IP Library › Granted Patent US 8,143,258

Granted Patent B2

US 8,143,258 · App. 12/628,697 · Granted Mar 27, 2012

Benzothiazole compounds useful for Raf inhibition

Assignee: Takeda Pharmaceutical Company Limited

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,143,258
App. No.: 12/628,697
Granted: Mar 27, 2012
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Provided is a fused heterocycle derivative showing a strong Raf inhibitory activity. A compound represented by the formula wherein each symbol is as defined in the present specification, or a salt thereof.

Claims (89)

1. A compound represented by the formula

wherein

R 1 is methyl or cyclopropyl;

X is —O;

Y is

wherein ring A is a benzene ring optionally having 1 to 3 halogen atoms;

Z is a group represented by

(1) —NHCO—;

(2) —NHCO—W 1b —,

wherein W 1b is —CH 2 — or —CH(CH 3 ) 2 —;

(3) —NHCONH—; or

(4) —CONH—;

R 5 is phenyl optionally having 1 to 3 substituents selected from the group consisting of:

(a) a halogen atom,

(b) a C 1-6 alkyl optionally having 1 to 3 substituents selected from the group consisting of:

(i) a halogen atom, and

(ii) cyano; and

R 6 is

a cyano group,

or a salt thereof.

2. 2-Chloro-N-[3-({7-cyano-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide, or a salt thereof.

3. 2-Chloro-N-[3-({7-cyano-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide.

4. N-{7-Cyano-6-[4-fluoro-3-({[4-(trifluoromethyl)phenyl] carbamoyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide, or a salt thereof.

5. N-{7-Cyano-6-[4-fluoro-3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide.

6. N-{7-Cyano-6[3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide, or a salt thereof.

7. N-{7-Cyano-6-[3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide.

8. N-{7-Cyano-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide, or a salt thereof.

9. N-{7-Cyano-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide.

10. A medicament comprising the compound of claim 1 and a pharmacologically acceptable carrier, said medicament being for oral or parenteral administration.

11. The compound according to claim 1 , which is selected from a group consisting of:

N-{3-({7-cyano-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)phenyl}-3-(1-cyano-1-methylethyl)benzamide,

2-chloro-N-[3-({7-cyano-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide,

N-[3-({7-cyano-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)phenyl]-3,4-bis(trifluoromethyl)benzamide,

N-[3-({7-cyano-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)phenyl]-3-(trifluoromethoxy)benzamide,

N-{7-cyano-6-[3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide,

N-(3-{[2-(acetylamino)-7-cyano-1,3-benzothiazol-6-yl]oxy}phenyl)-3-(1-cyano-1-methylethyl)benzamide,

N-(3-{[2-(acetylamino)-7-cyano-1,3-benzothiazol-6-yl]oxy}phenyl)-2-chloro-3-(1-cyano-1-methylethyl)benzamide,

N-(3-{[2-(acetylamino)-7-cyano-1,3-benzothiazol-6-yl]oxy}phenyl)-2-(3-bromophenyl)-2-methylpropanamide,

N-{7-cyano-6-[3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-1,3-benzothiazol-2-yl}acetamide,

N-(3-{[2-(acetylamino)-7-cyano-1,3-benzothiazol-6-yl]oxy}phenyl)-4-chloro-3-(1-cyano-1-methylethyl)benzamide,

N-{6-[3({[2-chloro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-7-cyano-1,3-benzothiazol-2-yl}acetamide,

N-{7-cyano-6-[3-({[4-(trifluoromethoxy)phenyl]carbamoyl}amino)phenoxy]-1,3-benzothiazol-2-yl}acetamide,

N-{7-cyano-6-[3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-1,3-benzothiazol-2-yl}acetamide,

N-{6-[3-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-7-cyano-1,3-benzothiazol-2-yl}acetamide,

N-[6-(3-{[(4-tert-butylphenyl)carbamoyl]amino}phenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide,

2-chloro-N-[4-chloro-5-({7-cyano-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide,

N-[4-chloro-5-({7-cyano-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)-2-fluorophenyl]-3-(trifluoromethoxy)benzamide,

N-{6-[2-chloro-4-fluoro-5-({[4-(trifluoromethyl)phenyl]carbamoyl}amino) phenoxy]-7-cyano-1,3-benzothiazol-2-yl}cyclopropanecarboxamide,

N-{7-cyano-6-[4-fluoro-3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino) phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide,

2-chloro-N-[5-({7-cyano-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide,

N-(5-{[2-(acetylamino)-7-cyano-1,3-benzothiazol-6-yl]oxy}-2-fluorophenyl)-2-chloro-3-(1-cyano-1-methylethyl)benzamide,

N-(5-{[2-(acetylamino)-7-cyano-1,3-benzothiazol-6-yl]oxy}-2-fluorophenyl)-3-(1-cyano-1-methylethyl)benzamide,

N-(3-{[2-(acetylamino)-7-cyano-1,3-benzothiazol-6-yl]oxy}phenyl)-2-[3-(trifluoromethyl)phenyl]acetamide,

N-{7-cyano-6-[3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide, and

N-{7-cyano-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide,

and a salt thereof.

12. The compound according to claim 1 , which is selected from a group consisting of:

N-[3-({7-cyano-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide,