Substituted diphenyl isoxazoles, pyrazoles and oxadiazoles useful for treating HCV infection
View Patent ↗The present invention relates to substituted diphenyl heterocycle compounds and pharmaceutical compositions thereof that inhibit replication of HCV virus. The present invention also relates to the use of the compounds and/or compositions to inhibit HCV replication and/or proliferation and to treat or prevent HCV infections.
1. A compound according to structural formula (I):
including the pharmaceutically acceptable salts, hydrates, solvates, N-oxides and prodrugs thereof, wherein:
X and Y are each, independently of one another, N or O, provided that X and Y are not both O;
Z is N or —CH—, provided that Z is —CH— when X and Y are both N;
R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 and R 13 are each, independently of one another, selected from the group consisting of hydrogen, —OH, —SH, —CN, —NO 2 , halo, fluoro, chloro, bromo, iodo, lower alkyl, substituted lower alkyl, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, lower haloalkyl, monohalomethyl, dihalomethyl, trihalomethyl, trifluoromethyl, lower alkylthio, substituted lower alkylthio, lower alkoxy, substituted lower alkoxy, methoxy, substituted methoxy, lower heteroalkoxy, substituted lower heteroalkoxy, cycloalkoxy, substituted cycloalkoxy, lower haloalkoxy, monohalomethoxy, dihalomethoxy, trihalomethoxy, trifluoromethoxy, amino, lower di- or monoalkylamino, substituted lower di- or monoalkylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, phenoxy, substituted phenoxy, arylalkyl, substituted arylalkyl, arylalkyloxy, substituted arylalkyloxy, benzyl, benzyloxy, carboxyl, lower alkoxycarbonyl, substituted lower alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, arylalkyloxycarbonyl, substituted arylalkyloxycarbonyl, carbamate, substituted carbamate, carbamoyl, substituted carbamoyl, sulfamoyl, substituted sulfamoyl and a group of the formula -L-R 14 , where “L” is a linker and R 14 is cycloalkyl, or substituted cycloalkyl;
R 11 is hydrogen or lower alkyl;
R 12 is dihalomethyl;
L is a linker; and
R 16 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, lower haloalkyl, monohalomethyl, dihalomethyl, trihalomethyl, trifluoromethyl, lower alkylthio, substituted lower alkylthio, lower alkoxy, substituted lower alkoxy, lower heteroalkoxy, substituted lower heteroalkoxy, cycloalkoxy, substituted cycloalkoxy, lower haloalkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, arylalkyl, substituted arylalkyl, arylalkyloxy, substituted arylalkyloxy, benzyl, benzyloxy, carboxyl, lower alkoxycarbonyl, substituted lower alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, arylalkyloxycarbonyl, substituted arylalkyloxycarbonyl, carbamate, substituted carbamate, carbamoyl, substituted carbamoyl, sulfamoyl, substituted sulfamoyl and a group of the formula -L-R 14 , where “L” is a linker and R 14 is cycloalkyl, or substituted cycloalkyl, with the provisios that
for (A), R 16 , is not a lower alkyl group;
for (B), R 16 , is not a cycloheteroalkyl; and
for (C), R 16 is not hydrogen.
2. The compound of claim 1 in which R 2 is Cl.
3. The compound of claim 2 in which R 11 is hydrogen and R 12 is dichloromethyl.
4. The compound of claim 2 in which Z is CH.
5. The compound of claim 3 in which X is O and Y is N.
6. The compound of claim 3 in which X is N and Y is O.
7. The compound of claim 3 in which X and Y are each N.
8. The compound of claim 2 in which Z is N.
9. The compound of any one of claims 2 – 8 in which R 8 , R 9 , R 10 and R 13 are each hydrogen.
10. The compound of any one of claims 2 – 8 in which R 3 , R 4 and R 5 are each hydrogen.
11. The compound of claim 1 in which R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 and R 13 are selected from the following:
Cmpd
R 2
R 3
R 4
R 5
R 6
R 8
R 9
R 10
R 13
500
Cl
H
H
H
H
H
H
H
503
Cl
H
H
H
H
H
H
H
504
Cl
H
H
H
H
H
H
H
505
Cl
H
H
H
H
H
H
H
509
Cl
H
H
H
H
H
H
H
510
Cl
H
H
H
H
H
H
H
511
Cl
H
H
H
H
H
H
H
514
Cl
H
H
H
H
H
H
H
516
Cl
H
H
H
H
H
H
H
518
Cl
H
H
H
H
H
H
H
524
Cl
H
H
H
H
H
H
H
527
Cl
H
H
H
H
H
H
H
528
Cl
H
H
H
H
H
H
H
529
Cl
H
H
H
H
H
H
H
531
Cl
H
H
H
H
H
H
H
532
Cl
H
H
H
H
H
H
H
533
Cl
H
H
H
H
H
H
H
534
Cl
H
H
H
H
H
H
H
535
Cl
H
H
H
H
H
H
H
540
Cl
H
H
H
H
H
H
H
541
Cl
H
H
H
H
H
H
H
546
Cl
H
H
H
H
H
H
H
547
Cl
H
H
H
H
H
H
H
548
Cl
H
H
H
H
H
H
H
549
Cl
H
H
H
H
H
H
H
551
Cl
H
H
H
H
H
H
H
557
Cl
H
H
H
H
H
H
H
559
Cl
H
H
H
H
H
H
H
562
Cl
H
H
H
H
H
H
H
565
Cl
H
H
H
H
H
H
H
566
Cl
H
H
H
H
H
H
H
567
Cl
H
H
H
H
H
H
H
568
Cl
H
H
H
H
H
H
H
569
Cl
H
H
H
H
H
H
H
570
Cl
H
H
H
H
H
H
H
571
Cl
H
H
H
H
H
H
H
573
Cl
H
H
H
H
H
H
H
574
Cl
H
H
H
H
H
H
H
575
Cl
H
H
H
H
H
H
H
576
Cl
H
H
H
H
H
H
H
577
Cl
H
H
H
H
H
H
H
578
Cl
H
H
H
H
H
H
H
579
Cl
H
H
H
H
H
H
H
580
Cl
H
H
H
H
H
H
H
581
Cl
H
H
H
H
H
H
H
582
Cl
H
H
H
H
H
H
H
583
Cl
H
H
H
H
H
H
H
584
Cl
H
H
H
H
H
H
H
585
Cl
H
H
H
H
H
H
H
586
Cl
H
H
H
H
H
H
H
587
Cl
H
H
H
H
H
H
H
589
Cl
H
H
H
H
H
H
H
590
Cl
H
H
H
H
H
H
H
591
Cl
H
H
H
H
H
H
H
592
Cl
H
H
H
H
H
H
H
593
Cl
H
H
H
H
H
H
H
595
Cl
H
H
H
H
H
H
H
596
Cl
H
H
H
H
H
H
H
597
Cl
H
H
H
H
H
H
H
604
Cl
H
H
H
H
H
H
H
605
Cl
H
H
H
H
H
H
H
611
H
H
H
H
H
H
H
H
612
H
H
H
H
H
H
H
H
616
Cl
H
H
H
H
H
H
H
617
Cl
H
H
H
H
H
H
H
618
Cl
H
H
H
H
H
H
H
619
Cl
H
H
H
H
H
H
H
620
Cl
H
H
H
H
H
H
H
622
Cl
H
H
H
H
H
H
H
624
Cl
H
H
H
H
H
H
H
625
Cl
H
H
H
H
H
H
H
626
Cl
H
H
H
H
H
H
H
627
Cl
H
H
H
H
H
H
H
628
Cl
H
H
H
H
H
H
H
629
Cl
H
H
H
H
H
H
H
630
Cl
H
H
H
H
H
H
H
632
Cl
H
H
H
H
H
H
H
634
Cl
H
H
H
H
H
H
H
635
Cl
H
H
H
H
H
H
H
636
Cl
H
H
H
H
H
H
H
637
Cl
H
H
H
H
H
H
H
638
Cl
H
H
H
H
H
H
H
639
Cl
H
H
H
H
H
H
H
640
Cl
H
H
H
H
H
H
H
641
Cl
H
H
H
H
H
H
H
642
Cl
H
H
H
H
H
H
H
644
Cl
H
H
H
H
H
H
H
645
Cl
H
H
H
H
H
H
H
647
Cl
H
H
H
H
H
H
H
648
Cl
H
H
H
H
H
H
H
649
Cl
H
H
H
H
H
H
H
651
Cl
H
H
H
H
H
H
H
654
Cl
H
H
H
H
H
H
H
655
Cl
H
H
H
H
H
H
H
657
Cl
H
H
H
H
H
H
H
658
Cl
H
H
H
H
H
H
H
659
Cl
H
H
H
H
H
H
H
660
Cl
H
H
H
H
H
H
H
661
Cl
H
H
H
H
H
H
H
662
Cl
H
H
H
H
H
H
H
663
Cl
H
H
H
H
H
H
H
664
Cl
H
H
H
H
H
H
H
665
Cl
H
H
H
H
H
H
H
670
Cl
H
H
H
H
H
H
H
671
Cl
H
H
H
H
H
H
H
672
Cl
H
H
H
H
H
H
H
673
Cl
H
H
H
H
H
H
H
674
Cl
H
H
H
H
H
H
H
675
Cl
H
H
H
H
H
H
H
676
Cl
H
H
H
H
H
H
H
679
Cl
H
H
H
H
H
H
H
681
Cl
H
H
H
H
H
H
H
682
Cl
H
H
H
H
H
H
H
683
Cl
H
H
H
H
H
H
H
684
Cl
H
H
H
H
H
H
H
685
Cl
H
H
H
H
H
H
H
689
Cl
H
H
H
H
H
H
H
690
Cl
H
H
H
H
H
H
H
697
Cl
H
H
H
H
H
H
H
and
698
Cl
H
H
H
H
H
H
H.
12. The compound of claim 11 which is selected from a corresponding pyrazole, isoxazole or oxadiazole analog or regioisomer thereof.
13. The compound of claim 12 which inhibits HCV replication and/or proliferation with an IC 50 of 10 μM or less, as measured in an in vitro assay.
14. A composition comprising a pharmaceutically acceptable vehicle and a compound according to claim 1 .
15. The composition of claim 14 which is a liposome suspension.
16. The composition of claim 15 which comprises from about 0.5–30 mg/ml of the compound and about 100–200 mg/ml of a phospholipid in water.
17. The composition of claim 16 which further includes about 5 mg/ml of cholesterol.