Granted Patent B2

US 8,232,283 · App. 13/105,957 · Granted Jul 31, 2012

Abstract

Claims (89)

1. A compound having a structure represented by formula (I)

or any tautomeric form thereof, wherein

R 1 is selected from hydrogen, —NH 2 , and substituted or unsubstituted: —NH—C 1-6 -alkyl, —NH-cycloalkyl, —NH-heterocycloalkyl, —NH—C 1-6 -alkylene-OR 7 , and —NH—C 1-6 -alkylene-NR 7 2 ;

R 2 is selected from hydrogen, -halogen, -methyl, —CH 2 F, —CHF 2 , —CF 3 , —O—methyl, —O—CH 2 F, —O—CHF 2 , and —O—CF 3 ;

one of R 3 and R 4 is hydrogen, and the other is —NH—C(═O)—(NH) x —(CH 2 ) y —R 6 , wherein x and y are independently selected from 0 and 1;

R 5 is selected from hydrogen, and substituted or unsubstituted: -alkyl, -alkenyl, -alkynyl, -cycloalkyl, -cycloalkenyl, —(C-linked-heterocycloalkyl), —(C-linked-heterocycloalkenyl), -aryl, and -heteroaryl;

R 6 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R 7 is independently selected from hydrogen and —C 1-6 -alkyl;

or any pharmaceutically acceptable salt or N-oxide thereof; provided, however, that compound (A) is excluded:

2. The compound of claim 1 , wherein R 1 is substituted or unsubstituted —NH—C 1-6 -alkylene-N(R 7 ) 2 .

3. The compound of claim 1 , wherein R 2 is selected from hydrogen and chlorine.

4. The compound of claim 1 , wherein R 5 is selected from substituted or unsubstituted -alkyl, and substituted or unsubstituted -cycloalkyl.

5. The compound of claim 4 , wherein R 5 is -methyl.

6. The compound of claim 1 having a structure represented by formula (Ia)

or any tautomeric or stereoisomeric form thereof, wherein X is selected from —O— and —NR 7 .

7. The compound of claim 6 , wherein X is —NR 7 .

8. The compound of claim 1 , wherein the compound is selected from:

4-Chloro-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;

5-tert-Butyl-2H-pyrazole-3-carboxylic acid {4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-amide;

3,4-Dichloro-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-benzamide;

5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid {4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-amide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-fluoro-4-trifluoromethyl-benzamide;

1-Methyl-1H-indole-2-carboxylic acid {4-chloro-3-[2-(2-dimethylamino-ethylamino) -8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-amide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-methoxy-5-trifluoromethyl-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-methoxy-4-trifluoromethyl-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-(4-chloro-3-trifluoromethyl-phenyl)-acetamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-4-fluoro-3-trifluoromethyl-benzamide;

3-Chloro-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-benzamide;

5-tert-Butyl-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-2-methoxy-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-fluoro-4-trifluoromethyl-benzamide;

3-Chloro-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-4-methoxy-benzamide;

3,5-Dichloro-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-fluoro-5-trifluoromethyl-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-(3-trifluoromethyl-phenyl)-acetamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-morpholin-4-yl-isonicotinamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-4-phenoxy-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-fluoro-5-trifluoromethyl-benzamide;

2-Chloro-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-5-trifluoromethyl-benzamide;

4-Chloro-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethoxy-benzamide;

5-tert-Butyl-2-phenyl-2H-pyrazole-3-carboxylic acid {4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin -6-yl]-phenyl-amide;

3-Chloro-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-4-(3-fluoro-benzyloxy)-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-4-trifluoromethyl-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3,5-bis-trifluoromethyl-benzamide,

2-Chloro-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-benzamide;

4-tert-Butyl-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyriniidin-6-yl]-phenyl}-benzamide;

4-Chloro-N-{4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-benzamide;

N-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-fluoro-3-trifluoromethyl-benzamide;

6-Fluoro-1H-benzoimidazole-2-carboxylic acid {4-chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin -6-yl]-phenyl}-amide;

1-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-(3-chloro-4-methoxy-phenyl)-urea;

1-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea;

1-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-(4-fluoro-3-trifluoromethyl-phenyl)-urea;

1-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-(3-chloro-phenyl)-urea;

1-(4-tert-Butyl-phenyl)-3-{4-chloro-3-[2-(2-dimethylamino-ethylamino) -8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-urea;

1-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-(4-phenoxy-phenyl)-urea;

1-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-(4-chloro-phenyl)-urea;

1-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-(4-methyl-3-trifluoromethyl-phenyl)-urea;

1-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-(2-fluoro-3-trifluoromethyl-phenyl)-urea;

1-{4-Chloro-3-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea;

1-(3,5-Bis-trifluoromethyl-phenyl)-3-{4-chloro-3-[2-(2-dimethylamino-ethylamino) -8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-urea;

4-Chloro-N-{3-chloro-4-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;

N-{3-Chloro-4-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-methoxy-4-trifluoromethyl-benzamide;

4-Chloro-N-{3-chloro-4-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]]-phenyl}-3-trifluoromethoxy-benzamide;

N-{3-Chloro-4-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-benzamide;

N-{3-Chloro-4-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-morpholin-4-yl-isonicotinamide;

3-Chloro-N-{3-chloro-4-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-4-(3-fluoro-benzyloxy)-benzamide;

5-tert-Butyl-2-phenyl-2H-pyrazole-3-carboxylic acid {3-chloro-4-[2-(2-dimethylamino-ethylamino) -8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-amide;

N-{3-Chloro-4-[2-(2-dimethylamino-ethylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido [2,3-d]pyrimidin-6-yl]-phenyl}-2-(4-chloro-3-trifluoromethyl-phenyl)-acetamide;

2,6-Dichloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl]-phenyl]-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-pyrrolidin-1-yl-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-phenyl)-6-dimethylamino-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-phenyl)-6-pyperidin-1-yl-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-phenyl)-6-morpholin-4-yl-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-phenyl)-6-(4-methyl-piperazin-1-yl)-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-(i]pyrimidin-6-yl)-phenyl)-6-diethylamino-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-phenyl)-6-ethylamino-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-phenyl)-6-isopropylamino-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-phenyl)-6-(2-dimethylaminoethylamino)-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-phenyl)-6-1-methyl-piperdine-4-ylamino)-isonicotinamide;

2-Chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-phenyl)-6-(4-(4-methylpiperazin-1-yl)-benzylamino)-isonicotinamide;

N-(4-chloro-3-(8-methoxy-2-(2-methoxy-ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-phenyl)-benzamide;

N-(4-chloro-3-(2-ethylamino-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-3-trifluormethyl-benzamide;

N-(3-(2-amino-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-chloro-phenyl)-3-trifluormethyl-benzamide;

N-(4-chloro-3-(8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d ]pyrimidin-6-yl)-phenyl) -3-trifluormethyl-benzamide; and

N-{4-Chloro-3-[2-(3-dimethylamino-propylamino)-8-methoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethyl-benzamide.

9. A method for inhibiting cellular proliferation of colon cancer cell lines or colon tumor growth in an individual, said method comprising administering a therapeutically effective amount of the compound of claim 1 .

10. The method of claim 9 , wherein said individual is a mammal selected from: domestic mammal, cat, dog, horse, sheep, cow, rodent, and human.

11. The method of claim 10 , wherein said mammal is a human.

Assignments (8)