You’re using a public version of DrugPatentWatch with 5 free searches available | Register to unlock more free searches. CREATE FREE ACCOUNT

Last Updated: March 29, 2024

Claims for Patent: 7,081,454


✉ Email this page to a colleague

« Back to Dashboard


Summary for Patent: 7,081,454
Title:Tyrosine kinase inhibitors
Abstract: The present invention provides compounds of formula I ##STR00001## and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase enzymes thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases which can be treated by inhibiting tyrosine kinase enzymes.
Inventor(s): Wittman; Mark D. (Wallingford, CT), Balasubramanian; Neelakantan (Madison, CT), Velaparthi; Upender (North Haven, CT), Zimmermann; Kurt (Durham, CT), Saulnier; Mark G. (Higgannum, CT), Liu; Peiying (Madison, CT), Sang; Xiaopeng (Glastonbury, CT), Frennesson; David B. (Nauatuck, CT), Stoffan; Karen M. (Hartford, CT), Tarrant; James G. (Hamden, CT), Marinier; Anne (Kirkland, CA), Roy; Stephan (St-Lambert, CA)
Assignee: Bristol-Myers Squibb Co. (Princeton, NJ)
Application Number:10/263,448
Patent Claims:1. A compound according to formula I ##STR00732## its enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, prodrugs and solvates thereof; wherein X is C; Y is O; W is N, R.sup.3 is an optionally substituted morpholine, or homomorpholine; R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, --OR.sup.60, --NO.sub.2, --OH, --SR.sup.60, --NR.sup.60R.sup.61, --CN, --CO.sub.2R.sup.60, --CONR.sup.60R.sup.61, OCONR.sup.60R.sup.61, --NR.sup.62CONR.sup.60R.sup.61, --NR.sup.60SO.sub.2R.sup.61, --SO.sub.2NR.sup.60R.sup.61, --SO.sub.2R.sup.63, --C(NR.sup.62)NR.sup.60R.sup.61, aryl, --(CH.sub.2).sub.nOR.sup.60, --(CH.sub.2).sub.nNR.sup.60R.sup.61, --(CH.sub.2).sub.nSR.sup.60, --(CH.sub.2).sub.naryl, --NH-Z-aryl, and; wherein n is 1 to 3; and Z is selected from the group consisting of C.sub.1 C.sub.4 alkyl, alkenyl, and alkynyl chain; Z having one or more hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, NR.sup.60SO.sub.2R.sup.61 groups; Z optionally incorporating one or more groups selected from the group consisting of CO, CNOH, CNOR.sup.60, CNNR.sup.60, CNNCOR.sup.60 and CNNSO.sub.2R.sup.60; and R.sup.60, R.sup.61, R.sup.62, and R.sup.63 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, and alkyl-R.sup.25; R.sup.25 is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, cyano, halo, sulfoxy, sulfonyl, --NR.sup.30COOR.sup.31, --NR.sup.30C(O)R.sup.31, --NR.sup.30SO.sub.2R.sup.31, --C(O)NR.sup.30R.sup.31; and R.sup.30 and R.sup.31 are, independently, hydrogen, alkyl, or cycloalkyl.

2. The compound according to claim 1 wherein R.sup.1, R.sup.7, R.sup.8 and R.sup.9 are H; R.sup.2 and R.sup.4 are H or F; R.sup.5 is selected from the group consisting of H, methyl, ethyl, isopropyl, secondary butyl, cyclopropyl, F, and CF.sub.3; R.sup.6 is selected from the group consisting of H, NHCH.sub.2CH(OH)aryl, and NHCH(CH.sub.2OH)CH.sub.2aryl; R.sup.60 is selected from the group consisting of H, alkyl, cycloalkyl, and alkyl-R.sup.25 wherein R.sup.25 is hydrogen, alkenyl, hydroxy, thiol, thioalkoxy, alkoxy, thioalkoxy, halo, cyano, sulfoxy, sulfonyl, --NR.sup.30COOR.sup.31, --NR.sup.30C(O)R.sup.31, --NR.sup.30SO.sub.2R.sup.31, or (O)NR.sup.30R.sup.31; and R.sub.30 and R.sub.31 are, independently, hydrogen, alkyl, or cycloalkyl.

3. A compound according to claim 2 wherein R.sup.3 is morpholine, homomorpholine.

4. The compound according to claim 3 wherein said morpholine, or homomorpholine is substituted with hydroxy, thiol, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, alkyl-R.sup.25 --NHC(O)R.sup.15, or --NHCO.sub.2R.sup.15, wherein R.sup.15 is hydrogen, alkyl, aryl or alkyl-R.sup.25.

5. The compound according to claim 1 wherein R.sup.1 is --CO.sub.2R.sup.60.

6. The compound according to claim 1 wherein R.sup.9 is --SO.sub.2R.sup.63 and R.sup.63 is a haloalkyl.

7. The compound according to claim 2 wherein R.sup.6 is selected from the group consisting of H, NHCH.sub.2CH(OH)aryl, and NHCH(CH.sub.2OH)CH.sub.2aryl.

8. The compound according to claim 7 wherein said aryl is an optionally substituted phenyl.

9. The compound according to claim 8 wherein said phenyl is substituted with at least one Br, Cl, F, --CN, methoxy, or --NHSO.sub.2CH.sub.3.

10. The compound according to claim 8 wherein said substituent is 3-Br, 3-Cl or 3-F.

11. The compound according to claim 8 wherein said substituent is 4-F or 4-methoxy.

12. A compound having the formula: ##STR00733## wherein R.sup.12 and R.sup.13 are, independently, hydrogen, alkyl, or alkyl-R.sup.25 wherein R.sup.25 is hydrogen, hydroxy, thiol, alkenyl, amino, alkoxy, thioalkoxy, halo, cyano, sulfoxy, sulfonyl, --CO.sub.2H, --C(O)NR.sup.30R.sup.31, --NR.sup.30SO.sub.2R.sup.31, --NR.sup.30C(O)R.sup.31, --NR.sup.30C(O)OR.sup.31; R.sup.17, R.sup.18 and R.sup.19 are, independently, hydrogen, halogen, or alkoxy; and R.sup.30and R.sup.31 are, independently, hydrogen, or alkyl.

13. The compound according to claim 12 wherein R.sup.12 is hydrogen, methyl, hydroxymethyl, methoxymethyl, CH.sub.2F, CH.sub.2CN, CO.sub.2H, or --CONR.sup.30R.sup.31 wherein R.sup.30 and R.sup.31 are, hydrogen.

14. The compound according to claim 12 wherein R.sup.12 and R.sup.13 are each independently H or methyl; R.sup.17 is Br, F, or Cl; R.sup.18 is methoxy or fluoro; and R.sup.19 is H.

15. The compound according to claim 12 wherein R.sup.12 and R.sup.13 are methyl; R.sup.17 is Br, F or Cl, R.sup.18 is hydrogen or methoxy; and R.sup.19 is H.

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

17. The pharmaceutical composition according to claim 16 further comprising at least one other anti-cancer agent formulated as a fixed dose.

18. The pharmaceutical composition according to claim 17, wherein said anti-cancer agent is selected from the group consisting of: tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene, megestrol acetate, anastrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotephan, vincristine, taxol, taxotere, etoposide, teniposide, amsacrine, irinotecan, topotecan, an epothilone, Iressa, OSI-774, angiogenesis inhibitors, EGF inhibitors, MEK inhibitors, VEGF inhibitors, CDK inhibitors, Her1 and Her2 inhibitors and monoclonal antibodies.

19. A compound according to claim 1 having the formula (S)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-morpholin-- 4-yl-1H-benzoimidazol-2-yl)-1H-pyridin-2-one.

20. A compound according to claim 1 selected from the group consisting of: (.+-.)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-mor- pholin-4-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one; (.+-.)-4-[2-(3-Bromo-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-morpholi- n-4-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one; (.+-.)-4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-- 6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one; (S)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-morpholin-- 4-yl-1H-benzoimidazol -2-yl)-1H-pyridin-2-one; (S)-4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-m- orpholin-4-yl-1H-benzoimidazol-2-yl)-1H-pyridin-2-one; (S)-4-[2-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-m- orpholin-4-yl-1H-benzoimidazol-2-yl)-1H-pyridin-2-one; (S)-4-[2-(3-Chloro-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-- morpholin-4-yl-1H-benzoimidazol-2-yl)-1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-2(S)-hydroxy-ethylamino]-3-[4-methyl-6-[2(S),6(R)-- dimethyl-morpholine-4-yl]-1H-benzoimidazol-2-yl]-1H-pyridine-2-one; 4-[2-(3-Bromo-4-methoxy-phenyl)-2(S)-hydroxy-ethylamino]-3-[4-methyl-6-[2- (S),6(R)-dimethyl-morpholine-4-yl]-1H-benzoimidazol-2-yl]-1H-pyridine-2-on- e; 4-[2-(3-Chloro-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-fluorometh- yl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-chloro-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-fluoromethyl- -morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-flu- oromethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-flu- oromethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-fl- uoromethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one- ; 4-[2-(3-chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-f- luoromethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-on- e; 4-[2-(7-Bromo-2,3-dihydro-benzofuran-5-yl)-(S)-2-hydroxy-ethylamino]-3-- {6-[(R)-2-fluoromethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-p- yridin-2-one; 4-[2-(3-Chloro-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-hydroxymethy- l-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-chloro-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-hydroxy-meth- yl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-hyd- roxymethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one- ; 4-[2-(3-bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-hy- droxy-methyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-o- ne; 4-[2-(3-Chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2- -hydroxymethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2- -one; 4-[2-(3-chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)- -2-hydroxy-methyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridi- n-2-one; 4-[2-(3-Chloro-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-meth- yl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-chloro-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-methyl-morph- olin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-met- hyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-met- hyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-me- thyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-me- thyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Chloro-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-methoxymethy- l-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-chloro-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-methoxy-meth- yl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one; 4-[2-(3-Bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-met- hoxymethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one- ; 4-[2-(3-bromo-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(S)-2-me- thoxymethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-on- e; 4-[2-(3-Chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[(R)-2-- methoxymethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-- one; and 4-[2-(3-chloro-4-methoxy-phenyl)-(S)-2-hydroxy-ethylamino]-3-{6-[- (S)-2-methoxymethyl-morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyri- din-2-one.

Make Better Decisions: Try a trial or see plans & pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.