Inhibitors of HCV NS5A
Provided herein are compounds, pharmaceutical compositions and combination therapies for inhibition of hepatitis C.
1. A compound having formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A′ is 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, O or S,
the carbons of the heteroaryl group are each independently optionally substituted with a substituent selected from the group consisting of halogen, —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,
wherein B is alternatively attached to either side of A′ so that in the example of A′ being
the W-B-A′ is
B and B′ are each phenyl, such that the moiety B-B′ is naphthyl;
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;
each r is independently 0, 1, 2 or 3;
W is independently selected from
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, O or S,
W is optionally substituted with one or more substituents 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,
W and ring B′ are connected through a carbon atom on B′, and
each R c , R d , R e and R f is 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 , 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 5-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 5-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 1-3 amino acids,
—[U—(CR 4 2 ) t —NR 5 —C(R 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 , 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
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 5-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 5-membered heterocycle.
3. The compound of claim 2 wherein
a) 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, or
b) 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.
4. The compound of claim 1 having formula III:
wherein
A′ is selected from the group consisting of a single bond,
and
each X c is independently C or N.
5. The compound of claim 4 having formula selected from the group consisting of:
a) formula IIIa:
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,
b) formula IIIc:
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,
c) formula IIId:
d) formula IIIe:
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,
e) formula IIIf:
and
f) formula IIIg:
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.
6. The compound of claim 1 , having formula IIIk:
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.
7. The compound of claim 1 , having formula IIIm:
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.
8. The compound of claim 1 , having formula IIIq:
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, and each X b is C and each X c is independently C or N.
9. The compound of claim 1 , 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 5-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 5-membered heterocycle.
10. The compound of claim 1 , wherein each R a is independently —CN, —OCHF 2 , —OCF 3 , —CF 3 , or —F.
11. The compound of claim 1 , wherein one of Y and Y′ is N.
12. The compound of claim 1 , wherein A′ is
13. The compound of claim 1 , wherein Z and Z′ are each 1-3 amino acids.
14. The compound of claim 13 wherein the amino acids are in the D configuration.
15. The compound of claim 1 , selected from the group consisting of
16. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipients or vehicles.
17. A method of treating hepatitis C comprising administering to a subject in need thereof, a therapeutically effective amount of claim 1 .