Quinolinone compounds as 5-HT4 receptor agonists

• US 7,446,114 B2
• Filed: 03/01/2006
• Issued: 11/04/2008
• Est. Priority Date: 03/02/2005
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Choi, Seok-ki, Jiang, Lan, Gendron, Roland, Long, Daniel D., Turner, S. Derek, Fatheree, Paul R., Marquess, Daniel, Goldblum, Adam A.
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US11/365,320
• Publication Number:
  US 20060199839A1
• Time in Patent Office: 979 Days
• Field of Search: 546/126, 514/304
• US Class Current: 514/304
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 451/04 with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems

Abstract

The invention provides novel quinolinone-carboxamide 5-HT₄ receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT₄ receptor activity, and processes and intermediates useful for preparing such compounds.

Claims

1. A compound of formula (I):

2. The compound of claim 1 wherein R¹ is hydrogen or halo, R² is C_3-4alkyl, and d is 0.

3. The compound of claim 2, wherein:

X is carbon and Q is -A-;

or X is nitrogen and Q is selected from —

OC(O)—

, —

S(O)₂—

, —

S(O)₂(CH₂)₂—

, and -A(CH₂)₂—

.

4. The compound of claim 3, wherein:

X is carbon and Q is selected from —

N{C(O)R⁵}—

, —

N{C(O)NR^6aR^6b}—

, —

N{S(O)₂C_1-3alkyl}—

, and —

S(O)₂N(R^7a)—

;

or X is nitrogen and Q is selected from —

OC(O)—

, —

S(O)₂—

, —

S(O)₂(CH₂)₂—

, —

S(O)₂N(R^7a)(CH₂)₂—

, —

N{C(O)R⁵}(CH₂)₂—

, and —

N{S(O)₂C_1-3alkyl}(CH₂)₂.

5. The compound of claim 3, wherein:

G is W and c is 0, wherein W is selected from —

N{C(O)R⁹}—

, —

N{S(O)₂R¹⁰}—

, —

N{C(O)NR¹³R¹⁴}—

, —

N{R¹⁶}—

, and —

S(O)₂—

;

or G is carbon, c is 1, and Y is a moiety of formula (b), wherein W′

is selected from —

N(R⁸)C(O)R⁹, —

N(R⁸)S(O)₂R¹⁰, —

S(R¹¹)(O)₂, —

N(R⁸)C(O)NR¹³R¹⁴, —

OR¹⁵, and —

N(R⁸)R¹⁶.

6. The compound of claim 5, wherein G is W and c is 0.

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically-acceptable carrier.

13. A process for preparing a compound of formula (I):

14. A process for preparing a compound of formula (I-a):

15. A process for preparing a compound of formula (I-b):

7. A compound of formula (I):

8. The compound of claim 7, wherein Z is a moiety of formula (c), wherein X is nitrogen and Q is selected from —

OC(O)—

, —

S(O)₂—

, —

S(O)₂(CH₂)₂—

, —

S(O)₂N(R^7a)(CH₂)₂—

, —

N{C(O)C_1-3alkoxy}(CH₂)₂—

, and —

N{S(O)₂C_1-3alkyl}(CH₂)₂—

.

9. The compound of claim 7, wherein Z is a moiety of formula (c), wherein X is carbon and Q is selected from —

N{C(O)C_1-3alkoxy}-, —

N{C(O)NR^6aR^6b}—

, —

N{S(O)₂C_1-3alkyl}-, and —

S(O)₂N(R^7a)—

.

10. The compound of claim 7, wherein Z is a moiety of formula (d), wherein Q is selected from —

OC(O)— and

—

S(O)₂—

.

11. The compound of claim 7, wherein the compound is selected from:

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(4-methanesulfonylpiperazine-1-sulfonyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(3-dimethylaminopyrrolidine-1-sulfonyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{3-[4-hydroxyethyl)piperazine-1-sulfonyl]propyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(4-methylpiperazine-1-sulfonyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[methanesulfonyl-(1-propylpiperidin-4-yl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [(1S,3R,5R)-8-(3-{[1-(2-methoxyethyl)piperidin-4-yl]methsulfamoyl}propyl)-8-azabicyclo[3.2.1]oct-3-yl]amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{3-[(1-methanesulfonylpiperidin-4-yl)methylsulfamoyl]propyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [(1S,3R,5R)-8-(3-{[1-(2-cyanoethyl)piperidin-4-yl]methylsulfamoyl}propyl)-8-azabicyclo[3.2.1]oct-3-yl]amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[(1,1-dioxotetrahydro-1λ

⁶-thiophen-3-yl)methanesulfonylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[1-(1,1-dioxotetrahydro-1λ

⁶-thiophen-3-yl)-3,3-dimethylureido]ethyl}-8-azabicyclo[3.2.1]-oct-3-yl)amide;

(1,1-dioxo-tetrahydro-1λ

⁶-thiophen-3-yl)-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}ethyl)-carbamic acid methyl ester;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [(1S,3R,5R)-8-(2-{[2-(4-dimethylcarbamoylpiperazin-1-yl)ethyl]methanesulfonylamino}ethyl)-8-azabicyclo-[3.2.1]oct-3-yl]amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[2-(4-methanesulfonylpiperazin-1-yl)ethanesulfonyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [(1S,3R,5R)-8-(2-{2-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]ethanesulfonyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[2-(4-ethanesulfonylpiperazin-1-yl)ethanesulfonyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

(1,1-dioxo-hexahydro-1λ

⁶-thiopyran-4-yl)-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}ethyl)-carbamic acid methyl ester;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[1-(1,1-dioxotetrahydro-1λ

⁶-thiophen-3-yl)-3-methylureido]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)-amino]-8-azabicyclo[3.2.1]oct-8-yl}ethyl)-[2-(4-methanesulfonylpiperazin-1-ylethyl]-carbamic acid methyl ester;

[2-(4-dimethylcarbamoylpiperazin-1-yl)ethyl]-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}-ethyl)-carbamic acid methyl ester;

[2-(4-acetyl-piperazin-1-yl)ethyl]-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}ethyl)-carbamic acid methyl ester;

[2-(1,1-dioxo-1λ

⁶-thiomorpholin-4-yl)ethyl]-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}ethyl)-carbamic acid methyl ester;

(1,1-dioxo-tetrahydro-1λ

⁶-thiophen-3-yl)-(3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}propyl)-carbamic acid methyl ester;

((S)-1,1-dioxo-tetrahydro-1λ

⁶-thiophen-3-yl)-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}ethyl)-carbamic acid methyl ester;

1-isopropyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(methyl-{2-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]ethyl}sulfamoyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{3-[4-(tetrahydrofuran-2-carbonyl)piperazine-1-sulfonyl]propyl}-8-azabicyclo-[3.2.1]oct-3-yl)amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(4-acetylpiperazine-1-sulfonyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

4-methanesulfonyl-piperazine-1-carboxylic acid 3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}propyl ester;

4-(tetrahydrofuran-2-carbonyl)piperazine-1-carboxylic acid 3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-aza-bicyclo[3.2.1]oct-8-yl}propyl ester;

4-acetyl-piperazine-1-carboxylic acid 3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}propyl ester; and

4-hydroxypiperidine-1-carboxylic acid 3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}-propyl ester;

and pharmaceutically-acceptable salts and solvates and stereoisomers thereof.