IP Library › Granted Patent US 7,348,431
Granted Patent B2
US 7,348,431 · App. 10/510,609 · Granted Mar 25, 2008

Tyrosine kinase inhibitors

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Quick Facts
Patent No.
US 7,348,431
App. No.
10/510,609
Granted
Mar 25, 2008
Kind
B2
Abstract

The present invention relates to compounds that are capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases. The compounds of the instant invention possess a core structure that comprises a benzazocine moiety. The present invention is also related to the pharmaceutically acceptable salts, hydrates and stereoisomers of these compounds.

Claims (115)

1. A compound of Formula I

wherein

R is H,

R 1a is independently selected from

1) H,

2) C 1 -C 6 alkyl, and

3) OR 4 ;

R 1b is independently selected from

1) H, and

2) C 1 -C 6 alkyl;

X is selected from

1) a bond,

2) C(O), and

3) O,

R 1 is independently selected from

1) H,

2) halo,

3) OR 4 ,

4) NO 2 ,

5) C 1 -C 10 alkyl,

6) —C(O)R 4 ,

7) C(O)OR 4 ,

8) C(O)N(R 4 ) 2 ,

9) N(R 4 ) 2 ;

V is selected from phenyl, benzofuran, benzodioxo and oxazolo;

R 2 is independently selected from

1) H,

2) C 1 -C 10 alkyl,

3) —(CR 1b ) t OR 4 ,

4) Halo,

5) CN,

6) NO 2 ,

7) CF 3 ,

8) —(CR 1b ) t N(R 4 ) 2 ,

9) —C(O)OR 4 ,

10) —C(O)R 4 ,

11) —(CR 1b ) t NR 4 (CR 1b ) t R 5 ,

12) —(CR 1b ) t S(O) m NR 4 ,

13) —C(O)OR 4 R 5 ,

14) —NR 4 C(O)R 4 ,

R 4 is independently selected from

1) H,

2) C 1 -C 10 alkyl,

3) C 3 -C 10 cycloalkyl,

4) aryl, and

5) CF 3 ;

R 5 aryl, and

m is independently 0, 1 or 2;

n is 0 to 4;

p is 0 to 4;

q is 0 to 4;

s is 0 to 16; and

t is independently 0 to 6;

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound according to claim 1 wherein R, R 1b , R 4 , R 5 , V and variables m, n, p, q and t are as defined in claim 1 and

R 1a is independently selected from

1) H, and

2) C 1 -C 6 alkyl;

X is selected from

1) a bond, and

2) C(O);

R 1 is independently selected from

1) H,

2) halo,

3) OR 4 ,

4) N(R 4 ) 2 ,

5) NO 2 , and

R 2 is independently selected from

1) H,

2) C 1 -C 10 alkyl, and

4) Halo,

s is 0 to 6;

or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound according to claim 2 wherein R, R 1b , X, R 1 , R 2 , R 4 , R 5 and variables m and t are as defined in claim 2 and:

R 1a is independently selected from

1) H, and

2) C 1 -C 6 alkyl;

V is phenyl;

n is 0 to 1;

p is 0 to 3;

q is 0 to 3;

or a pharmaceutically acceptable salt or stereoisomer thereof.

4. A compound that is:

(6R,9S,11R)-11-phenyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9R,11S)-11-phenyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11R)-11-phenyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11S)-11-benzyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11S)-11-benzyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11R)-11-benzyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9S,11S)-11-benzyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9S,11R)-11-benzyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11S)-11-(3-bromobenzyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11R)-11-(3-bromobenzyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9S,11S)-11-(3-bromobenzyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9S,11R)-11-(3-bromobenzyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11S)-11-(1-benzofuran-2-ylmethyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[8]annulene;

(6S,9R,11R)-11-(1-benzofuran-2-ylmethyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9S,11S)-11-(1-benzofuran-2-ylmethyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9S,11R)-11-(1-benzofuran-2-ylmethyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11S)-11-(1,3-oxazol-2-ylmethyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11R)-11-(1,3-oxazol-2-ylmethyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9S,11S)-11-(1,3-oxazol-2-ylmethyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9S,11R)-11-(1,3-oxazol-2-ylmethyl)-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11S)-11-isopentyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11R)-11-isopentyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9S,11S)-11-isopentyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9S,11R)-11-isopentyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

or a pharmaceutically acceptable salt or stereoisomer thereof.

5. A compound according to claim 4 that is:

(6R,9S,11R)-11-phenyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6R,9R,11S)-11-phenyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11R)-11-phenyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

(6S,9R,11S)-11-phenyl-5,6,7,8,9,10-hexahydro-6,9-(epiminomethano)benzo[a][8]annulene;

or a pharmaceutically acceptable salt or stereoisomer thereof.

6. A composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

Assignments (2)
CHANGE OF NAME Recorded Jan 29, 2010
From: MERCK & CO., INC.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 023861/0910 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 13, 2007
From: KIM, ANNETTE
To: MERCK & CO., INC.
Reel/Frame 020107/0832 →