US2015246917A1PendingUtilityA1
Inhibitors of hepatitis c virus replication
Est. expiryMar 27, 2029(~2.7 yrs left)· nominal 20-yr term from priority
A61P 31/14A61P 31/12A61P 31/00A61P 1/16C07K 5/06C07D 413/14C07D 403/12A61K 38/05A61K 31/437A61K 31/5383A61K 31/5365C07D 498/04A61K 31/404C07D 471/04C07D 405/14A61K 31/4439C07D 401/14C07D 487/04C07D 498/10C07K 5/06052C07D 403/14A61K 31/423C07D 409/14A61K 31/506C07D 405/12A61K 31/4985A61K 31/5377C07K 5/06043A61K 31/4184A61K 31/4178A61K 45/06A61K 38/06C07K 5/06139A61K 31/4025A61K 38/00C07K 5/08A61K 31/553C07K 5/06078
51
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5A inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5A activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
Claims
exact text as granted — not AI-modified1 . (canceled)
2 . (canceled)
3 . (canceled)
4 . (canceled)
5 . (canceled)
6 . (canceled)
7 . (canceled)
8 . (canceled)
9 . (canceled)
10 . (canceled)
11 . A compound having structural formula (I):
and/or a pharmaceutically acceptable salt thereof, wherein:
is chosen from the group consisting of 9-membered bicyclic aryl ring systems that contain from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and that are substituted on C or N atoms by u substituents R 1 ,
each R 1 is independently chosen from the group consisting of hydrogen, halogen, —OR 3a , —CN, —(CH 2 ) 0-6 C(O)R 3 , —CO 2 R 3a , —C(O)N(R 3a ) 2 , —SR 3a , —S(O)R 3a , —S(O 2 )R 3a , —(CH 2 ) 0-6 N(R 3a ) 2 , —N(R 3a )SO 2 R 3a , —N(R 3a )CO 2 R 3a , —N(R 3a )C(O)R 3 , —N(R 3a )COR 3a , —N(R 3a )C(O)N(R 3a ), C 1-6 alkyl, C 3-8 carbocycle containing from 0 to 3 heteroatoms chosen from N, O and S, and phenyl, and the C 1-6 alkyl, C 3-8 carbocycle and phenyl are substituted by from 0 to 3 substitutents independently chosen from the group consisting of hydrogen, halogen, —OR 3a , —CN,
—CO 2 R 3a , —C(O)N(R 3a ) 2 , —N(R 3a ) 2 , —N(R 3a )CO 2 R 3a , —SR 3a , —S(O)R 3a , —S(O 2 )R 3a , —N(R 3a )SO 2 R 3a ,
—N(R 3a )CO 2 R 3a , —N(R 3a )C(O)N(R 3a ), C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and C 3-8 cycloalkyl,
u is from 0 to 4,
each R 3 is independently chosen from the group consisting of hydrogen, C 1-6 alkyl, —OH, —O—C 1-6 alkyl and C 3-8 cycloalkyl, and
each R 3a is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl;
is a group chosen from the group consisting of
(a) —C≡C— and
(b) aryl ring systems B′chosen from the group consisting of:
(i) 5- to 7-membered monocyclic ring systems and
(ii) 8- to 10-membered bicyclic ring systems,
and the aryl ring systems B′ containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by v substituents R 2 ,
each R 2 is independently chosen from the group consisting of hydrogen, halogen, —OR 4a , —CN, —CO 2 R 4a , —C(O)R 4a , —C(O)N(R 4a ) 2 , —N(R 4a ) 2 , —N(R 4a )COR 4 ,
—N(R 4a )CO 2 R 4a , —N(R 4a )C(O)N(R 4a ), —N(R 4a )SO 2 R 4a , —SR 4a , —S(O)R 4a , —S(O 2 )R 4a , C 1-6 alkyl substituted by from 0 to 4 R 4 and C 3-8 cycloalkyl substituted by from 0 to 4 R 4 ,
v is from 0 to 4,
each R 4 is independently chosen from the group consisting of hydrogen, —OH, C 1-6 alkyl and C 3-8 cycloalkyl;
each R 4a is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl;
wherein said
and said
are taken together with one said substituent R 1 and one said substituent R 2 to form a 5- to 9-membered carbocyclic ring containing 1 or 2 heteroatoms independently chosen from the group consisting of N, O and S, represented by a group chosen from the group consisting of:
where
W is chosen from the group consisting of —(CH 2 ) 1-3 —, —(CH 2 ) 0-2 NH(CH 2 ) 0-2 —,
—(CH 2 ) 0-2 N(C 1-6 alkyl)(CH 2 ) 0-2 —, —(CH 2 ) 0-2 O(CH 2 ) 0-2 —and —(CH 2 ) 0-2 C(O)(CH 2 ) 0-2 —, where W is substituted by from 0 to 4 R w , where each R w is independently selected from C 1-6 alkyl and
C 3-8 cycloalkyl;
V is chosen from the group consisting of —C(O)— and —CH 2 —, and where V is —CH 2 —, V is substituted by from 0 to 2 R v , where each R v is independently selected from the group consisting of C 1-6 -alkyl, phenyl and C 3-8 cycloalkyl;
each D is a group independently chosen from the group consisting of:
(a) a single bond,
(b) —C(O)N(R 5 )—,
(c) —N(R 5 )C(O)—, and
(d) a 5- or 6-membered aryl ring system D′ containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by from 0 to 2 substituents R 5 ,
each R 5 is independently chosen from the group consisting of hydrogen, halogen, —OR 6 , —CN, —CO 2 R 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )COR 6 , —SR 6 , —S(O)R 6 ,
—S(O 2 )R 6 , —N(R 6 )SO 2 R 6 , —NCO 2 R 6 , —NC(O)N(R 6 ) 2 , C 1-6 alkyl substituted by from 0 to 3 R 6 and C 3-8 cycloalkyl substituted by from 0 to 3 R 6 , and
each R 6 is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl;
each E is a group independently chosen from the group consisting of:
(a) a single bond,
(b) —(C(R 7 ) 2 ) 0-2 NR 7 C(O)O 0-1 , and
(c) a pyrrolidinyl derivative chosen from the group consisting of:
I is a bivalent group chosen from —C(O)—, —CO 2 — and —C(O)N(R 7 )—,
J is a fused ring system chosen from the group consisting of 3- to 7-membered carbocycles and 5- or 6-membered aryl rings containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by substituents R 9 ,
each R 8a is independently chosen from the group consisting of hydrogen, halogen, —OH, —OC 1-6 alkyl and C 1-6 alkyl, or two R 8a may be taken together to form oxo,
each R 8b is independently chosen from the group consisting of hydrogen, halogen, —OH, —OC 1-6 alkyl and C 1-6 alkyl, or two R 8b may be taken together to form oxo,
each R 8c is independently chosen from the group consisting of hydrogen and C 1-6 alkyl,
or any two groups selected from R 8a , R 8b and R 8c may be taken together to form a spiro-bicyclic or bridged bicyclic ring;
each R 9 is independently chosen from the group consisting of hydrogen, halogen, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NH—C 1-6 alkyl and —NHC(O)—C 1-6 alkyl,
each R 7 is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and phenyl, and the C 1-6 alkyl and phenyl are substituted by from 0 to 3 substitutents independently chosen from the group consisting of hydrogen, halogen, C 1-6 alkyl, —O—C 1-6 alkyl and —S—C 1-6 alkyl; and
each G is independently chosen from the group consisting of:
(a) hydrogen,
(b) —OR 10a ,
(c) —CN,
(d) —CO 2 R 10a ,
(e) —C(O)N(R 10 ) 2 ,
(f) —SR 10a ,
(g) —S(O)R 10a ,
(h) —S(O 2 )R 10a ,
(i) —N(R 10 ) 2 ,
(j) —N(R 10 )SO 2 R 10a ,
(k) —NCO 2 R 10a ,
(l) —NC(O)N(R 10 ) 2 ,
(m) C 1-6 alkyl having 0 to 4 substituents R 11 ,
each R 11 is independently chosen from the group consisting of:
(i) —OH,
(ii) —N(R 10 ) 2 ,
(iii) ═NR 10 ,
(iv) —O—C 1-6 alkyl,
(v) —C(O)R 10 ,
(vi) —S—C 1-6 alkyl,
(vii) —SO 2 —C 1-6 alkyl,
(viii) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, and having from 0 to 3 substitutents R 12 on N or C atoms, and each R 12 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl having from 0 to 3 substituents chosen from R 10 ,
—O—C 1-6 alkyl, —S—C 1-6 alkyl, —OR 10a , —CN, —C(O)R 10 , —CO 2 R 10a , —C(O)N(R 10 ) 2 , —SR 10a , —S(O)R 10a ,
—S(O 2 )R 10a , —N(R 10 )SO 2 R 10a , —NCO 2 R 10a , —NC(O)N(R 10 ) 2 and —N(R 10 ) 2 , or two R 12 are taken together to form oxo, and
(ix) 5- or 6-membered aryl containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, and having from 0 to 3 substitutents R 13 on N or C atoms, and each R 13 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, —O—C 1-6 alkyl and 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S,
(n) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, and having from 0 to 3 substitutents R 10 on N or C atoms; and
(o) aryl ring systems G′ chosen from the group consisting of:
(i) 5- to 7-membered monocyclic ring systems and
(ii) 8- to 10-membered bicyclic ring systems,
and the aryl ring systems G′ containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by 0 to 3 substitutents R 10 ;
each R 10 is independently chosen from the group consisting of
(i) hydrogen,
(ii) —CN,
(iii) C 1-6 alkyl,
(iv) —O—C 0-6 alkyl,
(v) —S—C 0-6 alkyl,
(vi) C 1-6 alkyl-O—R 14 ,
(vii) —C(O)R 14 ,
(viii) —CO 2 R 14 ,
(ix) —SO 2 R 14 ,
(x) —N(R 14 ) 2 ,
(xi) —N(R 14 )SO 2 R 14 ,
(xii) —NCO 2 R 14 ,
(xiii) —NC(O)N(R 14 ) 2 , and
(xiv) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S,
or two R 10 may be taken together to form oxo;
each R 10a is independently chosen from the group consisting of
(i) hydrogen,
(ii) —CN,
(iii) C 1-6 alkyl,
(iv) C 1-6 alkyl-O—R 14 ,
(v) —C(O)R 14 ,
(vi) —CO 2 R 14 ,
(vii) —SO 2 R 14 ,
(x) —N(R 14 ) 2 ,
(xi) —N(R 14 )SO 2 R 14 ,
(xii) —NCO 2 R 14 ,
(xiii) —NC(O)N(R 14 ) 2 , and
(xiv) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S,
and two R 10 or R 10a groups can be taken together with the N to which they are attached to form a ring, which may be substituted by from 0 to 3 substituents R 14 , and
each R 14 is independently chosen from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, —(CH 2 ) 0-3 C 3-8 cycloalkyl and phenyl.
12 . The compound according to claim 11 , wherein said
and said
taken together with one said substituent R 1 and one said substituent R 2 , are represented by a group chosen from the group consisting of:
13 . The compound according to claim 12 , wherein W is chosen from the group consisting of —CH 2 —, —NH—, —N(C 1-6 alkyl)-, —C(O)—, —CH 2 NH—, —CH 2 N(C 1-6 alkyl)-, —CH 2 CH 2 —, —C(O)CH 2 —, —CH 2 C(O)—, —CH 2 O—, —CH 2 CH 2 CH 2 —, —C(O)CH 2 CH 2 —, —CH 2 C(O)CH 2 —, —CH 2 OCH 2- , —CH 2 CH 2 C(O)—, —CH 2 CH 2 O—, —CH 2 CH 2 NH—, —CH 2 CH 2 N(C 1-6 alkyl)-, —CH 2 NHCH 2 —, —CH 2 N(C 1-6 alkyl)CH 2 —, —NHCH 2 CH 2 —, and —N(C 1-6 alkyl)CH 2 CH 2 —.
14 . The compound according to any one of claims 11 - 13 , wherein each D is independently chosen from the group consisting of a single bond,
—C(O)N(R 5 )—, —NR 5 C(O)—,
where
R 5 is independently chosen from the group consisting of hydrogen, halogen, —OR 6 , —CN, —CO 2 R 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )COR 6 , —SR 6 , —S(O)R 6 , —S(O 2 )R 6 ,
—N(R 6 )SO 2 R 6 , —NCO 2 R 6 , —NC(O)N(R 6 ) 2 , C 1-6 alkyl substituted by from 0 to 3 substituents R 6 and C 3-8 cycloalkyl substituted by from 0 to 3 substituents R 6 , and
each R 6 is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl.
15 . The compound according to claim 14 , wherein each D is independently chosen from the group consisting of
16 . The compound according to any one of claims 11 - 15 , wherein each E is independently chosen from the group consisting of a single bond, —CH 2 NHC(O)—,
—CH 2 N(CH 3 )C(O)—, —C(CH 3 )HNHC(O)—, —C(CH 3 )HN(CH 3 )C(O)—, —C(CH 3 ) 2 NHC(O)—, —C(CH 3 ) 2 N(CH 3 )C(O)—, —CH 2 NHC(O)O—, —CH 2 N(CH 3 )C(O)O—, —C(CH 3 )HNHC(O)O—, —C(CH 3 )HN(CH 3 )C(O)O—, —C(CH 3 ) 2 NHC(O)O—, —C(CH 3 ) 2 N(CH 3 )C(O)O—,
where one of R 8a and R 8b is —OH or fluorine.
17 . The compound according to claim 16 , wherein each E is independently chosen from the group consisting of a single bond,
where one of R 8a and R 8b is —OH or fluorine.
18 . The compound according to any one of claims 11 - 17 , wherein each G is independently chosen from the group consisting of:
(a) C 1-6 alkyl having 0 to 4 substituents R 11 , (b) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, and having from 0 to 3 substitutents R 10 on N or C atoms; and (c) aryl ring systems G′ chosen from the group consisting of:
(i) 5- to 7-membered monocyclic ring systems and
(ii) 8- to 10-membered bicyclic ring systems,
and the aryl ring systems G′ containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by 0 to 3 substitutents R 10 .
19 . The compound according to any one of claims 11 - 17 , wherein each G is independently chosen from the group consisting of
(a) hydrogen, (b) —CN, (c) C 1-5 alkyl having 1 to 3 substituents R 11 ,
each R 11 is independently chosen from the group consisting of —OH, —NH 2 , —NCH 3 H, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , ═NH, ═NCH 3 , —C(O)H, —C(O)OH, —C(O)CH 3 , —C(O)OCH 3 , —NHC(O)H, —NHC(O)OH, —NHC(O)CH 3 , —NHC(O)OCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl, and oxacyclohexyl, phenyl, pyridinyl, pyrimidinyl and pyrrolyl, where
the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and oxacyclohexyl are substituted by from 0 to 2 substitutents R 12 on N or C atoms, and each R 12 is independently selected from the group consisting of hydrogen, halogen, carboxy, C 1-6 alkyl, —O—C 1-6 alkyl and —S—C 1-6 alkyl; and
the phenyl, pyridinyl, pyrimidinyl and pyrrolyl are substituted by from 0 to 3 substitutents R 13 on N or C atoms, and each R 13 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and 3- to 8-membered cycloalkyl containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S,
(d) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and oxacyclohexyl having from 0 to 3 substitutents R 10 on N or C atoms, said R 10 independently selected from the group consisting of hydrogen, halogen, carboxy, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, phenyl and benzyl, and (e) aryl ring systems G′ chosen from the group consisting of: phenyl, pyridinyl and 9-membered bicyclic ring systems containing from 0 to 2 heteroatoms independently chosen from the group consisting of N and O.
20 . The compound according to claim 19 , wherein each G is independently chosen from the group consisting of C 1-4 alkyl having 1 to 2 substituents R 11 , wherein each R 11 is independently chosen from the group consisting of —OH, —NH 2 , —NCH 3 H, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —C(O)OCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl, oxacyclohexyl, phenyl, pyridinyl, pyrimidinyl and pyrrolyl.
21 . (canceled)
22 . (canceled)
23 . (canceled)
24 . (canceled)
25 . (canceled)
26 . (canceled)
27 . The compound according to according to any one of claims 1 - 23 , wherein the compound having structural formula (Ia) is a compound having structural formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein said
is substituted by u substituents R 1 , and said
and said
taken together with one said substituent R 1 and one said substituent R 2 , are represented by a group chosen from the group consisting of:
28 . The compound according to according to claim 27 , wherein said
and said
taken together with one said substituent R 1 and one said substituent R 2 , are represented by
wherein V is —CH 2 —, W is —(CH 2 ) 0-2 O(CH 2 ) 0-2 —, R 1 is fluorine, and both instances of G are
29 . The compound according to according to claim 11 , wherein the compound having structural formula (Ia) is a compound having structural formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein said
and said
taken together with one said substituent R 1 and one said substituent R 2 , are represented by
wherein V is —CH 2 —, W is —(CH 2 ) 0-2 O(CH 2 ) 0-2 —, R 1 is fluorine, and both instances of G are
30 . The compound according to claim 11 , wherein
said
and said
taken together with one said substituent R 1 and one said substituent R 2 , are represented by a group chosen from the group consisting of:
where
W is chosen from the group consisting of —(CH 2 ) 1-3 —, —(CH 2 ) 0-2 NH(CH 2 ) 0-2 —,
—(CH 2 ) 0-2 N(C 1-6 alkyl)(CH 2 ) 0-2 —, —(CH 2 ) 0-2 O(CH 2 ) 0-2 —and —(CH 2 ) 0-2 C(O)(CH 2 ) 0-2 —, where W is substituted by from 0 to 4 R w , where each R w is independently selected from C 1-6 alkyl and
C 3-8 cycloalkyl; and
V is chosen from the group consisting of —C(O)— and —CH 2 —, and where V is
—CH 2 —, V is substituted by from 0 to 2 R v , where each R v is independently selected from the group consisting of C 1-6 alkyl and C 3-8 cycloalkyl;
each R 1 is independently chosen from the group consisting of hydrogen, halogen, —OR 3 , —CN, —C(O)R 3 , —CO 2 R 3 , —C(O)N(R 3a ) 2 , —SR 3 , —S(O)R 3 , —S(O 2 )R 3 , —N(R 3a ) 2 ,
—(CH 2 ) 0-6 N(R 3a ) 2 , —N(R 3a )SO 2 R 3 , —N(R 3a )CO 2 R 3 , —N(R 3a )COR 3 , —N(R 3a )C(O)N(R 3a ), C 1-6 alkyl,
C 3-8 carbocycle containing from 0 to 3 heteroatoms chosen from N, O and S, and phenyl, and the C 1-6 alkyl, C 3-8 carbocycle and phenyl are substituted by from 0 to 3 substitutents independently chosen from the group consisting of hydrogen, halogen, —OR 3a , —CN, —CO 2 R 3a , —C(O)N(R 3a ) 2 ,
—N(R 3a ) 2 , —N(R 3a )CO 2 R 3a , —SR 3a , —S(O)R 3a , —S(O 2 )R 3a , —N(R 3a )SO 2 R 3a , —N(R 3a )CO 2 R 3a , —N(R 3a )C(O)N(R 3a ), C 1-6 alkyl, —O—C 1-6 alkyl and —S—C 1-6 alkyl,
each R 3 is independently chosen from the group consisting of hydrogen, C 1-6 alkyl, —OH, —O—C 1-6 alkyl and C 3-8 cycloalkyl, and
each R 3a is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl;
each R 2 is independently chosen from the group consisting of hydrogen, halogen, —OR 4a , —CN, —CO 2 R 4a , —C(O)N(R 4a ) 2 , —N(R 4a ) 2 , —N(R 4a )CO 2 R 4a , —SR 4a , —S(O)R 4a , —S(O 2 )R 4a ,
—N(R 4a )SO 2 R 4a , —N(R 4a )CO 2 R 4a , —N(R 4a )C(O)N(R 4a ), C 1-6 alkyl substituted by from 0 to 4 R 4 and C 3-8 cycloalkyl substituted by from 0 to 4 R 4 ,
each R 4 is independently chosen from the group consisting of hydrogen,
—OH, C 1-6 alkyl and C 3-8 cycloalkyl, and
each R 4a is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl;
wherein each D is independently chosen from the group consisting of a single bond, —C(O)N(R 5 )—, —NR 5 C(O)—,
where
R 5 is independently chosen from the group consisting of hydrogen, halogen, —OR 6 , —CN, —CO 2 R 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )COR 6 , —SR 6 , —S(O)R 6 , —S(O 2 )R 6 ,
—N(R 6 )SO 2 R 6 , —NCO 2 R 6 , —NC(O)N(R 6 ) 2 , C 1-6 alkyl substituted by from 0 to 3 substituents R 6 and C 3-8 cycloalkyl substituted by from 0 to 3 substituents R 6 , and
each R 6 is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl;
wherein each E is independently chosen from the group consisting of a single bond, —CH 2 NHC(O)—, —CH 2 N(CH 3 )C(O)—, —C(CH 3 )HNHC(O)—, —C(CH 3 )HN(CH 3 )C(O)—,
—C(CH 3 ) 2 NHC(O)—, —C(CH 3 ) 2 N(CH 3 )C(O)—, —CH 2 NHC(O)O—, —CH 2 N(CH 3 )C(O)O—, —C(CH 3 )HNHC(O)O—, —C(CH 3 )HN(CH 3 )C(O)O—, —C(CH 3 ) 2 NHC(O)O—, —C(CH 3 ) 2 N(CH 3 )C(O)O—,
where one of R 8a and R 8b is —OH or fluorine;
wherein each G is independently chosen from the group consisting of
(a) hydrogen,
(b) —CN,
(c) C 1-5 alkyl having 1 to 3 substituents R 11 ,
each R 11 is independently chosen from the group consisting of —OH, —NH 2 , —NCH 3 H, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , ═NH, ═NCH 3 , —C(O)H, —C(O)OH, —C(O)CH 3 , —C(O)OCH 3 , —NHC(O)H, —NHC(O)OH, —NHC(O)CH 3 , —NHC(O)OCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl, and oxacyclohexyl, phenyl, pyridinyl, pyrimidinyl and pyrrolyl, where
the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and oxacyclohexyl are substituted by from 0 to 2 substitutents R 12 on N or C atoms, and each R 12 is independently selected from the group consisting of hydrogen, halogen, carboxy, C 1-6 alkyl, —O—C 1-6 alkyl and —S—C 1-6 alkyl; and
the phenyl, pyridinyl, pyrimidinyl and pyrrolyl are substituted by from 0 to 3 substitutents R 13 on N or C atoms, and each R 13 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and 3- to 8-membered cycloalkyl containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S,
(d) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and oxacyclohexyl having from 0 to 3 substitutents R 10 on N or C atoms, said R 10 independently selected from the group consisting of hydrogen, halogen, carboxy, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, phenyl and benzyl, and
(e) aryl ring systems G′ chosen from the group consisting of: phenyl, pyridinyl and 9-membered bicyclic ring systems containing from 0 to 2 heteroatoms independently chosen from the group consisting of N and O.
31 . A compound according to claim 11 , chosen from the group consisting of:
(2S,2′S)—N,N′-5,6,7,12-tetrahydrobenzo[6,7]cyclohepta[1,2-b]indole-3,9-diylbis[1-(phenylacetyl)pyrrolidine-2-carboxamide]; (2S,2′S)—N,N′-6,11-dihydro-5H-benzo[a]carbazole-3,8-diylbis[1-(phenylacetyl)pyrrolidine-2-carboxamide]; dibenzyl(2S,2′S)-2,2′-(6,11-dihydro-5H-benzo[a]carbazole-3,8-diyldicarbamoyl)dipyrrolidine-1-carboxylate; N-(8-bromo-6,11-dihydro-5H-benzo[a]carbazol-3-yl)-1-(phenylacetyl)-L-prolinamide; di-tert-butyl (6,11-dihydro-5H-benzo[a]carbazole-3,8-diylbis {carbamoyl(2 S)pyrrolidine-2,1-diyl[(1S)-2-oxo-1-phenylethane-2,1-diyl]})biscarbamate; tert-butyl[(1S)-2-{(2S)-2-[(8-bromo-6,11-dihydro-5H-benzo[a]carbazol-3-yl)carbamoyl]pyrrolidin-1-yl}-2-oxo-1-phenylethyl]carbamate; (2S,2′S)—N,N′-6,11-dihydro-5H-benzo[a]carbazole-3,8-diylbis{1-[(2R)-2-(dimethylamino)-2-phenylacetyl]pyrrolidine-2-carboxamide}; N-(6,11-dihydro-5H-benzo[a]carbazol-3-yl)-1-{(2S)-2-[(3,3-dimethylbutanoyl)amino]-2-phenylacetyl}-L-prolinamide; tert-butyl {(1R)-2-[(2S)-2-(6,11-dihydro-5H-benzo[a]carbazol-3-ylcarbamoyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate; methyl[(2S)-1-{(2S)-2-[5-(10-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}indolo[1,2-c][1,3]benzoxazin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; methyl[(2S)-1-{(2S)-2-[5-(12-fluoro-10-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}indolo[1,2-c][1,3]benzoxazin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; dimethyl(indolo[1,2-c][1,3]benzoxazine-3,10-diylbis{1H-imidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl[(1R)-2-oxo-1-phenylethane-2,1-diyl]})biscarbamate; methyl[(2S)-1-{(2S)-2-[5-(11-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-6,7-dihydroindolo[1,2-d][1,4]benzoxazepin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; methyl[(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-6,6-dimethylindolo[1,2-c][1,3]benzoxazin-10-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; methyl[(2S)-1-{(2S)-2-[5-(12-fluoro-10-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-6-methylindolo[1,2-c][1,3]benzoxazin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; methyl[(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}indolo[1,2-c]quinazolin-10-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; methyl[(2S)-1-{(2S)-2-[5-(12-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; methyl[(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-6-oxo-5,6-dihydroindolo[1,2-c]quinazolin-10-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; methyl[(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-6-methylindolo[1,2-c]quinazolin-10-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; methyl[(2S)-1-{(2S)-2-[5-(10′-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}spiro[cyclohexane-1,6′-indolo[1,2-c][1,3]benzoxazin]-3′-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; methyl[(2S)-1-{(2S)-2-[5-(1,12-difluoro-10-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}indolo[1,2-c][1,3]benzoxazin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; methyl[(2S)-1-{(2S)-2-[5-(12-cyano-10-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}indolo[1,2-c][1,3]benzoxazin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; and pharmaceutically acceptable salts thereof.
32 . (canceled)
33 . (canceled)
34 . A pharmaceutical composition comprising an effective amount of the compound according to any one of claim 11 , and a pharmaceutically acceptable carrier.
35 . The pharmaceutical composition according to claim 34 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
36 . The pharmaceutical composition according to claim 34 , further comprising a second therapeutic agent selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
37 . (canceled)
38 . A method of treating a patient infected with HCV comprising the step of administering an amount of the compound according to any one of claim 11 , effective to prevent and/or treat infection by HCV in a subject in need thereof.
39 . A method of treating a patient infected with HCV comprising the step of administering an amount of the compound according to any one of claim 11 , effective to inhibit HCV viral replication and/or viral production.
40 . A compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
each occurrence of R a is independently C 1-6 alkyl or phenyl;
Rb is H, halogen or —CN;
Rc is H or halogen;
each occurrence of R d is independently selected from H and C 1-6 alkyl, or one occurrence of R d is H and the other occurrence of R d is phenyl, or both R d groups and the common carbon atom to which they are attached combine to form a spirocyclic C 3-8 cycloalkyl group; and
p is 0, 1 or 2.
41 . The compound of claim 40 , wherein each occurrence of R a is isopropyl; R b and R c are each H or F; and p is 1.Join the waitlist — get patent alerts
Track US2015246917A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.