IP Library › Granted Patent US 8,003,664

Granted Patent B2

US 8,003,664 · App. 12/842,389 · Granted Aug 23, 2011

Indazole-carboxamide compounds

Assignee: Theravance, Inc.

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Quick Facts

Patent No.: US 8,003,664
App. No.: 12/842,389
Granted: Aug 23, 2011
Kind: B2

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Abstract

The invention provides novel indazole-carboxamide 5-HT 4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT 4 receptor activity, and processes and intermediates useful for preparing such compounds.

Claims (105)

1. A method of treating a disorder of reduced motility of the gastrointestinal tract in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I-a):

wherein:

R 1 is hydrogen, halo or C 1-4 alkyl;

R 2 is isopropyl or C 4-5 cycloalkyl;

R 3 is hydroxy, C 1-3 alkoxy, or OC(O)NR a R b ;

W is selected from

(a) Y, wherein Y is selected from —N(R 8a )C(O)R 9 , —N(R 8a )S(O) 2 R 10 , —N(R 8a )C(O)OR 12 , —N(R 8a )C(O)NR 13 R 14 , and —N(R 8a )S(O) 2 NR 13 R 14 ; and

(b) a moiety of formula (b):

wherein

X is selected from —N(R 8 )C(O)R 9 , —N(R 8 )S(O) 2 R 10 , —S(R 11 )O 2 , —N(R 8 )C(O)OR 12 , —N(R 8 )C(O)NR 13 R 14 , —N(R 8 )S(O) 2 NR 13 R 14 , —C(O)NR 13 R 14 , —OC(O)NR 13 R 14 , —C(O)OR 12 , —OR 15 , —NR 8 R 16 , cyano, —SR 15 , CF 3 , pyridinyl, pyrrolyl, 1,1-dioxoisothiazolidinyl, imidazolyl, and pyrrolidinyl, wherein pyrrolidinyl is optionally substituted with oxo;

R 5 is hydrogen, C 1-3 alkyl, or C 1-3 alkyl substituted at the terminal position with hydroxy;

R 6 and R 7 at each occurrence are independently hydrogen, hydroxy, halo or cyano;

R 8 and R 8a are hydrogen or C 1-3 alkyl;

or R 5 and R 8 or R 5 and R 6 together form a C 2-5 alkylene;

or R 3 and R 5 or R 3 and R 8a taken together are —OCH 2 CH 2 —;

R 9 is hydrogen, tetrahydrofuranyl, pyridinyl, or C 1-3 alkyl;

R 10 is C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with —S(O) 2 C 1-3 alkyl, or with from 1 to 3 halo;

R 11 is —NR a R b , or C 1-3 alkyl, where C 1-3 alkyl is optionally substituted with from 1 to 3 halo;

or R 5 and R 11 or R 6 and R 11 taken together form C 2-5 alkylenyl;

R 12 is C 1-3 alkyl;

R 13 , R 14 , and R 15 are independently hydrogen or C 1-3 alkyl;

R 16 is —CH 2 —C(O)NR a R b , —CH 2 —C(O)-morpholinyl, —CH 2 -pyridinyl, —CH 2 -pyrimidinyl, or —CH 2 -tetrahydrofuranyl;

R 18 is —C(O)OCH 3 , —S(O) 2 CH 3 , or —C(O)CH 3 ;

R a and R b are independently hydrogen or C 1-3 alkyl;

a is 0 or 1; and

n is an integer of 1, 2, or 3; provided that when n is 1, X is —SR 15 , or X forms a carbon-carbon bond with the carbon atom bearing the substituents R 6 and R 7 ;

or a pharmaceutically-acceptable salt or stereoisomer thereof.

2. The method of claim 1 wherein W is selected from:

(a) Y, wherein Y is selected from —N(R 8a )C(O)R 9 , —N(R 8a )S(O) 2 R 10 , and —N(R 8a )C(O)NR 13 R 14 ; and

(b) a moiety of formula (b) wherein X is selected from —N(R 8 )C(O)R 9 , —N(R 8 )S(O) 2 R 10 , —N(R 8 )C(O)OR 12 , —N(R 8 )C(O)NR 13 R 14 , —N(R 8 )S(O) 2 NR 13 R 14 , —C(O)NR 13 R 14 , —OR 15 , and cyano.

3. The method of claim 2 wherein W is selected from Y, wherein R 8a is hydrogen or methyl; R 9 is hydrogen, tetrahydrofuranyl, pyridinyl, or methyl.

4. The method of claim 1 wherein W is selected from —NHC(O)H, —N(CH 3 )C(O)H, —NHC(O)CH 3 , —N(CH 3 )C(O)CH 3 , —N(CH 3 )S(O) 2 CH 3 , —N(CH 3 )C(O)NHCH 3 , —N(CH 3 )CH 2 CH 2 CN, 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.

5. The method of claim 1 wherein the compound of formula (I-a) is 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-{3-[(2-cyano-ethyl)methylamino]-2-hydroxypropyl}-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

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

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

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

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

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

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

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

pharmaceutically-acceptable salts thereof.

6. The method of claim 1 wherein the disorder of reduced motility is chronic constipation, constipation-predominant irritable bowel syndrome, diabetic and idiopathic gastroparesis, or functional dyspepsia.

7. The method of claim 5 wherein the disorder of reduced motility is chronic constipation, constipation-predominant irritable bowel syndrome, diabetic and idiopathic gastroparesis, or functional dyspepsia.

8. A method of treating a mammal having a medical condition ameliorated by treatment with a 5-HT 4 receptor agonist, wherein the medical condition is irritable bowel syndrome, chronic constipation, functional dyspepsia, delayed gastric emptying, gastroesophageal reflux disease, gastroparesis, post-operative ileus, intestinal pseudo-obstruction, or drug-induced delayed transit, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I-a):

wherein:

R 1 is hydrogen, halo or C 1-4 alkyl;

R 2 is isopropyl or C 4-5 cycloalkyl;

R 3 is hydroxy, C 1-3 alkoxy, or OC(O)NR a R b ;

W is selected from

(a) Y, wherein Y is selected from —N(R 8a )C(O)R 9 , —N(R 8a )S(O) 2 R 10 , —N(R 8a )C(O)OR 12 , —N(R 8a )C(O)NR 13 R 14 , and —N(R 8a )S(O) 2 NR 13 R 14 ; and

(b) a moiety of formula (b):

wherein

R 5 is hydrogen, C 1-3 alkyl, or C 1-3 alkyl substituted at the terminal position with hydroxy;

R 6 and R 7 at each occurrence are independently hydrogen, hydroxy, halo or cyano;

R 8 and R 8a are hydrogen or C 1-3 alkyl;

or R 5 and R 8 or R 5 and R 6 together form a C 2-5 alkylene;

or R 3 and R 5 or R 3 and R 8a taken together are —OCH 2 CH 2 —;

R 9 is hydrogen, tetrahydrofuranyl, pyridinyl, or C 1-3 alkyl;

R 10 is C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with —S(O) 2 C 1-3 alkyl, or with from 1 to 3 halo;

R 11 is —NR a R b , or C 1-3 alkyl, where C 1-3 alkyl is optionally substituted with from 1 to 3 halo;

or R 5 and R 11 or R 6 and R 11 taken together form C 2-5 alkylenyl;

R 12 is C 1-3 alkyl;

R 13 , R 14 , and R 15 are independently hydrogen or C 1-3 alkyl;

R 16 is —CH 2 —C(O)NR a R b , —CH 2 —C(O)-morpholinyl, —CH 2 -pyridinyl, —CH 2 -pyrimidinyl, or —CH 2 -tetrahydrofuranyl;

R 18 is —C(O)OCH 3 , —S(O) 2 CH 3 , or —C(O)CH 3 ;

R a and R b are independently hydrogen or C 1-3 alkyl;

a is 0 or 1; and

n is an integer of 1, 2, or 3; provided that when n is 1, X is —SR 15 , or X forms a carbon-carbon bond with the carbon atom bearing the substituents R 6 and R 7 ;

or a pharmaceutically-acceptable salt or stereoisomer thereof.

9. The method of claim 8 wherein W is selected from:

(a) Y, wherein Y is selected from —N(R 8a )C(O)R 9 , —N(R 8a )S(O) 2 R 10 , and —N(R 8a )C(O)NR 13 R 14 ; and

10. The method of claim 9 wherein W is selected from Y, wherein R 8a is hydrogen or methyl; R 9 is hydrogen, tetrahydrofuranyl, pyridinyl, or methyl.

11. The method of claim 8 wherein W is selected from —NHC(O)H, —N(CH 3 )C(O)H, —NHC(O)CH 3 , —N(CH 3 )C(O)CH 3 , —N(CH 3 )S(O) 2 CH 3 , —N(CH 3 )C(O)NHCH 3 , —N(CH 3 )CH 2 CH 2 CN, 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.

12. The method of claim 8 wherein the compound of formula (I-a) is selected from the group consisting of: