Substituted piperaziniums for the treatment of emesis
Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NK 1 ) receptor. The compounds have the general formula (I):
1. A compound of formula (VI):
or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 is independently hydrogen, halogen, alkyl, alkylNR 101 R 102 , alkenyl,—C(O)R 101 , —C(O)NR 101 R 102 , —C(O)OR 101 , —NR 101 R 102 , —NR 101 C(O)R 102 , —OR 101 , —SR 101 , —S(O) 2 R 102 , —S(O) 2 NR 101 R 102 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more independently selected R 103 substituents;
each R 2 is independently hydrogen, halogen, alkyl, alkylNR 101 R 102 , alkenyl,—C(O)R 101 , —C(O)NR 101 R 102 , —C(O)OR 101 , —NR 101 R 102 , —NR 101 C(O)R 102 , —OR 101 , —SR 101 , —S(O) 2 R 102 , —S(O) 2 NR 101 R 102 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more independently selected R 103 substituents;
R 5 is hydrogen, halogen, alkyl, alkylNR 101 R 102 , alkenyl,—C(O)R 101 , —C(O)NR 101 R 102 , —C(O)OR 101 , —NR 101 R 102 , —NR 101 C(O)R 102 , —OR 101 , —SR 101 , —S(O) 2 R 102 , —S(O) 2 NR 101 R 102 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more independently selected R 103 substituents;
R 6 is hydrogen, halogen, alkyl, alkylNR 101 R 102 , alkenyl,—C(O)R 101 , —C(O)NR 101 R 102 , —C(O)OR 101 , —NR 101 R 102 , —NR 101 C(O)R 102 , —OR 101 , —SR 101 , —S(O) 2 R 102 , —S(O) 2 NR 101 R 102 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more independently selected R 103 substituents;
each R 7 is independently hydrogen, halogen, alkyl, alkenyl, amino, —OR 104 , or cycloalkyl, wherein the alkyl, alkenyl, amino and cycloalkyl are each optionally substituted with one or more independently selected R 103 substituents;
R 200 is hydrogen, alkyl, or cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted with one or more independently selected R 103 substituents;
R 300 is hydrogen, alkyl, or cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted with one or more independently selected R 103 substituents;
R 101 is hydrogen, halogen, cyano, nitro, oxide, alkyl, alkenyl, —C(O)OR 104 , —C(O)NR 104 R 105 , —C(O)OR 104 , —NR 104 R 105 , —NR 104 C(O)R 105 , —NR 104 S(O) 2 R 105 , —OR 104 , —SR 104 , —S(O) 2 NR 104 R 105 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more independently selected R 103 substituents;
R 102 is hydrogen, halogen, cyano, nitro, oxide, alkyl, alkenyl, —C(O)OR 104 , —C(O)NR 104 R 105 , —C(O)OR 104 , —NR 104 R 105 , —NR 104 C(O)R 105 , —NR 104 S(O) 2 R 105 , —OR 104 , —SR 104 , —S(O) 2 NR 104 R 105 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more independently selected R 103 substituents; or
R 101 and R 102 , together with the atoms to which they are attached, form a fused or non-fused monocyclic, bicyclic or tricyclic carbocyclic or heterocyclic ring, which is optionally and independently substituted with one or more independently selected R 103 substituents;
each R 103 is independently halogen, cyano, nitro, oxide, alkyl, alkenyl, —C(O)OR 104 , —C(O)NR 104 R 105 , —C(O)OR 104 , —NR 104 R 105 , —NR 104 C(O)R 105 , —NR 104 S(O) 2 R 105 , —OR 104 , —SR 104 , —S(O) 2 NR 104 R 105 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 104 is hydrogen, halogen, cyano, nitro, oxide, alkyl, hydroxyalkyl, alkoxyalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, alkenyl, amino, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 105 is hydrogen, halogen, cyano, nitro, oxide, alkyl, hydroxyalkyl, alkoxyalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, alkenyl, amino, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
m is 0, 1, 2, 3, or 4;
each p is independently 0 or 1; and
s is 0, 1, 2, 3, or 4;
with a proviso that if a non-pyridine N-Oxide is present on the compound of formula (VI), then the total number of N-Oxides on the compound of formula (VI) is greater than one.
2. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.