COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS
The present invention provides novel compounds represented by formula I: or pharmaceutically acceptable salts thereof useful for treating flaviviridae viral infection.
1 .- 97 . (canceled)
98 . A compound of formula I:
or a pharmaceutically acceptable salt thereof;
wherein,
X is
M is
J is
Y 1 is a bond;
Y is COOH;
R 1 is C 2-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-14 aryl, C 3-12 heterocycle, C 3-18 heteroaralkyl or C 6-18 aralkyl;
R 2 is C 2-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-14 aryl, C 3-12 heterocycle, C 3-18 heteroaralkyl, or C 6-18 aralkyl;
R 3 is H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-14 aryl, C 3-12 heterocycle, C 3-18 heteroaralkyl or C 6-18 aralkyl; and
Z is H, halogen, or C 1-6 alkyl;
with the proviso that: when X is Benzamide and R 1 is phenyl, then R 3 is other than hydrogen;
wherein
alkyl in R 1 , R 2 , R 3 , and Z is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido;
alkenyl in R 1 , R 2 , and R 3 is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido;
alkynyl in R 1 , R 2 , and R 3 is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido;
aryl in R 1 , R 2 , and R 3 is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido;
aralkyl in R 1 , R 2 , and R 3 is in each case an aryl group attached to the adjacent atom by a C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, and the aryl group is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido;
heterocycle in R 1 , R 2 , and R 3 is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido;
heteroaralkyl in R 1 , R 2 , and R 3 in each case an heterocycle group attached to the adjacent atom by a C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, and the heterocycle group is in each case optionally substituted by one or more of: halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino or guanido; and
R 12 , R c , R d , R 13 and R 14 , are each independently H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-14 aryl, C 3-12 heterocycle, C 3-18 heteroaralkyl, or C 6-18 aralkyl, or R c and R d are taken together with the oxygens to form a 5 to 10 membered heterocycle, or R 13 and R 14 are taken together with the nitrogen to form a 3 to 10 membered heterocycle,
in each case above alkyl groups include alkyls in which one or more hydrogen atoms are each replaced by a halogen, and
sulfur atoms are in the form of S, SO, or SO 2 .
99 . A compound according to claim 98 , wherein said compound is of formula Ia:
or a pharmaceutically acceptable salt thereof.
100 . A compound according to claim 98 , wherein X is
101 . A compound according to claim 98 , wherein Z is H.
102 . A compound according to claim 98 , wherein R 1 is C 2-12 alkyl, C 6-14 aryl, or C 3-12 heterocycle, which in each case is substituted or unsubstituted.
103 . A compound according to claim 98 , wherein R 3 is H, C 1-12 alkyl, C 6-18 aralkyl, C 3-12 heterocycle, or C 3-18 heteroaralkyl, which in each case is substituted or unsubstituted.
104 . A compound according to claim 98 , wherein
R 3 is H, or R 3 is methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmethyl, dioxanyl, azepanyl or benzyl, which in each case is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino, and guanido; and
R 12 , R c , R d , R 13 and R 14 are each independently H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-14 aryl, C 3-12 heterocycle, C 3-18 heteroaralkyl, or C 6-18 aralkyl,
or R c and R d , taken together with the oxygens, form a 5 to 10 membered heterocycle,
or R 13 and R 14 , taken together with the nitrogen, form a 3 to 10 membered heterocycle.
105 . A compound according to claim 104 , wherein R 3 is isopropyl or cyclohexyl, which in each case is substituted or unsubstituted.
106 . A compound according to claim 98 , wherein R 2 is C 2-12 alkyl, C 6-14 aryl, or C 3-12 heterocycle, which in each case is substituted or unsubstituted.
107 . A compound according to claim 98 , wherein
R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, 2-(cyclopentyl)-ethyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, butenyl isobutyl, pentyl, neopentyl or t-butyl, which in each case is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino, and guanido; and
R 12 , R c , R d , R 13 and R 14 are each independently H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-14 aryl, C 3-12 heterocycle, C 3-18 heteroaralkyl, or C 6-18 aralkyl,
or R c and R d , taken together with the oxygens, form a 5 to 10 membered heterocycle,
or R 13 and R 14 , taken together with the nitrogen, form a 3 to 10 membered heterocycle.
108 . A compound according to claim 99 , wherein X is
109 . A compound according to claim 99 , wherein Z is H.
110 . A compound according to claim 99 , wherein R 1 is C 2-12 alkyl, C 6-14 aryl, or C 3-12 heterocycle, which in each case is substituted or unsubstituted.
111 . A compound according to claim 99 , wherein R 3 is H, or R 3 is C 1-12 alkyl, C 6-18 aralkyl, C 3-12 heterocycle, or C 3-18 heteroaralkyl, which in each case is substituted or unsubstituted.
112 . A compound according to claim 99 , wherein
R 3 is H, or R 3 is methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmethyl, dioxanyl, azepanyl or benzyl, which in each case is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino, and guanido; and
R 12 , R c , R d , R 13 and R 14 are each independently H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-14 aryl, C 3-12 heterocycle, C 3-18 heteroaralkyl, or C 6-18 aralkyl,
or R c and R d , taken together with the oxygens, form a 5 to 10 membered heterocycle,
or R 13 and R 14 , taken together with the nitrogen, form a 3 to 10 membered heterocycle.
113 . A compound according to claim 99 , wherein R 3 is H, or R 3 is methyl, isopropyl, piperidinyl, piperidinylmethyl, dioxolanyl or cyclohexyl, which in each case is substituted or unsubstituted.
114 . A compound according to claim 99 , wherein R 2 is C 2-12 alkyl, C 6-14 aryl, or C 3-12 heterocycle, which in each case is substituted or unsubstituted.
115 . A compound according to claim 99 , wherein Z is H and X is
116 . A compound according to claim 115 , wherein
R 1 is C 2-12 alkyl, C 6-14 aryl, or C 3-12 heterocycle, which in each case is substituted or unsubstituted;
R 3 is H, or R 3 is C 1-12 alkyl, C 6-18 aralkyl, C 3-12 heterocycle, or C 3-18 heteroaralkyl, which in each case is substituted or unsubstituted; and
R 2 is C 2-12 alkyl, C 6-14 aryl, or C 3-12 heterocycle, which in each case is substituted or unsubstituted.
117 . A compound according to claim 115 , wherein
R 3 is H, or R 3 is methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmethyl, dioxanyl, azepanyl or benzyl, which in each case is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino, and guanido;
R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl cyclohexyl, cycloheptyl, 2-(cyclopentyl)-ethyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, butenyl isobutyl, pentyl, neopentyl or t-butyl, which in each case is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO 3 R 12 , PO 3 R c R d , CONR 13 R 14 , 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 3-10 heterocycle, hydroxyl, NR 13 R 14 , C(O)OR 12 , cyano, azido, amidino, and guanido; and
R 12 , R c , R d , R 13 and R 14 are each independently H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-14 aryl, C 3-12 heterocycle, C 3-18 heteroaralkyl, or C 6-18 aralkyl,
or R c and R d , taken together with the oxygens, form a 5 to 10 membered heterocycle,
or R 13 and R 14 , taken together with the nitrogen, form a 3 to 10 membered heterocycle.
118 . A method for treating a Hepatitis C virus (HCV) infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to claim 98 .