Indazole-carboxamide compounds as 5-HT4 receptor agonists

• US 7,351,704 B2
• Filed: 02/17/2005
• Issued: 04/01/2008
• Est. Priority Date: 02/18/2004
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Liu, Jyanwei, Gendron, Roland, Long, Daniel D., Turner, S. Derek, Fatheree, Paul R., Marquess, Daniel, Goldblum, Adam A., Choi, Seok-Ki
• Primary Examiner(s): Seaman; Margaret D.
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US11/060,195
• Publication Number:
  US 20050197335A1
• Time in Patent Office: 1,139 Days
• Field of Search: 546/126, 544/362, 544/62, 514/304, 514/253.04, 514/228.2
• US Class Current: 514/228.2
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• 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: G01N 2333/70571 for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: G01N 33/5008 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/5044 involving specific cell types

Abstract

The invention provides novel indazole-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.

3. The compound of claim 1 wherein R² is isopropyl or C_4-5cycloalkyl.

4. The compound of claim 1 wherein W is a group of formula (II).

5. The compound of claim 4 wherein R^a is C_1-3alkyl and R^b is methyl.

6. The compound of claim 1 wherein W is a group of formula (III).

7. The compound of claim 6 wherein p is 0.

8. The compound of of claim 6 wherein n is 1.

9. The compound of claim 1 wherein W is a group of formula (IV).

10. The compound of claim 1 wherein m is 1 and q is 1.

11. The compound of claim 1 wherein:

R¹ is hydrogen or halo;

R² is C_3-4alkyl or C_4-5cycloalkyl; and

W is selected from the group consisting of;

(i) a group of formula (II) wherein X is NC(O)CH₃, S(O)₂, or NS(O)₂CH₃;

(ii) a group of formula (III) wherein p is 0, n is 1, and Y is NCH₃C(O)CH₃; and

(iii) a group of formula (IV) wherein R^z is methyl, m is 1, q is 1, and Z is NC(O)CH₃, S(O)₂, or NS(O)₂CH₃.

12. The compound of claim 11 wherein W is a group of formula (II) wherein X is NC(O)CH₃, S(O)₂, or NS(O)₂CH₃.

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

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)-ethyl]8-azabicyclo[3.2.1]oct-3-yl}amide;

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

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(1,1-dioxo-1λ

⁶-thiomorpholin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

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

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(4-cyclohexylmethanesulfonylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(4-methanesulfonylmethanesulfonylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(3-(acetyl-methylamino)pyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(3-(acetyl-amino)pyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((R)-3-(acetyl-amino)pyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((S)-3-(acetyl-amino)pyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[3-((S)-2-hydroxypropionylamino)pyrrolidin-1-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(3S,4S)-3-(acetylmethylamino)-4-hydroxypyrrolidin-1-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((R)-3-ethanesulfonylaminopyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((R)-3-cyclohexylmethanesulfonylaminopyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[3-(acetyl-methylamino)piperidin-1-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(3-acetylaminopiperidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(3-methanesulfonylaminopiperidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((S)-3-methanesulfonylaminopiperidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((S)-3-ethanesulfonylaminopiperidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((S)-3-methanesulfonylmethanesulfonylaminopiperidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(1-acetylpyrrolidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[((R)-1-acetylpyrrolidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[((S)-1-acetylpyrrolidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(1-methanesulfonylpyrrolidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[((R)-1-methanesulfonylpyrrolidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(1,1-dioxo-tetrahydro-1λ

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

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(1,1-dioxo-tetrahydro-1λ

⁶-thiophen-3-yl)-(2-hydroxyethyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(1-acetylpiperidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(1,1-dioxo-hexahydro-1λ

⁶-thiopyran-4-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(1-methanesulfonylpiperidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

5-fluoro-1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-propyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-butyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-cyclobutyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-cyclopentyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((R)-3-(acetylmethylamino)pyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((S)-3-(acetylmethylamino)pyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[((S)-1-methanesulfonylpyrrolidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(R)-(1,1-dioxo-tetrahydro-1λ

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

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(S)-(1,1-dioxo-tetrahydro-1λ

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

pharmaceutically-acceptable salts and stereoisomers thereof.

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

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)-ethyl]8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(1,1-dioxo-1λ

⁶-thiomorpholin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(3-(acetylmethyl-amino)pyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((R)-3-(acetyl-methyl-amino)pyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((S)-3-(acetyl-methylamino)pyrrolidin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-[(1-acetylpyrrolidin-3-yl)methylamino]ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-[((R)-1-acetylpyrrolidin-3-yl)methylamino] ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-[((S)-1-acetyl-pyrrolidin-3-yl)methylamino]ethyl]-8-azabicyclo[3.2.1] oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[(1-methanesulfonyl-pyrrolidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[((R)-1-methanesulfonyl-pyrrolidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-[((S)-1-methanesulfonyl-pyrrolidin-3-yl)methylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((1,1-dioxo-tetrahydro-1λ

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

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((R)-(1,1-dioxo-tetrahydro-1λ

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

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-((S)-(1,1-dioxo-tetrahydro-1λ

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

pharmaceutically-acceptable salts and stereoisomers thereof.

16. A pharmaceutical composition comprising of the compound of claim 1 or claim 15 and a pharmaceutically acceptable carrier.

17. A process for preparing a compound of claim 1, the process comprising reacting a compound of formula 5:

19. A process for preparing a compound of claim 1, the process comprising reacting a compound of formula 2:

15. A compound having the chemical name 1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}amide;

or a pharmaceutically-acceptable salt thereof.

18. A compound of formula 5: