Claims for Patent: 7,674,810

Summary for Patent: 7,674,810

Title:	1,1-dioxo-1H-1.LAMBDA..sup.6-benzo[d]isothiazol-3-yl)-4-hydroxy-1,5-dihydr- o-pyrrol-2-one inhibitors of HCV polymerase
Abstract:	Compounds having the formula i wherein m, R.sup.1, R.sup.2, R.sup.4 and X.sup.1 are herein defined are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for inhibiting hepatitis replication, processes for making the compounds and synthetic intermediates used in the process. ##STR00001##
Inventor(s):	Blake; James F. (Longmont, CO), Fell; Jay Bradford (Longmont, CO), Fischer; John P. (Longmont, CO), Hendricks; Robert Than (San Carlos, CA), Spencer; Stacey Renee (Lyons, CO), Stengel; Peter J. (Longmont, CO)
Assignee:	Roche Palo Alto LLC (Palo Alto, CA)
Application Number:	11/413,872
Patent Claims:	1. A compound according to formula I ##STR00047## wherein: A is A-3; X.sup.1 is a bond; R.sup.1 in each occurrence is independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.1-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-6 alkoxy, optionally substituted phenyl, optionally substituted heteroaryl selected from the group consisting of pyridine, pyridone, pyrimidine, pyrimidone, pyrazole and imidazole, optionally substituted aryl-C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-3 alkoxy-C.sub.1-6 alkyl, optionally substituted phenoxy, optionally substituted phenyl-C.sub.1-3 alkoxy, C.sub.1-6 heteroalkoxy, hydroxyl, halogen, (CH.sub.2).sub.o.sub.1NR.sup.aR.sup.b, X.sup.2(CH.sub.2).sub.uNR.sup.aR.sup.b, X.sup.2(CH.sub.2).sub.o.sub.1COR.sup.9, X.sup.2(CH.sub.2).sub.o.sub.1SO.sub.2NR.sup.cR.sup.d, (CH.sub.2).sub.r.sub.1SO.sub.2R.sup.5, O(CH.sub.2).sub.o.sub.1SO.sub.2--C.sub.1-6 alkyl, COR.sup.9, nitro, and cyano wherein optionally substituted phenyl or heteroaryl groups are independently substituted with one to three substituents selected from the group consisting of C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, halogen, NR.sup.cR.sup.d, cyano and nitro; R.sup.2 in each occurrence is independently selected from the group consisting of C.sub.1-6 alkyl, pyrid-2-on-5-ylmethyl, thien-2-ylmethyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl, and phenyl-C.sub.1-3 alkyl optionally substituted with one to three substituents selected from the group consisting of C.sub.1-3 alkyl, C.sub.3-6-cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, halogen, NR.sup.cR.sup.d, cyano and nitro; R.sup.4 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-6 heteroalkyl, phenyl or phenyl-C.sub.1-4 alkyl said phenyls optionally independently substituted with one to three groups selected from the group consisting of C.sub.1-6 alkyl, halogen, C.sub.1-6 alkoxy, hydroxyl, cyano and nitro; R.sup.5 is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl, --NR.sup.cR.sup.d, amino-C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, thiophen-2-yl, 1,2-dimethyl-imidazol-4-yl, phenyl or phenyl-C.sub.1-3 alkyl said phenyl each optionally independently substituted with one to three C.sub.1-3 alkyl, C.sub.1-3 alkoxy, halogen, nitro or cyano; R.sup.6a and R.sup.6b are independently hydrogen or C.sub.1-3 alkyl; R.sup.8 is C.sub.1-6 acyl or hydrogen or C.sub.1-3 alkyl; R.sup.9 is hydroxyl, C.sub.1-6 alkoxy, amino, --NR.sup.cR.sup.d, providing that R.sup.9 is other than hydroxyl when o.sub.1 is zero; R.sup.10 is alkoxy, amino, --NR.sup.cR.sup.d, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl or C.sub.1-6 heteroalkoxy; R.sup.a and R.sup.b are (i) independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6 heteroalkyl, C.sub.1-6 alkyl-C.sub.1-3 alkoxy, C.sub.1-3 alkyl-amino-C.sub.1-6 alkyl, or (ii) one of R.sup.a and R.sup.b is (CH.sub.2).sub.r.sub.2CONR.sup.6aR.sup.6a, COR.sup.10 or (CH.sub.2).sub.o.sub.2SO.sub.2R.sup.5, and the other of R.sup.a and R.sup.b is hydrogen, C.sub.1-6 alkyl or C.sub.1-6 acyl, or (iii) taken together are (CH.sub.2).sub.q, (CH.sub.2).sub.wSO.sub.2, (CH.sub.2).sub.wNR.sup.6aSO.sub.2, (CH.sub.2).sub.2X.sup.3(CH.sub.2).sub.2, or taken together with the nitrogen atom to which they are attached are 3-amino pyrrolidine, 3-methylsulfonylpyrrolidine or 3-acetamido-pyrrolidine; R.sup.c and R.sup.d are (i) independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6 sulfonyl or C.sub.1-6 heteroalkyl, or (ii) taken together are (CH.sub.2).sub.q, (CH.sub.2).sub.2X.sup.3(CH.sub.2).sub.2, or 3-hydroxy-pyrrolidin-1-yl; X.sup.2 is O, or NR.sup.6a; X.sup.3 is O or NR.sup.8; m is an integer from 0 to 3; o.sub.1 and o.sub.2 are independently integers from 0 to 6; q is an integer from 3 to 6; r.sub.1 and r.sub.2 are independently integers from 1 to 6; u is an integer from 2 to 6; w is an integer from 2 to 4; and, pharmaceutically acceptable salts thereof. 2. A compound of claim 1 wherein: R.sup.1 is hydroxyl, (CH.sub.2).sub.o.sub.1NR.sup.aR.sup.b, X.sup.2(CH.sub.2).sub.uNR.sup.aR.sup.b, X.sup.2(CH.sub.2).sub.o.sub.1COR.sup.9, X.sup.2(CH.sub.2).sub.o.sub.1SO.sub.2NR.sup.cR.sup.d, (CH.sub.2).sub.r.sub.1SO.sub.2R.sup.5, optionally substituted aryl, optionally substituted heteroaryl or halogen; R.sup.2 is C.sub.1-6 alkyl, aryl-C.sub.1-4 alkyl or C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl; and, R.sup.4 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl or aryl-C.sub.1-4 alkyl said aryl optionally substituted independently with one to three groups selected from the group consisting of C.sub.1-6 alkyl, halogen, C.sub.1-6 alkoxy, hydroxyl, cyano and nitro. 3. A compound of claim 2 wherein m is one, R.sup.1 is (CH.sub.2).sub.o.sub.1NR.sup.aR.sup.b, X.sup.2(CH.sub.2).sub.o.sub.1COR.sup.9 or X.sup.2(CH.sub.2).sub.o.sub.1SO.sub.2NR.sup.cR.sup.d and R.sup.5 is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl or NR.sup.cR.sup.d. 4. A compound according to claim 3 wherein the R.sup.1 substituent is attached to the 7-position of the 1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl ring. 5. A compound according to claim 4 wherein R.sup.1 is (CH.sub.2).sub.o.sub.1NR.sup.aR.sup.b, and o.sub.1 is an integer from zero to two, R.sup.a is (CH.sub.2).sub.o.sub.2SO.sub.2R.sup.5, o.sub.2 is zero and R.sup.b is hydrogen. 6. A compound according to claim 4 wherein R.sup.1 is X.sup.2(CH.sub.2).sub.o.sub.1SO.sub.2NR.sup.cR.sup.d, X.sup.2 is O, o.sub.1 is an integer from one to three. 7. A compound according to claim 4 wherein R.sup.1 is X.sup.2(CH.sub.2).sub.o.sub.1COR.sup.9, X.sup.2 is O, o.sub.1 is an integer from one to three. 8. A compound according to claim 2 wherein R.sup.1 is optionally substituted aryl or optionally substituted heteroaryl ring and the R.sup.1 substituent is attached to the 7-position of the 1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl ring. 9. A method for treating a Hepatitis C Virus (HCV) infection comprising administering to a patient in need thereof, a therapeutically effective quantity of a compound according to claim 1. 10. The method of claim 9 further comprising co-administering at least one immune system modulator selected from the group consisting of interferon .alpha.-2a, interferon .alpha.-2b, PEGASYS and PEGINTRON and/or at least one antiviral selected from ribavirin or viramidine. 11. The method of claim 10 wherein the immune system modulator is selected from the group consisting of interferon .alpha.-2a, interferon .alpha.-2b, PEGASYS and PEGINTRON. 12. The method of claim 10 wherein the antiviral compound is ribavirin or viramidine. 13. A pharmaceutical composition comprising a therapeutically effective quantity of a compound according to claim 1 admixed with at least one pharmaceutically acceptable carrier, diluent or excipient. 14. A compound according to claim 1 selected from the group consisting of: (S)-1-benzyl-5-cyclohexyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isot- hiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-1-benzyl-5-tert-butyl-3-(1,1-dioxo-1-H-1.lamda..sup.6-benzo[d]isothia- zol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; 5-tert-butyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1-(4- -fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; 5-tert-butyl-3-(7-chloro-1,1-dioxo-1-H-1.lamda..sup.6-benzo[d]isothiazol-- 3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-methoxy-1,1-dioxo-1H-- 1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1,5-dihydro-pyrrol-2-one; 5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-hydroxy-1,1-dioxo-1H-1.la- mda..sup.6-benzo[d]isothiazol-3-yl)-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl--3-(1,1-dioxo-1H-1.lamda..sup.6-naphtho[2,1-d]isothiazol- -3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-3-(7-chloro-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1-(4- -fluoro-benzyl)-4-hydroxy-5-isobutyl-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-- 4-hydroxy-1-(4-methyl-benzyl)-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-- 1-(4-fluoro-3-methoxy-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-- 4-hydroxy-1-thiophen-2-ylmethyl-1,5-dihydro-pyrrol-2-one; (S)-5-cyclohexyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-- 1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; sodium salt; (S)-5-tert-butyl-1-(4-chloro-benzyl)-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo- [d]isothiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; 4-[(S)-2-tert-butyl-4-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-y- l)-3-hydroxy-5-oxo-2,5-dihydro-pyrrol-1-ylmethyl]-benzonitrile; (S)-5-tert-butyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-- 1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-5-((S)-sec-butyl)-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3- -yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-1-cyclobutylmethyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[- d]isothiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1-(4-fluoro-b- enzyl)-4-hydroxy-5-isobutyl-1,5-dihydro-pyrrol-2-one; 3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1-(4-fluoro-benzy- l)-4-hydroxy-5-isobutyl-1,5-dihydro-pyrrol-2-one; (R)-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1-(4-fluoro-b- enzyl)-4-hydroxy-5-isobutyl-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-1-(3,3-dimethyl-butyl)-3-(1,1-dioxo-1H-1.lamda..sup.6-be- nzo[d]isothiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-1-(3-bromo-4-fluoro-benzyl)-5-tert-butyl-3-(1,1-dioxo-1H-1.lamda..sup- .6-benzo[d]isothiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-m- ethanesulfonamide; (S)-5-tert-butyl-1-(3,4-difluoro-benzyl)-3-(1,1-dioxo-1H-1.lamda..sup.6-b- enzo[d]isothiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; 5-[(S)-2-tert-butyl-4-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-y- l)-3-hydroxy-5-oxo-2,5-dihydro-pyrrol-1-ylmethyl]-2-fluoro-benzonitrile; (S)-5-tert-butyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-- 1-(4-fluoro-3-trifluoromethyl-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1-(4-fluoro-b- enzyl)-4-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one; (S)-5-benzyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1-(4- -fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; 5-[(S)-2-tert-butyl-4-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-y- l)-3-hydroxy-5-oxo-2,5-dihydro-pyrrol-1-ylmethyl]-1H-pyridin-2-one; (S)-5-tert-butyl-1-(3-cyclopropyl-4-fluoro-benzyl)-3-(1,1-dioxo-1H-1.lamd- a..sup.6-benzo[d]isothiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-1-(3-chloro-4-fluoro-benzyl)-3-(1,1-dioxo-1H-1.lamda..su- p.6-benzo[d]isothiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-3-(1,1-dioxo-7-pyridin-3-yl-1H-1.lamda..sup.6-benzo[d]is- othiazol-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-[7-(6-methoxy-pyridin-3-- yl)-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl]-1,5-dihydro-pyrro- l-2-one; 5-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-di- hydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl}- -1H-pyridin-2-one; N-{3-[5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyr- rol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-N-met- hyl-methanesulfonamide; (S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-[7-(2-methoxy-pyrimidin-- 5-yl)-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl]-1,5-dihydro-pyr- rol-2-one; N-(3-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2- ,5-dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-- 7-yl}-phenyl)-acetamide; N-{3-[5-tert-butyl-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-2,5-dihyd- ro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmeth- yl}-methanesulfonamide; dimethylamino-sulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; 2-{3-[5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-- pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yloxy}-aceta- mide; amino-sulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; pyrrolidine-1-sulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; 5-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro- -1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl}-1H-p- yrimidin-2-one; (S)-5-tert-butyl-3-(1,1-dioxo-7-pyrimidin-5-yl-1H-1.lamda..sup.6-benzo[d]- isothiazol-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; cyclopropanesulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; ethanesulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; 6-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro- -1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl}-1H-p- yridin-2-one; (S)-5-tert-butyl-3-[1,1-dioxo-7-(1H-pyrazol-4-yl)-1H-1.lamda..sup.6-benzo- [d]isothiazol-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one- ; (R)-5-tert-butyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)- -1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-- 1-(3-ethyl-4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-3-(7-amino-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-5-ter- t-butyl-1-(4-fluoro-benzyl)-4-liydroxy-1,5-dihydro-pyrrol-2-one; 2-({3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1- H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-- amino)-acetamide; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl }-acetamide; (S)-5-tert-butyl-3-[7-(1,1-dioxo-1.lamda..sup.6-isothiazolidin-2-ylmethyl- )-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl]-1-(4-fluoro-benzyl)- -4-hydroxy-1,5-dihydro-pyrrol-2-one; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-N- -methylcarbamoylmethyl-acetamide; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-3-methoxy-benzyl)-4-hydroxy-2-oxo-2,5-- dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-y- lmethyl}-methanesulfonamide; 2-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylamino}-N,- N-dimethyl-acetamide; 2-({3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1- H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl }-amino)-N-methyl-acetamide; N-{3-[(S)-5-tert-butyl-1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-d- ihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl- methyl}-methanesulfonamide; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl}-methane- sulfonamide; 2-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yloxy}-N,N-- dimethyl-acetamide; (S)-5-tert-butyl-1-(2-cyclopropyl-ethyl)-3-(1,1-dioxo-1H-1.lamda..sup.6-b- enzo[d]isothiazol-3-yl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; (S)-3-(1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1-(4-fluoro-b- enzyl)-4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one; {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yloxy}-methan- esulfonamide; 2-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yloxy}-N-me- thyl-acetamide; 2-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylamino}-ac- etamide; {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihy- dro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylami- no}-acetic acid ethyl ester; (S)-3-hydroxy-pyrrolidine-1-sulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; N-{3-[(S)-1-(3-bromo-4-fluoro-benzyl)-5-tert-butyl-4-hydroxy-2-oxo-2,5- -dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-- ylmethyl}-methanesulfonamide; N-{3-[(S)-5-cyclohexyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-m- ethanesulfonamide; N-{3-[(S)-5-tert-butyl-1-(2-cyclopentyl-ethyl)-4-hydroxy-2-oxo-2,5-dihydr- o-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethy- l}-methanesulfonamide; N-{3-[1-(4-fluoro-3-methyl-benzyl)-5-(4-fluoro-phenyl)-4-hydroxy-2-oxo-2,- 5-dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7- -ylmethyl}-methanesulfonamide; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-b- enzenesulfonamide; 1-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-3- -methyl-urea; (S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-[7-(2-methanesulfonyl-et- hyl)-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl]-1,5-dihydro-pyrr- ol-2-one; (S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-methyl-1,1-d- ioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1,5-dihydro-pyrrol-2-one; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-2,5-d- ihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl- methyl}-N-methyl-methanesulfonamide; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-2,5-d- ihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl- methyl}-sulfamide; 2-amino-ethanesulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; (S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-isobutoxy-1,1-diox- o-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1,5-dihydro-pyrrol-2-one; (S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-methanesulfonylmethox- y-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1,5-dihydro-pyrrol-- 2-one; dimethyl-sulfamic acid 3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-py- rrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl ester; {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl}-methanesu- lfonamide; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-- dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-y- lmethyl}-N-methyl-N',N'-dimethyl-sulfamide; (S)-5-tert-butyl-3-[7-(1,1-dioxo-1.lamda..sup.6-[1,2]thiazinan-2-ylmethyl- )-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl]-1-(4-fluoro-benzyl)- -4-hydroxy-1,5-dihydro-pyrrol-2-one; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-N- -(2-methoxy-ethyl)-methanesulfonamide; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-N- -(2-methylamino-ethyl)-methanesulfonamide; (S)-5-tert-butyl-3-[7-(1,1-dioxo-1.lamda..sup.6-[1,2,5]thiadiazolidin-2-y- lmethyl)-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl]-1-(4-fluoro-- benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; C-{3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H- -pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yloxy}-N-me- thyl-methanesulfonamide; morpholine-4-sulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; piperazine-1-sulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; 4-acetyl-piperazine-1-sulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazo1-7-ylmethyl}-ami- de; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-2,- 5-dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7- -ylmethyl}-N-propionyl-methanesulfonamide; N-{3-[(S)-5-tert-butyl-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-2,5-d- ihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl- methyl}-N-butyryl-methanesulfonamide; (S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-methylaminomethyl-1,1- -dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl)-1,5-dihydro-pyrrol-2-one- ; (S)-5-tert-butyl-3-(7-dimethylaminomethyl-1,1-dioxo-1H-1.lamda..sup.6-be- nzo[d]isothiazol-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-- one; (S)-3-(7-aminomethyl-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3- -yl)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; C-{3-[(S)-5-tert-butyl-1-(4-fluoro-3-methyl-benzyl)-4-hydroxy-2-oxo-2,5-d- ihydro-1H-pyrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-yl- oxy}-N,N-dimethyl-methanesulfonamide; (S)-5-tert-butyl-3-[7-(1,1-dioxo-1.lamda..sup.6-[1,2,6]thiadiazinan-2-ylm- ethyl)-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-3-yl]-1-(4-fluoro-be- nzyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one; thiophene-2-sulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; and, 1,2-dimethyl-1H-imidazole-4-sulfonic acid {3-[(S)-5-tert-butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-p- yrrol-3-yl]-1,1-dioxo-1H-1.lamda..sup.6-benzo[d]isothiazol-7-ylmethyl}-ami- de; or, a pharmaceutically acceptable salt thereof. 15. A compound according to claim 1 selected from the group consisting of II-98, II-99, II-100, II-101 and II-102 wherein the compounds have the following structure: ##STR00048## or, a pharmaceutically acceptable salt thereof.

Details for Patent 7,674,810

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	PEGINTRON	peginterferon alfa-2b	Injection	103949	01/19/2001		2039-02-26
Merck Sharp & Dohme Corp.	SYLATRON	peginterferon alfa-2b	For Injection	103949	03/29/2011		2039-02-26
Zr Pharma& Gmbh	PEGASYS	peginterferon alfa-2a	Injection	103964	10/16/2002		2039-02-26