US2010099695A1PendingUtilityA1
HCV NS3 Protease Inhibitors
Est. expiryOct 27, 2026(~0.3 yrs left)· nominal 20-yr term from priority
Inventors:Nigel J. LivertonVincenzo SummaMaria Emilia Di FrancescoMarco FerraraKevin F. GilbertSteven HarperJohn A. MccauleyCharles McintyreAlessia PetrocchiMarco PompeiJoseph J. RomanoMichael T. RuddJohn W. ButcherM. Katharine Holloway
C07K 5/0808C07D 498/22A61K 31/439C07K 5/0804C07D 498/18A61K 38/00C07K 5/0806A61K 31/4192C07K 5/0812A61P 31/14A61K 31/437C07D 498/08A61K 31/407A61K 45/06A61P 43/00A61P 31/12A61K 38/06A61K 31/12
55
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein:
is one or more rings selected from the group consisting of:
1) aryl rings,
2) C 3 -C 8 cycloalkyl rings, and
3) heterocyclic rings in which the heterocyclic ring system attaches to Z and X at points that are two independently selected ring atoms that are either two carbon ring atoms or one carbon ring atom and one nitrogen ring atom, and the heterocyclic ring system is selected from the group consisting of:
a) 5- or 6-membered saturated or unsaturated monocyclic rings with 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O or S,
b) 8-, 9- or 10-membered saturated or unsaturated bicyclic rings with 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O or S, and
c) 11- to 15-membered saturated or unsaturated tricyclic rings with 1, 2, 3, or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S,
wherein
is substituted with 0 to 4 independently selected substituents W, R 5 or oxo; wherein for stable heterocyclic rings containing S or N, the heterocyclic ring is unsubstituted at the S or N atom or is substituted at the S or N atom by oxo; wherein said W and R 5 substitutions are located on one or more ring atoms selected from C and N; and provided that the 10-membered unsaturated bicyclic ring is not quinoline, quinazoline or isoquinoline with the following modes of attachment
R 1 is selected from the group consisting of —CO 2 R 10 , —CONR 10 SO 2 R 6 , —CONR 10 SO 2 NR 8 R 9 , tetrazolyl, —CONHP(O)R 11 R 12 , and —P(O)R 11 R 12 ;
R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 3 -C 8 cycloalkyl, wherein said R 2 are substituted with 0 to 3 independently selected halogen atoms;
R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, phenyl(C 1 -C 8 )alkyl, naphthyl(C 1 -C 8 )alkyl, and Het groups, wherein when R 3 is not H, said R 3 is substituted with 0 to 3 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 ;
Het is selected from the group consisting of substituted and unsubstituted 5- and 6-membered saturated heterocyclic rings having 1 or 2 heteroatoms independently selected from N, O and S, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 ;
R 5 is selected from the group consisting of H, halogen atoms, —OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —CN, —CF 3 , —OCF 3 , —C(O)OH, —C(O)CH 3 , —SR 10 , —SO 2 (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 7 ) 2 , phenyl, naphthyl, —O-phenyl, —O-naphthyl, heteroaryl and heterocyclyl groups; wherein:
said R 5 heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 5 heteroaryl is attached through a ring atom selected from C or N,
said R 5 heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 5 heterocyclyl is attached through a ring atom selected from C or N, and
said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups are substituted with 0 to 4 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 , and 2 adjacent substituents of said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups may be taken together to form a 3-6-membered cyclic ring containing 0 to 3 heteroatoms independently selected from N, O and S;
R 6 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 6 are substituted with 0 to 2 independently selected W substituents,
each R 6 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 6 heteroaryl is attached through a ring atom selected from C or N, and
each R 6 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 6 heterocyclyl is attached through a ring atom selected from C or N;
Y is selected from the group consisting of —C(O)—, —SO 2 —, —OC(O)—, —C(O)N(D)L- and -LN(D)C(O)—. and -LN(D)C(O)—, where
D is selected from the group consisting of H, C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups,
L is selected from the group consisting of a direct bond, -G-(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-G-, -G-(C 1 -C 6 alkenylene)-, and —(C 1 -C 6 alkenylene)-G-, groups, where said G is selected from the group consisting of a direct bond, —O—, —N— and —S—, said alkylene and alkenylene groups are substituted with 0 to 4 substituents E independently selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups, and
said D and E may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from N, O and S;
Z is selected from the group consisting of —C(O)— and a direct bond;
M is selected from the group consisting of C 1 -C 12 alkylenes and C 2 -C 12 alkenylenes, wherein said M is substituted with 0 to 2 substituents F independently selected from the group consisting of C 1 -C 8 alkyl, ═CH 2 , C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), and aryl(C 1 -C 8 alkyl), and 2 adjacent substituents F may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and one or more adjacent substituents F may be taken together and/or with an adjacent D or E to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
X is selected from the group consisting of —O—, —CH 2 O—, —NHC(O)O—, —CH 2 NHC(O)O—, —C≡CH 2 O—, —C(O)O—, —(CH 2 ) 3 O—, —OC(O)NH—, —(CH 2 ) 2 C(O)NH—, —C(O)NH— and a direct bond;
each R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
when R 7 is not H, said R 7 are substituted with 0 to 2 W substituents,
each R 7 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 7 heteroaryl is attached through a ring atom selected from C or N, and
each R 7 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 7 heterocyclyl is attached through a ring atom selected from C or N, and
said R 7 may be taken together with the atom to which it is attached and a second R 7 substituent to form a 4- to 7-membered heterocyclic ring;
each W is independently selected from the group consisting of halogen atoms, —OR 10 , C 1 -C 6 alkyl, —CN, —CF 3 , —NO 2 , —SR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —C(O)R 10 , —N(R 10 )C(O)R 10 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 10 SO 2 R 10 , —SO 2 N(R 10 ) 2 , —NHCOOR 10 , —NHCONHR 10 , phenyl, naphthyl, heteroaryl and heterocyclyl groups; wherein
said W heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said W heteroaryl is attached through a ring atom selected from C or N,
said W heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said W heterocyclyl is attached through a ring atom selected from C or N;
R 8 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclic, heteroaryl(C 1 -C 4 alkyl), and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 8 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 8 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 8 heteroaryl is attached through a ring atom selected from C or N,
each R 8 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 8 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 8 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
R 9 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclyl, heteroaryl(C 1 -C 4 alkyl), or heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 9 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 9 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 9 heteroaryl is attached through a ring atom selected from C or N,
each R 9 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 9 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 9 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S, and
R 8 and R 9 may be taken together, with the N to which they are attached, to form a 4- to 8-membered monocyclic ring containing 0 to 2 additional heteroatoms independently selected from N, O and S;
each R 10 is independently selected from the group consisting of H and C 1 -C 6 alkyl;
each R 11 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 4 alkenyl, —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , —N(R 10 )(R 13 ), —R 14 , and —N(R 10 SO 2 R 6 ;
each R 12 is independently selected from the group consisting of —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , and —N(R 10 )(R 13 );
R 11 and R 12 may be taken together, with the phosphorus atom to which they are attached, to form a 5- to 7-membered monocyclic ring;
each V is independently selected from the group consisting of —CH(R 15 )— and —(C 1 -C 4 alkylene)-CH(R 15 )—;
each R 13 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, wherein
when R 13 is not H, said R 13 is substituted with 0 to 2 substituents independently selected from the group consisting of phenyl, naphthyl, phenyl(C 1 -C 4 alkyl), naphthyl(C 1 -C 4 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 4 alkyl), heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, heterocyclyl(C 1 -C 4 alkyl), C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 13 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 13 heteroaryl is attached through a ring atom selected from C or N,
each R 13 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 13 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 13 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
R 14 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
each R 14 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 14 heteroaryl is attached through a ring atom selected from C or N, and
said R 14 phenyl, naphthyl or heteroaryl may be substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 lkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ; and
each R 15 is independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, phenyl, naphthyl, heteroaryl, and heterocyclyl groups, wherein
said R 15 are substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 15 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 15 heteroaryl is attached through a ring atom selected from C or N,
each R 15 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 15 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 15 are optionally taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S.
2 . The compound according to claim 1 , wherein
is selected from the group consisting of:
1) aryl rings,
2) cyclohexyl rings, and
3) heterocyclic rings in which the heterocyclic ring system attaches to Z and X at points that are two independently selected ring atoms that are either two acarbon ring atoms or one carbon ring atom and one nitrogen ring atom, and the heterocyclic ring system is selected from the group consisting of:
a) 5- or 6-membered saturated or unsaturated monocyclic rings containing 1, 2, or 3 nitrogen atoms, and
b) 8-, 9- or 10-membered saturated or unsaturated bicyclic rings containing 1 or 2 nitrogen atoms,
wherein said
is substituted with 0 to 4 independently selected substituents W, R 5 or oxo; wherein for stable heterocyclic rings containing S or N, the heterocyclic ring is unsubstituted at the S or N atom or is substituted at the S or N atom by oxo; wherein said W and R 5 substitutions are located on one or more ring atoms selected from C and N; and provided that the 10-membered unsaturated bicyclic ring is not quinoline, quinazoline or isoquinoline.
3 . The compound according to claim 2 , wherein
is unsubstituted or mono-substituted with a moiety selected from the group consisting of —Br, —Cl, —CN, phenyl, —O-phenyl, —OCF 3 , —OCH 3 , —C(O)OH, —CH 3 and —C(O)CH 3 .
4 . The compound according to claim 1 , wherein
is selected from the group consisting of the group of rings consisting of:
5 . The compound according to claim 4 , wherein each R 5 is independently selected from the group consisting of H, —Br, —Cl, —CN, phenyl, —O-phenyl, —OCF 3 , —OCH 3 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —CF 3 , —C(O)OH, and —C(O)CH 3 .
6 . The compound according to claim 1 , wherein R 1 is selected from the group consisting of —CO 2 R 10 and —CONR 10 SO 2 R 6 .
7 . The compound according to claim 6 , wherein R 1 is selected from the group consisting of —C(O)OH and —C(O)NHSO 2 cyclopropyl.
8 . The compound according to claim 1 , wherein R 2 is selected from the group consisting of C 1 -C 6 alkyl and C 2 -C 6 alkenyl.
9 . The compound according to claim 8 , wherein R 2 is selected from the group consisting of —CH═CH 2 , —CH 2 CH 3 , and —CH 2 CH═CH 2 .
10 . The compound according to claim 1 , wherein R 3 is selected from the group consisting of H, C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl.
11 . The compound according to claim 10 , wherein R 3 is selected from the group consisting of H, —C(CH 3 ) 3 , —(CH 2 ) 3 CH 3 , cyclohexyl, and —CH(CH 3 ) 2 .
12 . The compound according to claim 1 , wherein M is selected from the group consisting of C 1 -C 12 alkylene or C 2 -C 12 alkenylene, wherein M is substituted with 0 to 2 substituents F selected from the group consisting of C 1 -C 8 alkyl, and ═CH 2 .
13 . The compound according to claim 12 , wherein M is selected from the group consisting of —CH═CH(CH 2 ) 5 , —(CH 2 ) 7 —, —CH 2 CH═CH(CH 2 ) 4 —, —(CH 2 ) 6 —, —CH═CH(CH 2 ) 4 —, —CH═CH(CH 2 ) 3 C(CH 3 ) 2 CH 2 —, —CH═CH(CH 2 ) 3 —, —(CH 2 ) 5 —, —CH═CH(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 3 —, —CH═H(CH 2 ) 2 C(CH 3 ) 2 CH 2 —, —(CH 2 ) 4 C(CH 3 ) 2 CH 2 —, —C(═CH 2 )(CH 2 ) 5 —, —C(═CH 2 )(CH 2 ) 3 —, and —CH 2 CH═CH(CH 2 ) 3 —.
14 . The compound according to claim 13 , wherein M is selected from the group consisting of
15 . The compound according to claim 1 , wherein Y is —C(O)N(D)L- and -LN(D)C(O)—.
16 . The compound according to claim 1 , wherein one or more substituents F are taken together and/or with one or more substituents chosen from substituents D and E to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from the group consisting of N, O and S.
17 . A compound selected from the group consisting of:
18 . A pharmaceutical composition comprising an effective amount of the compound according to claim 1 , and a pharmaceutically acceptable carrier.
19 . The pharmaceutical composition according to claim 16 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
20 . The pharmaceutical composition according to claim 16 , further comprising a second therapeutic agent selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
21 . A method of preparing a medicament for inhibiting HCV NS3 protease activity in a subject in need thereof, said method comprising providing a compound of formula (I):
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein:
is one or more rings selected from the group consisting of:
1) aryl rings,
2) C 3 -C 8 cycloalkyl rings, and
3) heterocyclic rings in which the heterocyclic ring system attaches to Z and X at points that are two independently selected ring atoms that are either two acarbon carbon ring atoms or one carbon ring atom and one nitrogen ring atom, and the heterocyclic ring system is selected from the group consisting of:
a) 5- or 6-membered saturated or unsaturated monocyclic rings with 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O or S,
b) 8-, 9- or 10-membered saturated or unsaturated bicyclic rings with 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O or S, and
c) 11- to 15-membered saturated or unsaturated tricyclic rings with 1, 2, 3, or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S,
wherein
is substituted with 0 to 4 independently selected substituents W, R 5 or oxo; wherein for stable heterocyclic rings containing S or N, the heterocyclic ring is unsubstituted at the S or N atom or is substituted at the S or N atom by oxo; wherein said W and R 5 substitutions are located on one or more ring atoms selected from C and N; and provided that the 10-membered unsaturated bicyclic ring is not quinoline, quinazoline or isoquinoline with the following modes of attachment
R 1 is selected from the group consisting of —CO 2 R 10 , —CONR 10 SO 2 R 6 , —CONR 10 SO 2 NR 8 R 9 , tetrazolyl, —CONHP(O)R 11 R 12 , and —P(O)R 11 R 12 ;
R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 3 -C 8 cycloalkyl, wherein said R 2 are substituted with 0 to 3 independently selected halogen atoms;
R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, phenyl(C 1 -C 8 )alkyl, naphthyl(C 1 -C 8 )alkyl, and Het groups, wherein when R 3 is not H, said R 3 is substituted with 0 to 3 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 ;
Het is selected from the group consisting of substituted and unsubstituted 5- and 6-membered saturated heterocyclic rings having 1 or 2 heteroatoms independently selected from N, O and S, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 ;
R 5 is selected from the group consisting of H, halogen atoms, —OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —CN, —CF 3 —OCF 3 , —C(O)OH, —C(O)CH 3 , —SR 10 , —SO 2 (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 7 ) 2 , phenyl, naphthyl, —O-phenyl, —O-naphthyl, heteroaryl and heterocyclyl groups; wherein:
said R 5 heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 5 heteroaryl is attached through a ring atom selected from C or N,
said R 5 heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 5 heterocyclyl is attached through a ring atom selected from C or N, and
said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups are substituted with 0 to 4 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 , and 2 adjacent substituents of said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups may be taken together to form a 3-6-membered cyclic ring containing 0 to 3 heteroatoms independently selected from N, O and S;
R 6 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 6 are substituted with 0 to 2 independently selected W substituents,
each R 6 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 6 heteroaryl is attached through a ring atom selected from C or N, and
each R 6 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 6 heterocyclyl is attached through a ring atom selected from C or N;
Y is selected from the group consisting of —C(O)—, —SO 2 —, —OC(O)—, —C(O)N(D)L- and -LN(D)C(O)—. and -LN(D)C(O)—, where
D is selected from the group consisting of H, C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups,
L is selected from the group consisting of a direct bond, -G-(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-G-, -G-(C 1 -C 6 alkenylene)-, and —(C 1 -C 6 alkenylene)-G-, groups, where said G is selected from the group consisting of a direct bond, —O—, —N— and —S—, said alkylene and alkenylene groups are substituted with 0 to 4 substituents E independently selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups, and
said D and E may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from N, O and S;
Z is selected from the group consisting of —C(O)— and a direct bond;
M is selected from the group consisting of C 1 -C 12 alkylenes and C 2 -C 12 alkenylenes, wherein said M is substituted with 0 to 2 substituents F independently selected from the group consisting of C 1 -C 8 alkyl, ═CH 2 , C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), and aryl(C 1 -C 8 alkyl), and 2 adjacent substituents F may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and one or more adjacent substituents F may be taken together and/or with an adjacent D or E to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
X is selected from the group consisting of —O—, —CH 2 O—, —NHC(O)O—, —CH 2 NHC(O)O—, —C≡CH 2 O—, —C(O)O—, —(CH 2 ) 3 O—, —OC(O)NH—, —(CH 2 ) 2 C(O)NH—, —C(O)NH— and a direct bond;
each R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
when R 7 is not H, said R 7 are substituted with 0 to 2 W substituents,
each R 7 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 7 heteroaryl is attached through a ring atom selected from C or N, and
each R 7 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 7 heterocyclyl is attached through a ring atom selected from C or N, and
said R 7 may be taken together with the atom to which it is attached and a second R 7 substituent to form a 4- to 7-membered heterocyclic ring;
each W is independently selected from the group consisting of halogen atoms, —OR 10 , C 1 -C 6 alkyl, —CN, —CF 3 , —NO 2 , —SR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —C(O)R 10 , —N(R 10 )C(O)R 10 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 10 SO 2 R 10 , —SO 2 N(R 10 ) 2 , —NHCOOR 10 , —NHCONHR 10 , phenyl, naphthyl, heteroaryl and heterocyclyl groups; wherein
said W heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said W heteroaryl is attached through a ring atom selected from C or N,
said W heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said W heterocyclyl is attached through a ring atom selected from C or N;
R 8 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclic, heteroaryl(C 1 -C 4 alkyl), and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 8 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 8 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 8 heteroaryl is attached through a ring atom selected from C or N,
each R 8 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 8 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 8 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
R 9 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclyl, heteroaryl(C 1 -C 4 alkyl), or heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 9 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 9 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 9 heteroaryl is attached through a ring atom selected from C or N,
each R 9 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 9 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 9 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S, and
R 8 and R 9 may be taken together, with the N to which they are attached, to form a 4- to 8-membered monocyclic ring containing 0 to 2 additional heteroatoms independently selected from N, O and S;
each R 10 is independently selected from the group consisting of H and C 1 -C 6 alkyl;
each R 11 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 4 alkenyl, —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , —N(R 10 )(R 13 ), —R 14 , and —N(R 10 SO 2 R 6 ;
each R 12 is independently selected from the group consisting of —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , and —N(R 10 )(R 13 );
R 11 and R 12 may be taken together, with the phosphorus atom to which they are attached, to form a 5- to 7-membered monocyclic ring;
each V is independently selected from the group consisting of —CH(R 15 )— and —(C 1 -C 4 alkylene)-CH(R 15 )—;
each R 13 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, wherein
when R 13 is not H, said R 13 is substituted with 0 to 2 substituents independently selected from the group consisting of phenyl, naphthyl, phenyl(C 1 -C 4 alkyl), naphthyl(C 1 -C 4 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 4 alkyl), heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, heterocyclyl(C 1 -C 4 alkyl), C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 13 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 13 heteroaryl is attached through a ring atom selected from C or N,
each R 13 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 13 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 13 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
R 14 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
each R 14 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 14 heteroaryl is attached through a ring atom selected from C or N, and
said R 14 phenyl, naphthyl or heteroaryl may be substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ; and
each R 15 is independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, phenyl, naphthyl, heteroaryl, and heterocyclyl groups, wherein
said R 15 are substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 15 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 15 heteroaryl is attached through a ring atom selected from C or N,
each R 15 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 15 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 15 are optionally taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S.
22 . A method of preparing a medicament for preventing or treating infection by HCV in a subject in need thereof, said method comprising providing a compound of formula (I):
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein:
is one or more rings selected from the group consisting of:
1) aryl rings,
2) C 3 -C 8 cycloalkyl rings, and
3) heterocyclic rings in which the heterocyclic ring system attaches to Z and X at points that are two independently selected ring atoms that are either two acarbon carbon ring atoms or one carbon ring atom and one nitrogen ring atom, and the heterocyclic ring system is selected from the group consisting of:
a) 5- or 6-membered saturated or unsaturated monocyclic rings with 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O or S,
b) 8-, 9- or 10-membered saturated or unsaturated bicyclic rings with 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O or S, and
c) 11- to 15-membered saturated or unsaturated tricyclic rings with 1, 2, 3, or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S,
wherein
is substituted with 0 to 4 independently selected substituents W, R 5 or oxo; wherein for stable heterocyclic rings containing S or N, the heterocyclic ring is unsubstituted at the S or N atom or is substituted at the S or N atom by oxo; wherein said W and R 5 substitutions are located on one or more ring atoms selected from C and N; and provided that the 10-membered unsaturated bicyclic ring is not quinoline, quinazoline or isoquinoline with the following modes of attachment
R 1 is selected from the group consisting of —CO 2 R 10 , —CONR 10 SO 2 R 6 , —CONR 10 SO 2 NR 8 R 9 , tetrazolyl, —CONHP(O)R 11 R 12 , and —P(O)R 11 R 12 ;
R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 3 -C 8 cycloalkyl, wherein said R 2 are substituted with 0 to 3 independently selected halogen atoms;
R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl. C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, phenyl(C 1 -C 8 )alkyl, naphthyl(C 1 -C 8 )alkyl, and Het groups, wherein when R 3 is not H, said R 3 is substituted with 0 to 3 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 ;
Het is selected from the group consisting of substituted and unsubstituted 5- and 6-membered saturated heterocyclic rings having 1 or 2 heteroatoms independently selected from N, O and S, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 ;
R 5 is selected from the group consisting of H, halogen atoms, —OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —CN, —CF 3 —OCF 3 , —C(O)OH, —C(O)CH 3 , —SR 10 , —SO 2 (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 7 ) 2 , phenyl, naphthyl, —O-phenyl, —O-naphthyl, heteroaryl and heterocyclyl groups; wherein:
said R 5 heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 5 heteroaryl is attached through a ring atom selected from C or N,
said R 5 heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 5 heterocyclyl is attached through a ring atom selected from C or N, and
said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups are substituted with 0 to 4 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 , and 2 adjacent substituents of said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups may be taken together to form a 3-6-membered cyclic ring containing 0 to 3 heteroatoms independently selected from N, O and S;
R 6 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 6 are substituted with 0 to 2 independently selected W substituents,
each R 6 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 6 heteroaryl is attached through a ring atom selected from C or N, and
each R 6 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 6 heterocyclyl is attached through a ring atom selected from C or N;
Y is selected from the group consisting of —C(O)—, —SO 2 —, —OC(O)—, —C(O)N(D)L- and -LN(D)C(O)—. and -LN(D)C(O)—, where
D is selected from the group consisting of H, C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups,
L is selected from the group consisting of a direct bond, -G-(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-G-, -G-(C 1 -C 6 alkenylene)-, and —(C 1 -C 6 alkenylene)-G-, groups, where said G is selected from the group consisting of a direct bond, —O—, —N— and —S—, said alkylene and alkenylene groups are substituted with 0 to 4 substituents E independently selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups, and
said D and E may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from N, O and S;
Z is selected from the group consisting of —C(O)— and a direct bond;
M is selected from the group consisting of C 1 -C 12 alkylenes and C 1 -C 12 alkenylenes, wherein said M is substituted with 0 to 2 substituents F independently selected from the group consisting of C 1 -C 8 alkyl, ═CH 2 , C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), and aryl(C 1 -C 8 alkyl), and 2 adjacent substituents F may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and one or more adjacent substituents F may be taken together and/or with an adjacent D or E to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
X is selected from the group consisting of —O—, —CH 2 O—, —NHC(O)O—, —CH 2 NHC(O)O—, —C≡CH 2 O—, —C(O)O—, —(CH 2 ) 2 O—, —OC(O)NH—, —(CH 2 ) 2 C(O)NH—, —C(O)NH— and a direct bond;
each R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
when R 7 is not H, said R 7 are substituted with 0 to 2 W substituents,
each R 7 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 7 heteroaryl is attached through a ring atom selected from C or N, and
each R 7 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 7 heterocyclyl is attached through a ring atom selected from C or N, and
said R 7 may be taken together with the atom to which it is attached and a second R 7 substituent to form a 4- to 7-membered heterocyclic ring;
each W is independently selected from the group consisting of halogen atoms, —OR 10 , C 1 -C 6 alkyl, —CN, —CF 3 , —NO 2 , —SR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —C(O)R 10 , —N(R 10 )C(O)R 10 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 10 SO 2 R 10 , —SO 2 N(R 10 ) 2 , —NHCOOR 10 , —NHCONHR 10 , phenyl, naphthyl, heteroaryl and heterocyclyl groups; wherein
said W heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said W heteroaryl is attached through a ring atom selected from C or N,
said W heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said W heterocyclyl is attached through a ring atom selected from C or N;
R 8 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclic, heteroaryl(C 1 -C 4 alkyl), and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 8 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 8 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 8 heteroaryl is attached through a ring atom selected from C or N,
each R 8 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 8 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 8 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
R 9 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclyl, heteroaryl(C 1 -C 4 alkyl), or heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 9 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 9 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 9 heteroaryl is attached through a ring atom selected from C or N,
each R 9 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 9 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 9 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S, and
R 8 and R 9 may be taken together, with the N to which they are attached, to form a 4- to 8-membered monocyclic ring containing 0 to 2 additional heteroatoms independently selected from N, O and S;
each R 10 is independently selected from the group consisting of H and C 1 -C 6 alkyl;
each R 11 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 4 alkenyl, —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , —N(R 10 )(R 13 ), —R 14 , and —N(R 10 SO 2 R 6 ;
each R 12 is independently selected from the group consisting of —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , and —N(R 10 )(R 13 );
R 11 and R 12 may be taken together, with the phosphorus atom to which they are attached, to form a 5- to 7-membered monocyclic ring;
each V is independently selected from the group consisting of —CH(R 15 )— and —(C 1 -C 4 alkylene)-CH(R 15 )—;
each R 13 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, wherein
when R 13 is not H, said R 13 is substituted with 0 to 2 substituents independently selected from the group consisting of phenyl, naphthyl, phenyl(C 1 -C 4 alkyl), naphthyl(C 1 -C 4 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 4 alkyl), heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, heterocyclyl(C 1 -C 4 alkyl), C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 13 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 13 heteroaryl is attached through a ring atom selected from C or N,
each R 13 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 13 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 13 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
R 14 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
each R 14 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 14 heteroaryl is attached through a ring atom selected from C or N, and
said R 14 phenyl, naphthyl or heteroaryl may be substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ; and
each R 15 is independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, phenyl, naphthyl, heteroaryl, and heterocyclyl groups, wherein
said R 15 are substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 15 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 15 heteroaryl is attached through a ring atom selected from C or N,
each R 15 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 15 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 15 are optionally taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S.
23 . A method of inhibiting HCV NS3 protease in a subject in need thereof, said method comprising administering to the subject an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein:
is one or more rings selected from the group consisting of:
1) aryl rings,
2) C 3 -C 8 cycloalkyl rings, and
3) heterocyclic rings in which the heterocyclic ring system attaches to Z and X at points that are two independently selected ring atoms that are either two carbon ring atoms or one carbon ring atom and one nitrogen ring atom, and the heterocyclic ring system is selected from the group consisting of:
a) 5- or 6-membered saturated or unsaturated monocyclic rings with 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O or S,
b) 8-, 9- or 10-membered saturated or unsaturated bicyclic rings with 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O or S, and
c) 11- to 15-membered saturated or unsaturated tricyclic rings with 1, 2, 3, or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S,
wherein
is substituted with 0 to 4 independently selected substituents W, R 5 or oxo; wherein for stable heterocyclic rings containing S or N, the heterocyclic ring is unsubstituted at the S or N atom or is substituted at the S or N atom by oxo; wherein said W and R 5 substitutions are located on one or more ring atoms selected from C and N; and provided that the 10-membered unsaturated bicyclic ring is not quinoline, quinazoline or isoquinoline with the following modes of attachment
R 1 is selected from the group consisting of —CO 2 R 10 , —CONR 10 SO 2 R 6 , —CONR 10 SO 2 NR 8 R 9 , tetrazolyl, —CONHP(O)R 11 R 12 , and —P(O)R 11 R 12 ;
R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 3 -C 8 cycloalkyl, wherein said R 2 are substituted with 0 to 3 independently selected halogen atoms;
R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, phenyl(C 1 -C 8 )alkyl, naphthyl(C 1 -C 8 )alkyl, and Het groups, wherein when R 3 is not H, said R 3 is substituted with 0 to 3 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 ;
Het is selected from the group consisting of substituted and unsubstituted 5- and 6-membered saturated heterocyclic rings having 1 or 2 heteroatoms independently selected from N, O and S, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 ;
R 5 is selected from the group consisting of H, halogen atoms, —OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —CN, —CF 3 , —OCF 3 , —C(O)OH, —C(O)CH 3 , —SR 10 , —SO 2 (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 7 ) 2 , phenyl, naphthyl, —O-phenyl, —O-naphthyl, heteroaryl and heterocyclyl groups; wherein:
said R 5 heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 5 heteroaryl is attached through a ring atom selected from C or N,
said R 5 heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 5 heterocyclyl is attached through a ring atom selected from C or N, and
said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups are substituted with 0 to 4 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 , and 2 adjacent substituents of said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups may be taken together to form a 3-6-membered cyclic ring containing 0 to 3 heteroatoms independently selected from N, O and S;
R 6 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 6 are substituted with 0 to 2 independently selected W substituents,
each R 6 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 6 heteroaryl is attached through a ring atom selected from C or N, and
each R 6 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 6 heterocyclyl is attached through a ring atom selected from C or N;
Y is selected from the group consisting of —C(O)—, —SO 2 —, —OC(O)—, —C(O)N(D)L- and -LN(D)C(O)—. and -LN(D)C(O)—, where
D is selected from the group consisting of H, C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups,
L is selected from the group consisting of a direct bond, -G-(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-G-, -G-(C 1 -C 6 alkenylene)-, and —(C 1 -C 6 alkenylene)-G-, groups, where said G is selected from the group consisting of a direct bond, —O—, —N— and —S—, said alkylene and alkenylene groups are substituted with 0 to 4 substituents E independently selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups, and
said D and E may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from N, O and S;
Z is selected from the group consisting of —C(O)— and a direct bond;
M is selected from the group consisting of C 1 -C 12 alkylenes and C 2 -C 12 alkenylenes, wherein said M is substituted with 0 to 2 substituents F independently selected from the group consisting of C 1 -C 8 alkyl, ═CH 2 , C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), and aryl(C 1 -C 8 alkyl), and 2 adjacent substituents F may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and one or more adjacent substituents F may be taken together and/or with an adjacent D or E to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
X is selected from the group consisting of —O—, —CH 2 O—, —NHC(O)O—, —CH 2 NHC(O)O—, —C≡CH 2 O—, —C(O)O—, —(CH 2 ) 3 O—, —OC(O)NH—, —(CH 2 ) 2 C(O)NH—, —C(O)NH— and a direct bond;
each R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
when R 7 is not H, said R 7 are substituted with 0 to 2 W substituents,
each R 7 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 7 heteroaryl is attached through a ring atom selected from C or N, and
each R 7 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 7 heterocyclyl is attached through a ring atom selected from C or N, and
said R 7 may be taken together with the atom to which it is attached and a second R 7 substituent to form a 4- to 7-membered heterocyclic ring;
each W is independently selected from the group consisting of halogen atoms, —OR 10 , C 1 -C 6 alkyl, —CN, —CF 3 , —NO 2 , —SR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —C(O)R 10 , —N(R 10 )C(O)R 10 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 10 SO 2 R 10 , —SO 2 N(R 10 ) 2 , —NHCOOR 10 , —NHCONHR 10 , phenyl, naphthyl, heteroaryl and heterocyclyl groups; wherein
said W heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said W heteroaryl is attached through a ring atom selected from C or N,
said W heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said W heterocyclyl is attached through a ring atom selected from C or N;
R 8 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclic, heteroaryl(C 1 -C 4 alkyl), and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 8 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 8 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 8 heteroaryl is attached through a ring atom selected from C or N,
each R 8 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 8 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 8 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
R 9 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclyl, heteroaryl(C 1 -C 4 alkyl), or heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 9 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 9 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 9 heteroaryl is attached through a ring atom selected from C or N,
each R 9 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 9 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 9 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S, and
R 8 and R 9 may be taken together, with the N to which they are attached, to form a 4- to 8-membered monocyclic ring containing 0 to 2 additional heteroatoms independently selected from N, O and S;
each R 10 is independently selected from the group consisting of H and C 1 -C 6 alkyl;
each R 11 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 4 alkenyl, —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , —N(R 10 )(R 13 ), —R 14 , and —N(R 10 SO 2 R 6 ;
each R 12 is independently selected from the group consisting of —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , and —N(R 10 )(R 13 );
R 11 and R 12 may be taken together, with the phosphorus atom to which they are attached, to form a 5- to 7-membered monocyclic ring;
each V is independently selected from the group consisting of —CH(R 15 )— and —(C 1 -C 4 alkylene)-CH(R 15 )—;
each R 13 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, wherein
when R 13 is not H, said R 13 is substituted with 0 to 2 substituents independently selected from the group consisting of phenyl, naphthyl, phenyl(C 1 -C 4 alkyl), naphthyl(C 1 -C 4 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 4 alkyl), heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, heterocyclyl(C 1 -C 4 alkyl), C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 13 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 13 heteroaryl is attached through a ring atom selected from C or N,
each R 13 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 13 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 13 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
R 14 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
each R 14 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 14 heteroaryl is attached through a ring atom selected from C or N, and
said R 14 phenyl, naphthyl or heteroaryl may be substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ; and
each R 15 is independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, phenyl, naphthyl, heteroaryl, and heterocyclyl groups, wherein
said R 15 are substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 15 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 15 heteroaryl is attached through a ring atom selected from C or N,
each R 15 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 15 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 15 are optionally taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S.
24 . A method of preventing or treating infection by HCV in a subject in need thereof, said method comprising administering to the subject an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein:
is one or more rings selected from the group consisting of:
1) aryl rings,
2) C 3 -C 8 cycloalkyl rings, and
3) heterocyclic rings in which the heterocyclic ring system attaches to Z and X at points that are two independently selected ring atoms that are either two carbon ring atoms or one carbon ring atom and one nitrogen ring atom, and the heterocyclic ring system is selected from the group consisting of:
a) 5- or 6-membered saturated or unsaturated monocyclic rings with 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O or S,
b) 8-, 9- or 10-membered saturated or unsaturated bicyclic rings with 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O or S, and
c) 11- to 15-membered saturated or unsaturated tricyclic rings with 1, 2, 3, or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S,
wherein
is substituted with 0 to 4 independently selected substituents W, R 5 or oxo; wherein for stable heterocyclic rings containing S or N, the heterocyclic ring is unsubstituted at the S or N atom or is substituted at the S or N atom by oxo; wherein said W and R 5 substitutions are located on one or more ring atoms selected from C and N; and provided that the 10-membered unsaturated bicyclic ring is not quinoline, quinazoline or isoquinoline with the following modes of attachment
R 1 is selected from the group consisting of —CO 2 R 10 , —CONR 10 SO 2 R 6 , —CONR 10 SO 2 NR 8 R 9 , tetrazolyl, —CONHP(O)R 11 R 12 , and —P(O)R 11 R 12 ;
R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 3 -C 8 cycloalkyl, wherein said R 2 are substituted with 0 to 3 independently selected halogen atoms;
R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, phenyl(C 1 -C 8 )alkyl, naphthyl(C 1 -C 8 )alkyl, and Het groups, wherein when R 3 is not H, said R 3 is substituted with 0 to 3 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 ;
Het is selected from the group consisting of substituted and unsubstituted 5- and 6-membered saturated heterocyclic rings having 1 or 2 heteroatoms independently selected from N, O and S, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 ;
R 5 is selected from the group consisting of H, halogen atoms, —OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —CN, —CF 3 , —OCF 3 , —C(O)OH, —C(O)CH 3 , —SR 10 , —SO 2 (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 7 ) 2 , phenyl, naphthyl, —O-phenyl, —O-naphthyl, heteroaryl and heterocyclyl groups; wherein:
said R 5 heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 5 heteroaryl is attached through a ring atom selected from C or N,
said R 5 heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 5 heterocyclyl is attached through a ring atom selected from C or N, and
said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups are substituted with 0 to 4 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10 , and —CON(R 10 ) 2 , and 2 adjacent substituents of said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups may be taken together to form a 3-6-membered cyclic ring containing 0 to 3 heteroatoms independently selected from N, O and S;
R 6 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 6 are substituted with 0 to 2 independently selected W substituents,
each R 6 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 6 heteroaryl is attached through a ring atom selected from C or N, and
each R 6 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 6 heterocyclyl is attached through a ring atom selected from C or N;
Y is selected from the group consisting of —C(O)—, —SO 2 —, —OC(O)—, —C(O)N(D)L- and -LN(D)C(O)—. and -LN(D)C(O)—, where
D is selected from the group consisting of H, C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups,
L is selected from the group consisting of a direct bond, -G-(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-G-, -G-(C 1 -C 6 alkenylene)-, and —(C 1 -C 6 alkenylene)-G-, groups, where said G is selected from the group consisting of a direct bond, —O—, —N— and —S—, said alkylene and alkenylene groups are substituted with 0 to 4 substituents E independently selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups, and
said D and E may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from N, O and S;
Z is selected from the group consisting of —C(O)— and a direct bond;
M is selected from the group consisting of C 1 -C 12 alkylenes and C 2 -C 12 alkenylenes, wherein said M is substituted with 0 to 2 substituents F independently selected from the group consisting of C 1 -C 8 alkyl, ═CH 2 , C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), and aryl(C 1 -C 8 alkyl), and 2 adjacent substituents F may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and one or more adjacent substituents F may be taken together and/or with an adjacent D or E to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
X is selected from the group consisting of —O—, —CH 2 O—, —NHC(O)O—, —CH 2 NHC(O)O—, —C≡CH 2 O—, —C(O)O—, —(CH 2 ) 3 O—, —OC(O)NH—, —(CH 2 ) 2 C(O)NH—, —C(O)NH— and a direct bond;
each R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
when R 7 is not H, said R 7 are substituted with 0 to 2 W substituents,
each R 7 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 7 heteroaryl is attached through a ring atom selected from C or N, and
each R 7 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 7 heterocyclyl is attached through a ring atom selected from C or N, and
said R 7 may be taken together with the atom to which it is attached and a second R 7 substituent to form a 4- to 7-membered heterocyclic ring;
each W is independently selected from the group consisting of halogen atoms, —OR 10 , C 1 -C 6 alkyl, —CN, —CF 3 , —NO 2 , —SR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —C(O)R 10 , —N(R 10 )C(O)R 10 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 10 SO 2 R 10 , —SO 2 N(R 10 ) 2 , —NHCOOR 10 , —NHCONHR 10 , phenyl, naphthyl, heteroaryl and heterocyclyl groups; wherein
said W heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said W heteroaryl is attached through a ring atom selected from C or N,
said W heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said W heterocyclyl is attached through a ring atom selected from C or N;
R 8 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclic, heteroaryl(C 1 -C 4 alkyl), and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 8 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 8 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 8 heteroaryl is attached through a ring atom selected from C or N,
each R 8 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 8 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 8 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
R 9 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclyl, heteroaryl(C 1 -C 4 alkyl), or heterocyclyl(C 1 -C 8 alkyl) groups, wherein
said R 9 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 9 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 9 heteroaryl is attached through a ring atom selected from C or N,
each R 9 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 9 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 9 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S, and
R 8 and R 9 may be taken together, with the N to which they are attached, to form a 4- to 8-membered monocyclic ring containing 0 to 2 additional heteroatoms independently selected from N, O and S;
each R 10 is independently selected from the group consisting of H and C 1 -C 6 alkyl;
each R 11 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 4 alkenyl, —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , —N(R 10 )(R 13 ), —R 14 , and —N(R 10 SO 2 R 6 ;
each R 12 is independently selected from the group consisting of —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , and —N(R 10 )(R 13 );
R 11 and R 12 may be taken together, with the phosphorus atom to which they are attached, to form a 5- to 7-membered monocyclic ring;
each V is independently selected from the group consisting of —CH(R 15 )— and —(C 1 -C 4 alkylene)-CH(R 15 )—;
each R 13 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, wherein
when R 13 is not H, said R 13 is substituted with 0 to 2 substituents independently selected from the group consisting of phenyl, naphthyl, phenyl(C 1 -C 4 alkyl), naphthyl(C 1 -C 4 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 4 alkyl), heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, heterocyclyl(C 1 -C 4 alkyl), C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 13 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 13 heteroaryl is attached through a ring atom selected from C or N,
each R 13 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 13 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 13 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
R 14 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
each R 14 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 14 heteroaryl is attached through a ring atom selected from C or N, and
said R 14 phenyl, naphthyl or heteroaryl may be substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ; and
each R 15 is independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, phenyl, naphthyl, heteroaryl, and heterocyclyl groups, wherein
said R 15 are substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
each R 15 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 15 heteroaryl is attached through a ring atom selected from C or N,
each R 15 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 15 heterocyclyl is attached through a ring atom selected from C or N, and
2 adjacent substituents of said R 15 are optionally taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.