Indazole-carboxamide compounds as 5-HT4 receptor agonists
AssigneeTheravance, Inc.
InventorsDaniel Marquess, Seok-Ki Choi, Paul R. Fatheree, Roland Gendron, Adam A. Goldblum, Daniel D. Long, S. Derek Turner, Jyanwei Liu
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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.
Claims10
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):
- wherein:
- R1 is hydrogen, halo, hydroxy, C1-4alkyl, or C1-4alkoxy;
- R2 is C3-4alkyl, or C3-6cycloalkyl;
- and
- W is selected from:
- (i) a group of formula (II):
- wherein X is:
- NC(O)Ra, wherein Ra is C1-3alkyl or tetrahydrofuranyl, wherein C1-3alkyl is optionally substituted with —OH or C1-3alkoxy;
- S(O)2;
- or
- NS(O)2Rb, wherein Rb is methyl, optionally substituted with —OH, C1-3alkoxy, C5-6cycloalkyl, or —S(O)2—C1-3alkyl;
- (ii) a group of formula (III):
- wherein:
- Ry is —OH or C1-3alkoxy;
- p is 0 or 1;
- n is 1 or 2;
- and
- Y is:
- NRcC(O)Rd, wherein Rc is hydrogen or C1-3alkyl and Rd is C1-3alkyl, optionally substituted with —OH or C1-3alkoxy, or
- NReS(O)2Rf, wherein Re is hydrogen and Rf is C1-3alkyl, optionally substituted with —OH, C1-3alkoxy, C5-6cycloalkyl, or —S(O)2—C1-3alkyl;
- and
- (iii) a group of formula (IV):
- wherein:
- Rz is hydrogen, C1-3alkyl, or C2-3alkyl substituted with —OH or C1-3alkoxy;
- m is 1 or 2;
- q is 1 or 2, provided that the sum of m and q is not equal to 4;
- and
- Z is:
- NC(O)Rg, wherein Rg is C1-3alkyl, optionally substituted with —OH or C1-3alkoxy,
- S(O)2;
- or
- NS(O)2Rh, wherein Rh is methyl, optionally substituted with —OH, C1-3alkoxy, C5-6cycloalkyl, or —S(O)2—C1-3alkyl;
- or a pharmaceutically-acceptable salt or stereoisomer thereof.
A method of treating a mammal having a medical condition ameliorated by treatment with a 5-HT4 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):
- wherein:
- R1 is hydrogen, halo, hydroxy, C1-4alkyl, or C1-4alkoxy;
- R2 is C3-4alkyl, or C3-6cycloalkyl;
- and
- W is selected from:
- (i) a group of formula (II):
- wherein X is:
- NC(O)Ra, wherein Ra is C1-3alkyl or tetrahydrofuranyl, wherein C1-3 alkyl is optionally substituted with —OH or C1-3alkoxy;
- S(O)2;
- or
- NS(O)2Rb, wherein Rb is methyl, optionally substituted with —OH, C1-3alkoxy, C5-6cycloalkyl, or —S(O)2—C1-3alkyl;
- (ii) a group of formula (III):
- wherein:
- Ry is —OH or C1-3alkoxy;
- p is 0 or 1;
- n is 1 or 2;
- and
- Y is:
- NRcC(O)Rd, wherein Rc is hydrogen or C1-3alkyl and Rd is C1-3alkyl optionally substituted with —OH or C1-3alkoxy, or
- NReS(O)2Rf, wherein Re is hydrogen and Rf is C1-3alkyl, optionally substituted with —OH, C1-3alkoxy, C5-6cycloalkyl, or —S(O)2—C1-3alkyl;
- and
- (iii) a group of formula (IV):
- wherein:
- Rz is hydrogen, C1-3alkyl, or C2-3alkyl substituted with —OH or C1-3alkoxy;
- m is 1 or 2;
- q is 1 or 2, provided that the sum of m and q is not equal to 4;
- and
- Z is:
- NC(O)Rg, wherein Rg is C1-3alkyl, optionally substituted with —OH or C1-3alkoxy,
- S(O)2;
- or
- NS(O)2Rh, wherein Rh is methyl, optionally substituted with —OH, C1-3alkoxy, C5-6cycloalkyl, or —S(O)2—C1-3alkyl;
- or a pharmaceutically-acceptable salt or stereoisomer thereof.
Dependencies are inferred from the claim text.