Details for Patent: 9,309,279

Title:	Macrocyclic hepatitis C serine protease inhibitors
Abstract:	The present invention relates to novel macrocyclic compounds and methods of treating a hepatitis C infection in a subject in need of such therapy with said macrocyclic compounds. The present invention further relates to pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts, esters, or prodrugs thereof, in combination with a pharmaceutically acceptable carrier or excipient.
Inventor(s):	Ku; Yiyin (Buffalo Grove, IL), McDaniel; Keith F. (Wauconda, IL), Chen; Hui-Ju (Grayslake, IL), Shanley; Jason P. (Chicago, IL), Kempf; Dale J. (Libertyville, IL), Grampovnik; David J. (Waukegan, IL), Sun; Ying (Waltham, MA), Liu; Dong (Newton, MA), Gai; Yonghua (North Grafton, MA), Or; Yat Sun (Watertown, MA), Wagaw; Seble H. (Evanston, IL), Engstrom; Kenneth (Mundelein, IL), Grieme; Tim (Chicago, IL), Sheikh; Ahmad (Deerfield, IL), Mei; Jianzhang (Lake Forest, IL)
Assignee:	AbbVie Inc. (Abbott Park, IL) Enanta Pharmaceuticals, Inc. (Boston, MA)
Filing Date:	Jan 31, 2014
Application Number:	14/170,199
Claims:	1. A method of preparing a compound of formula I, or a pharmaceutically acceptable salt thereof: ##STR00030## the method comprising deprotecting ##STR00031## to form ##STR00032## which is then reacted with H-G to form said compound, wherein PG.sub.N is an amino protecting group and PG.sub.C is a carboxylic acid protecting group; J is absent, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, --C(O)--, --O--C(O)--,--N(R.sub.3)--C(O)--, --C(S)--, --C(.dbd.NR.sub.4)--, --S(O)--, --S(O.sub.2)--, or --N(R.sub.3)--; A is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted carbocyclic; Each R.sub.1 is independently selected from (i) halogen, hydroxy, amino, --CN, --CF.sub.3, --N.sub.3, --NO.sub.2, --OR.sub.4, --SR.sub.4, --SOR.sub.4, --SO.sub.2R.sub.4, --N(R.sub.3)S(O).sub.2--R.sub.4, --N(R.sub.3) S(O.sub.2)NR.sub.3R.sub.4, --NR.sub.3R.sub.4, --C(O)OR.sub.4, --C(O)R.sub.4, --C(O)NR.sub.3R.sub.4, or --N(R.sub.3)C(O)R.sub.4; (ii) optionally substituted aryl; (iii) optionally substituted heteroaryl; (iv) optionally substituted heterocyclic; (v) optionally substituted carbocyclic; or (vi) optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; G is -E-R.sub.5; wherein E is absent; optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; or --O--, --S--, --N(R.sub.3)--, --N(R.sub.3)S(O.sub.p)--, --N(R.sub.3)C(O)--, --N(R.sub.3) C(O)S(O.sub.p)--, --OS(O.sub.p)--, --C(O)S(O.sub.p)--, or --C(O)N(R.sub.3)S(O.sub.p)--; p is 0, 1, or 2; R.sub.5 is H; optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; R.sub.3 and R.sub.4 are each independently selected at each occurrence from the following: optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen; L is absent or is selected from optionally substituted alkylene, optionally substituted alkenylene or optionally substituted alkynylene, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; Y is N or --C(R'')--; wherein A, R.sub.1, R' and/or R'' can be taken together form a ring; j=0, 1, 2, 3, or 4; k=0, 1, 2, or 3; m=0, 1, or 2; n is 0, 1, 2, 3, or 4; denotes a carbon-carbon single or double bond, wherein if Y is N, then R' is optionally substituted heterocyclic or optionally substituted carbocyclic, and comprises two or more fused rings, and wherein R' is not ##STR00033## wherein if Y is --C(R'')--, then R' and R'' taken together with the carbon atoms to which they are attached form an aryl or heteroaryl ring, each said ring is optionally substituted; provided that said compound is not tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-1- 4a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,- 14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopenta- decin-6-ylcarbamate. 2. The method of claim 1, wherein R' is H, Y is N, and wherein k=3, j=1, and L is absent. 3. The method of claim 2, wherein R.sub.1 is hydrogen or halogen, E is --NHS(O)-- or --NHS(O.sub.2)--, and R.sub.5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or imidazolyl, each of which is optionally substituted. 4. The method of claim 2, wherein J is --C(O)-- and A is optionally substituted --C.sub.1-C.sub.8 alkyl, containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted --C.sub.1-C.sub.8 alkoxy, optionally substituted heteroaryl, optionally substituted --C.sub.3-C.sub.12 cycloalkyl, or optionally substituted --C.sub.3-C.sub.12 heterocycloalkyl. 5. The method of claim 1, wherein Y is --C(R'')--, and R' and R'' taken together with the carbon atoms to which they are attached form an aryl or heteroaryl ring, each said ring is optionally substituted, and wherein k=3, j=1 and L is absent. 6. The method of claim 5, wherein R.sub.1 is hydrogen or halogen; E is --NHS(O)-- or --NHS(O.sub.2)--, and R.sub.5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or imidazolyl, each of which is optionally substituted. 7. The method of claim 5, wherein J is --C(O)-- and A is optionally substituted --C.sub.1-C.sub.8 alkyl, containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted --C.sub.1-C.sub.8 alkoxy, optionally substituted heteroaryl, optionally substituted --C.sub.3-C.sub.12 cycloalkyl, or optionally substituted --C.sub.3-C.sub.12 heterocycloalkyl. 8. The method of claim 5, wherein R' and R'' together form an optionally substituted aryl. 9. The method of claim 5, wherein R' and R'', and the atoms to which each is attached, form an aryl which is substituted by (R.sub.2).sub.x, wherein each R.sub.2 is independently selected from (i) halogen, hydroxy, amino, --CN, --CF.sub.3, --N.sub.3, --NO.sub.2, --OR.sub.4, --SR.sub.4, --SOR.sub.4, --SO.sub.2R.sub.4, --NHS(O.sub.2)--R.sub.4, --NHS(O.sub.2)NR.sub.3R.sub.4, --NR.sub.3R.sub.4, --C(O)OR.sub.4, --C(O)R.sub.4, --C(O)NR.sub.3R.sub.4, or --N(R.sub.3)C(O)R4; (ii) optionally substituted aryl; (iii) optionally substituted heteroaryl; (iv) optionally substituted heterocyclic; (v) optionally substituted carbocyclic; or (iv) optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; and x is 0, 1, 2, 3, or 4. 10. The method of claim 1, wherein the compound of formula I is selected from the following: (2) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N- -(cyclopropylsulfonyl)-6-(isonicotinamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,1- 1,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazac- yclopentadecine-14a-carboxamide; (3) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N- -(cyclopropylsulfonyl)-6-(2-fluorobenzamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10- ,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diaz- acyclopentadecine-14a-carboxamide; (4) N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy- )-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,- 14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclope- ntadecin-6-yl)-5-methylisoxazole-3-carboxamide; (5) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N- -(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3- ,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,- 2-a][1,4]diazacyclopentadecine-14a-carboxamide; (6) N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy- )-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,- 14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclope- ntadecin-6-yl)isoxazole-5-carboxamide; (7) N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy- )-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,- 14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclope- ntadecin-6-yl)thiazole-4-carboxamide; (8) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N- -(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1- ,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrol- o[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide; (9) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N- -(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7- ,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1- ,4]diazacyclopentadecine-14a-carboxamide; (10) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N- -(cyclopropylsulfonyl)-6-(1,3-dimethyl-1H-pyrazole-4-carboxamido)-5,16-dio- xo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]py- rrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide; (11) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N- -(cyclopropylsulfonyl)-6-(3-fluorobenzamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10- ,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diaz- acyclopentadecine-14a-carboxamide; (12) tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-14a-(c- yclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,1- 5,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin- -6-ylcarbamate; (13) N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-14a- -(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14- a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentade- cin-6-yl)-5-methylisoxazole-3-carboxamide; (14) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyc- lopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3,5,6,- 7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][- 1,4]diazacyclopentadecine-14a-carboxamide; (15) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyc- lopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,- 5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2- -a][1,4]diazacyclopentadecine-14a-carboxamide; (16) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyc- lopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,- 2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo- [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide; and (17) (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyc- lopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,- 10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]di- azacyclopentadecine-14a-carboxamide. 11. The method of claim 1, wherein the compound of formula I is selected from the following: (24) tert-butyl (2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-- (phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadec- ahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate; (25) (2R,6S,13aS,14aR,16aS,Z)--N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phen- anthridin-6-yloxy)-6-(pyrazine-2-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14- ,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopent- adecine-14a-carboxamide; (26) Cyclopentyl (2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-- (phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadec- ahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate; (27) (2R,6S,13aS,14aR,16aS,Z)--N-(cyclopropylsulfonyl)-6-(5-methyl-1H-pyr- azole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,- 10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]di- azacyclopentadecine-14a-carboxamide; (28) N-((2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo- -2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexa- decahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-meth- ylisoxazole-3-carboxamide; (29) (2R,6S,13aS,14aR,16aS,Z)--N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-c- arboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a- ,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclop- entadecine-14a-carboxamide; (30) N-((2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo- -2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexa- decahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)thiazol- e-5-carboxamide; (31) (2R,6S,13aS,14aR,16aS,Z)--N-(cyclopropylsulfonyl)-6-(2-fluorobenzamido)-5- ,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16- ,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14- a-carboxamide; (32) (2R,6S,13aS,14aR,16aS,Z)--N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthr- idin-6-yloxy)-6-(pyridazine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14- a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentade- cine-14a-carboxamide; (33) (2R,6S,13aS,14aR,16aS,Z)--N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthr- idin-6-yloxy)-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14- a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentade- cine-14a-carboxamide; (34) (2R,6S,13aS,14aR,16aS,Z)--N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole- -3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11- ,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacy- clopentadecine-14a-carboxamide; (35) (2R,6S,13aS,14aR,16aS,Z)--N-(cyclopropylsulfonyl)-6-(2-hydroxy-2-methylpr- opanamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,- 14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclope- ntadecine-14a-carboxamide; (36) (2R,6S,13aS,14aR,16aS,Z)--N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyra- zole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,1- 0,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]dia- zacyclopentadecine-14a-carboxamide; (37) Cyclopentyl (2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(2-fluoroph- enanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a- -hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcar- bamate; (38) tert-Butyl (2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(2,9-difluo- rophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a, 15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadec- in-6-ylcarbamate; (39) tert-butyl (2R,6S,13aR,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(p- henanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyc- lopentadecin-6-ylcarbamate; (40) Cyclopentyl (2R,6S,13aR,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(p- henanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyc- lopentadecin-6-ylcarbamate; and (41) tert-Butyl (2R,6S,13aR,14aR,16aS)-5,16-dioxo-2-(phenanthridin-6-yloxy)-14a-(thiophen- -2-ylsulfonylcarbamoyl)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazac- yclopentadecin-6-ylcarbamate. 12. The method of claim 1, wherein E is --N(R.sub.3)S(O.sub.p)--, R.sub.3 is H, p is 2, and R.sub.5 is optionally substituted carbocyclic. 13. The method of claim 12, wherein R.sub.5 is optionally substituted cyclopropyl. 14. The method of claim 1, wherein E is --N(R.sub.3)S(O.sub.p)--, R.sub.3 is H, p is 2, and R.sub.5 is optionally substituted heteroaryl. 15. The method of claim 1, wherein J is --C(O)-- and A is optionally substituted heteroaryl. 16. The method of claim 15, wherein A is substituted heteroaryl. 17. The method of claim 15, wherein A is pyrazinyl.