IP Library Granted Patent US 8,759,520
Granted Patent B2
US 8,759,520 · App. 13/132,429 · Granted Jun 24, 2014

Compounds for treating cancer

Inventors: Stephen Peter East (Wallingford, GB); Mark Whittaker (Abingdon, GB); Osamu Ichihara (Didcot, GB); Adrian Kotei Kotey (Didcot, GB); Smantha Jayne Bamford (Didcot, GB)
Assignee: Boehringer Ingelheim International GmbH
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Quick Facts
Patent No.
US 8,759,520
App. No.
13/132,429
Granted
Jun 24, 2014
Kind
B2
Abstract

Compounds of general formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are as defined herein are inhibitors of Bcl-2 and are useful for treating diseases characterized by abnormal cell growth and/or dysregulated apoptosis.

Claims (113)

1. A compound of the formula (I):

wherein

X is (CH 2 ) m optionally substituted with one or more substituents selected from the group consisting of methyl and ethyl, when m is 1; or

X is (CH 2 ) m optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, OH and halo, when m is 2, 3 or 4;

m is an integer from 1 to 4;

R 1 is R 7 , OR 7 , SR 7 , NHR 7

R 7 is H, aryl or heteroaryl optionally substituted with halo, —NO 2 , —CN, —R 8 , —OR 8 , —C(O)OR 8 , —C(O)R 8 , —C(O)N(R 8 ) 2 , —C(O)NHSO 2 R 8 , —SOR 8 , —SO 2 R 8 , —SO 2 N(R 8 ) 2 , —N(R 8 ) 2 , —NR 8 C(O)R 8 ,

each R 8 is independently H or C 1 -C 4 alkyl;

Y is (CH 2 ) n

n is an integer from 1 to 6;

R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, —OR 14 , —C(O)N(R 14 ) 2 , —S(O)R 14 , —S(O) 2 R 14 , —S(O) 2 N(R 14 ) 2 , —N(R 14 ) 2 , —NR 14 C(O)R 14 , —C(O)OR 14 , —C(O)R 14 , —SR 14 , NO 2 and CN;

R 14 is hydrogen or C 1 -C 6 alkyl, phenyl or a 5- or 6-membered heteroaryl group, wherein the alkyl, phenyl and heteroaryl groups may optionally be substituted with one or more substituents chosen from halo, CF 3 , CN, NO 2 , OCH 3 , and, for phenyl and heteroaryl groups, C 1 -C 4 alkyl; and

R 2 is a group R 10 , where R 10 is a 5- or 6-membered aryl or heteroaryl group substituted by a group R 12 , where R 12 is a 5- or 6-membered carbocyclic or heterocyclic group, —(C 1 -C 4 alkyl)(C 5 -C 6 carbocyclyl) or —(C 1 -C 4 alkyl)(C 5 -C 6 heterocyclyl) which, in turn is optionally substituted by a group R 13 ;

R 13 is -carbocyclyl, -heterocyclyl, -aryl, -heteroaryl, —C 1 -C 6 alkyl(carbocyclyl), —C 1 -C 6 alkyl(heterocyclyl), -C 1 -C 6 alkyl(aryl) or

—C 1 -C 6 alkyl(heteroaryl), which is optionally substituted with one or more substituents chosen from halo and C 1 -C 6 alkyl, -carbocyclyl,

-heterocyclyl, -aryl, -heteroaryl, any of which may optionally be substituted with one or more substituents chosen from halo, CN, NO 2 , O(C 1 -C 4 alkyl) and C 1 -C 4 alkyl;

or a tautomer or pharmaceutically acceptable salt thereof.

2. A compound of the formula (I), as claimed in claim 1 , wherein R 12 is a 5- or 6-membered carbocyclic or heterocyclic group which may be substituted by one or more substituents including a group R 13 .

3. A compound of the formula (I), as claimed in claim 1 , wherein R 12 is piperazine, for example 1,4-piperazine optionally substituted with a substituent R 13 at the 4-position.

4. A compound of the formula (I), as claimed in claim 1 , wherein R 13 is C 5 -C 6 carbocyclyl, C 5 -C 6 aryl, —CH 2 (C 5 -C 6 carbocyclyl) or —CH 2 (C 5 -C 6 aryl), any of which may optionally be substituted with one or more substituents chosen from halo and C 1 -C 6 alkyl, -carbocyclyl,

-heterocyclyl, -aryl, -heteroaryl, any of which may optionally be substituted with one or more substituents chosen from halo, CN, NO 2 , O(C 1 -C 4 alkyl) and C 1 -C 4 alkyl.

5. A compound of the formula (I), as claimed in claim 1 , wherein R 13 is —CH 2 (C 5 -C 6 carbocyclyl) or —CH 2 (C 5 -C 6 aryl), either of which may optionally be substituted with one or more halo or methyl groups and/or with a 5- or 6-membered aryl or heteroaryl group which is in turn optionally substituted with halo.

6. A compound of the formula (I), as claimed in claim 1 , wherein R 13 is —CH 2 (biphenyl) optionally substituted with halo or —CH 2 (2-phenyl-1,2-cyclohexenyl) optionally substituted with one or two methyl groups and/or with one or more halo substituents.

7. A compound of the formula (I), as claimed in claim 1 , wherein Y is CH 2 .

8. A compound of the formula (I), as claimed in claim 1 , wherein:

X is (CH 2 ) m , where m is 1 to 3 and which, when m is 2 or 3, is optionally substituted with OH; and

R 1 is OR 7 or SR 7 , where R 7 is phenyl optionally substituted with halo, C(O)OR 8 .

9. A compound as claimed in claim 1 selected from the group consisting of:

1-Benzyl-3-pyridin-2-ylmethyl-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-Benzyl-3-pyridin-3-ylmethyl-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-Benzyl-3-pyridin-4-ylmethyl-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-Benzyl-3-(tetrahydro-pyran-4-ylmethyl)-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(4-Bromo-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(3-Bromo-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(4-Bromo-benzyl)-3-(2-phenylsulfanyl-ethyl)-1,3-dihydro-benzoimidazol-2-ylideneamine;

{3-[3-(4-Fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-acetic acid ethyl ester;

1-[3-(4-Chloro-phenoxy)-propyl]-3-pyridin-4-ylmethyl-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(3-Chloro-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(3,4-Dichloro-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(4-Bromo-benzyl)-3-[3-(4-chloro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(4-Bromo-benzyl)-3-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(4-Bromo-benzyl)-3-[3-(4-nitro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

3-{3-[3-(4-Fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzoic acid methyl ester;

1-(4′-Fluoro-biphenyl-4-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-3-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-Benzyl-3-[4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(4-Chloro-benzyl)-piperazin-1-yl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(2-Chloro-benzyl)-piperazin-1-yl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(3-Chloro-benzyl)-piperazin-1-yl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[4-(4-Benzyl-piperazin-1-yl)-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(4-{4-[2-(4-Chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(4′-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-O-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[3-(4-Biphenyl-2-ylmethyl-piperazin-1-O-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{3-[4-(4′-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-O-benzyl]-3-(3-phenoxy-propyl)-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[3-(4-Biphenyl-2-ylmethyl-piperazin-1-O-benzyl]-3-(3-phenoxy-propyl)-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(4′-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-3-(3-phenoxy-propyl)-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(3-{4-[2-(4-Chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(4-{4-[2-(4-Chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-3-(3-phenoxy-propyl)-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(4′-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-3-(2-phenylsulfanyl-ethyl)-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(2-Chloro-thiazol-4-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[2-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-thiazol-4-ylmethyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{2-[4-(4′-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-thiazol-4-ylmethyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(2-{4-[2-(4-Chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-thiazol-4-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[2-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(4-Chloro-benzyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[3-(4-Fluoro-phenoxy)-propyl]-3-[4-(4-phenyl-piperazin-1-ylmethyl)-benzyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(3-Chloro-phenyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

N-(2-Chloro-phenyl)-2-(4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzylamino)-acetamide;

1-{4-[4-(2-Chloro-phenyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

N-(4-Chloro-phenyl)-2-(4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzylamino)-acetamide;

1-[4-(4-Benzyl-piperazin-1-ylmethyl)-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(3-Chloro-benzyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{4-[4-(2-Chloro-benzyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-ylmethyl)-benzyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

N-(3-Chloro-phenyl)-2-(4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzylamino)-acetamide;

2-(4-{3-[3-(4-Fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzylamino)-N-phenyl-acetamide;

1-(6-Chloro-pyridin-3-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[6-(4-Benzyl-piperazin-1-yl)-pyridin-3-ylmethyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{6-[4-(3-Chloro-benzyl)-piperazin-1-yl]-pyridin-3-ylmethyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{6-[4-(4-Chloro-benzyl)-piperazin-1-yl]-pyridin-3-ylmethyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-[6-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-pyridin-3-ylmethyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-{6-[4-(2-Chloro-benzyl)-piperazin-1-yl]-pyridin-3-ylmethyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

3-(4-Bromo-benzyl)-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine;

3-(4-Bromo-benzyl)-5-fluoro-1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(4-Bromo-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-5-trifluoromethyl-1,3-dihydro-benzoimidazol-2-ylideneamine;

1-(4-Bromo-benzyl)-5-fluoro-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

3-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine;

3-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-5-fluoro-1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

3-(4-{4-[2-(4-Chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-5-fluoro-1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine;

3-{3-[3-(4-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid ethyl ester;

4-{3-[3-(4-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid methyl ester;

4-{3-[3-(3-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid methyl ester;

3-{3-[3-(3-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid ethyl ester;

3-(3-{3-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid ethyl ester;

3-(3-{3-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid;

3-[3-(3-Benzyl-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester;

3-{3-[3-(4-Fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzoic acid;

3-[3-(3-{4-[4-(4′-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester;

3-[3-(3-{4-[4-(4′-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid;

3-{3-[3-(3-{4-[2-(4-Chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid;

1-[3-(3-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-3-(4-fluoro-phenoxy)-propan-2-ol;

1-[3-(4-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-3-(4-fluoro-phenoxy)-propan-2-ol;

1-(3-Benzyl-2-imino-2,3-dihydro-benzoimidazol-1-yl)-3-phenoxy-propan-2-ol;

1-{3-[3-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-3-(4-fluoro-phenoxy)-propan-2-ol;

1-{3-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-3-(4-fluoro-phenoxy)-propan-2-ol;

3-{3-[3-(3-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid;

3-{3-[3-(4-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid; and

N-(3-{3-[3-(3-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoyl)-methanesulfonamide;

or a tautomer, or pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 12, 2011
From: EAST, STEPHEN PETER; WHITTAKER, MARK; ICHIHARA, OSAMU; KOTEY, ADRIAN KOTEI; BAMFORD, SAMANTHA JAYNE
To: BOEHRINGER-INGELHEIM INTERNATIONAL GMBH
Reel/Frame 026885/0404 →
Priority Claims (2)
EP 08253914 · Dec 8, 2008 · regional
GB 0914322.3 · Aug 14, 2009 · national
Continuity (1)
Related Publication 20110312969A1 · Dec 22, 2011