Substituted pyridines as P2X
Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X 3 and/or a P2X 2/3 receptor antagonists and methods of making the compounds.
1. A method for modulating P2X 3 and P2X 2/3 receptor activity in a subject, comprising administering to a subject in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is C 1-6 alkyl or halo;
R 2 is C 3-6 cycloalkyl, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl or heteroaryl-C 1-6 alkyl, wherein heteroaryl is pyrazinyl, pyridazinyl or pyrimidinyl, each optionally substituted once with methyl;
R 3 is hydrogen, halo, C 1-6 alkyl or C 1-6 alkoxy-carbonyl;
R 4 is hydrogen, halo or C 1-6 alkyl; or
R 3 and R 4 , together with the atoms to which they are attached, may form a fused 6-membered aromatic ring that optionally includes one or two nitrogens and which is optionally substituted with 0, 1 or 2 R 8 substituents, wherein R 8 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-sulfonyl, halo-C 1-6 alkyl or halo; or
R 3 and R 4 , together with the atom to which they are attached, may form C 3-6 cycloalkyl;
R 5 , R 6 and R 7 are each independently hydrogen or fluoro;
X is —N—; and
Y is —O— or —NR c —, wherein R c is hydrogen or C 1-6 alkyl.
2. The method of claim 1 , wherein:
R 5 , R 6 and R 7 are independently hydrogen;
R 1 is methyl; and
R 2 is cyclopropyl, 2-methoxy-1-methylethyl, 2-hydroxy-1-methylethyl, 5-methyl-pyrazin-2-ylmethyl, 1-pyrazin-2-ylethyl, pyrimidin-5-ylmethyl, 6-methyl-pyridazin-3-ylmethyl, pyridazin-3-ylmethyl, 5-methyl-pyrimidin-2-ylmethyl or 2-methyl-pyrimidin-5-ylmethyl.
3. The method of claim 2 , wherein:
R 2 is 2-hydroxy-1-methylethyl, 5-methyl-pyrazin-2-ylmethyl or 1-pyrazin-2-ylethyl.
4. A method for modulating P2X 3 and P2X 213 receptor activity in a subject, comprising administering to a subject in need thereof an effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is C 1-6 alkyl or halo;
R 2 is C 3-6 cycloalkyl, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl or heteroaryl-C 1-6 alkyl, wherein heteroaryl is pyrazinyl, pyridazinyl or pyrimidinyl, each optionally substituted once with methyl;
X is —N—;
Y is —O—, —CH 2 — or —NH—;
R 8 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-sulfonyl, halo-C 1-6 alkyl or halo; and
n is 0, 1 or 2.