Indazole-carboxamide compounds

• US 7,786,136 B2
• Filed: 01/15/2008
• Issued: 08/31/2010
• Est. Priority Date: 12/22/2004
• Status: Expired due to Fees

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Fatheree, Paul, Long, Daniel D, Goldblum, Adam A, Gendron, Roland, Turner, S. Derek, Marquess, Daniel, Choi, Seok-Ki
• Primary Examiner(s): Andres; Janet L
• Assistant Examiner(s): Gallis; David E
• Application Number:
  US12/008,840
• Publication Number:
  US 20080132491A1
• Time in Patent Office: 959 Days
• Field of Search: 514/304, 546/126, 546/200, 548/362.5
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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

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, R² is isopropyl or C_4-5cycloalkyl, and R⁴ is hydrogen.

3. The compound of claim 2 wherein R³ is hydroxy, methoxy, hydroxymethyl, —

OC(O)NHCH₃, or —

OC(O)N(CH₃)₂ or R³ and R⁵ taken together form —

OCH₂CH₂—

.

4. The compound of claim 1, which is a compound of formula (I-a):

5. The compound of claim 4 wherein W is a moiety of formula (b′

) wherein X is selected from —

N(R⁸)C(O)R⁹, —

N(R⁸)S(O)₂R¹⁰, —

N(R⁸)C(O)OR¹², —

N(R⁸)C(O)NR¹³R¹⁴, —

N(R⁸)S(O)₂NR¹³R¹⁴, —

C(O)NR¹³R¹⁴, —

OR¹⁵, and cyano.

6. The compound of claim 4 wherein W is a moiety of formula (b′

) wherein;

(i) X is cyano;

or

(ii) n is 2, R⁶ and R⁷ are hydrogen, R⁵ and R⁸ taken together form C₂alkylenyl, and X is selected from —

N(R⁸)C(O)R⁹, —

N(R⁸)S(O)₂R¹⁰, and —

N(R⁸)C(O)NR¹³R¹⁴.

7. The compound of claim 4 wherein W is selected from 1-methanesulfonylpiperazin-4-yl, 1-dimethylaminocarbonylpiperazin-4-yl, 1-(tetrahydrofuran-2-yl)carbonylpiperazin-4-yl, 3-(methoxycarbonylamino)pyrrolidin-1-yl, and 2-(methoxymethylene)pyrrolidin-1-yl.

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

10. A process for preparing a compound of formula (I), wherein R¹, R², R³, R⁴, and W are defined as in claim 1, or a salt or stereoisomer thereof, the process comprising:

(a) reacting a compound of formula (II);

11. A process for preparing a compound of formula (I), wherein R³ is hydroxy and R¹, R², R⁴, and W are defined as in claim 1, or a salt or stereoisomer thereof, the process comprising:

(a) reacting a compound of formula (II);

8. A compound selected from the group consisting of:

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

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

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

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

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

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

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

[1-(2-hydroxy-3-{(1S,3R,5R)-3-[(1-isopropyl-1H-indazole-3-carbonyl)-amino]-8-azabicyclo[3.2.1]oct-8-yl}propyl)pyrrolidin-3-yl]carbamic acid methyl ester; and

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

pharmaceutically-acceptable salts and stereoisomers thereof.