Tetrazole-substituted arylamides as P2X
Compounds of the formula V: or a pharmaceutically acceptable salt thereof, wherein, R 2 is optionally substituted phenyl, optionally substituted pyridin-2-yl or optionally substituted thienyl, and R 3 , R 4 , R 5 , R 6 and R 13 are as defined herein. Also provided are methods of using the compounds for treating diseases associated with the P2X 3 and/or a P2X 2/3 receptor antagonist and methods of making the compounds.
1. A compound of formula (IIc):
or a pharmaceutically acceptable salt thereof,
wherein:
R 5 is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkylsulfanyl-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, amino-C 1-6 alkyl, N—C 1-6 alkyl-amino-C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, heteroaryl or heterocyclyl-C 1-6 alkyl;
wherein said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-isoxazolyl, tetrazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and benzimidazolyl; and wherein the phenyl and heteroaryl each may be optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, halo-C 1-6 alkyl, halo, amino, N—C 1-6 alkyl-amino, and N,N-di-(C 1-6 alkyl)-amino;
wherein said heterocyclyl-C 1-6 alkyl is selected from morpholino-methyl, piperidinyl-methyl, piperazinyl-methyl, thiomorpholinyl-methyl, pyrrolidinyl-methyl, or azetidinyl-methyl and wherein the heterocyclyl portion of said heterocyclyl-C 1-6 alkyl may be optionally substituted once or twice with a substituent independently selected from methyl, methoxy, halo, methanesulfonyl, oxo or acetyl;
R 11 is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy, halo, C 1-6 haloalkyl, hetero-C 1-6 alkyl, C 1-6 alkylsulfonyl or cyano;
R 12 is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy, halo, C 1-6 haloalkyl, hetero-C 1-6 alkyl, C 1-6 alkylsulfonyl or cyano; and
R 13 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, hetero-C 1-6 alkyl, C 3-6 -cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl or cyano.
2. The compound of claim 1 , wherein R 5 is hydroxymethyl, methoxymethyl, morpholin-4-ylmethyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl or thiazolyl.
3. The compound of claim 1 , wherein R 5 is pyridinyl, pyrimidinyl, or pyrazinyl.
4. The compound of claim 1 , wherein R 5 is C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, heteroaryl or heterocyclyl-C 1-6 alkyl.
5. The compound of claim 1 , wherein R 5 is methoxymethyl, hydroxymethyl or pyridazin-2-yl.
6. The compound of claim 1 , wherein R 11 is halo or methyl.
7. The compound of claim 1 , wherein R 12 is hydrogen, halo or methyl.
8. The compound of claim 1 , wherein R 11 is methyl and R 12 is halo.
9. The compound of claim 1 , wherein R 13 is C 1-6 alkyl or C 1-6 haloalkyl.
10. The compound of claim 1 , wherein R 13 is C 1-6 alkyl.
11. A compound of formula (IIIc):
wherein:
R 5 is C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, pyridinyl, pyrimidinyl or pyrazinyl, wherein the pyridinyl, pyrimidinyl, and pyrazinyl each may be substituted once or twice with methyl;
R 12 is hydrogen, halo or methyl; and
R 13 is C 1-6 alkyl or C 1-6 haloalkyl.
12. The compound of claim 11 , wherein R 5 is pyrazin-2-yl.
13. The compound of claim 11 , wherein R 5 is 5-methyl-pyrazin-2-yl.
14. The compound of claim 11 , wherein R 5 is methoxymethyl.
15. The compound of claim 11 , wherein R 5 is hydroxymethyl.
16. The compound of claim 11 , wherein R 12 is halo.
17. The compound of claim 11 , wherein R 12 is fluoro.
18. The compound of claim 11 , wherein R 13 is C 1-6 alkyl.
19. The compound of claim 11 , wherein R 13 is isopropyl.
20. The compound of claim 11 , wherein R 13 is trifluoromethyl.
21. A compound of formula (IVc):
or a pharmaceutically acceptable salt thereof,
wherein:
R 5 is C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkylsulfanyl-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, amino-C 1-6 alkyl, N—C 1-6 alkyl-amino-C 1-6 alkyl, N,N-di-C 1-6 alkyl-amino-C 1-6 alkyl, C 3-7 cycloalkyl, heterocyclyl-C 1-6 alkyl, heteroaryl or phenyl optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, halo-C 1-6 alkyl, halo, amino, N—C 1-6 alkyl-amino, and N,N-di-(C 1-6 alkyl)-amino;
R 11 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo, C 1-6 haloalkyl, hetero-C 1-6 alkyl, C 1-6 alkylsulfonyl or cyano;
R 12 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo, C 1-6 haloalkyl, hetero-C 1-6 alkyl, C 1-6 alkylsulfonyl or cyano; and
R 13 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, hetero-C 1-6 alkyl, C 3-6 -cycloalkyl; C 3-6 cycloalkyl-C 1-6 alkyl or cyano.
22. A compound 2′-fluoro-5-(5-isopropyltetrazol-1-yl)-4′-methylbiphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methylethyl)amide, or a pharmaceutically acceptable salt thereof.
23. A compound 2′-fluoro-5-(5-isopropyltetrazol-1-yl)-4′-methylbiphenyl-3-carboxylic acid (5-methylpyrazin-2-ylmethyl)amide, or a pharmaceutically acceptable salt thereof.
24. A compound 2′-fluoro-5-(5-isopropyltetrazol-1-yl)-4′-methylbiphenyl-3-carboxylic acid (2-methoxy-1-methylethyl)amide, or a pharmaceutically acceptable salt thereof.
25. A compound 5-(5-isopropyltetrazol-1-yl)-4′-methylbiphenyl-3-carboxylic acid (2-hydroxy-1-methylethyl)amide, or a pharmaceutically acceptable salt thereof.
26. A compound 2′-fluoro-5-(5-isopropyltetrazol-1-yl)-4′-methylbiphenyl-3-carboxylic acid (1-pyrazin-2-ylethyl)amide, or a pharmaceutically acceptable salt thereof.