US2017313745A1PendingUtilityA1
Inhibitors of hepatitis c virus
Est. expiryMar 15, 2033(~6.6 yrs left)· nominal 20-yr term from priority
Inventors:Kyla BjornsonKapil Kumar KarkiJohn O. LinkHyung-Jung PyunAdam J. SchrierKirk L. StevensJames G. TaylorRandall W. VivianJeff ZablockiSheila Zipfel
A61P 31/20A61P 31/14A61P 1/16C07D 498/22C07D 487/00C07D 487/02A61K 31/437A61K 31/519C07K 7/64C07D 203/02
47
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Claims
Abstract
Compounds of formula I: or pharmaceutically acceptable salts thereof, wherein the various substituents are defined herein, methods of using said compounds, and pharmaceutical compositions containing said compounds.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
is T 1 , T 2 , T 3 , T 4 , T 5 , or T 6 ;
L is L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 or L 12 ;
X is —O—, —CH 2 —, —OC(O)—, —C(O)O—, —C(O)—, —SO 2 —, —S(O)—, —N(R 16 )—, —S—, ═N—O— or a bond;
M is a bond, C 1 -C 6 alkylene, —O—, or —N(R 16 )—;
Q is Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 or Q 7 ;
E is E 1 , E 2 , E 3 , E 4 , E 5 , or E 6 ;
is aryl, heteroaryl or heterocyclic group wherein is optionally substituted with 1-4 W groups;
J is —O—, —CH 2 —, —CF 2 —, —C(O)—, or —N(R 16 )—;
G is —CO 2 H, —CONHSO 2 Z 2 , tetrazolyl, —CONHP(O)(R 16 ) 2 , —P(O)(OH)(R 16 ), or —P(O)(R 16 ) 2 ;
T 1 is C 5 -C 12 spiro bicyclic carbocyclene that is attached to J and M through two adjacent carbons, wherein said spiro bicyclic carbocyclene is optionally substituted with 1-4 Z 1 groups;
T 2 is C 5 -C 12 fused bicyclic carbocyclene that is attached to J and M through two adjacent carbons, wherein said fused bicyclic carbocyclene is optionally substituted with 1-4 Z 1 groups;
T 3 is C 5 -C 12 bridged bicyclic carbocyclene that is attached to J and M through two adjacent carbons, wherein said bridged bicyclic carbocyclene is optionally substituted with 1-4 Z 1 groups;
T 4 is C 5 -C 12 spiro bicyclic heterocyclene that is attached to J and M through two adjacent atoms, wherein said spiro bicyclic heterocyclene is optionally substituted with 1-4 Z 1 groups;
T 5 is C 5 -C 12 fused bicyclic heterocyclene that is attached to J and M through two adjacent atoms, wherein said fused bicyclic heterocyclene is optionally substituted with 1-4 Z 1 groups;
T 6 is C 5 -C 12 bridged bicyclic heterocyclene that is attached to J and M through two adjacent atoms, wherein said bridged bicyclic heterocyclene is optionally substituted with 1-4 Z 1 groups;
L 1 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene;
L 2 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene wherein said C 1 -C 8 alkylene or said C 2 -C 8 alkenylene is substituted with 1-4 halogen atoms;
L 3 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene wherein said C 1 -C 8 alkylene or said C 2 -C 8 alkenylene is substituted with 1-4 Z 3 groups and wherein said C 1 -C 8 alkylene or C 2 -C 8 alkenylene is optionally substituted with 1-4 halogen atoms;
L 4 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene substituted with two geminal C 1 -C 4 alkyl groups that come together to form a spiro C 3 -C 8 cycloalkyl group, wherein L 4 is optionally substituted with 1-4 Z 1 groups;
L 5 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene substituted with two geminal Z 1 groups that come together to form a spiro 4-8 membered heterocyclyl group, wherein L 5 is optionally substituted with 1-4 additional Z 1 groups;
L 6 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene;
L 7 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene, wherein the carbon atoms of said heteroalkylene or heteroalkenylene is substituted with 1-4 halogen atoms;
L 8 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene, wherein said heteroalkylene or heteroalkenylene is substituted with 1-4 Z 3 groups and said heteroalkylene or heteroalkenylene is optionally substituted with 1-4 halogen atoms;
L 9 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene substituted with two geminal C 1 -C 4 alkyl groups that come together to form a spiro C 3 -C 8 carbocyclyl group, wherein said L 9 is optionally substituted with 1-4 Z 1 groups;
L 10 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene substituted with two geminal Z 1 groups that come together to form a spiro 4-8 membered heterocyclyl group, wherein L 10 is optionally substituted with 1-4 additional Z 1 groups;
L 11 is L 11A -L 11B -L 11C where L 11A and L 11C are each independently selected from C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, C 2 -C 6 alkenylene or a bond and L 11B is a 3- to 6-membered saturated or unsaturated ring containing 0 to 3 heteroatoms selected from N, O, or S, wherein L 11A and L 11C connect to L 11B at two different ring atoms and L 11 is optionally substituted with 1-4 Z 1 groups;
L 12 is C 3 -C 8 alkynylene that is optionally substituted with 1-4 Z 1 groups;
Q 1 is H, C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein when Q 1 is not H, said Q 1 is optionally substituted with 1-3 substituents independently selected from halogen, —OR 6 , —SR 6 , —N(R 6 ) 2 , C 6 -C 10 aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —CN, —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 6 SO 2 Z 2 , —SO 2 NR 17 R 18 , —NHCOOR 16 , —NHCOZ 2 , —NHCONHR 16 , —CO 2 R 6 , —C(O)R 6 , or —CON(R 6 ) 2 ;
Q 2 is C 5 -C 10 spiro bicyclic carbocyclyl that is optionally substituted with 1-4 Z 1 groups;
Q 3 is C 5 -C 10 fused bicyclic carbocyclyl that is optionally substituted with 1-4 Z 1 groups;
Q 4 is C 5 -C 10 bridged bicyclic carbocyclyl that is optionally substituted with 1-4 Z 1 groups;
Q 5 is 4-8 membered heterocyclyl having 1 heteroatom selected from N, O or S wherein Q 5 is optionally substituted with 1-4 Z 1 groups;
Q 6 is C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein Q 6 is substituted with 1 oxo group and optionally substituted with 1 to 3 substituents independently selected from halogen, —OR 6 , —SR 6 , —N(R 6 ) 2 , C 6 -C 10 aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 6 SO 2 Z 2 , —SO 2 NR 17 R 18 , —NHCOOR 16 , —NHCOZ 2 , —NHCONHR 16 , —CO 2 R 6 , —C(O)R 6 , and —CON(R 6 ) 2 ;
Q 7 is selected from C 3 -C 8 carbocyclyl, wherein Q 7 is substituted with 4-8 F atoms and each carbon of Q 7 is substituted with 0-2 F atoms;
E 1 is C 2 -C 6 alkenyl;
E 2 is C 1 -C 6 alkyl;
E 3 is C 1 -C 6 haloalkyl;
E 4 is C 2 -C 6 haloalkenyl;
E 5 is C 3 -C 6 carbocyclyl;
E 6 is C 1 -C 6 alkyl substituted with —OCH 3 , —OCD 3 , —OCF 3 , or —OCF 2 H;
W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 ;
W 1 is oxo, halogen, —OR 6 , C 1 -C 6 alkyl, —CN, —CF 3 , —SR 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —C(O)R 6 , —N(R 6 )C(O)R 6 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 carbocyclyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 6 ) 2 , —NR 6 (C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 6 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCONHR 6 , C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl or —O(4-10 membered heterocyclyl), wherein said C 1 -C 6 alkyl, C 3 -C 8 carbocyclyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), C 6 -C 10 aryl, 5-14 membered heteroaryl, or 4-10 membered heterocyclyl is optionally substituted with 1-4 Z 1c groups;
W 2 is C 1 -C 6 alkoxy substituted with a 5-14 membered heteroaryl or C 6 -C 10 aryl; wherein said heteroaryl or aryl is substituted with 1-4 Z 1c groups;
W 3 is C 2 -C 6 alkynyl substituted with an C 6 -C 10 aryl, C 3 -C 8 carbocyclyl, C 1 -C 8 alkyl, C 1 -C 6 haloalkyl, 4-10 membered heterocyclyl, or 5-14 membered heteroaryl; wherein said aryl, carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl is optionally substituted with 1-4 Z 1 groups;
W 4 is —SF 5 ;
W 5 is —O(C 2 -C 6 alkyl)OR 22 wherein R 22 is an C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl that is optionally substituted with 1-4 Z 1 groups;
W 6 is —O(C 2 -C 6 alkyl)NR 16 R 22 wherein R 22 is an C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl that is optionally substituted with 1-4 Z 1 groups;
W 7 is —O(5-14 membered heteroaryl); wherein said —O(5-14 membered heteroaryl) is optionally substituted with 1-4 Z 1 groups and 2 adjacent substituents of said —O(5-14 membered heteroaryl) may be taken together to form a 3- to 6-membered cyclic ring containing 0 to 3 heteroatoms independently selected from N, O, or S;
R 6 is H, C 1 -C 6 alkyl or C 6 -C 10 aryl, wherein said C 6 -C 10 aryl or C 1 -C 6 alkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 8 carbocyclyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, halo(C 1 -C 6 alkoxy), —OH, —O(C 1 -C 6 alkyl), —SH, —S(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —C(O)(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —NHCOO(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCONH(C 1 -C 6 alkyl), —CO 2 (C 1 -C 6 alkyl), and —C(O)N(C 1 -C 6 alkyl) 2 ;
R 16 is H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, wherein said C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl of R 16 is optionally substituted with 1-4 Z 1c groups;
R 17 and R 18 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, —C(O)R 16 , —C(O)OR 16 , C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of R 17 or R 18 is optionally substituted with 1-4 Z 1c groups, or R 17 and R 18 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl group, wherein said 4-7 membered heterocyclyl group is optionally substituted with 1-4 Z 1c groups;
each Z 1 is independently oxo, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R 16 , —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)R 16 , —NR 16 C(O)NR 17 R 18 , —NR 16 S(O) 2 R 16 , —NR 16 S(O) 2 NR 17 R 18 , —NR 16 S(O) 2 OR 16 , —OR 16 , —OC(O)R 16 , —OC(O)NR 17 R 18 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 or —S(O) 2 NR 17 R 18 wherein said alkyl, alkenyl, alkynyl, carbocyclyl, bicyclic carbocyclyl, aryl, heteroaryl or heterocyclyl of Z 1 is optionally substituted with 1-4 Z 1a groups;
each Z 1a is independently oxo, halogen, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R 16 , —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)R 16 , —NR 16 C(O)OR 16 , —NR 16 C(O)NR 17 R 18 , —NR 16 S(O) 2 R 16 , —NR 16 S(O) 2 NR 17 R 18 , —NR 16 S(O) 2 OR 16 , —OR 16 , —OC(O)R 16 , —OC(O)NR 17 R 18 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 or —S(O) 2 NR 17 R 18 wherein said alkenyl, alkynyl, carbocyclyl, bicyclic carbocyclyl, aryl, heteroaryl or heterocyclyl of Z 1a is optionally substituted with 1-4 Z 1c groups;
each Z 1c is independently oxo, halogen, C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)(C 1 -C 8 alkyl), —C(O)O(C 1 -C 8 alkyl), —C(O)N(C 1 -C 8 alkyl) 2 , —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —NHC(O)O(C 1 -C 8 alkyl), —NHC(O)(C 1 -C 8 alkyl), —NHC(O)NH(C 1 -C 8 alkyl), —OH, —O(C 1 -C 8 alkyl), C 3 -C 8 cycloalkoxy, C 5 -C 10 bicyclic carbocyclyloxy, —S(C 1 -C 8 alkyl) or —S(O) 2 N(C 1 -C 8 alkyl) 2 wherein said alkyl, carbocyclyl, bicyclic carbocyclyl, aryl, heteroaryl, heterocyclyl or cycloalkoxy portion of Z 1c is optionally substituted with 1-4 halogen atoms or C 1 -C 6 alkoxy groups;
each Z 2 is independently C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —NR 17 R 18 or —OR 16 wherein any alkyl, carbocyclyl, bicyclic carbocyclyl, aryl, heteroaryl or heterocyclyl portion of Z 2 is optionally substituted with 1-4 Z 2a groups;
each Z 2a is independently hydrogen, oxo, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, -(C 2 -C 8 alkynyl)aryl, -(C 2 -C 8 alkynyl)heteroaryl, —CN, —C(O)(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)O(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)NH(C 1 -C 6 alkyl), —OH, —O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), C 3 -C 8 cycloalkoxy, —S(C 1 -C 6 alkyl), or —SO 2 N(C 1 -C 6 alkyl) 2 ; wherein any alkyl, alkynyl, carbocyclyl, cycloalkoxy, bicyclic carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z 2a is optionally substituted with 1-4 halogen or C 1 -C 6 alkoxy groups;
each Z 3 is independently oxo, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)NR 17 R 18 , —OR 16 , —SR 16 or —SO 2 R 16 , wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portion of Z 3 is optionally substituted with 1-4 halogen.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M is —O— or a direct bond.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —OC(O)—, —O—, or a direct bond.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is —CO 2 H or —CONHSO 2 Z 2 .
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is:
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein is T 1 , T 2 , or T 3 .
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein is T 1 , T 2 , or T 3 ; and wherein
T 1 is
T 2 is
T 3 is
wherein T 1 , T 2 , or T 3 is optionally substituted with 1-4 Z 1 groups.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein is T 2 , and wherein T 2 is optionally substituted with 1-4 Z 1 groups.
9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein T 2 is:
10 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein T 2 is:
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein J is —O— or —N(R 16 )—.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein J is selected from —CH 2 —, —CF 2 —, or —C(O)—.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein J is selected from —CH 2 — or —CF 2 —.
14 . A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
L is L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 or L 12 ;
Q is Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 or Q 7 ;
E is E 1 , E 2 , E 3 , E 4 , E 5 , or E 6 ;
J is —CH 2 — or —CF 2 —;
is U 1 , U 2 , U 3 , U 4 , U 5 , U 6 , U 7 or U 8 ;
L 1 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene;
L 2 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene wherein said C 1 -C 8 alkylene or said C 2 -C 8 alkenylene is substituted with 1-4 halogen atoms;
L 3 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene wherein said C 1 -C 8 alkylene or said C 2 -C 8 alkenylene is substituted with 1-4 Z 3 groups and wherein said C 1 -C 8 alkylene or C 2 -C 8 alkenylene is optionally substituted with 1-4 halogen atoms;
L 4 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene substituted with two geminal C 1 -C 4 alkyl groups that come together to form a spiro C 3 -C 8 cycloalkyl group, wherein L 4 is optionally substituted with 1-4 Z 1 groups;
L 5 is C 1 -C 8 alkylene or C 2 -C 8 alkenylene substituted with two geminal Z 1 groups that come together to form a spiro 4-8 membered heterocyclyl group, wherein L 5 is optionally substituted with 1-4 additional Z 1 groups;
L 6 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene;
L 7 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene, wherein the carbon atoms of said heteroalkylene or heteroalkenylene is substituted with 1-4 halogen atoms;
L 8 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene, wherein said heteroalkylene or heteroalkenylene is substituted with 1-4 Z 3 groups and said heteroalkylene or heteroalkenylene is optionally substituted with 1-4 halogen atoms;
L 9 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene substituted with two geminal C 1 -C 4 alkyl groups that come together to form a spiro C 3 -C 8 carbocyclyl group, wherein said L 9 is optionally substituted with 1-4 Z 1 groups;
L 10 is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene substituted with two geminal Z 1 groups that come together to form a spiro 4-8 membered heterocyclyl group, wherein L 10 is optionally substituted with 1-4 additional Z 1 groups;
L 11 is L 11A -L 11B -L 11C wherein L 11A and L 11C are each independently selected from C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, C 2 -C 6 alkenylene or a bond and L 11B is a 3- to 6- membered saturated or unsaturated ring containing 0 to 3 heteroatoms selected from N, O, or S, wherein L 11A and L 11C connect to L 11B at two different ring atoms and L 10 is optionally substituted with 1-4 Z 1 groups;
L 12 is C 3 -C 8 alkynylene that is optionally substituted with 1-4 Z 1 groups;
Q 1 is H, C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein when Q 1 is not H, said Q 1 is optionally substituted with 1-3 substituents independently selected from halogen, —OR 6 , —SR 6 , —N(R 6 ) 2 , C 6 -C 10 aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —CN, —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 6 SO 2 Z 2 , —SO 2 NR 17 R 18 , —NHCOOR 16 , —NHCOZ 2 , —NHCONHR 16 , —CO 2 R 6 , —C(O)R 6 , or —CON(R 6 ) 2 ;
Q 2 is C 5 -C 10 spiro bicyclic carbocyclyl that is optionally substituted with 1-4 Z 1 groups;
Q 3 is C 5 -C 10 fused bicyclic carbocyclyl that is optionally substituted with 1-4 Z 1 groups;
Q 4 is C 5 -C 10 bridged bicyclic carbocyclyl that is optionally substituted with 1-4 Z 1 groups;
Q 5 is 4-8 membered heterocyclyl having 1 heteroatom selected from N, O or S wherein Q 5 is optionally substituted with 1-4 Z 1 groups;
Q 6 is selected from C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein Q 6 is substituted with 1 oxo group and with 0 to 3 substituents independently selected from halogen, —OR 6 , —SR 6 , —N(R 6 ) 2 , C 6 -C 10 aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 6 SO 2 Z 2 , —SO 2 NR 17 R 18 , —NHCOOR 16 , —NHCOZ 2 , —NHCONHR 16 , —CO 2 R 6 , —C(O)R 6 , or —CON(R 6 ) 2 ;
Q 7 is C 3 -C 8 carbocyclyl, wherein Q 7 is substituted with 4-8 F atoms and each carbon of Q 7 is substituted with 0-2 F atoms;
E 1 is C 2 -C 6 alkenyl;
E 2 is C 1 -C 6 alkyl;
E 3 is C 1 -C 6 haloalkyl;
E 4 is C 2 -C 6 haloalkenyl;
E 5 is C 3 -C 6 carbocyclyl;
E 6 is C 1 -C 6 alkyl substituted with —OCH 3 , —OCD 3 , —OCF 3 , or —OCF 2 H;
U 1 is
wherein each U 1 is optionally substituted with 1-2 W groups;
U 2 is
wherein each U 2 is optionally substituted with 1-2 W groups;
U 3 is
wherein each U 3 is optionally substituted with 1-2 W groups;
U 4 is
wherein each U 4 is optionally substituted with 1-2 W groups;
U 5 is
wherein each U 5 is optionally substituted with 1-2 W groups;
U 6 is
wherein each U 6 is optionally substituted with 1-2 W groups;
U 7 is
wherein each U 7 is optionally substituted with 1-2 W groups;
U 8 is
wherein each U 8 is optionally substituted with 1-2 W groups;
each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 ;
each W 1 is oxo, halogen, —OR 6 , C 1 -C 6 alkyl, —CN, —CF 3 , —SR 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —C(O)R 6 , —N(R 6 )C(O)R 6 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 carbocyclyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 6 ) 2 , —NR 6 (C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 6 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCONHR 6 , C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl or —O(4-10 membered heterocyclyl), wherein said W 1 alkyl, carbocyclyl, cycloalkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1-4 Z 1c groups;
each W 2 is C 1 -C 6 alkoxy substituted with a 5-14 membered heteroaryl or C 6 -C 10 aryl; wherein said heteroaryl or aryl is substituted with 1-4 Z 1c groups;
each W 3 is C 2 -C 6 alkynyl substituted with an C 6 -C 10 aryl, C 3 -C 8 carbocyclyl, C 1 -C 8 alkyl, C 1 -C 6 haloalkyl, 4-10 membered heterocyclyl, or 5-14 membered heteroaryl; wherein said aryl, carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl is optionally substituted with 1-4 Z 1 groups;
each W 4 is —SF 5 ;
each W 5 is —O(C 2 -C 6 alkyl)OR 22 wherein R 22 is an C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl that is optionally substituted with 1-4 Z 1 groups;
each W 6 is —O(C 2 -C 6 alkyl)NR 16 R 22 wherein R 22 is an C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl that is optionally substituted with 1-4 Z 1 groups;
each W 7 is —O(5-14 membered heteroaryl); wherein said —O(5-14 membered heteroaryl) is optionally substituted with 1-4 Z 1 groups and 2 adjacent substituents of said —O(5-14 membered heteroaryl) may be taken together to form a 3- to 6-membered cyclic ring containing 0 to 3 heteroatoms independently selected from N, O, or S;
each R 6 is independently selected from H, C 1 -C 6 alkyl or C 6 -C 10 aryl, wherein said aryl or alkyl is optionally substituted with 1 to 4 substituents independently selected from halogen atoms, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 8 carbocyclyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, halo(C 1 -C 6 alkoxy), —OH, —O(C 1 -C 6 alkyl), —SH, —S(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —C(O)(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —NHCOO(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCONH(C 1 -C 6 alkyl), —CO 2 (C 1 -C 6 alkyl), or —C(O)N(C 1 -C 6 alkyl) 2 ;
each R 16 is independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of R 16 is optionally substituted with 1-4 Z 1c groups;
R 17 and R 18 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, —C(O)R 16 , —C(O)OR 16 , C 6 -C 10 aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of R 17 or R 18 is optionally substituted with 1-4 Z 1c groups, or R 17 and R 18 together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl group, wherein said 4-7 membered heterocyclyl group is optionally substituted with 1-4 Z 1c groups;
each Z 1 is independently selected from oxo, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R 16 , —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)R 16 , —NR 16 C(O)NR 17 R 18 , —NR 16 S(O) 2 R 16 , —NR 16 S(O) 2 NR 17 R 18 , —NR 16 S(O) 2 OR 16 , —OR 16 , —OC(O)R 16 , —OC(O)NR 17 R 18 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 or —S(O) 2 NR 17 R 18 wherein any alkyl, alkenyl, alkynyl, carbocyclyl, bicyclic carbocyclyl, aryl, heteroaryl or heterocyclyl of Z 1 is optionally substituted with 1-4 Z 1a groups;
each Z 1a is independently selected from oxo, halogen, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R 16 , —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)R 16 , —NR 16 C(O)OR 16 , —NR 16 C(O)NR 17 R 18 , —NR 16 S(O) 2 R 16 , —NR 16 S(O) 2 NR 17 R 18 , —NR 16 S(O) 2 OR 16 , —OR 16 , —OC(O)R 16 , —OC(O)NR 17 R 18 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 or —S(O) 2 NR 17 R 18 wherein any alkenyl, alkynyl, carbocyclyl, bicyclic carbocyclyl, aryl, heteroaryl or heterocyclyl of Z 1a is optionally substituted with 1-4 Z 1c groups;
each Z 1c is independently selected from oxo, halogen, C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)(C 1 -C 8 alkyl), —C(O)O(C 1 -C 8 alkyl), —C(O)N(C 1 -C 8 alkyl) 2 , —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —NHC(O)O(C 1 -C 8 alkyl), —NHC(O)(C 1 -C 8 alkyl), —NHC(O)NH(C 1 -C 8 alkyl), —OH, —O(C 1 -C 8 alkyl), C 3 -C 8 cycloalkoxy, C 5 -C 10 bicyclic carbocyclyloxy, —S(C 1 -C 8 alkyl) or —S(O) 2 N(C 1 -C 8 alkyl) 2 wherein any alkyl, carbocyclyl, bicyclic carbocyclyl, aryl, heteroaryl, heterocyclyl or cycloalkoxy portion of Z 1c is optionally substituted with 1-4 halogen atoms or C 1 -C 6 alkoxy groups;
each Z 2 is independently selected from C 1 -C 8 alkyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —NR 17 R 18 or —OR 16 wherein any alkyl, carbocyclyl, bicyclic carbocyclyl, aryl, heteroaryl or heterocyclyl portion of Z 2 is optionally substituted with 1-4 Z 2a groups;
each Z 2a is independently selected from hydrogen, oxo, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, -(C 2 -C 8 alkynyl)aryl, -(C 2 -C 8 alkynyl)heteroaryl, —CN, —C(O)(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)O(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)NH(C 1 -C 6 alkyl), —OH, —O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), C 3 -C 8 cycloalkoxy, —S(C 1 -C 6 alkyl), or —SO 2 N(C 1 -C 6 alkyl) 2 ; wherein any alkyl, alkynyl, carbocyclyl, cycloalkoxy, bicyclic carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z 2a is optionally substituted with 1-4 halogen or C 1 -C 6 alkoxy groups;
each Z 3 is independently selected from oxo, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 5 -C 10 bicyclic carbocyclyl, C 1 -C 8 haloalkyl, C 6 -C 10 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)OR 16 , —C(O)NR 17 R 18 , —NR 17 R 18 , —NR 16 C(O)NR 17 R 18 , —OR 16 , —SR 16 or —SO 2 R 16 , wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portion of Z 3 is optionally substituted with 1-4 halogen.
15 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein: L is L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 or L 12 ; and wherein
L 1 is
L 2 is
L 3 is
L 4 is
L 5 is
L 6 is
L 7 is
L 8 is
L 9 is
L 10 is
L 11 is
L 12 is
16 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein L is
17 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein L is
18 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein L is
19 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein L is
20 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein L is
21 . The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein Z 2a is
22 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein Z 2a is
23 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein is optionally substituted with one W at any substitutable position, and each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 wherein is
24 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein is optionally substituted with one W at any substitutable position, and each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 wherein is
25 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein is optionally substituted with one W at any substitutable position, and each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 wherein is
26 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein is optionally substituted with one W at any substitutable position, and each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 wherein is
27 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein each W is independently W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 , and wherein
W 1 is
W 2 is
W 3 is
W 5 is
W 6 is
or
W 7 is
28 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein W is
29 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein W is
30 . The compound of claim 14 , or pharmaceutically acceptable salt thereof, wherein Q is Q 1 , Q 2 , Q 3 , Q 4 , Q 5 or Q 7 ; and wherein
Q 1 is
Q 2 is
Q 3 is
Q 4 is
Q 5 is
or
Q 7 is
31 . The compound of claim 14 , or pharmaceutically acceptable salt thereof, wherein Q is
32 . The compound of claim 14 , or pharmaceutically acceptable salt thereof, wherein Q is
33 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein E is E 1 , E 2 , E 3 , or E 4 and wherein:
E 1 is
E 2 is
E 3 is
E 4 is
34 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein E is E 3 .
35 . The compound of claim 14 , or pharmaceutically acceptable salt thereof, wherein E is
36 . The compound of claim 14 , or pharmaceutically acceptable salt thereof, wherein E is
37 . The compound of claim 14 , or pharmaceutically acceptable salt thereof, wherein E is
38 . The compound of claim 14 , or pharmaceutically acceptable salt thereof, wherein E is
39 . The compound of claim 14 , or pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIa):
40 . The compound of claim 14 , or pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIb):
41 . A compound of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
L is C 1 -C 8 alkylene, C 4 -C 8 carbocyclylalkylene or C 2 -C 8 alkenylene wherein said C 1 -C 8 alkylene, C 4 -C 8 carbocyclylalkylene, or said C 2 -C 8 alkenylene is optionally substituted with one or more R 25 , wherein each R 25 is independently selected from halogen, C 3 -C 6 carbocyclyl, 3 to 6 membered heteroalkyl, —OH, or oxo;
Q is H, C 1 -C 8 alkyl, 4-8 membered heterocyclyl, or C 3 -C 8 carbocyclyl wherein said C 1 -C 8 alkyl, 4-8 membered heterocyclyl, or C 3 -C 8 carbocyclyl is optionally substituted with one or more halogens.
E is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, wherein E is optionally substituted with or more halogen atoms;
J is —CH 2 — or —CF 2 —;
is a bicyclic or tricyclic aryl, heteroaryl or heterocyclyl, optionally substituted with 1-2 W groups;
each W is independently halogen, —OR 6 , C 1 -C 6 alkyl, —CN, —CF 3 , or C 1 -C 6 haloalkyl;
each R 6 is independently selected from H, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; and
Z 2a is hydrogen or C 1 -C 4 alkyl.
42 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein J is —CH 2 .
43 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein L is C 3 -C 8 alkylene, C 4 -C 8 carbocyclylalkylene or C 3 -C 8 alkenylene, wherein L is optionally substituted with up to two halogen atoms.
44 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein: L is
45 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein L is
46 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein Z 2a is
47 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein is
and wherein is optionally substituted with one W at any substitutable position.
48 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein each W is Cl, F, −OCH 3 , —OCHF 2 , —OCF 3 or —CN.
49 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein Q is C 1 -C 6 alkyl, or C 3 -C 8 carbocyclyl.
50 . The compound of claim 41 , or pharmaceutically acceptable salt thereof, wherein Q is
51 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein E is C 1 -C 4 alkyl substituted with one or more halogen atoms.
52 . The compound of claim 41 , or pharmaceutically acceptable salt thereof, wherein E is
53 . The compound of claim 41 , or pharmaceutically acceptable salt thereof, wherein E is
54 . The compound of claim 41 , or pharmaceutically acceptable salt thereof, wherein E is
55 . The compound of claim 41 , or pharmaceutically acceptable salt thereof, wherein E is
56 . The compound of claim 41 , or pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIIa):
57 . The compound of claim 41 , or pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIIb):
58 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
59 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
60 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
61 . A method of treating HCV in a patient in need thereof, comprising administering to said patient a compound of claim 1 .Join the waitlist — get patent alerts
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