US2005101651A1PendingUtilityA1
Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
Priority: Apr 14, 2000Filed: Nov 12, 2004Published: May 12, 2005
Est. expiryApr 14, 2020(expired)· nominal 20-yr term from priority
A61P 31/12A61P 43/00C07D 401/04C07D 405/14C07D 207/26C07D 405/04C07K 5/0205C07D 207/333A61K 38/00C07D 403/12C07D 413/04C07D 207/34A61K 31/40Y02A50/30
56
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Claims
Abstract
Compounds of the formula: where the formula variables are as defined in the disclosure, advantageously inhibit or block the biological activity of the picomaviral 3C protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with one or more picomaviruses, such as RVP. Intermediates and synthetic methods for preparing such compounds are also described.
Claims
exact text as granted — not AI-modified1 - 11 . (canceled)
12 . An antipicornaviral compound having the formula:
wherein:
R 1 is H, halo or an alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, where the alkoxy, alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
R 2 and R 3 are each independently H, halo or an alkoxy or lower alkyl group, where the alkoxy or lower alkyl group is unsubstituted or substituted with one or more suitable substituents;
or R 1 together with R 2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents;
R 4 and R 6 are each independently H or a lower alkyl group, unsubstituted or substituted with one or more suitable substituents;
R 5 is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
R 7 is a moiety having the formula:
wherein:
R 8 and R 9 are each independently H or a lower alkyl group;
m is 0 or 1;
p is an integer of from 0 to 5;
A 1 is CH or N;
when p is 1, 2, 3, 4, or 5, A 2 is C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C(R 10 )(R 11 )(R 12 ), N(R 10 )(R 12 ), S(R 10 ), S(O)(R 10 ), S(O) 2 (R 10 ), or O(R 10 ) where each R 10 , R 11 and R 12 is independently H or a lower alkyl group;
each A 3 present is independently C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A 4 is N(R 13 ), C(R 10 )(R 11 ), or O, and when p is 0, A 4 is N(R 13 )(R 14 ), C(R 10 )(R 11 )(R 12 ), and O(R 14 ), where each R 10 , R 11 and R 12 is each independently H or a lower alkyl group, each R 13 is H or an alkyl, aryl, or acyl group, and each R 14 is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A 1 , (A 2 ) m , (A 3 ) p , A 4 , and C═O, where each dotted line in the ring depicts a single bond when A 2 is present and a hydrogen atom when A 2 is absent; and
Z and Z 1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, —C(O)R 15 , —CO 2 R 15 , —CN, —C(O)NR 15 R 16 , —C(O)NR 15 OR 16 , —C(S)R 15 , —C(S)OR 15 , —C(S)NR 15 R 16 , —C(═NR 15 )R 16 , —C(═NR 15 )OR 16 , —NO 2 , —SOR 16 , —SO 2 R 15 , —SO 2 NR 15 R 16 , —SO 2 (NR 15 )(OR 16 ), —SONR 15 , —SO 3 R 15 , —PO(OR 15 ) 2 , —PO(OR 15 )(OR 16 ), —PO(NR 15 R 16 )(OR 17 ), —PO(NR 15 R 16 )(NR 17 R 18 ), —C(O)NR 15 NR 16 R 17 , —C(S)NR 15 NR 16 R 17 , where R 15 , R 16 , R 17 and R 18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R 15 , R 16 , R 17 and R 18 , taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents,
or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z 1 are as defined above;
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof of said compound.
13 . An antipicornaviral compound having the formula:
wherein:
R 1 is H, halo or an alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group, where the alkoxy, alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
R 2 and R 3 are each independently H, halo or an alkoxy or lower alkyl group, where the alkoxy or lower alkyl group is unsubstituted or substituted with one or more suitable substituents;
or R 1 together with R 2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents;
R 4 and R 6 are each independently H or a lower alkyl group, unsubstituted or substituted with one or more suitable substituents;
R 5 is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
R 7 is a moiety having the formula:
wherein:
R 8 and R 9 are each independently H or a lower alkyl group;
m is 0 or 1, provided that when m is 0 and R 1 together with R 2 form an aryl ring, the aryl ring is unsubstituted;
p is an integer of from 0 to 5;
A 1 is CH or N;
when p is 1, 2, 3, 4, or 5, A 2 is C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C(R 10 )(R 11 )(R 12 ), N(R 10 )(R 12 ), S(R 10 ), S(O)(R 10 ), S(O) 2 (R 10 ), or O(R 10 ) where each R 10 , R 11 and R 12 is independently H or a lower alkyl group;
each A 3 present is independently C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A 4 is N(R 13 ), C(R 10 )(R 11 ), or O, and when p is 0, A 4 is N(R 13 )(R 14 ), C(R 10 )(R 11 )(R 12 ), and O(R 14 ), where each R 10 , R 11 and R 12 is independently H or a lower alkyl group, each R 13 is H or an alkyl, aryl, or acyl group, and each R 14 is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A 1 , (A 2 ) m , (A 3 ) p , A 4 , and C═O, where each dotted line in the ring depicts a single bond when A 2 is present and a hydrogen atom when A 2 is absent; and
Z and Z 1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, —C(O)R 15 , —CO 2 R 15 , —CN, —C(O)NR 15 R 16 , —C(O)NR 15 OR 16 , —C(S)R 15 , —C(S)OR 15 , —C(S)NR 15 R 6 , —C(═NR 15 )R 16 , —C(═NR 15 )OR 16 , —NO 2 , —SOR 16 , —SO 2 R 15 , —SO 2 NR 15 R 16 , —SO 2 (NR 15 )(OR 16 ), —SONR 15 , —SO 3 R 15 , —PO(OR 15 ) 2 , —PO(OR 15 )(OR 16 ), —PO(NR 15 R 16 )(OR 17 ), —PO(NR 15 R 16 )(NR 17 R 18 ), —C(O)NR 15 NR 16 R 17 , —C(S)NR 15 NR 16 R 17 , where R 15 , R 16 , R 17 and R 18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R 15 , R 16 , R 17 and R 18 , taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents,
or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z 1 are as defined above;
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
14 . The compound according to claim 13 , having the formula:
wherein:
each R z is H or a suitable substituent and n z is an integer from 1 to 4;
R 7 is a moiety having the formula:
wherein:
R 8 and R 9 are each independently H or a lower alkyl group;
p is an integer of from 1 to 5;
A 1 is CH or N;
when p is 1, 2, 3, 4, or 5, A 2 is C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C(R 10 )(R 11 )(R 12 ), N(R 10 )(R 12 ), S(R 10 ), S(O)(R 10 ), S(O) 2 (R 10 ), or O(R 10 ) where each R 10 , R 11 and R 12 is independently H or a lower alkyl group;
each A 3 present is independently C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group;
A 4 is N(R 13 ), C(R 10 )(R 11 ), or O, where R 10 and R 11 are each independently H or a lower alkyl group, and R 13 is H or an alkyl, aryl or acyl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A 1 , (A 2 ) m , (A 3 ) p , A 4 , and C═O; and
R 3 , R 4 , R 5 , R 6 , Z and Z 1 are defined as in claim 13 .
15 . The compound according to claim 14 , wherein each R z is independently selected from H, halo, alkoxy, unsubstituted lower alkyl, haloalkyl, and lower alkoxyalkyl.
16 . The compound according to any one of claims 12 , 13 or 14 , wherein:
A 1 is CH or N; A 2 is C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; each A 3 present is independently C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5, A 4 is N(R 13 ), C(R 10 )(R 11 ), or O, and when p is 0, A 4 is N(R 13 )(R 14 ), C(R 10 )(R 11 )(R 12 ), and O(R 14 ), where each R 10 , R 11 and R 12 is independently H or a lower alkyl group, each R 13 is H or an alkyl, aryl, or acyl group, and each R 14 is H or an alkyl or aryl group; provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A 1 , (A 2 ) m , (A 3 ) p , A 4 , and C═O, where each dotted line in the ring depicts a single bond when A 2 is present and a hydrogen atom when A 2 is absent; and Z and Z 1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, —C(O)R 15 , —CO 2 R 15 , —CN, —C(O)NR 15 R 16 , —C(O)NR 15 OR 16 , —C(S)R 15 , —C(S)NR 15 R 16 , —NO 2 , —SOR 16 , —SO 2 R 15 , —SO 2 NR 15 R 16 , —SO 2 (NR 15 )(OR 16 ), —SONR 15 , —SO 3 R 15 , —PO(OR 15 ) 2 , —PO(OR 15 )(OR 16 ), —PO(NR 15 R 16 )(OR 17 ), —PO(NR 15 R 16 )(NR 17 R 18 ), —C(O)NR 15 NR 16 R 17 —C(S)NR 15 NR 16 R 17 , where R 15 , R 16 , R 17 and R 18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R 15 , R 16 , R 17 and R 18 , taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents, or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z 1 are as defined above.
17 . The compound according to any one of claims 12 , 13 or 14 , wherein said substituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl comprises one or more substituents independently selected from an alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, cyano, halo, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto, thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, arylthio and heteroarylthio group, where any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted with one or more suitable substituents.
18 . The compound according to any one of claims 12 , 13 or 14 , wherein said substituted alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties may be further substituted with one or more suitable substituents selected from nitro, amino, cyano, halo, haloalkyl, haloaryl, hydroxyl, keto, hydroxamino, alkylamino, dialkylamino, mercapto, and unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, alkylthio or arylthio groups and wherein said aryl or heteroaryl moieties may be substituted with alkylenedioxy.
19 . An antipicornaviral compound having the formula:
wherein:
R a′ is an alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, unsubstituted or substituted with one or more suitable substituents,;
R 5 is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents,;
each R 6 is independently H or a lower alkyl group, unsubstituted or substituted with one or more suitable substituents,;
R 7 is a moiety having the formula:
wherein:
R 8 and R 9 are each independently H or a lower alkyl group;
m is 0 or 1;
p is an integer of from 0 to 5;
A 1 is CH or N;
when p is 1, 2, 3, 4, or 5, A 2 is C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, and when p is 0, A 2 is C(R 10 )(R 11 )(R 12 ), N(R 10 )(R 12 ), S(R 10 ), S(O)(R 10 ), S(O) 2 (R 10 ), or O(R 10 ), where each R 10 , R 11 and R 12 is independently H or a lower alkyl group;
each A 3 present is independently C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is each independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A 4 is N(R 13 ), C(R 10 )(R 11 ), or O, and when p is 0, A 4 is N(R 13 )(R 14 ), C(R 10 )(R 11 )(R 12 ), and O(R 14 ), where each R 10 , R 11 and R 12 is independently H or a lower alkyl group, each R 13 is H or an alkyl, aryl, or acyl group, and each R 14 is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A 1 , (A 2 ) m , (A 3 ) p , A 4 , and C═O, where each dotted line in the ring depicts a single bond when A 2 is present and a hydrogen atom when A 2 is absent; and
Z and Z 1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, —C(O)R 15 , —CO 2 R 15 , —CN, —C(O)NR 15 R 16 , —C(O)NR 15 OR 16 , —C(S)R 15 , —C(S)OR 15 , —C(S)NR 15 R 16 , —C(═NR 15 )R 16 , —C(═NR 15 )OR 16 , —NO 2 , —SOR 16 , —SO 2 R 15 , —SO 2 NR 15 R 16 , —SO 2 (NR 15 )(OR 16 ), —SONR 15 , —SO 3 R 15 , —PO(OR 15 ) 2 , —PO(OR 15 )(OR 16 ), —PO(NR 15 R 16 )(OR 17 ), —PO(NR 15 R 16 )(NR 17 R 18 ), —C(O)NR 15 NR 16 R 17 , —C(S)NR 15 NR 16 R 17 , where R 15 , R 16 , R 17 and R 18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R 15 , R 16 , R 17 and R 18 , taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents,
or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z 1 are as defined above;
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
20 . The compound according to claim 19 , wherein:
A 1 is CH or N; A 2 is C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; each A 3 present is independently C(R 10 )(R 11 ), N(R 12 ), S, S(O), S(O) 2 , or O, where each R 10 , R 11 and R 12 is independently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5, A 4 is N(R 13 ), C(R 10 )(R 11 ), or O, and when p is 0, A 4 is N(R 13 )(R 14 ), C(R 10 )(R 11 )(R 12 ), and O(R 14 ), where each R 10 , R 11 and R 12 is independently H or a lower alkyl group, each R 13 is H or an alkyl, aryl, or acyl group, and each R 14 is H or an alkyl or aryl group; provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A 1 , (A 2 ) m , (A 3 ) p , A 4 , and C═O, where each dotted line in the ring depicts a single bond when A 2 is present and a hydrogen atom when A 2 is absent; and Z and Z 1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, —C(O)R 15 , —CO 2 R 15 , —CN, —C(O)NR 15 R 16 , —C(O)NR 15 OR 16 , —C(S)R 5 , —C(S)NR 15 R 16 , —NO 2 , —SOR 16 , —SO 2 R 15 , —SO 2 NR 15 R 16 , —SO 2 (NR 15 )(OR 16 ), —SONR 15 , —SO 3 R 15 , —PO(OR 15 ) 2 , —PO(OR 15 )(OR 16 ), —PO(NR 15 R 16 )(OR 17 ), —PO(NR 15 R 16 )(NR 17 R 18 ), —C(O)NR 15 NR 16 R 17 , —C(S)NR 15 NR 16 R 17 , where R 15 , R 16 , R 17 and R 18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R 15 , R 16 , R 17 and R 18 , taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents, or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z 1 are as defined above.
21 . The compound according to any one of claims 12 , 13 , 14 , 19 or 20 , wherein R 5 is H or a lower alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group, a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where said lower alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents.
22 . The compound according to claim 21 , wherein R 5 is H or a methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl group, unsubstituted or substituted with one or more suitable substituents.
23 . The compound according to claim 16 , wherein R 5 is H or a methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl group, unsubstituted or substituted with one or more suitable substituents.
24 . The compound according to claim 21 , wherein said substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl group is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio.
25 . The compound according to claim 21 , wherein the thienyl moiety of the -methylthienyl group is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo.
26 . The compound according to claim 21 , wherein the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo.
27 . The compound according to any one of claims 12 , 13 , 14 , 19 or 20 , wherein R 5 is H, ethyl, 2-propyn-1-yl, methylcyclohexyl, or substituted or unsubstituted benzyl, where the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from lower alkyl, lower alkoxy and halo.
28 . The compound according to claim 16 , wherein R 5 is H, ethyl, 2-propyn-1-yl, methylcyclohexyl, or substituted or unsubstituted benzyl, where the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from lower alkyl, lower alkoxy and halo.
29 . The compound, prodrug, pharmaceutically acceptable salt, pharmaceuticaly active metabolite, or pharmaceutically acceptable salt according to any one of claims 12 , 13 , 14 , 19 or 20 , where m is 0 and p is 0 or m is 1 and p is 1 or 2.
30 . The compound according to any one of claims 12 , 13 , 14 , 19 or 20 , wherein R 7 is selected from —CH 2 CH 2 C(O)NH 2 ; —CH 2 CH 2 C(O)NH-alkyl; —CH 2 NHC(O)CH 3 ; and
where n is 1 or 2.
31 . The compound according to claim 16 , wherein R 7 is selected from —CH 2 CH 2 C(O)NH 2 ; —CH 2 CH 2 C(O)NH-alkyl; —CH 2 NHC(O)CH 3 ; and
where n is 1 or 2.
32 . The compound according to any one of claims 12 , 13 , 14 , 19 or 20 , wherein R 7 is
33 . The compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate according to any one of claims 12 , 13 or 19 , wherein Z and Z 1 are each independently selected from H, alkyl, where the alkyl is unsubstituted or substituted with one or more suitable substituents, and —CO 2 R 15 or taken together with the atom to which they are attached, form a heterocycloalkyl group, which is optionally substituted with one or more suitable substituents.
34 . (canceled)
35 . The compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate according to claim 16 , wherein Z and Z 1 are each independently selected from H, lower alkyl which is unsubstituted or substituted with one or more suitable substituents, —CO 2 H, —CO 2 -alkyl and —CO 2 -cycloalkyl, or taken together with the atom to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more of keto or thioketo.
36 . The compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate according to claim 20 , wherein Z and Z 1 are each independently selected from H, lower alkyl which is unsubstituted or substituted with one or more suitable substituents, —CO 2 H, —CO 2 -alkyl and —CO 2 -cycloalkyl, or taken together with the atom to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more of keto or thioketo.
37 . The compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate according to any one of claims 12 , 13 or 19 , wherein Z and Z 1 are not both H.
38 . (canceled)
39 . The compound according to claim 16 , wherein Z 1 is H and Z is —CO 2 CH 2 CH 3 , —CO 2 (CH(CH 3 ) 2 ), —CO 2 (C(CH 3 ) 3 ), —CO 2 CH 2 (C(CH 3 ) 3 ), —CO 2 (cyclo-C 5 H 9 )or Z 1 and Z taken together with the atom to which they are attached form
40 . The compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate according to any one of claims 12 , 13 or 19 , wherein Z 1 is H or a lower alkyl and Z is —CO 2 H, —CO 2 -alkyl, —CO 2 -alkylaryl, —CO 2 -alkylheteroaryl, —CO 2 -cycloalkyl group, where the lower alkyl, -alkyl, -cycloalkyl, -alkylaryl, -alkylheteroaryl moieties thereof are unsubstituted or substituted with one or more suitable substituents, or Z 1 and Z taken together with the atom to which they are attached form a heterocycloalkyl group, which is optionally substituted.
41 . The compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate according one of claims 12 , 13 , 19 or 20 , wherein Z is selected from ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, (2,2-dimethylpropyl)-oxycarbonyl, benzyloxycarbonyl, pyridylmethyleneoxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonyl, where the ethoxy, t-butoxy, isopropoxy, (2,2-dimethylpropyl)-oxy, benzyl, pyridylmethylene, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl moieties thereof are unsubstituted or substituted with one or more suitable substituents, or Z 1 and Z taken together with the atom to which they are attached form
42 . The compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate according claim 41 , wherein Z is selected from ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, (2,2-dimethylpropyl)-oxycarbonyl, benzyloxycarbonyl, pyridylmethyleneoxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonyl, or Z 1 and Z taken together with the atom to which they are attached form
43 . (canceled)
44 . (canceled)
45 . The compound according to claim 12 , having the formula:
wherein R 1 is an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, and each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Z and Z 1 are defined as in claim 12 .
46 . The compound according to claim 13 , having the formula:
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Z and Z 1 are defined as in claim 13 .
47 . The compound according to claim 14 , having the formula:
wherein R z , R 3 , R 4 , R 5 , R 6 , R 7 , Z and Z 1 are defined as in claim 14 .
48 . The compound according to claims 12 or 13 , wherein R 1 is selected from H and a lower alkyl, phenyl, naphthyl, pyridyl, quinoyl, isoquinoyl or isoxazoyl group, where the lower alkyl, phenyl, naphthyl, pyridyl, quinoyl, isoquinoyl or isoxazoyl group is unsubstituted or substituted with one or more substituents selected from alkyl, hydroxy, halo, haloalkyl, alkoxy, haloalkoxy and alkylenedioxy moiety.
49 . An antipicornaviral compound having the formula:
wherein:
R a is (C 1 -C 4 )alkylcarbonyl-(C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkylcarbonyl-(C 1 -C 4 )alkyl, arylcarbonyl-(C 1 -C 4 )alkyl, heteroarylcarbonyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonylamino-(C 1 -C 4 )alkyl, (C 3 -C 8 ) cycloalkylcarbonylamino-(C 1 -C 4 )alkyl, heterocycloalkylcarbonylamino-(C 1 -C 4 )alkyl, arylcarbonylamino-(C 1 -C 4 )alkyl, heteroarylcarbonylamino-(C 1 -C 4 )alkyl, (C 1 -C 4 alkylaminocarbonyl-(C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkylaminocarbonyl-(C 1 -C 4 )alkyl, heterocycloalkylaminocarbonyl-(C 1 -C 4 )alkyl, arylaminocarbonyl-(C 1 -C 4 )alkyl, heteroarylaminocarbonyl-(C 1 -C 4 )alkyl, wherein each (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof is unsubstituted or substituted with one or more suitable substituents;
R b and R d are each independently H or C 1 -C 4 alkyl;
R c is selected from —CH 2 CH 2 C(O)NH 2 ; —CH 2 CH 2 C(O)NH-alkyl; —CH 2 NHC(O)CH 3 ; and
where n is 1 or 2; and
Z 1 is H or C 1 -C 4 alkyl and Z is —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -alkylaryl or —CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are attached form
provided that R c is
where n is 1 or 2 when R a is an indolylcarbonylamino-(C 1 -C 4 )alkyl group where the indolyl moiety thereof is substituted with one or more suitable substituents or R a is is not an amino-substituted (C 1 -C 4 )alkylcarbonylamino-(C 1 -C 4 )alkyl or R a is is not an amino-substituted (C 1 -C 4 )alkylcarbonyl-(C 1 -C 4 )alkyl; and R c is selected from —CH 2 CH 2 C(O)NH 2 ; —CH 2 CH 2 C(O)NH-alkyl; —CH 2 NHC(O)CH 3 ; and
where n is 1 or 2, when R a is an indolylcarbonylamino-(C 1 -C 4 )alkyl group where the indolyl moiety thereof is unsubstituted or R a is a (C 1 -C 4 ) alkylaminocarbonyl-(C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkylaminocarbonyl-(C 1 -C 4 )alkyl, heterocycloalkylaminocarbonyl-(C 1 -C 4 )alkyl, arylaminocarbonyl-(C 1 -C 4 )alkyl, heteroarylaminocarbonyl-(C 1 -C 4 )alkyl, or heteroarylcarbonylamino-(C 1 -C 4 )alkyl group, wherein each (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof is unsubstituted or substituted with one or more suitable substituents.
50 . The compound according to claim 49 , wherein:
R a is (C 1 -C 4 )alkylcarbonyl-(C 1 -C 4 )alkyl, (C 5 -C 6 )cycloalkylcarbonyl-(C 1 -C 4 )alkyl, arylcarbonyl-(C 1 -C 4 )alkyl, heteroarylcarbonyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonylamino-(C 1 -C 4 )alkyl, C 3 -C 8 cycloalkylcarbonylamino-(C 1 -C 4 )alkyl, heterocycloalkylcarbonylamino-(C 1 -C 4 )alkyl, arylcarbonylamino-(C 1 -C 4 )alkyl, heteroarylcarbonylamino-(C 1 -C 4 )alkyl, (C 1 -C 4 alkylaminocarbonyl-(C 1 -C 4 )alkyl, (C 5 -C 6 )cycloalkylaminocarbonyl-(C 1 -C 4 )alkyl, heterocycloalkylaminocarbonyl-(C 1 -C 4 )alkyl, arylaminocarbonyl-(C 1 -C 4 )alkyl, heteroarylaminocarbonyl-(C 1 -C 4 )alkyl, wherein each (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof is unsubstituted or substituted with one or more suitable substituents; R c is —CH 2 CH 2 C(O)NH 2 or where n is 1; and Z 1 is H and Z is —CO 2 CH 2 CH 3 , —CO 2 (CH(CH 3 ) 2 ), —CO 2 (C(CH 3 ) 3 ), —CO 2 CH 2 (C(CH 3 ) 3 ), —CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form R c is where n is 1, when R a is an indolylcarbonylamino-(C 1 -C 4 )alkyl group where the indolyl moiety thereof is substituted with one or two substituents independently selected from halo, C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 alkyl and C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, and heteroaryl where the aryl, heterocycloalkyl and heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; and R c is selected from —CH 2 CH 2 C(O)NH 2 ; —CH 2 CH 2 C(O)NH-alkyl; —CH 2 NHC(O)CH 3 ; and where n is 1, when R a is (C 1 -C 4 )alkylcarbonyl-(C 1 -C 4 )alkyl, (C 5 -C 6 )cycloalkyl carbonyl-(C 1 -C 4 )alkyl, arylcarbonyl-(C 1 -C 4 )alkyl, heteroarylcarbonyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonylamino-(C 1 -C 4 )alkyl, C 3 -C 8 cycloalkylcarbonylamino-(C 1 -C 4 )alkyl, heterocycloalkylcarbonylamino-(C 1 -C 4 )alkyl, arylcarbonylamino-(C 1 -C 4 )alkyl, heteroarylcarbonylamino-(C 1 -C 4 )alkyl, (C 1 -C 4 alkylaminocarbonyl-(C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkylaminocarbonyl-(C 1 -C 4 )alkyl, heterocycloalkylaminocarbonyl-(C 1 -C 4 )alkyl, arylaminocarbonyl-(C 1 -C 4 )alkyl, heteroarylaminocarbonyl-(C 1 -C 4 )alkyl, wherein each (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof unsubstituted or substituted with one or more suitable substituents.
51 . The compound according to claim 49 , wherein:
R a is (C 1 -C 4 )alkylcarbonyl-(C 1 -C 4 )alkyl, phenylcarbonyl-(C 1 -C 4 )alkyl, naphthylcarbonyl-(C 1 -C 4 )alkyl, pyrrolylcarbonyl-(C 1 -C 4 )alkyl, indolylcarbonyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonylamino-(C 1 -C 4 )alkyl, pyrrolylcarbonylamino-(C 1 -C 4 )alkyl, indolylcarbonylamino-(C 1 -C 4 )alkyl, phenylcarbonylamino-(C 1 -C 4 )alkyl, naphthylcarbonylamino-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylaminocarbonyl-(C 1 -C 4 )alkyl, phenylaminocarbonyl-(C 1 -C 4 )alkyl, naphthylaminocarbonyl-(C 1 -C 4 )alkyl, wherein each (C 1 -C 4 )alkyl, phenyl, naphthyl, pyrrolyl, and indolyl moiety thereof is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyl or heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; R b and R d are each H; R c is —CH 2 CH 2 C(O)NH 2 or and Z 1 is H and Z is —CO 2 CH 2 CH 3 or Z 1 and Z taken together with the atom to which they are attached form provided that R c is when R a is an indolylcarbonylamino-(C 1 -C 4 )alkyl group where the indolyl moiety thereof is substituted with one or two substituents independently selected from halo, C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 alkyl and C 1 -C 4 haloalkyl; and and R c is —CH 2 CH 2 C(O)NH 2 or when R a is (C 1 -C 4 )alkylcarbonyl-(C 1 -C 4 )alkyl, phenylcarbonyl-(C 1 -C 4 )alkyl, naphthylcarbonyl-(C 1 -C 4 )alkyl, pyrrolylcarbonyl-(C 1 -C 4 )alkyl, indolylcarbonyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonylamino-(C 1 -C 4 )alkyl, pyrrolylcarbonylamino-(C 1 -C 4 )alkyl, indolylcarbonylamino-(C 1 -C 4 )alkyl, phenylcarbonylamino-(C 1 -C 4 )alkyl, naphthylcarbonylamino-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylaminocarbonyl-(C 1 -C 4 )alkyl, phenylaminocarbonyl-(C 1 -C 4 )alkyl, naphthylaminocarbonyl-(C 1 -C 4 )alkyl, wherein each (C 1 -C 4 )alkyl, phenyl, naphthyl and pyrrolyl moiety thereof is group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyl and heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; and said indolyl moiety is unsubstituted.
52 . The compound according to claim 49 having the formula:
wherein:
R a′ is a (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, aryl or heteroaryl group, wherein the (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, aryl and heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from (C 1 -C 4 )alkyl, aryl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl, (C 1 -C 4 )alkoxy, alkylenedioxy, aryloxy, (C 3 -C 8 )cycloalkoxy, heteroaryloxy, and carboxyl where the (C 1 -C 4 )alkyl, aryl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl, heteroaryl moieties thereof are optionally substituted by one or more of (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl or aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio;
R b and R d are each independently H or C 1 -C 4 alkyl;
n is 1,2 or 3;
R x is H and R y is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents;
R c is
where n is 1 or 2; and
Z 1 is H or C 1 -C 4 alkyl and Z is —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -alkylaryl or —CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are attached form
53 . The compound according to claim 52 , wherein:
R a′ is a (C 1 -C 4 )alkyl, pyrrolyl, indolyl, phenyl or naphthyl group, where the (C 1 -C 4 )alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy and the pyrrolyl, indolyl, phenyl or naphthyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl and heteroaryl, where the aryl, heterocycloalkyl and heteroaryl is unsubstituted or substituted by one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy R b and R d are each H; n is 1 or 2; R x is H and R y is substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; R c is where n is 1; and Z 1 is H and Z is —CO 2 CH 2 CH 3 , —CO 2 (CH(CH 3 ) 2 ), —CO 2 (C(CH 3 ) 3 ), —CO 2 CH 2 (C(CH 3 ) 3 ), —CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form
54 . The compound according to claim 52 , wherein:
R a′ is an unsubstituted (C 1 -C 4 )alkyl, or a pyrrolyl, indolyl, phenyl or naphthyl group, where the pyrrolyl, indolyl, phenyl or naphthyl group is unsubstituted or substituted by one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or a phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; R b and R d are each H; n is 2; R x is H and R y is ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halo; R c is and Z 1 is H and Z is —CO 2 CH 2 CH 3 or Z 1 and Z taken together with the atom to which they are attached form
55 . The compound according to claim 49 , having the formula:
wherein:
R a′ is a (C 1 -C 4 )alkyl, phenyl, naphthyl, pyrrolyl or indolyl group, where the (C 1 -C 4 )alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy and the phenyl, naphthyl, pyrrolyl or indolyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyl or heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy;
n is 1, 2 or 3,
R x is H and R y is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents.
R b and R d are each independently H or C 1 -C 4 alkyl;
R c is
where n is 1 or 2; and
Z 1 is H or C 1 -C 4 alkyl and Z is —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -alkylaryl or —CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are attached form
56 . The compound according to claim 55 , wherein:
R a′ is a pyrrolyl or indolyl group, where the pyrrolyl or indolyl group is unsubstituted or substituted by one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or a phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted or substituted with one or more substituents independently selected from: halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; R b and R d are each H; n is 1 or 2; R x is H and R y is substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; R c is where n is 1; and Z 1 is H and Z is —CO 2 CH 2 CH 3 , —CO 2 (CH(CH 3 ) 2 ), —CO 2 (C(CH 3 ) 3 ), —CO 2 CH 2 (C(CH 3 ) 3 ), —CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form
57 . The compound according to claim 55 , wherein:
R a′ is a pyrrolyl group that is unsubstituted or substituted by phenyl, α-naphthyl, β-naphthyl, 2-chlorophenyl, 2-α,α,α-trifluoromethylphenyl, 3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl, 3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl (o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl; R b and R d are each H; n is 1; R x is H and R y is ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halo; R c is and Z 1 is H and Z is —CO 2 CH 2 CH 3 or Z 1 and Z taken together with the atom to which they are attached form
58 . The compound according to claim 49 , having the formula:
wherein:
R a′ is a (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, wherein the (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
n is 1,2 or 3;
R x is H and R y is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents;
R c is selected from —CH 2 CH 2 C(O)NH 2 ; —CH 2 CH 2 C(O)NH-alkyl;
—CH 2 NHC(O)CH 3 ; and
where n is 1 or 2; and
Z 1 is H or C 1 -C 4 alkyl and Z is —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -alkylaryl or —CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are attached form
59 . The compound according to claim 58 , wherein:
R a′ is a (C 1 -C 4 )alkyl, phenyl or naphthyl group, where the (C 1 -C 4 )alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy and the phenyl or naphthyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, methylenedioxy and phenyl, where the phenyl is unsubstituted or substituted by one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; n is 1 or 2; R b and R d are each H; R x is H and R y is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; R c is —CH 2 CH 2 C(O)NH 2 or where n is 1; and Z 1 is H and Z is —CO 2 CH 2 CH 3 , —CO 2 (CH(CH 3 ) 2 ), —CO 2 (C(CH 3 ) 3 ), —CO 2 CH 2 (C(CH 3 ) 3 ), —CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form
60 . The compound according to claim 58 , wherein:
R a′ is a halo-substituted phenyl group; n is 2; R b and R d are each H; R x is H and R y is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halo; R c is —CH 2 CH 2 C(O)NH 2 or and Z 1 is H and Z is —CO 2 CH 2 CH 3 or Z 1 and Z taken together with the atom to which they are attached from
61 . The compound according to any one of claims 52 - 60 , wherein R y is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl.
62 . An antipicornaviral compound having the formula:
wherein:
W is CH or N;
R a′ is a C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, aryl or heteroaryl group, where the C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituens, provided that R a′ is not an amino-substituted alkyl group;
R 4 and R 6 are each independently H or C 1 -C 4 alkyl;
R 5 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents;
R 7 is
where n is 1 or 2; and
Z 1 is H or C 1 -C 4 alkyl and Z is —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -alkylaryl or —CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are attached form
63 . The compound according to claim 62 , wherein:
R a′ is a C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, phenyl, naphthyl or heteroaryl group, where the phenyl, naphthyl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyl and heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; R 4 and R 6 are each H; R 5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; R 7 is where n is 1; and Z 1 is H and Z is —CO 2 CH 2 CH 3 , —CO 2 (CH(CH 3 ) 2 ), —CO 2 (C(CH 3 ) 3 ), —CO 2 CH 2 (C(CH 3 ) 3 ), —CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form
64 . The compound according to claim 62 , wherein:
R a′ is a C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, phenyl, naphthyl, pyrrolyl or indolyl, group, where the phenyl, naphthyl, pyrrolyl or indolyl, group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, methylenedioxy and a phenyl, naphthyl, isoquinoyl, pyridyl or isoxazolyl group, wherein the phenyl, naphthyl, isoquinoyl, pyridyl and isoxazolyl group is unsubstituted or substituted by one ore more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; R 4 and R 6 are each H; R 5 is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halo; R 7 is and Z 1 is H and Z is —CO 2 CH 2 CH 3 or Z 1 and Z taken together with the atom to which they are attached form
65 . The compound according to claim 62 , having the formula:
66 . The compound according to claim 62 , having the formula:
67 . An antipicornaviral compound having the formula:
wherein:
R 1 is H, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or an aryl or heteroaryl group, where the aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
R 2 and R 3 are each independently H or C 1 -C 4 alkyl; or
or R 1 together with R 2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents;
R 4 and R 6 are each independently H or C 1 -C 4 alkyl;
R 5 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents;
R 7 is selected from —CH 2 CH 2 C(O)NH 2 ; —CH 2 CH 2 C(O)NH-alkyl;
—CH 2 NHC(O)CH 3 ; and
where n is 1 or 2; and
Z 1 is H or C 1 -C 4 alkyl and Z is —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -alkylaryl or —CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are attached form
68 . The compound according to claim 67 , wherein:
R 1 is H, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or a phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted or substituted with one or more substituents independently selected from: halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; R 2 and R 3 are each H; or R 1 together with R 2 form a phenyl ring, which is unsubstituted or substituted with one or more suitable substituents and R 3 is H; R 4 and R 6 are each H; R 5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; R 7 is —CH 2 CH 2 C(O)NH 2 or where n is 1; and Z 1 is H and Z is —CO 2 CH 2 CH 3 , —CO 2 (CH(CH 3 ) 2 ), —CO 2 (C(CH 3 ) 3 ), —CO 2 CH 2 (C(CH 3 ) 3 ), —CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form
69 . The compound according to claim 67 , wherein:
R 1 is H, phenyl, α-naphthyl, β-naphthyl, 2-chlorophenyl, 2-α,α,α-trifluoromethylphenyl, 3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl, 3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl; R 2 and R 3 are each H; R 4 and R 6 are each H; R 5 is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halo; R 7 is —CH 2 CH 2 C(O)NH 2 or and Z 1 is H and Z is —CO 2 CH 2 CH 3 or Z 1 and Z taken together with the atom to which they are attached form
70 . An antipicomaviral compound having the formula:
wherein:
R 1 is H, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or an aryl or heteroaryl group, where the aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
R 2 and R 3 are each independently H or C 1 -C 4 alkyl; or
or R 1 together with R 2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents;
R 4 and R 6 are each independently H or C 1 -C 4 alkyl;
R 5 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents;
R 7 is selected from —CH 2 CH 2 C(O)NH 2 ; —CH 2 CH 2 C(O)NH-alkyl;
—CH 2 NHC(O)CH 3 ; and
where n is 1 or 2; and
Z 1 is H or C 1 -C 4 alkyl and Z is —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -alkylaryl or —CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are attached form
provided that when R 1 together with R 2 form a phenyl ring and the phenyl ring is substituted, R 7 is
where n is 1 or 2.
71 . The compound according to claim 70 , wherein:
R 1 is H, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or a phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; R 2 and R 3 are each H; or R 1 together with R 2 form an unsubstituted phenyl ring and R 3 is H; R 4 and R 6 are each H; R 5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; R 7 is —CH 2 CH 2 C(O)NH 2 or where n is 1; and Z 1 is H and Z is —CO 2 CH 2 CH 3 , —CO 2 (CH(CH 3 ) 2 ), —CO 2 (C(CH 3 ) 3 ), —CO 2 CH 2 (C(CH 3 ) 3 ), —CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form
72 . The compound according to claim 70 , wherein:
R 1 is H, phenyl, α-naphthyl, β-naphthyl, 2-chlorophenyl, 2-α,α,α-trifluoromethylphenyl, 3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl, 3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl; R 2 and R 3 are each H; R 4 and R 6 are each H; R 5 is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halo; R 7 is —CH 2 CH 2 C(O)NH 2 or and Z 1 is H and Z is —CO 2 CH 2 CH 3 or Z 1 and Z taken together with the atom to which they are attached form
73 . An antipicomaviral compound having the formula:
wherein:
each R z is independently selected from halo and a C 1 -C 4 alkoxy, C 1 -C 4 alkyl, aryl, heterocycloalkyl or heteroaryl group where the C 1 -C 4 alkoxy or C 1 -C 4 alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy and the aryl, heterocycloalkyl or heteroaryl group is unsubstituted or substituted by one ore more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy or two R z at adjacent positions are methylenedioxy; and n z is an integer from 1 to 4;
R 3 is H, halo, C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 alkoxyalkyl;
R 4 and R 6 are each independently H or C 1 -C 4 alkyl;
R 5 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents;
R 7 is
where n is 1 or 2; and
Z 1 is H or C 1 -C 4 alkyl and Z is —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -alkylaryl or —CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are attached form
74 . The compound according to claim 73 , wherein
each R z is independently selected from halo, C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxyalkyl and n z is an integer from 1 to 2; R 3 is H or C 1 -C 4 alkyl; R 4 and R 6 are each H; R 5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; R 7 is where n is 1; and Z 1 is H and Z is —CO 2 CH 2 CH 3 , —CO 2 (CH(CH 3 ) 2 ), —CO 2 (C(CH 3 ) 3 ), —CO 2 CH 2 (C(CH 3 ) 3 ), —CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form
75 . The compound according to claim 73 , wherein each R z is independently selected from halo, C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 alkyl and C 1 -C 4 haloalkyl, and n z is 1 or 2;
R 3 is H; R 4 and R 6 are each H; R 5 is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halo; R 7 is and Z 1 is H and Z is —CO 2 CH 2 CH 3 or Z 1 and Z taken together with the atom to which they are attached form
76 . An antipicornaviral compound having the formula:
wherein:
R a′ is a C 1 -C 4 alkyl, aryl, C 3 -C 7 cycloalkyl, heterocycloalkyl or heteroaryl group, where the C 1 -C 4 alkyl, aryl, C 3 -C 7 cycloalkyl, heterocycloalkyl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio, aryl or heteroaryl, where the aryl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy;
each R 6 is independently H or C 1 -C 4 alkyl;
R 5 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents;
R 7 is selected from —CH 2 CH 2 C(O)NH 2 ; —CH 2 CH 2 C(O)NH-alkyl;
—CH 2 NHC(O)CH 3 ; and
where n is 1 or 2; and
Z 1 is H or C 1 -C 4 alkyl and Z is —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -alkylaryl or —CO 2 -alkylheterocycloaryl, or Z 1 and Z taken together with the atom to which they are attached form
77 . The compound according to claim 76 , wherein:
R a′ is a C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, phenyl, naphthyl, C 5 -C 6 cycloalkyl, isoquinoyl, pyridyl or pyrrolyl group, where the phenyl, naphthyl, isoquinoyl, pyridyl or pyrrolyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and methylenedioxy; each R 6 is H; R 5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; R 7 is —CH 2 CH 2 C(O)NH 2 or where n is 1; and Z 1 is H and Z is —CO 2 CH 2 CH 3 , —CO 2 (CH(CH 3 ) 2 ), —CO 2 (C(CH 3 ) 3 ), —CO 2 CH 2 (C(CH 3 ) 3 ), —CO 2 (cyclo-C 5 H 9 ) or Z 1 and Z taken together with the atom to which they are attached form
78 . The compound according to claim 76 , wherein:
R a′ is a phenyl group, where the phenyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 alkoxy; each R 6 is H; R 5 is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and halo; R 7 is —CH 2 CH 2 C(O)NH 2 or and Z 1 is H and Z is —CO 2 CH 2 CH 3 or Z 1 and Z taken together with the atom to which they are attached form
79 . The compound according to any one of claims 62 to 78 , where
R 5 is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl.
80 . The compound according to any one of claims 12 , 13 , 14 , 19 , 20 , 49 , 62 , 67 , 70 , 73 or 76 having antipicornaviral activity corresponding to an EC 50 less than or equal to 100 μM in an H1-HeLa cell culture assay.
81 . The compound according to claim 16 , having antipicornaviral activity corresponding to an EC 50 less than or equal to 100 μM in an H1-HeLa cell culture assay.
82 . A pharmaceutical composition comprising:
a therapeutically effective amount of at least one antipicornaviral agent selected from compounds, prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable solvates defined in any one of claims 12 , 13 , 14 , 19 , 20 , 49 , 62 , 67 , 70 , 73 or 76 ; and a pharmaceutically acceptable carrier, diluent, vehicle, or excipient.
83 . The method of treating a mammalian disease condition mediated by picornaviral protease activity, comprising administering to a mammal in need thereof a therapeutically effective amount of at least one compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate defined in any one of claims 12 , 13 , 14 , 19 , 20 , 49 , 62 , 67 , 70 , 73 or 76 .
84 . The method of inhibiting the activity of a picornaviral 3C protease, comprising contacting the picornaviral 3C protease with an effective amount of at least one compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate defined in any one of claims 12 , 13 , 14 , 19 , 20 , 49 , 62 , 67 , 70 , 73 or 76 .
85 . The method as defined in claim 53 , wherein the picornaviral 3C protease is a rhinoviral protease.
86 . A compound selected from:
87 . The compound according to claim 86 , selected from the group consisting of:Join the waitlist — get patent alerts
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