US2015038501A1PendingUtilityA1
Inhibitors of hcv ns5a
Assignee: PRESIDIO PHARMACEUTICALS INCPriority: Dec 3, 2008Filed: Oct 20, 2014Published: Feb 5, 2015
Est. expiryDec 3, 2028(~2.4 yrs left)· nominal 20-yr term from priority
A61P 31/14A61P 31/12A61P 43/00A61P 1/16C07D 233/64C07D 417/14C07D 403/14C07D 401/14C07D 405/14A61K 31/4178C07D 413/14
57
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Claims
Abstract
Provided herein are compounds, pharmaceutical compositions and combination therapies for inhibition of hepatitis C.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound having formula I:
wherein,
A and A′ are independently selected from the group consisting of a single bond, —(CR 2 ) n —C(O)—(CR 2 ) p —, —(CR 2 ) n —O—(CR 2 ) p —, —(CR 2 ) n —N(R N )—(CR 2 ) p —, —(CR 2 ) n S(O) k —N(R N )—(CR 2 ) p —, —(CR 2 ) n —C(O)—N(R N )—(CR 2 ) p —, —(CR 2 ) n —N(R N )—C(O)—N(R N )—(CR 2 ) p —, —(CR 2 ) n —C(O)—O—(CR 2 ) p —, —(CR 2 ) n —N(R N )—S(O) k —N(R N )—(CR 2 ) p — and —(CR 2 ) n —N(R N )—C(O)—O—(CR 2 ) p — and a heteroaryl group selected from the group consisting of
wherein
X 1 is CH 2 , NH, O or S,
Y 1 , Y 2 and Z 1 are each independently CH or N,
X 2 is NH, or
V is —CH 2 —CH 2 —, —CH═CH—, —N═CH—, (CH 2 ) a —N(R)—(CH 2 ) b or —(CH 2 ) a —O—(CH 2 ) b —, wherein a and b are independently 0, 1, 2, or 3 with the proviso that a and b are not both 0,
optionally includes 1 or 2 nitrogens as heteroatoms on the phenyl residue,
the carbons of the heteroaryl group are each independently optionally substituted with a substituent selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino,
the nitrogens, if present, of the heteroaryl group are each independently optionally substituted with a substituent selected from the group consisting of —OH, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide,
a and b are independently 1, 2, or 3.
c and d are independently 1 or 2,
n and p are independently 0, 1, 2 or 3,
k is 0, 1, or 2,
each R is independently selected from the group consisting of hydrogen, —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino,
each R N is independently selected from the group consisting of hydrogen, —OH, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide, and
wherein for each A and A′, B may be attached to either side of A and A′ so that in the example of A or A′ being
the A-B-A′ can be any of:
B is selected from the group consisting of a single bond, triple bond,
wherein each W is independently selected from the group consisting of a cycloalkenyl group, aryl group and heteroaryl group, with the proviso that a triple bond does not attach to W at a heteroatom;
R c , R d , R e and R f are each independently selected from the group consisting of: hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, aralkyl and a 4- to 8-membered ring which may be cycloalkyl, heterocycle, heteroaryl or aryl, wherein,
each hetero atom, if present, is independently N, O or S,
each of R c C, R d , R e and R f may optionally be substituted by C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, aralkyl, or a 4- to 8-membered ring which may be cycloalkyl, heterocycle, heteroaryl or aryl and wherein each heteroatom, if present, is independently N, O or S,
R c and R d are optionally joined to form a 4- to 8-membered heterocycle which is optionally fused to another 3- to 6-membered heterocycle or heteroaryl ring, and
R e and R f are optionally joined to form a 4- to 8-membered heterocycle which is optionally fused to another 3- to 6-membered heterocycle or heteroaryl ring;
Y and Y′ are each independently carbon or nitrogen; and
Z and Z′ are independently selected from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, 1-3 amino acids, —[U—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t ] u —U—(CR 4 2 ) t —NR 7 —(CR 4 2 ) t —R 8 , —U—(CR 4 2 )—R 8 and —[U—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t ] u —U—(CR 4 2 ) t —O—(CR 4 2 ) t —R 8 , wherein,
U is selected from the group consisting of —C(O)—, —C(S)— and —S(O) 2 —,
each R 4 , R 5 and R 7 is independently selected from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl,
R 8 is selected from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, —C(O)—R 81 , —C(S)—R 81 , —C(O)—O—R 81 , —C(O)—N—R 81 2 , —S(O) 2 —R 81 and —S(O) 2 —N—R 81 2 , wherein each R 81 is independently chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl and aralkyl,
optionally, R 7 and R 8 together form a 4-7 membered ring,
each t is independently 0, 1, 2, 3, or 4, and
u is 0, 1, or 2.
2 . The compound of claim 1 wherein each W is independently optionally substituted with one or more substituents each independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino, and if W is not aromatic, it is optionally substituted with oxo.
3 . The compound of claim 2 wherein each W is independently optionally substituted with one of the group consisting of —CN, —OCF 3 , —OCHF 2 , —CF 3 and —F.
4 . The compound of claim 1 wherein, B is selected from the group consisting of a triple bond,
wherein:
is a divalent aryl or heteroaryl group which may be polycyclic with varying connective patterns,
each r is independently 0, 1, 2, 3, or 4, and
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino.
5 . The compound of claim 4 , wherein
is selected from the group consisting of:
wherein * indicates attachment points to the remainder of the compound and each phenyl residue independently optionally includes 1 or 2 nitrogens as heteroatoms.
6 . The compound of claim 4 , wherein
when present, is selected from the group consisting of:
wherein * indicates attachment points to the remainder of the compound, the phenyl residue optionally includes 1 or 2 nitrogens as heteroatoms, and R N is selected from the group consisting of hydrogen, —OH, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.
7 . The compound of claim 4 , wherein
is selected from the group consisting of:
wherein * indicates attachment points to the remainder of the compound and the phenyl residue optionally includes 1 or 2 additional nitrogens as heteroatoms with the proviso that there are no more than 2 total nitrogens on the phenyl residue.
8 . The compound of claim 4 wherein each R a is independently selected from the group consisting of —CN, —OCF 3 , —OCHF 2 , —CF 3 and —F.
9 . The compound of any one of claims 1 to 8 wherein A and A′ are independently selected from the group consisting of a single bond, —(CR 2 ) n —O—(CR 2 ) p —, —(CR 2 ) n —N(R N )—(CR 2 ) p —, —(CR 2 ) n —C(O)—N(R N )—(CR 2 ) p —, —(CR 2 ) n —N(R N )—C(O)—N(R N )—(CR 2 ) p — and —(CR 2 ) n —N(R N )—C(O)—O—(CR 2 ) p — and a heteroaryl group selected from the group consisting of
10 . The compound of claim 9 wherein A and A′ are independently selected from the group consisting of a single bond,
wherein.
11 . The compound of any of the preceding claims wherein
R c C, R d , R e and R f are each independently selected from the group consisting of: hydrogen, C 1 to C 8 alkyl and C 1 to C 8 heteroalkyl, wherein,
each hetero atom, if present, is independently N, O or S,
R c C and R d are optionally joined to form a 4- to 8-membered heterocycle which is optionally fused to another 3- to 6-membered heterocycle, and
R e and R f are optionally joined to form a 4- to 8-membered heterocycle which is optionally fused to another 3- to 6-membered heterocycle.
12 . The compound of claim 11 wherein one or both of R c and R d or R e and R f are optionally joined to form a 4- to 8-membered heterocycle which is optionally fused to another 3- to 6-membered heterocycle.
13 . The compound of claim 11 wherein R c and R d are joined and form a heterocyclic fused ring system selected from the group consisting of:
wherein R N is selected from the group consisting of hydrogen, —OH, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.
14 . The compound of claim 11 or 13 wherein R e and R f are joined and form a heterocyclic fused ring system selected from the group consisting of:
wherein R N is selected from the group consisting of hydrogen, —OH, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.
15 . The compound of claim 1 having formula III
wherein
A and A′ are independently selected from the group consisting of single bond,
—(CR 2 ) n —O—(CR 2 ) p — and —(CR 2 ) n —C(O)—N(R N )—(CR 2 ) p —;
each
optionally independently includes 1 or 2 nitrogens as heteroatoms;
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; and
each r is 0, 1, 2, 3 or 4.
16 . The compound of claim 15 having formula IIIa:
17 . The compound of claim 16 having formula IIIb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
18 . The compound of claim 1 having formula IV:
wherein
A is selected from the group consisting of a single bond,
—(CR 2 ) n —O—(CR 2 ) p —, —(CR 2 ) n —C(O)N(R N )—(CR 2 ) p — and —(CR 2 ) n —N(R N )C(O)CR 2 ) p —;
optionally includes 1 or 2 nitrogens as heteroatoms;
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino;
r is 0, 1, 2, or 3; and
r′ is 0, 1, 2, 3, or 4.
19 . The compound according to claim 18 wherein A is a single bond,
—(CR 2 ) n —C(O)N(R N )—(CR 2 ) p —, or —(CR 2 ) n —N(R N )C(O)CR 2 ) p —.
20 . The compound of claim 18 having formula IVa:
21 . The compound of claim 20 having formula IVb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
22 . The compound of claim 1 having formula V:
wherein
A and A′ are independently selected from the group consisting of single bond,
—(CR 2 ) n —O—(CR 2 ) p — and —(CR 2 ) n —C(O)N(R N )—(CR 2 ) p —;
optionally includes 1 or 2 nitrogens as heteroatoms;
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; and
r is 0, 1, 2, 3, or 4.
23 . The compound of claim 22 having formula Va:
24 . The compound of claim 23 having formula Vb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
25 . The compound of claim 22 wherein:
A is selected from the group consisting of
and
A′ is selected from the group consisting of
—(CR 2 ) n —O—(CR 2 ) p —, —(CR 2 ) n —C(O)N(R N )—CR 2 ) p — and —(CR 2 ) n —N(R N )C(O)—(CR 2 ) p —.
26 . The compound of claim 25 wherein A′ is
27 . The compound of claim 26 having formula Vc:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
28 . The compound of claim 25 wherein A′ is selected from the group consisting of
29 . The compound of claim 28 having formula Vd:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
30 . The compound of claim 1 having formula VI:
wherein
A and A′ are independently selected from the group consisting of single bond,
—(CR 2 ) n —O—(CR 2 ) p — and —(CR 2 ) n —C(O)N(R N )—(CR 2 ) p —;
optionally includes 1 or 2 nitrogens as heteroatoms;
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; and
r is 0, 1, 2, 3 or 4.
31 . The compound of claim 30 having formula VIa:
32 . The compound of claim 31 having formula VIb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
33 . The compound of claim 1 having formula VII:
wherein,
A and A′ are independently selected from the group consisting of single bond,
—(CR 2 ) n —O—(CR 2 ) p — and —(CR 2 ) n —C(O)N(R N )—CR 2 ) p —;
each
optionally independently includes 1 or 2 nitrogens as heteroatoms;
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; and
each r is independently 0, 1, 2, 3 or 4.
34 . The compound of claim 33 having formula VIIa:
35 . The compound of claim 34 having formula VIIb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
36 . The compound of claim 1 having formula VIII:
wherein
A′ is selected from the group consisting of single bond,
—(CR 2 ) n —O—(CR 2 ) p —, —(CR 2 ) n —C(O)N(R N )—(CR 2 ) p — and —(CR 2 ) n —N(R N )C(O)—(CR 2 ) p —;
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; and
r is 0, 1, 2, or 3.
37 . The compound according to claim 36 wherein A′ is a single bond,
—(CR 2 ) n —C(O)N(R N )—(CR 2 ) p —, or —(CR 2 ) n —N(R N )C(O)—(CR 2 ) p —.
38 . The compound of claim 36 having formula VIIIa:
39 . The compound of claim 38 having formula VIIIb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
40 . The compound of claim 1 having formula IX:
wherein
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; and
each r is independently 0, 1, 2, or 3.
41 . The compound of claim 40 having formula IXa:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 , —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
42 . The compound of claim 1 having formula X:
wherein
A and A′ are independently selected from the group consisting of single bond,
—(CR 2 ) n —O—(CR 2 ) p — and —(CR 2 ) n —C(O)N(R N )—(CR 2 ) p —;
optionally includes 1, 2, 3 or 4 nitrogens as heteroatoms;
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; and
each r is independently 0, 1, 2, or 3.
43 . The compound of claim 42 having formula Xa:
44 . The compound of claim 43 having formula Xb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
45 . The compound of claim 42 wherein:
A is selected from the group consisting of
and
A′ is
46 . The compound of claim 42 having formula Xc:
wherein:
A is selected from the group consisting of
and
X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
47 . The compound of claim 1 having formula Xd:
wherein:
r is 0, 1, 2, or 3; and
r′ is 0, 1, 2, 3, or 4.
48 . The compound of claim 47 having formula Xe:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
49 . The compound of claim 1 having formula XI:
wherein A and A′ are independently selected from the group consisting of
50 . The compound of claim 49 having formula XIa:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
51 . The compound of claim 1 having formula XII:
wherein:
A and A′ are independently selected from the group consisting of single bond,
—(CR 2 ) n —O—(CR 2 ) p — and —(CR 2 ) n —C(O)N(R N )—(CR 2 ) p —;
optionally includes 1, 2, 3 or 4 nitrogens as heteroatoms;
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; and
each r is independently 0, 1, 2, or 3.
52 . The compound of claim 51 having formula XIIa:
53 . The compound of claim 52 having formula XIIb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
54 . The compound of claim 1 having formula XIII:
wherein
A and A′ are independently selected from the group consisting of single bond,
—(CR 2 ) n —O—(CR 2 ) p — and —(CR 2 ) n —C(O)N(R N )—(CR 2 ) p —;
optionally includes 1, 2, 3 or 4 nitrogens as heteroatoms;
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; and
each r is independently 0, 1, 2, or 3.
55 . The compound of claim 54 having formula XIIIa:
56 . The compound of claim 55 having formula XIIIb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
57 . The compound of claim 1 having formula XIV:
wherein:
A is selected from the group consisting of a single bond,
—(CR 2 ) n —O—(CR 2 ) p —, —(CR 2 ) n —C(O)N(R N )—(CR 2 ) p — and —(CR 2 ) n —N(R N )C(O)—(CR 2 ) p —;
optionally includes 1 or 2 nitrogens as heteroatoms;
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino;
r is 0, 1, 2, or 3; and
r′ is 0, 1, 2, 3, or 4.
58 . The compound according to claim 57 wherein A is a single bond,
—(CR 2 ) n —C(O)N(R N )—(CR 2 ) p —, or —(CR 2 ) n —N(R N )C(O)—(CR 2 ) p —.
59 . The compound of claim 57 having formula XIVa:
60 . The compound of claim 59 having formula XIVb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
61 . The compound of claim 57 having formula XIVc:
62 . The compound of claim 61 having formula XIVd:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
63 . The compound of claim 57 having formula XIVc:
64 . The compound of claim 63 having formula XIVf:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
65 . The compound of claim 1 having formula XV:
wherein:
A is selected from the group consisting of
each R a is independently selected from the group consisting of —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino; and
r is 0, 1, 2, or 3.
66 . The compound of claim 65 having formula XVa:
67 . The compound of claim 66 having formula XVb:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and
68 . The compound of claim 65 having formula XVc:
69 . The compound of claim 68 having formula XVd:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
70 . The compound of claim 65 having formula XVe:
71 . The compound of claim 70 having formula XVf:
wherein X and X′ are each independently selected from the group consisting of a bond, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —O—, —S—, —S(O) 1-2 —, —CH 2 O—, —CH 2 S—, —CH 2 S(O) 1-2 — and —CH 2 N(R 1 )—, wherein R 1 is chosen from the group consisting of hydrogen, C 1 to C 8 alkyl, C 1 to C 8 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkanoyl, alkoxycarbonyl, carbamoyl and substituted sulfonyl.
72 . The compound according to any one of claims 15 , 16 , 18 , 20 , 22 , 23 , 30 , 31 , 33 , 34 , 36 , 38 , 40 , 42 , 43 , 47 , 49 , 51 , 52 , 54 , 55 , 57 , 58 , 60 , 62 , 64 , 65 , 67 , or 69 wherein R c , R d , R e and R f are each independently selected from the group consisting of: hydrogen, C 1 to C 8 alkyl and C 1 to C 8 heteroalkyl, wherein,
each hetero atom, if present, is independently N, O or S,
R c and R d are optionally joined to form a 4- to 8-membered heterocycle which is optionally fused to another 3- to 6-membered heterocycle, and
R e and R f are optionally joined to form a 4- to 8-membered heterocycle which is optionally fused to another 3- to 6-membered heterocycle.
73 . The compound according to claim 72 wherein one of R c and R d or R e and R f are joined to form a 4- to 8-membered heterocycle which is optionally fused to another 3- to 6-membered heterocycle.
74 . The compound according to claim 72 wherein both of R c and R d and R e and R f are joined to form a 4- to 8-membered heterocycle which is optionally fused to another 3- to 6-membered heterocycle.
75 . The compound according to any one of claims 15 - 74 wherein each R is independently —CN, —OCF 3 , —OCHF 2 , —CF 3 , or —F.
76 . The compound according to any one of claims 15 , 16 , 18 , 20 , 22 , 23 , 30 , 31 , 33 , 34 , 36 , 38 , 40 , 42 , 43 , 47 , 49 , 51 , 52 , 54 , 55 , 57 , 58 , 60 , 62 , 64 , 65 , 67 , or 69 wherein one of Y and Y′ is N.
77 . The compound according to claim 76 wherein both Y and Y′ are N.
78 . The compound according to any one of claims 15 , 22 , 30 , 33 , 42 , 51 , or 54 wherein A and A′ are each independently
or —(CR 2 ) n —C(O)N(R N )—CR 2 ) p —.
79 . The compound according to any one of claims 1 - 78 wherein Z and Z′ are each 1-3 amino acids.
80 . The compound according to claim 79 wherein the amino acids are in the D configuration.
81 . The compound of any one of claims 1 - 78 wherein Z and Z′ are each independently selected from the group consisting of —[U—(CR 4 2 ) t NR 5 —(CR 4 2 ) t ] u —U—(CR 4 2 ) t —NR 7 —(CR 4 2 ) t —R 8 , —U—(CR 4 2 ) t —R 8 and —[U—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t ] u —U—(CR 4 2 ) t —O—(CR 4 2 ) t —R 8 .
82 . The compound of claim 81 wherein one or both of Z and Z′ are —[U—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t ] u —U—(CR 4 2 ) t —NR 7 —(CR 4 2 ) t —R 8 .
83 . The compound of claim 82 wherein one or both of Z and Z′ are —U—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t —U—(CR 4 2 ) t —NR 7 —(CR 4 2 )—R 8 .
84 . The compound of claim 82 wherein one or both of Z and Z′ are —U—(CR 4 2 ) t —NR 7 —(CR 4 2 ) t —R 8 .
85 . The compound of claim 82 wherein either one or both of Z and Z′ are —[C(O)—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t ] u —U—(CR 4 2 ) t —NR 7 —(CR 4 2 ) t —R 8 .
86 . The compound of claim 85 wherein one or both of Z and Z′ are —C(O)—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t —U—(CR 4 2 ) t —NR 7 —(CR 4 2 ) t —R 8 .
87 . The compound of claim 85 wherein one or both of Z and Z′ are —[C(O)—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t ] u —C(O)—(CR 4 2 ) t —NR 7 —(CR 4 2 ) t —R 8 .
88 . The compound of claim 87 wherein one or both of Z and Z′ are —C(O)—(CR 4 2 ) t —NR 5 —(CR 4 2 )—C(O)—(CR 4 2 ) t —NR 7 —(CR 4 2 ) t —R 8 .
89 . The compound of claim 85 wherein one or both of Z and Z′ are —C(O)—(CR 4 2 ) t —NR 7 —(CR 4 2 ) t —R 8 .
90 . The compound of claim 89 wherein one or both of Z and Z′ are —C(O)—(CR 4 2 ) n —NR 7 —(CR 4 2 ) n —C(O)—R 81 .
91 . The compound of claim 90 wherein one or both of Z and Z′ are —C(O)—(CR 4 2 ) n —NR 7 —C(O)—R 81 .
92 . The compound of claim 89 wherein one or both of Z and Z′ are —C(O)—(CR 4 2 ) n —NR 7 —(CR 4 2 ) n —C(O)—O—R 81 .
93 . The compound of claim 92 wherein one or both of Z and Z′ are —C(O)—(CR 4 2 ) n —NR 7 —C(O)—O—R 81 .
94 . The compound of claim 81 wherein one or both of Z and Z′ are —U—(CR 4 2 ) t —R 8 .
95 . The compound of claim 94 wherein one or both of Z and Z′ are —C(O)—(CR 4 2 ) t —R 8 .
96 . The compound of claim 81 wherein one or both of Z and Z′ are —[U—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t ] u —U—(CR 4 2 ) t —O—(CR 4 2 ) t —R 8 .
97 . The compound of claim 96 wherein one or both of Z and Z′ are —U—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t —U—(CR 4 2 ) t —O—(CR 4 2 ) t —R 8 .
98 . The compound of claim 64 wherein one or both of Z and Z′ are —C(O)—(CR 4 2 ) t —NR 5 —(CR 4 2 ) t —C(O)—(CR 4 2 ) t —O—(CR 4 2 ) t —R 8 .
99 . The compound of claim 96 wherein one or both of Z and Z′ are —U—(CR 4 2 ) t —O—(CR 4 2 ) t —R 8 .
100 . The compound of claim 99 wherein one or both of Z and Z′ are —C(O)CR 4 2 ) t —O—(CR 4 2 ) t —R 8 .
101 . The compound of claim 81 wherein one or both of Z and Z′ are —C(O)—(CR 4 2 ) n —NR 7 —R 8 wherein R 7 and R 8 together form a 4-7 membered ring.
102 . A pharmaceutical composition comprising any one of the compounds of claims 1 - 101 .
103 . The use of the compound of any one of claims 1 - 101 in the manufacture of a medicament.
104 . The use of a compound of claim 103 wherein the medicament is for the treatment of hepatitis C.
105 . A method of treating hepatitis C comprising administering to a subject in need thereof, a therapeutically effective amount of any one of the compounds of claims 1 - 102 .Cited by (0)
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