Compounds and methods for the treatment or prevention of
Compounds represented by formula: Wherein X, Y and Z are as defined herein, pharmaceutically acceptable salts thereof, and related compounds, are suitable for use in treating or preventing a Flaviviridae viral infection in a host.
1. A compound of formula:
or pharmaceutically acceptable salts thereof;
wherein;
Z is piperidinyl or N—C 1-6 alkyl-piperidinyl;
Y is 6-10 membered aryl;
X is 3-10 membered cycloalkyl;
m is an integer from 0-1;
provided that when Y is unsubstituted phenyl then X is other than 4-methylcyclohexane.
2. A compound according to claim 1 , wherein Z is piperidinyl or N—(C 1-6 alkyl)-piperidinyl, N—(C 1-6 alkyl)-piperidinylmethyl, or piperidinylmethyl, which in each case is unsubstituted or substituted by one or more substituent chosen from halogen, nitro, nitroso, SO 3 Rf, SO 2 Rf, PO 3 RcRd, CONRgRh, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-12 aralkyl, C 6-12 aryl, C 1-6 alkyloxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 6-12 aryloxy, C(O)C 1-6 alkyl, C(O)C 2-6 alkenyl, C(O)C 2-6 alkynyl, C(O)C 6-12 aryl, C(O)C 6-12 aralkyl, C(O)NHRf, C 3-10 heterocycle, hydroxyl, NRgRh, C(O)ORf, cyano, azido, amidino or guanido;
wherein Rf, Rc, Rd, Rg and Rh in each case is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 heterocycle, C 3-10 heteroaralkyl or C 6-10 aralkyl;
or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle;
or Rg and Rh are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
3. A compound according to claim 1 , wherein Z is piperidinyl unsubstituted or substituted by one or more substituent chosen from halogen, SO 2 Rf, CONRgRh, C 1-6 alkyl, C 6-12 aralkyl, C 6-12 aryl, C 1-6 alkyloxy, C(O)C 1-6 alkyl, C(O)NHRf, C 3-10 heterocycle, hydroxyl, NRgRh, C(O)Orf or cyano;
wherein Rf, Rg and Rh in each case is H or C 1-6 alkyl.
4. A compound according to claim 1 , wherein Z is N—(C 1-6 alkyl)-piperidinyl unsubstituted or substituted by one or more substituent chosen from halogen, SO 2 Rf, CONRgRh, C 1-6 alkyl, C 6-12 aralkyl, C 6-12 aryl, C 1-6 alkyloxy, C(O)C 1-6 alkyl, C(O)NHRf, C 3-10 heterocycle, hydroxyl, NRgRh, C(O)Orf or cyano;
wherein Rf, Rg and Rh in each case is H or C 1-6 alkyl.
5. A compound according to claim 1 , wherein X is 6-membered cycloalkyl.
6. A compound according to claim 1 , wherein X is cyclohexyl unsubstituted or substituted by one or more substituent chosen from halogen, nitro, nitroso, SO 3 Rf, SO 2 Rf, PO 3 RcRd, CONRgRh, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-12 aralkyl, C 6-12 aryl, C 1-6 alkyloxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 6-12 aryloxy, C(O)C 1-6 alkyl, C(O)C 2-6 alkenyl, C(O)C 2-6 alkynyl, C(O)C 6-12 aryl, C(O)C 6-12 aralkyl, C(O)NHRf, C 3-10 heterocycle, hydroxyl, NRgRh, C(O)ORf, cyano, azido, amidino or guanido;
wherein Rf, Rc, Rd, Rg and Rh in each case is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 heterocycle, C3-10 heteroaralkyl or C6-10 aralkyl;
or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle;
or Rg and Rh are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
7. A compound according to claim 1 , wherein X is cyclohexyl substituted by one or more substituent chosen from C 1-6 alkyl, halogen, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkyloxy.
8. A compound according to claim 1 , wherein X is 4-methyl-cyclohexyl or 2-hydroxy-4-methyl-cyclohexyl.
9. A compound according to claim 1 , wherein Y is phenyl unsubstituted or substituted by one or more substituent chosen from halogen, nitro, nitroso, SO 3 Rf, SO 2 Rf, PO 3 RcRd, CONRgRh, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-12 aralkyl, C 6-12 aryl, C 1-6 alkyloxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 6-12 aryloxy, C(O)C 1-6 alkyl, C(O)C 2-6 alkenyl, C(O)C 2-6 alkynyl, C(O)C 6-12 aryl, C(O)C 6-12 aralkyl, C(O)NHRf, C 3-10 heterocycle, hydroxyl, NRgRh, C(O)ORf, cyano, azido, amidino or guanido;
wherein Rf, Rc, Rd, Rg and Rh in each case is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 heterocycle, C 3-10 heteroaralkyl or C 6-10 aralkyl;
or Rc and Rd are taken together with the oxygens to form a 5 to 10 membered heterocycle;
or Rg and Rh are taken together with the nitrogen to form a 3 to 10 membered heterocycle.
10. A compound according to claim 1 , wherein Y is phenyl substituted by one or more substituent chosen from halogen, nitro, SO 2 Rf, C 1-6 alkyl, C 1-6 alkyloxy, C(O)C 1-6 alkyl, C(O)Orf, cyano or azido.
11. A compound according to claim 1 , wherein Y is phenyl.
12. A compound chosen from:
3-{[(2-carboxy-5-phenyl-thiophen-3-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-methyl}-piperidinium; trifluoro-acetate;
2-{[(2-carboxy-5-phenyl-thiophen-3-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-methyl}-piperidinium; trifluoro-acetate;
4-[(2-carboxy-5-phenyl-thiophen-3-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-1-methyl-piperidinium chloride;
4-[[2-carboxy-5-(4-fluoro-phenyl)-thiophen-3-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-1-methyl-piperidinium chloride;
3-[(4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-{[(2-carboxy-5-phenyl-thiophen-3-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-methyl}-1-methyl-piperidinium chloride;
4-{[(2-carboxy-5-phenyl-thiophen-3-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-methyl}-1-methyl-piperidinium chloride;
3-[(1-ethyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(1-isopropyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid;
4-[(2-carboxytolyl-thiophen-3-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-1-methyl-piperidinium chloride;
3-[(1-acetyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(1-benzyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
4-[[2-carboxy-5-(3-fluoro-phenyl)-thiophen-3-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-1-methyl-piperidinium; chloride;
4-[[2-carboxy-5-(4-methoxy-phenyl)-thiophen-3-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-1-methyl-piperidinium; chloride;
4-[[2-carboxy-5-(4-nitro-phenyl)-thiophen-3-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-1-methyl-piperidinium; chloride;
4[[2-carboxy-5-(4-chloro-phenyl)-thiophen-3-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-1-methyl-piperidinium chloride;
4-[[2-carboxy-5-(4-cyano-phenyl)-thiophen-3-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-1-methyl-piperidinium chloride;
3-[(1-formyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(4-methyl-cyclohexanecarbonyl)-(1-methyl-1-oxy-piperidin-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(4-methyl-cyclohexanecarbonyl)-(1-methyl-1-oxy-piperidin-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(1-methanesulfonyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(1-methylcarbamoyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(1-methylcarbamoyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(4-methyl-cyclohexanecarbonyl)-(1-methyl-2-oxo-piperidin-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(1-cyano-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(1-carbamoyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
3-[(1-aminooxalyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid;
or pharmaceutically acceptable salts thereof.
13. A compound as defined in claim 12 ; wherein said pharmaceutically acceptable salt is sodium salt.
14. A pharmaceutical composition comprising at least one compound as defined in claim 1 .