US 7,321,063 B2
Sulfonamide inhibitors of aspartyl protease
Roger D Tung, Arlington, Mass. (US); Mark A Murcko, Holliston, Mass. (US); and Govinda R Bhisetti, Lexington, Mass. (US)
Assigned to Vertex Pharmaceuticals Incorporated, Cambridge, Mass. (US)
Filed on Feb. 24, 2004, as Appl. No. 10/786,997.
Application 10/094763 is a division of application No. 09/409808, filed on Sep. 30, 1999, granted, now 6,392,046.
Application 09/409808 is a division of application No. 09/115394, filed on Jul. 14, 1998, granted, now 5,977,137.
Application 09/115394 is a division of application No. 08/393460, filed on Feb. 23, 1995, granted, now 5,783,701.
Application 10/786997 is a continuation of application No. 10/094763, filed on Mar. 08, 2002, granted, now 6,720,335.
Application 08/393460 is a continuation in part of application No. 08/142327, filed on Nov. 24, 1993, granted, now 5,585,397.
Application 08/142327 is a continuation in part of application No. 07/941982, filed on Sep. 08, 1992, abandoned.
Prior Publication US 2004/0167116 A1, Aug. 26, 2004
Int. Cl. C07L 311/04 (2006.01); C07L 311/01 (2006.01)
U.S. Cl. 564—80  [546/336; 546/337; 546/169; 514/311; 514/312; 514/345; 514/350; 574/376; 574/424; 564/84; 564/86; 564/87; 564/88; 564/90; 564/95; 564/96; 564/97] 7 Claims
 
1. A compound of formula I:

OG Complex Work Unit Drawing
wherein:
A is selected from the group consisting of —R1—C1-C6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C4 alkoxy, —NR2—CO—N(R2)(R2) and —CO—N(R2)(R2);
each R1 is independently selected from the group consisting of —C(O)—, —S(O)2—, —C(O)—C(O)—, —O—C(O)—, —O—S(O)2, —NR2—S(O)2—, —NR2—C(O)— and —NR2—C(O)—C(O)—;
each R2 is independently selected from the group consisting of H and C1-C3 alkyl optionally substituted with Ar; with the proviso that when R2 is C1-C3 alkyl substituted with Ar, said Ar may not be substituted with an Ar-containing moiety;
B, when present, is —N(R2)—C(R3)(R3)—C(O)—;
x is 0 or 1;
each R3 is independently selected from the group consisting of H, Het, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl and C5-C6 cycloalkenyl, wherein any member of said R3, except H, may be optionally substituted with one or more substituents selected from the group consisting of —OR2, —C(O)—NH—R2, —S(O)n—N(R2)(R2), Het, —CN, —SR2, —CO2R2, NR2—C(O)—R2;
each n is independently 1 or 2;
D and D′ are independently selected from the group consisting of Ar; C1-C4 alkyl, which may be optionally substituted with one or more groups selected from C3-C6 cycloalkyl, —OR2, —R3, —O—Ar and Ar; C2-C4 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of C3-C6 cycloalkyl, —OR2, —R3, —O—Ar and Ar; C3-C6 cycloalkyl, which may be optionally substituted with or fused with Ar; and C5-C6 cycloalkenyl, which may be optionally substituted with or fused with Ar;
each Ar is independently selected from the group consisting of phenyl; 3-6 membered carbocyclic ring, wherein said carbocyclic ring may be saturated or unsaturated and optionally substituted with one or more groups selected from the group consisting of oxo, —OR2, —R2, —N(R2)(R2), —N(R2)—C(O)—R2, C1-C3 alkyl substituted with —OH and optionally substituted with Ar, —CN, —CO2R2, —C(O)—N(R2)(R2), halo and —CF3;
E is selected from the group consisting of Het; O-Het; Het-Het; —O—R3; —NR2R3; C1-C6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of R4 and Het; C2-C6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of R4 and Het; C3-C6 saturated carbocycle, which may optionally be substituted with one or more groups selected from the group consisting of R4 and Het; and C5-C6 unsaturated carbocycle, which may optionally be substituted with one or more groups selected from the group consisting of R4 and Het;
each Het is independently selected from the group consisting of C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C6-C10 aryl; and 5-7 membered saturated or unsaturated heterocycle, containing one heteroatom selected from N, N(R2), O, S and S(O)n, wherein said heterocycle may optionally be benzofused; and wherein any member of said Het may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR2, —R2, —N(R2)(R2), —R2—OH, —CN, —CO2R2, —C(O)—N(R2)(R2), —S(O)2—N(R2)(R2), —N(R2)—C(O)—R2, —C(O)—R2, —S(O)n—R2, —OCF3, —S(O)n—Ar, methylenedioxy, —N(R2)—S(O)2(R2), halo, —CF3, —NO2, Ar and —O—Ar; and
each R4 is independently selected from the group consisting of —OR2, —C(O)—NHR2, —S(O)2—NHR2, halo, —NR2—C(O)—R2 and —CN.