiment, in the embodiment of L.sub.1, L.sub.2 or E, R.sup.# and R.sup.# on adjacent atoms can be taken together to form bond, and R.sup.#′ and R.sup.#′ on adjacent atoms can be taken together to form bond;

[0207] In another specific embodiment, in the embodiment of L.sub.1, L.sub.2 or E, R.sup.# and R.sup.#′ on the same atom can be taken together to form =O, or C.sub.3-7 cycloalkyl, 4- to 8-membered heterocyclyl, C.sub.6-10 aryl or 5- to 6-membered heteroaryl, each of which is optionally substituted with R.sub.x group; in another specific embodiment, in the embodiment of L.sub.1, L.sub.2 or E, R.sup.# and R.sup.#′ on different atoms can be taken together to form C.sub.3-7 cycloalkyl, 4- to 8-membered heterocyclyl, C.sub.6-10 aryl or 5- to 6-membered heteroaryl, each of which is optionally substituted with R.sub.x group.

[0208] In a specific embodiment, m is 0; in another specific embodiment, m is 1; in another specific embodiment, m is 2; in another specific embodiment, m is 3; in another specific embodiment, m is 4; in another specific embodiment, m is 5; in another specific embodiment, m is 6; in another specific embodiment, m is 7; in another specific embodiment, m is 8; in another specific embodiment, m is 9; in another specific embodiment, m is 10.

X.SUB.1

[0209] In a specific embodiment, X.sub.1 is C atom; in another specific embodiment, X.sub.1 is N atom.

X.SUB.2

[0210] In a specific embodiment, X.sub.2 is C atom; in another specific embodiment, X.sub.2 is N atom.

X.SUB.3

[0211] In a specific embodiment, X.sub.3 is C atom; in another specific embodiment, X.sub.3 is N atom.

X.SUB.4

[0212] In a specific embodiment, X.sub.4 is O atom; in another specific embodiment, X.sub.4 is S atom; in another specific embodiment, X.sub.4 is C atom; in another specific embodiment, X.sub.4 is N atom; in another specific embodiment, X.sub.4 is substituted with one R.sub.2; in another specific embodiment, X.sub.4 is substituted with two R.sub.2.

X.SUB.5

[0213] In a specific embodiment, X.sub.5is O atom; in another specific embodiment, X.sub.5is S atom; in another specific embodiment, X.sub.5is C atom; in another specific embodiment, X.sub.5is N atom.

X.SUB.6

[0214] In a specific embodiment, X.sub.6 is C atom; in another specific embodiment, X.sub.6 is N atom.

X.SUB.7

[0215] In a specific embodiment, X.sub.7 is O atom; in another specific embodiment, X.sub.7 is S atom; in another specific embodiment, X.sub.7 is C atom; in another specific embodiment, X.sub.7 is N atom.

[0216] In a specific embodiment, the ring where X.sub.4, X.sub.5, X.sub.6 and X.sub.7 are located is pyrazole ring; in another specific embodiment, the ring where X.sub.4, X.sub.5, X.sub.6 and X.sub.7 are located is imidazole ring; in another specific embodiment, the ring where X.sub.4, X.sub.5, X.sub.6 and X.sub.7 are located is thiazole ring; in another specific embodiment, the ring where X.sub.4, X.sub.5, X.sub.6 and X.sub.7 are located is oxazole ring; in another specific embodiment, the ring where X.sub.4, X.sub.5, X.sub.6 and X.sub.7 are located is triazole ring; in another specific embodiment, the ring where X.sub.4, X.sub.5, X.sub.6 and X.sub.7 are located is tetrazole ring; in another specific embodiment, the ring where X.sub.4, X.sub.5, X.sub.6 and X.sub.7 are located is

##STR00037##