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1. (WO2017096100) HETEROCYCLE COMPOUNDS AND USES THEREOF
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

is claimed is:

A compound of formula (I):


(1)

or a geometric isomer, a pliannaecutically acceptable salt, prodrug or solvate thereof, wherein

Ar is aryl; substituted aryl; heteroaryi; substituted heteroaryi; heterocyclyl, cycloalkenyl, cycloalkyi aryl; aryl fused heteroaryi; heteroaryi fused aryl; straight or branched, substituted or unsubstituted alkyl aryl or heteroaryi; substituted or unsubstituted alkenyl aryl or heteroaryi; substituted or unsubstituted alkynyl aryl or heteroaryi; arylakyl; arylalkenyl; arylalkynyl; heteroarylalkenyi; heteroarylalkenyl; heteroarylalkynyl;

one of W and Z is CH, and W is O, S, NH, NR.3 when Z is CH and Z is O, S, NH, NR3 when W is CH,

A is H, C1-C6 alkyl, -(CH2)nNR4R5, wherein n=l-6;

B is H, C 1-C6 alkyl, -(CH2)nN R4R5, wherein n=l-6;

R! is H, halogen, SH, OH, N02, CN, Ci-g alkyl, Q . alkoxy, Ci-e alkoxycarbonyl, di-Ci-g alkylamino C2-6 alkylcarbonyl, amino, C1-(5 alkylamino, di-C 1-0 alkylamino, carbamoyl, Ci_6 alkylcarbamoyl, di(Ci_6 alkyl)carbamoyl, diCi-c alkylamino C2-6 alkylcarbamoyl, sulfamoyl, Cj-6 alkylsulfonyl, Cj-s alkylsultmyl, diCi-6 alkylaminoC^ alkylsulfamoyl, di C1-0 alkylphsophonyl C}_6 alkyl, hydroxyC2-6 alkoxy, hydroxycarbonyl Ci-6 alkyl, Ci_6 alkoxy Q -e alkyl, alkylaminoC2-6 alkylamino, substituted diCi-e alkylamino C2-6 alkylamino, amino C alkyl, diCi_6 alkylaminoacetyl, hydroxydiC2-6 alkylamino, C|_6 alkylaminoC2-6 alkoxy, diCi-6 alkylaminoC2-6 alkoxy, heteroaryi, heterocycle, heterocyclic oxy, heterocyclicthio, heterocyclicsulfinyl, heterocyclic sulfonyl, heterocyclic sulfamoyl, heterocyclic C1-(s alkyl, heterocyclic Cue; alkoxy, heterocyclic amino, heterocyclic Ci-6 alkylamino, heterocyclic carbonyl, heterocyclic Ci-6 alkyl carbon yl; wherein a heterocycle is saturated or partially unsaturated 3 to 8 membered cyclic or bicvclic hetero ring with one or more N, O, S, SO, and SO2, in which C or the hetero atom may have one or more substituents that consists of C1-6 alkyl, hydroxy, hydroxy Ch alk !, Cj-6 alkylcarbonyl, C e alkyl amino, di Ci-6 alkylamino;

R2 is H, halogen, SH, OH, N02, CN, C,-6alkyl, C^ alkoxy, C^ alkoxycarbonyl, diC,_6 alkylaminoC2-6 alkylcarbonyl, amino, C 1-6 alkylamino, diCi-e alkylamino, carbamoyl, Ci-c, alkylcarbamoyl, di(Ci_6 alkyl)carbamoyl, diC;-6 alkylaminoC?^ alkylcarbamoyl, sulfamoyl, Ci-g alkylsulfonyl, C e alkylsulfinyl, diC i-6 alkyl aminoC2-<) alkylsulfamoyl, diCi-g

alkylphsophonylCi-6 alkyl, hydroxyC2-6 alkoxy, hydroxycarbonylCj.6 alkyl, Cj.6 alkoxyCj-e alkyl, diCi_6 lkylam oC2-6 alkylamino, substituted diCi-6 alkylaminoC2-6 alkylamino, aminoCi-6 alkyl, diCi-t, alkylaminoacetyl, hydroxydiC2-6 alkylamino, Ci-6 alkylaminoC2-6 alkoxy, diC1-6 alkyiaminoC2-6 alkoxy, heteroaryl, heterocycle, heterocyclic oxy,

heterocyclicthio, heterocyclicsulfinyl, heterocyclic sulfonyl, heterocyclic sulfamoyl, heterocyclic Ci -6 alkyl, heterocyclic C e alkoxy, heterocyclic amino, heterocyclic Ci-6 alkylamino, heterocyclic carbonyl, heterocyclic Ci_ alkylcarbonyl, wherein a heterocycle is saturated or partially unsaturated 3 to 8 membered cyclic or bicvclic hetero ring with one or more N, O, S, SO, and SO2, in which C or the hetero atom may have one or more substituents that consists of Ci-6 alkyl, hydroxy, hydroxy Ci-6 alkyl, C 1-6 alkylcarbonyl, Ci-6 alkyl amino, di Cj -6 alkylamino;

R" is Cj.6 alkyl, hydroxy Ci-6 alkyl, Ci-6 alkylamino C2-6 alkyl, di Ci-c, alkylaminoC2-6 alkyl, Cj. 6 alkylcarbonyl;

R4 is Ci- alkyl, hydroxy Ci-6 alkyl, C e alkylamino C2- alkyl, di Ci- alkylaminoC2-6 alkyl, Ci. 6 alkylcarbonyl; and

R5 is H, Ci-6 alkyl, hydroxy Ci.6 alkyl, Cs.e alkylamino C2- alkyl, di Cj-e alkylaminoC2-6 alkyl, Ci.6 alkylcarbonyl.

Y is H, Ci-6 alkyl, aryl; substituted aryl; heteroaryl; substituted heteroaryl: heterocyclyl, cycloalkenyl, or cycloalkyl aryl.

2. A compound according to Claim 1 , wherein W is CH.

3. A compound of claim 2 wherein Z is S.

4. A compound according to Claim 1 , wherein Z is CH.

5. A compound of claim 4 wherein W is S.

6. A compound according to Claim 1 represented by formula (II):


(Π)

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof.

7, A compound of claim 6, wherein R1 is selected from the group consisting of:


8. A compound according to Claim 1 represented by formula (III):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof.

9. A compound of claim 8, wherein R is selected from the group consisting:


I


10. A compound according to Claim 1 , wherein the compound is represented by formula (IV):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof,.

11. A compound of claim 10, wherein R1 is selected from the group consisting of:


12. A compound according to Claim 1, wherein the compound is represented by formula (V):

(V)

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof.

A com ound of claim 12, wherein R1 is selected from the group consisting


A compound according to Claim 1 represented by formula (VI):

(VI)

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof.

15. A compound of claim 14, wherein R is selected from the group consisting of:


16. A compound according to Claim 1, selected from the group consisting of

1 : N-[2-[2-(dimethylamino)ethyl-methyl-amino]-5-[[4-(l H-indol-3-yl)thieno[3,2-d]pyi-imidin-2-yl]amino]-4-methoxy-phenyl]prop-2-enamide,

2: N 2-[4-(dimethylamino)-l-piperidyl]-5 [4-(lH-indol-3-yl)thieno[3,2-d] yl]ammo]-4-methoxy-phenyl]prop-2-enamide,

3: N-[5-[[4-(lH-indol-3-yl)thieno[3,2-d]pyrimidin-2-yl]amino]-4-met oxy-2

(methylamino)- 1 -piperidyl]phenyl]prop-2~enamide,

4: N-[2-(dimethylamino)-5-[[4-[3-(dim

d]p>'Timidin-2-yl]amino]-4-methoxy-phenyl]prop-2-enamide,

5: N-[5-[[4-[3-(tert-biitylamino)p enyl]-4,4a-dihydrothieno[3,2-d]pyrimidin-2-(dimethylamino)-4-methoxy-plienyl]pi p-2-enamide,

6: N-[5-[[4-[3-(dimethylaiTuno)phenyl]-4,4a-dihydrothieno[3,2-d]p Timidi

methoxy-2-(4-methylpiperazin- 1 -yl)p enyl]prop-2-enamide,

7: N-[4-methoxy-5-[[4-[3-(methylamino)phenyl]-4,4a-dihydrothieno[3,2-d]pyrimidin-2-yl]amino]-2-(4-methylpiperazin-l-yl)phenyl]prop-2-enamide,

8 : N- [5- [ [4-[3 -( dimethyl amino)phenyl]-4,4a-dihydrothieno[3 ,2-d]pyrimidin-2-yl jamino] -4-methoxy-2-[methyl(2-morphoiinoethyl)amino]phenyl]prop-2-enamide,

9: N-[4-methoxy-5-[[4-[3-(methylainino)phenyl]-4,4a-cUhydrothieno[3,2-d]pyrimidin-2-yl]amino]-2-[methyl(2-morpholinoethyl)amino]phenyl]prop-2-enamide,

10: N-[5-[[4-[3-(dimethylamino)phenyl]-4,4a-dih)'drothieno[3,2-d]pyrn

metlioxy-2-morpholino-plienyl]prop-2-enamide,

11: N-[5-[[4-[3-(tert-butylaiTiino)phenyl]-4,4a-dihydrot eno[3,2-d]pyrimidin-2-yl]amino]-4-methoxy-2-morpholino-phenyl]prop-2-enamide,

12: N-[2-[2-(dimethylamino)ethoxy]-5-[[4-[3-(dimethylamino)phenyl]-4,4a-dihydrothieno[3,2-d]p Timidin-2-yl]amino]-4-methoxy-phenyl]prop-2-enamide,

13: N-[2-[2-(dimethylamino)ethox

dihydrothieno[3,2-d]pyrimidin-2-yl]amino]phenyl]prop-2-enamide,

14: N-[5-[[4-[3-(dimethylamino)pheny^

methoxy-2-[2-(l-piperidyl)ethoxy]p enyl]prop-2-enamide,

15: N-[4-methoxy-5-[[4-[3-(methylamino

yl]amino]-2-[2-( 1 -piperidyl)ethoxy]p enyl]prop-2-enamide,

16: l-[4-[[4-[3-(dimethylamino)phenyl]-4,4a-d&^

methoxy-2-(prop-2-enoylamino)phenyl]-N,N-dimethyl-piperidine-4-carboxaniide,

17: l-[5-methoxy-4-[[4-[3-(methylamino)phenyl]-4,4^

yl]amino]-2-(prop-2-enoylamino)phenyl]-N,N-dimethyl-piperidme-4-carboxamide,

18: N-[4-methoxy-2-(4-methylpiperazin-l-yl)-5-[(4-phenyl-4,4a-dihydroth d]pyrimidiii-2-yl)amino]phenyl]prop-2-enamide,

19: N-[5-[[4-(3-aminophenyl)-4,4a-dihydrotM^

(4-methylpiperazin- 1 -yl)phenyl]prop-2-enamide,

20: N-[2-[4-(dimethylamino)-l-piperidyl]-4-meihoxy-5-[[4-(3-methoxyphenyl) dihydrothieno[3,2-d]pyrimidin-2-yl]amino]phenyl]prop-2-enamide,

21 : N-[5-[[4-(m-indol-3-yl)tliieno[3,2-d]pyrimidin-2-yl]amino]-4-methoxy-2-(4-methylpiperazin-l-yl)phenyl]prop-2-enamide,

22: N-[4-methoxy-5-[[4-(l-methylindoI-3-yl)thieno[3,2-d]pyrimidin-2-yl]amino]-2-(4-methylpiperazin- 1 -yl)phenyl]prop-2-enamide,

23: N-[5-[[4-(lH-indol-3-yl)thieno[3,2-d]pyrimidin^

phenyl]prop-2-enamide,

24: N-[5-[[4-[3-(dimeihylamino)phenyl]tl ieno[3,2-d]p Timidm-2-yl]amino]-4-met methylpiperazin- 1 -yl)phenyl]prop-2-enamide,

25 : N- [4-methoxy-5 - [ [4- [4-(methylamino)phenyi] thieno [3 ,2 -d]pyrimidin-2 -yl] amino] -2 -(4-methylpiperazin- 1 ~yl)phenyl]prop-2-enamide,

26 : N- [4-methoxy-2 -(4-methylpiperazin- 1 -yl )- 5 - [(4-phenylthieno [3,2 -d]pyrimidin-2 -yl)amino]phenyl]prop-2-enamide,

27: N-[5-[[4-[4-(tert-butylamino)phenyl]tme

(4-methylpiperazin- 1 -yl )phenyl]piOp-2 -enamide .

28: N-[2-[4-(dimethylamino)-l-piperidyl]-4-methoxy-5-[[4-(3-methoxyphenyi)-5-med^^ 4,4a-dihydropyrrolo[3.2-d]pyrimidin-2-yl3amino]plienyl]piOp-2-enamide.

29: N-[4-methoxy-5-[[4-[2-(methylamino)phenyl]thieno[3,2-d]pyrimidin-2-yl]amino]-2-(4-methylpiperazin- 1 -yl)phenyl]prop-2-enamide,

30: N-[4-methoxy-2-(4-methylpiperazin-i-yl)-5-[(4-phenylthieno[3,2-d]pyrimidin-2-yl)amino]phenyl]prop-2-enamide,

31 : N-[2-[2-(dimethylamino)ethyl-meihyl-amino]-4-methoxy-5-[[4-[2-(methylamino)phenyl]thieno[3,2-d]pyrimidin-2-yl]amino]phenyl]prop-2-enamide,

32: N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[(4-phenylthieno[2,3-d]p Timidin-2-yl)amino]phenyl]prop-2-enamide,

33 : N- [2- [2-(dimethylamino)ethyl-methyl- amino] -4-methoxy-5 - [ [4- [3 -(methylamino)p enyl]thieno[2,3-d]pyrimidin-2-yl]amino]phenyl]prop-2 -enamide,

34: N-[4-methoxy-5-[[4-(l -methylindol-3-yl)thieno[3,2-d]pyTimidin-2-yl]ami

ιηοφ1ιο1ίηοεί1ιοχ>')ρ1ΐ6η)Ί]ρΐΌρ-2 -enamide.

35: N-[4-methoxy~5-[[4-[3-(methylamino)ph

mo^")holinoet oxy)phenyl]prop-2-enamide,

36: N-[4-methoxy-5-[[4-(l-methylindo

morpholino-phenyl]prop~2-enamide,

37: N-[4-methoxy-5-[[4-[4-(methylamino)phenyl]thieno[3,2-d]pyrimicUn-2-yl]amino]-2-morpholino-phenyl]prop-2-enamide,

38: N-[2-(dimethylamino)-4-metlioxy-5-[[4-(l-methylmdol-3-yl)t ieno[3,2-yl]amino]phenyl]prop-2-enamide,

39 : N- [2- [ethyl(methyl)amino] -4-methoxy-5 - [ [4- [4-(metliylamino)phenyl] thieno [3,2-d]pyrimidin-2-yl]amino]phenyl]prop-2-enamide,

40: N-[2-[ethyl(methyl)amino]-4-methoxy-5-[(4-p enylthieno[2,3-d]pyrimidin-2-yl)amino]phenyl]prop-2-enamide,

41 : N-[2-[ethyl(methyI)ammo]-4-methoxy~5-[[4-[3^

d]p Timidin-2-yl]amino]phenyl]prop-2-enamide,

42: N-[4-methoxy-2-(4-methylpiperazin-l-yl)-5-[(4-phenyithieno[2,3-d]p>Timidin-2-yl)amino]phenyl]prop-2-enamide,

43: N-[4-methoxy-5-[[4-[2-(methylamino)phen^

methylpiperazin-l-yl)phenyl]prop-2-enamide,

44: N-[4-methoxy-5-[[4-(l-methylindol-7-yl)thieno[3,2-d]pyrimidin-2-yl]amino]-2-(4-methylpiperazin- i -yl)phenyl]prop-2-enamide,

45: N-[5-[[4-(lH-indol-7-yl)thieno[3,2-d]pyrimidin-2-yl]amino]-4-methoxy-2-(4-methylpiperazin-l-yl)phenyl]prop-2-enamide,

46: N-[4-methoxy~2-(4-methylpipera^

d]pyrimidin-2-yl]amino]phenyl]prop-2-enamide,

47: N-[4-methoxy-2-(4-methylpiperazin-l-yl)-5-[[4-(lH^yrroi-3-yl)thie

2-yl]amino]phenyl]prop-2-enamide,

48: N-[4-methoxy-2-(4-methylpiperazin-l -yl)-5-[[4-( 1 -methylpyrrol-3-yi)thieno[3,2-d]pyrimidin-2-yl]amino]phenyl]prop-2-enamide,

49: N-[4-methoxy-2-(4-memylpiperazin^

2-yl]amino]phenyl]prop-2-enamide, and

50: N-[5 [4-[2-(dmiethylam o)phenyl]tM

methylpiperazin- 1 -yl)phenyl]prop-2-enamide.

51: N-[5-[[4-(lH-indol-3-yl)thieno[3,2~d]p}Tm

mo^")holino-phenyl]prop-2-enamide

52: N-[4-methoxy-5-[met yl-[4-(l-methylindol-3-yl)thieno[3,2-d]pyrim^

2-morpliolino-phenyl]prop-2-enamide

53: N-[2-[2-(dimethylamino)e l-methyl-amino]-5-[[4-(lH-indol-3-yl)thieno[3,2-d]p Timidin-2-yl]-methyl-amino]-4-methoxy-phenyl]prop-2-enamide

54: N-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[methyl-[4-(l-metl ylindol-3-yl)thieno[3,2-d]pyrimidin-2-yl]amino]phenyl]prop-2-enamide

17. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a geometric isomer, enaniiomer, diastereomer, racemate, pharmaceutically acceptable salt, prodrugs or solvate thereof, and a pharmaceutically acceptable excipient.

18. A method for inhibiting the growth of a cancer cell which overexpresses Bruton's tyrosine kinase, ITK, JAK3, and epidermal growth factor receptor (EGFR), comprising administering an effective amount of a compound of claim 1 to the cell.

19. A method for mhibitmg the growth of a cancer cell according to claim 18, wherein the cancer cell overexpresses BTK.

20. A method for treating a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 17.

21. The method of claim 20, wherein the subject suffers from a hematological cancer.

22. The method of claim 21, wherein the hematological cancer is CLL of DLBCL.

23. A method for inhibiting the growth of a cancer ceil according to claim 18, wherein the EGFR expressed by the cancer cell is a mutant EGFR.

24. A method for inhibiting the growth of a cancer cell according to claim 23, wherein the a mutant EGFR is a T709M mutant, an L858R mutant or a delE746-A750 mutant.

25. The method according to claim 24, wrherein the subject is a human, and suffers from a diseased caused by abnormal cell proliferation.

26. The method according to claim 25, wherein the abnormal cell proliferation is caused by overexpression of EGFR.

27. The method according to claim 26, wherein the abnormal cell proliferation is caused by overexpression of EGFR selected from the group consisting of ErbBl, ErbB32, ErbB3, and ErbB4.

28. The method according to claim 26, wherein the disease is a relapsed or acquired resistant malignant disease.

The method according to claim 23, wherein the subject is a human suffering from