US2013116169A1PendingUtilityA1
Inhibitors of serine proteases, particularly hcv ns3-ns4a protease
Est. expirySep 5, 2023(expired)· nominal 20-yr term from priority
A61P 43/00A61P 37/02A61P 31/14A61P 31/20A61P 31/18A61P 31/12A61P 1/16A61K 31/497C07D 403/14A61K 31/501C07K 5/0207C07D 401/12C07D 403/12A61K 45/06A61K 31/517A01N 43/60A61K 31/506C07K 7/02A61K 38/00C07D 401/14C04B 35/632A61K 31/4439C07K 5/1027C07K 5/1016C07K 5/0202A61K 31/4178
54
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Claims
Abstract
The present invention relates to compounds that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The invention further relates to compositions comprising these compounds either for ex vivo use or for administration to a patient suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a patient by administering a composition comprising a compound of this invention. The invention further relates to processes for preparing these compounds.
Claims
exact text as granted — not AI-modified1 . (canceled)
2 . A compound of formula I:
wherein:
n is 0 or 1;
Ar is a 5- to 10-membered aromatic ring having up to 4 heteroatoms selected from O, S, N(H), SO, and SO 2 , wherein 1 to 3 ring atoms are optionally and independently substituted with J;
R 1 , R 2 , R 12 , and R 13 are independently:
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
[(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C6-C10)-heteroaryl-(C1-C12)aliphatic-,
wherein up to 3 aliphatic carbon atoms in R 1 and R 2 may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2 in a chemically stable arrangement;
wherein each of R 1 and R 2 is independently and optionally substituted at each substitutable position with up to 3 substituents independently selected from J;
R 3 and R 3′ are independently hydrogen or (C1-C12)-aliphatic, wherein any hydrogen is optionally replaced with halogen; wherein any terminal carbon atom of R 3 is optionally substituted with sulfhydryl or hydroxy; or R 3 is phenyl or —CH-phenyl, wherein said phenyl group is optionally substituted with up to 3 substituents independently selected from J; or
R 3 and R 3′ together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, O, SO, and SO 2 ; wherein the ring has up to 2 substituents selected independently from J;
R 4 and R 4′ are independently:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C3-C10)-heterocyclyl-; or
(C5-C10)-heteroaryl-;
wherein up to two aliphatic carbon atoms in R 4 and R 4′ may be replaced by a heteroatom selected from O, N, S, SO, and SO 2 ;
wherein each of R 4 and R 4′ is independently and optionally substituted with up to 3 substituents independently selected from J;
W is:
wherein
Y is —CO 2 H, a derivative of —CO 2 H, or a bioisostere of —CO 2 H;
each R 6 is independently:
hydrogen-,
(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-cycloalkyl- or cycloalkenyl-,
[(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,
(C3-C10)-heterocyclyl-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)heteroaryl-, or
(C5-C10)heteroaryl-(C1-C12)-aliphatic-, or
two R 6 groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a (C3-C10)-heterocyclic ring;
wherein R 6 is optionally substituted with up to 3 J substituents;
wherein each R 8 is independently —OR′; or the R 8 groups together with the boron atom, is a (C3-C10)-membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NH, O, SO, and SO 2 ;
T is:
(C1-C12)-aliphatic-;
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C5-C10)heteroaryl-, or
(C5-C10)heteroaryl-(C1-C12)-aliphatic-;
wherein each T is optionally substituted with up to 3 J substituents; and
wherein up to 3 aliphatic carbon atoms in T may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2 in a chemically stable arrangement;
provided that if T is pyrrole, the pyrrole is not substituted at the 3-position with J, with J being —C(O)R′, —C(O)C(O)R′, —C(O)CH 2 C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —C(O)C(O)OR′, —C(O)C(O)N(R) 2 , —C(O)N(R′) 2 , —C(S)N(R′) 2 , —C(═NH)N(R′) 2 , —C(O)N(OR′)R′, —C(═NOR′)R′;
J is halogen, —OR′, —NO 2 , —CN, —CF 3 , —OCF 3 , —R′, oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, ═N(R′), ═N(OR′), —N(R′) 2 , —SOR′, —SO 2 R′, —SO 2 N(R′) 2 , —SO 3 R′, —C(O)R′, —C(O)C(O)R′, —C(O)CH 2 C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —C(O)C(O)OR′, —C(O)C(O)N(R′) 2 , —OC(O)R′, —C(O)N(R′) 2 , —OC(O)N(R′) 2 , —C(S)N(R′) 2 , —(CH 2 ) 0-2 NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′) 2 , —N(R′)SO 2 R′, —N(R′)SO 2 N(R′) 2 , —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′) 2 , —N(R′)C(S)N(R) 2 , —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R) 2 , —C(O)N(OR′)R′, —C(═NOR′)R′, —OP(O)(OR′) 2 , —P(O)(R′) 2 , —P(O)(OR′) 2 , or —P(O)(H)(OR′);
R′ is:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein R′ is optionally substituted with up to 3 J groups;
wherein two R′ groups bound to the same atom form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, O, S, SO, or SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C 3 -C 10 )cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J.
3 - 25 . (canceled)
26 . The compound according to claim 2 wherein the compound is:
No.
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27 . A composition comprising a compound according to claim 2 or 26 or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit a serine protease; and an acceptable carrier, adjuvant or vehicle.
28 - 31 . (canceled)
32 . A method of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with a compound according to claim 2 or 26 .
33 . (canceled)
34 . A method of treating an HCV infection in a patient comprising the step of administering to said patient a composition according to claim 27 .
35 - 36 . (canceled)
37 . A method of eliminating or reducing HCV contamination of a biological sample or medical or laboratory equipment, comprising the step of contacting said biological sample or medical or laboratory equipment with a compound according to claim 2 or 26 .
38 - 40 . (canceled)Cited by (0)
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