IP Library › Granted Patent US 7,250,427

Granted Patent B2

US 7,250,427 · App. 11/168,107 · Granted Jul 31, 2007

Aryl-substituted benzimidazole and imidazopyridine ethers

Assignee: Janssen Pharmaceutica, N.V.

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Quick Facts

Patent No.: US 7,250,427
App. No.: 11/168,107
Granted: Jul 31, 2007
Kind: B2

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Abstract

Aryl substituted benzimidazole and imidazo[4,5]pyridine ethers are described as inhibitors of Cds1 and useful as adjuvants to chemotherapy or radiation therapy in the treatment of cancer.

Claims (152)

1. A compound having Cds1 modulating activity of formula (I):

wherein

W is —COOH, —(CO)NH 2 , or —(SO 2 )NH 2 ;

Q is N or CH;

R a and R b are each independently selected from —H and halogen;

R c is absent or is independently selected from the group consisting of —OH, —CF 3 , —C 1-4 alkyl, —OC 1-4 alkyl, —NO 2 , and halo;

n is selected from the group consisting of 0, 1, and 2;

m is selected from the group consisting of 0, 1, and 2;

R d is —H or —C 1-4 alkyl, optionally mono- or di-substituted with a substituent selected from the group consisting of —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —OH, and —OC 1-4 alkyl;

A is selected from the group consisting of —CR e OH and —R y R z , where if A is —NR y R z , m+n must be greater than zero;

R e is —H or —C 1-4 alkyl, optionally mono- or di-substituted —C 1-4 alkyl with a substituent selected from the group consisting of —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —OH, —OC 1-4 alkyl, —CF 3 , and fluoro;

alternatively, R d and R e may be taken together with their carbons of attachment to form an aliphatic hydrocarbon ring, said ring having four to seven members, optionally having one or two unsaturated bonds in the ring, and optionally substituted with a substituent selected from the group consisting of —C 1-4 alkyl, —OC 1-4 alkyl, and fluoro;

R y is independently selected from the group consisting of —H, —C 1-4 alkyl optionally substituted with —OC 1-4 alkyl, and benzyl optionally mono- or di-substituted with —OC 1-4 alkyl, —C 1-4 alkyl, or halo;

alternatively, R d and R y may be taken together with their atoms of attachment to form a five to eight-membered heterocyclic ring, with the heterocyclic ring having zero or one unsaturated bonds, having zero, one, or two carbon members which is a carbonyl, having zero or one additional heteroatom members selected from the group consisting of O, S, —N═, >NH, and >NC 1-4 alkyl and separated from the nitrogen of R y attachment by at least one carbon member, and optionally having a substituent selected from the group consisting of —C 1-4 alkyl, —OC 1-4 alkyl, and fluoro;

R z is —H or is selected from the group consisting of —C 1-6 alkyl, —C 3-6 cycloalkyl, —C 1-4 alkylC 3-6 cycloalkyl, phenyl, benzyl, pyridylmethyl, —C(O)C 1-6 alkyl, —C(O)phenyl, —C(O)pyridyl, —C(O)OC 1-6 alkyl, and —C(O)Obenzyl, each optionally mono-, di-, or tri-substituted with a substituent selected from the group consisting of —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —OH, —OC 1-4 alkyl, —C 1-4 alkyl, and halo; and

alternatively, R y and R z may be taken together with the nitrogen of attachment to form an otherwise aliphatic hydrocarbon ring, said ring having five to seven members, optionally having one carbon replaced with >O, >S(═O) 0-2 , ═N—, >NH, and >N(C 1-4 alkyl), optionally having one or two unsaturated bonds in the ring, and optionally having a substituent selected from the group consisting of —C 1-4 alkyl, —OC 1-4 alkyl, and fluoro;

and enantiomers, diastereomers, and pharmaceutically acceptable salts, esters or amides thereof.

2. The compound of claim 1 wherein W is —(CO)NH 2 .

3. The compound of claim 1 wherein Q is CH.

4. The compound of claim 1 wherein R a and R b are each independently —H, —Cl, or —F.

5. The compound of claim 1 wherein R a is —H and R b is —Cl or —F.

6. The compound of claim 1 wherein R a and R b are —H.

7. The compound of claim 1 wherein R c is absent or is selected from the group consisting of —OH, —CH 3 , —CH 2 CH 3 , —F, —Cl, —Br, —I, —CF 3 , and —OCH 3 .

8. The compound of claim 1 wherein R c is selected from the group consisting of —F, —Cl, —CH 3 , and —OCH 3 .

9. The compound of claim 1 wherein R c is absent.

10. The compound of claim 1 wherein R d is selected from the group consisting of —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , and —C(CH 3 ) 3 , where the alkyl members are optionally mono- or di-substituted.

11. The compound of claim 1 wherein R d is selected from the group consisting of —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 OCH 3 , and —CH 2 CH 2 N(CH 3 ) 2 .

12. The compound of claim 1 wherein R d is —H.

13. The compound of claim 1 wherein R e is selected from the group consisting of —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , and —C(CH 3 ) 3 , where the alkyl members are optionally mono- or di-substituted.

14. The compound of claim 1 wherein R e is selected from the group consisting of —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 OCH 3 , and —CH 2 CH 2 N(CH 3 ) 2 .

15. The compound of claim 1 wherein R e is —H or —CH 3 .

16. The compound of claim 1 wherein R d and R e taken together with their carbons of attachment form a hydrocarbon ring selected from the group consisting of cyclopentyl, cyclopentenyl, cyclohexyl, fluorocyclohexyl, methoxycyclohexyl, and cycloheptyl.

17. The compound of claim 1 wherein R d and R e taken together with their carbons of attachment form cyclopentyl or cyclohexyl.

18. The compound of claim 1 wherein R y is selected from the group consisting of —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 (CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , and —C(CH 3 ) 3 , where the alkyl members are optionally mono- or di-substituted.

19. The compound of claim 1 wherein R y is selected from the group consisting of —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , and —CH 2 CH 2 CH 2 CH 3 .

20. The compound of claim 1 wherein R y is —H or —CH 3 .

21. The compound of claim 1 wherein R d and R y taken together with their atoms of attachment form a heterocyclic ring selected from the group consisting of pyrrolidine, pyrrolidinone, 2,3-dihydropyrrole, piperidine, piperidinone, morpholine, thiomorpholine, piperazine, and piperazinone, where the rings are optionally substituted.

22. The compound of claim 1 wherein R d and R y taken together with their atoms of attachment form a heterocyclic ring selected from the group consisting of pyrrolidinyl, piperidinyl, 4-fluoropiperidinyl, 4-methoxy piperidinyl, and 3-methylpiperidinyl.

23. The compound of claim 1 wherein R d and R y taken together with their atoms of attachment form a piperidine ring.

24. The compound of claim 1 wherein R z is —H or is selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , cyclopentyl, cyclohexyl, cyclopropylethyl, phenyl, benzyl, pyridylmethyl, acetyl, propionyl, benzoyl, —C(O)pyridyl, —C(O)OC(CH 3 ) 3 , and —C(O)Obenzyl, where each group member is optionally mono-, di-, or tri-substituted.

25. The compound of claim 1 wherein R z is selected from the group consisting of —CH 3 , 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, acetyl, trifluoroacetyl, benzoyl, and —C(O)C(CH 3 ) 3 .

26. The compound of claim 1 wherein R y and R z are taken together with the nitrogen of attachment to form a ring selected from the group consisting of pyrrolidine, pyrrolidinone, 2,3-dihydropyrrole, piperidine, piperidinone, morpholine, thiomorpholine, piperazine, and piperazinone, where said rings are optionally substituted.

27. The compound of claim 1 wherein R y and R z are taken together with the nitrogen of attachment to form a ring selected from the group consisting of pyrrolidinyl, piperidinyl, 4-fluoropiperidinyl, 4-methoxypiperidinyl, and 3-methylpiperidinyl.

28. The compound of claim 1 wherein R y and R z taken together with their atoms of attachment form a piperidine ring.

29. A compound selected from the group consisting of:

2-[4-(3-Hydroxy-propoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(2-Hydroxy-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(3-Hydroxy-cyclopentyloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(4-Hydroxy-cyclohexyloxy)-phenyl]-1H-benzoimidazole-5-arboxylic acid amide;

2-[4-(4-Hydroxy-cyclohexylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide (cis and trans isomers);

2-[3-(3-Dimethylamino-propoxy)phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(3-Dimethylamino-propoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Methyl-piperidin-4-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Benzyl-piperidin-4-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Benzyl-piperidin-3-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Methyl-pyrrolidin-3-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Benzyl-pyrrolidin-3-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-{2-[4-(5-Carbamoyl-1H-benzoimidazol-2-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester;

4-{2-[4-(5-Carbamoyl-1H-benzoimidazol-2-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester;

3-[4-(5-Carbamoyl-1H-benzoimidazol-2-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester;

4-[4-(5-Carbamoyl-1H-benzoimidazol-2-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl-ester;

4-[4-(5-Carbamoyl-1H-benzoimidazol-2-yl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester;

3-[4-(5-Carbamoyl-1H-benzoimidazol-2-yl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester;

2-[4-(2-Piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(2-Piperidin-4-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(Piperidin-3-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(Piperidin-4-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(Piperidin-4-ylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(Piperidin-3-ylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-(4-Methyl-benzyl)-piperidin-2-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-(4-Methoxy-benzyl)-piperidin-2-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-(4-Chloro-benzyl)-piperidin-2-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-(3,4-Dichloro-benzyl)-piperidin-2-yl]-ethoxy}-henyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-(1-Benzyl-piperidin-2-yl)-ethoxy-}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[2-(1-Benzyl-piperidin-4-yl)-ethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-(4-Methyl-benzyl)-piperidin-4-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-(4-Methoxy-benzyl)-piperidin-4-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-(4-Chloro-benzyl)-piperidin-4-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-3,4-Dichloro-benzyl)-piperidin-4-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[1-(4-Chloro-benzyl)-piperidin-3-yloxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Benzyl-piperidin-3-ylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[1-(4-Methyl-benzyl)-piperidin-3-ylmethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[1-(4-Methoxy-benzyl)-piperidin-3-ylmethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[1-(4-Chloro-benzyl)-piperidin-3-ylmethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[1-(3,4-Dichloro-benzyl)-piperidin-3-ylmethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Benzyl-piperidin-4-ylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[1-(4-Methyl-benzyl)-piperidin-4-ylmethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[1-(4-Methoxy-benzyl)-piperidin-4-ylmethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylmethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[2-(1-Acetyl-piperidin-2-yl)-ethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[2-(1-Acetyl-piperidin-4-yl)-ethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Acetyl-piperidin-3-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Acetyl-piperidin-4-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Acetyl-piperidin-4-ylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Acetyl-piperidin-3-ylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[2-(1-Benzoyl-piperidin-2-yl)-ethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[2-(1-Benzoyl-piperidin-4-yl)-ethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; and

2-[4-(1-Benzoyl-piperidin-4-ylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide.

30. The compound of claim 1 selected from the group consisting of:

2-[4-(2-Hydroxy-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

cis-2-[4-(4-Hydroxy-cyclohexylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Benzyl-piperidin-4-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

2-[4-(1-Benzyl-piperidin-3-yloxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide;

3-[4-(5-Carbamoyl-1H-benzoimidazol-2-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester;

4-[4-(5-Carbamoyl-1H-benzoimidazol-2-yl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester;

2-(4-{2-[1-(4-Methylbenzyl)-piperidin-2-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-(4-Methoxybenzyl)-piperidin-2-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-(4-Chloro-benzyl)-piperidin-2-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-(4-{2-[1-(3,4-Dichloro-benzyl)-piperidin-2-yl]-ethoxy}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;

2-{4-[2-(1-Benzyl-piperidin-2-yl)-ethoxy]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide;